JPH11209356A - Condensed cyclic compound, its production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound, a non-peptidic compound, having excellent somatostatin receptor agonistic action, and useful as a preventive/therapeutic agent for e.g. diabetes. SOLUTION: This compound is shown by formula I [A-ring and B-ring are each a (substituted) aromatic hydrocarbon or (substituted) aromatic heterocycle; Z is a (substituted) cyclic group or (substituted) chain hydrocarbon; R<1> is H, a (substituted) hydrocarbon or the like; R<2> is a (substituted) amino; D and G are each a lone pair or (substituted) bivalent hydrocarbon; E is a lone pair, CON(R<a> ) or the like; I is a bivalent group; X is two Hs, O or N; formula II represents a single or double bond; Y is N when formula II represents a double bond, being O or the like when formula II represents a single bond], pref. 3,5- trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-biphenylmethyl)- 7-chloro-2- oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or the like. It is recommended that the compound of formula I is obtained, for example, by condensation reaction between a compound of formula III and a compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel fused ring compound having a somatostatin receptor agonizing action, a process for producing the same, and a medicament containing the same.

[0002]

2. Description of the Related Art Somatostatin has been isolated from sheep hypothalamus tissue as a peptide consisting of 14 amino acids (SST-14) having a growth hormone secretion inhibiting action. At present, somatostatin (SST-28) consisting of 28 amino acids has been isolated and identified. This somatostatin is not only the hypothalamus, for example, cerebrum, limbic system, spinal cord, vagus nerve, autonomic ganglion, gastrointestinal mucosa, pancreatic Langerhans islet, brain and intestinal peptide widely distributed, Suppresses the secretion of pituitary and gastrointestinal hormones such as growth hormone, thyroid stimulating hormone, gastrin, insulin and glucagon. Also, gastric acid secretion,
It also suppresses pancreatic exocrine secretion, gastrointestinal motility and blood flow. Somatostatin receptors have been type 1 to 5 (SSTR1, SSTR2, SSTR3, SSTR4,
SSTR5) is known, and it has been recognized that they show different expression in each of the central and peripheral sites [Life Sciences,
Vol. 57, No. 13, p. 1249 (1995)]. Currently, clinically, peptidic somatostatin analogs that suppress secretion of specific hormones are being developed. Condensed 4,1-benzoxazepine compounds having a substituent at the 3-position are described in Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), No. 34 (1).
Vol. 140-149 (1986), JP-A-5
7-35576, JP-A-6-239843, JP-A-7-179429, JP-A-7-179
444, JP-A-7-267939, WO9
3/07129, WO96 / 09827,
Japanese Patent Application Laid-Open Nos. 8-259,947 and 8-15736
No. 9 discloses this. With respect to 2,3,4,5-tetrahydro-2-oxo (or thioxo) -1H-1,4-fused diazepine compounds having a substituent at the 3-position and 5-position, see Journal of Organic Chemistry (J. Org. Chem.), 38 (20), 1973. Condensed 4,1-benzothiazehin compounds having a substituent at the 3- and 5-positions are disclosed in
-259,47, WO 96/09827.

[0003]

The compounds that are currently being developed as somatostatin receptor agonists are peptidic compounds and have many problems in terms of action time, administration method, specificity, side effects, and the like. In terms of solving these problems, it is very significant to create and develop a compound that is a non-peptidic compound and has an excellent somatostatin receptor agonistic action.

[0004]

Means for Solving the Problems In view of the above circumstances, the present inventors have made various studies and found that the following general formula (I):
General formula (I) having a chemical structural feature in that an amino group is bonded to an aromatic ring B via a divalent group.

Embedded image Or S (O) n (n represents 0, 1 or 2)
Is shown. A compound represented by the formula: As a result, the present invention has been completed based on these.

That is, the present invention relates to (1) the compound (I) or a salt thereof, (2) Z is a cyclic group which may have a substituent, and G is a divalent group which may have a substituent. The compound according to the above (1), wherein the ring B does not form a non-aromatic condensed nitrogen-containing heterocyclic ring with R ^2.

Embedded image The compound according to the above (1), which is -N (R ⁴ )-(R ⁴ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group), (4)

Embedded image (5) The compound according to the above (1), wherein the ring B is a benzene ring which may have a substituent, and (6) the compound (6) wherein the ring B is an aromatic heterocyclic ring which may have a substituent. The compound according to 1), (7) the compound according to (1), wherein the ring B is a benzene ring or a thiophene ring, and the (1), wherein the ring A is a benzene ring which may have a substituent. The compound described,
(9) The above (1), wherein the ring A is a benzene ring optionally substituted with halogen, hydroxy or C _1-6 alkoxy.
(10) The compound according to (1), wherein R ¹ is a hydrocarbon group which may have a substituent, (11)
R ¹ is (1) hydroxy, (2) phenyl or (3) C _1-6 alkyl - carbonyl or C _1-6 alkylsulfonyl C _1-6 alkyl optionally substituted by even an amino substituted with sulfonyl Or the compound according to the above (1), which is a C _7-14 aralkyl group,

(12) The compound according to the above (1), wherein X is an oxygen atom, (13) the compound according to the above (1), wherein Y is an oxygen atom, and (14) a compound wherein L has a substituent. Often,
And the compound according to the above (1), which is a divalent hydrocarbon group optionally containing -O- or -S-, (15) L is C
The compound according to the above (1), which is a _1-6 alkylene group;
6) The compound according to (1), wherein Z is a phenyl group which may have a substituent, (17) the compound according to (1), wherein Z is a phenyl group substituted with halogen, (1)
8) the compound according to the above (1), wherein D is a divalent hydrocarbon group which may have a substituent, (19) the compound according to the above (1), wherein D is a C _1-6 alkylene group, (20) The compound according to the above (1), wherein E is -CON (Ra)-(Ra represents a hydrogen atom or a hydrocarbon group which may have a substituent). (21) E is -CONH- (22) The compound according to (1), wherein G is a C _1-6 alkylene group; and (23) the compound according to (1), wherein R ² is an unsubstituted amino group. The compound, (24) the compound according to (1), wherein the ring formed by bonding the ring B and R ² is a tetrahydroisoquinoline ring, and (25) a benzene ring in which the ring A may have a substituent; Ring has a substituent

Embedded image (26) a benzene ring in which ring A may be substituted with halogen, hydroxy or C _1-6 alkoxy, a benzene ring in ring B, a phenyl group in which Z is substituted with halogen, and R ¹
(1) hydroxy, (2) phenyl or (3) C _1-6 alkyl - carbonyl or C _1-6 optionally substituted by even an amino substituted with alkylsulfonyl C _1-6 alkyl group or a C _7-14 the compound according to the above (1), which is an aralkyl group, (27) a benzene ring in which ring A may have a substituent, and ring B has a substituent.

Embedded image (28) a benzene ring in which ring A may be substituted with halogen, hydroxy or C _1-6 alkoxy, a thiophene ring in ring B, a phenyl group in which Z is substituted with halogen, and R ¹
Is (1) hydroxy, (2) phenyl or (3) C _1-6 alkyl-
The carbonyl or C _1-6 alkylsulfonyl optionally substituted with amino which may be substituted with alkylsulfonyl C _1-6 alkyl or C _7-14 aralkyl group (1) compounds described,

(29) A ring is halogen, hydroxy, C
_1-6 alkoxy, halogeno-C _1-6 alkoxy, C _7-14 aralkyloxy, benzoyl-C _1-6 alkoxy, hydroxy-C _1-6 alkoxy, C _1-6 alkoxy-carbonyl-C _1-6 alkoxy, Substituted with C _3-14 cycloalkyl-C _1-6 alkoxy, imidazol-1-yl-C _1-6 alkoxy, C _7-14 aralkyloxy-carbonyl-C _1-6 alkoxy or hydroxyphenyl-C _1-6 alkoxy Benzene ring or thiophene ring in which ring B may be substituted with C _1-6 alkoxy, Z is halogen, formyl, halogeno-C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl - carbonyl, oxo and 1 to 3 substituents C _6-14 aryl optionally having substituents selected from pyrrolidinyl, C _3-10 cycloalkyl, piperidyl, thienyl, pretend , Pyridyl, thiazolyl, indolyl or C _1-6 alkyl group, D is C _1-6
An alkylene group, C wherein G may contain a bond or phenylene and may be substituted by phenyl;
_1-6 alkylene group, R ¹ is hydrogen atom, (1) halogen, (2) nitro, (3) C _1-6 alkyl optionally substituted by C _1-6 alkyl-carbonyl, benzoyloxycarbonyl and C _1-6 Amino optionally having one or two substituents selected from _1-6 alkylsulfonyl, (4) (i) hydroxy,
C _1-6 alkyl - carbonyl, carboxy or C _1-6 alkoxy - optionally substituted with a carbonyl C _1-6 alkyl, optionally substituted with (ii) hydroxyphenyl, (iii) benzoyl or (iv Hydroxy) optionally substituted with mono- or di- _{Ci_6} alkylamino-carbonyl, (5) _{C3_6} cycloalkyl, (6) hydroxy or halogeno- _{Ci_6} alkyl A phenyl or (7) thienyl, furyl, thiazolyl, indolyl or benzyloxycarbonylpiperidyl optionally substituted C _1-6 alkyl group, C _2-6 alkenyl group, C
_6-14 aryl group or C _7-14 aralkyl group, R ² is (1) unsubstituted amino group, (2) piperidyl group or (3) (i) benzyl,
(ii) C _{1-6 optionally} substituted with amino or phenyl
Alkyl, (iii) mono- or di-C _1-6 alkyl-carbamoyl, (iv) C _1-6 alkoxy-carbonyl, (v) C _1-6
Alkyl-sulfonyl, (vi) piperidylcarbonyl and
(vii) C _{1-6 optionally} substituted with halogen or amino
An amino group optionally having one or two substituents selected from alkyl-carbonyl, E is a bond, -CON
(R ^a )-, -N (R ^a ) CO-, -N (R ^b ) CON (R ^c )-,
-COO-,

Embedded image (R ^a, R ^b and R ^c are each a hydrogen atom or a C _1-6 alkyl group), it may also be via the L is -O-, and optionally substituted by C _1-6 alkyl C _{1- 6} alkylene group, X
Is an oxygen atom,

Embedded image —N (R ⁴ ) — (R ⁴ is a hydrogen atom or a C _1-6 alkyl group),
And the compound according to the above (1), wherein the ring formed by bonding the ring B to R ² is a tetrahydroisoquinoline ring;

(30) 3,5-trans-N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -1
-(4-biphenylmethyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, (3S, 5S) -N-
(2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-
N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -1- [2- (4-biphenyl) ethyl] -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl)
-5- (4-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5- (2-aminomethylthiophene-5
-Yl) -1- (4-biphenylmethyl) -7-chloro-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5
-Trans-N- (2-fluorobenzyl) -5- [3-
[(1-amino-1-methyl) ethyl] phenyl] -1- (4
-Biphenylmethyl) -7-chloro-2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5-trans-N
-(2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-1- (4-hydroxybenzyl)
-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
5-trans-N- (2-fluorobenzyl) -1- (4
-Acetylaminobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -7-
Chloro-1- (4-methanesulfonylaminobenzyl)-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5
-Trans-N- (2-fluorobenzyl) -5- (3-
(Aminomethylphenyl) -1- (4-biphenylmethyl)
-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
5-trans-N- (2-fluorobenzyl) -5- (3
-Aminomethylphenyl) -1- (4-hydroxybenzyl) -7-methyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5- [4-[(1-amino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl)-
5- (3-aminomethylphenyl) -7-chloro-1-
[2- (4-hydroxyphenyl) ethyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5-trans-N- (2-Fluorobenzyl) -5- (3-aminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide or a salt thereof or 3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -7-chloro-2-
Oxo-1,2,3,5-tetrahydro-5- (1,2,3,
4-tetrahydroisoquinolin-5-yl) -4,1-
The compound according to the above (1), which is benzoxazepine-3-acetamide or a salt thereof,

(31) General formula

Embedded image [The symbols in the formula have the same meanings as described in the above (1). ] Or a salt thereof and a general formula

Embedded image [The symbols in the formula have the same meanings as described in the above (1). A compound represented by the general formula:

Embedded image [The symbols in the formula have the same meanings as described in the above (1). (32) The method for producing a compound represented by the formula (1):
(3) A medicament characterized by containing the compound described in (3).
3) The medicament according to the above (32), which is a somatostatin receptor agonist, (34) the medicament according to the above (32), which is an agent for preventing or treating diabetes, obesity, diabetic complications or intractable diarrhea. In the above formula, ring A represents an aromatic hydrocarbon which may have a substituent or an aromatic heterocyclic ring which may have a substituent. As the ring A, for example, an aromatic hydrocarbon which may have a substituent is preferable, and particularly, a benzene ring which may have a substituent is generally used. The "aromatic hydrocarbon" represented by ring A includes, for example, 6 to 1
An aromatic hydrocarbon composed of 4 carbon atoms (for example,
Benzene, naphthalene, anthracene, phenanthrene, and other C _6-14 aryl), and benzene is particularly widely used.

The "aromatic heterocyclic ring" represented by ring A includes, for example, a monocyclic aromatic heterocyclic ring and a polycyclic aromatic condensed heterocyclic ring. As the “monocyclic aromatic heterocycle”, for example, a group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom
Or a 6-membered monocyclic aromatic heterocycle and the like, specifically, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,
Imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, furazane, 1,
2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, triazine and the like are used. Can be Examples of the “polycyclic fused aromatic heterocycle” include a benzene ring and 2 or 3 of the “monocyclic aromatic heterocycle”.
Examples thereof include a fused bicyclic or tricyclic aromatic heterocyclic ring formed by condensing individuals, and specifically, for example, benzofuran, isobenzofuran, benzo [b] thiophene, indole,
Isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzoisoxazole, benzothiazole, 1,2-benzoisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine , Purine, pteridine, carbazole, α-carboline, β-carboline, γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxatiin, thianthrene, phenatridine, phenatroline, indolizine, pyrrolo [1,
2-b] pyridazine, pyrazolo [1,5-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,
5-a] pyridine, imidazo [1,2-a] pyridazine, imidazo [1,2-a] pyrimidine, 1,2,4-
Triazolo [4,3-a] pyridine, 1,2,4-triazolo [4,3-b] pyridazine and the like are used. As the "aromatic heterocycle" represented by ring A, for example, the "monocyclic aromatic heterocycle" is preferable, and in particular, furan, thiophene, pyridine and the like are widely used.

Said "aromatic hydrocarbon", "aromatic heterocycle"
And the substituent that the “benzene ring” may have, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl group (eg, methyl,
Ethyl, propyl, butyl, sec-butyl, t-butyl,
Isopropyl, etc.), a halogeno-C _1-6 alkyl group (for example, C 1 -C 5 substituted with 1 to 5 said “halogen atoms”)
_1-6 alkyl group and the like; for example, trifluoromethyl and the like, phenyl group, benzyl group, C _1-6 alkoxy group (for example,
Methoxy, ethoxy, propoxy, butoxy, sec-butoxy, t-butoxy, isopropoxy, etc., halogeno-C _1-6 alkoxy group (for example, C _1-6 substituted by 1 to 5 of said “halogen atoms”) Alkoxy group; trifluoromethoxy, chloropropyloxy, etc.), phenoxy group, C _7-14 aralkyloxy group (eg, benzyloxy, phenethyloxy, phenylpropyloxy, etc.), formyloxy group, C _1-6 alkyl-carbonyloxy Group (eg, acetyloxy, etc.), C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, butylthio, sec-butylthio, t-butylthio,
Isopropylthio, etc.), a halogeno-C _1-6 alkylthio group (for example, a C _1-6 alkylthio group substituted with 1 to 5 of said “halogen atoms”; for example, trifluoromethylthio, etc.), a hydroxy group, a mercapto group , A cyano group, a nitro group, a carboxy group, a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, etc.), a benzoyl group, a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, etc.), phenoxycarbonyl group,
An amino group, a mono- or di-C _1-6 alkylamino group (for example, methylamino, ethylamino, dimethylamino,
Diethylamino, etc.), formylamino group, C _1-6 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group (eg, N -Methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, etc.), sulfo group, C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), benzoyl -C _1-6 alkoxy group (for example, benzoylmethyloxy etc.), hydroxy-C _1-6 alkoxy group (for example, hydroxyethyloxy etc.), C _1-6 alkoxy-carbonyl-C _1-6 alkoxy group (for example, methoxycarbonylmethyl oxy, etc.), C _3-14 cycloalkyl C _1-6 alkoxy group (e.g., cyclohexylmethyloxy, etc.), imidazol-1-yl -C _1-6 alkoxy group (e.g., imidazol-1-yl-propyloxy, etc.), C _{7 - 14} aralkyloxy - carbonyl -C _1-6 alkoxy group (for example, benzyloxycarbonylmethyloxy and the like), hydroxyphenyl-C _1-6 alkoxy group (for example, [3- (4-hydroxyphenyl) propyl] oxy and the like), C _7-14 aralkyloxy- Carbonyl group (for example, benzyloxycarbonyl and the like), mono- or di-C _1-6 alkylamino-
C _1-6 alkoxy (eg, methylaminomethoxy, ethylaminoethoxy, dimethylaminomethoxy, etc.), mono- or di-C _1-6 alkylamino-carbonyloxy (eg, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylamino Carbonyloxy, etc.), and the "halogen atom" is widely used. The “aromatic hydrocarbon ring”, “aromatic heterocycle” and “benzene ring” may have 1 to 4 substituents selected from these substituents. The substituent in the ring A is preferably substituted at the 7-position or the 8-position, and the number of substituents is preferably 1 or 2.

The ring A is preferably, for example, a benzene ring which may have a substituent, among which halogen, hydroxy, C _1-6 alkoxy, halogeno-C _1-6 alkoxy,
C _7-14 aralkyloxy, benzoyl-C _1-6 alkoxy, hydroxy-C _1-6 alkoxy, C _1-6 alkoxy-
Carbonyl -C _1-6 alkoxy, C _3-14 cycloalkyl -C _1-6 alkoxy, imidazol-1-yl -C _1-6 alkoxy, C _{7 - 14} aralkyloxy - carbonyl -C
_A benzene ring or the like which may be substituted with _1-6 alkoxy or hydroxyphenyl-C _1-6 alkoxy is more preferable, and a halogen (preferably a base or the like), hydroxy or C
_A benzene ring optionally substituted with _1-6 alkoxy (preferably methoxy or the like) is most preferred. In the above formula, ring B represents an aromatic hydrocarbon which may have a substituent or an aromatic heterocyclic ring which may have a substituent. As the ring B, for example, an aromatic hydrocarbon which may have a substituent is preferable, and in particular, a benzene ring which may have a substituent is generally used. Examples of the "aromatic hydrocarbon" represented by ring B include aromatic hydrocarbons composed of 6 to 14 carbon atoms (for example, C _6-14 aryl such as benzene, naphthalene, anthracene, and phenanthrene). And the like. In particular, benzene is widely used.

The "aromatic heterocyclic ring" represented by ring B includes, for example, monocyclic aromatic heterocyclic rings, polycyclic aromatic condensed heterocyclic rings and the like. As the “monocyclic aromatic heterocycle”, for example, a group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom
Or a 6-membered monocyclic aromatic heterocycle and the like, specifically, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,
Imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, furazane, 1,
2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, triazine and the like are used. Can be Examples of the “polycyclic fused aromatic heterocycle” include a benzene ring and 2 or 3 of the “monocyclic aromatic heterocycle”.
Examples thereof include a fused bicyclic or tricyclic aromatic heterocyclic ring formed by condensing individuals, and specifically, for example, benzofuran, isobenzofuran, benzo [b] thiophene, indole,
Isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzoisoxazole, benzothiazole, 1,2-benzoisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine , Purine, pteridine, carbazole, α-carboline, β-carboline, γ-carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxatiin, thianthrene, phenatridine, phenatroline, indolizine, pyrrolo [1,
2-b] pyridazine, pyrazolo [1,5-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,
5-a] pyridine, imidazo [1,2-a] pyridazine, imidazo [1,2-a] pyrimidine, 1,2,4-
Triazolo [4,3-a] pyridine, 1,2,4-triazolo [4,3-b] pyridazine and the like are used. As the “aromatic heterocycle” represented by ring B, for example, the “monocyclic aromatic heterocycle” is preferable, and furan, thiophene, pyridine and the like (particularly thiophene and the like) are widely used. Examples of the substituent which the “aromatic hydrocarbon ring”, “aromatic heterocyclic ring” and “benzene ring” may have include, for example, those which the “aromatic hydrocarbon” in ring A has The same substituents as the good substituents are exemplified. The "aromatic hydrocarbon ring", "aromatic heterocycle" and "benzene ring"
May have 1 to 4 substituents selected from these substituents.

The ring B is, for example, preferably a benzene ring or an aromatic heterocyclic ring, each of which may have a substituent. Among them, C _1-6 alkoxy (preferably methoxy, etc.) is preferable.
A benzene ring or a thiophene ring which may be substituted with is more preferable, and an unsubstituted benzene ring or a thiophene ring is most preferable. The ring B may be bonded to R ² to form a “optionally substituted non-aromatic condensed nitrogen-containing heterocyclic ring”. Examples of the “non-aromatic condensed nitrogen-containing heterocycle” formed by bonding ring B and R ² include, for example, a benzene ring and one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. And a bicyclic non-aromatic fused nitrogen-containing heterocyclic ring formed by condensing a 5- or 6-membered monocyclic non-aromatic heterocycle. Specific examples thereof include tetrahydroisoquinoline (for example, 1,2 , 3,4-tetrahydroisoquinoline), tetrahydroquinoline (eg 1,2,3,4-tetrahydroquinoline), isoindoline, indoline, 2,3-dihydrobenzothiazole,
2,3-dihydrobenzoxazole, 3,4-dihydro-2H-1,4-benzothiazine, 3,4-dihydro-2
H-1,4-benzoxazine, 1,2,3,4-tetrahydroquinoxaline, 2,3,4,5-tetrahydro-1,4
-Benzoxazepine and the like are used, and among them, tetrahydroisoquinoline is preferable. Examples of the substituent which the “non-aromatic condensed nitrogen-containing heterocycle” may have include, for example, the “aromatic hydrocarbon ring”, the “aromatic heterocycle” and the “benzene ring” in the ring B. And the same as the substituents which may be mentioned. The "non-aromatic nitrogen-containing heterocycle" may have 1 to 4 substituents selected from these substituents. In the above formula, Z represents a cyclic group which may have a substituent or a chain hydrocarbon group which may have a substituent. Examples of the “cyclic group” represented by Z include a cyclic hydrocarbon group and a heterocyclic group. Z is preferably, for example, an aromatic hydrocarbon group which may have a substituent, an aromatic heterocyclic group which may have a substituent, and the like, particularly a phenyl group which may have a substituent. Are commonly used. As the “cyclic hydrocarbon group”, for example, 3 to 1
Examples thereof include an alicyclic hydrocarbon composed of 4 carbon atoms and an aromatic hydrocarbon group composed of 6 to 14 carbon atoms. Examples of the “alicyclic hydrocarbon group” include C _3-14 cycloalkyl (eg, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, etc.),
C _3-14 cycloalkenyl (eg, cyclopentenyl,
Cyclohexenyl), C _5-14 cycloalkadienyl (eg, 2,4-cyclopentadienyl, 1,3-cyclohexadienyl, etc.), indanyl and the like.
Examples of the “aromatic hydrocarbon group” include C _6-14 aryl (for example, phenyl, naphthyl, anthranyl, phenanthryl and the like). Examples of the “heterocyclic group” include a monocyclic heterocyclic group, a polycyclic fused heterocyclic group, and the like. Examples of the “monocyclic heterocyclic group” include a 5- or 6-membered monocyclic heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. And specifically, for example, a monocyclic aromatic heterocyclic group (for example, furyl, thienyl, pyrrolyl,
Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3 4-thiadiazolyl, 1,2,
3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl and the like, monocyclic non-aromatic heterocyclic group (for example, oxiranyl, azetidinyl, oxetanyl, thietanyl,
Pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like). As the “polycyclic fused heterocyclic group”, for example, a 2- or 3-cyclic fused aromatic heterocyclic group formed by condensing two or three of a benzene ring and the “monocyclic aromatic heterocycle” And partially reduced forms thereof. Specific examples thereof include polycyclic aromatic fused heterocyclic groups (for example, benzofuryl, isobenzofuryl, benzo [b] thienyl, indolyl, isoindolyl,
H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl,
Quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α
-Carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatridinyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5 -A] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-a] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4 -Triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc., polycyclic non-aromatic condensed heterocycles (for example, isochromanyl, chromanyl, indolyl, isoindolyl, 1 , 2,3,4-tetrahydroisoquinolyl, 1,2,3 4-tetrahydroquinolyl) and the like.

The substituent which the "cyclic group" represented by Z may have is, for example, the same as the substituent which the "aromatic hydrocarbon" in the ring A may have. And oxo and thioxo groups. The “cyclic group” may have 1 to 5 substituents selected from these substituents. Examples of the “chain hydrocarbon group” represented by Z include those similar to the “aliphatic hydrocarbon group” in the “hydrocarbon group” described below represented by R ¹ . Examples of the substituent that the “chain hydrocarbon group” represented by Z may have include, for example, the same as the substituents that the following “hydrocarbon group” represented by R ¹ may have And the like. Z is, for example, halogen, formyl, halogeno-C _1-6 alkyl, C _1-6 alkoxy, C
_1-6 alkyl optionally having 1 to 3 substituents selected from alkyl-carbonyl, oxo and pyrrolidinyl
_6-14 aryl group (preferably phenyl or the like), C _3-10 cycloalkyl group, piperidyl group, thienyl group, furyl group,
A pyridyl group, a thiazolyl group, an indolyl group, a C _1-6 alkyl group and the like are preferable, and among them, a phenyl group substituted with a halogen (preferably fluorine) is preferable. The substitution position of the substituent in the cyclic group represented by Z is preferably an ortho position, and the number of substituents is preferably one. In the above formula, D
Represents a bond or a divalent hydrocarbon group which may have a substituent, and a divalent hydrocarbon group which may have a substituent is preferable. As the “divalent hydrocarbon group” represented by D, for example, a linear divalent hydrocarbon group having 1 to 10 carbon atoms and the like are used, and specifically, for example, C _{1- 10} alkylene groups (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, peptamethylene, octamethylene, etc.) and the like;
Examples thereof include a _1-6 alkylene group (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene and the like). The “divalent hydrocarbon group” may be, for example, a C _3-6 cycloalkylene (eg,
1,4-cyclohexylene), phenylene (eg, 1,4-phenylene, 1,2-phenylene, etc.), and the like. Examples of the substituent which the “divalent hydrocarbon group” represented by D may have include, for example, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), halogeno-C _{1 -6} alkyl group (for example, a C _1-6 alkyl group substituted with 1 to 5 of said “halogen atoms”; for example, trifluoromethyl and the like), a phenyl group, a benzyl group and the like. The “divalent hydrocarbon group”
You may have 1 to 3 of these substituents. D
For example, a C _1-6 alkylene group (for example, methylene, ethylene, propylene and the like, preferably methylene and the like) and the like are widely used. In the above formula, G represents a bond or a divalent hydrocarbon group which may have a substituent. Examples of the “divalent hydrocarbon group optionally having a substituent” represented by G include, for example, the aforementioned “divalent hydrocarbon group optionally having a substituent” represented by D ” Similar ones are used. G is for example a bond, or may contain a phenylene, a C _1-6 alkylene group and the like are preferably substituted by phenyl, for example C _1-6 alkylene group (e.g., methylene, ethylene, propylene Etc.) are commonly used. Here, the C _1-6 alkylene group represented by G may have phenylene interposed between the C _1-6 alkylene group and E or Z;
_A phenylene may be present in the _1-6 alkylene group.
In the above formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. As R ¹ , a hydrocarbon group which may have a substituent is preferable.

The "hydrocarbon group" represented by R ¹ includes, for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aralkyl group and the like. Commonly used. Examples of the “aliphatic hydrocarbon group” include an aliphatic hydrocarbon group having 1 to 10 carbon atoms (eg, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, etc.). No. Examples of the “C _1-10 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-methylpropyl, hexyl, isohexyl, , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, heptyl and the like, and preferably, for example, C _3-5
Examples include an alkyl group (for example, propyl, isopropyl, isobutyl, neopentyl and the like), and particularly, isobutyl, neopentyl and the like are widely used. Examples of the “C _2-10 alkenyl group” include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-
1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1
-Butenyl, 2-methyl-1-butenyl, 3-methyl-
2-butenyl, 1-pentenyl, 2-pentenyl, 3-
Pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like, and particularly a C _2-6 alkenyl group (for example, vinyl, Allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2
-Butenyl, etc.) are commonly used. As the “C _2-10 alkynyl group”, for example, ethynyl, 1-propynyl, 2-
Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like In particular, a C _2-6 alkynyl group (eg, ethynyl, 1-propynyl, 2-propynyl, etc.) is widely used.

As the "alicyclic hydrocarbon group", for example, an alicyclic hydrocarbon group having 3 to 10 carbon atoms (for example, C
_3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C
_5-10 cycloalkadienyl group). Examples of the “C _3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. The “C _3-10 cycloalkenyl group”
For example, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl And the like. Examples of the “C _5-10 cycloalkadienyl group” include 2,4-cyclopentadien-1-yl,
2,5-cyclohexadien-1-yl and the like. Examples of the “aryl group” include a C _6-14 aryl group (eg, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc.). Examples of the “aralkyl group” include a C _7-14 aralkyl group (eg, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 2-naphthylmethyl, etc.). Examples of the substituent which the `` hydrocarbon group '' may have include, for example, a halogen atom, a nitro group, a cyano group, an imino group, an amino group which may have a substituent, And a carboxy group which may have a substituent, a cycloalkyl group, a cycloalkenyl group and a heterocyclic group which may have a substituent. In the “hydrocarbon group”, regarding the group containing an aromatic ring, an alkyl group, a halogenoalkyl group, and an aryl group which may have a substituent are included in addition to the above-mentioned substituents. It may be. These substituents are
The "hydrocarbon group" may be substituted with 1 to 5 (preferably 1 to 3). Examples of the “halogen atom” which is a substituent of the “hydrocarbon group” include fluorine, chlorine, bromine, iodine and the like.

The "amino group optionally having substituent (s)" which is a substituent of the "hydrocarbon group" includes, for example, (1) (i) substituted with 1 to 5 of the "halogen atoms". C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl, etc.), phenyl group, benzyl group, (ii) formyl group, C
_1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), benzoyl group, (iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec.
-Propoxycarbonyl, butoxycarbonyl, etc.), C
_7-14 aralkyloxy-carbonyl groups (eg, benzyloxycarbonyl, etc.), (iv) sulfo groups, C _1-6 alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec-propylsulfonyl, butylsulfonyl, 1 or 2 selected from (t-butylsulfonyl, etc.) and (v) a C _1-6 alkylamino-carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, dimethylaminocarbonyl, etc.). And optionally substituted amino groups, and (2) a pyrrolidinyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group, a 4-methylpiperidyl group, a 4-phenylpiperidyl group, and the like.

Examples of the substituent which the "hydroxy group optionally having" which is a substituent of the "hydrocarbon group" may have (i) a substituent An optionally substituted C _1-6 alkyl group, (ii) an optionally substituted C _6-10 aryl group, (iii) an optionally substituted C _7-14 aralkyl group, and (iv) And a) an acyl group. The “optionally substituted C _1-6 alkyl group”
Examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like. The “C _1-6 alkyl group” includes, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxy group, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), Formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), carboxy group, C
_1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
sec-propoxycarbonyl, butoxycarbonyl, etc.), amino group, mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), pyrrolidyl group, piperidyl group, morpholinyl group, Thiomorpholinyl group, 4-methylpiperidyl group, 4-phenylpiperidyl group, carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl , N, N-diethylcarbamoyl, etc.), phenoxy group, mono- or di-
C _1-6 alkyl-carbamoyloxy group (for example, N-
Methylcarbamoyloxy, N-ethylcarbamoyloxy, N, N-dimethylcarbamoyloxy, N, N-
Diethylcarbamoyloxy, etc.), formylamino group,
A C _1-6 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.),
It may have 1 to 3 substituents selected from a formyloxy group and a C _1-6 alkyl-carbonyloxy group (for example, acetoxy and the like). “C _6-10 aryl group” of the “C _6-10 aryl group _optionally having substituent (s)”
Examples thereof include phenyl, naphthyl and the like.
The “C _6-10 aryl group” includes, for example, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) in addition to the substituents that the “C _1-6 alkyl group” may have. ) And a halogeno-C _1-6 alkyl group (for example, a C _1-6 alkyl group substituted with one to five such “halogen atoms” such as trifluoromethyl, etc.) and the like; It may have a group. Examples of the “C _7-14 aralkyl group” of the “optionally substituted C _7-14 aralkyl group” include benzyl, phenethyl and the like. Examples of the substituent that the “C _7-14 aralkyl group” may have include the same substituents as those that the “C _6-10 aryl group” may have, and the like. The radix is 1 to 5. Examples of the “acyl group” include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, t-butylcarbonyl, etc.), a benzoyl group, a C _1-6 alkoxy-carbonyl group (eg, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), benzyloxycarbonyl group, C _1-6 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec- Propylsulfonyl, butylsulfonyl, t-butylsulfonyl, etc.), carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N ,
N-diethylcarbamoyl and the like, and further, for example, a halogen atom (for example, fluorine, chlorine,
Bromine, iodine, etc.), hydroxy group, C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.) ,
Carboxy group, C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl, etc.), amino group, mono- or di-C _1-6 alkylamino group (for example, , Methylamino, ethylamino, dimethylamino, diethylamino, etc.), pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, 4-methylpiperidyl, 4-phenylpiperidyl, 4-benzyloxycarbonylpiperidyl, carbamoyl, mono — Or di-C _1-6 alkyl-carbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), phenoxy group, mono- or di-C _1-6 alkyl-
A carbamoyloxy group (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), a formylamino group, a C _1-6 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), It may have 1 to 3 substituents selected from a formyloxy group and a C _1-6 alkyl-carbonyloxy group (for example, acetoxy and the like).

Examples of the substituent which the “carboxy group optionally having” which is a substituent of the “hydrocarbon group” may have include, for example, a C _1-6 alkyl group (for example,
Methyl, ethyl, propyl, isopropyl, butyl, t
-Butyl or the like), a benzyl group, a mono- or di-C _1-6 alkylamino group (for example, methylamino, ethylamino,
Dimethylamino, diethylamino, etc.).
Examples of the "cycloalkyl group" that is a substituent of the "hydrocarbon group" include cyclopropyl, cyclobutyl,
And C _3-6 cycloalkyl groups such as cyclopentyl and cyclohexyl. Examples of the “cycloalkenyl group” that is a substituent of the “hydrocarbon group” include 1-cyclobuten-1-yl, 1-cyclopenten-1-yl,
2-cyclopenten-1-yl, 3-cyclopenten-
And C _3-6 cycloalkenyl groups such as 1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl. As the "heterocyclic group" of the "heterocyclic group optionally having substituent (s)" which is a substituent of the "hydrocarbon group", for example, a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom are selected. 5 having 1 to 4 heteroatoms
Or a 6-membered monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, Pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.), and a benzene ring, and a two- or three-ring formed by condensing the "5- or 6-membered monocyclic heterocycle" Formula fused heterocyclic groups (eg, benzofuryl, isobenzofuryl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl , 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,
Carbazolyl, α-carbolinyl, β-carbolinyl,
γ-carbolinyl, acridinyl, phenoxazinyl,
Phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [ 1,5-a] pyridyl, imidazo [1,2-a] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4- Triazolo [4,3-b] pyridazinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, etc.). Examples of the substituent that the “heterocyclic group” may have include, for example, those similar to the substituents that the “aromatic hydrocarbon” in the ring A may have, an oxy group, And a pyrrolidinyl group. The “heterocyclic group” may have 1 to 5 substituents selected from these substituents.

The "alkyl group" which is a substituent of the "hydrocarbon group" includes, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, t-
And C _1-6 alkyl groups such as butyl. The “halogenoalkyl group” as a substituent of the “hydrocarbon group” includes 1 to 5 halogen atoms (for example, fluorine,
C _1-6 alkyl group substituted with chlorine, bromine, iodine, etc. (eg, trifluoromethyl, trichloromethyl, etc.)
And the like. Examples of the “aryl group” of the “aryl group which may have a substituent” which is a substituent of the “hydrocarbon group” include, for example, phenyl, naphthyl, 2-biphenyl, 3-biphenyl, anthryl, phenanthryl,
And C _6-14 aryl groups such as acenaphthylenyl. The “phenyl group” includes, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), halogeno- A C _1-6 alkyl group (for example, a C _1-6 alkyl group substituted with 1 to 5 of the “halogen atoms”; for example, trifluoromethyl and the like), a C _1-6 alkoxy group (for example, methoxy, ethoxy, Propoxy, isopropoxy, t-butoxy, etc.),
C _7-14 aralkyloxy group (for example, benzyloxy, etc.), hydroxy group, amino group, mono- or di-C _1-6
Alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), carboxy group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl etc.), C _1-6 alkoxy-
It may have 1 to 5 substituents selected from a carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl, etc.), a nitro group and a cyano group.

As the "heterocyclic group optionally having substituent (s)" for R ¹ , the "optionally substituted heterocyclic group" which is exemplified as the substituent on the above-mentioned "hydrocarbon group" The same as the “heterocyclic group” are used. Examples of R ¹ include a hydrogen atom, (1) halogen, (2) nitro, (3) C _1-6 alkyl optionally substituted with C _1-6 alkyl-carbonyl, benzoyloxycarbonyl and C _1-6 An amino optionally having one or two substituents selected from alkylsulfonyl, (4) (i) hydroxy, substituted with C _1-6 alkyl-carbonyl, carboxyl or C _1-6 alkoxy-carbonyl Optionally substituted with C _1-6 alkyl, (ii) phenyl optionally substituted with hydroxy, (iii) benzoyl or (iv) optionally substituted with mono- or di-C _1-6 alkylamino-carbonyl Hydroxy, (5) C _3-6
Cycloalkyl, (6) phenyl _optionally substituted with hydroxy or halogeno-C _1-6 alkyl or (7) C _1-6 optionally substituted with thienyl, furyl, thiazolyl, indolyl or benzyloxycarbonylpiperidyl.
Alkyl groups, C _2-6 alkenyl groups, C _6-14 an aryl group or a C _7-14 aralkyl group are preferable, and hydroxy, phenyl or C _1-6 alkyl - substituted by a carbonyl or C _1-6 alkylsulfonyl And a C _1-6 alkyl group or a C _7-14 aralkyl group each of which may be substituted with an optionally substituted amino. The substitution position of the substituent in the aralkyl group represented by R ¹ is preferably the para position. In the above formula, R ² represents an amino group which may be substituted. Examples of the “optionally substituted amino group” include (i) an unsubstituted amino group, (ii) a hydrocarbon group optionally having a substituent, and a heterocyclic group optionally having a substituent. Examples include an amino group having one or two substituents selected from a ring group and an acyl group, and (iii) a nitrogen-containing heterocyclic group optionally having a substituent. As the “hydrocarbon group optionally having substituent (s)”, those similar to the “hydrocarbon group optionally having substituent (s)” represented by R ¹ can be used. As the “heterocyclic group optionally having substituent (s)”, those similar to the “heterocyclic group optionally having substituent (s)” represented by R ¹ can be used.

The "acyl group" includes, for example, formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), benzoyl group,
_1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
sec-propoxycarbonyl, butoxycarbonyl, t-
Butoxycarbonyl), a C _7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl), a piperidin-4-ylcarbonyl group, a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec) -Propylsulfonyl,
Butylsulfonyl, t-butylsulfonyl, etc.), carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.)
And further include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxy group, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), a formyl group , C
_1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), carboxy group, C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl, etc.) An amino group, a mono- or di-C _1-6 alkylamino group (for example,
Methylamino, ethylamino, dimethylamino, diethylamino, etc.), pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, 4-methylpiperidyl, 4-phenylpiperidyl, carbamoyl, mono- or di-C _1-6 alkyl A carbamoyl group (for example,
Methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), a phenoxy group, a mono - or di -C _1-6 alkyl - carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy etc. ), Formylamino group, C _1-6
It has one to three substituents selected from an alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), a formyloxy group, and a C _1-6 alkyl-carbonyloxy group (eg, acetoxy, etc.). It may be.

The "nitrogen-containing heterocyclic group" of the "nitrogen-containing heterocyclic group optionally having substituent (s)" is selected from, for example, nitrogen atom, oxygen atom and sulfur atom in addition to the nitrogen atom having a bond. A 5- to 7-membered nitrogen-containing heterocyclic group optionally having 1 to 4 heteroatoms (for example, 1-imidazolyl, 1-pyrazolyl, 1-pyrrolyl, 1-pyrrolidinyl, 1-piperidyl, morpholinyl, A ring in which benzene, pyridine or the like is condensed to a 5- to 7-membered nitrogen-containing heterocyclic group (eg, 1-benzimidazolyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2) , 3,4-tetrahydroquinolin-1-yl, 1-indolyl, etc.).
As the substituent which the "nitrogen-containing heterocyclic group" may have, for example, the same substituents as those which the "aromatic hydrocarbon" in the ring A may have, and the like are preferably used. Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl group (eg, methyl, ethyl, propyl, butyl, sec-butyl, t-butyl, isopropyl, etc.), C _1-6 alkoxy group (For example, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, t-butoxy, isopropoxy, etc.), and the number of substituents is 1 to 5. R ² is, for example, an unsubstituted amino group, piperidyl group or C _1-6 alkyl optionally substituted with benzyl, amino or phenyl, mono- or di-C _1-6 alkyl-carbamoyl, C _1-6 Alkoxy-
Carbonyl, C _1-6 alkyl - sulfonyl, optionally substituted with piperidyl carbonyl and halogen or amino C _1-6 alkyl - 1 or 2 selected from carbonyl
Amino group which may have a plurality of substituents is preferable,
A substituted or unsubstituted amino group is preferred.

[0025]

Embedded image And R ^a , R ^b , R ^c , R ^d ,
R ^e and R ^f are each preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl or the like), and particularly a hydrogen atom is widely used. ). As the “optionally substituted hydrocarbon group”, for example, those similar to the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ can be used. As E, for example, -CON (R ^a )-(R ^a has the same meaning as described above and is preferably a hydrogen atom or an alkyl group) or the like is used, and a bond,

Embedded image (R ^a , R ^b and R ^c have the same meanings as above, and are preferably a hydrogen atom or a C _1-6 alkyl group).
Among them, -CONH is particularly widely used.

In the above formula, L represents a divalent group. As the “divalent group”, for example,-which may have a substituent,
Examples thereof include a divalent hydrocarbon group which may be via O- or -S-. L is preferably, for example, a divalent hydrocarbon group which may have a substituent, and particularly a C _1-6 alkylene group which may have a substituent is generally used. Examples of the “divalent hydrocarbon group optionally having substituent (s)” include, for example, those similar to the “divalent hydrocarbon group optionally having substituent (s)” represented by D, and the like. Is used. Examples of the “C _1-6 alkylene group” of the “ _optionally substituted C _1-6 alkylene group” include methylene, ethylene, propylene, butylene and the like. The “C _1-6 alkylene group” is, for example, 1 to 5 C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl,
Butyl, etc.). For example, L is-
A C _1-6 alkylene group which may be via O— and may be substituted with a C _1-6 alkyl is preferable.
_{A 1-6} alkylene group (preferably methylene or the like) and the like are preferable. In the above formula, X represents two hydrogen atoms, or an oxygen atom or a sulfur atom. Preferably, it is an oxygen atom or a sulfur atom, and particularly an oxygen atom is widely used.

Embedded image

Embedded image

The “optionally substituted hydrocarbon group” represented by R ⁴ is the same as the “optionally substituted hydrocarbon group” described for R ¹ . The thing etc. are used. Examples of the “acyl group” represented by R ⁴ include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), a benzoyl group, a C _1-6 alkoxy-carbonyl group (eg, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), benzyloxycarbonyl group, C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec. -Propylsulfonyl, butylsulfonyl, t-
Butylsulfonyl, etc.), carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), and the like. For example, fluorine, chlorine,
Bromine, iodine, etc.), hydroxy group, C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.) ,
Carboxy group, C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl, etc.), amino group, mono- or di-C _1-6 alkylamino group (for example, , Methylamino, ethylamino, dimethylamino, diethylamino, etc.), pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, 4-methylpiperidyl, 4-phenylpiperidyl, carbamoyl, mono- or di-C _1-6 Alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), phenoxy group, mono- or di-C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy, ethylcarbamoyl) Moyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.),
1 selected from a formylamino group, a C _1-6 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), a formyloxy group and a C _1-6 alkyl-carbonyloxy group (eg, acetoxy, etc.) It may have from 3 to 3 substituents.

R ⁴ is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.).

Embedded image As the compound represented by the formula (I), for example, ring A is halogen, hydroxy, C _1-6 alkoxy, halogeno-C
_1-6 alkoxy, C _7-14 aralkyloxy, benzoyl-C _1-6 alkoxy, hydroxy-C _1-6 alkoxy, C
_1-6 alkoxy-carbonyl-C _1-6 alkoxy, C _3-14
Cycloalkyl-C _1-6 alkoxy, imidazole-1
-Yl-C _1-6 alkoxy, C _7-14 aralkyloxy-
A benzene ring optionally substituted with carbonyl-C _1-6 alkoxy or hydroxyphenyl-C _1-6 alkoxy, a benzene ring or thiophene ring in which ring B may be optionally substituted with C _1-6 alkoxy, or R ² And a tetrahydroisoquinoline ring, Z is halogen, formyl,
Halogeno -C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl - carbonyl, 1 to 3 substituents substituted C _6-14 aryl group selected from oxo and pyrrolidinyl, C _3-10 cycloalkyl group, piperidyl group, thienyl group, furyl group, pyridyl group, thiazolyl group, indolyl group or C _1-6 alkyl group, D is C _1-6 alkylene group, G is a bond, or contains phenylene A C _1-6 alkylene group which may be substituted with phenyl, R ¹ is a hydrogen atom, (1) halogen, (2) nitro, (3)
C _1-6 optionally substituted with C _1-6 alkyl-carbonyl
Amino optionally having one or two substituents selected from _1-6 alkyl, benzoyloxycarbonyl and C _1-6 alkylsulfonyl, (4) (i) hydroxy, C _1-6 alkyl-carbonyl, Carboxy or C _1-6 alkoxy-
C _1-6 alkyl optionally substituted with carbonyl, (i
i) phenyl optionally substituted with hydroxy, (iii)
Benzoyl or (iv) hydroxy optionally substituted with mono- or di-Ci_ ₆ alkylamino-carbonyl,
(5) C _3-6 cycloalkyl, (6) phenyl _optionally substituted with hydroxy or halogeno-C _1-6 alkyl or
(7) thienyl, furyl, thiazolyl, indolyl or benzyloxycarbonylpiperidyl optionally substituted with a C _1-6 alkyl group, C _2-6 alkenyl group, C _6-14 aryl group or C _7-14 aralkyl group,

R ² is (1) an unsubstituted amino group, (2) piperidyl group or (3) (i) benzyl, (ii) C _1-6 alkyl _optionally substituted with amino or phenyl, (iii) ) Mono- or di-C _1-6 alkyl-carbamoyl, (iv) C _1-6 alkoxy-carbonyl, (v) C _1-6 alkyl-sulfonyl, (vi) piperidylcarbonyl and (vii) substituted with halogen or amino An amino optionally having one or two substituents selected from C _1-6 alkyl-carbonyl,
E is a bond, -CON ( ^Ra )-, -N ( ^Ra ) CO-, -N
( ^Rb ) CON ( ^Rc )-,

Embedded image (R ^a, R ^b and R ^c are each a hydrogen atom or a C _1-6 alkyl group), it may also be via the L is -O-, and optionally substituted by C _1-6 alkyl C _{1- 6} alkylene group, X
Is an oxygen atom,

Embedded image The case where —N (R ⁴ ) — (R ⁴ is a hydrogen atom or a C _1-6 alkyl group) is preferred. Among them, a ring A is a benzene ring optionally substituted with halogen, hydroxy or C _1-6 alkoxy, a ring B is bonded to a benzene ring or thiophene ring or R ² and a tetrahydroisoquinoline ring, and Z is substituted with halogen. A phenyl group, D may be a C _1-6 alkylene group, G may be a C _1-6 alkylene group, and R ¹ may be (1) hydroxy, (2) phenyl or (3) C _1-6 alkyl-carbonyl or C ₁ C _1-6 alkyl basic or C _7-14 aralkyl group optionally substituted with amino which may be substituted with _-6 alkylsulfonyl, R ² is an unsubstituted amino group, and E is-
CONH-, L is a C _1-6 alkylene group, X is

Embedded image As the compound represented by the formula (I), the substituent at the 3-position (-DEGG-Z) of the benzoxazepine ring has the S configuration, and the substituent at the 3-position and the 5-position (ring B). Those having a relative configuration in a trans form are preferred.

Preferred examples of the compound represented by the formula (I) include 3,5-trans-N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -1
-(4-biphenylmethyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, (3S, 5S) -N-
(2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-
N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -1- [2- (4-biphenyl) ethyl] -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl)
-5- (4-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5- (2-aminomethylthiophene-5
-Yl) -1- (4-biphenylmethyl) -7-chloro-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5
-Trans-N- (2-fluorobenzyl) -5- [3-
[(1-amino-1-methyl) ethyl] phenyl] -1- (4
-Biphenylmethyl) -7-chloro-2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5-trans-N
-(2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-1- (4-hydroxybenzyl)
-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
5-trans-N- (2-fluorobenzyl) -1- (4
-Acetylaminobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-1- (4-methanesulfonylaminobenzyl) -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-
Trans-N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -1- (4-biphenylmethyl)-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5
-Trans-N- (2-fluorobenzyl) -5- (3-
(Aminomethylphenyl) -1- (4-hydroxybenzyl) -7-methyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, , 5-trans-N- (2-fluorobenzyl) -5- [4-[(1-amino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl)-
5- (3-aminomethylphenyl) -7-chloro-1-
[2- (4-hydroxyphenyl) ethyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5-trans-N- (2-Fluorobenzyl) -5- (3-aminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide or a salt thereof and 3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -7-chloro-2-
Oxo-1,2,3,5-tetrahydro-5- (1,2,3,
4-tetrahydroisoquinolin-5-yl) -4,1-
Benzoxazepine-3-acetamide or a salt thereof and the like. The compound represented by the general formula (I) or a salt thereof can be produced by the following method or a method analogous thereto. Among the compounds represented by the general formula (I),
General formula (Ia):

Embedded image [In the formula, R ^2a is a group having a protecting group (for example, t-butoxycarbonyl, benzyloxycarbonyl, trityl, and the like) in R ² , and other symbols have the same meanings as described above. Or a salt thereof is represented by, for example, the following general formulas (IIIa), (IIIb) and (IIIc) obtained by (Method A), (Method B) and (Method C) shown below. Or a salt thereof as a production intermediate, which has the general formula (IV), (IV ′) or (IV ″):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof.

Embedded image [Wherein Le is a leaving group (eg, chlorine, bromine, iodine,
Methylsulfonyloxy, toluenesulfonyloxy, etc.), R ^1a is a group obtained by removing a methylene chain from an optionally substituted hydrocarbon group represented by R ¹ , and other symbols have the same meanings as described above. ]

[0031]

Embedded image [The symbols in the formula are as defined above. ]

The general formula (IIIa-) in the above (Method A)
The compound represented by the general formula (IIIa-)
In the reaction to the compound represented by 2) or a salt thereof, the reduction reaction of the carbonyl of the compound represented by the general formula (IIIa-1) or a salt thereof is performed, for example, by a protic solvent (for example, methanol, ethanol, propanol, Butanol) or an aprotic solvent (eg, ethyl ether, tetrahydrofuran, dioxane, etc.)
For example, it can be produced by treating with a metal hydride complex compound (for example, lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium borohydride, etc.).
Such a metal hydride complex compound is used in an amount of about 0.3 to 5 molar equivalents, preferably about 0.5 to 2 molar equivalents, per 1 mol of the compound represented by the general formula (IIIa-1) or a salt thereof. Used. The reaction temperature at this time is about -20 to 100 ° C, preferably about 20 to 50 ° C, and the reaction time is about 0.5 to 24 hours. The reaction from the compound represented by the general formula (IIIa-2) or a salt thereof to the compound represented by the general formula (IIIa-5) or a salt thereof in the above (Method A) is carried out, for example, by using an ether solvent (for example, diethyl). In a solvent such as ether, tetrahydrofuran, dioxane), a hydrocarbon solvent (eg, benzene, toluene, hexane, heptane, etc.), an alcohol solvent (eg, methanol, ethanol, propanol, etc.), acetone, dimethylformamide, etc., if necessary. Bases (eg, sodium bicarbonate, potassium bicarbonate,
Sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like). In this reaction, the compound represented by the general formula (IIIa-3) or its salt is used in an amount of about 1 to 10 molar equivalents, preferably 1 mol, per 1 mol of the compound represented by the general formula (IIIa-2) or its salt. Is used in about 1 to 2 molar equivalents. The reaction temperature at this time is about 0 to 100 ° C, preferably about 20 to 50 ° C.
C., and the reaction time is about 1 to 24 hours, preferably about 3 to 10 hours. Further, the compound represented by the general formula (IIIa-5) or a salt thereof is, for example, an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), a hydrocarbon solvent (eg,
In a solvent such as benzene, toluene, hexane, heptane or the like, or an alcoholic solvent (eg, methanol, ethanol, propanol, butanol, etc.), a compound represented by the general formula (IIIa-
The compound represented by the formula (2) or a salt thereof and the general formula (IIIa-4)
And a salt thereof, for example, by applying catalytic reduction, reductive amination using sodium borohydride or sodium cyanoborohydride, or the like. At this time, the general formula (II
The compound represented by the general formula (IIIa-4) or a salt thereof is about 1 mol per 1 mol of the compound represented by Ia-2) or a salt thereof.
To 10 molar equivalents, preferably about 1 to 2 molar equivalents, and the reducing agent is used in about 0.3 to 5 molar equivalents, preferably about 0.5 to 1 molar equivalent. The reaction temperature at this time is about 0 to 100 ° C, preferably about 10 to 70 ° C.
° C, and the reaction time is about 1 to 24 hours, preferably about 3 to 10 hours.

The formula (IIIa-) in the above (Method A)
Reaction of the compound represented by 5) or a salt thereof with monoethyl chlorofumarate and the compound represented by the general formula (IIIa-5) or the salt thereof represented by the general formula (IIIb-1) in the above (Method B) )) Or a salt thereof,
It can be carried out using an acylation reaction known per se.
In this acylation reaction, for example, an ether solvent (for example,
Diethyl ether, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), dimethylformamide, dimethyl sulfoxide, In a solvent such as an ester solvent (ethyl acetate, methyl acetate, etc.), if necessary, water and a base (for example, 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, (Potassium carbonate, sodium hydride, potassium hydride, etc.). At this time, the compound represented by the general formula (IIIb-5)
The compound represented by -1) or a salt thereof and an acid chloride (eg, monoethyl chloride fumarate) are used in about 1 to 10 molar equivalents, preferably about 1 to 3 molar equivalents. The reaction temperature at this time is about −50 to 100 ° C., preferably about 0 to 50 ° C., and the reaction time is about 1 to 48 hours, preferably about 5 to 10 hours. In the (method A), the cyclization reaction from the compound represented by the general formula (IIIa-6) or a salt thereof to the compound represented by the general formula (IIIa-7) or a salt thereof is performed, for example, using an ether solvent (for example, , Diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), alcohol solvents (eg, methanol, ethanol, propanol, butanol, etc.), acetone, dimethylformamide, etc. Medium, if necessary, the reaction can be carried out in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like). At this time, these bases are used in an amount of about 1-5 molar equivalents, preferably about 1-2 molar equivalents, per 1 mol of the compound represented by the general formula (IIIa-6) or a salt thereof. The reaction temperature at this time is about −20 to 200 ° C., preferably about 2 ° C.
The reaction temperature is about 0 to 100 ° C., and the reaction time is about 1 to 20 hours, preferably about 2 to 5 hours.

The general formula (IIIb-) in the above (Method B)
The compound represented by the formula (IIIb-)
The cyclization reaction to the compound represented by 3) or a salt thereof includes, for example, an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), a hydrocarbon solvent (eg, benzene, toluene, hexane, heptane, etc.), In a solvent such as an alcoholic solvent (eg, methanol, ethanol, propanol, butanol, etc.), acetone, dimethylformamide, etc., if necessary, a base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, hydrogen) (Potassium iodide, etc.). At this time, the general formula (IIIb-
These bases are used in an amount of about 1-5 molar equivalents, preferably about 1-2 molar equivalents, per 1 mol of the compound represented by 2) or a salt thereof. The reaction temperature at this time is about -20 to 100 ° C, preferably about 20 to 100 ° C, and the reaction time is about 1 to 20 hours, preferably about 2 to 5 hours. The method for producing the compound represented by the general formula (IIIa) or the salt thereof in (Method A) and the compound represented by the general formula (IIIb) or the salt thereof in (Method B) are represented by the general formula (IIIa-
7) and can be produced by treating the compound represented by (IIIb-3) or a salt thereof with an acid or a base. That is, these compounds have the general formula (IIIa-7)
Or a compound represented by (IIIb-3) or a salt thereof, for example, a mineral acid (eg, nitric acid, hydrochloric acid, hydrobromic acid, iodic acid,
Sulfuric acid or the like) or an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) in an aqueous solution at about 0 to 150 ° C., preferably about 20 to 50 ° C. Can be manufactured. The strength of the acid and the base at this time is preferably about 1 to 10 normal, and preferably about 4 to 10 normal. The reaction time at this time is about 1 to 24 hours, preferably about 2 to 10 hours.

The compound represented by the general formula (Ia) or a salt thereof may be a compound represented by the general formula (IIIa) or (IIIb) or a salt thereof and a compound represented by the general formula (IV), (IV ′) or (IV) The compound represented by '') or a salt thereof can be produced by using a condensing agent in a solvent, if necessary, in the presence of a base. Examples of the solvent to be used include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), and halogen solvents (eg, dichloromethane, dichloroethane, chloroform,
Carbon tetrachloride), acetonitrile, dimethylformamide and the like. Examples of the base used include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine and the like.
Examples of the condensing agent used include condensing agents used for peptide synthesis, and specifically, for example, dicyclohexylcarbodiimide, diethyl cyanophosphate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and the like are used. Can be At this time, the compound represented by the general formula (IV) or a salt thereof is about 0.5 to 2 molar equivalents, preferably 1 mol of the compound represented by the general formula (IIIa) or (IIIb) or a salt thereof. Is used in about 1 to 1.2 molar equivalents, and the condensing agent is used in about 0.5 to 5 molar equivalents, preferably about 1 to 2 molar equivalents. The reaction temperature at this time is about 0 to 100 ° C, preferably about 20 to 50 ° C, and the reaction time is about 0.5 to 24 hours.
It is preferably about 1 to 5 hours. General formula (I)
Among the compounds represented by the general formula (Ib):

Embedded image [The symbols in the formula are as defined above. The compound represented by the general formula (IIIc) obtained by the following (Method C) or (Method D) or a salt thereof is used as a production intermediate, and the compound represented by the general formula It can be produced by, for example, reacting the compound represented by (IV) or a salt thereof.

[0036]

Embedded image [Wherein, Le ¹ has the same meaning as Le, but Le ¹ and Le are not the same at the same time, and the other symbols have the same meanings as above. ]

Embedded image [The symbols in the formula are as defined above. ]

The formula (IIIa-) in the above (Method C)
The compound represented by the general formula (IIIc-)
The method for producing the compound represented by the formula (1) or a salt thereof includes the compound represented by the general formula (IIIa-2) shown in the above (Method A) or a salt thereof, and the general formula (IIIa-3) or ( IIIa-4)
In the reaction with the compound represented by the general formula (IIIa)
It can be produced by the same method as in producing the compound represented by -5) or a salt thereof. From the compound represented by the general formula (IIIc-1) or a salt thereof in the above (Method C) and (Method D), a compound represented by the general formula (IIIc-3) or a salt thereof, or a compound represented by the general formula (IIIa-1) The method for producing a compound represented by the general formula (IIId-1) or a salt thereof from a compound represented by the formula (IIId-1) or a salt thereof includes, for example, an ether solvent (eg, diethyl ether, tetrahydrofuran,
Dioxane, etc.), hydrocarbon solvents (eg, benzene,
In a solvent such as toluene, hexane, heptane, a halogen-based solvent (eg, dichloromethane, dichloroethane, chloroform, etc.), acetonitrile, dimethylformamide, etc., a condensing agent (eg, diethyl cyanophosphate, dicyclohexylcarbodiimide, etc.) is used. In the presence of a base (eg, triethylamine, 4-dimethylaminopyridine, N-methylpiperidine, etc.). The compound represented by the general formula (IIIc-1) or (IIIa-1) or 1 mol of a salt thereof is added to the compound represented by the general formula (IIIc-1)
The compound represented by -2) or a salt thereof is used in about 1 to 5 molar equivalents, preferably about 1 to 1.5 molar equivalents. The reaction temperature at this time is about 0 to 100 ° C., preferably about 20 to 50 ° C., and the reaction time is
It is about 1 to 24 hours, preferably about 2 to 5 hours. The condensing agent used at this time is represented by the general formula (IIIc-
The amount is about 1 to 5 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of the compound represented by 1) or (IIIa-1) or a salt thereof.

In the above (Method C), the compound represented by the general formula (IIIc-
From the compound represented by 3) or a salt thereof, the compound represented by the general formula (IIIc-
From the compound represented by 4) or a salt thereof, or the compound represented by the general formula (IIId-1) or the salt thereof in the above (Method D) to the compound represented by the general formula (IIId-2) or a salt thereof Are produced by, for example, ether-based solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon-based solvents (eg, benzene, toluene,
Hexane, heptane, etc.), alcoholic solvents (for example,
In a solvent such as methanol, ethanol, propanol, butanol, a halogen-based solvent (eg, dichloromethane, dichloroethane, chloroform, etc.), acetone, acetonitrile, dimethylformamide, etc., a method known per se is used. For example, when Le ¹ is a carbobenzyloxy group, for example, by catalytic reduction using palladium, platinum or the like as a catalyst, when Le ¹ is a t-butoxycarbonyl group,
For example, acids (eg, hydrochloric acid, bromic acid, trifluoroacetic acid, etc.)
The compound obtained by removing Le ¹ by dissolving or suspending the compound in an ether solvent (for example, diethyl ether, tetrahydrofuran, dioxane, etc.), a hydrocarbon solvent (for example, benzene, toluene, hexane, Heptane, etc.), alcohol solvents (eg, methanol, ethanol, propanol, butanol, etc.), solvents such as acetonitrile, dimethylformamide, etc., if necessary, acids (eg, hydrochloric acid, bromic acid, propionic acid, methanesulfonic acid, toluenesulfonic acid) , Sulfuric acid, etc.). The reaction temperature at this time is about 0 to 100 ° C., preferably about 30 to 70 ° C.,
The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours. In the above (Method D), a method for producing a compound represented by the general formula (IIIc-4) or a salt thereof from the compound represented by the general formula (IIId-2) or a salt thereof is the same as that in the above (Method A). The same method as the reaction between the compound represented by the general formula (IIIa-2) or a salt thereof and the compound represented by the general formula (IIIa-3) or a salt thereof is used.
Further, the method for producing a compound represented by the general formula (IIIc) or a salt thereof from the compound represented by the general formula (IIIc-4) or a salt thereof in the above (Method C) and (Method D) is as described in the above ( The same method as the method for producing the compound represented by the general formula (IIIa) or a salt thereof from the compound represented by the general formula (IIIa-7) or a salt thereof in the method A) is used.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ic):

Embedded image [The symbols in the formula are as defined above. ] Or a salt thereof can be produced by reducing the compound represented by the general formula (Ib) or a salt thereof. That is, for example, water, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), alcohol solvents (eg, methanol,
Production using a reducing agent such as sodium borohydride, lithium aluminum hydride or sodium cyanoborohydride in a solvent such as ethanol, propanol, butanol, or a halogen-based solvent (eg, dichloromethane, chloroform, etc.). Can be. This reaction is performed based on 1 mol of the compound represented by the general formula (Ib) or a salt thereof.
About 0.2 to 5 molar equivalents of reducing agent, preferably 0.3
Or about 1 molar equivalent. The reaction temperature at this time is
The reaction temperature is about 0-100 ° C, preferably about 20-50 ° C, and the reaction time is about 0.5-10 hours, preferably about 1-3 hours.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Id):

Embedded image [Wherein, R ^4a represents a hydrocarbon group which may have a substituent,
Other symbols are as defined above. The compound represented by the general formula (Ic) or a salt thereof is represented by the general formula (IVa) or (IVb):

Embedded image [In the formula, R ^4aa is a hydrocarbon group which may have a substituent, and other symbols are as defined above. Or a salt thereof. For example, the reaction between the compound represented by the general formula (Ic) or a salt thereof and the compound represented by the general formula (IVa) or a salt thereof is represented by the general formula (IIIa-2) in the above (Method A). Can be produced under the same conditions as in the reaction of the compound or a salt thereof with the compound represented by the general formula (IIIa-3) or a salt thereof. The reaction between the compound represented by the general formula (Ic) or a salt thereof and the compound represented by the general formula (IVb) or a salt thereof includes, for example, an ether solvent (for example, diethyl ether, tetrahydrofuran, dioxane, etc.), Halogen solvents (eg, dichloromethane, dichloroethane,
It can be carried out in a solvent such as chloroform, acetonitrile, dimethylformamide and the like, if necessary, using a base. Examples of the base used include organic bases such as triethylamine, 4-dimethylaminopyridine, triethylenediamine, and tetramethylethylenediamine. In this reaction, the compound represented by the general formula (IVb) or its salt is used in an amount of about 0.5 to 3 molar equivalents, preferably about 1 mol, per 1 mol of the compound represented by the general formula (Ic) or its salt. To 1.5 molar equivalents. The reaction temperature at this time is about 0 to 150 ° C., preferably about 30 to 100 ° C., and the reaction time is about 0.5 to 24 hours, preferably about 1 to 3 hours.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ie):

Embedded image [The symbols in the formula are as defined above. The compound represented by the general formula (V):

Embedded image [The symbols in the formula are as defined above. A compound represented by the general formula (VI):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof, and the compound represented by the general formula (VII):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof.

The compound represented by the general formula (VI) or a salt thereof is obtained by reacting the compound represented by the general formula (V) or a salt thereof with diphenylphosphoryl azide in a solvent in the presence of a base. Can be produced by treating the obtained product with an acid in a solvent. Examples of the solvent used in the reaction of the compound represented by the general formula (V) or a salt thereof with diphenylphosphoryl azide include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.) and halogen solvents (eg, dichloromethane) , Dichloroethane, chloroform and the like), dimethylformamide and the like. Examples of the base used at this time include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine and the like. In this reaction, diphenylphosphoryl azide is used in an amount of about 1 to 10 molar equivalents, preferably about 1.5 to 3 molar equivalents, per 1 mol of the compound represented by the formula (V) or a salt thereof. The reaction temperature at this time is about -20 to 50 ° C, preferably about 0 to 20 ° C, and the reaction time is about 0.5 to 5 hours, preferably about 1 to 2 hours. When the product obtained by the above reaction is treated with an acid, examples of a solvent to be used include water, dioxane, dimethylformamide and the like, and examples of the acid to be used include sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid and the like. Mineral acids. The reaction temperature at this time is about 20 to 200 ° C., preferably about 50 to 100 ° C., and the reaction time is about 0.
It is about 5 to 5 hours, preferably about 1 to 2 hours. The condensation reaction between the compound represented by the general formula (VI) or a salt thereof and the compound represented by the general formula (VII) or a salt thereof is performed, for example, when the compound represented by the general formula (Ia) or a salt thereof is produced. The same conditions as in the condensation reaction of the compound represented by the general formula (IIIa) or (IIIb) or a salt thereof with the compound represented by the general formula (IV) or a salt thereof are used.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (If):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof, or a general formula (Ig):

Embedded image [The symbols in the formula are as defined above. The method for producing the compound represented by the general formula (VI) or a salt thereof may be carried out under the same conditions as those for producing the compound represented by the general formula (VI) or the salt thereof, for example, the compound represented by the general formula (V) or a salt thereof. By reacting the salt with diphenylphosphoryl azide, the compound represented by the general formula (VII)
I):

Embedded image [The symbols in the formula are as defined above. ], And then the intermediate represented by the general formula (IX) or (X):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. This production method can be performed, for example, under the same conditions as in the reaction of the compound represented by the general formula (Ic) or a salt thereof with the compound represented by the general formula (IVb) or a salt thereof.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ih):

Embedded image [The symbols in the formula are as defined above. The compound represented by the general formula (VI) or a salt thereof and the compound represented by the general formula (XI):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. This reaction is performed, for example, using an ether solvent (for example,
In a solvent such as diethyl ether, tetrahydrofuran, dioxane, an alcohol solvent (eg, methanol, ethanol, propanol, butanol, etc.), acetone, dimethylformamide, etc., if necessary, a base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate) , Potassium carbonate, sodium hydride, potassium hydride, triethylamine and the like). In this reaction, the compound represented by the general formula (XI) or a salt thereof is added in an amount of about 1 to 10 molar equivalents, preferably about 1 to 2 mols per mol of the compound represented by the general formula (VI) or 1 mol thereof. Use about molar equivalent. The reaction temperature at this time is about 0 to 100 ° C., preferably about 20 to 50 ° C., and the reaction time is about 1 to 24 hours, preferably about 3 to 10 hours.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ii):

Embedded image [The symbols in the formula are as defined above. The compound represented by the general formula (V) or a salt thereof is represented by the general formula (XII):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. For example, a compound represented by the general formula (V) or a salt thereof and a compound represented by the general formula (XII) or a salt thereof can be produced by using a condensing agent in a solvent, if necessary, in the presence of a base. it can. Examples of the solvent used include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), acetonitrile, dimethylformamide and the like. Examples of the base used include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine and the like. Examples of the condensing agent used include condensing agents used for peptide synthesis, and specifically, for example, dicyclohexylcarbodiimide, diethyl cyanophosphate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and the like. No. In this reaction, the compound represented by the general formula (XII) or a salt thereof is added in an amount of about 0.5 to 2 molar equivalents, preferably about 1 to 1 mol of the compound represented by the general formula (V) or 1 mol thereof. To 1.2 molar equivalents, and the condensing agent is used in about 0.5 to 5 molar equivalents, preferably about 1 to 2 molar equivalents. The reaction temperature at this time is about 0 to 100 ° C, preferably about 2 ° C.
0 to 50 ° C. and the reaction time is about 0.5 to 2
4 hours, preferably about 1 to 5 hours.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ij):

Embedded image [The symbols in the formula are as defined above. The compound represented by the general formula (XIII):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof, and a compound represented by the general formula (XIV):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. The compound represented by the general formula (XIII) or a salt thereof is a compound represented by the general formula (V) or a salt thereof, for example, a protic solvent (eg, methanol, ethanol,
Propanol, butanol, etc.) or an aprotic solvent (eg, ethyl ether, tetrahydrofuran,
In a solvent such as dioxane, for example, it can be produced by treating with a metal hydride complex compound (eg, lithium aluminum hydride, sodium aluminum hydride, sodium borohydride, etc.). The metal hydride complex is used in an amount of about 0.3 to 5 molar equivalents, preferably about 0.5 to 2 molar equivalents, per 1 mol of the compound represented by the general formula (V) or a salt thereof. The reaction temperature at this time is about -20 to 100 ° C, preferably about 0 to 20 ° C, and the reaction time is about 0.5 to 1 ° C.
0 hour, preferably about 1 to 3 hours.

In the reaction of the compound represented by the general formula (XIII) or a salt thereof with the compound represented by the general formula (XIV) or a salt thereof, the solvent used includes, for example, an aprotic solvent (eg, ethyl Ether, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, etc.), and if necessary, for example, an inorganic base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.), an organic base (eg, triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, etc.), sodium hydride, cesium fluoride, or the like may be used. In this reaction, the compound represented by the general formula (XIV) or a salt thereof is added in an amount of about 0.5 to 5 molar equivalents, preferably about 1 mol, per 1 mol of the compound represented by the general formula (XIII) or a salt thereof. 1
Or 2 molar equivalents. The reaction temperature at this time is about 0
To 200 ° C., preferably about 20 to 100 ° C., and the reaction time is about 10 minutes to 5 hours, preferably about 30 minutes to 2 hours.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ik):

Embedded image [The symbols in the formula are as defined above. A compound represented by the general formula (XV):

Embedded image [In the formula, Le ² is a halogen (eg, chlorine, bromine, iodine, etc.), and other symbols are as defined above. Or a salt thereof, and a compound represented by the general formula (XVI):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof.

The compound represented by the general formula (XV) or a salt thereof can be obtained by converting the compound represented by the general formula (VI) or a salt thereof into, for example, hydrochloric acid, hydrobromic acid or hydroiodic acid. After diazotization with sodium, it can be produced by heating. The reaction temperature at this time is about 20 to 2
The reaction temperature is about 00 ° C., preferably about 50 to 100 ° C., and the reaction time is about 5 minutes to 2 hours, preferably about 15 to 30 minutes. The reaction between the compound represented by the general formula (XV) or a salt thereof and the compound represented by the general formula (XVI) or a salt thereof is performed when the compound represented by the general formula (Ij) or the salt thereof is produced. The reaction can be carried out under the same conditions as in the reaction of the compound represented by the general formula (XIII) or a salt thereof with the compound represented by the general formula (XIV) or a salt thereof. General formula (I)
Embedded image or a salt thereof, represented by the general formula (Il):

Embedded image [The symbols in the formula are as defined above. ] Or a salt thereof can be produced by oxidizing a compound represented by the general formula (Ik) or a salt thereof. In this reaction, for example, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane,
Dichloroethane, chloroform, etc.), acetonitrile,
In a solvent such as dimethylformamide, metachloroperbenzoic acid is used in an amount of about 1 to 5 mole equivalents, preferably about 2 to 3 moles, per mole of the compound represented by the general formula (Im) or a salt thereof.
Use about molar equivalent. The reaction temperature at this time is about 0 to 100 ° C., preferably about 0 to 30 ° C.,
The reaction time is about 1 to 10 hours, preferably about 1 to 2 hours.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Im):

Embedded image [The symbols in the formula are as defined above. A compound represented by the general formula (XIII) or a salt thereof, a compound represented by the general formula (VII) or a salt thereof, and a compound represented by the general formula (Ii) Or, when producing a salt thereof, it is produced by reacting the compound represented by the general formula (V) or a salt thereof with the compound represented by the general formula (XII) or a salt thereof under the same conditions as the reaction. be able to. Among the compounds represented by the general formula (I) or a salt thereof,
General formula (In):

Embedded image [The symbols in the formula are as defined above. The compound represented by the general formula (XIII) or a salt thereof is represented by the general formula (XVII):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof. In this reaction, as a solvent used,
Examples include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), acetonitrile, dimethylformamide, etc., and if necessary, bases (eg, triethylamine, 4-dimethyl). Aminopyridine, triethylenediamine, tetramethylethylenediamine, etc.) are used.
In this reaction, the compound represented by the general formula (XVII) or a salt thereof is used in an amount of about 0.5 to 3 molar equivalents, preferably about 1 mol per mol of the compound represented by the general formula (XIII) or 1 mol thereof.
To about 1.5 molar equivalents. The reaction temperature at this time is about 0 to 150 ° C, preferably about 30 to 10 ° C.
At 0 ° C., the reaction time is about 0.5 to 24 hours, preferably about 1 to 3 hours.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Io):

Embedded image [Wherein E ¹ is -CON (R ^a )-, -N (R ^b ) CON
^{(R c) -, - N} (R d) COO- or -N (R ^e) SO ₂
-And other symbols have the same meanings as described above. Or a salt thereof] are the compounds of formula (Io), E ¹ is -
When CON (R ^a ) —, the general formula (Iaa):

Embedded image [The symbols in the formula are as defined above. A compound represented by the general formula (Ibb):

Embedded image [The symbols in the formula are as defined above. A compound represented by the general formula (Idd):

Embedded image [The symbols in the formula are as defined above. Or a salt thereof, and a compound represented by the general formula (XIX): ^Ra- Le (XIX) wherein the symbols have the same meanings as described above. Or a salt thereof.

In this reaction, for example, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), alcohol solvents (eg, methanol, ethanol, etc.) The reaction can be carried out in a solvent such as propanol, acetone, dimethylformamide and the like, if necessary, in the presence of a base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.). .
In this reaction, the compound represented by the general formula (XIX) or a salt thereof is added to the compound represented by the general formula (Iaa), (Ibb) or (Idd) or 1 mol thereof in an amount of about 1 to 10 It is used in a molar equivalent, preferably about 1 to 2 molar equivalents. The reaction temperature at this time is about 0 to 100 ° C, preferably about 20 to 50 ° C, and the reaction time is about 1 to 24 hours, preferably about 3 to 10 hours. In the general formula (Io), E ¹ is —N (R ^b ) CON
^{(R c) -, - N} (R d) COO -, - N (R e) SO 2 -
Can be produced in the same manner as in the case where E ¹ is —CON (R ^a ) —.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ip):

Embedded image [Wherein, R ^2b is deprotected R ^2a , and other symbols are as defined above. A compound represented by the general formula (Iq):

Embedded image [The symbols in the formula are as defined above. ] Or the salt thereof is removed by a method known per se. In the removal of the protecting group, when the protecting group is a t-butoxycarbonyl group, a trityl group, or a benzyloxycarbonyl group, for example, an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), an alcohol solvent (eg, methanol, ethanol, etc.) , Propanol, etc.), halogenated solvents (eg, dichloromethane, dichloroethane, chloroform, etc.) such as hydrogen chloride, hydrogen bromide,
The protecting group can be removed by treating with an acid such as hydrochloric acid, bromic acid, nitric acid, sulfuric acid, and trifluoroacetic acid. When the protecting group is a benzyloxycarbonyl group, for example, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), alcohol solvents (eg, methanol, ethanol, propanol, etc.), dimethylformamide, ethyl acetate, acetic acid For example, the protective group can be removed by hydrolysis in a solvent such as a palladium-based catalyst (for example, metal palladium, palladium / carbon catalyst, etc.). In this reaction, when an acid treatment is performed, the reaction temperature is about -20 to 100 ° C, preferably about 0 to 30 ° C, and the reaction time is about 0.1 to 5 hours, preferably about 0.5 to 5 hours. It is about one hour. In this reaction, when hydrolyzing, the reaction temperature is -20 to 150 ° C, preferably about 0 to 50 ° C, and the reaction time is about 0.1 to 10 hours, preferably about 0.5 to 3 hours. And the hydrogen pressure is about 1 to 100 atm, preferably about 1 to 3 atm.
Atmospheric pressure. The catalyst used at this time is about 0.001 to 0.5 mole equivalent, preferably about 0.01 to 0.5 mole equivalent, per 1 mole of the compound represented by the formula (Ia) or a salt thereof.
One molar equivalent.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (Ir):

Embedded image [Wherein, Y ¹ represents an oxygen atom or —N (R ^4a ) — (R ^4a represents a hydrocarbon group which may have a substituent), and other symbols have the same meanings as described above. The compound represented by the general formula (Is):

Embedded image [The symbols in the formula are as defined above. And a salt thereof, and a compound represented by the general formula (XX) or (XXI):

Embedded image [Wherein, R ^2c and R ^2d each represent a hydrocarbon group which may have a substituent, a heterocyclic group or an acyl group which may have a substituent, and other symbols are as defined above. . Or a salt thereof. The reaction between the compound represented by the general formula (Is) or a salt thereof and the compound represented by the general formula (XX) or a salt thereof is carried out by the general formula (IIIa-
The compound represented by 2) or a salt thereof, and a compound represented by the general formula (IIIa-3)
Can be carried out under the same conditions as in the reaction with the compound represented by or a salt thereof. Further, the reaction between the compound represented by the general formula (Is) or a salt thereof and the compound represented by the general formula (XXI) or the salt thereof is performed by reacting the compound represented by the general formula (Ic) or the salt thereof with the general formula The reaction can be carried out under the same conditions as in producing the compound represented by the general formula (Id) or a salt thereof by reacting the compound represented by the (IVb) or a salt thereof.

Among the compounds represented by the general formula (I) or salts thereof, the general formula (It):

Embedded image [The symbols in the formula are as defined above. The compound represented by the general formula (I) or a salt thereof may be a compound represented by the formula (I) wherein X is an oxygen atom or a salt thereof, for example, an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), a hydrocarbon solvent (Eg, benzene, toluene, hexane, heptane, etc.), alcohol solvents (eg, methanol, ethanol, propanol, etc.), halogen solvents (eg, dichloromethane, chloroform, etc.), hexamethylphosphoric triamide, dimethyl sulfoxide, etc. It can be produced by reacting Lawson's reagent or phosphorus pentasulfide in a solvent. The Lawesson's reagent or phosphorus pentasulfide used in this case is used in an amount of about 1 to 10 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of the compound or a salt thereof in the general formula (I) wherein X is an oxygen atom. is there. The reaction temperature at this time is about 0 to 150 ° C., preferably about 50 to 100 ° C., and the reaction time is about 1 to 24 hours, preferably about 3 to 10 hours.

The compound represented by the general formula (Iu) is obtained by using the production intermediate (IIIe) and the compound of the general formula (IV) in the same manner as in the method for producing the compound represented by the above (Ia). be able to.

Embedded image At this time, the production intermediate represented by the general formula (IIIe) can be obtained by the following method. That is, the general formula (IIIa-5)
Is reacted with a compound represented by the general formula (IIIe-1) or a salt thereof in a hydrocarbon solvent (eg, benzene, toluene, xylene, etc.) in an organic acid (eg, It can be produced by reacting with mercaptosuccinic acid in the presence of methanesulfonic acid, p-toluenesulfonic acid, oxalic acid and the like. At this time, the organic acid is used in an amount of 0.05 equivalent to 5 equivalents, preferably (0.05 equivalent to 0.1 equivalent) to 1 equivalent of the general formula (IIIa-5).
1 equivalent) and the reaction time is 1 to 24 hours, preferably 1 to 2 hours. The reaction temperature is from 20 ° C to 140 ° C, preferably from 80 ° C to 100 ° C.

Embedded image The reaction from the compound represented by the general formula (IIIe-1) or a salt thereof to the compound represented by the general formula (IIIe) or a salt thereof is carried out by a hydrocarbon solvent (eg, benzene, toluene, xylene, etc.). Can be produced by reacting in a solution. At this time, the reaction temperature is between 40 ° C. and 150 ° C.
Preferably at 100 ° C to 140 ° C, the reaction time is 1
Hours to 24 hours, preferably 12 hours to 20 hours.

The compound represented by the general formula (Iv, Iw) can be produced by an oxidation reaction of the compound represented by the general formula (Iu). In this reaction, an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), a hydrocarbon solvent (eg, benzene, toluene,
Hexane, heptane and the like), and a solvent of a halogen-based solvent (for example, dichloromethane, dichloroethane, chloroform and the like), and per 1 mol of the compound represented by the general formula (Iu), per 1 mol of the compound represented by the general formula (Iu), 1 to 1.2 equivalents of metachloroperbenzoic acid At a reaction temperature (−10 ° C. to 5 ° C.), preferably 0 ° C.
When the reaction time is 1 minute to 10 minutes, a compound represented by the general formula (Iv) is obtained, and methacryloperbenzoic acid (2 to 2.5 equivalents) and the reaction temperature (10 ° C. to 50
C), preferably (10 ° C to 20 ° C) for 2 hours to 5 hours to obtain the compound represented by the general formula (Iw).

Embedded image

The starting compound and the production intermediate of the present invention may form a salt, and are not particularly limited as long as the reaction proceeds. Salts of these compounds include, for example, inorganic acid salts (eg, hydrochloride, sulfate,
Hydrobromide, phosphate, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, maleate,
Fumarate, propionate, citrate, tartrate, malate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc., alkali metal salts (eg, sodium salt, potassium salt) Etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), organic base salts (eg, trimethylamine salts, triethylamine salts, pyridine salts, piperidine salts, ethanolamine salts, etc.), aluminum salts, ammonium salts and the like. Used. In addition, the starting compound and the production intermediate of the present invention can be isolated according to a conventional method, but can also be used as they are in the next reaction step without isolation. In each of the reactions according to the present invention, when the compound has an amino group, a carboxy group, or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups. The desired compound can be obtained by removing the protecting group if necessary after the reaction. Examples of the amino-protecting group include a formyl group, a C _1-6 alkyl-carbonyl group (for example, acetyl, ethylcarbonyl, etc.), a benzyl group, t
-Butyloxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, phenylcarbonyl group, C
_{A 1-6} alkyloxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), a C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.),
A trityl group, a phthaloyl group, an N, N-dimethylaminomethylene group and the like are used. These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro groups and the like.

As the protecting group for the carboxy group, for example, C
_1-6 alkyl groups (eg, methyl, ethyl, propyl,
Isopropyl, butyl, t-butyl, etc.), phenyl group,
A silyl group, benzyl group, allyl group and the like are used. These groups may be substituted with one to three halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro groups and the like. Examples of the protecting group for the hydroxy group include a methoxymethyl group, an allyl group, a t-butyl group, a C _7-10 aralkyl group (eg, benzyl and the like), a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, Ethylcarbonyl), a benzoyl group, a _C7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), a pyranyl group, a furanyl group, a trialkylsilyl group and the like are used. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), a phenyl group , A C _7-10 aralkyl group (for example,
Benzyl), a nitro group and the like. As a method for removing these protecting groups, a method known per se or a method analogous thereto is used.For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, A method using palladium acetate or the like is used. When a compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method, and when obtained as a salt, converted to a free form or another salt according to a conventional method. You can also. The compound (I) of the present invention or a salt thereof thus obtained can be isolated and purified from the reaction solvent by a known means, for example, phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography, and the like. Can be. When the compound (I) of the present invention or a salt thereof exists as a diastereomer, a conformer, or the like, each can be isolated by a usual separation and purification means, if desired. When the compound (I) or a salt thereof of the present invention is in a racemic form, it can be separated into a d-form and a 1-form by ordinary optical resolution means.

When the compound (I) of the present invention contains a basic group, it can be obtained as a pharmaceutically acceptable acid addition salt by a method known per se or a method analogous thereto. Examples of the acid used to form such an acid addition salt include inorganic acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.) and organic acids (eg, acetic acid, trifluoroacetic acid, succinic acid) , Maleic acid, fumaric acid, propionic acid, citric acid, tartaric acid, malic acid, lactic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) and amino acids (eg, glutamic acid, aspartic acid, etc.). When compound (I) of the present invention contains an acidic group, it can be converted into a salt with a pharmaceutically acceptable base by a method known per se or a method analogous thereto. As the base used to form a salt with such a base, for example, an alkali metal (eg, sodium, potassium, etc.), an alkaline earth metal (eg, calcium, magnesium, etc.), an organic base (eg, trimethylamine,
Triethylamine, pyridine, piperidine, ethanolamine, etc.), aluminum, ammonium and the like.

The compound (I) or a salt thereof of the present invention has low toxicity and little side effects, and can be used in various mammals (for example, humans, cows, horses, dogs, cats, monkeys, mice, rats, etc., particularly humans). It can be used as a prophylactic, diagnostic or therapeutic agent. The compound (I) of the present invention or a salt thereof suppresses or regulates the production or secretion of various hormones, growth factors, physiologically active substances and the like. Examples of the “hormone” include growth hormone (G
H), thyroid stimulating hormone (TSH), prolactin,
Insulin, glucagon and the like. Examples of the “growth factor” include IGF-1 and the like. Examples of the “physiologically active substance” include bathoactive intestinal polypeptide (VIP), gastrin, glucagon-like peptide-1, amylin, substance-
P, CGRP, CCK (cholecystokinin), amylase and the like. In addition, the "physiologically active substance" includes interleukins and cykines such as TNF-α. These compounds also act via various intracellular signaling systems involving somatostatin. These intracellular signaling systems include adenylate cyclase, K
⁺ Channel, Ca ²⁺ channel, protein dephosphorylation, phospholipase C / inositol 3-phosphate producing system, MA
P kinase, Na ⁺ / H ⁺ exchange system, phospholipase A2,
It includes an intracellular signal transduction system involving a transcription factor such as NF-κB. In addition, these compounds and salts thereof regulate a direct or indirect cytostatic or apoptotic effect involving somatostatin. Therefore, the compound (I) or a salt thereof of the present invention can be used for diseases involving abnormal production or secretion of these hormones, growth factors, physiologically active substances, etc., abnormalities of these intracellular signal transduction systems (for example, excessive enhancement or suppression). Or a disease associated with abnormal cell growth control. In particular,
For example, (1) acromegaly, TSH-producing tumor, non-secretory (non-functional) pituitary tumor, ectopic ACTH (adrenocorticotropin) -producing tumor, medullary thyroid cancer, VIP-producing tumor, glucagon-producing tumor, gastrin Therapeutic agents for tumors such as producing tumors, insulinomas, carcinoids, etc., (2) insulin-dependent or non-dependent diabetes or various diseases related to these diabetes, for example, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy , Dawn syndrome,
A therapeutic agent for orthostatic hypotension, etc., (3) a therapeutic agent for obesity, bulimia, etc. due to improvement of hyperinsulinemia or suppression of appetite, and (4) suppression or regulation of exocrine secretion in the digestive tract. Remedies for acute pancreatitis, chronic pancreatitis, pancreatic / intestinal fistula, hemorrhagic ulcer, peptic ulcer, gastritis, hyperacidity, etc., (5) ameliorating agents for various symptoms associated with Helicobacter pylori infection, such as increased gastrin secretion (6) Amylase secretion inhibitor associated with endoscopic cholangiopancreatography, and also a prognostic agent for pancreatic surgery, (7) Reduced intestinal absorption, increased secretion or abnormal gastrointestinal motility Induced diarrhea (eg, short bowel syndrome), diarrhea caused by drugs such as cancer chemotherapy, diarrhea caused by congenital small bowel atrophy, diarrhea caused by neuroendocrine tumors such as VIP-producing tumors, and AIDS. Diarrhea, diarrhea due to graft reaction against the host associated with bone marrow transplantation, diarrhea due to diabetes, diarrhea due to blockade of the celiac plexus, diarrhea due to systemic sclerosis, and eosinophilia For diarrhea, etc., (8) for dumping syndrome, irritable colitis, Crohn's disease, inflammatory bowel disease, etc., (9) for insulin, IGF-1, or other growth factors Tumors or cancers due to abnormal cell growth suppression due to cancer or other reasons (for example, thyroid cancer, colon cancer, breast cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, gastric cancer, bile duct cancer, Liver cancer, bladder cancer, ovarian cancer,
Uterine cancer, melanoma, osteosarcoma, chondrosarcoma, malignant pheochromocytoma, neuroblastoma, brain tumor, thymoma, kidney cancer, etc., leukemia (eg leukemia of basophil leukocytes, chronic lymphocytic leukemia, chronic myeloid) Therapeutic agents such as leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, etc. (therapeutic agents used for these cancers can be used alone or with other anticancer agents such as tamoxifen,
LHRH agonists, LHRH antagonists, interferon-α, interferon-β and inderferon-γ, interleukin-2, etc. can be used in combination), (10) hypertrophic cardiomyopathy, arteriosclerosis, valvular heart disease, myocardium Infarction (especially myocardial infarction after percutaneous transluminal coronary angioplasty), prophylactic / therapeutic agent for revascularization, (11) therapeutic agent for esophageal varices hemorrhage, cirrhosis, peripheral vascular disease, (12) action on immune system Inhibits or regulates the secretion of physiologically active substances (e.g., substance P, tachykinin, cytokines, etc.), such as diseases associated with systemic or local inflammation, such as polyarteritis, rheumatoid arthritis, psoriasis, Remedies for sunburn, eczema, allergies (eg, asthma, atopic dermatitis, allergic rhinitis, etc.), (13) neuromodulation From affecting the production and secretion of a child, for example, dementia (for example, Alzheimer's disease,
Alzheimer-type senile dementia, vascular / multiple dementia, etc.), headache, migraine, schizophrenia, epilepsy, depression,
Remedies for general anxiety disorders, sleep disorders, multiple sclerosis, etc.
(14) analgesics, (15) acute bacterial meningitis, acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia,
Severe systemic fungal infection, tuberculosis, spinal cord injury, fracture, liver failure, pneumonia, alcoholic hepatitis, hepatitis A, hepatitis B, C
Hepatitis, AIDS infection, human papillomavirus infection, influenza infection, cancer metastasis, multiple myeloma, osteomalacia, osteoporosis, osteopechitis, reflux esophagitis,
Remedies for nephritis, renal failure, sepsis, septic shock, hypercalcemia, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, systemic lupus erythematosus, transient cerebral ischemic attack, alcoholic hepatitis, etc. (16) organ transplants, burns,
Healing of wounds, alopecia, etc., (17) eye diseases (eg, glaucoma), (18) radioactive substances (eg, ¹²³ °, ¹²⁵ °, ¹¹¹ ) directly or through an appropriate spacer to the present compound.
Ιn etc.) and imaging of a tumor having a somatostatin receptor, and (19) targeting of a tumor having a somatostatin receptor by introducing a carcinostatic agent into the present compound directly or via an appropriate spacer. .

The compound (I) of the present invention or a salt thereof can be used as it is, but is usually formulated with an appropriate amount of a carrier for pharmaceutical preparations according to a conventional method. Examples of the “carrier for pharmaceutical preparations” include excipients (eg, calcium carbonate, kaolin, sodium bicarbonate, lactose, D-mannitol, starches, crystalline cellulose, talc, granulated sugar, porous substances, etc.), binding Agents (eg, dextrin,
Gums, pregelatinized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose,
Pullulan, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid derivatives, etc.), disintegrants (eg, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized) Starch, etc.), solvents (eg, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc.), dispersants (eg, Tween 80, HCO60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), solubilizers (For example, polyethylene glycol, propylene glycol, D-mannitol,
Benzyl benzoate, ethanol, trisaminomethane,
Triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, benzalkonium chloride, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, etc.), soothing agents (eg, , Benzyl alcohol, etc.), tonicity agents (eg, sodium chloride, glycerin, etc.), buffers (eg, phosphates, acetates, carbonates, citrates, etc.), lubricants (eg, magnesium stearate) , Calcium stearate, talc, starch, sodium benzoate, etc.), coloring agents (eg, tar dye, caramel, iron sesquioxide, titanium oxide, riboflavins, etc.), flavoring agents (eg, sweeteners,
Perfumes, etc.), stabilizers (eg, sodium sulfite, ascorbic acid, etc.) and preservatives (eg, parabens, sorbic acid, etc.) are used. The medical prophylactic / therapeutic agent of the present invention, which may contain the carrier for pharmaceutical preparations, comprises the compound (I) of the present invention or a pharmaceutically acceptable compound thereof in an amount necessary for preventing / treating various diseases. Containing salt. The content of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the preparation of the present invention is usually about 0.1 to about 100% by weight of the whole preparation. Specific examples of the dosage form include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules,
Fine granules, powders, drops, syrups, emulsions, suspensions, injections, inhalants, ointments, suppositories, troches, cataplasms and the like are used. These preparations are prepared according to a conventional method (for example, the method described in Japanese Pharmacopoeia 12th Edition).

The production methods of the main preparations in the present invention are shown below, but are not limited thereto. (1) Tablets The compound of the present invention as it is, or a mixture obtained by adding an excipient, a binder, a disintegrant or other appropriate additives and uniformly mixing the resulting mixture to obtain a granule by an appropriate method, is then lubricated. Add the agent and compression molding. Then, if necessary, the skin may be coated with a suitable coating agent for the purpose of taste masking, enteric coating or persistence. (2) Injection A certain amount of the compound of the present invention is added, if necessary, to a stabilizer, a solubilizer, a suspending agent, an emulsifier, a buffer, a preservative, and the like.
Dissolve, suspend or emulsify in water for injection to make a fixed dose. (3) Suppository Based on an oily base, water-soluble base or other suitable substance, add an emulsifier, a suspending agent, etc., if necessary, add the compound of the present invention to the base, mix and equalize. After that, it is made into an appropriate shape. (4) Capsules The compound of the present invention and additives such as suitable excipients are uniformly mixed, or granulated by an appropriate method, or the granules are coated with an appropriate coating agent. The capsules are filled as they are or lightly.

The pharmaceutical preparation of the present invention is useful as a prophylactic / therapeutic agent for the above-mentioned diseases, because it has low toxicity, high safety, and excellent somatostatin receptor agonistic action. The amount of the compound of the present invention to be used in the pharmaceutical preparation varies depending on the compound selected, the species of the animal to be administered, the number of times of administration, and the like, but it exerts its efficacy over a wide range.
For example, for an adult patient with acromegaly, diabetic complications, intractable laxatives, diabetes or obesity, the daily dose when the pharmaceutical preparation of the present invention is orally administered is the same as that of the compound (I) of the present invention. An effective amount is usually about 0.001 to about 20 mg / kg body weight, preferably about 0.2 to about 3 mg / kg.
Although the dose is mg / kg body weight, in the case of parenteral administration, it is generally smaller than these dosages when it is used in combination with other active ingredients or in combination with other pharmaceutical preparations. However, the amount of the compound to be actually administered is determined by the conditions such as the selection of the compound, various formulation forms, the age, weight, sex, degree of the disease, the degree of the disease, the administration route, the administration period and interval of the administration. It can be changed at any time according to the judgment of the doctor. The administration route of the pharmaceutical preparation is not particularly limited by various circumstances, and for example, can be administered by an oral or parenteral route. As used herein, "parenteral" includes intravenous, intramuscular, subcutaneous, intranasal, rectal,
Including vaginal and intraperitoneal administration. The administration period and interval of the pharmaceutical preparation are to be changed according to various situations, and are determined at any time by a doctor's judgment,
There are methods such as divided administration, daily administration, intermittent administration, short-term large dose administration, and repeated administration. For example, in the case of oral administration, 1
It is desirable to administer the drug in several divided doses (particularly 1 to 3 times a day). It is also possible to perform intravenous infusion over a long period of time.

[0065]

DETAILED DESCRIPTION OF THE INVENTION The present invention further includes the following examples,
Although described in detail with experimental examples, these examples are merely implementations and do not limit the present invention, and may be changed without departing from the scope of the present invention. The abbreviations in Reference Examples and Examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, d
t: double triplet, m: multiplet, br:
Wide, j: coupling constant, room temperature: 0-30 ° C

[0066]

EXAMPLES Example 1 3,5-trans-N- (2-fluorobenzyl) -1
-Benzyl-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide (A), 3,5-cis-N- (2-fluorobenzyl) -1-benzyl-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (B) (1) N-methyl-N-methyloxy-2-amino-5
-Chlorobenzamide (24.8 g) and N-tert-butoxycarbonyl-3-bromobenzylamine (22.0
g) in tetrahydrofuran (300 ml) at -78 ° C
And a hexane solution of n-butyllithium (1.6 mol / L) (240 ml) was gradually added dropwise thereto. After dropping, water (300 ml) and ethyl acetate (300 ml) were added.
ml) was added. The organic layer was washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. Hexane (4
00 ml), and the mixture was crystallized. The crystals were collected by filtration to give 2-amino-3'-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (1
2.5 g) were obtained. (2) To a solution of 2-amino-3′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (7 g) in methanol (70 ml) was added sodium borohydride (1.1 g), and the mixture was stirred at room temperature for 30 minutes. . Ethyl acetate (100 ml) was added, and after washing with water, anhydrous MgS was added.
It was dried over O ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound, 2-amino-5-chloro-α- (3-tert-
Butoxycarbonylaminomethylphenyl) benzyl alcohol (6.9 g) was obtained. NMR (CDCl ₃ ) δ: 1.44 (9H, s), 4.30 (2H, d, J = 5.8H
z), 4.80-4.95 (1H, br), 5.77 (1H, s), 6.58 (1H, d, J = 8.4H
z), 7.04-7.38 (6H, m)

(3) 2-amino-5-chloro-α- (3
To a solution of -tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.7 g) in methanol (7 ml) was added benzaldehyde (229 mg) and acetic acid (130 ml).
g) was added and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (135 mg) was added thereto, and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. Acetic acid ethyl ester (50 ml) was added,
After washing with water, it was dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to obtain the desired colorless oily compound 2-benzylamino-5.
-Chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.91 g) was obtained. NMR (CDCl ₃ ) δ: 1.44 (9H, m), 2.55-2.65 (1H, b
r), 4.24 (2H, s), 4.28 (2H, d, J = 5.8Hz), 4.70-4.97 (2H, b
r), 5.80 (1H, s), 6.52 (1H, d, J = 8.8Hz), 7.01-7.38 (1H,
m) (4) 2-benzylamino-5-chloro-α- (3-te
rt-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.91 g) ethyl acetate (1
0 ml), water (4 ml) and 1N aqueous sodium hydroxide solution (3 ml) were added, and monoethyl fumarate chloride (3 ml
30 mg) and stirred for 1 hour under ice cooling. Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous MgS.
Dried over O ₄ . The solvent was distilled off, the residue was dissolved in ethanol (10 ml), potassium carbonate (400 mg) was added, and the mixture was stirred at room temperature overnight. The insolubles were collected by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give a colorless oily compound, 1-benzyl-5- (3-
tert-butoxycarbonylaminomethylphenyl) -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
4,1-Benzoxazepine-3-acetic acid ethyl ester (1.06 g) was obtained. NMR (CDCl ₃ ) δ: 1.24 (3/10 × 3H, t, J = 7.0 Hz), 1.
25 (7/10 × 3H, t, J = 7.0Hz), 2.76 (7/10 × 1H, dd, J = 5.4,16.
8Hz), 2.88 (3/10 × 1H, dd, J = 5.4,16.8Hz), 3.13 (7/10 × 1
H, dd, J = 8.4,16.8Hz), 3.22 (3/10 × 1H, dd, J = 8.4,16.8H)
z), 3.68 (3/10 × 1H, d, J = 15.6Hz), 4.14 (2H, q, J = 7.0Hz),
4.20-4.32 (2H, m), 4.44-4.90 (3H, m), 5.37 (7/10 × 1H,
s), 5.44 (7/10 × 1H, d, J = 14.6Hz), 5.89 (3/10 × 1H, s),
6.50 (7/10 × 1H, d, J = 2.0Hz), 6.97-7.39 (11H + 3/10 × 1H,
m)

(5) Compound obtained in (4) (0.98 g)
A 1N aqueous solution of sodium hydroxide (2 ml) was added to a solvent of ethanol (10 ml), and the mixture was stirred at 60 ° C. for 3 hours. Ethyl acetate (50 ml) and 1 N hydrochloric acid (50 ml) were added for extraction. The organic layer was separated, washed with water and dried over anhydrous MgSO ₄
And dried. The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and a colorless non-crystalline solid 1-benzyl-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid (0.74 g) was obtained. NMR (CD ₃ OD) δ: 1.39-1.45 (9H, m), 2.72 (1H, d
d, J = 5.6,17.0Hz), 3.01 (1H, dd, J = 8.4,17.0Hz), 4.15-4.
96 (5H, m), 5.33 (7/10 × 1H, s), 5.50 (7/10 × 1H, d, J = 13.8
Hz), 5.70 (3/10 × 1H, d, J = 13.8Hz), 6.39 (7/10 × 1H, s),
6.94-7.54 (11H + 3/10 × 1H, m) (6) To a solution of the compound (0.74 g) obtained in (5) and 2-fluorobenzylamine (184 mg) in dimethylformamide (7 ml) was added diethyl cyanophosphate (7 ml). 262 mg) and triethylamine (203 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
Two colorless oil compounds 3,5-trans-N- (2-fluorobenzyl) -1-benzyl-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2 , 3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (A) (0.44
g), 3,5-cis-N- (2-fluorobenzyl)-
1-benzyl-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,
2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (B) (0.07 g) was obtained. (A), NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.70 (1H,
dd, J = 5.8,14.4Hz), 2.93 (1H, dd, J = 7.4,14.4Hz), 4.27 (2
(H, d, J = 5.4Hz), 4.37-4.61 (3H, m), 4.76-4.84 (1H, br),
4.80 (1H, d, J = 14.6Hz), 5.34 (1H, s), 5.46 (1H, d, J = 14.6H)
z), 6.23-6.30 (1H, br), 6.48 (1H, d, J = 2.2Hz), 6.93-7.3
4 (15H, m) (B), NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.83 (1H,
dd, J = 5.8,14.2Hz), 3.04 (1H, dd, J = 7.2,14.2Hz), 3.70 (1
H, d, J = 13.8Hz), 4.24 (2H, d, J = 5.8Hz), 4.48 (2H, d, J = 6.2
Hz), 4.60-4.72 (2H, m), 4.80-4.93 (1H, br), 5.88 (1H,
s), 6.35-8.45 (1H, br), 6.93-7.44 (15H, m)

Example 2 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1-benzyl-7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide monohydrochloride 3,5-trans-N- (2-fluorobenzyl) -1-benzyl-5- (3-tert-butoxycarbonylaminomethyl obtained in Example 1 Phenyl) -7-chloro-2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.44 g) was dissolved in 4N hydrogen chloride in ethyl acetate (5 ml), and the solution was dissolved at room temperature for 30 minutes. Stirred for minutes. The solvent was distilled off, the residue was washed with diethyl ether / n-hexane, and the insoluble matter was collected by filtration to obtain a colorless amorphous solid (0.39 g). NMR (CD ₃ OD) δ: 2.78 (1H, dd, J =
6.8, 15.0 Hz), 2.91 (1H, dd, J)
= 6.8, 15.0 Hz), 4.05 (2H, s),
4.43 (2H, s), 4.53 (1H, t, J =
6.8 Hz), 4.94 (1H, d, J = 15.0H)
z), 5.45 (1H, s), 5.52 (1H,
d, J = 15.0 Hz), 6.38 (1H, d, J =
2.2Hz), 7.01-7.56 (15H, m)

Example 3 3,5-cis-N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -1-benzyl-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamido monohydrochloride 3,5-cis-N- (2-fluorobenzyl) -1-benzyl-5- (3-tert-butoxycarbonylaminomethylphenyl obtained in Example 1 ) -7-Chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.07 g) in 4N hydrogen chloride in ethyl acetate (1 ml) )
Thereafter, the same operation as in Example 2 was performed to obtain a colorless amorphous solid (0.04 g). NMR (CD ₃ OD) δ: 2.89 (1H, dd, J = 6.6,15.4Hz),
3.04 (1H, dd, J = 7.2,15.4Hz), 3.89 (1H, d, J = 15.6Hz), 4.0
6 (2H, s), 4.37 (1H, d, J = 15.0Hz), 4.49 (1H, d, J = 15.0Hz),
4.60 (1H, d, J = 15.6Hz), 4.74 (1H, t, J = 6.8Hz), 6.02 (1H,
s), 6.97-7.66 (1H, dd, J = 6.6,7.2Hz)

Example 4 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) 2-amino-5-chloro-α- (3) obtained in Example 1- (2) To a solution of -tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (4.0 g) in methanol (80 ml) was added 4-biphenylcarboxaldehyde (2.2 g) and acetic acid (0.8 g), and the mixture was stirred at room temperature for 10 minutes. . Sodium cyanoborohydride (0.83 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water, and anhydrous MgS
It was dried over O ₄ and the solvent was distilled off. The residue was dissolved in ethyl acetate (50 ml), and 1N aqueous sodium hydroxide solution (30 ml) was added. To this was added ethyl acetate (4 ml) of fumaric acid monoethyl ester (1.9 g).
The solution was added dropwise at room temperature with stirring. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, washed with water, and dried over anhydrous MgSO ₄ .
The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain an oily compound (5.0 g).
This oily compound was dissolved in ethanol (120 ml), potassium carbonate (2.5 g) was added thereto, and the mixture was heated with stirring at 60 ° C. for 2 hours. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
The colorless oily compound 3,5-trans-1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,
2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (2.4 g) was obtained. NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7 Hz), 1.44 (9H,
s), 2.77 (1H, dd, J = 5.2,15Hz), 3.15 (1H, dd, J = 8.6,14.6H
z), 4.0-4.3 (4H, m), 4.5 (1H, dd,), 4.25 (1H, m), 4.96 (1
H, d, J = 14.6Hz), 5.45 (1H, d, J = 15Hz), 5.39 (1H, s), 6.50
(1H, brs), 6.9-7.65 (15H, m) (2) The 3,5-trans form (2.0 g) obtained in (1) was treated with tetrahydrofuran (20 ml) and methanol (120 ml).
And a 1N aqueous solution of sodium hydroxide (15 ml) was added thereto, followed by heating and stirring at 60 ° C. for 2 hours.
After cooling, water (200 ml) was added, and the mixture was neutralized with potassium hydrogen sulfate. After extraction with acetic acid ethyl ester (50 ml × 2) and drying over anhydrous MgSO ₄ , the solvent was distilled off. The residue was recrystallized from diethyl ether to give colorless crystals having a melting point of 140-142 ° C, 3,5-trans-1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro. -2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetic acid (0.91 g) was obtained. (3) The compound obtained in (2) (0.9 g), 2-fluorobenzylamine (0.21 g), triethylamine (0.2 g).
To a solution of 27 g) of dimethylformamide (9 ml) was added diethyl cyanophosphate (0.3 g), and the mixture was stirred at room temperature for 20 minutes. Water (50 ml) was added, and the mixture was extracted with ethyl acetate. After washing with water and drying over anhydrous MgSO ₄ , the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.93 g). NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.72 (1H, dd,), 2.
96 (1H, dd), 4.2 (2H, m), 4.35-4.65 (3H, m), 4.25 (1H, m),
4.92 (1H, d, J = 15Hz), 5.36 (1H, s), 5.48 (1H, d, J = 16Hz),
6.26 (1H, t), 6.49 (1H, d, J = 1.8Hz), 6.9-7.7 (19H, m)

Example 5 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride The compound obtained in Example 4 (0.9 g) was dissolved in a 4N solution of hydrogen chloride in ethyl acetate (15 ml). Stirred for hours. The solvent was distilled off and the residue was recrystallized from diethyl ether to obtain colorless crystals (0.84 g) having a melting point of 250-252 ° C. _{NMR (DMSO-d 6) δ} : 2.66 (1H, dd, J = 5.6,15.0H
z), 2.886 (1H, dd, J = 7.8,15.0Hz), 4.000 (2H, s), 4.316
(2H, d, J = 5.6Hz), 4.488 (1H, t, J = 5.8Hz), 5.10 (1H, d, J = 1
5.2Hz), 5.387 (1H, d, J = 15.2Hz), 5.555 (1H, s), 6.395 (1
(H, d, J = 2.2Hz), 7.03-7.68 (19H, m), 8.25-8.62 (3H, m)

Example 6 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-1
Hydrochloride (1) To a solution of 2-amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (4.0 g) obtained in Example 1- (2) in methanol (80 ml). , Trimethylacetaldehyde (1.
04 g) and acetic acid (0.8 g) were added, and the mixture was stirred at room temperature for 10 minutes. And sodium cyanoborohydride (0.8
3g) was added and stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was dissolved in ethyl acetate (50 ml), and 1N aqueous sodium hydroxide solution (30 ml) was added. To this, a solution of monoethyl chloride fumarate (1.9 g) in ethyl acetate (4 ml) was added dropwise with stirring at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, washed with water, and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain an oily compound (4.3 g). This oily compound was dissolved in ethanol (120 ml), potassium carbonate (2.5 g) was added thereto, and the mixture was heated with stirring at 60 ° C. for 2 hours. The insoluble material was removed by filtration, and the solvent was distilled off. -Chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (2.6 g) was obtained. This compound (2.6
g) in tetrahydrofuran (20 ml) and methanol (1
20 ml), and 1N aqueous sodium hydroxide solution (15 ml) was added thereto, followed by heating and stirring at 60 ° C. for 2 hours. After cooling, water (200 ml) was added, and the mixture was neutralized with potassium hydrogen sulfate. Acetic acid ethyl ester (50ml ×
After extraction in 2) and drying over anhydrous MgSO ₄ , the solvent was distilled off. The residue was recrystallized from diethyl ether to give a melting point of 217-.
Colorless crystals at 219 ° C, 3,5-trans-5- (3-ter
t-butoxycarbonylaminomethylphenyl) -7-
Chloro-1-neopentyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid (2.2 g) was obtained.

(2) Compound (0.32) obtained in (1)
g), 2-fluorobenzylamine (0.11 g) and triethylamine (0.11 g) in dimethylformamide (5 ml) were added to cyanophosphate diethyl ester (0.1 ml).
12g) and stirred at room temperature for 20 minutes. Water (50m
l) was added and extracted with ethyl acetate. After washing with water
After drying over anhydrous MgSO ₄ and evaporating the solvent, the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.37 g). This compound (0.24
g) in 4N hydrogen chloride in acetic acid ethyl ester (5
ml) and stirred for 0.5 hours at room temperature. Removal of the solvent gave a colorless amorphous solid (0.23 g). NMR (DMSO-d ₆ ) δ: 0.88 (9H, s), 2.60-2.80 (2
H, m), 3.26 (1H, d, J = 13.4Hz), 4.00-4.10 (2H, m), 4.26-
4.20 (4H, m), 5.08 (1H, s), 6.41 (1H, s), 7.13-7.80 (11H,
m), 8.15-8.60 (3H, br)

Example 7 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) -2-oxo-
7- (3-phenylpropyloxy) -1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide (1) 2-amino-5-hydroxy-benzoic acid (3.0
g) was dissolved in a 1N aqueous solution of sodium hydroxide (50 ml), and carboxybenzyloxychloride (3.5 ml) was added.
g) was added dropwise. After stirring at room temperature for 1 hour, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. From the residue, black-brown crystals of 2-benzyloxycarbonylamino-5-hydroxybenzoic acid (2.
9 g) were obtained. To a solution of 2-benzyloxycarbonylamino-5-hydroxybenzoic acid (6.0 g) and N, O-dimethylhydroxylamine hydrochloride (2.5 g) in methylene chloride (80 ml) was added 1-ethyl-3-.
(3-Dimethylaminopropyl) -carbodiimide hydrochloride (4.6 g) and triethylamine (5 ml) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to obtain N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide as a yellow oil (5.0 g). NMR (CDCl ₃ ) δ: 3.322 (3H, s), 3.520 (3H, s), 5.
171 (2H, s), 6.10 (1H, m), 6.8-7.5 (6H, m), 7.70-8.10 (2H,
m) (2) N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide (1.5 g), 3-phenylpropyl bromide (0.9)
g), potassium carbonate (0.6 g) and N, N-dimethylformamide (10 ml) solution were stirred at 70 ° C. for 3 hours.
The reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
The residue was separated and purified by silica gel column chromatography to obtain N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5- (3-phenylpropyloxy) benzamide as a yellow oil (1.4 g). Was. NMR (CDCl ₃ ) δ: 2.0-2.2 (2H, m), 2.803 (2H, t, J = 8H
z), 3.34 (3H, s), 3.526 (3H, s), 3.934 (2H, t, J = 6.2Hz),
5.176 (2H, s), 6.9-7.5 (11H, m), 7.9-8.3 (2H, m)

(3) N-methyl-N-methyloxy-2
-Benzyloxycarbonylamino-5- (3-phenylpropyloxy) benzamide (1.4 g) was dissolved in ethyl acetate (10 ml) and methanol (10 ml).
% Palladium on carbon (0.3 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The reaction was filtered and evaporated.
An orange oil (1.0 g) of N-methyl-N-methyloxy-2-amino-5- (3-phenylpropyloxy) benzamide was obtained from the residue. NMR (CDCl ₃ ) δ: 2.05 (2H, m), 2.794 (2H, t, J = 8H
z), 3.342 (3H, s), 3.595 (3H, s), 3.890 (2H, t, J = 6.2Hz),
6.6-7.4 (8H, m) (4) N-methyl-N-methyloxy-2-amino-5
-(3-phenylpropyloxy) benzamide (1.
0 g) and N-tert-butoxycarbonyl 3-bromobenzylamine (0.92 g) in tetrahydrofuran (2
0 ml) was cooled to -70 ° C, and n-butyllithium in hexane (1.6 mol / L) was stirred while stirring.
12 ml were added dropwise over 20 minutes. After the addition, water (50 ml) and ethyl acetate (50 ml) were added. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography to give 2-amino-3'-tert-butoxycarbonylaminomethyl-5.
A yellow oil of-(3-phenylpropyloxy) benzophenone was obtained (0.75 g). NMR (CDCl ₃ ) δ: 1.451 (9H, s), 1.9-2.1 (2H, m),
2.751 (2H, t, J = 8.2Hz), 3.779 (2H, t, J = 6.2Hz), 4.37 (2H, t, J = 6.2Hz)
d, J = 6.2Hz), 4.87 (1H, m), 5.719 (2H, m), 6.7-7.6 (12H,
m) (5) Dissolve 2-amino-3'-tert-butoxyaminomethyl-5- (3-phenylpropyloxy) benzophenone (0.75 g) in methanol (20 ml) and add sodium borohydride (0.15 g). ) Was added. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate (80 ml).
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -5- (3-phenylpropyloxy) benzyl alcohol was obtained as a yellow oil (0.7 g). NMR (CDCl ₃ ) δ: 1.445 (9H, s), 2.05 (2H, m), 2.7
86 (2H, t, J = 8Hz), 3.883 (2H, t, J = 6.4Hz), 4.30 (2H, d, J =
5.8Hz), 4.85 (1H, m), 5.801 (1H, s), 6.6-7.4 (12H, m)

(6) 2-amino-α- (3-tert-butoxycarbonylaminophenyl) -5- (3-phenylpropyloxy) benzyl alcohol (0.7 g) and 4
-Benzyloxybenzaldehyde (0.38 g) and acetic acid (0.1 g) were dissolved in methanol (12 ml), and sodium cyanoborohydride (0.11 g) was added.
Stirred at 0 ° C. for 30 minutes. The reaction solution was concentrated, and ethyl acetate (50 ml) and water (100 ml) were added. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2- (4-benzyloxybenzyl) -α- (3-te
rt-butoxycarbonylaminomethylphenyl) -5
A yellow oil of (3-phenylpropyloxy) benzyl alcohol (0.95 g) was obtained. NMR (CDCl ₃ ) δ: 1.442 (9H, s), 2.05 (sH, m), 2.7
81 (2H, t, J = 8.2Hz), 3.877 (2H, t, J = 6.4Hz), 4.12 (2H, m),
4.28 (1H, m), 5.05 (2H, s), 5.817 (1H, s), 6.6-7.5 (21H,
m) (7) 2- (4-benzyloxybenzyl) -α- (3
-Tert-butoxycarbonylaminomethylphenyl)-
5- (3-phenylpropyloxy) benzyl alcohol (0.95 g), 1N sodium hydroxide (5 ml),
While stirring the solution of ethyl acetate and ethyl acetate (15 ml) at room temperature, monoethyl fumarate chloride (0.25 g) was added dropwise. After stirring for 20 minutes, the organic layer was separated, washed with water,
It was dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml) and potassium carbonate (0.6 g)
Was added and stirred at 60 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and extracted by adding water (50 ml) and ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography, and 3,5-trans-1- (4-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -2-oxo-7-
A colorless oil (0.42 g) of (3-phenylpropyloxy) -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester was obtained.

NMR (CDCl ₃ ) δ: 1.246 (3H, t, J = 7.2
Hz), 1.437 (9H, s), 2.0 (2H, m), 2.6-2.85 (3H, m), 3.11
(1H, dd, J = 8.4Hz, 16Hz), 3.75 (2H, m), 4.0-4.35 (4H, m),
4.47 (1H, dd, J = 5.6Hz, 8.2Hz), 4.73 (1H, d, J = 14.6Hz), 5.
046 (2H, s), 5.38 (1H, d, J = 14.6Hz), 6.03 (1H,, J = 3Hz),
6.8-7.5 (20H, m) (8) 3,5-trans-1- (4-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -2-oxo-7- (3- Phenylpropyloxy) -1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetic acid ethyl ester (0.4
g) in tetrahydrofuran (5 ml) and methanol (10
1N sodium hydroxide (4 ml), and the mixture was stirred at 60 ° C. for 40 minutes. The reaction solution was concentrated under reduced pressure, and 5
And then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in N, N-dimethylformamide (10 ml) and 2-fluorobenzylamine (7
0 mg) and diethyl cyanophosphate (0.1 g) and triethylamine (0.1 ml) were added with stirring under ice cooling. After the reaction solution was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate (50 ml). Wash the organic layer with water,
It was dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography.
-Trans-N- (2-fluorobenzyl) -1- (4
-Benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -2-oxo-7
A colorless oil (0.38 g) of-(3-phenylpropyloxy) -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide was obtained.

NMR (CDCl ₃ ) δ: 1.429 (9H, s), 2.0
0 (2H, m), 2.6-2.8 (3H, m), 2.93 (1H, dd, J = 7.2Hz, 16Hz),
3.75 (2H, m), 4.2-4.6 (5H, m), 4.67 (1H, d, J = 14.4Hz), 5.
04 (2H, s), 5.303 (1H, s), 5.40 (1H, d, J = 14.4Hz), 6.02 (1
(H, d, J = 2.6 Hz), 6.38 (1H, m), 6.8-7.5 (24H, m) (9) 3,5-trans-N- (2-fluorobenzyl) -1- (4-benzyloxy Benzyl) -5- (3
-Tert-butoxycarbonylaminomethylphenyl)-
2-oxo-7- (3-phenylpropyloxy)-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.38 g) was added to ethyl acetate (1
0 ml) and methanol (10 ml), and 10% palladium on carbon (0.1 g) was added thereto.
Stirred for hours. The reaction was filtered and evaporated under reduced pressure. From the residue, 3,5-trans-N- (2-fluorobenzyl)
-5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) -2-oxo-7- (3-phenylpropyloxy) -1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
An acetamide colorless amorphous solid (0.33 g) was obtained. NMR (CDCl ₃ ) δ: 1.43 (9H, m), 2.05 (2H, m), 2.6-
3.0 (4H, m), 3.78 (2H, m), 4.0-4.6 (6H, m), 4.87 (1H, s),
5.0 (1H, m), 5.8 (1H, m), 5.95 (1H, d, J = 2Hz), 6.18 (1H, m
m), 6.6-7.5 (19H, m)

By the same operation as in Example 6, the compounds shown in Examples 8 to 24 were obtained. Example 8 3,5-trans-N- (3-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-1
Hydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.83 (9H, s), 2.
70-2.96 (4H, m), 3.33 (1H, d,
J = 13.2 Hz), 3.80-3.92 (2H,
m), 4.11-4.44 (4H, m), 5.91
(1H, s), 6.53 (1H, s), 6.81-
7.59 (11H, m) Example 9 3,5-trans-N- (4-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-1
Hydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.84 (9H, s), 2.70-2.90 (2H, m),
3.31 (1H, d, J = 13.0Hz), 3.78-3.96 (2H, m), 4.08-4.15 (1
H, m), 4.30-4.46 (3H, m), 5.89 (1H, s), 6.52 (1H, s), 6.8
4-7.56 (11H, m) Example 10 3,5-trans-N- (2-fluorophenylethyl) -5- (3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1 , 2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.87 (9H, s), 2.60-2.83 (4H , m),
3.29-3.45 (3H, m), 4.00-4.10 (2H, m), 4.35-4.46 (2H, m
m), 5.94 (1H, s), 6.54 (1H, s), 6.67 (1H, br), 6.29-7.59
(11H, m)

Example 11 3,5-trans-N- (2-chlorobenzyl) -5
(3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.85 (9H, s), 2.70-3.00 (2H, m),
3.32 (1H, d, J = 14.8Hz), 3.90-4.00 (2H, m), 4.35-4.50 (4
H, m), 5.92 (1H, s), 6.53 (1H, s), 7.09-7.57 (10H, m) Example 12 3,5-trans-N- (2-methoxybenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-1
Hydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.87 (9H, s), 2.64-2.92 (2H, m),
3.32 (1H, d, J = 11.8Hz), 3.76 (3H, s), 3.84-4.02 (2H, m),
4.24-4.50 (4H, m), 5.95 (1H, s), 6.53 (1H, s), 6.79-7.50
(10H, m) Example 13 3,5-trans-N- (2,4-difluorobenzyl)
-5- (3-Aminomethylphenyl) -7-chloro-1
-Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.85 (9H, s), 2.66-2.96 (2H, m),
3.32 (1H, d, J = 13.8Hz), 3.92-4.02 (2H, m), 4.20-4.44 (4
H, m), 5.89 (1H, s), 6.52 (1H, s), 6.67-7.58 (9H, m)

Example 14 3,5-trans-N- [3,5-bis (trifluoromethyl) benzyl] -5- (3-aminomethylphenyl)
-7-chloro-1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide monohydrochloride NMR (CDCl ₃ ) δ: 0.90 (9H, s), 2.80 (1H, dd, J = 5.
8,14.2Hz), 2.96 (1H, dd, J = 7.8,14.2Hz), 3.34 (1H, d, J = 1
3.6Hz), 4.04 (2H, s), 4.30-4.74 (4H, m), 5.99 (1H, s),
6.57 (1H, d, J = 2.0Hz), 7.19-7.76 (9H, m) Melting point: 165-170 ° C Example 15 3,5-trans-N- (benzyl) -5- (3-aminomethylphenyl) -7-chloro-1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.84 (9H, s), 2.7-2.9 (2H, m),
3.32 (1H, d, J = 14.0Hz), 4.08-4.20 (2H, m), 4.32-4.50 (4
H, m), 5.91 (1H, s), 6.52 (1H, s), 7.09-7.48 (11H, m) Example 16 3,5-trans-N- (2-fluorobenzyl) -N
-Methyl-5- (3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride NMR (CDCl ₃ ) δ: 0.93, 0.94 (total 9H, each s), 2.7
2-2.85 (1H, m), 2.89 (3/10 × 3H, s), 3.03 (6/10 × 3H, s),
3.18-3.31 (1H, m), 3.39 (1H, d, J = 14.2Hz), 3.85-4.05 (2
H, br), 4.44-4.80 (4H, m), 6.00,6.02 (total 1H, each s),
6.59 (1H, s), 6.98-7.42 (10H, m)

Example 17 3,5-trans-N- (pyridin-2-yl) methyl-5- (3-aminomethylphenyl) -7-chloro-1
-Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamido dihydrochloride (non-crystalline solid) NMR (CD ₃ OD) δ: 0.95 (9H , s), 2.86 (2H, d, J = 5.
6,15.0Hz), 3.02 (2H, dd, J = 8.2,15.0Hz), 3.57 (1H, d, J = 1
4.2Hz), 4.18 (2H, s), 4.37-4.48 (2H, m), 4.64 (1H, d, J = 1
6.4Hz), 4.79 (1H, d, J = 16.4Hz), 6.06 (1H, s), 6.51 (1H,
d, J = 2.2Hz), 7.44-7.61 (6H, m), 7.87-8.04 (2H, m), 8.53
-8.77 (2H, m) Example 18 3,5-trans-N- (furan-2-yl) methyl-
5- (3-aminomethylphenyl) -7-chloro-1-
Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide
Monohydrochloride (non-crystalline solid) NMR (CD ₃ OD) δ: 0.94 (9H, s), 2.74 (2H, d, J = 6.6)
Hz), 3.58 (1H, d, J = 14.0Hz), 4.15 (2H, s), 4.33-4.47 (4
H, m), 6.04 (1H, s), 6.21-6.35 (2H, m), 6.49 (1H, d, J = 2.6
Hz), 7.40-7.65 (7H, m) Example 19 3,5-trans-N- (thiophen-2-yl) methyl-5- (3-aminomethylphenyl) -7-chloro-
1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.94 (9H , s), 2.74 (2H, d, J = 6.6H
z), 3.58 (1H, d, J = 13.6Hz), 4.13 (2H, s), 4.40-4.54 (4H,
m), 6.04 (1H, s), 6.49 (1H, d, J = 2.2Hz), 6.90-6.94 (2H,
m), 7.21-7.65 (7H, m)

Example 20 3,5-trans-N- (2-trifluoromethylbenzyl) -5- (3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3 , 5-Tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.94 (9H, s), 2.85 (2H, d, J = 6.6) H
z), 3.58 (1H, d, J = 14.6Hz), 4.11 (2H, s), 4.42-4.57 (4H,
m), 6.06 (1H, s), 6.50 (1H, s), 7.36-7.70 (10H, m) Example 21 3,5-trans-N- (2,6-difluorobenzyl)
-5- (3-Aminomethylphenyl) -7-chloro-1
-Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamido monohydrochloride (non-crystalline solid) NMR (CD ₃ OD) δ: 0.93 (9H , s), 2.71 (2H, d, J = 6.6H
z), 3.57 (1H, d, J = 13.2Hz), 4.17 (2H, s), 4.38-4.45 (4H,
m), 6.02 (1H, s), 6.48 (1H, s), 6.91-7.36 (9H, m) Example 22 3,5-trans-N- (indol-3-yl) methyl] -5- (3 -Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (non-crystalline solid) NMR (CD ₃ OD) δ: 0.90 (9H, s),
2.72 (2H, d, J = 6.2 Hz), 2.93
(2H, t, J = 7.3 Hz), 3.42-3.66
(3H, m), 4.12 (2H, s), 4.39-
4.48 (2H, m), 6.05 (1H, s),
6.51 (1H, d, J = 2.2 Hz), 6.98 −
7.62 (11H, m)

Example 23 3,5-trans-N- (cyclohexylmethyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-1
Hydrochloride (non-crystalline solid) NMR (CD ₃ OD) δ: 0.94 (9H, s), 1.16-1.73 (11H,
m), 2.72 (2H, d, J = 6.8 Hz), 3.00 (2H, d, J = 6.6 Hz), 3.59 (1
H, d, J = 14.0Hz), 4.18 (2H, s), 4.40-4.47 (2H, m), 6.05 (1
H, s), 6.50 (1H, d, J = 2.4 Hz), 7.42-7.56 (6H, m) Example 24 3,5-trans-N- [2- (pyrrolidin-1-yl) ethyl] -5 -(3-aminomethylphenyl) -7
-Chloro-1-neopentyl-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide dihydrochloride (non-crystalline solid) NMR (DMSO-d ₆ ) δ: 0.87 (9H, s), 1.75-2.10 (4
H, m), 2.67 (2H, m), 2.96 (2H, m), 3.15 (2H, m), 3.34-3.7
0 (5H, m), 4.08 (2H, m), 4.20-4.40 (2H, m), 5.88 (1H, s),
6.44 (1H, d, J = 2.4Hz), 7.30-7.80 (6H, m), 8.3-8.6 (4H, m)

Example 25 (3S, 5S) -N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide monohydrochloride (1) 3,5-trans-5 obtained in (1) of Example 6
(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-
To a solution of 1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.6 g) and L-leucine methyl ester monohydrochloride (0.22 g) in dimethylformamide (6 ml) , Cyanophosphoric acid diethyl ester (0.
20 g) and triethylamine (0.25 g).
Stirred at 30 ° C. for 30 minutes. Acetic acid ethyl ester (50 ml)
After washing with water, the organic layer was dried over anhydrous MgSO ₄ .
The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and (3R, 5R) -N- [5- (3
-Tert-butoxycarbonylaminomethylphenyl)-
7-chloro-1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetyl] -L-leucine methyl ester (0.3
7g) and (3S, 5S) -N- [5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4, 1-benzoxazepine-3-acetyl] -L-leucine methyl ester (0.40 g) was obtained. (3R, 5R) form: NMR (CDCl ₃ ) δ: 0.92 (15H, s), 1.44 (9H, s), 1.5
5-1.65 (3H, m), 2.70 (1H, dd, J = 6.8,14.8Hz), 2.87 (1H, d
d, J = 6.8,14.8Hz), 3.35 (1H, d, J = 13.8Hz), 3.72 (3H, s),
4.33-4.57 (5H, m), 5.13-5.22 (1H, br), 6.01 (1H, s), 6.2
1 (1H, d, J = 7.6Hz), 6.57 (1H, d, J = 2.0Hz), 7.18-7.64 (6H,
m) (3S, 5S) form: NMR (CDCl ₃ ) δ: 0.88-0.92 (15H, m), 1.45 (9H,
s), 1.55-1.65 (3H, m), 2.69 (1H, dd, J = 6.0,14.6Hz), 2.9
2 (1H, dd, J = 6.8,14.6Hz), 3.37 (1H, d, J = 14.0Hz), 3.71 (3
H, s), 4.33-4.60 (5H, m), 4.85-5.00 (1H, br), 6.00 (1H,
s), 6.43 (1H, d, J = 8.4Hz), 6.58 (1H.s), 7.23-7.41 (6H,
m)

(2) The (3S, 5S) form obtained in (1) (0.
To a solution of 40 g) in methanol (4 ml) was added a 1N aqueous solution of sodium hydroxide (0.65 ml), and the mixture was heated with stirring at 60 ° C for 1 hour. Water (50 ml) was added, the mixture was neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate. Extract the solution with anhydrous Na ₂
After drying over SO ₄ and evaporating the solvent, a colorless amorphous solid (3S, 5S) -N- [5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl is obtained. -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl] -L-leucine (0.25 g) was obtained. (3) Concentrated hydrochloric acid (1 ml) was added to a methanol (2 ml) solution of the compound (0.10 g) obtained in (2), and the mixture was heated under reflux for 3 days. Water (50 ml) was added, the mixture was made basic with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off to give a colorless oily compound (3S, 5S) -5- (3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-.
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid methyl ester (80 mg) was obtained. NMR (CDCl ₃ ) δ: 0.93 (9H, s), 2.79 (1H, dd, J = 5.
8,16.4Hz), 3.07 (1H, dd, J = 8.0,16.4Hz), 3.37 (1H, d, J = 1
4.0Hz), 3.67 (3H, s), 3.9-4.0 (2H, br), 4.41 (1H, dd, J =
5.8,8.0Hz), 4.50 (1H, d, J = 14.0Hz), 6.02 (1H, s), 6.61
(1H, d, J = 1.8Hz), 7.19-7.45 (6H, m)

(4) To a solution of the compound obtained in (3) (80 mg) in ethyl acetate (1 ml) was added di-tert-butyl dicarbonate (0.03 ml) and dimethylaminopyridine (10 mg).
Was added and stirred at room temperature for 30 minutes. After the reaction was completed, ethyl acetate (50 ml) was added, and the mixture was washed with water and then dried over anhydrous Na ₂ SO _4.
And dried. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound (6).
0 mg). To a solution of the oily compound (60 mg) in methanol (1 ml) was added a 1N aqueous sodium hydroxide solution (0.1 ml).
25 ml), and the mixture was heated and stirred at 60 ° C. for 30 minutes. Water (50 ml) was added, the mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. After the extract is washed with water, anhydrous Na ₂ SO ₄
Then, the solvent was distilled off to obtain a colorless oily compound (40 mg). To a solution of this compound (40 mg) in dimethylformamide (1 ml) was added 2-fluorobenzylamine (20 mg) and diethyl cyanophosphate (20 ml).
g) and triethylamine (30 mg).
Stirred for minutes. Acetic acid ethyl ester (50 ml) was added,
After washing with water, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (40 mg). This compound (40 mg) was dissolved in a 4N solution of hydrogen chloride in ethyl acetate (1 ml) and left at room temperature for 30 minutes.
By evaporating the solvent, a colorless amorphous solid (33
mg). Light intensity [α] _D ²² + 165.6 ° (c = 0.15, methanol)

Example 26 (3R, 5R) -N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide monohydrochloride (3R, 5R) compound (0.37) obtained in Example 25 (1).
g) was used as a raw material, and an amorphous solid (20 mg) was obtained in the same manner as in Example 25. Light intensity [α] _D ²² −166.0 ° (c = 0.13, methanol) 3,5-trans-1- (4-) obtained in (2) of Example 4
Biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid as a raw material The following compounds were obtained by the same operation as in Example 4, (3), and subsequently in Example 5. Example 27 3,5-trans-N- [3,5-bis (trifluoromethyl) benzyl] -5- (3-aminomethylphenyl)
-1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (colorless crystals) NMR ( CDCl ₃ ) δ: 2.77 (1H, dd), 3.04 (1H, dd), 3.
75 (2H, br), 4.3-4.7 (3H, m), 4.78 (1H, d), 5.33 (1H, s),
5.55 (1H, d), 6.52 (1H, d), 6.8-7.8 (19H, m) Melting point: 238-240 ° C

Example 28 3,5-trans-N- (3,4,5-trimethoxybenzyl) -5- (3-aminomethylphenyl) -1- (4
-Biphenylmethyl) -7-chloro-2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride NMR (CDCl ₃ ) δ: 2.75 (1H, dd), 2.96 (1H, dd), 3.
6-3.9 (11H, m), 4.37 (2H, dd), 4.57 (1H, dd), 4.87 (1H,
d), 5.38 (1H, s), 5.45 (1H, d), 6.32 (1H, t), 6.49 (2H,
s), 6.52 (1H, d), 6.85-7.6 (15H, m) Example 29 3,5-trans-N-benzhydryl-5- (3-aminomethylphenyl) -1- (4-biphenylmethyl)
-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide.
Monohydrochloride (colorless crystals) NMR (CDCl ₃ ) δ: 2.78 (1H, dd), 3.0 (1H, dd), 3.7
2 (2H, s), 4.52 (1H, dd), 4.83 (1H, d), 5.36 (1H, s), 5.53
(1H, d), 6.23 (1H, d), 6.52 (1H, d), 6.65 (1H, s), 6.85-7.
7 (25H, m) Melting point: 200-202 ° C Example 30 3,5-trans-N- (2-biphenylmethyl) -5
(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide / 1-hydrochloric acid Salt (non-crystalline solid) NMR (CDCl ₃ ) δ: 2.65 (1H, dd), 2.87 (1H, dd), 3.
73 (2H, s), 4.25-4.6 (3H, m), 4.85 (1H, d), 5.35 (1H, s),
5.48 (1H, d), 6.06 (1H, t), 6.50 (1H, d), 6.8-7.7 (24H, m)

Example 31 3,5-trans-N- (4-biphenylmethyl) -5
(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide / 1 hydrochloric acid Salt (non-crystalline solid) NMR (CDCl ₃ ) δ: 2.77 (1H, dd), 2.98 (1H, dd), 3.
75 (2H, s), 4.35-4.65 (3H, m), 4.87 (1H, d), 5.39 (1H, s),
5.50 (1H, d), 6.32 (1H, t), 6.53 (1H, d), 6.9-7.6 (24H,
m) Example 32 3,5-trans-N- (4-ethoxycarbonylbenzyl) -5- (3-aminomethylphenyl) -1- (4
-Biphenylmethyl) -7-chloro-2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (colorless crystal) NMR (CDCl ₃ ) δ: 1.37 (3H, t), 2.77 (1H, dd), 2.9
8 (1H, dd), 3.76 (2H, br), 4.34 (2H, q), 4.44-4.62 (2H, m),
4.88 (1H.d), 5.38 (1H, s), 5.47 (1H, d), 6.34 (1H, t),
6.53 (1H, d), 6.9-8.0 (19H, m) Melting point: 220-222 ℃

Example 33 3,5-trans-N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -1- (4-hydroxybenzyl) -2-oxo-7- (3-phenylpropyloxy) -1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetamide hydrochloride 3,5-trans-N- (2-fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) obtained in Example 7.
-2-oxo-7- (3-phenylpropyloxy)-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.28 g) was added to ethyl acetate (5 ml).
l), 4N hydrochloric acid (ethyl acetate solution) (3ml)
Was added and stirred for 2 hours. The reaction solution was distilled off under reduced pressure, and a non-crystalline solid (0.22 g) of the title compound was obtained from the residue. NMR (CDCl ₃ ) δ: 1.95 (2H, m), 2.6-2.9 (4H, m),
3.6-4.6 (8H, m), 4.808 (1H, s), 5.63 (1H, d, J = 13.8Hz),
5.95 (1H, d, J = 2.8Hz), 6.3-7.4 (20H, m)

Example 34 3,5-trans-5- (3-aminomethylphenyl)
-7-chloro-1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetic acid 2-fluorobenzyl ester / hydrochloride 3,5-trans-5- (3-t obtained in (1) of Example 6
ert-butoxycarbonylaminomethylphenyl) -7
-Chloro-1-neopentyl-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetic acid (100 mg) and 2-fluorobenzyl chloride (3
To a solution of 0 mg) in dimethylformamide (1 ml) was added potassium carbonate (39 mg), and the mixture was heated with stirring at 60 ° C for 1 hour. Ethyl acetate (50 ml) was added, washed with water, and the organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound. This was dissolved in 4N hydrogen chloride in ethyl acetate (1 ml) and stirred at room temperature for 1 hour.
The solvent was distilled off to give a colorless amorphous solid (58%).
mg). NMR (CDCl ₃ ) δ: 0.90 (9H, s), 2.86 (1H, dd, J = 6.
4,15.6Hz), 3.10 (1H, dd, J = 8.0,15.6Hz), 3.33 (1H, d, J = 1
4.0Hz), 4.08 (2H, br), 4.35-4.50 (2H, m), 5.11 (1H, d, J =
11.6Hz), 5.20 (1H, d, J = 11.6Hz), 5.99 (1H, s), 6.55 (1H,
s), 6.98-7.55 (10H, m)

Example 35 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-3- (2-fluorophenylacetyl) aminomethyl-1-neopentyl-1,2, 3,5-tetrahydro-4,1-benzoxazepin-2-one (1) 3,5-trans-5--5 obtained in (1) of Example 6
(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid (0.2 g) in dimethylformamide (2 m
l) Triethylamine (44 mg) and diphenylphosphoryl azide (114 mg) were added to the solution, and the mixture was stirred at room temperature for 30 minutes. Add water, extract with ethyl acetate,
After washing with water, it was dried over anhydrous Na ₂ SO ₄ . The solvent was removed and the residue was dissolved in toluene (2ml). After heating the solution to reflux for 1 hour, 9-fluorenylmethanol (89 mg) was added, and the mixture was further heated to reflux overnight. The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and a colorless non-crystalline solid 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-3- (Fluoren-9-yl) oxycarbonylaminomethyl-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one (0.24
g) was obtained. (2) Compound (0.24 g) obtained in Example (1) was added to piperidine (0.15 ml) in dimethylformamide (3 ml).
The solution was stirred at room temperature for 10 minutes. Ethyl acetate (50 ml) was added, and after washing with water, the organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to give a colorless non-crystalline solid 3,5-trans-3-aminomethyl-5- (3-tert.
-Butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one (0.17 g)
I got NMR (CDCl ₃ ) δ: 0.93 (9H, s), 1.45 (9H, s), 3.36
(1H, d, J = 14.0Hz), 3.55-3.70 (2H, m), 3.95 (1H, t, J = 5.8H
z), 4.16-4.40 (5H, m), 4.51 (1H, d, J = 14.0Hz), 4.83-4.9
0 (1H, br), 5.25-5.30 (1H, br), 5.99 (1H, s), 6.60 (1H,
s), 7.26-7.77 (14H, m) (3) Compound (0.1 g) obtained in (2) and 2-fluorophenylacetic acid (34 mg) in dimethylformamide (1 m).
g) Diethyl cyanophosphate (36 mg) and triethylamine (30 mg) were added to the solution, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, and after washing with water, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.13 g). NMR (CDCl ₃ ) δ: 0.9 (9H, s), 1.45 (9H, s), 3.33
(1H, d, J = 14.2Hz), 3.54 (2H, s), 3.64-3.70 (2H, m), 3.92
(1H, d, J = 6.1Hz), 4.35 (1H, d, J = 5.6Hz), 4.45 (1H, d, J = 1
4.2Hz), 4.85-4.95 (1H, br), 5.93 (1H, s), 6.05-6.11 (1
H, br), 6.57 (1H, d, J = 2.2Hz), 7.03-7.41 (10H, m)

Example 36 3,5-trans-5- (3-aminomethylphenyl)
-7-chloro-3- (2-fluorophenylacetyl)
Aminomethyl-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one-1
Hydrochloride The compound (0.12 g) obtained in Example 35 was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (1 ml) and left at room temperature for 30 minutes. The solvent was distilled off to obtain a colorless amorphous solid (69 mg). NMR (CDCl ₃ ) δ: 0.94 (9H, s), 3.47-3.72 (5H, m),
3.99 (1H, t, J = 5.8Hz), 4.17 (2H, s), 4.44 (1H, d, J = 14.2H
z), 6.02 (1H, s), 6.50 (1H, d, J = 2.2Hz), 6.98-7.61 (10H,
m)

Example 37 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) -7- (isobutyloxy) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxase Pin-3-acetamide (1) N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide (3.0 g), isobutyl iodide (2.2 g), potassium carbonate (2.0 g) , N, N-dimethylformamide (20
ml) solution was stirred at 70 ° C. for 15 hours. The reaction solution was added to water and extracted with ethyl acetate (80 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography.
An orange oil (1.0 g) of -methyl-N-methyloxy-2-benzyloxycarbonylamino-5-isobutyloxybenzamide was obtained. NMR (CDCl ₃ ) δ: 1.01 (6H, d, J = 6.8 Hz), 2.05 (1H,
m), 3.345 (3H, s), 3.542 (3H, s), 3.69 (2H, d, J = 6.6Hz),
5.175 (2H, s), 6.9-7.5 (7H, m), 7.8-8.3 (2H, m) (2) N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-isobutyloxybenzamide (1 2.0 g) was dissolved in ethyl acetate (10 ml) and methanol (10 ml) and 10% palladium on carbon (0.2
g) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours.
The reaction was filtered and evaporated to give N-methyl-N-methyloxy-2-amino-5-isobutyloxybenzamide as a yellow oil (0.6 g). NMR (CDCl ₃ ) δ: 1.03 (6H, d, J = 6.
8Hz), 2.05 (1H, m), 3.35 (3
H, s), 3.614 (3H, s), 3.64 (2
H, d, J = 6.6 Hz), 6.65-6.95 (3
H, m)

(3) N-methyl-N-methyloxy-2
-Amino-5-isobutyloxybenzamide (0.6
g) and N-tert-butoxycarbonyl 3-bromobenzylamine (0.76 g) in tetrahydrofuran (18 m
The solution dissolved in l) was cooled to -78 ° C, and 9 ml of a hexane solution of n-butyllithium (1.6 mol / L) was stirred while stirring.
Was added dropwise over 20 minutes. The reaction solution was added with water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2-amino-3'-tert.
A yellow oil (0.38 g) of -butoxycarbonylaminomethyl-5-isobutyloxy-benzophenone was obtained. NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.455 (9H,
s), 2.0 (1H, m), 3.56 (2H, d, J = 6.6Hz), 4.41 (2H, d, J = 6.2
Hz), 4.90 (1H, m), 5.70 (2H, m), 6.65-7.6 (7H, m) (4) 2-amino-3'-tert-butoxycarbonylaminomethyl-5-isobutyloxy-benzophenone (0 .38 g) was dissolved in methanol (12 ml) and sodium borohydride (50 mg) was added with stirring at room temperature. The reaction solution was concentrated, water was added, and ethyl acetate (50 m
Extracted in l). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated, and yellow oily substance of 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -5-isobutyloxybenzyl alcohol (0.36 g) was obtained.
I got NMR (CDCl ₃ ) δ: 1.02 (6H, d, J = 6.6 Hz), 1.449 (9H,
s), 2.05 (1H, m), 3.64 (2H, d, J = 6.6Hz), 4.31 (2H, d, J = 5.
6Hz), 4.85 (1H, m), 6.797 (1H, s), 6.6-7.5 (7H, M)

(5) 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -5-isobutyloxybenzyl alcohol (0.36 g), 4-benzyloxy-benzaldehyde (0.2 g), acetic acid ( 0.
Sodium cyanoborohydride (0.065 g) to a solution of methanol (12 g) and methanol (12 ml).
Stirred for 0 minutes. Water (60 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated, and 2- (4-benzyloxybenzylamino) -α- (3-tert-butoxycarbonylaminomethylphenyl) -5-isobutyloxybenzyl alcohol was yellow oily. (0.45 g). NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.8 Hz), 1.443 (9
H, s), 2.05 (1H, m), 3.63 (2H, d, J = 6.4Hz), 4.11 (2H, s),
4.28 (2H, m), 5.094 (2H, s), 5.815 (1H, s), 6.6-7.5 (16H,
m) (6) 2- (4-benzyloxybenzyl) -α- (3
-Tert-butoxycarbonylaminomethylphenyl)-
5-isobutyloxybenzyl alcohol (0.45
g) was dissolved in ethyl acetate (20 ml), 1N sodium hydroxide (3 ml) was added, and while stirring at room temperature, monoethyl fumarate (0.13 g) was added. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (15 ml), potassium carbonate (0.3 g) was added, and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was distilled off, and ethyl acetate (50 ml) and water (60 ml) were added. The organic layer was washed with water and dried over anhydrous sodium sulfate.
The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and 3,5-trans-1- (4-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7- Isobutyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-
A colorless oil of benzoxazepine-3-acetic acid ethyl ester (0.2 g) and a 3,5-cis form (60 mg) were obtained. NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.6 Hz), 1.27 (3H,
t, J = 7Hz), 1.95 (1H, m), 2.75 (1H, dd, J = 5.2Hz, 16.6Hz),
3.10 (1H, dd, J = 8Hz, 16.6Hz), 3.53 (2H, dd, J = 2Hz, 6.7Hz),
4.13 (2H, q, J = 7Hz), 4.2-4.5 (3H, m), 4.73 (1H, d, J = 14.4
Hz), 5.043 (2H, s), 5.319 (1H, s), 5.40 (1H, d, J = 14.4H
z), 6.02 (1H, d, J = 2.8Hz), 6.8-7.5 (15H, m)

(7) 3,5-trans-1- (4-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-isobutyloxy-2-oxo-1,2,3 , 5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.4
g) in tetrahydrofuran (5 ml) and methanol (10
ml), add 3 ml of 1N sodium hydroxide and add 60 ml.
Stirred at 40 ° C. for 40 minutes. The reaction solution was concentrated and water (20 ml)
And neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in N, N-dimethylformamide (6 ml), 2-fluorobenzylamine (73 mg) was added, and while stirring at 0 ° C., diethyl cyanophosphate (95 mg) and triethylamine (0.1 mg) were added.
1 ml) was added. After stirring the reaction at room temperature for 30 minutes,
Ice water was added and extracted with ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography, and 3,5-trans-N- (2-fluorobenzyl)
-1- (4-benzyloxybenzyl) -5- (3-te
rt-butoxycarbonylaminomethylphenyl) -7-
A colorless oil (0.21 g) of isobutyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide was obtained. NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 6.6 Hz), 1.432 (9
H, s), 1.95 (1H, m), 2.70 (1H, dd, J = 5.9Hz, 15.8Hz), 2.93
(1H, dd, J = 7.2Hz, 15.8Hz), 3.53 (2H, dd, J = 2.2Hz, 6.4Hz),
4.25 (2H, d, J = 5.9Hz), 4.3-4.6 (3H, m), 4.67 (1H, d, J = 1
4.3Hz), 4.83 (1H, m), 5.04 (2H, s), 5.29 (1H, s), 5.41 (1
H, d, J = 14.3Hz), 6.00 (1H, d, J = 2.8Hz), 6.37 (1H, m), 6.8
-7.5 (19H, m)

(8) 3,5-trans-N- (2-fluorobenzyl) -1- (4-benzyloxybenzyl)
-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-isobutyloxy-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide (0.21 g) was dissolved in ethyl acetate (6 ml) and methanol (10 ml), 10% palladium on carbon (0.06 g) was added, and the mixture was stirred under a hydrogen gas atmosphere for 3 hours. The reaction was filtered, evaporated, water was added to the residue and extracted with ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and 3,5-trans-N- (2-fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) -7- was obtained from the residue.
A colorless oil (0.16 g) of isobutyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide was obtained. NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6 Hz), 1.45 (9H,
s), 2.0 (1H, m), 2.67 (1H, dd, J = 6.2Hz, 16Hz), 2.86 (1H, d
d, J = 7.2Hz, 16Hz), 3.56 (1H, dd, J = 3.8Hz, 6.4Hz), 4.0-4.7
(6H, m), 4.87 (1H, s), 5.02 (1H, m), 5.7-7.5 (14H, m)

Example 38 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-3- [3-
(2-Fluorobenzyl) ureido] methyl-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one Instead of 9-fluorenylmethanol of Example 35,
The same operation as in Example 37 was performed using 2-fluorobenzylamine to obtain a colorless amorphous solid (0.26 g). NMR (CDCl ₃ ) δ: 0.91 (9H, s), 1.40 (9H, s), 3.32
(1H, d, J = 13.6Hz), 3.45-3.65 (1H, m), 3.71-3.85 (1H, m),
3.96 (1H, t, J = 6.1Hz), 4.10-4.22 (1H, m), 4.30-4.51 (4
H, m), 4.95-5.05 (1H, br), 5.35-5.45 (1H, br), 5.98 (1H, br
s), 6.55 (1H, d, J = 2.0Hz), 6.95-7.48 (11H, m)

Example 39 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-hydroxybenzyl) -7-isobutyloxy-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 3,5-trans-N- (2-fluorobenzyl) -5- (3- tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) -7-isobutyloxy-2-oxo-1,2,3,
5-Tetrahydro-2-oxo-4,1-benzoxazepine-3-acetamide (0.16 g) was dissolved in ethyl acetate (2 ml), and 4N hydrochloric acid (ethyl acetate solution) (2
ml) and stirred for 2 hours. The reaction solution was distilled off, and a colorless amorphous solid (0.11 g) of the title compound was obtained from the residue. NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.6 Hz), 1.95 (1H,
m), 2.6-2.9 (2H, m), 3.4-3.6 (2H, m), 3.80 (2H, br), 4.0
-4.65 (6H, m), 4.795 (1H, s), 5.63 (1H, d, J = 13.8Hz), 5.9
5 (1H, d, J = 2.8Hz), 6.39 (1H, br), 6.5-7.4 (14H, m)

Example 40 3,5-trans-5- (3-aminomethylphenyl)
-7-chloro-3- [3- (2-fluorobenzyl) ureido] methyl-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one.
Monohydrochloride Using the compound (0.20 g) obtained in Example 38, and by the same operation as in Example 36, a colorless amorphous solid (0.15 g)
g) was obtained. NMR (CD ₃ OD) δ: 0.94 (9H, s), 3.56 (1H, d, J = 13.
8Hz), 3.57 (1H, d, J = 6.0Hz), 3.95 (1H, t, J = 6.0Hz), 4.18
(2H, s), 4.32 (2H, s), 4.47 (1H, d, J = 13.8Hz), 6.05 (1H,
s), 6.51 (1H, d, J = 2.4Hz), 7.00-7.64 (10H, m)

Example 41 3,5-trans-N- (2-fluorobenzyl) -5
-(3-benzylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (1 ) N-methyl-N-methyloxy-2-amino-5
-A solution of 2-chlorobenzamide (2 g) and 2- (3-bromophenyl) -1,3-dioxolane (2.1 g) in tetrahydrofuran (65 ml) was cooled to -78 DEG C.
-Butyl lithium hexane solution (1.6 mol / L) (1
1.6 ml) was gradually added dropwise, and after completion of the addition, water (300 m
l) and ethyl acetate (50 ml) were added. The organic layer was washed with water and dried over anhydrous Na ₂ SO ₄ , and the solvent was distilled off.
The residue was separated and purified by silica gel column chromatography to give a colorless oily compound, 2- [3- (2-amino-5-
Chlorobenzoyl) phenyl-1,3-dioxolane (1.61 g) was obtained. NMR (CDCl ₃ ) δ: 4.00-4.18 (4H, m), 6.08 (2H, b
r), 6.69 (1H, d, J = 8.8 Hz), 7.21-7.76 (6H, m) (2) The methanol (15.8 g) of the compound (15.8 g) obtained by repeating the step (1) several times Sodium borohydride (2.5 g) was added to the solution (100 ml).
Stirred at 30 ° C. for 30 minutes. Acetic acid ethyl ester (200m
l) was added, washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound 2- [3-
(2-amino-5-chloro-α-hydroxybenzyl)
Phenyl] -1,3-dioxolane (9.5 g) was obtained.

(3) To a solution of the compound (0.6 g) obtained in (2) in methanol (10 ml) was added pivalaldehyde (19).
0 mg) and acetic acid (150 mg) were added, and the mixture was stirred at room temperature for 10 minutes. And sodium cyanoborohydride (150m
g) was added and stirred at 60 ° C. for 30 minutes. Ethyl acetate (50 ml) was added, washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the desired colorless oily compound 2- [3- (5-chloro-α-hydroxy-2-neopentylaminobenzylphenyl] -1,3-dioxolane (0.86 g) NMR (CDCl ₃ ) δ: 0.82 (9H, s), 2.73 (2H, s), 3.9
7-4.15 (4H, m), 5.76 (1H, s), 5.78 (1H, s), 6.55 (1H, d, J =
9.8Hz), 7.04 (1H, d, J = 2.6Hz), 7.14 (1H, dd, J = 2.6,8.4H
z), 7.35-7.53 (4H, m) (4) Sodium hydrogen carbonate (0.29) was added to the ethyl acetate (10 ml) of the compound (0.86 g) obtained in (3).
g), and fumaric acid monoethyl ester (370) was added.
mg) and stirred at room temperature for 10 minutes. Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous Na ₂ S.
Dried over O ₄ . The solvent was distilled off, the residue was dissolved in ethanol (10 ml), potassium carbonate (270 mg) was added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane to give colorless crystals of 3,5-trans-7-chloro-5- [3 -(1,3-dioxolan-2-yl) phenyl] -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.1%). 62 g) were obtained.

(5) To a solution of the compound (2 g) obtained by repeating the operation of (4) in ethanol (20 ml) was added a 1N aqueous sodium hydroxide solution (4 ml).
Stirred for hours. After neutralization, ethyl acetate (100ml)
Was added, washed with water, and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless non-crystalline solid 3,5-trans-7.
-Chloro-5- [3- (1,3-dioxolan-2-yl) phenyl] -1-neopentyl-2-oxo-1,
2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid (1.7 g) was obtained. NMR (CDCl ₃ ) δ: 0.93 (9H, s), 2.83 (1H, dd, J = 5.
2,16.4Hz), 3.09 (1H, dd, J = 7.6,16.4Hz), 3.38 (1H, d, J = 1
4.4Hz), 4.00-4.19 (4H, m), 4.35 (1H, dd, J = 5.2,7.6Hz),
4.50 (1H, d, J = 14.4Hz), 5.86 (1H, s), 6.03 (1H, s), 6.61
(1H, d, J = 2.0Hz), 7.17-7.53 (6H, m) (6) The compound (1.7 g) obtained in (5) and 2-fluorobenzylamine (0.52 g) in dimethylformamide (20 ml) ) Solution in diethyl cyanophosphate (0.73)
g) and triethylamine (0.5 g).
Stirred for 0 minutes. Ethyl acetate (100 ml) was added, washed with water, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and 3,5-trans-N- (2-fluorobenzyl) -7-chloro-5- [3- (1,3-dioxolane-2) was used. -Yl) phenyl] -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (2.0 g) was obtained. NMR (CDCl ₃ ) δ: 0.92 (9H, s), 2.69 (1H, d, J = 6.
2,14.8Hz), 2.88 (1H, dd, J = 7.0,14.8Hz), 3.35 (1H, d, J = 1
4.0Hz), 4.00-4.18 (4H, m), 4.38-4.50 (4H, m), 5.83 (1H,
s), 6.11 (1H, s), 6.30 (1H, br), 6.58 (1H, d, J = 2.2Hz),
6.98-7.55 (10H, m)

(7) A solution of the compound (2.0 g) obtained in (6) in acetone (8 ml) was added with p-toluenesulfonic acid / 1.
Hydrate (0.2 g) and water (1 ml) were added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate (50 ml) was added, and after washing with water, the organic layer was dried over anhydrous Na ₂ SO ₄ . By evaporating the solvent, a colorless amorphous solid, 3,5-trans-
N- (2-fluorobenzyl) -7-chloro-5- (3
-Formylphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1.76 g) was obtained. NMR (CDCl ₃ ) δ: 0.93 (9H, s), 2.71 (1H, dd, J = 6.
4,14.8Hz), 2.90 (1H, dd, J = 7.2,14.8Hz), 3.37 (1H, d, J = 1
4.8Hz), 4.37-4.62 (4H, m), 6.08 (1H, s), 6.24-6.30 (1H,
br), 6.49 (1H, d, J = 2.0Hz), 6.98-7.96 (10H, m), 10.04 (1
H, s) (8) To a solution of the compound (0.1 g) obtained in (7) in methanol (1 ml) was added benzylamine (22 mg) and acetic acid (1).
3 mg) and stirred at room temperature for 10 minutes. To this solution was added sodium cyanoborohydride (14 mg), and the mixture was stirred at room temperature for 1 hour. Water (10 ml) was added and extracted with ethyl acetate (50 ml). After washing the extract with water, anhydrous Na
_After drying over ₂ SO ₄ , the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound. This was dissolved in 4N hydrogen chloride ethyl acetate (0.2 ml), and the solvent was distilled off to obtain a colorless amorphous solid (83 mg). NMR (CDCl ₃ ) δ: 0.92 (9H, s), 2.69 (1H, dd, J = 5.
8,14.8Hz), 2.89 (1H, dd, J = 7.4,14.8Hz), 3.35 (1H, d, J = 1
3.6Hz), 3.73-3.83 (4H, m), 4.39-4.51 (4H, m), 6.00 (1H,
s), 6.26-6.36 (1H, br), 6.58 (1H, d, J = 2.2Hz), 6.97-7.3
9 (15H, m) 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-5- (3-formylphenyl) -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,
Using 1-benzoxazepine-3-acetamide in the same manner as in Example 41 (8), reductive amination reaction with various amines to give the following Example compounds 42-44.
Was synthesized.

Example 42 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-1-neopentyl-2-oxo-5- [3-
(Piperidin-1-yl) methylphenyl] -1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.92 (9H, s), 1.40-1.63 (6H,
m), 2.35-2.45 (4H, m), 2.70 (1H, dd, J = 5.8,14.2Hz), 2.8
9 (1H, dd, J = 7.0,14.2Hz), 3.35 (1H, d, J = 13.6Hz), 3.51 (2
H, s), 4.39-4.51 (4H, m), 5.99 (1H, s), 6.30-6.40 (1H, b
r), 6.60 (1H, d, J = 2.0 Hz), 6.95-7.39 (10H, m) Example 43 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-5- (3-methylaminomethylphenyl)-
1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamido monohydrochloride (non-crystalline solid) NMR (CDCl ₃ ) δ: 0.92 (9H , s), 2.47 (3H, s), 2.7
0 (1H, dd, J = 5.4,13.8Hz), 2.88 (1H, dd, J = 7.4,13.8Hz), 3.
35 (1H, d, J = 14.4Hz), 3.77 (2H, s), 4.39-4.51 (4H, m), 5.
99 (1H, s), 6.30-6.40 (1H, br), 6.58 (1H, d, J = 2.2Hz), 6.
98-7.39 (10H, m)

Example 44 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-5- (3-dimethylaminomethylphenyl)
-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamido monohydrochloride NMR (CDCl ₃ ) δ: 0.92 (9H, s), 2.25 (6H, s), 2.70
(1H, dd, J = 6.0,14.4Hz), 2.89 (1H, dd, J = 7.4,14.4Hz), 3.
35 (1H, d, J = 13.8Hz), 3.46 (2H, s), 4.38-4.50 (4H, m), 6.
00 (1H, s), 6.30-6.40 (1H, br), 6.58 (1H, d, J = 1.8Hz), 7.
02-7.42 (10H, m)

By the same operation as in Example 1, the compounds shown in Tables 1 to 4 were obtained.

[Table 1]

[0111]

[Table 2]

[0112]

[Table 3]

[0113]

[Table 4]

Example 75 3,5-trans-N- (2-fluorobenzyl) -5
-(2-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) N-methyl-N-methyloxy-2-amino-5
-Chlorobenzamide (4.3 g) and N-tert-butoxycarbonyl-2-bromobenzylamine (3.82)
A solution of g) in tetrahydrofuran (30 ml) was cooled to -78 ° C, and a hexane solution of n-butyllithium (1.6 mol / l) (42 ml) was slowly added dropwise. After completion of the dropwise addition, water (100 ml) and ethyl acetate (100 ml)
Was added. After washing the organic layer with water, drying over anhydrous MgSO ₄ ,
The solvent was distilled off. The remaining oily compound was separated and purified by silica gel column chromatography, and the yellow solid was recrystallized from n-hexane-isopropyl ether, and filtered to give 2-amino-2'-ter as pale yellow crystals.
There was obtained t-butoxycarbonylaminomethyl-5-chlorobenzophenone (1.3 g). (2) To a solution of 2-amino-2'-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.5 g) in methanol (5 ml) was added sodium borohydride (79 mg), and the mixture was stirred at room temperature for 3 hours. . Ethyl acetate (100 ml) was added, washed with water, and dried over anhydrous MgSO _4.
And the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to obtain the desired colorless oily compound 2-amino-5-chloro-α- (2-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g). NMR (CDCl ₃ ) δ: 1.40 (9H, s), 3.95-4.10 (2H, b
r), 4.30 (1H, dd, J = 6.6,15.0Hz), 4.41 (1H, dd, J = 5.8,15.
0Hz), 5.00-5.10 (1H, br), 6.10 (1H, s), 6.62 (1H, d, J = 8.
4Hz), 6.95 (1H, d, J = 2.2Hz), 7.07 (1H, dd, J = 2.6,8.4Hz),
7.26-7.38 (5H, m)

(3) 2-amino-5-chloro-α- (2
To a solution of -tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) in methanol (5 ml) was added trimethylacetaldehyde (132 mg) and acetic acid (92 mg), and the mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (97 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 ml) was added, washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound 5-chloro-α-
(2-tert-butoxycarbonylaminomethylphenyl) -2-neopentylaminobenzyl alcohol (0.61 g) was obtained. NMR (CDCl ₃ ) δ: 0.85 (9H, s), 1.40 (9H, s), 1.5
9-1.70 (1H, br), 2.79 (2H, s), 4.29 (1H, dd, J = 6.0,14.8H
z), 4.45 (1H, dd, J = 6.2,14.8Hz), 4.98-5.09 (1H, br), 6.
05 (1H, s), 6.59 (1H, d, J = 8.8Hz), 6.97-7.39 (6H, m) (4) 5-chloro-α- (2-tert-butoxycarbonylaminomethylphenyl) -2- Water (3 ml) and a 1N aqueous sodium hydroxide solution (1.5 ml) were added to ethyl acetate (6 ml) of neopentylaminobenzyl alcohol (0.61 g), and monoethyl ester of fumaric chloride (236 mg) was added. The mixture was stirred for 1 hour under cooling. Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous M.
and dried over gSO _4. The solvent was distilled off, the residue was dissolved in ethanol (10 ml), potassium carbonate (360 mg) was added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography, recrystallized from hexane, melting point 153-156.
3,5-trans-5- (2-tert-butoxycarbonylaminomethylphenyl) -7-chloro-
1-Neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.75 g) was obtained. NMR (CDCl ₃ ) δ: 0.93 (9H, s), 1.24 (3H, t, J = 7.2H
z), 1.40 (9H, s), 2.78 (1H, dd, J = 6.2,16.4Hz), 3.04 (1H,
dd, J = 7.4,16.4Hz), 3.40 (1H, d, J = 13.8Hz), 4.01-4.21 (4
H, m), 4.43-4.60 (3H, m), 6.14 (1H, s), 6.57 (1H, s), 7.3
4-7.57 (6H, m)

(5) Compound obtained in (4) (0.75 g)
To a solution of the above in ethanol (8 ml) was added a 1N aqueous sodium hydroxide solution (1.5 ml), and the mixture was stirred at 60 ° C. for 1 hour. After neutralization, ethyl acetate (50 ml) was added, and the organic layer was washed with water and dried over anhydrous Na ₂ SO ₄ . Evaporate the solvent,
The residue was recrystallized from ethyl ether-n-hexane to give colorless crystals (0.23 g) having a melting point of 149-152 ° C. (6) Dimethylformamide (1 mg) of the compound (0.1 g) obtained in (5) and 2-fluorobenzylamine (26 mg)
ml) solution, diethyl cyanophosphate (37 mg) and triethylamine (28 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.12 g). NMR (CDCl ₃ ) δ: 0.92 (9H, s), 1.40 (9H, s), 2.6
9 (1H, dd, J = 6.2,14.6Hz), 2.87 (1H, dd, J = 6.6,14.6Hz), 3.
39 (1H, d, J = 14.0Hz), 3.90-4.15 (2H, m), 4.37-4.65 (5H,
m), 6.11 (1H, s), 6.28 (1H, br), 6.54 (1H, s), 6.98-7.5
0 (10H, m)

Example 76 3,5-trans-N- (2-fluorobenzyl) -5
-(2-Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-1
Hydrochloride The compound (0.12 g) obtained in Example 75 was dissolved in a 4N solution of hydrogen chloride in ethyl acetate (2 ml) and left at room temperature for 30 minutes. The solvent was distilled off to obtain a colorless amorphous solid (80 mg). NMR (CDCl ₃ ) δ: 0.93 (9H, s), 2.81 (2H, d, J = 6.2
Hz), 3.60 (1H, d, J = 14.4Hz), 3.97 (1H, d, J = 13.6Hz), 4.1
3 (1H, d, J = 13.6Hz), 4.41 (2H, s), 4.52 (1H, t, J = 6.2Hz),
6.15 (1H, s), 6.47 (1H, s), 6.99-7.68 (10H, m) Example 77 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (2-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 2-amino-5-chloro-α obtained in (2) of Example 75
Using-(2-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol, a colorless oily compound was obtained in the same manner as in Example 4. NMR (CDCl ₃ ) δ: 1.30 (9H, s), 2.76 (1H, dd, J = 5.
2,14.8Hz), 2.95 (1H, dd, J = 7.0,15.0Hz), 3.55 (2H, m),
4.3-4.65 (3H, m), 4.92 (1H, d, J = 17.0Hz), 5.53 (1H, d, J = 1
6.8Hz), 6.3-6.5 (2H, m), 6.9-7.6 (19H, m)

Example 78 3,5-trans-N- (2-fluorobenzyl) -5
-(2-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine monohydrochloride A colorless amorphous solid (0.14 g) was obtained from the compound (0.18 g) obtained in Example 77 by the same operation as in Example 2. NMR (CDCl ₃ ) δ: 2.8-3.2 (2H, m), 3.9-4.6 (5H,
m), 4.73 (1H, d), 5.37 (1H, s), 5.57 (1H, d), 6.38 (1H,
d), 6.47 (1H, d), 6.8-7.8 (19H, m) Example 79 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminophenyl)-
7-chloro-1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide (1) N-methyl-N-methyloxy-2-amino-5
A solution of -chlorobenzamide (4.3 g) and N-tert-butoxycarbonyl-3-bromoaniline (3.79 g) in tetrahydrofuran (30 ml) was cooled to -78 ° C,
In addition, a hexane solution of n-butyllithium (1.6 mol /
l) (42 ml) was slowly added dropwise. After dropping, add water (1
00 ml) and ethyl acetate (300 ml).
The organic layer was washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and 2-amino-3'-tert.
-Butoxycarbonylamino-5-chlorobenzophenone (0.7 g) was obtained. (2) To a solution of 2-amino-3'-tert-butoxycarbonylamino-5-chlorobenzophenone (0.4 g) in methanol (5 ml) was added sodium borohydride (66 ml).
g) was added and stirred at room temperature for 1 hour. Ethyl acetate (100 ml) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the desired colorless oily compound, 2-amino-5-chloro-α- (3-tert-butoxycarbonylaminophenyl) benzyl alcohol (0.4)
g) was obtained. NMR (CDCl ₃ ) δ: 1.50 (9H, s), 3.91-3.99 (2H, b
r), 5.74 (1H, s), 6.52 (1H, br), 6.58 (1H, d, J = 8.8Hz),
7.00-7.40 (6H, m)

(3) 2-amino-5-chloro-α- (3
-Tert-butoxycarbonylaminophenyl) benzyl alcohol (0.4 g) in methanol (4 ml),
Trimethylacetaldehyde (109 mg) and acetic acid (76
mg) and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (79 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 ml) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography,
The desired colorless non-crystalline solid 5-chloro-α- (3-
(tert-butoxycarbonylaminophenyl) -2-neopentylaminobenzyl alcohol (0.48 g) was obtained. NMR (CDCl ₃ ) δ: 0.84 (9H, s), 1.50 (9H, s), 2.7
4 (2H, s), 4.11 (1H, br), 5.74 (1H, s), 6.47 (1H, br), 6.55
(1H, d, J = 8.8Hz), 7.04-7.36 (6H, m) (4) 5-chloro-α- (3-tert-butoxycarbonylaminophenyl) -2-neopentylaminobenzyl alcohol (0.48 g) ) Ethyl acetate (5m
l) into water (2 ml) and 1N aqueous sodium hydroxide solution (1.
5 ml), and fumaric acid monoethyl ester (19) was added.
5 mg) and stirred for 10 minutes under ice cooling. Ethyl acetate (100 ml) was added, and the organic layer was washed with water and dried over anhydrous Na.
Dried over ₂ SO ₄ . The solvent was distilled off, the residue was dissolved in ethanol (10 ml), potassium carbonate (200 mg) was added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 3,5-trans-5- (3
-Tert-butoxycarbonylaminophenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.55 g) was obtained. NMR (CDCl ₃ ) δ: 0.92 (9H, s), 1.24 (3H, t, J = 7.0
Hz), 1.52 (9H, s), 2.76 (1H, dd, J = 5.6,16.6Hz), 3.05 (1
H, dd, J = 7.8,16.6Hz), 3.36 (1H, d, J = 14.0Hz), 4.12 (2H, d
q, J = 1.0,7.0Hz), 4.38 (1H, dd, J = 5.6,7.8Hz), 4.50 (1H,
d, J = 14.0Hz), 5.97 (1H, s), 6.55 (1H, s), 6.65 (1H, d, J =
1.8Hz), 6.14-7.60 (6H, m)

(5) Compound obtained in (4) (0.55 g)
To a solution of the above in ethanol (5 ml) was added a 1N aqueous solution of sodium hydroxide (1.2 ml), and the mixture was stirred at 60 ° C. for 1 hour. After neutralization, ethyl acetate (50 ml) was added, and the organic layer was washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.53 g). NMR (CDCl ₃ ) δ: 0.92 (9H, s), 1.52 (9H, s), 2.8
6 (1H, dd, J = 6.2,16.4Hz), 3.04 (1H, dd, J = 7.2,16.4Hz), 3.
36 (1H, d, J = 14.0Hz), 4.35 (1H, dd, J = 6.2,7.2Hz), 4.50 (1
H, d, J = 14.0Hz), 5.99 (1H, s), 6.65 (1H, d, J = 1.8Hz), 6.7
5-6.80 (1H, br), 6.93 (1H, d, J = 7.8 Hz), 7.27-7.60 (5H, m) (6) Compound (0.1 g) obtained in (5) and 2-fluorobenzylamine (27 mg) of dimethylformamide (1
ml) solution, diethyl cyanophosphate (35 mg) and triethylamine (29 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and a colorless non-crystalline solid of 3,5-trans-N- (2-fluorobenzyl) -5- (3-tert-butoxycarbonylamino) was obtained. Phenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.12 g) was obtained. NMR (CDCl ₃ ) δ: 0.91 (9H, s), 1.51 (9H, s), 2.7
0 (1H, dd, J = 6.4,14.6Hz), 2.86 (1H, dd, J = 6.8,14.6Hz), 3.
35 (1H, d, J = 14.0Hz), 4.37-4.55 (4H, m), 5.96 (1H, s), 6.
31-6.39 (1H, br), 6.53-6.57 (1H, br), 6.63 (1H, d, J = 2.4H
z), 6.88-7.61 (10H, m)

Example 80 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminophenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamide monohydrochloride The compound (0.12 g) obtained in Example 79 was dissolved in a 4N solution of hydrogen chloride in ethyl acetate (2 ml) and allowed to stand at room temperature for 30 minutes. The solvent was distilled off to obtain a colorless amorphous solid (0.09 g). NMR (CDCl ₃ ) δ: 0.94 (9H, s), 2.74 (1H, d, J = 4.
6,15Hz), 2.85 (1H, dd, J = 4.2,15.4Hz), 3.58 (1H, d, J = 14.
2Hz), 4.41-4.94 (3H, m), 6.07 (1H, s), 6.46 (1H, d, J = 2.4
Hz), 7.05-7.68 (10H, m)

Example 81 3,5-trans-N- (2-fluorobenzyl) -5
-(4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) N-methyl-N-methyloxy-2-amino-5
-Chlorobenzamide (3.21 g) and N-tert-butoxycarbonyl-4-bromobenzylamine (2.86)
A solution of g) in tetrahydrofuran (30 ml) was cooled to -78 ° C, and a hexane solution of n-butyllithium (1.6 mol / l) (31 ml) was slowly added dropwise. After completion of the dropwise addition, water (100 ml) and ethyl acetate (100 ml)
Was added. After washing the organic layer with water, drying over anhydrous MgSO ₄ ,
The solvent was distilled off. The residue was separated and purified by silica gel column chromatography, crystallized, and collected by filtration to give 2-amino-4'-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.9 g) as pale yellow crystals. I got (2) To a solution of 2-amino-4'-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.9 g) in methanol (10 ml) was added sodium borohydride (0.28 g) and the mixture was allowed to stand at room temperature for 30 minutes. Stirred. Acetic acid ethyl ester (100 ml) was added, and after washing with water, anhydrous Na was added.
_It was dried over ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound, 2-amino-5-chloro-α- (4-tert.
-Butoxycarbonylaminomethylphenyl) benzyl alcohol (0.85 g) was obtained. NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.6-2.8 (1H, br),
3.80-4.00 (1H, br), 4.31 (2H, d, J = 6.0Hz), 4.80-4.95 (1
H, br), 5.78 (1H, s), 6.59 (1H, d, J = 8.8Hz), 7.05-7.37 (6
H, m)

(3) 2-amino-5-chloro-α- (4
-Tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.83 g) in methanol (8 ml)
Trimethylacetaldehyde (220 mg) and acetic acid (170 mg) were added to the solution, and the mixture was stirred at room temperature for 10 minutes. Add sodium cyanoborohydride (160mg) to it,
Stirred at room temperature overnight. Acetic acid ethyl ester (100 ml)
Was added, washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to obtain the desired colorless oily compound 5-chloro-α.
-(4-tert-Butoxycarbonylaminomethylphenyl) -2-neopentylaminobenzyl alcohol (0.99 g) was obtained. NMR (CDCl ₃ ) δ: 0.83 (9H, s), 1.45 (9H, s), 2.74 (2H,
s), 4.29 (2H, d, J = 6.2Hz), 4.75-4.85 (1H, br), 5.77 (1H,
s), 6.56 (1H, d, J = 8.8 Hz), 7.05-7.39 (6H, m) (4) 5-chloro-α- (4-tert-butoxycarbonylaminomethylphenyl) -2-neopentylaminobenzyl Water (3 ml) and 1N aqueous sodium hydroxide solution (2.5 ml) were added to ethyl acetate (10 ml) of alcohol (0.99 g), monoethyl ester of fumaric chloride (370 mg) was added, and the mixture was cooled on ice for 30 minutes. Stirred. Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, the residue was dissolved in ethanol (20 ml), and potassium carbonate (700 mg)
Was added and stirred at room temperature overnight. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give a colorless oily compound, 3,5-trans-5
-(4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-
There was obtained 1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.08 g). NMR (CDCl ₃ ) δ: 0.92 (9H, s), 1.24 (3H, t, J = 7.2
Hz), 1.48 (9H, s), 2.76 (1H, dd, J = 6.2,16.4Hz), 3.03 (1
H, dd, J = 7.4,16.4Hz), 3.36 (1H, d, J = 14.2Hz), 4.12 (2H, d
q, J = 1.6,7.2Hz), 4.36-4.43 (3H, m), 4.50 (1H, d, J = 14.2H
z), 4.85-4.95 (1H, br), 6.00 (1H, s), 6.60 (1H, s), 7.20
-7.38 (6H, m)

(5) Compound obtained in (4) (1.08 g)
To a solution of the above in ethanol (10 ml) was added a 1N aqueous sodium hydroxide solution (2 ml), and the mixture was stirred at 60 ° C. for 2 hours. Acetic acid ethyl ester (100 ml) was added, and after washing with water, anhydrous Na was added.
Dried over ₂ SO ₄ . The solvent was distilled off, and the residue was recrystallized from ethyl ether-n-hexane, melting point 237-238 ° C.
To give colorless crystals (0.90 g). (6) Dimethylformamide (2 mg) of the compound (0.2 g) obtained in (5) and 2-fluorobenzylamine (52 mg)
ml) solution, diethyl cyanophosphate (74 mg) and triethylamine (57 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and the residue was recrystallized from hexane to obtain colorless crystals (0.25 g) having a melting point of 183-185 ° C.

Example 82 3,5-trans-N- (2-fluorobenzyl) -5
-(4-Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide-1
Hydrochloride The compound (0.15 g) obtained in Example 81 was dissolved in ethyl acetate (4 ml) of 4N hydrogen chloride, and the solution was dissolved at room temperature for 30 minutes.
Let stand for minutes. The solvent was distilled off to obtain a colorless amorphous solid (135 mg). NMR (CDCl ₃ ) δ: 0.93 (9H, s), 2.77 (2H, d, J = 6.
6Hz), 3.56 (1H, d, J = 14.0Hz), 4.19 (2H, s), 4.41-4.48 (4
H, m), 6.04 (1H, s), 6.45 (1H, d, J = 2.2Hz), 7.02-7.63 (10
H, m)

Example 83 3,5-trans-N- (2-fluorobenzyl) -5
-[3- (2-Aminoethyl) phenyl] -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide / 1 hydrochloride Salt (1) 3,5-trans-N- (2-
(Fluorobenzyl) -7-chloro-5- (3-formylphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide (0.5 g) in tetrahydrofuran (5 m
l) To the solution was added (carboethoxymethylene) triphenylphosphorane (0.35 g), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (50 ml) was added, washed with water, and the organic layer was dried over Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound (0.53 g). NMR (CDCl ₃ ) δ: 0.93 (9H, s), 1.32 (3H, t, J = 7.0
Hz), 2.70 (1H, dd, J = 5.8,14.2Hz), 2.90 (1H, dd, J = 7.0,1
4.2Hz), 3.36 (1H, d, J = 13.8Hz), 4.26 (2H, q, J = 7.0Hz),
4.38-4.52 (4H, m), 6.00 (1H, s), 6.25-6.40 (1H, br), 6.4
6 (1H, d, J = 16.2Hz), 6.55 (1H, d, J = 2.2Hz), 6.97-7.73 (11
(H, m) (2) A catalytic reduction reaction was performed at room temperature and normal pressure on a solution of the compound (0.53 g) obtained in (1) in ethyl acetate (10 ml) using a 10% palladium-carbon catalyst. The catalyst was removed, and the solvent of the filtrate was distilled off to obtain a colorless amorphous solid (0.48 g). NMR (CDCl ₃ ) δ: 0.92 (9H, s), 1.21 (3H, t, J = 7.2
Hz), 2.59-2.74 (3H, m), 2.84-3.01 (3H, m), 3.35 (1H, d, J =
14.0Hz), 4.11 (2H, q, J = 7.2Hz), 4.38-4.55 (4H, m), 5.97
(1H, s), 6.25-6.35 (1H, br), 6.58 (1H, d, J = 1.8Hz), 6.98
-7.33 (10H, m) (3) To a solution of the compound (0.48 g) obtained in (2) in ethanol (5 ml) was added a 1N aqueous sodium hydroxide solution (0.4%).
8 ml), and the mixture was heated and stirred at 60 ° C. for 3 hours. After neutralization
The mixture was extracted with ethyl acetate (100 ml), and the extract was washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off to obtain a colorless amorphous solid (0.39 g).

(4) To a solution of the compound (0.2 g) obtained in (3) in dimethylformamide (2 ml) was added triethylamine (40 mg) and diphenylphosphoryl azide (104 m2).
g) and stirred at room temperature for 30 minutes, then water (50 ml) was added. After extraction with ethyl acetate (50 ml), the extract was washed with water and dried over colorless Na ₂ SO ₄ . Excluding the solvent,
The residue was dissolved in toluene (2 ml) and heated under reflux for 1 hour. 9-Fluorenylmethanol (135 m
g) was added and the mixture was further heated under reflux overnight. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.12 g). NMR (CDCl ₃ ) δ: 0.91 (9H, s), 2.67 (1H, dd, J = 5.
2,14.6Hz), 2.82-2.92 (3H, m), 3.35 (1H, d, J = 14.2Hz),
3.40-3.55 (2H, m), 4.20 (1H, t, J = 7.0Hz), 4.37-4.54 (6H,
m), 4.75-4.85 (1H, br), 5.97 (1H, s), 6.20-6.30 (1H, b
r), 6.59 (1H, d, J = 1.8 Hz), 7.04-7.78 (18H, m) (5) Piperidine was added to a solution of the compound (0.12 g) obtained in (4) in dimethylformamide (1.5 ml). (0.1 ml)
Was added and stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, and after washing with water, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography. The oily compound obtained was dissolved in 4N hydrogen chloride ethyl acetate (1 ml), and the solvent was distilled off to give a colorless non-aqueous compound. A crystalline solid (53 mg) was obtained. NMR (CDCl ₃ ) δ: 0.94 (9H, s), 2.78 (2H, d, J = 7.2
Hz), 2.95-3.02 (2H, m), 3.15-3.24 (2H, m), 3.57 (1H, d, J =
14.2Hz), 4.41-4.48 (4H, m), 6.02 (1H, s), 6.52 (1H, d, J =
2.2Hz), 7.01-7.63 (6H, m)

Example 84 3,5-trans-N- (2-fluorobenzyl) -5
-[4- (2-tert-butoxycarbonylaminoethyl) phenyl] -1- (4-biphenylmethyl) -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide (1) N-methyl-N-methyloxy-2-amino-5
-Chlorobenzamide (6.4 g) and N-tert-butoxycarbonyl-3-bromophenethylamine (6.0
A solution of g) in tetrahydrofuran (70 ml) was cooled to -78 ° C, and a hexane solution of n-butyllithium (1.6 mol / l) (67 ml) was slowly added dropwise. After dropping, water (300ml) and ethyl acetate (300ml)
Was added. After washing the organic layer with water, drying over anhydrous MgSO ₄ ,
The solvent was distilled off. The remaining oily compound was separated and purified by silica gel column chromatography, and the residue was recrystallized from hexane to give 2-amino-4 'as pale yellow crystals.
-(2-tert-butoxycarbonylaminoethyl) -5
-Chlorobenzophenone (3.97 g) was obtained. (2) 2-amino-4 '-(2-tert-butoxycarbonylaminoethyl) -5-chlorobenzophenone (2.
Sodium borohydride (0.5 g) was added to a solution of 0 g) in methanol (40 ml) and stirred at room temperature for 30 minutes. Ethyl acetate (100 ml) was added and washed with water.
It was dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound 2-amino-5-chloro-α-
[4- (2-tert-butoxycarbonylaminoethyl)
[Phenyl] benzyl alcohol (2.2 g) was obtained. (3) 2-amino-5-chloro-α- [4- (2-tert
-Butoxycarbonylaminoethyl) phenyl] benzyl alcohol (1.0 g) in methanol (20 ml) was added to 4-biphenylcarboxaldehyde (0.53).
g) and acetic acid (200 mg) were added, and the mixture was stirred at room temperature for 10 minutes. And sodium cyanoborohydride (180mg)
Was added and stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ .
The solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound 2-
(4-biphenylmethylamino) -5-chloro-α-
[4- (2-tert-butoxycarbonylaminoethyl)
[Phenyl] benzyl alcohol (1.2 g) was obtained.

(4) 2- (4-biphenylmethylamino) -5-chloro-α- [4- (2-tert-butoxycarbonylaminoethyl) phenyl] benzyl alcohol (1.2 g) in acetic acid ethyl ester (20 ml) ), A 1N aqueous sodium hydroxide solution (8 ml) was added, monoethyl fumarate chloride (400 mg) was added, and the mixture was stirred for 1 hour under ice cooling. Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, the residue was dissolved in ethanol (25 ml), potassium carbonate (800 mg) was added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and the residue was recrystallized from hexane to give colorless crystals of melting point 178-180 ° C 3,5-trans-1- ( 4-biphenylmethyl) -5- [4-
(2-tert-butoxycarbonylaminoethyl) phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.6 g) ) Got. NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 1.43 (9
H, s), 2.8 (3H, m), 3.13 (1H, dd, J = 8.2,16.2Hz), 3.35 (2
H, m), 4.15 (2H, q, J = 7.3,12Hz), 4.5 (1H, dd, J = 5.4,10H
z), 4.92 (1H, d, J = 14.8Hz), 5.40 (1H, s), 5.48 (1H, d, J = 1
4.6Hz), 6.55 (1H, d, J = 1.4Hz), 7.0-7.6 (15H, m) (5) 1N hydroxylation in ethanol (10ml) solution of the compound (0.6g) obtained in (4) Sodium aqueous solution (4m
l) was added and the mixture was stirred at 60 ° C for 2 hours. After neutralization, ethyl acetate (50 ml) was added, and the organic layer was washed with water and dried over anhydrous M.
and dried over gSO _4. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
Colorless crystals (0.34 g) at -225 ° C were obtained. (6) To a solution of the compound obtained in (5) (0.33 g) and 2-fluorobenzylamine (80 mg) in dimethylformamide (8 ml), diethyl cyanophosphate (110 mg) and triethylamine (100 mg) were added, and the mixture was added at room temperature for 30 minutes. Stirred for minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
A colorless oily compound (0.2 g) was obtained. NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.1-3.0 (4H, m),
3.35 (2H, m), 4.3-4.7 (3H, m), 4.83 (1H, d, J = 14.8Hz), 5.
36 (1H, s), 5.49 (1H, d, J = 14.8Hz), 6.40 (1H, m), 6.50 (1H, s)
(H, d, J = 1.8Hz), 6.9-7.6 (19H, m)

Example 85 3,5-trans-N- (2-fluorobenzyl) -5
-[4- (2-aminoethyl) phenyl] -1- (4-
(Biphenylmethyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide monohydrochloride The compound (0.2 g) obtained in Example 84 was dissolved in 4N hydrogen chloride in ethyl acetate (2 ml), and the mixture was allowed to stand for 30 minutes. Solid (0.1
4 g) were obtained. NMR (CDCl ₃ ) δ: 2.10 (2H, m), 2.6-3.1 (6H, m),
4.3-4.6 (3H, m), 4.83 (1H, d, J = 15.0Hz), 5.36 (1H, s), 5.
48 (1H, d, J = 14.8Hz), 6.46 (1H, m), 6.53 (1H, d, J = 2Hz),
6.9-7.6 (19H, m) Example 86 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 2-amino-5-chloro-α obtained in (2) of Example 81
Using-(4-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol, colorless crystals having a melting point of 194-195 ° C were obtained in the same manner as in Example 4. NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.73 (1H, dd, J = 6.
2,17Hz), 2.93 (1H, dd, J = 7.0,16.8Hz), 4.31 (2H, d, J = 5.4
Hz), 4.35-4.65 (3H, m), 4.65 (1H, d, J = 14.4Hz), 5.36 (1
H, s), 5.51 (1H, d, J = 14.6Hz), 6.23 (1H, m), 6.50 (1H, d, J
= 1.8Hz), 6.9-7.6 (19H, m)

Example 87 3,5-trans-N- (2-fluorobenzyl) -5
-(4-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride The compound obtained in Example 86 (0.2 g) is dissolved in 4N hydrogen chloride ethyl acetate (3 ml) and left at room temperature for 3 hours. Thereafter, the solvent was distilled off to obtain a colorless amorphous solid (0.16%).
g) was obtained. NMR (CDCl ₃ ) δ: 2.73 (1H, dd, J = 6.0,16.0Hz),
2.94 (1H, dd, J = 7.0,16.0Hz), 3.87 (2H, s), 4.3-4.65 (3H,
m), 4.85 (1H, d, J = 14.8Hz), 5.38 (1H, s), 5.50 (1H, d, J = 1
4.6Hz), 6.33 (1H, m), 6.53 (1H, d, J = 2Hz), 6.9-7.6 (19H,
m) Example 88 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (2-tert-butoxycarbonylaminomethylthiophen-5-yl) -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide (A), 3,5-cis-N- (2-fluorobenzyl)
-1- (4-biphenylmethyl) -5- (2-tert-butoxycarbonylaminomethylthiophen-5-yl)
-7-Chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (B) (1) N-methyl-N-methyloxy-2-amino- 5
-Chlorobenzamide (4.96 g) and 2-bromo-5
A solution of -tert-butoxycarbonylaminomethylthiophene (5.45 g) in tetrahydrofuran (60 ml) was cooled to -78 ° C, and a hexane solution of n-butyllithium (1.6 mol / l) (47 ml) was gradually added dropwise. . After the addition, water (200 ml) and ethyl acetate (20 ml) were added.
0 ml) was added. The organic layer was washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The remaining oily compound was separated and purified by silica gel column chromatography to obtain a yellow oily compound, 2- (2-tert-butoxycarbonylaminomethylthiophen-5-yl) carbonyl-4-chloroaniline (0.5 g). To a solution of this compound (0.15 g) in methanol (8 ml) was added sodium borohydride (60 ml).
mg) and stirred at room temperature for 30 minutes. Ethyl acetate (100 ml) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. To a solution of the residue in methanol (5 ml) was added 4-biphenylcarboxaldehyde (100 ml).
g) and acetic acid (40 mg) were added, and the mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (40 mg) was added thereto, and the mixture was heated and stirred at 60 ° C. for 30 minutes. Ethyl acetate (50 ml) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off to obtain 0.2 g of a residue.

This compound was treated with ethyl acetate (8 ml).
To the mixture was added a 1N aqueous sodium hydroxide solution (2 ml), monoethyl fumarate chloride (40 mg) was added, and the mixture was stirred under ice cooling for 20 minutes. Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, the residue was dissolved in ethanol (6 ml), potassium carbonate (100 mg) was added, and the mixture was heated and stirred at 60 ° C. for 30 minutes. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound (0.4 g). This compound (0.2 g) was dissolved in ethanol (10 ml), 1N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 60 ° C. for 1 hour. After neutralization, ethyl acetate (50 ml) was added, and the organic layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off and the residue was dissolved in dimethylformamide (4 ml).
-Fluorobenzylamine (40 mg), diethyl cyanophosphate (80 mg) and triethylamine (60 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Acetic acid ethyl ester (5
0 ml), washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to give a colorless oily compound 3,3.
5-cis form (20 mg) and 3,5-trans form (50 mg)
I got 3,5-cis form (B) NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.78 (1H, dd), 3.
0 (1H, dd), 4.05 (1H, d), 4.35 (2H, d), 4.48 (2H, d), 4.77
(1H, dd), 4.86 (1H, m), 5.03 (1H, d), 6.01 (1H, s), 6.40 (1
H, t), 6.52 (1H, m), 6.73 (1H, d), 6.9-7.6 (16H, m) 3,5-trans form (A) NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.70 (1H, dd), 2.
93 (1H, dd), 4.3-4.6 (5H, m), 4.95 (1H, d), 5.36 (1H, d),
5.64 (1H, s), 6.35 (1H, t), 6.57 (1H, d), 6.8-7.6 (17H, m)

Example 89 3,5-trans-N- (2-fluorobenzyl) -5
-(2-aminomethylthiophen-5-yl) -1-
(4-biphenylmethyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride 3,5-trans form (A) obtained in Example 88 (50 mg)
In 4N hydrogen chloride in ethyl acetate solution,
After standing at room temperature for 30 minutes, the solvent was distilled off to obtain a colorless amorphous solid (30 mg). NMR (CDCl ₃ ) δ: 2.72 (1H, dd), 2.93 (1H, dd),
4.00 (2H, s), 4.3-4.65 (3H, m), 4.93 (1H, d), 5.4 (1H, d),
5.63 (1H, s), 6.27 (1H, t), 6.57 (1H, d), 6.75-7.7 (17H,
m) Example 90 3,5-trans-N- (2-fluorobenzyl) -5
-(2-tert-butoxycarbonylaminomethylthiophen-5-yl) -7-chloro-1- (4-methoxybenzyl) -2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide A colorless oily compound was obtained in the same manner as in Example 88. NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.68 (1H, dd, J = 6.
2,16.0Hz), 2.88 (1H, dd, J = 7.2,15.8Hz), 3.77 (3H, s),
4.3-4.6 (5H, m), 4.73 (1H, d, J = 14.6Hz), 4.9 (1H, m), 5.3
3 (1H, d, J = 14.6Hz), 5.55 (1H, s), 6.33 (1H, m), 6.55 (1H,
d, J = 3.8Hz), 6.7-7.5 (12H, m)

Example 91 3,5-trans-N- (2-fluorobenzyl) -5
-(2-aminomethylthiophen-5-yl) -7-chloro-1- (4-methoxybenzyl) -2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride The compound (0.1 g) obtained in Example 90 was dissolved in 4N hydrogen chloride in ethyl acetate (1 ml). ) And allowed to stand for 30 minutes, after which the solvent was distilled off to give a colorless amorphous solid (70 mg). NMR (CDCl ₃ ) δ: 2.1-3.0 (2H, m), 3.71 (3H, s),
4.0-4.6 (5H, m), 4.8 (1H, d, J = 15Hz), 5.11 (1H, d, J = 14.8H
z), 5.62 (1H, s), 6.55 (1H, br), 6.7-7.5 (12H, m)

Example 92 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (A) , 3,5-cis-N- (2-fluorobenzyl) -5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -1- (4-
(Biphenylmethyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide (B) (1) To a solution of 3-bromobenzonitrile (18 g) in toluene (200 ml) was added methylmagnesium bromide (3).
(mol / l ethyl ether solution) (120 ml) was added, and the ethyl ether was distilled off under normal pressure, followed by heating under reflux for 6 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (200 ml). After the extract was washed with 1N hydrochloric acid (150 ml), the aqueous layer was made basic with a 1N aqueous sodium hydroxide solution (200 ml) and then extracted with ethyl acetate (200 ml). Extract the solution with anhydrous MgSO
After drying with ₄ and evaporating the solvent, the residue was dissolved in ethyl ether (100 ml), 1N aqueous sodium hydroxide solution (100 ml) was added, and di-t-butyl dicarbonate (15 ml) was added.
g) was added and stirred at room temperature for 5 hours. Ethyl ether (100 ml) was added, and the organic layer was washed with water and dried over anhydrous MgSO.
Dried at ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give a colorless oily compound, 1-[(1-tert-butoxycarbonylamino-1).
-Methyl) ethyl] -3-bromobenzene (7.0 g)
I got NMR (CDCl ₃ ) δ: 1.37 (9H, s, br), 1.59 (6H, s),
4.95 (1H, s, br), 7.15-7.38 (3H, m), 7.50-7.55 (1H, m)

(2) N-methyl-N-methyloxy-2
A solution of -amino-5-chlorobenzamide (3.21 g) and the compound obtained in (1) (3.14 g) in tetrahydrofuran (50 ml) was cooled to -78 ° C, and a hexane solution of n-butyllithium (1. 6 mol / l) (32 ml) was slowly added dropwise. After the addition was completed, water (100 ml) and ethyl acetate (100 ml) were added. After washing the organic layer with water,
It was dried over anhydrous MgSO ₄ and the solvent was distilled off. The remaining oily compound was separated and purified by silica gel column chromatography, and 2-amino-3 '-(1-te) as a pale yellow oily compound was obtained.
rt-butoxycarbonylamino-1-methyl) ethyl-
5-Chlorobenzophenone (1.5 g) was obtained. (3) To a solution of 2-amino-3 '-(1-tert-butoxycarbonylamino-1-methyl) ethyl-5-chlorobenzophenone (1.2 g) in methanol (20 ml) was added sodium borohydride (0.3 g). ) At room temperature for 30
Stirred for minutes. Ethyl acetate (100 ml) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was dissolved in methanol (20 ml) and 4-biphenylcarboxaldehyde (0.73 g) and acetic acid (0.7 ml).
25 g) and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (0.25 g) was added thereto, and
Stirred at 40 ° C. for 40 minutes. Acetic acid ethyl ester (50 ml)
Was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the desired colorless oily compound, 2- (4-biphenylmethylamino) -5-chloro-α- [3-[(1
-Tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] benzyl alcohol (1.5 g) was obtained. Ethyl acetate (2 g) of this compound (1.5 g)
(0 ml), 1N aqueous sodium hydroxide solution (10 ml) was added, monoethyl fumarate chloride (600 mg) was added, and the mixture was stirred for 1 hour under ice cooling. Acetic acid ethyl ester (30
ml), and the organic layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, the residue was dissolved in ethanol (25 ml), potassium carbonate (1 g) was added, and the mixture was stirred at 60 ° C for 2 hours. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give a colorless oily compound, 3,5-trans-5- [3-[(1-tert
-Butoxycarbonylamino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid ethyl ester (0.1
6g) and 3,5-cis-5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.25
g) and mixtures thereof (1.1 g) were obtained as colorless oils. 3,5-trans NMR (CDCl ₃ ) δ: 1.1-1.5 (18H, m), 2.90 (1H, d
d), 3.28 (1H, dd), 3.63 (1H, d), 4.15 (2H, q), 4.6-4.75
(2H, m), 5.00 (1H, m), 5.91 (1H, s), 6.8-7.7 (16H, m) 3
5-cis NMR (CDCl ₃ ) δ: 1.0-1.5 (18H, m), 2.77 (1H, d
d), 3.13 (1H, d), 4.13 (2H, q), 3.47 (1H, dd), 4.84 (1H,
d), 5.28 (1H, s), 5.53 (1H, d), 6.56 (1H, s), 6.9-7.7 (15
H, m)

(4) A mixture (1.1 g) of the 3,5-trans form and the 3,5-cis form obtained in (3) was dissolved in a mixed solvent of tetrahydrofuran (6 ml) and methanol (15 ml). A normal aqueous sodium hydroxide solution (8 ml) was added, and 6
Stirred at 0 ° C. for 40 minutes. After neutralization, ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ . The residue was separated and purified by silica gel column chromatography to give a colorless non-crystalline solid (0.6).
5 g) were obtained. To a solution of this compound (0.25 g) and 2-fluorobenzylamine (60 mg) in dimethylformamide (6 ml) were added diethyl cyanophosphate (75 mg) and triethylamine (60 mg), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water,
Dried over anhydrous MgSO ₄ . The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and two kinds of colorless oily compounds 3,5-trans-N- (2-fluorobenzyl) -5- [3-[(1-tert- Butoxycarbonylamino-1-methyl) ethyl] phenyl] -1-
(4-biphenylmethyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (A) (0.2 g), 3,5-cis-N- (2-fluorobenzyl) -5- [3 -[(1
-Tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide (B) (6
0 mg). 3,5-trans form (A) NMR (CDCl ₃ ) δ: 1.0-1.6 (15H, m), 2.72 (1H, d
d), 2.94 (1H, dd), 4.5 (3H, m), 4.78 (1H, d), 5.24 (1H,
s), 5.54 (1H, d), 6.33 (1H, t), 6.55 (1H, s), 6.8-7.7 (19
H, m) 3,5-cis form (B) NMR (CDCl ₃ ) δ: 1.34 (9H, brs), 1.58, 1.59 (each 3
H, s), 2.87 (1H, dd), 3.08 (1H, dd), 3.64 (1H, d), 4.35-
4.8 (4H, m), 4.98 (1H, s), 5.91 (1H, s), 6.5 (1H, m), 5.8-
7.6 (20H, m)

Example 93 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-Amino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride 4N hydrogen chloride of compound A (0.2 g) obtained in Example 92 Ethyl acetate (3 ml) was allowed to stand at room temperature for 30 minutes and then evaporated with a solvent to give a colorless amorphous solid (100 mg). NMR (CDCl ₃ ) δ: 1.36, 1.37 (3H, s), 2.73 (1H,
dd), 3.97 (1H, dd), 4.35-4.6 (3H, m), 4.9 (1H, d), 5.41
(1H, s), 5.46 (1H, d), 6.33 (1H, t), 6.54 (1H, d), 6.9-7.
6 (19H, m) Example 94 3,5-cis-N- (2-fluorobenzyl) -5
[3-[(1-amino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamido monohydrochloride The compound B (60 mg) obtained in Example 92 was prepared in Example 93.
By the same operation as described above, a colorless amorphous solid (45 mg) was obtained. NMR (CDCl ₃ ) δ: 1.51 (6H, s), 2.7-3.2 (4H, m),
3.63 (1H, d), 4.48 (2H, d), 4.62 (1H, d), 4.72 (1H, t), 5.
92 (1H, s), 6.65-7.7 (20H, m)

Example 95 3,5-trans-N- (4-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-1- (4-) obtained in Example 4 (2).
Biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0 .2g) and 4-fluorobenzylamine (0.05g) were reacted in the same manner as in Example 4 (3) to give the title compound (0.22g) as a colorless oil. NMR (CDCl ₃ ) δ: 1.433 (9H, s), 2.73 (1H, dd, J =
5.6,15.8Hz), 2.95 (1H, dd, J = 7.6,15.8Hz), 4.0-4.6 (5H,
m), 4.73 (1H, m), 4.90 (1H, d, J = 14.4Hz), 5.362 (1H, s),
5.45 (1H, d, J = 14.8Hz), 6.24 (1H, m), 6.50 (1H, d, J = 2Hz),
6.8-7.7 (19H, m) Example 96 3,5-trans-N- (4-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-aminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride The compound obtained in Example 95 (0.22
g) was dissolved in ethyl acetate (3 ml), 4N hydrochloric acid (ethyl acetate solution) (2 ml) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated, and crystals obtained from the residue were recrystallized from ethanol and ethyl acetate to obtain the title compound (0.18 g). 268-270 ° C NMR (CDCl ₃ ) δ: 2.67 (1H, dd, J = 6.4,18Hz), 2.9
2 (1H, dd, J = 8.6,15.8Hz), 4.04 (2H, s), 4.27 (2H, d, J = 5.2H
z), 4.49 (1H, m), 5.18 (1H, d, J = 15.8Hz), 5.40 (1H, d, J = 1
5.8Hz), 5.568 (1H, s), 6.40 (1H, d, J = 2Hz), 7.0-7.7 (19
H, m), 8.32 (2H, m), 8.58 (1H, m)

Example 97 N- (2-Fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2,3-dihydro-2
-Oxo-1H-1,4-benzodiazepine-3-acetamide (1) N- (9-fluorenylmethyl) oxycarbonyl-D, L-aspartic acid β-methyl ester (0.
A solution of 5 g) in tetrahydrofuran (2.5 ml) was cooled on ice, N-methylmorpholine (0.2 g) and ethyl chloroformate (0.2 g) were added thereto, and the mixture was stirred at 0 ° C for 20 minutes. Then, 2-amino-3'-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.4
g) in tetrahydrofuran (3 ml) was added and stirred at room temperature overnight. After adding water (100 ml) and extracting with ethyl acetate, the extract was washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give a colorless oily compound (0.27).
g) was obtained. A solution of this compound (0.27 g) and piperidine (0.15 ml) in dimethylformamide (3 ml) was stirred at room temperature for 10 minutes, and ethyl acetate (50 ml) was added.
Was washed with water, the organic layer was dried over anhydrous Na ₂ SO ₄ , and the solvent was distilled off. The residue was treated with dimethylformamide (3 ml)
Then, acetic acid (0.15 ml) was added, and the mixture was stirred at 60 ° C for 1 hour. Ethyl acetate (100 ml) was added, washed with water, dried over anhydrous Na ₂ SO ₄ , the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
Colorless amorphous solid 5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3
-Acetic acid methyl ester (90 mg) was obtained. NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.19 (1H, dd, J = 6.
4,17.0Hz), 3.45 (1H, dd, J = 7.6,17.0Hz), 3.74 (3H, s),
4.16 (1H, dd, J = 6.4,7.6Hz), 4.34 (2H, d, J = 6.0Hz), 4.85-
5.00 (1H, br), 7.12 (1H, d, J = 8.6Hz), 7.27-7.52 (5H, m),
8.01 (1H, s), 8.7-8.9 (1H, br)

(2) To a solution of the compound obtained in (1) (120 mg) in dimethylformamide (1 ml) was added 4-chloromethylbiphenyl (57 mg), sodium iodide (8 mg),
Potassium carbonate (53 mg) was added, and the mixture was stirred with heating at 60 ° C for 1 hour. Ethyl acetate (50 ml) was added, the mixture was washed with water, and the organic layer was dried over anhydrous Na ₂ SO ₄ .
The residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound (0.10 g). NMR (CDCl ₃ ) δ: 1.45 (9H, s),
3.21 (1H, dd, J = 6.0, 17.0 Hz),
3.59 (1H, dd, J = 8.2, 17.0H
z), 3.75 (3H, s), 4.21-4.28
(3H, m), 4.72-4.83 (1H, br),
4.81 (1H, d, J = 15.6 Hz), 5.6
2 (1H, d, J = 15.6 Hz), 6.98-7.
51 (16H, m) (3) 1N sodium hydroxide aqueous solution (0.2 ml) was added to methanol (1 ml) of the compound (0.1 g) obtained in (2).
Was added and stirred at 60 ° C. for 1 hour. After neutralization, ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.10 g). To a solution of this compound (0.1 g) and 2-fluorobenzylamine (22 mg) in dimethylformamide (1 ml) were added diethyl cyanophosphate (29 mg) and triethylamine (24 mg), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
An amorphous solid (0.12 g) was obtained. NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.12 (1H, dd, J = 6.
6,14.8Hz), 3.31 (1H, dd, J = 7.0,14.8Hz), 4.11-4.30 (3H,
m), 4.47 (1H, dd, J = 5.0,15.0Hz), 4.63 (1H, dd, J = 5.8,15.
0Hz), 4.65-4.75 (1H, br), 4.76 (1H, d, 15.4Hz), 5.62 (1
(H, d, J = 15.4Hz), 6.55-6.65 (1H, br), 6.97-7.44 (20H, m)

Example 98 N- (2-Fluorobenzyl) -5- (3-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2,3-dihydro-2-oxo-1H- 1,4-
Benzodiazepine-3-acetamide monohydrochloride The compound (0.12 g) obtained in Example 97 was dissolved in 4N hydrogen chloride in acetic acid ethyl ester (2 ml), left for 30 minutes, and then the solvent was distilled off. A colorless amorphous solid (84 mg) was obtained. NMR (CDCl ₃ ) δ: 3.18-3.32 (2H, m), 4.04 (2H,
s), 4.42 (1H, t, J = 7.0Hz), 4.47 (2H, s), 4.93 (1H, d, J = 15.
4 Hz), 5.68 (1H, d, J = 15.4 Hz), 7.03-7.77 (20H, m) Example 99 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro- 3- (2-fluorobenzyl) aminomethyl-1-neopentyl-
1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one 3,5-trans-3-aminomethyl-5- (3-tert- obtained in Example 35 (2). (Butoxycarbonylaminomethylphenyl) -7-chloro-1-neopentyl-
Acetic acid (27 mg) and 2-fluorobenzaldehyde (8) were added to a solution of 1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one (0.11 g) in methanol (2 ml).
0 mg), sodium cyanoborohydride (29 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water, and the organic layer was dried over anhydrous N.
a ₂ SO ₄ dried. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound (40 mg). NMR (CDCl ₃ ) δ: 0.91 (9H, s), 1.45 (9H, s), 2.9
7 (1H, dd, J = 6.2,12.0Hz), 3.10 (1H, dd, J = 6.0,12.0Hz), 3.
32 (1H, d, J = 14.0Hz), 3.85 (2H, s), 4.01 (1H, t, J = 6.2Hz),
4.36 (2H, d, J = 6.2Hz), 4.49 (1H, d, J = 14.0Hz), 4.87-4.9
5 (1H, br), 5.99 (1H, s), 6.57 (1H, d, J = 2.2Hz), 6.96-7.4
1 (10H, m)

Example 100 3,5-trans-5- (3-aminomethylphenyl)
-7-Chloro-3- (2-fluorobenzyl) aminomethyl-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one dihydrochloride Example 99 The obtained compound (40 mg) was dissolved in 4N hydrogen chloride in ethyl acetate (1 ml), left for 30 minutes, and the solvent was distilled off to obtain a colorless amorphous solid (35 mg). NMR (CDCl ₃ ) δ: 0.95 (9H, s), 3.42-3.62 (3H,
m), 4.20 (2H, s), 4.28-4.33 (1H, m), 4.37 (2H, s), 4.38-
4.49 (1H, m), 6.13 (1H, s), 6.57 (1H, s), 7.23-7.63 (10H,
m) Example 101 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-hydroxybenzyl)-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide The compound obtained in Example 57 (0.65 g) was subjected to ethyl acetate (20 ml) and methanol (10 ml). And a catalytic hydrogen reduction reaction was carried out at room temperature and pressure using 10% palladium-carbon (0.1 g) as a catalyst. The catalyst was removed by filtration, washed with water, and the organic layer was dried over anhydrous Na ₂ SO _{4. The} solvent was distilled off to give a colorless amorphous solid (0.48).
g) was obtained. NMR (CDCl ₃ ) δ: 1.4 (9H, m), 2.68 (1H, dd), 2.8
8 (1H, dd), 4.0-4.65 (5H, m), 4.81 (1H, s), 4.9-5.1 (2H,
m), 5.7-6.5 (4H, m), 6.65-7.6 (14H, m)

Example 102 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(4-hydroxybenzyl) -2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide monohydrochloride The compound (0.22 g) obtained in Example 101 was dissolved in 4N hydrogen chloride in ethyl acetate (5 ml), and the solution was added.
After standing for 1 minute, the solvent was distilled off to obtain a colorless amorphous solid (0.21 g). NMR (CDCl ₃ ) δ: 2.8 (2H, m), 3.7-4.1 (4H, m),
4.3-4.65 (4H, m), 4.85 (1H, s), 4.91 (1H, d), 5.63 (1H,
d), 6.41 (1H, d), 6.5-7.5 (14H, m) Example 103 3,5-trans-N- (2-fluorobenzyl) -1
-(4-acetyloxybenzyl) -5- (3-aminomethylphenyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide monohydrochloride To a solution of the compound obtained in Example 101 (100 mg) in dichloromethane (8 ml) was added acetic anhydride (0.2 ml) and triethylamine (0.2 ml), and the mixture was stirred at room temperature for 40 minutes.
The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain an oily compound (80 mg).
This was mixed with 4N hydrogen chloride in ethyl acetate (2m
After dissolving in l) and allowing to stand for 30 minutes, the solvent was distilled off to obtain a colorless amorphous solid (70 mg). NMR (CDCl ₃ ) δ: 2.30, 2.29 (3H, each s), 2.5-3.0
(2H, m), 3.83 (2H, m), 4.2-4.6 (3H, m), 4.73,4.92 (1H, each
d, J = 15.0Hz), 5.23, 5.29 (1H, each s), 5.47, 5.
68 (1H, each d, J = 15.0 Hz), 6.3
7.5 (15H, m)

Example 104 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-2-oxo-1- [4-[(3-phenoxypropyl) oxy] benzyl] -1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide monohydrochloride To a solution of the compound obtained in Example 101 (100 mg) in dimethylformamide (4 ml) was added 3-phenoxypropyl bromide (40 mg) and potassium carbonate (50 mg).
The mixture was heated and stirred at 80 ° C. for 1 hour. Acetic acid ethyl ester (5
0 ml), washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound (0.09 g). This was dissolved in 4N hydrogen chloride in ethyl acetate (2 ml), left at room temperature for 30 minutes, and the solvent was distilled off to obtain a colorless amorphous solid (65 mg). NMR (CDCl ₃ ) δ: 1.82 (2H, br), 1.97 (4H, m), 2.
72 (1H, dd), 2.92 (1H, dd), 3.83 (2H, s), 4.02 (4H, m), 4.
35-4.6 (3H, m), 4.7 (1H, d), 5.33 (1H, s), 5.43 (1H, d),
6.33 (1H, t), 6.49 (1H, d), 6.75-7.4 (19H, m) Example 105 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-2-oxo-1- (4-pivaloyloxybenzyl) -1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide monohydrochloride To a solution of the compound obtained in Example 101 (110 mg) in dichloromethane (10 ml) was added pivaloyl chloride (30 mg) and triethylamine (30 mg), and the mixture was stirred at room temperature for 20 minutes. Thereafter, the same operation as in Example 104 was carried out to obtain a colorless amorphous solid (78 mg). NMR (CDCl ₃ ) δ: 1.30 (9H, s),
2.63 (1H, dd), 2.87 (1H, dd),
4.03 (2H, s), 4.30 (2H, d),
4.44 (1H, t), 4.98 (1H, d),
5.43 (1H, d), 5.44 (1H, s),
6.36 (1H, d), 7.0-7.7 (14H,
m), 8.2-8.7 (3H, m)

Example 106 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(4-ethoxycarbonylmethyloxybenzyl) -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride To a solution of the compound obtained in Example 101 (100 mg) in acetonitrile (5 ml) was added ethyl bromoacetate. (30 mg) and potassium carbonate (35 mg) were added, and the mixture was heated under reflux for 1.5 hours.
Thereafter, the same operation as in Example 104 was performed to obtain a colorless amorphous solid (55 mg). NMR (CDCl ₃ ) δ: 1.27 (3H, s), 2.5-3.0 (4H, m),
3.85 (2H, s), 4.25 (2H, q), 4.5 (3H, m), 4.59 (2H, s), 4.7
2 (1H, d), 5.31 (1H, s), 5.42 (1H, d), 6.49 (1H, d), 6.75-
7.5 (14H, m)

Example 107 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
[4- (N, N-dimethylcarbamoylmethyloxy)
[Benzyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide.1
Hydrochloride To a solution of the compound obtained in Example 101 (130 mg) in acetonitrile (10 ml) was added dimethylcarbamoyl chloride (30 mg).
mg) and potassium carbonate (50 mg), and the mixture was stirred at 50-70 ° C for 3 hours. Thereafter, the same operation as in Example 104 was carried out to obtain a colorless amorphous solid (90 mg). NMR (CDCl ₃ ) δ: 2.3 (2H, br), 2.72 (1H, dd), 2.
93 (1H, dd), 3.00 (3H, s), 3.08 (3H, s), 3.83 (2H, br), 4.3
-4.6 (3H, m), 4.67 (1H, d), 5.29 (1H, s), 5.52 (1H, d), 6.
5 (2H, m), 6.9-7.4 (14H, m) Example 108 3,5-trans-N- (2-fluorobenzyl) -1
-[4- (2-acetoxyethyloxy) benzyl]-
5- (3-aminomethylphenyl) -7-chloro-2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride Dimethyl of the compound (100 mg) obtained in Example 101 and acetic acid 2-bromoethyl ester (30 mg) Sodium hydride (60% inoil, 8m) was added to formamide (8ml) solution.
g) was added and stirred at 70 ° C. for 30 minutes. Example 10 below
By the same operation as in 4, a colorless amorphous solid (18 mg) was obtained. NMR (CDCl ₃ ) δ: 2.09 (3H, s), 2.73 (1H, dd),
2.93 (1H, dd), 4.1-4.6 (9H, m), 4.73 (1H, d), 5.36 (1H,
s), 5.40 (1H, d), 6.48 (1H, t), 6.5 (1H, d), 6.8-7.5 (14
H, m)

Example 109 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
[4- (2-hydroxyethyloxy) benzyl] -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride Intermediate 3,5-trans-N- (2
-Fluorobenzyl) -1- [4- (2-acetoxyethyloxy) benzyl] -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5- Tetrahydro-4,1-benzoxazepine-3-acetamide (70 mg) was added to a mixed solvent of tetrahydrofuran (1 ml) and methanol (4 ml).
A normal aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at 60 ° C for 30 minutes. Ethyl acetate was added, washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off to obtain colorless crystals (52 mg) having a melting point of 170-172 ° C. This compound was subjected to the same operation as in Example 104 to obtain a colorless amorphous solid (36 mg). NMR (CDCl ₃ ) δ: 2.24 (2H, m), 2.73 (1H, dd),
2.93 (1H, dd), 3.7-4.6 (9H, m), 4.73 (1H, d), 5.35 (1H,
s), 5.40 (1H, d), 6.38 (1H, t), 6.5 (1H, d), 6.7-7.5 (14
H, m)

Example 110 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-carboxymethyloxybenzyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride Intermediate 3,5-trans-N- (2
-Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4
-Ethoxycarbonylmethyloxybenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.12 g) in tetrahydrofuran (2 ml) and methanol (5 ml). Dissolve in a mixed solvent and add 1N aqueous sodium hydroxide solution (2 ml)
Was added and stirred at 60 ° C. for 40 minutes. After neutralization, the mixture was extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was subjected to the same operation as in Example 104 to give
A colorless amorphous solid (58 mg) was obtained. NMR (CDCl ₃ ) δ: 2.4-3.0 (2H, m), 3.70 (2H, m),
4.0-4.6 (4H, m), 4.77 (2H, s), 5.72 (1H, d, J = 15Hz), 6.2
-7.6 (15H, m) Example 111 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(4-methoxycarbonylmethyloxybenzyl) -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride To a solution of the compound obtained in Example 101 (200 mg) in acetonitrile (8 ml) was added methyl bromoacetate. (55 mg) and potassium carbonate (100 mg) were added, and the mixture was stirred at 70 ° C. for 1.5 hours. Thereafter, a colorless amorphous solid (43 mg) was obtained in the same manner as in Example 104. NMR (CDCl ₃ ) δ: 2.72 (1H, dd), 2.92 (1H, dd),
3.78 (3H, s), 3.85 (2H, br), 4.3-4.55 (3H, m), 4.61 (2H,
s), 4.7 (1H, d), 5.31 (1H, s), 5.43 (1H, d), 6.4 (1H, t),
6.5 (1H, d), 6.75-7.4 (14H, m)

Example 112 3,5-trans-N- (2-fluorobenzyl) -5
-(3-acetylaminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide Obtained in Example 6. Compound (0.1 g) in pyridine (1 ml)
Acetic anhydride (20 mg) and dimethylaminopyridine (5 mg) were added to the solution, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give a colorless amorphous solid (7
2 mg) were obtained. NMR (CDCl ₃ ) δ: 0.91 (9H, s), 2.04 (3H, s), 2.
69 (1H, dd, J = 6.0,14.8Hz), 2.88 (1H, dd, J = 7.2,14.8Hz),
3.35 (1H, d, J = 14.0Hz), 4.35-4.59 (6H, m), 5.75-5.88 (1
H, br), 5.98 (1H, s), 6.27-6.39 (1H, br), 6.57 (1H, d, J =
2.2Hz), 6.97-7.40 (10H, m) Example 113 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-5- (3-methanesulfonylaminomethylphenyl) -1-neopentyl-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide To a solution of the compound obtained in Example 6 (0.1 g) in ethyl acetate (1 ml) was added triethylamine (44 mg) and methanesulfonyl chloride (22 mg), and the mixture was stirred at room temperature for 30 minutes. Thereafter, the same operation as in Example 112 was carried out to obtain a colorless amorphous solid (75 mg). NMR (CDCl ₃ ) δ: 0.92 (9H, s), 2.70 (1H, dd, J =
5.4,14.6Hz), 2.88 (3H, s), 2.88 (1H, dd, J = 7.0,14.6Hz),
3.36 (1H, d, J = 14.0Hz), 4.33-4.59 (6H, m), 4.75-4.85 (1
H, br), 6.00 (1H, s), 6.28-6.38 (1H, br), 6.51 (1H, d, J =
1.8Hz), 7.03-7.40 (10H, m)

Example 114 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-1-neopentyl-2-oxo-5- (3-
Trifluoroacetylaminomethylphenyl) -1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide A colorless amorphous solid (64 mg) was obtained in the same manner as in Example 112, using the compound (100 mg) obtained in Example 6 and trifluoroacetic anhydride (40 mg). NMR (CDCl ₃ ) δ: 0.91 (9H, s), 2.69 (1H, d, J = 6.
0,14.4Hz), 2.88 (1H, dd, J = 7.2,14.4Hz), 3.35 (1H, d, J = 1
3.6Hz), 4.38-4.57 (6H, m), 5.98 (1H, s), 6.28-6.38 (1H,
br), 6.54 (1H, d, J = 2.2Hz), 6.65-6.75 (1H, br), 6.96-7.
41 (10H, m) Example 115 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-5- (3-methoxycarbonylaminomethylphenyl) -1-neopentyl-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide To a solution of the compound (100 mg) obtained in Example 6 in tetrahydrofuran (1 ml) was added triethylamine (44 mg) and methoxycarbonyl chloride (18 mg), and the mixture was stirred at 0 ° C for 30 minutes. Thereafter, the same operation as in Example 112 was performed to obtain a colorless amorphous solid (67 mg). NMR (CDCl ₃ ) δ: 0.92 (9H, s), 2.69 (1H, dd, J =
5.8,14.2Hz), 2.88 (1H, dd, J = 7.2,14.2Hz), 3.35 (1H, d, J
= 14.0Hz), 3.70 (3H, s), 4.37-4.51 (6H, m), 4.95-5.05 (1
H, br), 5.98 (1H, s), 6.25-6.35 (1H, br), 6.56 (1H, d, J =
2.2Hz), 6.98-7.39 (10H, m)

Example 116 3,5-trans-N- (2-fluorobenzyl) -7
-Chloro-5- (3-methylureidomethylphenyl)
-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide To a solution of the compound obtained in Example 6 (100 mg) in tetrahydrofuran (3 ml) was added triethylamine. (44 mg) and triphosgene (28 mg) was added with stirring at 0 ° C. The mixture was further stirred at 0 ° C. for 30 minutes, a 30% aqueous solution of methylamine (0.038 ml) was added, and the mixture was further stirred at 0 ° C. for 30 minutes. Thereafter, a colorless amorphous solid (80 mg) was obtained in the same manner as in Example 112. NMR (CDCl ₃ ) δ: 0.91 (9H, s), 2.70 (1H, dd, J =
5.4,13.8Hz), 2.75,2.78 (3H, each s), 2.86 (1H, dd, J = 7.2,1
3.8Hz), 3.35 (1H, d, J = 13.6Hz), 4.38-4.50 (7H, m), 4.75-
4.85 (1H, br), 5.97 (1H, s), 6.35-6.50 (1H, br), 6.57 (1
(H, d, J = 2.2Hz), 6.96-7.34 (10H, m) Example 117 3,5-trans-N- (2-fluorobenzyl) -5
-(3-acetylaminomethylphenyl) -1- (4-
(Biphenylmethyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide The compound (40 mg) obtained in Example 5 and acetic anhydride (0.1 m
Using l) and the same operation as in Example 112, colorless crystals (38 mg) having a melting point of 168-170 ° C were obtained. NMR (CDCl ₃ ) δ: 1.95 (3H, s), 2.73 (1H, dd, J =
5.8,16Hz), 2.95 (1H, dd, J = 7.4,15.8Hz), 4.34 (2H, d, J =
5.8Hz), 4.35-4.65 (3H, m), 4.87 (1H, d, J = 14.6Hz), 5.37
(1H, s), 5.47 (1H, d, J = 14.6Hz), 5.63 (1H, m), 6.38 (1H,
m), 6.50 (1H, d, J = 2.2Hz), 6.9-7.7 (21H, m)

Example 118 3,5-trans-N- (2-fluorobenzyl) -1
-(4-aminobenzyl) -5- (3-N-tert-butoxycarbonylaminomethylphenyl) -7-chloro-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide To a solution of the compound obtained in Example 58 (1 g) in ethyl acetate (20 ml) was added 10% palladium. Carbon (0.1
Using g) as a catalyst, a catalytic hydrogen reduction reaction was carried out at normal temperature and normal pressure. The catalyst was removed by filtration, and the solvent was distilled off.
7 g) were obtained. NMR (CDCl ₃ ) δ: 1.28 (9H, s), 2.69 (1H, dd),
2.89 (1H, dd), 3.7-4.6 (6H, m), 5.13 (1H, s), 5.27 (1H,
m), 5.60 (1H, d), 6.34 (1H, m), 6.47 (1H, d), 6.5-7.5 (14
H, m) Example 119 3,5-trans-N- (2-fluorobenzyl) -1
-(4-acetylaminobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide monohydrochloride To a solution of the compound obtained in Example 118 (0.15 g) in dichloromethane (5 mL) was added acetic anhydride (0.1 mL) and triethylamine (0.1 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oil (0.12 g).
This compound was treated with 4N hydrogen chloride in ethyl acetate (1
ml), and the mixture was left at room temperature for 40 minutes. The solvent was distilled off to obtain a colorless amorphous solid (54 mg). NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.72 (1H, dd),
2.90 (1H, dd), 3.85 (2H, br), 4.3-4.6 (3H, m), 4.67 (1H,
d), 5.25 (1H, s), 5.48 (1H, d), 6.41 (1H, t), 6.48 (1H,
d), 6.8-7.9 (15H, m)

Example 120 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(4-methanesulfonylaminobenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride The compound obtained in Example 118 (0.15 g) ) In dichloromethane (5 ml) was added to methanesulfonyl chloride (0.05).
g) and triethylamine (0.04 g) were added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the same operation as in Example 119 was carried out to obtain a colorless amorphous solid (70 mg). NMR (CDCl ₃ ) δ: 2.72 (1H, dd), 2.94 (1H, dd),
3.39 (3H, s), 3.83 (2H, br), 4.3-4.6 (3H, m), 4.85 (1H,
d), 5.34 (1H, s), 5.47 (1H, d), 6.33 (1H, t), 6.53 (1H,
t), 6.9-7.5 (14H, m) Example 121 3,5-trans-N- (2-fluorobenzyl) -5
-(3-N-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-dimethylaminobenzyl) -2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide 2-amino-5-chloro-α- (3-te
A colorless oily compound (0.2 g) was obtained in the same manner as in Example 1 using (rt-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) and 4-dimethylaminobenzaldehyde (0.23 g). NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.6-3.0 (2H, m),
2.93 (6H, s), 4.23 (2H, d, J = 5.8Hz), 4.35-4.7 (4H, m),
4.95 (1H, m), 5.25 (1H, s), 5.47 (1H, d, J = 14.2Hz), 6.40 (1
H, t), 6.45 (1H, d, J = 1.6Hz), 6.6-7.4 (14H, m)

Example 122 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(4-dimethylaminobenzyl) -2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide dihydrochloride NMR (CDCl ₃ ) δ: 2.72 (1H, dd), 2.93 (6H, s),
3.82 (2H, m), 4.35-4.7 (4H, m), 5.28 (1H, s), 5.47 (1H, d,
J = 14.4Hz), 6.42 (1H, t), 6.47 (1H, d, J = 2Hz), 6.55-7.5
(14H, m) Example 123 3,5-trans-N- (2-fluorobenzyl) -5
-[3- (3-tert-butoxycarbonylaminopropyl) aminomethylphenyl] -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide Compound 3,5-trans-N obtained in (7) of Example 41
-(2-Fluorobenzyl) -7-chloro-5- (3-
(Formylphenyl) -1-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.2 g) and N-Boc-1,3
-A colorless amorphous solid (0.2 mg) was obtained using diaminopropane (71 mg) in the same manner as in (8) of Example 41.
8 g) were obtained. NMR (CDCl ₃ ) δ: 0.92 (9H, s), 1.43 (9H, s), 1.
61-1.70 (2H, m), 2.66-2.75 (3H, m), 2.89 (1H, dd, J = 7.0,1
4.2Hz), 3.18-3.26 (2H, m), 3.35 (1H, d, J = 13.8Hz), 3.79
(2H, s), 4.38-4.51 (4H, m), 5.10-5.15 (1H, br), 5.99 (1
H, s), 6.30-6.45 (1H, br), 6.59 (1H, d, J = 2.2Hz), 7.02-
7.38 (10H, m)

Example 124 3,5-trans-N- (2-fluorobenzyl) -5
-[3- (3-aminopropyl) aminomethylphenyl] -7-chloro-1-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide dihydrochloride The compound (0.20 g) obtained in Example 123 was dissolved in 4N hydrogen chloride in ethyl acetate (3 ml). ) And left at room temperature for 30 minutes, and then the solvent was distilled off to obtain a colorless amorphous solid (0.16 g). NMR (CDCl ₃ ) δ: 0.95 (9H, s), 2.01-2.20 (2H,
m), 2.77-2.85 (2H, m), 3.20-3.22 (4H, m), 3.75 (1H, d, J =
14.6Hz), 4.24 (2H, s), 4.42-4.48 (4H, m), 6.06 (1H, s),
6.49 (1H, d, J = 2.2 Hz), 7.01-7.59 (10H, m) Example 125 3,5-trans-N- (2-fluorobenzyl) -5
-(3-aminoacetylaminomethylphenyl) -1-
Benzyl-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride The compound (80 mg) obtained in Example 2 and N
To a solution of -Boc-glycine (40 mg) in dimethylformamide (3 ml) were added diethyl cyanophosphate (50 mg) and triethylamine (0.05 ml), and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the obtained oily compound (70 mg) was dissolved in a 4N solution of hydrogen chloride in ethyl acetate (2 ml), and the solution was allowed to stand at room temperature for 30 minutes. (47 mg) was obtained. NMR (CDCl ₃ ) δ: 2.72 (1H, dd), 2.93 (1H, dd),
3.41 (2H, s), 4.3-4.6 (5H, m), 4.85 (1H, d), 5.37 (1H, s),
5.93 (1H, d), 6.41 (1H, t), 6.50 (1H, d), 6.9-7.7 (16H,
m)

Example 126 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -7-chloro-2-oxo-5- [3-[(piperidin-4-yl) carbonylaminomethyl] phenyl] -1,2,3,5-tetrahydro-4,1- Benzoxazepine-3-acetamide ・ 1
Hydrochloride To a solution of the compound obtained in Example 5 (0.1 g) and N-Boc-piperidine-4-carboxylic acid (42 mg) in dimethylformamide (5 ml), diethyl cyanophosphate (30 mg).
And triethylamine (0.03 ml).
Stirred for minutes. Hereinafter, by the same operation as in Example 125,
A colorless amorphous solid (70 mg) was obtained. NMR (CDCl ₃ ) δ: 1.4-2.3 (5H, m), 2.5-3.2 (6H,
m), 4.2-4.6 (5H, m), 4.88 (1H, d, J = 14.6Hz), 5.37 (1H,
s), 5.45 (1H, d, J = 14.6Hz), 5.86 (1H, m), 6.48 (1H, d, J =
1.8Hz), 6.55 (1H, m), 6.8-7.7 (19H, m)

Example 127 3,5-trans-N- (2-fluorobenzyl) -5
-[2- (3-aminopropyloxy) phenyl] -7
-Chloro-1-isobutyl-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride (1) 3,5-trans-7-chloro-5- (2-hydroxyphenyl) -1-isobutyl-2-oxo-1 ,
In a solution of 2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.8 g) in dimethylformamide (15 ml), bromopropylphthalimide (0.6 g) and potassium carbonate (0.5 g) were added. 38g)
The mixture was heated and stirred at 60 ° C. for 4 hours. Acetic acid ethyl ester (5
0 ml), washed with water and dried over anhydrous Na ₂ SO _{4. The} solvent was distilled off to obtain a residue (1.1 g). This was dissolved in ethanol (20 ml), and hydrazine monohydrate (0.2 m
l) was added and the mixture was heated and stirred at 60 to 70 ° C for 3 hours. The insoluble material was removed by filtration, the solvent of the filtrate was distilled off, the residue was dissolved in tetrahydrofuran (20 ml), di-tert-butyl dicarbonate (0.46 g) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give a colorless oily compound, 3,5-trans-5- [2- (3-tert-butoxycarbonylaminopropyloxy) phenyl] -1-. Isobutyl-2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.0 g) was obtained. NMR (CDCl ₃ ) δ: 0.92 (3H, d), 0.99 (3H, d), 1.
26 (3H, t), 1.42 (9H, s), 1.66 (2H, m), 2.0 (1H, m), 2.5-3.
0 (3H, m), 3.45 (1H, dd), 3.7-4.0 (2H, m), 4.15 (2H, dq),
4.28 (1H, m), 4.42 (1H, dd), 6.09 (1H, s), 6.65 (1H, d),
6.8-7.7 (6H, m)

(2) The compound (0.8 g) obtained in (1) was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and methanol (10 ml), and 1N aqueous sodium hydroxide solution (4
ml), and the mixture was heated and stirred at 60-70 ° C for 1 hour. After neutralization, the mixture was extracted with ethyl acetate (30 ml), the extract was dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The obtained amorphous solid (0.15 g) was treated with dimethylformamide (6 m
l) To the solution were added 2-fluorobenzylamine (40 mg), triethylamine (0.05 ml) and diethyl cyanophosphate (60 mg), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (30 ml) was added, and after washing with water, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound (0.18 g). This compound (0.18 g)
Was dissolved in 4N hydrogen chloride in ethyl acetate (4 ml), left for 30 minutes, and the solvent was distilled off.
A colorless amorphous solid (0.1 g) was obtained. NMR (CDCl ₃ ) of free form: 0.92 (3H, d), 0.98
(3H, d), 1.5-2.5 (5H, m), 2.72 (1H, dd), 2.87 (1H, dd), 3.
42 (1H, m), 3.8-4.7 (8H, m), 6.07 (1H, s), 6.57 (1H, m),
6.62 (1H, d), 6.8-7.6 (10H, m)

Example 128 3,5-trans-N- (2-fluorobenzyl) -5
-[4- (3-Aminopropyloxy) -2-methoxyphenyl] -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3 -Acetamide monohydrochloride (1) 3,5-trans-7-chloro-5- (4-hydroxy-2-methoxyphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (3.0
g) and bromopropylphthalimide (1.8 g), and the same procedure as in (1) of Example 127, was carried out, to give a melting point of 1
Colorless crystals at 18-120 ° C 3,5-trans-5-
[4- (3-tert-butoxycarbonylaminopropyloxy) -2-methoxyphenyl] -1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3- Acetic acid ethyl ester (1.7
g) was obtained. (2) The compound (1.0 g) obtained in (1) was prepared in Example 127.
The compound having a melting point of 158-160 ° C. (0.15
g) and 2-fluorobenzylamine (40 mg),
By the same operation as in Example 127 (2), a colorless amorphous solid (0.125 g) was obtained. NMR (CDCl ₃ ) δ of free form: 0.91 (9H, s), 1.8-
2.2 (4H, m), 2.6-3.1 (4H, m), 3.33 (1H, d), 3.59 (3H, s),
4.3-4.6 (4H, m), 6.18 (1H, s), 6.4-7.5 (10H, m) Melting point of free form: 90-95 ° C

Example 129 3,5-trans-1- (4-biphenylmethyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-3- [1- (4-fluorophenyl) piperazin-4-yl-carbonylmethyl] -1,
2,3,5-Tetrahydro-4,1-benzoxazepin-2-one To a solution of the compound (0.15 g) obtained in Example 4, (2) in dimethylformamide (6 ml) was added 1- (4- (Fluorophenyl) piperazine (52 mg), triethylamine (0.04 g) and diethyl cyanophosphate (50 mg) were added, and the mixture was stirred at room temperature for 20 minutes. Acetic acid ethyl ester (50
ml), washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to give a colorless, colorless, amorphous solid (0.13 g).
I got NMR (CDCl ₃ ) δ of free form: 1.44 (9H, s), 2.80
(1H, dd), 2.9-3.4 (5H, m), 3.6-3.9 (4H, m), 4.22 (2H, d),
4.63 (1H, dd), 4.90 (1H, d, J = Hz), 5.36 (1H, s), 5.50 (1
H, d, J = 14.8Hz), 6.49 (1H, s), 6.8-7.7 (19H, m) Example 130 3,5-trans-5- (3-aminomethylphenyl)
-1- (4-biphenylmethyl) -7-chloro-3-
[1- (4-Fluorophenyl) piperazin-4-yl-carbonylmethyl] -1,2,3,5-tetrahydro-
4,1-benzoxazepin-2-one monohydrochloride The compound (0.12 g) obtained in Example 129 was dissolved in 4N hydrogen chloride in ethyl acetate (2 ml) and left at room temperature for 30 minutes. The solvent was distilled off to obtain a colorless amorphous solid (0.11 g). NMR (CDCl ₃ ) δ: 2.5-3.4 (8H, m), 3.6-3.9 (6H,
m), 4.63 (1H, dd), 4.90 (1H, d, J = 14.8Hz), 5.38 (1H, s),
5.50 (1H, d, J = 14.8Hz), 6.51 (1H, s), 6.8-7.6 (19H, m)

Example 131 3,5-trans-1- (4-biphenylmethyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-3- (4-phenylpiperidine-1
-Yl-carbonylmethyl) -1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one The compound (0.15 g) obtained in (2) of Example 4 and 4-phenylpiperidine (42 mg) and a colorless amorphous solid (0.14 g) was obtained in the same manner as in Example 128. NMR (CDCl ₃ ) δ: 1.1-2.0 (4H, m), 1.44 (9H, s),
2.5-3.4 (5H, m), 4.0-4.3 (3H, m), 4.6-5.0 (3H, m), 5.37
(1H, s), 5.53 (1H, m), 6.49 (1H, s), 6.9-7.7 (20H, m) Example 132 3,5-trans-5- (3-aminomethylphenyl)
-1- (4-biphenylmethyl) -7-chloro-3-
(4-phenylpiperidin-1-yl-carbonylmethyl) -1,2,3,5-tetrahydro-4,1-benzoxazepin-2-one monohydrochloride Obtained in Example 131 (0.1 g ) A colorless amorphous solid (0.07 g) was obtained in the same manner as in Example 129. NMR (CDCl ₃ ) δ: 1.4-2.0 (4H, m), 2.55-3.4 (6
H, m), 3.79 (2H, br), 4.65 (1H, m), 4.9 (1H, dd), 5.40 (1
H, s), 5.55 (1H, dd), 6.52 (1H, d, J = 1.8Hz), 6.9-7.65 (20
H, m)

Example 133 3,5-Trans-N- (2-fluorobenzyl) -7
-Chloro-1- (3,3-dimethylbutyl) -2-oxo-5- (3-tritylaminomethylphenyl) -1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (A), 3,5-cis-N- (2-
(Fluorobenzyl) -7-chloro-1- (3,3-dimethylbutyl) -2-oxo-5- (3-tritylaminomethylphenyl) -1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamide (B) (1) N-methyl-N-methyloxy-2-amino-5
-Chlorobenzamide (3.22 g) and N-trityl-
A solution of 3-bromobenzylamine (4.28 g) in tetrahydrofuran (30 ml) was cooled to -78 DEG C.
-Butyl lithium hexane solution (1.6 mol / l) (31
ml) was slowly added dropwise. After the addition was completed, water (70 ml) and ethyl acetate (100 ml) were added. The organic layer was washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The remaining oily compound was separated and purified by silica gel column chromatography, and the yellow oily compound, 2-amino-3'-tritylaminomethyl-5-chlorobenzophenone (2.2)
g) was obtained. (2) 2-amino-3'-tritylaminomethyl-5-
Chlorobenzophenone (2 g) in methanol (20 ml)
To the solution was added sodium borohydride (227 mg)
Stir at room temperature for 3 hours. Acetic acid ethyl ester (100m
l) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound 2-amino-
5-Chloro-α- (3-tritylaminomethylphenyl) benzyl alcohol (2.0 g) was obtained. NMR (CDCl ₃ ) δ: 3.34 (2H, s),
5.77 (1H, s), 6.58 (1H, d, J =
9.0Hz), 7.05-7.55 (21H, m)

(3) To a solution of the compound (2 g) obtained in (2) in ethyl acetate (20 ml) was added water (8 ml) and a 1N aqueous solution of sodium hydroxide (5 ml).
A solution of rt-butylacetyl chloride (0.59 g) in ethyl acetate (3 ml) was added, and the mixture was further stirred for 30 minutes. Ethyl acetate (100 ml) was added and washed with water.
It was dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and N- [4-chloro-2- (3-tritylaminomethyl-α-hydroxybenzyl) phenyl]-as a colorless oily compound was obtained.
3,3-Dimethylbutanamide (2.2 g) was obtained. To a solution of this compound (2 g) in dichloromethane (20 ml) was added
Boron hydride, tetra-n-butylammonium (2.
6 g) was added and the mixture was refluxed for 12 hours. Ethyl acetate (100 ml) was added, washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the colorless oily compound 5-
Chloro-2- (3,3-dimethylbutylamino) -α-
(3-Tritylaminomethylphenyl) benzyl alcohol (1.93 g) was obtained. NMR (CDCl ₃ ) δ: 0.88 (9H, s), 1.34-1.42 (2H,
m), 2.97-3.05 (2H, m), 3.34 (2H, s), 5.77 (1H, s), 6.58
(1H, d, J = 8.4Hz), 6.99 (1H, d, J = 2.6Hz), 7.13-7.51 (20H,
m) (4) 5-Chloro-2- (3,3-dimethylbutylamino) -α- (3-tritylaminomethylphenyl) benzyl alcohol (1.97 g) in ethyl acetate (20 ml) in water (7 ml) And 1N aqueous sodium hydroxide solution (4 ml) were added, and monoethyl fumarate chloride (0.55 g) was added, followed by stirring for 1 hour under ice cooling. Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, the residue was dissolved in ethanol (50 ml), potassium carbonate (500 mg) was added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give 7-chloro-1- (3,3) as a colorless oily compound.
3-dimethylbutyl) -1,2,3,5-tetrahydro-5- (3-tritylaminomethylphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid ethyl ester (2.0 g)
I got NMR (CDCl ₃ ) δ: 0.63 (1/2 × 9H, s), 0.97 (1/2 × 9
H, s), 1.17-1.29 (5H, m), 2.69-3.22 (3H, m), 3.27 (1 / 2x2
H, s), 3.37 (1 / 2x2H, s), 3.18-3.81 (1 / 2x2H, m), 4.04-4.
19 (2H, m), 4.41 (1 / 2x1H, dd, J = 5.8,8.0Hz), 4.51 (1 / 2x1
(H, t, J = 6.8Hz), 5.72 (1 / 2x1H, s),), 5.88 (1 / 2x1H, s),
6.64 (1 / 2x1H, d, J = 2.2Hz), 7.00-7.57 (21H + 1 / 2x1H, m)

(5) To a solution of the compound (1.9 g) obtained in (4) in ethanol (20 ml) was added a 1N aqueous sodium hydroxide solution (3 ml), and the mixture was stirred at 60 ° C. for 1 hour. After neutralization, ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (1.4 g). This compound (0.80
g) and 2-fluorobenzylamine (0.16 g) in dimethylformamide (8 ml) were added with diethyl cyanophosphate (227 mg) and triethylamine (176 mg), and the mixture was stirred at room temperature for 30 minutes. Acetic acid ethyl ester (5
0 ml), washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain two colorless oily compounds, 3,5-trans form (0.22 g) and 3,5-cis form (0.28 g). . 3,5-cis form (B) NMR (CDCl ₃ ) δ: 0.10-0.25 (1H, m), 0.45-0.58
(1H, m), 0.62 (9H, s), 2.79 (1H, dd, J = 6.0,14.4Hz), 2.95
-3.12 (2H, m), 3.27 (2H, s), 3.61-3.78 (1H, m), 4.45-4.5
4 (3H, m), 5.88 (1H, s), 6.34-6.40 (1H, br), 6.97-7.54 (2
6H, m) 3,5-trans form (A) NMR (CDCl ₃ ) δ: 0.97 (9H, s), 1.47-1.68 (2H,
m), 2.66 (1H, dd, J = 6.2,14.6Hz), 2.88 (1H, dd, J = 7.4,14.
6Hz), 3.36 (2H, s), 3.62-3.78 (1H, m), 4.18-4.33 (1H,
m), 4.39-4.45 (3H, m), 5.70 (1H, s), 6.23-6.29 (1H, br),
6.62 (1H, d, J = 2.2Hz), 6.95-7.58 (25H, m)

Example 134 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(3,3-dimethylbutyl) -2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide monohydrochloride Compound 3,5-trans form (B) obtained in Example 133
To a solution of (0.15 g) in acetone (1.8 ml) was added concentrated hydrochloric acid (0.2 ml), and the mixture was stirred at 60 ° C for 1 hour. After basification with a 1N aqueous sodium hydroxide solution, an ethyl acetate solution (50 ml) was added, the organic layer was washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography. The obtained oily compound was dissolved in 4N hydrogen chloride in ethyl acetate (0.1 ml), and the solvent was distilled off to give a colorless amorphous solid (83 mg). ) Got. NMR (CDCl ₃ ) δ: 0.99 (9H, s), 1.45-1.79 (2H,
m), 2.77-2.82 (2H, m), 3.73-3.88 (1H, m), 4.12 (2H, s),
4.22-4.35 (1H, m), 4.42-4.49 (3H, m), 5.79 (1H, s), 6.49
(1H, s), 7.01-7.51 (10H, m)

Example 135 3,5-trans-N- (2-fluorobenzyl) -1
-[4- (acetyloxymethyl) benzyl] -5-
(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) 2-amino-5 To a solution of -chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.45 g) and methyl 4-formylbenzoate (0.24 g) in methanol (12 ml),
Acetic acid (0.1 g) was added and the mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (120 mg) was added thereto, and the mixture was stirred at 60 ° C for 2 hours. Acetic acid ethyl ester (5
0 ml), washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the target colorless oily compound 5-chloro-2- (4-methoxycarbonylbenzyl) -α-
(3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.7 g) was obtained. A solution of this compound (0.7 g) in tetrahydrofuran (8 ml) was added.
The solution was added dropwise to a suspension of lithium aluminum hydride (0.14 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 30 minutes, water (0.15 ml) and 1N aqueous sodium hydroxide solution (0.3 ml) were added, insolubles were removed by filtration, and the filtrate was concentrated to give a colorless oily compound 5-chloro-2. −
(4-hydroxymethylbenzylamino) -α- (3-
(tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.6 g) was obtained. NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.0-4.4 (4H, m),
4.69 (2H, d, J = 8.8Hz), 4.8 (1H, m), 5.78 (1H, s), 6.55 (1
H, m), 6.9-7.5 (11H, m)

(2) To a solution of the compound obtained in (1) (0.6 g) in ethyl acetate (15 ml) was added a 1N aqueous sodium hydroxide solution (5 ml), and monoethyl ester of fumaric chloride (300 mg) was added. The mixture was stirred for 1 hour under ice cooling.
Ethyl acetate (30 ml) was added, and the organic layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was dissolved in ethanol (15 ml).
0 mg) and stirred at 50-60 ° C for 5 hours. The insoluble material was removed by filtration, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless oily compound. NMR (CDCl ₃ ) δ: 1.25 (3H, dt), 2.6-3.3 (2H,
m), 4.0-4.3 (4H, m), 4.44 (2 / 3x1H, dt), 4.6-4.8 (3H, m),
5.0 (1H, m), 5.24 (2 / 3x1H, s), 5.63 (2 / 3x1H, d), 5.90 (2
/ 3x1H, s), 6.46 (2 / 3x1H, s), 6.6-7.5 (10H, m) (3) 1N sodium hydroxide was added to a solution of the compound (0.4 g) obtained in (2) in ethanol (10 ml). Aqueous solution (3m
l) was added and the mixture was stirred at 60 ° C for 0.5 hour. After neutralization, ethyl acetate (50 ml) was added, and the organic layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain a colorless amorphous solid (0.3 g). This compound (0.3 g)
To a solution of 2-fluorobenzylamine (80 mg) and dimethylformamide (8 ml) was added diethyl cyanophosphate (1).
(00 mg) and triethylamine (100 mg), and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate (50 ml) was added, washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off, and the residue was dissolved in pyridine (2 ml).
ml) and stirred at room temperature for 1.5 hours. Ethyl acetate (50 ml) was added, washed with water, dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography to give a colorless oily compound (0.1
8 g) were obtained. NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.09 (3H, s), 2.
70 (1H, dd), 2.93 (1H, dd), 4.27 (2H, d, J = 6Hz), 4.35-4.6
(3H, m), 4.27 (1H, d, J = 14.8Hz), 5.09 (2H, s), 5.3-5.5 (2
H, m), 6.32 (1H, t), 6.5 (1H, d, J = 2.2Hz), 6.9-7.4 (14H,
m)

Example 136 3,5-trans-N- (2-fluorobenzyl) -1
-[4- (acetyloxymethyl) benzyl] -5-
(3-Aminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride Compound obtained in Example 135 ( 0.16 g) was dissolved in 4N hydrogen chloride in ethyl acetate (2 ml).
After standing for 1 minute, the solvent was distilled off and a colorless amorphous solid (80 m
g) was obtained. NMR (CDCl ₃ ) δ: 2.08 (3H, s), 2.73 (1H, dd),
2.93 (1H, dd), 3.6 (2H, m), 3.85 (2H, m), 4.3-4.6 (3H, m),
4.88 (1H, d, J = 15Hz), 5.07 (2H, s), 5.33 (1H, d, J = 14.6H
z), 5.39 (1H, s), 6.49 (1H, d, J = 2.2Hz), 6.62 (1H, t), 6.
8-7.5 (14H, m) Example 137 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
[4- (hydroxymethyl) benzyl] -2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide The compound (40 mg) obtained in Example 136 in methanol (2
1N aqueous sodium hydroxide solution (0.5 m
l) was added and stirred at 60 ° C. for 30 minutes. Ethyl acetate (20 ml) was added, washed with water, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off to obtain a colorless amorphous solid (20 mg). NMR (CDCl ₃ ) δ: 2.37 (2H, m), 2.68 (1H, dd),
2.88 (1H, dd), 3.83 (2H, s), 4.3-4.55 (3H, m), 4.61 (2H,
s), 4.95 (1H, s), 5.72 (1H, d, J = 14Hz), 6.2-6.6 (3H, m),
6.8-7.5 (14H, m)

Example 138 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) N-methyl-N-methyloxy-2-aminobenzamide (2.70 g) and N-tert-butoxycarbonyl A solution of -3-bromobenzylamine (2.86 g) in tetrahydrofuran (30 ml) was cooled to -78 ° C, and a solution of n-butyllithium in hexane (1.6 mol / l) was added.
(31 ml) was slowly added dropwise. After dropping, water (70m
l) and ethyl acetate (70 ml) were added. The organic layer was washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off.
The remaining oily compound was separated and purified by silica gel column chromatography, and the yellow oily compound, 2-amino-3'-
(Tert-Butoxycarbonylaminomethyl) benzophenone (1.2 g) was obtained. (2) To a solution of 2-amino-3 ′-(tert-butoxycarbonylaminomethyl) benzophenone (1 g) in methanol (20 ml) was added sodium borohydride (0.3).
g) was added and stirred at room temperature for 30 minutes. Ethyl acetate (100 ml) was added, washed with water, dried over anhydrous MgSO ₄ and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography, and the desired colorless oily compound 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (1.1 g) was obtained.
I got (3) A colorless oily compound (0.12 g) was obtained in the same manner as in Example 4. NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.75 (1H, dd, J =
5.8,16Hz), 2.95 (1H, dd, J = 7.2,16Hz), 4.1-4.8 (5H, m),
4.97 (1H, d, J = 14.6Hz), 5.43 (1H, s), 5.46 (1H, d, J = 14.6H
z), 6.54 (1H, d, J = 7.6Hz), 6.9-7.7 (20H, m)

Example 139 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamido-1
Hydrochloride Compound (0.12 g) obtained in Example 138 was dissolved in ethyl acetate (4 ml) of 4N hydrogen chloride, and the solution was dissolved at room temperature in 3 ml.
After standing for 0 minutes, the solvent was distilled off to give a colorless amorphous solid (45%).
mg). NMR (CDCl ₃ ) δ: 2.74 (1H, dd, J = 5.8,16Hz), 2.
97 (1H, dd, J = 7.2,16Hz), 3.76 (2H, s), 4.3-4.7 (3H, m), 4.
94 (1H, d, J = 14.6Hz), 5.44 (1H, s), 5.48 (1H, d, J = 14.6H
z), 6.43 (1 H, m), 6.57 (1 H, d, J = 7.8 Hz), 6.9-7.7 (20 H, m) Example 140 3,5-trans-N- (2-fluorobenzyl) -5
-(3-aminomethylphenyl) -1-neopentyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamido monohydrochloride 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol As a raw material, a colorless amorphous solid (0.1) was obtained in the same manner as in Example 6.
3 g) was obtained. NMR (CDCl ₃ ) δ: 0.92 (9H, s), 2.72 (1H, dd, J =
5.8,15.8Hz), 2.91 (1H, dd, J = 7.2,15.8Hz), 3.44 (1H, d, J
= 13.8Hz), 3.88 (2H, s), 4.3-4.6 (4H, m), 6.05 (1H, s),
6.56 (1H, m), 6.63 (1H, d, J = 7.8Hz), 6.9-7.5 (11H, m)

Example 141 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) -7-methyloxy-2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamide (1) N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5 obtained in Example 7 (1)
A solution of hydroxybenzamide (0.8 g), methyl iodide (0.2 g), potassium carbonate (0.5 g) and N, N-dimethylformamide (8 ml) was stirred at 60 ° C. for 3 hours. The reaction solution was added to ice water and extracted with ethyl acetate.
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography to obtain N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-methyloxy-benzamide as a yellow oil (0.55 g). NMR (CDCl ₃ ) δ: 3.349 (3H, s), 3.537 (3H, s), 3.
798 (3H, s), 5.178 (2H, s), 6.9-8.3 (9H, m). (2) N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-methyloxy-benzamide (0 .55 g) were dissolved in ethyl acetate (8 ml) and methanol (10 ml) and 10% -palladium on carbon (0.1
g), and the mixture is stirred at room temperature under normal pressure in a hydrogen stream for 40 minutes. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. From the residue, N-methyl-N-methyloxy-2-amino-
5-Methyloxy-benzamide (0.35 g) was obtained. NMR (CDCl ₃ ) δ: 3.354 (3H, s), 3.610 (3H, s), 3.753 (3
H, s), 6.65-7.0 (3H, s). (3) N-methyl-N-methyloxy-2-amino-
5-methyloxy-benzamide (0.35 g) and Nt
A solution of ert-butoxycarbonyl-3-bromobenzylamine (0.48 g) in tetrahydrofuran (15 ml) was cooled to -70 ° C, and stirred while stirring in a hexane solution of n-butyllithium (1.6 mol / L) 6. .2 ml)
It was dropped in 0 minutes. After the addition, water (40 ml) and ethyl acetate (40 ml) were added. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give 2-amino-3-tert-butoxycarbonylaminomethyl-5-methyloxybenzophenone as a yellow oil (0.18 g). NMR (CDCl ₃ ) δ: 1.453 (9H, s), 3.66 (3H, s), 4.3
8 (2H, d, J = 6.2Hz), 4.92 (1H, m), 5.33 (2H, m), 6.7-7.65
(7H, m). (4) 2-amino-3-tert-butoxycarbonylaminomethyl-5-methyloxybenzophenone (0.1
8 g) was dissolved in methanol (10 ml) and sodium borohydride (0.08 g) was added. Concentrate the reaction,
Water was added and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. An oily substance of 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -5-methyloxybenzyl alcohol (0.18 g) was obtained from the residue. NMR (CDCl ₃ ) δ: 1.450 (9H, s), 3.739 (3H, s), 4.
31 (2H, d, J = 6Hz), 4.83 (1H, m), 5.815 (1H, s), 6.6-7.4 (7
H, s).

(5) 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -5-methyloxybenzyl alcohol (0.18 g), 4-benzyloxy-benzaldehyde (0.12 g) and acetic acid ( 0.02 g) was dissolved in methanol (6 ml), and sodium cyanoborohydride (0.02 mg) was added thereto.
For 30 minutes. The reaction solution was concentrated, and ethyl acetate (3
0 ml) and water (50 ml) were added and shaken. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was separated and purified by silica gel column chromatography, and 2- (4-benzyloxybenzyl) -α- (3-
tert-butoxycarbonylaminomethylphenyl-5-
Colorless crystals of methyloxybenzyl alcohol (0.17
g) was obtained. Melting point: 86-87 ° C NMR (CDCl ₃ ) δ: 1.433 (9H, s), 3.721 (3H, s), 4.
132 (2H, s), 4.28 (2H, d, J = 6.2Hz), 4.78 (1H, m), 5.05 (2
H, s), 5.826 (1H, s), 6.6-7.5 (16H, m). (6) 2- (4-benzyloxybenzyl) -α-
(3-tert-butoxycarbonylmethylphenyl) -5
-Methyloxybenzyl alcohol (0.17 g), 1
Normal sodium hydroxide (2 ml) and ethyl acetate (6 m
While stirring the liquid mixture of l), monoethyl fumarate chloride (53 mg) was added. After stirring for 20 minutes, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (6 ml), potassium carbonate (50 mg) was added, and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, water (30 ml) and ethyl acetate (20 ml) were added and shaken. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was treated with tetrahydrofuran (3 ml) and methanol (5 ml)
And 1N sodium hydroxide (2 ml) was added to
Stirred at 0 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, adjusted to pH 3 with a 5% aqueous potassium hydrogen sulfate solution, and ethyl acetate (30%).
ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in N, N-dimethylformamide (4 ml), 2-fluorobenzylamine (32 mg) was added, and while stirring at 0 ° C., diethyl cyanophosphate (40 mg) and triethylamine (35 mg).
Was added. After the reaction solution was stirred at room temperature for 20 minutes, water was added, and the mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography to give 3,5.
-Trans-N- (2-fluorobenzyl) -1- (4
-Benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -5-methyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3 -Acetamide colorless oil (0.1 g) was obtained. NMR (CDCl ₃ ) δ: 1.431 (9H, s), 2.68 (1H, dd, J = 6.
2, 15.8Hz), 2.93 (1H, dd, J = 7.2,15.8Hz), 3.621 (3H,
s), 4.24 (2H, d, J = 6.4Hz), 4.30-4.60 (3H, m), 4.68 (1H,
d, J = 14.2Hz), 4.83 (1H, m), 5.043 (2H, s), 5.308 (1H, s),
5.40 (1H, d, J = 14.2Hz), 6.02 (1H, d, J = 2.8Hz), 6.35 (1H,
m), 6.80-7.50 (19H, m). (7) 3,5-trans-N- (2-fluorobenzyl) -1- (4-benzyloxybenzyl) -5- (3
-Tert-butoxycarbonylaminomethyloxyphenyl) -7-methyloxy-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide (0.1 g) was dissolved in ethyl acetate (5 ml) and methanol (54 ml) and 10% palladium on carbon (30 m
g) was added and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was distilled off under reduced pressure. 3,5 from residue
-Trans-N- (2-fluorobenzyl) -5- (3
-Tert-butoxycarbonylaminomethylphenyl)-
1- (4-hydroxybenzyl) -7-methyloxy-
Colorless oily substance of 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (70
mg). NMR (CDCl ₃ ) δ: 1.448 (9H, br), 2.69 (1H, dd, J = 6.
4,16Hz), 2.87 (1H, dd, J = 7,16Hz), 3.627 (3H, s), 4.0-
4.60 (5H, m), 4.85-5.20 (2H, m), 5.50-5.90 (1H, m), 5.96
(1H, br), 6.40-7.40 (15H, m).

Example 142 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-hydroxybenzyl) -7-methyloxy-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide hydrochloride 3,5-trans-N- (2-fluorobenzyl) 5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-hydroxybenzyl) -7- obtained in Example 141 Methyloxy-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide (70 mg) was dissolved in ethyl acetate (2 ml).
Normal hydrochloric acid (ethyl acetate solution, 1 ml) was added and stirred for 1 hour. The reaction solution was distilled off, and the title compound was obtained as a colorless amorphous solid (52 mg) from the residue. NMR (CDCl ₃ ) δ: 2.60-2.90 (2H, m), 3.617 (3H,
s), 3.775 (2H, br), 4.10-4.70 (4H, m), 4.831 (1H, s), 5.
63 (1H, d, J = 14Hz), 5.96 (1H, d, J = 3Hz), 6.424 (1H, br),
6.50-7.40 (15H, m).

Example 143 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -8-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) 2-amino-4-chloro-benzoic acid (3 g) and N, O-dimethylhydroxylamine hydrochloride Salt (1.9g)
Was dissolved in methylene chloride (40 ml) and N, N-dimethylformamide (4 ml), and stirred at room temperature with 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (3.6 g). Triethylamine (1.4
g) was added. After stirring for 90 minutes, the mixture was concentrated under reduced pressure, and ethyl acetate (100 ml) and water (100 ml) were added to the residue and shaken. The fixed phase was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give N-methyl-N-methyloxy-2.
-Amino-4-chlorobenzamide yellow oil (3.
0 g) were obtained. NMR (CDCl ₃ ) δ: 3.343 (3H, s), 3.571 (3H, s), 4.
83 (1H, m), 6.67 (2H, m), 7.36 (1H, d, J = 8.4Hz). (2) N-methyl-N-methyloxy-2-amino-
4-chlorobenzamide (3.6 g) and N-tert-butoxycarbonyl-3-bromobenzylamine (5.5
g) in tetrahydrofuran (50 ml) was cooled to −78 ° C., and a hexane solution of n-butyllithium (1.6 mol / L, 60 ml) was added dropwise with stirring over 40 minutes. Water was added to the reaction solution, and ethyl acetate (150 m
Extracted in l). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to obtain a yellow oil (2.3 g) of 2-amino-3-tert-butoxycarbonylaminomethyl-4-chlorobenzophenone. NMR (CDCl ₃ ) δ: 1.456 (9H, s), 4.37 (2H, d, J = 5.8
Hz), 4.92 (1H, m), 6.197 (2H, br), 6.50-6.80 (2H, m), 7.
30-7.60 (5H, m). (3) 2-Amino-3-tert-butoxycarbonylaminomethyl-4-chlorobenzophenone (2.3 g) was dissolved in methanol (30 ml) and hydrogenated with stirring at room temperature. Sodium borohydride (0.5 g) was added. After stirring for 30 minutes, the mixture was concentrated under reduced pressure, and water (100 ml) and ethyl acetate (80 ml) were added to the residue and shaken. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, colorless crystals of 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -4-chlorobenzyl alcohol (1.9 g) were obtained. Melting point: 88-89 ° C NMR (CDCl ₃ ) δ: 1.463 (9H, s), 2.43 (1H, d, J = 4.2)
Hz), 4.10 (2H, br), 4.30 (2H, d, J = 6.4Hz), 4.83 (1H, m),
5.82 (1H, d, J = 3.6 Hz), 6.60-7.40 (7H, m). (4) 2-amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -4-chlorobenzyl alcohol (1. 0 g) and 4-phenylbenzaldehyde (0.55 g) were dissolved in methanol (20 ml), acetic acid (0.2 g) was added, and sodium cyanoborohydride (0.21 g) was added with stirring at room temperature. Reaction solution 6
After stirring at 0 ° C. for 40 minutes, the mixture was concentrated, and ethyl acetate (50%) was added.
ml) and water (80 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography to give 2-
An oil (1.1 g) of (4-biphenylmethyl) amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -4-chlorobenzyl alcohol was obtained. NMR (CDCl ₃ ) δ: 1.428 (9H, s), 2.38 (1H, d, J = 3.8
Hz), 4.20-4.40 (4H, m), 4.76 (1H, m), 5.86 (1H, d, J = 3.6H
z), 6.60-7.70 (16H, m).

(5) 2- (4-biphenylmethyl) amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -4-chlorobenzyl alcohol (1.1
g) was dissolved in ethyl acetate (15 ml), 1N sodium hydroxide (5 ml) was added, and monoethyl fumarate chloride (0.35 g) was added dropwise with stirring at room temperature. The reaction solution was separated, the organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was dissolved in ethanol (25 ml), potassium carbonate (0.8 g) was added, and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was concentrated, and extracted by adding ethyl acetate (60 ml) and water (100 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was separated and purified by silica gel column chromatography, and 1- (4
-Biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -8-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethyl acetate Ester colorless oil (0.7
g) was obtained. NMR (CDCl ₃ ) δ: 1.432 (7.2H, s), 1.432 (1.8H,
s), 2.70-3.30 (2H, m), 4.0-4.40 (5.4H, m), 4.48 (4 / 5H, d
d, J = 5.2Hz, 8.6Hz), 4.95 (4 / 5H, d, J = 14.6Hz), 5.348 (4 / H
5, s), 5.46 (4 / 5H, d, J = 14.6Hz), 5.93 (1 / 5H, s), 6.48 (4 /
5H, d, J = 8.4Hz), 6.60-7.60 (15.2H, m). (6) 1- (4-biphenylmethyl) -5- (3-te
rt-butoxycarbonylaminomethylphenyl) -8-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetic acid ethyl ester (0.65 g) was dissolved in tetrahydrofuran (5 ml) and methanol (20 ml), and 1N sodium hydroxide (5 ml) was added.
ml) and stirred at 60 ° C. for 40 minutes. The reaction solution was concentrated, neutralized with 5% potassium hydrogen sulfate, and then ethyl acetate (30%).
ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -8-chloro-2-oxo-1,2,3,5-
An amorphous solid of tetrahydro-4,1-benzoxazepine-3-acetic acid (0.45 g) was obtained. NMR (CDCl ₃ ) δ: 1.423 (9H, s), 2.80-3.40 (2H,
m), 3.83 (1 / 3H, d, J = 15.2Hz), 4.10-4.70 (10 / 3H, m), 4.9
5 (1 / 3H, d, J = 14.6Hz), 5.416 (2 / 3H, s), 5.47 (2 / 3H, d, J = 1
4.6Hz), 5.947 (1 / 3H, s), 6.49 (2 / 3H, d, J = 8Hz), 6.80-7.
70 (15 1 / 3H, m). (7) 1- (4-biphenylmethyl) -5- (3-te
rt-butoxycarbonylaminomethylphenyl) -8-
Chloro-4,1-benzoxazepine-3-acetic acid (0.3
g) and 2-fluorobenzylamine (70 mg) with N, N
-Dissolved in dimethylformamide (8 ml) and added diethyl cyanophosphate (0.1 g) and triethylamine (80 mg) with stirring at 0 ° C. After the reaction solution was stirred at room temperature for 20 minutes, water (50 ml) and ethyl acetate (80 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography, and N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert.
-Butoxycarbonylaminomethylphenyl) -8-chloro-2-oxo-1,2,3,5-tetrahydro-4,1
A non-crystalline solid of -benzoxazepine-3-acetamide (0.35 g) was obtained. NMR (CDCl ₃ ) δ: 1.416 (3H, s), 1.428 (6H, s), 2.
60-3.20 (2H, m), 3.87 (1 / 3H, d, J = 16.0Hz), 4.0-4.78 (6 1
/ 3H, m), 4.88 (2 / 3H, d, J = 14.6Hz), 5.366 (1 / 3H, s), 5.48
(2 / 3H, d, J = 14.6Hz), 5.943 (1 / 3H, s), 6.20-6.40 (1H, m),
6.47 (2 / 3H, d, J = 8.4Hz), 6.90-7.70 (19 1 / 3H, m).

Example 144 N- (2-Fluorobenzyl) -5- (3-aminomethylphenyl) -1- (4-biphenylmethyl) -8-chloro-2-oxo-1,2,3,5- Tetrahydro-4,1
-Benzoxazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -8-chloro-2- Oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide (0.35 g) was dissolved in ethyl acetate (3 ml), 4N hydrochloric acid (ethyl acetate solution, 3 ml) was added, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was concentrated, and an amorphous solid (0.24 g) of the title compound was obtained from the residue. NMR (CDCl ₃ ) δ: 2.60-3.20 (2H, m), 3.75 (2H, b
r), 3.87 (1 / 3H, d, J = 15.8Hz), 4.30-4.80 (3 1 / 3H, m), 4.
86 (2 / 3H, d, J = 14.8Hz), 5.380 (2 / 3H, s), 5.52 (2 / 3H, d, J =
14.8Hz), 5.958 (1 / 3H, s), 6.48 (2 / 3H, d, J = 8.2Hz), 6.80
-7.70 (19 1 / 3H, m).

Example 145 3,5-trans-N- (2-fluorobenzyl) -5
-[4-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) To a Grignard reagent (100 ml solution of ethyl ether) prepared from metallic magnesium (2.3 g) and methyl iodide (15 g), ethyl 3-bromobenzoate (10 g) was added dropwise. After heating and refluxing the reaction solution for 1 hour, saturated ammonium chloride was added thereto under ice cooling to decompose, and the organic layer was separated. It was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue (3 g) was dissolved in toluene (20 ml), trimethylsilazide (1.6 g) was added, and while stirring at room temperature, boron trifluoride ethyl ether (2.4 g) was added dropwise over 10 minutes. Allow the reaction to proceed at room temperature
After stirring for 4 hours, water was added and the organic layer was separated. It was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 1-[(1-azido-1-methyl) ethyl] -4-
A yellow oil of bromobenzene (3.1 g) was obtained. NMR (CDCl ₃ ) δ: 1.615 (6H, s), 7.25-7.55 (4H,
m). (2) Raney nickel (15 g) was added to ethanol (15
0-ml) and 1-[(1-azido-1-methyl) ethyl] -4-bromobenzene (7.0 g) was added dropwise with stirring at room temperature. The reaction solution was filtered, the filtrate was concentrated, and 1N hydrochloric acid (50 ml) and hexane (50 ml) were added to the residue.
l) and ether (30 ml) were added for extraction. The aqueous layer was separated, made alkaline with 1 N sodium hydroxide, and extracted with ethyl acetate (150 ml). It was dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in tetrahydrofuran (80 ml), di-tert-butyl dicarbonate (6.5 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and colorless crystals of 1-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] -4-bromobenzene (6.
7 g) were obtained. Melting point: 89-90 ° C NMR (CDCl ₃ ) δ: 1.37 (9H, br), 1,591 (6H, s), 4.
92 (1H, m), 7.20-7.60 (4H, m). (3) N-methyl-N-methyloxy-2-amino-
A solution of 5-chlorobenzamide (0.74 g) and the compound obtained in (2) (1.0 g) in tetrahydrofuran (20 ml) was cooled to −80 ° C. or lower, and a hexane solution of n-butyllithium (1. 6 mol / l) (10 ml)
It was dropped in 0 minutes. The reaction solution was decomposed by adding water, and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was separated and purified by silica gel column chromatography to obtain pale yellow crystals of 2-amino-4- (1-tert-butoxycarbonylamino-1-methyl) ethyl-5-chlorobenzophenone (0.35 g). . Melting point: 165-166 ° C NMR (CDCl ₃ ) δ: 1.44 (9H, br), 4.98 (1H, br), 6.
005 (2H, br), 6.71 (1H, d, J = 8.8Hz), 7.20-7.70 (6H, m).

(4) The compound (0.6) obtained in (3)
While stirring a solution of g) in methanol (20 ml) at room temperature, sodium borohydride (0.1 g) was added. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2-amino-α- [4-[(1-tert-butoxycarbonulamino-1-methyl) ethyl] phenyl] -5-chloro-
Benzyl alcohol (0.5 g) was obtained as colorless crystals. _{Mp: 124-125 ℃ NMR (CDCl 3)} : 1.37 (9H, br), 1.617 (6H, s), 2.55
(1H, m), 3.95 (2H, m), 4.93 (1H, br), 5.771 (1H, s), 6.59
(1H, d, J = 8.8 Hz), 7.0-7.50 (6H, m). (5) The compound (0.4 g) obtained in (4), 4-biphenylcarboxaldehyde (0.22 g), and acetic acid (0.08 g) was dissolved in methanol (10 ml), and sodium cyanoborohydride (0.1 g) was added.
Stirred at 0 ° C. for 40 minutes. The reaction solution was concentrated, and extracted by adding ethyl acetate (50 ml) and water (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2- (4-biphenylmethylamino) -α- [4
An oil (0.55 g) of-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -5-chloro-benzyl alcohol was obtained. NMR (CDCl ₃ ) δ: 1.35 (9H, br), 1.639 (6H, s), 4.
313 (2H, s), 4.93 (1H, m), 5.85 (1H, br), 6.56 (1H, d, J = 9.2
(Hz), 7.0-7.70 (15H, m). (6) 1N sodium hydroxide (5 m) was added to a solution of the compound (0.55 g) obtained in (5) in ethyl acetate (15 ml).
l) was added, and while stirring at room temperature, a solution of monoethyl chloride fumarate (0.24 g) in ethyl acetate (1 ml) was added dropwise. After stirring the reaction solution for 20 minutes, it was separated, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (15 ml), potassium carbonate (0.4 g) was added, and the mixture was stirred at 60 ° C for 2 hours. Ethyl acetate (50 ml) was added, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography to give a colorless oil, 3,5-trans-5- [4-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -1.
-(4-Biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.35 g) was obtained. NMR (CDCl ₃ ) δ: 1.255 (3H, t, J =
7.2Hz), 1.349 (9H, br), 1.6
08 (6H, s), 2.77 (1H, dd, J = 5.
4, 16.6 Hz), 3.13 (1H, dd, J =
8.2, 16.6 Hz), 4.16 (2H, q, J
= 7.2), 4.51 (1H, dd, J = 5.4,
8.4 Hz), 4.70-5.0 (2H, m),
5.34-5.55 (2H, m), 6.59 (1H,
s), 7.0-7.70 (15H, m).

(7) 3,5-trans-5- [4-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -1- (4-biphenyl) obtained in (6) Methyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Ethyl acetate ethyl ester (0.35 g) was dissolved in tetrahydrofuran (3 ml) and methanol (10 ml), 1N sodium hydroxide (3 ml) was added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction solution was concentrated, neutralized with a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
The residue was purified by silica gel column chromatography, and 3,5-trans-5- [4-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl)- 7-chloro-2
-Oxo 1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid non-crystalline solid (0.14 g)
was gotten. NMR (CDCl ₃ ) δ: 1.30 (9H, br), 1.599 (6H, s), 2.
70-3.10 (1H, m), 3.16 (1H, dd, J = 8.4,16.0Hz), 4.47 (1H, m
m), 4.80-5.10 (1H, m), 5.30-5.60 (2H, m), 6.598 (1H, s),
7.0-7.70 (15H, m). (8) The 3,5-trans-5 obtained in (7)
[4-[(1-tert-butoxycarbonylamino-1-
Methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2-oxo-4,1-benzoxazepine-3-acetic acid (0.14 g) and 2-fluorobenzylamine (32 mg) Was dissolved in N, N-dimethylformamide (5 ml) and, while stirring at 0 ° C., diethyl cyanophosphate (80 mg) and triethylamine (0.06 g).
Was added. After the reaction solution was stirred at room temperature for 30 minutes, ice water and ethyl acetate (30 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography,
5-trans-N- (2-fluorobenzyl) -5
[4-[(1-tert-butoxycarbonylamino-1-
Methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide colorless oil (80 mg) was obtained. NMR (CDCl ₃ ) δ: 1.342 (9H, br), 1.604 (6H, s), 2.73 (1H,
dd, J = 6.0, 14.4Hz), 2.93 (1H, dd, J = 7.0, 14.4Hz), 4.35
-5.0 (5H, m), 5.380 (1H, s), 5.50 (1H, d, J = 14.4Hz), 6.26
1 (1H, t, J = 6.0Hz), 6.562 (1H, d, J = 1.8Hz), 6.90-7.65 (19
H, m).

Example 146 3,5-trans-N- (2-fluorobenzyl) -5
-[4-[(1-Amino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide monohydrochloride 4N hydrogen chloride (ethyl acetate solution) of the compound (80 mg) obtained in Example 145 (2 ml) The solution was stirred at room temperature for 2 hours. The reaction solution was distilled off, and the title compound (70
mg) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.489 (6H, s), 2.73 (1H, dd, J = 6.
2, 14.5Hz), 2.93 (1H, dd, J = 7.2Hz, 14.5Hz), 4.35-4.63
(3H, m), 4.84 (1H, d, J = 14.8Hz), 5.379 (1H, s), 5.49 (1H,
d, J = 14.8Hz), 6.35 (1H, m), 6.566 (1H, d, J = 1.8Hz), 6.95
-7.62 (19H, m).

Example 147 3,5-trans-N- (2-fluorobenzyl) -1
-(4-benzyloxybenzyl) -5- [3-[(1
-Tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide (1) 2-amino-α- [3 obtained in Example 92
Acetic acid was added to a solution of-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -5-chlorobenzyl alcohol (1.0 g) and 4-benzyloxybenzaldehyde (0.6 g) in methanol (20 ml). 0.1
8 g) and sodium cyanoborohydride (0.2 g)
Was added and stirred at 60 ° C. for 30 minutes. Concentrate the reaction,
Ethyl acetate (50 ml) and water (60 ml) were added for extraction. After washing the organic layer with water and drying over anhydrous sodium sulfate,
Distilled off. Purified by silica gel column chromatography, 2- (4-benzyloxybenzylamino) -α-
[3-[(1-tert-butoxycarbonylamino-1-
Methyl) ethyl] phenyl] -5-chlorobenzyl alcohol (1.3 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.356 (9H, br), 1.562 (6H, s),
4.187 (2H, s), 4.90 (1H, m), 5.04 (2H, s), 5.807 (1H, s),
6.53 (1H, d, J = 8.8 Hz), 6.83-7.50 (15H, m). (2) A solution of the compound (1.3 g) obtained in (1) in ethyl acetate (25 ml) and 1 N hydroxylation While stirring sodium (10 ml) at room temperature, fumaric acid monoethyl ester (0.38 g) was added. The reaction solution was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml) and potassium carbonate (0.8
g) was added and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was diluted with ethyl acetate (50 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
Cis-1- (4-benzyloxybenzyl) -5- [3
-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.21 g) (A)
5-trans-1- (4-benzyloxybenzyl)-
5- [3-[(1-tert-butoxycarbonylamino-
1-Methyl) ethyl] phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.02 g)
(B) was each obtained as a colorless oil. Cis form (A) NMR (CDCl ₃ ) δ: 1.240 (3H, t, J = 7.2 Hz), 1.363 (9
H, br), 2.89 (1H, dd, J = 5.8,16.7Hz), 3.23 (1H, dd, J = 7.
8, 16.7Hz), 3.53 (1H, d, J = 15.6Hz), 4.05-4.20 (2H, m),
5.015 (2H, s), 6.70-7.50 (16H, m). Trans form (B) NMR (CDCl ₃ ) δ: 1.247 (3H, t, J =
7.2 Hz), 1.315 (9H, br), 2.7
3 (1H, dd, J = 5.6, 16.5 Hz),
3.12 (1H, dd, J = 8.6, 16.5H
z), 4.15 (2H, q, J = 7.2 Hz),
4.43 (1H, dd, J = 5.4, 8.6 Hz),
4.67 (1H, d, J = 13.8 Hz), 5.0
(1H, m), 5.057 (2H, d, J = 1.4H
z), 5.248 (1H, s), 5.52 (1H,
d, J = 13.8 Hz), 6.539 (1H, s),
6.9-7.5 (15H, m).

(3) The trans form (B) (1.02 g) obtained in (2) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml), and 1N sodium hydroxide (8 ml) was added thereto. Stirred at 40 ° C. for 40 minutes. The reaction solution was concentrated, neutralized with a 5% aqueous solution of potassium hydrogen sulfate, extracted with ethyl acetate (50 ml), washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
Trans-1- (4-benzyloxybenzyl) -5
[3-[(1-tert-butoxycarbonylamino-1-
Methyl) ethyl] phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.55 g) was obtained as a colorless amorphous solid. Was done. NMR (CDCl ₃ ) δ: 1.24 (9H, m), 2.70-3.20 (2H, m),
1.509 (3H, s), 1.586 (3H, s), 4.42 (1H, m), 4.70 (1H, d, J
= 13.0Hz), 5.05 (2H, s), 5.31 (1H, m), 5.50 (1H, d, J = 13.0
Hz), 6.51 (1H, br), 6.80-7.50 (15H, m). (4) The compound (0.5 g) obtained in (3) and 2-fluorobenzylamine (0.12 g) were mixed with N, N -Dissolved in dimethylformamide (10 ml) and added diethyl cyanophosphate (0.15 g) and triethylamine (0.11 g) with stirring at 0 ° C. The reaction solution was stirred at room temperature for 20 minutes, added to water (50 ml) and extracted with ethyl acetate (60 ml). The organic layer was washed with 5% potassium hydrogen sulfate, washed with water, and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-
N- (2-fluorobenzyl) -1- (4-benzyloxybenzyl) -5- [1-[(1-tert-butoxycarbonylamino) ethyl] phenyl] -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.49 g) was obtained as colorless crystals. Melting point: 120-121 ° C NMR (CDCl ₃ ) δ: 1.29 (9H, br), 1.573 (3H, s), 1.
598 (3H, s), 2.68 (1H, dd, J = 6.0,14.4Hz), 2.93 (1
H, dd, J = 7.0, 14.4 Hz), 4.35
-4.70 (4H, m), 5.045 (2H, d, J
= 2.2 Hz), 5.222 (1H, s), 5.5
1 (1H, d, J = 14.8 Hz), 6.29 (1
H, m), 6.53 (1H, d, J = 2.0 Hz),
6.80-7.50 (19H, m).

Example 148 3,5-trans-N- (2-fluorobenzyl) -5
-[1- (1-amino) ethyl] phenyl] -1- (4
-Benzyloxybenzyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride The compound obtained in Example 147 (80 mg). Was added with 4N hydrogen chloride (ethyl acetate solution) (3 ml), and the mixture was stirred at room temperature for 90 minutes. The reaction solution was distilled off, and the title compound (48 mg) was obtained as a non-crystalline solid from the residue. NMR (CDCl ₃ ) δ: 1.479 ((3H, s), 1.500 (3H, s),
2.72 ((1H, dd, J = 6.0,14.5Hz), 2.93 (1H, dd, J = 7.2,14.5
Hz), 4.35-4.60 (3H, m), 4.734 (1H, d, J = 14.6Hz), 5.013
(2H, s), 5.358 (1H, s), 5.378 (1H, d, J = 14.6Hz), 6.444 (1
H, m), 6.513 (1H, d, J = 2.0Hz), 6.85-7.60 (19H, m).

Example 149 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -7-chloro-1- (4
-Hydroxybenzyl) -2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide The compound (0.35 g) obtained in Example 147 was dissolved in ethyl acetate (12 ml) and methanol (2 ml), and 10% palladium on carbon (50 mg) was added. And stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered and the solvent was distilled off. The residue was extracted with ethyl acetate (60 ml), and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the title compound (0.3 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.075 (9H, br),
1.434 (3H, s,), 1.557 (3H,
s), 2.67 (1H, dd, J = 6.4, 14.
4 Hz), 2.88 (1H, dd, J = 6.8, 1
4.4Hz), 4.30-4.90 (5H, m),
5.196 (1H, s), 5.88 (1H, m),
6.10-6.30 (2H, m), 6.430 (1
H, s), 6.65-7.50 (12H, m),
8.52 (1H, m).

Example 150 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-amino) ethyl] phenyl] -7-chloro-1- (4-hydroxybenzyl) -2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 4N hydrogen chloride (ethyl acetate solution) (4 ml) was added to the compound (0.25 g) obtained in Example 149. ) And add at room temperature
Stirred for hours. The reaction solution was distilled off, and the title compound (0.23 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.482 (6H, s), 2.70-2.95 (2H,
m), 4.20-4.80 (5H, m), 5.613 (1H, d, J = 13.6Hz), 6.41 (1
(H, d, J = 2.2Hz), 6.35-7.45 (14H, m).

Example 151 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- [2- (2-tert-
(Butoxycarbonylaminoethyl) phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamide (1) N-tert-butoxycarbonyl-2-bromophenethylamine (1.2 g) and N-methyl-N-methyloxy-2-amino-5-chloro-benzamide (0.1 g).
85 g) in tetrahydrofuran (30 ml).
The mixture was cooled to 78 ° C., and a hexane solution of n-butyllithium (1.6 mol / L) (12 ml) was added dropwise with stirring over 30 minutes. Water (50 ml) was added to the reaction solution, and ethyl acetate (6
0 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography to give 2-amino-2 '-(2-t
A yellow oil (ert-butoxycarbonylaminoethyl) -5-chloro-benzophenone was obtained (0.7 g). NMR (CDCl ₃ ) δ: 1.407 (9H, s), 2.777 (2H, t, J = 7H
z), 3.25-3.50 (2H, m), 4.93 (1H, m), 6.41 (2H, br), 6.68
(1H, d, J = 8.8Hz), 7.10-7.50 (6H, m). (2) Dissolve the compound (0.7 g) obtained in (1) in methanol (20 ml) and stir at room temperature while stirring. Sodium borohydride (0.2 g) was added. After stirring the reaction for 20 minutes, it was diluted with water (50 ml) and ethyl acetate (6 ml) was added.
0 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2-amino-α-
Yellow needles (0.54 g) of [2 '-(2-tert-butoxycarbonylaminoethyl) phenyl] -5-chloro-benzyl alcohol were obtained. NMR (CDCl ₃ ) δ: 1.342 (9H, s), 2.60-3.50 (4H,
m), 4.75 (1H, m), 6.08 (1H, d, J = 3.4Hz), 6.62 (1H, d, J = 8.
(3 Hz), 7.00-7.40 (6H, m). (3) The compound (0.3 g) obtained in (2) and 4-phenylbenzaldehyde (0.16 g) were dissolved in methanol (12 ml), and acetic acid (0. 0.06 g) and sodium cyanoborohydride (0.0 with stirring at room temperature).
7g) was added. After stirring the reaction at 60 ° C. for 40 minutes, it was diluted with water (40 ml) and extracted with ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2- (4-biphenylmethyl) -α-
[2 ′-(2-tert-Butoxycarbonylaminoethyl) phenyl] -5-chloro-benzyl alcohol (0.4 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.316 (9H, s), 2.60-3.50 (4H,
m), 4.35 (2H, br), 6.10 (1H.br), 6.58 (1H, d, J = 8.6Hz),
7.00-7.70 (15H, m).

(4) The compound (0.4) obtained in (3)
g) was dissolved in ethyl acetate (18 ml), 1N sodium hydroxide (8 ml) was added, and a solution of monoethyl ester of fumaric chloride (0.13 g) in ethyl acetate (1 ml) was added dropwise with stirring at room temperature. After stirring the reaction solution for 20 minutes, it was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml), potassium carbonate (0.3 g) was added, and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was diluted with ethyl acetate (60 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
Trans-1- (4-biphenylmethyl) -5- [2-
(2-tert-butoxycarbonylaminoethyl) phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester colorless oil ( 0.45 g) were obtained. NMR (CDCl ₃ ) δ: 1.262 (3H, t, J = 7.2 Hz), 1.370 (9
H, s), 2.00-2.20 (2H, m), 2.70-3.05 (3H, m), 3.14 (1H, dd,
J = 7.4, 16.7Hz), 4.00-4.30 (2H, m), 4.55 (1H, dd, J = 5.8,
7.3Hz), 4.94 (1H, d, J = 15.2Hz), 5.713 (1H, s), 7.10-7.
70 (15H, m). (5) The compound (0.45 g) obtained in (4) was dissolved in tetrahydrofuran (5 ml) and methanol (15 ml), 1N sodium hydroxide (5 ml) was added, and the mixture was heated to 60 ° C. For 50 minutes. Dilute the reaction with water (40 ml) and add 5
Neutralized with an aqueous solution of 60% potassium hydrogen sulfate, and ethyl acetate (60%
ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography to give 3,5-trans-1-
(4-biphenylmethyl) -5- [2- (2-tert-butoxycarbonylaminoethyl] phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-
A colorless amorphous solid of benzoxazepine-3-acetic acid (0.21 g) was obtained. NMR (CDCl ₃ ) δ: 1.384 (9H, s), 2.00-2.40 (2H,
m), 2.70-3.20 (4H, m), 4.32 (1H.m), 4.539 (1H, t, J = 6.6H
z), 4.93 (1H, d, J = 15Hz), 5.56 (1H, d, J = 15Hz), 5.67 (1H,
br), 6.548 (1H, s), 7.10-7.80 (15H, m). (6) The compound (0.15 g) obtained in (5) and 2-
Fluorobenzylamine (35 mg) was dissolved in N, N-dimethylformamide (6 ml) and stirred at 0 ° C.
Diethyl cyanophosphate (50 mg) and triethylamine (38 mg) were added. After stirring the reaction at room temperature for 20 minutes, it was diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-
N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- [2- (2-tert-butoxycarbonylaminoethyl) phenyl] -7-chloro-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.16 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.362 (9H, s),
2.00-2.30 (2H, m), 2.60-3.1
0 (4H, m), 4.32 (1H, m), 4.50
1 (2H, t, J = 6.4 Hz), 4.92 (1H,
d, J = 15.6 Hz), 5.55 (1H, d, J =
15.6 Hz), 5.68 (1H, s), 6.26
(1H, m), 6.515 (1H, s), 7.00
-7.70 (19H, m).

Example 152 3,5-trans-N- (2-fluorobenzyl) -5
-[2- (2-aminoethyl) phenyl] -1- (4-
(Biphenylmethyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide To a solution of the compound (0.12 g) obtained in Example 151 in ethyl acetate (2 ml) was added 4N hydrogen chloride (ethyl acetate solution) (2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was distilled off, and the title compound (92 mg) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.95 (2H, m), 2.35 (2H, m), 2.74
(1H, dd, J = 6.2,14.6Hz), 2.95 (1H, dd, J = 6.8,14.6Hz),
4.35-4.62 (3H, m), 4.73 (1H, d, J = 14.6Hz), 5.717 (1H, d, J
= 14.6Hz), 5.700 (1H, s), 6.37 (1H, m), 6.488 (1H, s), 6.
90-7.70 (19H, m).

Example 153 3,5-trans-N- (2-fluorobenzyl) -1
-(N-benzyloxycarbonylpiperidin-4-yl-methyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) 2-amino-5 obtained in Example 1 (2)
Chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (1.0 g) and N
-Benzyloxycarbonylpiperidine-4-carboxaldehyde (0.82 g) was dissolved in methanol (20 ml), acetic acid (0.2 g) was added, and sodium cyanoborohydride (0.2 g) was added with stirring at room temperature. Was added. The reaction solution was stirred at 60 ° C. for 30 minutes, concentrated, added with water (40 ml) and extracted with ethyl acetate (60 ml).
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 2- (N-benzyloxycarbonylpiperidin-4-yl-methyl) amino-5-chloro-α- (3
-Tert-Butoxycarbonylaminomethylphenyl) benzyl alcohol (1.5 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.446 (9H, s), 1.30-2.00 (4H,
m), 2.50-3.00 (7H, m), 4.30 (2H, m), 5.12 (2H, s), 5.76
(1H, s), 7.00-7.50 (12H, m). (2) The compound (1.5 g) obtained in (1) was dissolved in ethyl acetate (20 ml), and 1N sodium hydroxide (1
0 ml), and a solution of monoethyl chloride fumarate (0.45 g) in ethyl acetate (1 ml) was added dropwise with stirring at room temperature. The reaction solution was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml), and potassium carbonate (0.8 g) was added thereto.
Stirred for hours. The reaction solution was diluted with ethyl acetate (80 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give 3,5-trans-1- (N-benzyloxycarbonylpiperidin-4-yl-methyl) -5.
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester colorless oil ( 0.9 g) were obtained. NMR (CDCl ₃ ) δ: 1.00-2.20 (8H, m), 1.438 (9H,
s), 2.60-2.90 (3H, m), 3.08 (1H, dd, J = 8.2,16.0Hz), 3.
50-3.70 (1H, m), 4.00-4.50 (7H, m), 5.107 (2H, s), 5.777
(1H, s), 6.60 (1H, d, J = 2.4Hz), 7.10-7.50 (11H, m). (3) Tetrahydrofuran (5 ml) of the compound (1.3 g) obtained in (2) and methanol (10 ml), 1N sodium hydroxide (5 ml) was added to the solution, and the mixture was added at 60 ° C. for 40
Stirred for minutes. The reaction was diluted with water (50 ml), neutralized with 5% potassium bisulfate and extracted with ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was dissolved in N, N-dimethylformamide (8 ml) and treated with 2-fluorobenzylamine (0.1 ml).
22g) and diethyl cyanophosphate (0.33g) and triethylamine (0.21g) while stirring at 0 ° C.
g) was added. After stirring at room temperature for 30 minutes, water (40 m
l) was added and extracted with ethyl acetate (60 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2
-Fluorobenzyl) -1- (N-benzyloxycarbonylpiperidin-4-yl-methyl) -5- (3-te
rt-butoxycarbonylaminomethylphenyl) -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide (0.46
g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.10-2.10 (5H, m), 1.433 (9H,
s), 2.60-3.00 (4H, m), 3.55 (1H, m), 4.00-4.60 (8H, m),
5.107 (2H, s), 5.756 (1H, s), 6.23 (1H, m), 6.58 (1H, m),
6.90-7.50 (15H, m).

Example 154 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (N-benzyloxycarbonylpiperidin-4-yl-methyl) -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide hydrochloride 4N hydrogen chloride (ethyl acetate solution) was added to a solution of the compound (0.1 g) obtained in Example 153 in ethyl acetate (2 ml).
(1 ml) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was distilled off, and the title compound (60 mg) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.00-2.20 (5H, m), 2.60-3.00 (4
H, m), 3.55 (1H, m), 3.887 (2H, s), 4.05-4.60 (6H, m), 5.
109 (2H, s), 5.768 (1H, s), 6.37 (1H, m), 6.60 (1H, d, J = 2.
4Hz), 6.80-7.50 (15H, m).

Example 155 3,5-trans-N- (2-fluorobenzyl) -1
-(3-benzyloxybenzyl) -5- (3-tert-
(Butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide (1) 2-amino-5 obtained in Example 1 (2)
Chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.6 g) and 3-
Benzyloxybenzaldehyde (0.38 g) was dissolved in methanol (15 ml), acetic acid (0.12 g) was added, and sodium cyanoborohydride (0.13 g) was added with stirring at room temperature. After the reaction solution was stirred at 60 ° C. for 1 hour, water (50 ml) was added, and ethyl acetate (80 ml) was added.
Extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 2- (3-benzyloxybenzyl) -5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.9)
g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.432 (9H, s), 4.15-4.32 (3H,
m), 4.996 (2H, s), 5.790 (1H, s), 6.489 ((1H, d, J = 8.6H
z), 6.68-7.50 (15H, m). (2) 1N sodium hydroxide (10 ml) was added to a solution of the compound (0.9 g) obtained in (1) in ethyl acetate (20 ml).
ml) and stirring at room temperature, fumaric acid monoethyl ester (0.27 g) was added. After stirring for 20 minutes, the mixture was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was dissolved in ethanol (20 ml), potassium carbonate (0.6 g) was added, and the mixture was stirred at 60 ° C for 1.5 hours.
The reaction solution was diluted with ethyl acetate (60 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
3,5-trans-1- (3-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.62 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.261 (3H, t, J = 7.2 Hz), 1.457 (9
H, s), 2.77 (1H, dd, J = 5.2,16.8Hz), 3.16 (1H, d, J = 8.6,
16.8Hz), 4.13 (2H, q, J = 7.2Hz), 4.49 (1H, dd, J = 5.2,8.6
Hz), 4.73-4.87 (1H, m), 4.986 (1H, d, J = 15.2Hz), 5.038
(2H, s), 5.261 (1H, d, J = 15.2Hz), 5.470 (1H, s), 6.517 (1
(H, d, J = 2.2Hz), 6.82-7.46 (15H, m). (3) The compound (0.6 g) obtained in (2) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml). Normal sodium hydroxide (4 ml) was added and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was concentrated, diluted with water (50 ml), neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in N, N-dimethylformamide (10 ml), 2-fluorobenzylamine (0.11 g) was added, and the mixture was stirred at 0 ° C while stirring with diethyl cyanophosphate (0.15 g) and triethylamine (0.1 g). ) Was added. After the reaction solution was stirred at room temperature for 20 minutes, water (50 ml) was added, and the acetate (6 ml) was added.
0 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -1- (3-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethyl Phenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.47 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.450 (9H, s), 2.82 (1H, dd, J = 5.
6, 14.5Hz), 2.95 (1H, dd, J = 7.4, 14.5Hz), 4.254 (2H, d,
J = 6.2Hz), 4.33-4.60 (3H, m), 4.80 (1H, m), 4.884 (1H, d,
J = 14.8Hz), 5.011 (2H, s), 5.317 (1H, d, J = 14.8Hz), 5.43
8 (1H, s), 6.244 (1H, m), 6.498 (1H, d, J = 2.2Hz), 6.78-7.
40 (19H, m).

Example 156 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (3-benzyloxybenzyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide hydrochloride To the compound (80 mg) obtained in Example 155 was added 4N hydrogen chloride (ethyl acetate solution) (3 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was distilled off to obtain the title compound (63 mg) from the residue. NMR (CDCl ₃ ) δ: 2.73 (1H, dd, J = 5.8,14.5Hz),
2.96 (1H, dd, J = 7.4, 14.5Hz), 3.65-3.95 (2H, m), 4.839
(1H, d, J = 15.0Hz), 5.002 (2H, s), 5.301 (1H, d, J = 15.0H
z), 5.472 (1H, s), 6.408 (1H, t, J = 6.0Hz), 6.515 (1H, d, J
= 2.2Hz), 6.75-7.40 (18H, m).

Example 157 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (3-hydroxybenzyl)-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-N- (2-
(Fluorobenzyl) -1- (3-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.35 g) was dissolved in ethyl acetate (10 ml) and methanol (3 ml), and 10% palladium on carbon (50
mg) and stirred under a hydrogen atmosphere for 1.5 hours. The reaction was filtered and the filtrate was concentrated. The residue was treated with ethyl acetate (5
0 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the title compound (0.29) was obtained from the residue.
g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.438 (9H, s), 2.67 (1H, dd, J = 6.
0, 14.6Hz), 2.89 (1H, dd, J = 7.6,14.6Hz), 4.15-4.62 (5
H, m), 4.62-5.75 (3H, m), 6.315 (1H, m), 6.471 (1H, br),
6.53-7.45 (14H, m).

Example 158 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(3-hydroxybenzyl) -2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide hydrochloride To the compound (0.24 g) obtained in Example 157, 4N hydrogen chloride (ethyl acetate solution) (2 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the title compound (0.17 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 2.66 (1H, dd, J = 6.2,14.6Hz),
2.87 (1H, dd, J = 7.2,14.6Hz), 3.45-3.95 (4H, m), 4.28-
4.58 (3H, m), 4.643 (1H, d, J = 14.4Hz), 5.336 (1H, s), 5.41
6 (1H, d, J = 14.4Hz), 6.395 (1H, m), 6.512 ((1H, d, J = 1.2H
z), 6.64-7.42 (14H, m).

Example 159 3,5-trans-N- (2-fluorobenzyl) -5
(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- [2- (4-hydroxyphenyl) ethyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxa Zepin-3-acetamide (1) 2-amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) obtained in Example 1 (2) and 4- Benzyloxyphenylacetaldehyde (0.4 g) was dissolved in methanol (15 ml), and acetic acid (0.1 g) and sodium cyanohydride (0.11 g) were added.
Stirred at 40 ° C. for 40 minutes. The reaction solution was ethyl acetate (60 ml)
, Washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2- [2- (4-benzyloxyphenyl) ethyl] amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -5-chloro-benzyl alcohol (0.45 g) was obtained as a colorless oil. Was done. NMR (CDCl ₃ ) δ: 1.443 (9H, s), 2.70-2.85 (2H,
m), 3.20-3.40 (2H, m), 4.20-4.40 (2H, m), 4.7-4.90 (1H,
m), 5.053 (2H, s), 5.662 (1H, s), 6.61 (1H, d, J = 8.4Hz),
6.85-7.55 (15H, m). (2) The compound (0.45 g) obtained in (1) was dissolved in ethyl acetate (20 ml), 1N sodium hydroxide (10 ml) was added, and the mixture was stirred at room temperature. Ethyl acetate (1 ml) of fumaric chloride monoethyl ester (0.13 g)
The solution was added dropwise. After stirring the reaction solution for 20 minutes, it was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The obtained oil was dissolved in ethanol (15 ml),
Potassium carbonate (0.3 g) was added and the mixture was stirred at 60 ° C for 1.5 hours. The mixture was diluted with ethyl acetate (50 ml), washed with water and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography to give 3,5-trans-1.
-[2- (4-benzyloxyphenyl) ethyl] -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzozoxazepine-3-acetic acid ethyl ester (0.1%). 3g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.247 (3H, t, J = 7.2 Hz), 1.437 (9
H, s), 2.65-3.15 (4H, m), 3.75-4.00 (1H, m), 4.13 (2H, q, J
= 7.2Hz), 4.28 (2H, br), 4.37 (1H, dd, J = 5.6,7.6Hz), 4.
55-4.75 (1H, m), 4.95 (1H, m), 5.019 (2H, s), 5.305 (1H,
s), 6.512 (1H, d, J = 2.4Hz), 6.85-7.50 (15H, m).

(3) The compound obtained in (2) (0.3
g) in tetrahydrofuran (3 ml) and methanol (8 m
l), 1N sodium hydroxide (2 ml) was added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction solution was concentrated, neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in N, N-dimethylformamide (6 ml), 2-fluorobenzylamine (40 mg) was added, and the mixture was stirred at 0 ° C. while stirring at room temperature with diethyl cyanophosphate (55 mg) and triethylamine (50 mg). ) Was added. After the reaction solution was stirred at room temperature for 30 minutes, it was added to water and extracted with ethyl acetate (60 ml). Wash the organic layer with water,
Dry over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
5-trans-N- (2-fluorobenzyl) -1-
[2- (4-benzyloxyphenyl) ethyl] -5-
(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.26 g) is a colorless oil. Obtained as a product. NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.62-3.05 (4H, m),
2.85-3.98 (1H, m), 4.27 (2H, d, J = 6.0Hz), 4.36-4.75 (4
H, m), 4.85-5.00 (1H, m), 5.018 (2H, s), 5.286 (1H, s),
6.297 (1H, m), 6.50 (1H, d, J = 2.4Hz), 6.85-7.55 (19H, m). (4) The compound (0.26 g) obtained in (3) was treated with ethyl acetate (10 ml). And methanol (5 ml).
% Palladium on carbon (30 mg) and added under hydrogen atmosphere.
Stirred for hours. The reaction was filtered and concentrated. The residue was dissolved in ethyl acetate (30 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -5.
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- [2- (4-hydroxyphenyl) ethyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzo Oxazepine-3-acetamide (0.19 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.436 (9H, s), 2.55-3.28 (4H,
m), 3.75-4.02 (1H, m), 4.15-4.60 (5H, m), 4.75-5.20 (3
H, m), 6.39 (1H, d, J = 2.2Hz), 6.55-7.45 (14H, m).

Example 160 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
[2- (4-hydroxyphenyl) ethyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride Compound obtained in Example 159 ( 0.19 g) was added 4N hydrogen chloride (ethyl acetate solution) (3 ml), and the mixture was added at room temperature for 50 minutes.
Stirred for minutes. The reaction solution was distilled off, and the title compound (0.13 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 2.55-3.30 (4H, m), 3.70-4.60 (6
H, m), 4.639 (1H, s), 4.86-5.05 (1H, m), 6.44 (1H, d, J = 2.
6Hz), 6.42-6.75 (14H, m).

Example 161 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-methoxybenzyl) -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) 5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-
(Hydroxybenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.12 g), methyl iodide (0.15 g), potassium carbonate (0.15 g). A mixture of 1 g) and N, N-dimethylformamide (4 ml) was stirred at 60 ° C. for 2.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate (40 ml). The organic layer is washed with a 5% aqueous solution of potassium hydrogen sulfate, and then washed with water.
Dry over anhydrous sodium sulfate. The solvent was distilled off, and the title compound (0.105 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.445 (9H, s), 2.71 (1H, dd, J = 6.
2, 14.6Hz), 2.93 (1H, dd, J7.4, 14.6Hz), 3.792 (3H, s),
4.22-4.63 (5H, m), 4.699 (1H, d, J = 14.4Hz), 4.76-4.95
(1H, m), 5.300 (1H, s), 5.435 (1H, d, J = 14.4Hz), 6.18-6.
33 (1H, m), 6.476 (1H, d, J = 2.2Hz), 6.78-7.45 (14H, m).

Example 162 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(4-methoxybenzyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride The compound (70 mg) obtained in Example 161 was dissolved in 4N hydrogen chloride (ethyl acetate solution) (2 ml), and dissolved at room temperature in 40 ml.
Stirred for minutes. The reaction mixture was evaporated to give the title compound (65 mg) as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 2.73 (1H, dd, J = 6.0, 14.4 Hz),
2.93 (1H, dd, J = 7.2,14.4Hz), 3.781 (3H, s), 3.831 (2H, b
r), 4.36-4.62 (3H, m), 4.678 (1H, d, J = 14.4Hz), 5.307 (1
H, s), 5.445 (1H, d, J = 14.4Hz), 6.44 (1H, m), 6.482 (1H,
d, J = 2.2Hz), 6.78-7.42 (14H, m).

Example 163 3,5-trans-N- (2-fluorobenzyl) -5
-[3- [1-tert-butoxycarbonylamino-1-
Methyl) ethyl] phenyl] -7-chloro-1- (4-
(Methoxybenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) 2-amino-α-
[3 ′-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -5-chlorobenzyl alcohol (2.0 g), 4-methoxybenzaldehyde (0.8 g) and acetic acid (0.37 g) in methanol (3
0 ml) and sodium cyanoborohydride (0.1 ml).
38 g) and stirred at 60 ° C. for 1.5 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate (80 ml). The organic layer is washed with water, dried over anhydrous sodium sulfate,
Distilled off. From the residue, 2- (4-methoxybenzyl)
Amino-α- [3 ′-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -5-chlorobenzyl alcohol (2.6 g) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.35 (9H, br), 1.577 (6H, s), 3.
784 (3H, s), 4.183 (2H, s), 5.798 (1H, s), 6.5-7.5 (11H,
m). (2) The compound (2.6 g) obtained in (1) was dissolved in ethyl acetate (50 ml), and 1N sodium hydroxide (1 ml) was added.
5ml), and while stirring at room temperature, monoethyl fumarate chloride (0.85g) was added dropwise. After stirring for 10 minutes, the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (50 ml), potassium carbonate (2.0 g) was added, and the mixture was stirred at 70 ° C for 2 hours. The reaction solution was concentrated, dissolved in ethyl acetate (80 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was 3,5-cis and 3,5-trans-5- [3- [1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-chloro-1-. (4-methoxybenzyl) -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (2.9 g) was obtained as an oil. NMR (CDCl ₃ ) δ: 1.260 (3H, t, J = 7.2Hz), 1.0-1.4
5 (9H, m), 1.584 (4H, s), 1.619 (2H, s), 2.65-3.32 (2H, m),
3.795 (2H, s), 3.815 (1H, s), 4.14 (2H, dq), 4.43 (2 / 3H,
dd, J = 5.6, 8.3Hz), 5.18 (2 / 3H, s), 5.534 (2 / 3H, d, J = 14.
2Hz), 5.885 (1 / 3H, s), 6.75-7.50 (10 1 / 3H, m).

(3) Compound (2.9) obtained in (2)
g) in tetrahydrofuran (20 ml) and methanol (3
0 ml), 1N sodium hydroxide (10 ml) was added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction solution is concentrated and
After neutralization with 5% potassium hydrogen sulfate, the mixture was extracted with ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-5- [3- [1
-Tert-butoxycarbonylaminomethyl) ethyl] phenyl] -7-chloro-1- (4-methoxybenzyl)
2-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.85 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.05-1.40 (9H, m), 1.509 (3H,
s), 1.601 (3H, s), 2.75-3.30 (2H, m), 3.790 (3H, s), 4.3
0-4.80 (3H, m), 5.0-5.60 (2H, m), 6.509 (1H, s), 6.70-7.
40 (1H, m). (4) The compound (1.5 g) obtained in (3) and 2-fluorobenzylamine (0.37 g) were dissolved in N, N-dimethylformamide (10 ml), and the solution was dissolved at 0 ° C. While stirring at, diethyl cyanophosphate (0.5 g) was added, followed by triethylamine (0.35 g). After the reaction solution was stirred at room temperature for 30 minutes, water was added and ethyl acetate (10%) was added.
0 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5.
-Trans-N- (2-fluorobenzyl) -5- [3
-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-chloro-1- (4-methoxybenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1 -Benzoxazepine-3-acetamide (1.3 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.29 (9H, br), 1.478 (3H, s), 1.
604 (3H, s), 2.69 (1H, dd, J = 6.0, 14.4Hz), 2.93 (1H, dd, J
= 7.0, 14.4Hz), 3.791 (3H, s), 4.36-4.70 (4H, m), 4.85-
5.10 (1H, m), 5.15 (1H, m), 5.537 (1H, d, J = 14.0Hz), 6.30
1 (1H, m), 6.513 (1H, d, J = 1.8Hz), 6.75-7.42 (14H, m).

Example 164 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-Amino-1-methyl) ethyl] phenyl] -7-chloro-1- (4-methoxybenzyl) -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 3,5-trans-N- (2
-Fluorobenzyl) 5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl]
-7-Chloro-1- (4-methoxybenzyl) 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1.2 g) was added to 4N hydrogen chloride (1.2 g). Ethyl acetate solution) (8 ml) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was distilled off, and the residue was treated with ethyl acetate (5.
0 ml) and evaporated again. The title compound (1.15 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.452 (3H, s), 1.468 (3H, s), 2.
73 (1H, dd, J = 6.0, 14.4Hz), 2.93 (1H, dd, J = 7.0, 14.4H
z), 3.773 (3H, s), 4.35-4.62 (3H, m), 4.673 (1H, d, J = 14.
4Hz), 5.293 (1H, s), 5.458 (1H, d, J = 14.4Hz), 6.335 (1H,
m), 6.510 (1H, d, J = 2.0Hz), 6.75-7.55 (14H, m).

Example 165 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3 -Acetamide (1) N-methyl-N- obtained in Example 7 (1)
Methyloxy-2-benzyloxycarbonylamino-
5-Hydroxybenzamide (2.5 g) and 3,4-dihydro-2H-pyran (0.8 g) were added to ethyl acetate (30 ml).
l), P-toluenesulfonic acid (10 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give N-methyl-N-methyloxy-
2-benzyloxycarbonylamino-5- (tetrahydropyran-2-yl) oxy-benzamide (2.0
g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.40-2.10 (6H, m), 3.338 (3H,
s), 3.557 (3H, s), 3.45-3.95 (2H, m), 5.176 (2H, s), 5.3
6 (1H, m), 7.08-7.45 (7H, m), 7.90-8.40 (2H, m). (2) The compound (2.0 g) obtained in (1) was treated with ethyl acetate (15 ml) and methanol ( 15 ml) and 10
% Palladium on carbon (0.3 g) was added and the mixture was stirred at room temperature for 1.5 hours in a hydrogen stream. The reaction solution was filtered and the filtrate was distilled off. From the residue, N-methyl-N-methyloxy-2-amino-5- (tetrahydropyran-2-yl) oxy-
Benzamide (1.5 g) was obtained as an orange oil. NMR (CDCl ₃ ) δ: 1.40-2.10 (6H, m), 3.337 (3H,
s), 3.50-4.05 (2H, m), 3.617 (3H, s), 5.23 (1H, m), 6.60
-7.15 (3H, m). (3) N-methyl-N-methyloxy 2-amino-5- (tetrahydropyran-2-yl) oxybenzamide (1.4 g) obtained in (2) and N- tert-butoxycarbonyl-3-bromo-benzylamine (1.4
5 g) was dissolved in tetrahydrofuran (30 ml), and -7
Cool to 8 ° C. and stir with n-butyllithium (1.
6 mol, hexane solution) (15.6 ml) was added dropwise over 40 minutes. Water (50 ml) was added to the reaction solution, and ethyl acetate (7
0 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2-amino-3'-tert-
Butoxycarbonylaminomethyl-5- (tetrahydropyran-2-yl) oxy-benzophenone (0.8
g) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.459 (9H, s), 1.50-2.05 (6H,
m), 3.45-3.58 (1H, m), 3.82-3.94 (1H, m), 4.34-4.43 (2
H, m), 4.95-5.10 (1H, m), 5.153 (1H, t, J = 3.4Hz), 5.80 (2
H, m), 6.703 (1H, d, J = 9.0Hz), 7.07-7.62 (6H, m).

(4) Compound (0.8) obtained in (3)
g) was dissolved in methanol (30 ml), sodium borohydride (0.2 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, water was added, and ethyl acetate (50 ml) was added.
Extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2-amino-α- (3 ′
-Tert-butoxycarbonylaminomethylphenyl)-
5- (Tetrahydropyran-2-yl) oxy-benzyl alcohol (0.8 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.451 (9H, s), 1.52-2.10 (6H,
m), 3.48-3.63 (1H, m), 3.85-4.0 (1H, m), 4.305 (2H, d, J =
5.6Hz), 4.75-4.95 (1H, m), 5.20-5.30 (1H, m), 5.792 (1H
H, s), 6.618 (1H, d, J = 8.0 Hz), 6.80-7.40 (6H, m). (5) The compound (0.8 g) obtained in (4) and 4-phenylbenzaldehyde (0.4%). 38 g) was dissolved in methanol (20 ml), acetic acid (0.13 g) was added, the mixture was stirred for 5 minutes, and then sodium cyanoborohydride (0.1
4 g) was added. After the reaction solution was stirred at 60 ° C. for 30 minutes, ethyl acetate (50 ml) was added, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2- (4-biphenylmethyl) amino-α- (3-tert-butoxycarbonylaminomethylphenyl) -5- (tetrahydropyran-2-yl ) Oxybenzyl alcohol (0.7
g) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.434 (9H, s), 1.50-2.15 (6H,
m), 3.45-3.65 (1H, m), 3.86-4.0 (1H, m), 4.257 (2H, s),
4.299 (2H, d, J = 5.8Hz), 4.70-4.90 (1H, m), 5.856 (1H, s),
6.621 (1H, d, J = 8.6Hz), 6.83-7.65 (15H, m). (6) Dissolve the compound (0.7g) obtained in (5) in ethyl acetate (25ml) and add 1N water Sodium oxide (8
ml), and a solution of monoethyl fumarate chloride (0.2 g) in ethyl acetate (1 ml) was added dropwise with stirring at room temperature. The reaction solution was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml), and potassium carbonate (0.5 g) was added.
Stirred for minutes. The reaction solution was concentrated and ethyl acetate (60 ml)
Was added, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -2-oxo-1,2,3, 5-tetrahydro-7- (tetrahydropyran-2-yl) oxy-
4,1-Benzoxazepine-3-acetic acid ethyl ester (0.6 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.249 (3H, t, J = 7.2 Hz), 1.441 (9
H, s), 1.50-2.05 (6H, m), 2.68-2.86 (1H, m), 3.13 (1H, dd,
J = 8.0, 16.9Hz), 3.37-3.56 (1H, m), 3.67-3.86 (1H, m),
4.06-4.27 (4H, m), 4.53 (1H, dd, J = 5.4,8.4Hz), 4.70-4.
86 (1H, m), 4.913 (1H, d, J = 14.6Hz), 5.07-5.23 (1H, m),
5.35-5.50 (2H, m), 6.15-6.23 (1H, m), 6.90-7.62 (15H,
m).

(7) The compound (0.6) obtained in (6)
g) in tetrahydrofuran (5 ml) and methanol (10
1N sodium hydroxide (5 ml), and the mixture was stirred at 60 ° C. for 30 minutes. Concentrate the reaction mixture to 5%
Neutralized with potassium hydrogen sulfate and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-5- (3-tert-
Butoxycarbonylaminomethylphenyl) -1- (4
-Biphenylmethyl) -2-oxo-1,2,3,5-tetrahydro-7- (tetrahydropyran-2-yl) oxy-4,1-benzoxazepine-3-acetic acid (0.48
g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.436 (9H, s), 1.50-2.05 (6H,
m), 2.75-3.25 (2H, m), 3.35-3.90 (2H, m), 4.15-4.30 (2
H, m), 4.40-4.55 (1H, m), 4.70-5.55 (6H, m), 6.168 (1H, b
r), 6.80-7.65 (15H, m). (8) The compound (0.43 g) obtained in (7) and 2-
Fluorobenzylamine (0.95 g) was dissolved in N, N-dimethylformamide (8 ml) and diethyl cyanophosphate (0.12 g) followed by triethylamine (0.1 ml) were added with stirring at 0 ° C. The reaction was allowed to
After stirring for 0 minutes, water was added and extracted with ethyl acetate (60 ml). The organic layer was washed successively with a 5% aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -2-oxo-
1,2,3,5-tetrahydro-7- (tetrahydropyran-2-yl) oxy-4,1-benzoxazepine-
3-acetamide (0.4 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.435 (9H, s), 1.48-2.05 (6H,
m), 2.62-2.78 (1H, m), 2.94 (1H, dd, J = 7.4, 17.0Hz), 3.
35-3.95 (2H, m), 4.05-4.23 (2H, m), 4.35-4.63 (3H, m),
4.65-4.80 (1H, m), 4.86 (1H, d, J = 14.4Hz), 5.07-5.52 (3
H, m), 6.13-6.22 (1H, m), 6.32-6.46 (1H, m), 6.85-7.63
(19H, m). (9) The compound (0.4 g) obtained in (8) was dissolved in methanol (20 ml), and a 10% oxalic acid aqueous solution (2 m
l) was added and the mixture was stirred at 50-60 ° C for 40 minutes. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate (60 ml). The organic layer is washed with water, dried over anhydrous sodium sulfate,
Distilled off. From the residue, the title compound, 3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-hydroxy- 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.3 g) was obtained as colorless crystals. Melting point: 206-207 ° C NMR (CDCl ₃ ) δ: 1.397 (9H, s), 2.68 (1H, dd, J = 6.
2, 14.6Hz), 2.93 (1H, dd, J = 7.8,14.6Hz), 4.124 (2H, d,
J = 7.0Hz), 4.33-4.58 (3H, m), 4.738 (1H, d, J = 14.8Hz),
4.80 (1H, m), 5.231 (1H, s), 5.450 (1H, d, J = 14.8Hz), 5.9
01 (1H, d, J = 2.8Hz), 6.551 (1H, m), 6.73-7.68 (19H, m).

Example 166 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide hydrochloride 3,5-trans-N- (2
-Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.15 g) was added to 4N hydrogen chloride (ethyl acetate solution) (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated, and the title compound (0.14 g) was obtained from the residue.
Was obtained as colorless crystals. Melting point: 220-222 ° C NMR (CDCl ₃ ) δ: 2.72 (1H, dd, J = 5.8, 14.3 Hz),
2.82-3.52 (5H, m), 4.33-4.67 (3H, m), 4.737 (1H, d, J = 14.
2Hz), 5.256 (1H, s), 5.504 (1H, d, J = 14.2Hz), 5.854 (1H, s
d, J = 2.4Hz), 6.48-6.60 (1H, m), 6.75-7.65 (19H, m).

Example 167 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -5- (3-tert
-Butoxycarbonylaminomethylphenyl) -7-
(3-chloropropyloxy) -2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide 3,5-trans-N- (2
-Fluorobenzyl) 5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide (0.2 g) and 1-bromo-3-chloropropane (0.1 g) were combined with N, N-dimethylformamide (5 ml).
And added potassium carbonate (0.15 g) and
For 40 minutes. The reaction solution was diluted with ethyl acetate (50 ml), and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound (0.16 g) as a colorless oil. NMR (CDCl ₃ ) δ: 1.423 (9H, s), 2.05-2.18 (2H,
m), 2.713 (1H, dd, J = 6.0,14.4Hz), 2.934 (1H, dd, J = 7.
2, 14.4Hz), 3.648 (1H, t, J = 6.4Hz), 3.78-4.02 (2H, m),
4.05-4.02 (2H.m), 4.36-4.62 (3H, m), 4.63-4.76 (1H, m),
4.808 (1H, d, J = 14.2Hz), 5.312 (1H, s), 5.48 (1H, d, J = 1
4.2Hz), 6.016 (1H, d, J = 2.8Hz), 4.35-4.77 (1H, m), 6.87
-7.62 (19H, m).

Example 168 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7- (3-chloropropyloxy) -2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 3,5-trans-N- (2
-Fluorobenzyl) 5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7- (3-chloropropyloxy) -2-oxo-1,2,3,5-tetrahydro To 4-1,1-benzoxazepine-3-acetamide (70 mg), 4 N hydrogen chloride (ethyl acetate solution) (1 ml) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was distilled off, and the title compound (4
5 mg) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.05-2.18 (2H, m), 2.22-2.66 (2
H, m), 2.724 (1H, dd, J = 6.0,14.4Hz), 2.930 (1H, dd, J = 7.
0, 14.4Hz), 3.641 (2H, t, J = 6.4Hz), 3.68-3.97 (4H, m),
4.35-4.63 (3H, m), 4.799 (1H, d, J = 14.6Hz), 5.331 (1H,
s), 5.486 (1H, d, J = 14.6Hz), 6.039 (1H, d, J = 2.8Hz), 6.4
5-6.56 (1H, m), 6.87-7.62 (19H, m).

Example 169 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-benzoylmethyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine -3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.1 g), phenacyl bromide (0.0
3g), potassium carbonate (0.04g), and N, N-dimethylformamide (4ml) were stirred at 70 ° C for 2 hours. The reaction was diluted with water and extracted with ethyl acetate (40ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.105 g) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.433 (9H, s), 2.707 (1H, dd, J =
5.8, 14.2Hz), 2.941 (1H, dd, J = 7.4, 14.2Hz), 4.126 (2
(H, d, J = 6.2Hz), 4.37-4.63 (3H, m), 4.65-4.82 (1H, m),
4.888 (1H, d, J = 14.8Hz), 5.085 (2H, s), 5.346 (1H, s), 5.
387 (1H, d, J = 14.8Hz), 6.012 (1H, d, J = 3.0Hz), 6.27-6.40
(1H, m), 6.85-7.94 (24H, m).

Example 170 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-benzoylmethyloxy-1- (4-biphenylmethyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide -Hydrochloride 3,5-trans-N- (2) obtained in Example 169
-Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-benzoylmethyloxy-1- (4-biphenylmethyl) -5- (3-te
rt-butoxycarbonylaminomethylphenyl) -2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (70 mg) was dissolved in ethyl acetate (1 ml), and 4N hydrogen chloride (ethyl acetate solution)
(1 ml) was added and stirred at room temperature for 40 minutes. The reaction solution was distilled off, and the title compound (65 mg) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.899 (2H, br), 2.721 (1H, dd, J =
6.0, 14.3Hz), 2.937 (1H, dd, J = 7.4, 14.3Hz), .656 (2H,
s), 4.35-4.62 (3H, m), 4.859 (1H, d, J = 14.4Hz), 5.091 (2
H, s), 5.350 (1H, s), 5.414 (1H, d, J = 14.4Hz), 6.058 (1H,
d, J = 2.8Hz), 6.35-6.52 (1H, m), 6.85-7.92 (24H, m).

Example 171 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7- (2-hydroxyethyloxy) -2-oxo-1,2,3,5-tetrahydro-4,1- Benzoxazepine-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) 5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5-tetrahydro-4,1- Benzoxazepine-3-acetamide (50 mg), 2-bromoethyl acetate (60
mg), potassium carbonate (40 mg), and N, N-dimethylformamide (2 ml) was stirred at 80 ° C. for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. Dissolve the residue in methanol (3 ml)
Add 1N sodium hydroxide (0.5ml) and add 60 ℃
For 30 minutes. The reaction solution was diluted with ethyl acetate (20 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give the title compound (40 mg) as a colorless oil. NMR (CDCl ₃ ) δ: 1.414 (9H, s), 2.709 (1H, dd, J = 6.
0, 14.3Hz), 2.929 (1H, dd, J = 7.4, 14.3Hz), 3.843 (4H,
br), 4.05-4.22 (2H, m), 4.35-4.63 (3H, m), 4.65-4.87 (2
H, m), 5.302 (1H, s), 5.477 (1H, d, J = 14.8Hz), 6.059 (1H,
d, J = 2.8Hz), 6.43-6.54 (1H, m), 6.85-7.62 (19H, m).

Example 172 3,5 trans-N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -1- (4-biphenylmethyl) -7- (2-hydroxyethyloxy) -2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride The compound (40 mg) obtained in Example 171 was treated with 4N hydrogen chloride (ethyl acetate solution) (1 ml). ) And stirred at room temperature for 1 hour. The reaction solution was distilled off, and ethyl acetate and n
Addition of -hexane gave the title compound (25 mg) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.156 (2H, br), 2.73 (1H, dd, J =
6.2, 14.3Hz), 2.94 (1H, dd, J = 7.0, 14.3Hz), 3.63-4.02
(5H, m), 4.27-4.63 (4H, m), 4.794 (1H, d, J = 14.4Hz), 5.3
3 (1H, d), 5.53 (1H, dd), 6.09 (1H, m), 6.87-7.63 (19H,
m).

Example 173 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-methoxycarbonylmethyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxase Pin-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide (50 mg), bromoacetic acid methyl ester (3
A mixture of 7 mg), potassium carbonate (30 mg) and N, N-dimethylformamide (3 ml) was stirred at 80 ° C for 2 hours. The reaction solution was diluted with ethyl acetate (20 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give the title compound (55 mg) as a colorless oil. NMR (CDCl ₃ ) δ: 1.428 (9H, s), 2.73 (1H, dd, J = 5.
8, 14.4Hz), 2.96 (1H, dd, J = 7.4, 14.4Hz), 3.708 (3H,
s), 4.05-4.23 (2H, m), 4.32-4.62 (5H, m), 4.75-4.90 (1
H, m), 4.877 (1H, d, J = 14.6Hz), 5.354 (1H, s), 5.395 (1H,
d, J = 14.6Hz), 6.04 (1H, d, J = 2.8Hz), 6.46 (1H, t, J = 6.2H)
z), 6.86-7.63 (19H, m).

Example 174 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-methoxycarbonylmethyloxy-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride The compound (55 mg) obtained in Example 173 was treated with 4N hydrogen chloride (ethyl acetate solution) ( 1 ml) and stirred at room temperature for 1 hour. The reaction solution was distilled off, and the title compound (30 mg) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 2.05-2.41 (2H, m), 2.721 (1H, d
d, J = 6.0, 14.3Hz), 2.943 (1H, dd, J = 7.4, 14.3Hz), 3.71
9 (3H, s), 3.75 (2H, br), 4.35-4.62 (5H, m), 4.861 (1H, d
d, J = 14.8Hz), 5.357 (1H, s), 5.427 (1H, d, J = 14.8Hz), 6.
081 (1H, d, J = 2.8Hz), 6.35-6.47 (1H, m), 6.85-7.62 (19H,
m).

Example 175 3,5-trans-N- (2-fluorobenzyl) -7
-Benzyloxy-1- (4-biphenylmethyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) 5- (tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxase A mixture of pin-3-acetamide (0.1 g), benzyl bromide (28 mg), potassium carbonate (30 mg), and N, N-dimethylformamide (4 ml) was stirred at 70 ° C. for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.105 g) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.420 (9H, s), 2.708 (1H, dd, J) =
5.8, 14.4Hz), 2.939 (1H, dd, J = 7.2, 14.4Hz), 4.157 (2
(H, d, J = 5.8Hz), 4.38-4.73 (4H, m), 4.76-4.93 (3H, m), 5.
329 (1H, s), 5.434 (1H, d, J = 14.4Hz), 6.095 (1H, d, J = 2.8H
z), 6.25-6.42 (1H, m), 6.85-7.63 (24H, m).

Example 176 3,5-trans-N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -7-benzyloxy-
1- (4-biphenylmethyl) -2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide hydrochloride To the compound (70 mg) obtained in Example 175 was added 4N hydrogen chloride (ethyl acetate solution) (1 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was distilled off, and the residue was treated with ethyl acetate and n-hexane to give the title compound (65 mg) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.009 (2H, br), 2.722 (1H, dd, J =
6.0, 14.3Hz), 2.935 (1H, dd, J = 7.2, 14.3Hz), 3.726 (2
H, br), 4.35-4.62 (3H, m), 4.75-4.93 (3H, m), 5.337 (1H,
s), 5.452 (1H, d, J = 14.4Hz), 6.123 (1H, d, J = 3.0Hz), 6.3
5-6.52 (1H, m), 6.84-7.62 (24H, m).

Example 177 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-cyclohexylmethyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine -3-acetamide Compound (0.1 g) obtained in Example 165, cyclohexylmethyl bromide (30 mg), sodium hydride (7 m
g) and a solution of N, N-dimethylformamide (3 ml) was stirred at 60 ° C. for 40 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate (20 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (6
0 mg) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 0.83-1.82 (11H, m), 1.427 (9H,
s), 2.709 (1H, dd, J = 5.8,14.1Hz), 2.931 (1H, dd, J = 7.2,
14.1Hz), 3.546 (2H, d, J = 6.0Hz), 4.05-4.22 (2H, m), 4.
35-4.75 (4H, m), 4.814 (1H, d, J = 14.6Hz), 5.313 (1H, s),
5.472 (1H, d, J = 14.6Hz), 6.006 (1H, d, J = 3.0Hz), 6.28-6.
42 (1H, m), 6.85-7.62 (19H, m).

Example 178 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-cyclohexylmethyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide To the compound (50 mg) obtained in Example 177 was added 4 N hydrogen chloride (ethyl acetate solution) (1 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated to give the title compound (40 mg) as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 0.82-1.85 (11H, m), 2.25-2.65
(2H, m), 2.727 (1H, dd, J = 5.8, 14.3Hz), 2.926 (1H, dd, J =
5.8, 14.3Hz), 2.926 (1H, dd, J = 7.2, 14.3Hz), 3.543 (2
(H, d, J = 5.0Hz), 3.747 (2H, br), 4.35-4.62 (3H, m), 4.796
(1H, d, 14.4Hz), 5.319 (1H, s), 5.462 (1H, d, J = 14.4Hz),
6.02 (1H, d, J = 2.6Hz), 6.54-6.66 (1H, m), 6.85-7.62 (19
H, m).

Example 179 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7- [3- (imidazol-1-yl) propyloxy] -2-oxo-1,2,3,5- Tetrahydro-4,1-benzoxazepine-3-acetamide A solution of the compound obtained in Example 167 (50 mg), imidazole (15 mg), potassium carbonate (20 mg) and N, N-dimethylformamide (3 ml) was added to the solution. Stirred at C for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate (20 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (40 mg) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.425 (9H, s), 1.95-2.35 (2H,
m), 2.65-3.05 (2H, m), 3.65-3.75 (2H, m), 4.03-4.32 (4
H, m), 4.38-4.62 (3H, m), 4.83 (1H, d, J = 14.4Hz), 5.334
(1H, s), 5.45 (1H, d, J = 14.4Hz), 5.982 (1H, d, J = 2.8Hz),
6.50-7.85 (22H, m).

Example 180 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7- [3- (imidazol-1-yl) propyloxy] -2-oxo-1,2,3,5-tetrahydro-4, 1-benzoxazepine-3-acetamide dihydrochloride To the compound (30 mg) obtained in Example 179 was added 4N hydrogen chloride (ethyl acetate solution) (1 ml), and the mixture was stirred at room temperature for 50 minutes. The reaction solution was evaporated to give the title compound (20 mg) as a yellow non-crystalline solid from the residue. NMR (CDCl ₃ ) δ: 1.85-2.35 (4H, m), 2.723 (1H, d
d, J = 6.0, 14.4Hz), 2.943 (1H, dd, J = 7.0, 14.4Hz), 3.65
-3.85 (4H, m), 4.03-4.16 (2H, m), 4.35-4.63 (3H, m), 4.8
14 (1H, d, J = 14.4Hz), 5.348 (1H, s), 5.484 (1H, d, J = 14.4H
z), 6.026 (1H, d, J = 3.0Hz), 6.36-6.47 (1H, m), 6.83-7.8
5 (22H, m).

Example 181 3,5-trans-N- (2-fluorobenzyl) -7
-Benzyloxycarbonylmethyloxy-1- (4-
Biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide The compound obtained in Example 165 (0.1 g), benzyl bromoacetate (38 mg), potassium carbonate (40 m
g) and N, N-dimethylformamide (4 ml) was stirred at 60 ° C. for 1 hour. The reaction solution was added to water and extracted with ethyl acetate (20 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.11 g) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.423 (9H, s), 2.709 (1H, dd, J =
5.4, 14.3Hz), 2.948 (1H, dd, J = 7.2, 14.3Hz), 4.162 (2
(H, d, J = 5.6Hz), 4.36-4.62 (5H, m), 4.65-4.82 (1H, m), 4.
876 (1H, d, J = 14.4Hz), 5.348 (1H, s), 5.415 (1H, d, J = 14.4
Hz), 6.068 (1H, d, J = 2.8Hz), 6.25-6.37 (1H, m), 6.84-7.
62 (24H, m).

Example 182 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-benzyloxycarbonylmethyloxy-1- (4-biphenylmethyl) -2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamide hydrochloride To the compound (80 mg) obtained in Example 181 was added 4N hydrogen chloride (ethyl acetate solution) (1.5 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was distilled off, and the residue was treated with ethyl acetate and hexane to give the title compound (50 mg) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.721 (1H, dd, J = 5.8,14.4Hz),
2.825 (2H, br), 2.938 (1H, dd, J = 7.4,14.4Hz), 3.723 (2
H, s), 4.36-4.58 (5H, m), 4.850 (1H, d, J = 14.6Hz), 5.138
(2H, s), 5.348 (1H, s), 5.405 (1H, d, J = 14.6Hz), 6.090 (1
(H, d, J = 3.0Hz), 6.53-6.63 (1H, m), 6.83-7.58 (24H, m).

Example 183 3,5-Trans-N- (2-fluorobenzyl) -1-
(4-biphenylmethyl) -5- [3- (2-tert-butoxycarbonylaminoethyl) phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide (1) N-tert-butoxycarbonyl-3-bromophenethylamine (1.7 g) and N-methyl-N-methyloxy-2-amino-5-chloro-benzamide (1.
A solution of 9 g) in tetrahydrofuran (50 ml) was cooled to -70 ° C, and a hexane solution of n-butyllithium (1.6 mol / L) (18 ml) was added dropwise with stirring over 50 minutes. Water (100 ml) and ethyl acetate (8
0 ml) and shaken. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
2-amino-3 '-(2-tert-butoxycarbonylaminoethyl) -5-chloro-benzophenone (1.5
g) was obtained as yellow crystals. Melting point: 128-129 ° C NMR (CDCl ₃ ) δ: 1.430 (9H, s), 2.879 (2H, t, J = 7.
2Hz), 3.33-3.48 (2H, m), 4.48-4.67 (1H, m), 6.068 (2H, b
r), 6.701 (1H, d, J = 8.8 Hz), 7.22-7.53 (6H, m). (2) The compound (1.5 g) obtained in (1) was dissolved in methanol (30 ml), and the solution was stirred at room temperature. While stirring at, sodium borohydride (0.3 g) was added. After stirring for 30 minutes, concentrate and add water (50 ml) and ethyl acetate (80 ml).
And extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2-amino-α-
(3'-tert-butoxycarbonylaminoethylphenyl) -5-chloro-benzyl alcohol (1.45 g)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.424 (9H, s), 2.62-2.72 (1H,
m), 2.791 (2H, t, J = 7.2Hz), 3.27-3.43 (2H, m), 3.957 (2H,
br), 4.47-4.63 (1H, m), 5.776 (1H, d, J = 3.0Hz), 6.593 (1
(H, d, J = 9.0Hz), 7.03-7.46 (6H, m). (3) The compound (1.45 g) obtained in (2) and 4-
Phenylbenzaldehyde (0.8 g) was dissolved in methanol (15 ml), acetic acid (0.28 g) was added, and sodium cyanoborohydride (0.3) was added with stirring at room temperature.
g) was added. The reaction solution was stirred at 60 ° C. for 1 hour, concentrated, and extracted by adding water (60 ml) and ethyl acetate (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, 2- (4-biphenylmethyl) -α- [3 ′-(2-tert-butoxycarbonylaminoethyl) phenyl] -5-chloro-benzyl alcohol (1.95 g) was colorless from the residue. Obtained as an oil. NMR (CDCl ₃ ) δ: 1.414 (9H, s), 2.788 (2H, t, J = 6.
8Hz), 3.25-3.45 (2H, m), 4.299 (2H, s), 5.836 (1H, s), 6.
560 (1H, d, J = 8.6Hz), 7.05-7.73 (15H, m).

(4) Compound (1.9) obtained in (3)
5 g) was dissolved in ethyl acetate (40 ml), 1N sodium hydroxide (15 ml) was added, and while stirring at room temperature, fumaric acid monoethyl ester (0.6 g) was added.
After stirring for 10 minutes, the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (40 ml), and potassium carbonate (1.5 ml) was added.
g) was added and the mixture was stirred at 60 ° C. for 3 hours. The reaction solution was concentrated, and water (100 ml) and ethyl acetate (120 ml) were added to the residue for extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 3,5-trans-
1- (4-biphenylmethyl) -5- [3- (2-tert
-Butoxycarbonylaminoethyl) phenyl] -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetic acid ethyl ester (1.2 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.253 (3H, t, J = 7.0 Hz), 1.424 (9
H, s), 2.57-2.85 (3H, m), 4.16 (2H, q, J = 7.0Hz), 4.25-4.4
3 (1H, m), 4.483 (1H, dd, J = 5.2,8.4Hz), 4.878 (1H, d, J = 1
4.6Hz), 5.326 (1H, s), 5.497 (1H, d, J = 14.6Hz), 6.615 (1
H, s), 6.789 (1H, br), 6.95-7.64 (14H, m). (5) The compound (1.5 g) obtained in (4) was dissolved in tetrahydrofuran (8 ml) and methanol (20 ml). Add 1N sodium hydroxide (10 ml) and add 60 ml
Stirred at 40 ° C. for 40 minutes. The reaction solution was concentrated, neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (60 ml).
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-biphenylmethyl) -5- [3- (2-tert-butoxycarbonylaminoethyl) phenyl] -7-chloro-2. -Oxo-1,
2,3,5-tetrahedro-4,1-benzoxazepine-3-acetic acid (0.9 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.435 (9H, s), 2.65-3.60 (6H,
m), 4.43-4.75 (2H, m), 4.891 (1H, d, J = 14.8Hz), 5.35-5.
62 (2H, m), 6.323 (1H, s), 6.65-7.65 (15H, m). (6) The compound obtained in (5) (0.6 g) and 2-fluorobenzylamine (0.15 g) Was dissolved in N, N-dimethylformamide (10 ml), and diethyl cyanophosphate (0.18 g) and triethylamine (0.15 g) were added with stirring at 0 ° C. The reaction solution was stirred at room temperature for 20 minutes, added to ice water, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.45 g) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.415 (9H, s), 2.53-2.77 (3H,
m), 2.943 (1H, dd, J = 7.4, 14.5Hz), 3.05-3.25 (2H, m),
4.24-4.63 (4H, m), 4.816 (1H, d, J = 14.4Hz), 5.287 (1H,
s), 5.52 (1H, d, J = 14.4Hz), 6.18-6.42 (1H, m), 6.498 (1
(H, d, J = 2.0Hz), 6.723 (1H, br), 6.88-7.63 (18H, m).

Example 184 3,5-trans-N- (2-fluorobenzyl) -5
-[3- (2-aminoethyl) phenyl] -1- (4-
(Biphenylmethyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide hydrochloride To the compound (0.3 g) obtained in Example 183 was added 4 N hydrogen chloride (ethyl acetate solution) (5 ml), and the mixture was added at room temperature.
Stirred for 0 minutes. The reaction solution was distilled off, and the title compound (0.28 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.686 (2H, br),
2.53-2.86 (5H, m), 2.941 (1
H, dd, J = 7.2, 14.6 Hz), 4.34-
4.58 (3H, m), 4.797 (1H, d, J =
14.6 Hz), 5.300 (1H, s), 5.5
09 (1H, d, J = 14.6 Hz), 6.508
(1H, d, J = 1.8 Hz), 6.55-6.67
(1H, m), 6.747 (1H, br), 6.8
8-7.62 (18H, m).

Example 185 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- [3- [1-tert-
Butoxycarbonylamino-1-methyl) ethyl] phenyl] -7- (3-phenylpropyl) oxy-2-oxo-1.2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide ( 1) N-methyl- obtained in Example 165 (2)
N-methyloxy-2-amino-5- (tetrahydropyran-2-yl) oxy-benzamide (2.0 g) and 1-[(1-tert-butoxycarbonylamino-) obtained in Example 92 (1). 1-Methyl) ethyl] -3-bromobenzene (2.5 g) in tetrahydrofuran (80 ml)
Is cooled to −80 ° C. or lower, and while stirring, a hexane solution of n-butyllithium (1.6 mol /
L) (22 ml) was added dropwise over 40 minutes. Water (15
0 ml) and ethyl acetate (200 ml) were added for extraction, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2-amino-3 '-(1-tert-butoxycarbonylamino-1-methyl) ethyl-5- (tetrahydropyran-2-yl) oxy -Benzophenone (0.
6g) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.34 (9H, br), 1.576 (3H, s), 1.
656 (3H, s), 1.45-2.05 (6H, m), 3.45-3.57 (1H, m), 3.82-
3.96 (1H, m), 4.88-5.03 (1H, m), 5.152 (1H, br), 5.738 (2
H, br), 6.698 (1H, d, J = 8.8Hz), 7.07-7.76 (6H, m). (2) The compound (0.6 g) obtained in (1) was dissolved in methanol (20 ml). Sodium borohydride (0.2 g) was added while stirring at room temperature. After stirring for 20 minutes, the mixture was concentrated, and water (50 ml) and ethyl acetate (60 ml) were added to the residue.
ml) and extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2-amino-α- [3
-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -5- (tetrahydropyran-
2-yl) oxy-benzyl alcohol (0.5 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.522 (9H, br), 1.609 (6H, s),
1.50-2.15 (6H, m), 3.05-3.75 (3H, m), 3.87-4.05 (1H, m),
4.85-5.07 (1H, m), 5.20-5.27 (1H, m), 5.784 (1H, s), 6.
55-7.57 (7H, m). (3) The compound (0.5 g) obtained in (2) and 4-phenylbenzaldehyde (0.23 g) were dissolved in methanol (20 ml), and acetic acid (0.08 g) was dissolved. While stirring at room temperature while adding sodium cyanoborohydride (0.1%).
1 g) was added. The reaction solution was stirred at 60 ° C. for 30 minutes, concentrated, and extracted by adding water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2- (4-biphenylmethyl) amino-α- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl]-
5- (Tetrahydropyran-2-yl) oxy-benzyl alcohol (0.6 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.368 (9H, br), 1.569 (6H, s),
1.46-2.05 (6H, m), 3.45-3.62 (1H, m), 3.85-4.02 (1H, m),
4.947 (1H, br), 5.18-5.26 (1H, m), 5.863 (1H, s), 6.613
(1H, d, J = 8.6Hz), 6.83-7.75 (15H, m).

(4) The compound (0.6) obtained in (3)
g) was dissolved in ethyl acetate (20 ml), 1N sodium hydroxide (8 ml) was added, and while stirring at room temperature, fumaric acid monoethyl ester (0.17 g) was added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (15 ml), potassium carbonate (0.3 g) was added, and the mixture was stirred at 60 ° C for 2 hours. Ethyl acetate (50 ml) was added to the reaction solution, which was washed with water and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-biphenylmethyl) -5- [3-[(1
-Tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7- (tetrahydropyran-2-yl) oxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine -3-Acetic acid ethyl ester (0.25 g) was obtained as colorless crystals. Melting point: 150-151 ° C NMR (CDCl ₃ ) δ: 1.05-1.35 (12H, m), 1.34 (3H,
s), 1.578 (3H, s), 1.43-2.05 (6H, m), 2.65-2.83 (1H, m),
3.03-3.20 (1H, m), 3.38-3.53 (1H, m), 3.67-3.85 (1H, m
m), 4.13 (2H, q), 4.46-4.55 (1H, m), 4.56-4.73 (1H, m),
4.825 (1H, d, J = 14.2Hz), 5.10-5.57 (3H, m), 6.15-6.25 (1
H, m), 6.85-7.65 (15H, m). (5) The compound (0.32 g) obtained in (4) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml), and 1N sodium hydroxide ( 5 ml) and stirred at 60 ° C. for 40 minutes. The reaction solution was concentrated, neutralized with a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer is washed with water, dried over anhydrous sodium sulfate,
Distilled off. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-biphenylmethyl) -5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl]- 7- (tetrahydropyran-2-yl) oxy-2-oxo-1,
2,3,5-tetotahydro-4,1-benzoxazepine-
3-acetic acid (0.16 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 0.9-2.05 (21H, m), 2.65-3.25 (2
H, m), 3.35-3.85 (2H, m), 4.35-4.95 (3H, m), 5.05-5.65 (3
H, m), 6.12-6.23 (1H, m), 7.03-7.67 (15H, m). (6) The compound (0.25 g) obtained in (5) and 2-
Dissolve fluorobenzylamine (60 mg) in N, N-dimethylformamide (4 ml) and stir at 0 ° C.
Diethyl cyanophosphate (80 mg) and triethylamine (50 mg) were added. The reaction solution was stirred at room temperature for 20 minutes, added to ice water, and extracted with ethyl acetate (50 ml).
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- [3-
[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7- (tetrahydropyran-
2-yl) oxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.23 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 0.95-2.05 (21
H, m), 2.73 (1H, ddd,), 2.93
4 (1H, dd, J = 7.2, 14.3 Hz),
3.38-3.85 (2H, m), 4.25-4.8
5 (5H, m), 5.10-5.28 (2H, m),
5.502 (1H, d, J = 14.4 Hz);
15-6.25 (1H, m), 6.45-6.62
(1H, m), 6.85-7.65 (19H, m).

(7) The compound (0.2) obtained in (6)
3 g) was dissolved in methanol (10 ml), 10% oxalic acid aqueous solution (2 ml) was added, and the mixture was stirred at 60 ° C for 1 hour.
The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate (40 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and distilled. From the residue, 3,5-trans-N (2
-Fluorobenzyl) -1- (4-biphenylmethyl)
-5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-hydroxy-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.2 g) was obtained as an amorphous solid. NMR (CDCl ₃ ) δ: 1.03-1.43 (15H, m), 2.741 (1H, d
d, J = 6.0, 14.6Hz), 2.919 (1H, dd, J = 7.2, 14.6Hz), 4.25
-4.57 (3H, m), 4.60-4.95 (2H, m), 5.116 (1H, br), 5.45-5.
62 (1H, m), 6.75-7.64 (19H, m). (8) The compound obtained in (7) (0.1 g), 1-bromo-3-phenylpropane (35 mg), potassium carbonate (40 mg) And N, N-dimethylformamide (4 ml)
Was stirred at 80 ° C. for 2 hours. The reaction solution was added to water and extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- [3-
[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7- (3-phenylpropyloxy) -2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide (0.1
1g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.05-1.65 (15H, m), 1.87-2.07
(2H, m), 2.63-2.77 (3H, m), 2.93 (1H, dd, J = 7.0, 14.4H
z), 3.746 (2H, t, J = 6.2Hz), 4.35-4.82 (4H, m), 5.219 (1
H, s), 5.537 (1H, d, J = 14.2Hz), 6.04 (1H, br), 6.34-6.45
(1H, m), 6.85-7.65 (24H, m).

Example 186 3,5-Trans-N- (2-fluorobenzyl) -5
[3-[(1-amino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -2-oxo-7
-(3-Phenylpropyloxy) -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 4N based on the compound (0.1 g) obtained in Example 185 Hydrogen chloride (ethyl acetate solution) (1 ml) was added and stirred for 30 minutes. The reaction solution was distilled off, and the title compound (9
2 mg) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.399 (3H, s), 1.413 (3H, s), 1.
88-2.05 (2H, m), 2.63-3.02 (4H, m), 3.63-3.85 (2H, m),
4.32-4.60 (3H, m), 4.859 (1H, d, J = 14.6Hz), 5.359 (1H, m
s), 5.420 (1H, d, J = 14.6Hz), 6.05 (1H, d, J = 2.8Hz), 6.47
-6.62 (1H, m), 6.85-7.62 (24H, m).

Example 187 3,5-trans-N- (2-fluorobenzyl) -1
-[4- (4-benzyloxy) biphenylmethyl]-
5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) 4- ( 4'-Hydroxyphenyl) benzoic acid (2.0 g) was converted to N, N-dimethylformamide (30 ml).
And benzyl bromide (3.99 g) and potassium carbonate (3.86 g) were added thereto, followed by stirring at 80 ° C. for 3 hours. The reaction solution was added to water (100 ml), and ethyl acetate (150 ml) was added.
Extracted in l). The organic layer was washed with 5% potassium hydrogen sulfate, washed with water, dried over anhydrous sodium sulfate, and evaporated. From the residue, scaly crystals of 4- (4'-benzyloxyphenyl) -benzoic acid benzyl ester (3.
4 g) were obtained. Melting point: 138-140 ° C NMR (CDCl ₃ ) δ: 5.121 (2H, s), 5.384 (2H, s), 7.
066 (2H, d, J = 8.8Hz), 7.28-7.67 (14H, m), 8.119 (2H, d, J =
(8.4 Hz). (2) The compound (2.0 g) obtained in (1) was added to a suspension of lithium aluminum hydride (0.38 g) in tetrahydrofuran (40 ml) with stirring at room temperature. The reaction solution was heated under reflux for 3 hours, and then water (0.4) was added under ice cooling.
g) and 1N sodium hydroxide (1.2 ml). The reaction solution was filtered, and the filtrate was distilled off.
-(4-Benzyloxyphenyl) benzyl alcohol (1.2 g) was obtained as scaly crystals. _{Mp: 194-195 ℃ NMR (CDCl 3)} δ: 3.72-3.88 (1H, m), 4.691 (2H, d,
J = 5.8Hz), 5.113 (2H, s), 7.02-7.12 (2H, m), 7.18-7.58 (1
(1H, m). (3) The compound obtained in (2) (0.5 g) was added to a solution prepared from chromic anhydride (0.39 g) and pyridine (10 ml). After stirring at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate (50 ml). 5% organic layer
After washing with potassium hydrogen sulfate, the mixture was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, 4- (4
-Benzyloxyphenyl) -benzaldehyde (0.1
38 g) were obtained as colorless crystals. Melting point: 124-126 ° C NMR (CDCl ₃ ) δ: 5.134 (2H, s), 7.04-7.97 (13H,
m), 10.04 (1H, s). (4) The compound (0.33 g) obtained in (3) and the 2-amino-5-chloro-α- obtained in Example (1).
(3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.4 g) was added to methanol (1
Acetic acid (0.08 g) and sodium cyanoborohydride (0.1 g), and the mixture was stirred at 60 ° C for 1.5 hours. The reaction solution was concentrated, and the residue was extracted with water (50 ml) and ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2- [4- (4-benzyloxy) biphenylmethyl] amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.54 g) was obtained as colorless crystals. Was. Melting point: 119-120 ° C NMR (CDCl ₃ ) δ: 1.431 (9H, s), 4.26-4.35 (3H,
m), 5.110 (2H, s), 5.828 (1H, s), 6.560 (1H, d, J = 8.6Hz),
7.02-7.67 (19H, m).

(5) Compound (0.5) obtained in (4)
g) was dissolved in ethyl acetate (15 ml), 1N sodium hydroxide (5 ml) was added, and while stirring at room temperature, a solution of fumaric acid monoethyl ester (0.13 g) in ethyl acetate (1 ml) was added dropwise. . After stirring for 10 minutes, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
The residue was dissolved in ethanol (20 ml), potassium carbonate (0.3 g) was added, and the mixture was stirred at 60 ° C for 1.5 hours. The reaction was diluted with ethyl acetate (50 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-1- [4- (4-benzyloxy) biphenylmethyl] -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro- 2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.37 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.255 (3H, t, J = 7.2 Hz), 1.435 (9
H, s), 2.771 (1H, dd, J = 5.4,16.8Hz), 3.145 (1H, dd, J = 8.
4, 16.8Hz), 4.05-4.28 (4H, m), 4.485 (1H, dd, J = 5.4, 8.
3Hz), 4.65-4.82 (1H, m), 4.911 (1H, d, J = 15.0Hz), 5.118
(2H, s), 5.382 (1H, s), 5.401 (1H, d, J = 15.0Hz), 6.496 (1
H.br), 6.93-7.57 (19H, m). (6) The compound (0.36 g) obtained in (5) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml), and 1N sodium hydroxide ( 5 ml) and add 60 ° C
For 30 minutes. The reaction solution was concentrated, neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated.
The residue was dissolved in N, N-dimethylformamide (6 ml), and 2-fluorobenzylamine (0.05 g) was added thereto.
07g) and triethylamine (0.05g) were added.
The reaction solution was stirred at room temperature for 20 minutes, added to ice water, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl)
-1- [4- (4-benzyloxy) biphenylmethyl] -5- (3-tert-butoxycarbonylmethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1 -Benzoxazepine-3-acetamide (0.2 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.424 (9H, s), 2.711 (1H, dd, J =
6.0, 14.5Hz), 2.941 (1H, dd, J = 7.4, 14.5Hz), 4.05-4.2
5 (2H, m), 4.35-4.62 (3H.m), 4.63-4.83 (1H, m), 4.838 (1
H, d, J = 14.6Hz), 5.108 (2H, s), 5.345 (1H, s), 5.448 (1H,
d, J = 14.6Hz), 6.32-6.47 (1H, m), 6.484 (1H, d, J = 1.8Hz),
6.85-7.54 (23H, m).

Example 188 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- [4- (4-benzyloxy) biphenylmethyl] -7-chloro-2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride The compound (70 mg) obtained in Example 187 was treated with 4N hydrogen chloride (ethyl acetate solution) (1 .5 ml) and stirred at room temperature for 2 hours. The reaction solution was evaporated to give the title compound (60 mg) as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 2.723 (1H, dd, J = 6.0,14.4Hz),
2.941 (1H, dd, J = 7.4,14.4Hz), 3.759 (2H, br), 4.37-4.6
2 (3H, m), 4.825 (1H, d, J = 14.6Hz), 5.113 (2H, s), 5.363 (1
H, s), 5.475 (1H.d, J = 14.6Hz), 6.354 (1H, t, J = 6.2Hz),
6.506 (1H, d, J = 2.2Hz), 6.85-7.55 (23H, m).

Example 189 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- [4- (4-hydroxy) biphenylmethyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzo Oxazepine-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) -1- [4- (4-benzyloxy) biphenylmethyl] -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5- To a solution of tetrahydro-4,1-benzoxazepine-3-acetamide (0.15 g) in ethyl acetate (10 ml) and methanol (4 ml) was added 10% palladium on carbon (0.08 g), and the mixture was stirred for 1 hour in a stream of hydrogen. Stirred for .5 hours. The reaction solution was filtered, and the filtrate was distilled off. The title compound (95 mg) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.66-3.04 (2H, m),
4.02-4.26 (2H, m), 4.36-4.62 (3H, m), 4.65-4.83 (1H,
m), 4.84-5.05 (1H, m), 5.32-5.47 (2H, m), 5.85-6.12 (1
H, m), 6.25-6.58 (2H, m), 6.82-7.48 (18H, m).

Example 190 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- [4- (4-hydroxy) biphenylmethyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetamide hydrochloride To the compound (65 mg) obtained in Example 189 was added 4N hydrogen chloride (ethyl acetate solution) (1.5 ml) to dissolve the compound.
Stir for 2 hours. The reaction solution was evaporated to give the title compound (60 mg) as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.65-3.15 (5H, m), 3.624 (2H, b
r), 4.33-4.62 (3H, m), 4.654 (2 / 3H, d, J = 14.4Hz), 4.743
(1 / 3H, d, J = 14.2Hz), 5.147 (2 / 3H, s), 5.224 (1 / 3H, s),
5.579 (1 / 3H, d, J = 14.2Hz), 5.591 (1 / 3H, d, J = 14.4Hz), 6.
42-6.73 (3H, m), 6.77-7.55 (18H, m).

Example 191 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-fluorobenzyl) -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) Example (1), 2-amino-5-chloro-α- (3- tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) and 4-fluorobenzaldehyde (0.2 g)
l), acetic acid (0.1 g) and sodium cyanoborohydride (0.1 g) were added, and the mixture was stirred at 60 ° C for 40 minutes.
The reaction solution was concentrated, and water (60 ml) and ethyl acetate (50 ml) were used.
And extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 5-chloro-2
-(4-Fluorobenzylamino) -α- (3-tert-
Butoxycarbonylaminomethylphenyl) benzyl alcohol (0.56 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.445 (9H, s), 4.21 (2H, br), 4.2
96 (2H, d, J = 6.0Hz), 4.64-5.03 (3H, m), 5.812 (1H, s), 6.
494 (1H, d, J = 8.8 Hz), 6.92-7.62 (10H, m). (2) 1N sodium hydroxide was added to a solution of the compound (0.56 g) obtained in (1) in ethyl acetate (15 ml). (6m
l) was added thereto, and while stirring, a solution of monoethyl chloride fumarate (0.26 g) in ethyl acetate (1 ml) was added dropwise. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml), potassium carbonate (0.4 g) was added and the solution was added at 60 ° C. for 1.
Stir for 5 hours. The reaction was diluted with ethyl acetate (50 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography and 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-
(4-fluorobenzyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.45 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.453 (9
H, s), 2.759 (1H, dd, J = 5.2,16.7Hz), 3.131 (1H, dd, J = 8.
4, 16.7Hz), 4.143 (2H, q, J = 7.0Hz), 4.312 (2H, d, J = 5.4H
z), 4.466 (1H, dd, J = 5.2,8.6Hz), 4.867 (1H, d, J = 14.8H
z), 5.369 (1H, s), 5.371 (1H, d, J = 14.8Hz), 6.518 (1H, d,
J = 2.2Hz), 6.95-7.38 (10H, m).

(3) The compound (0.4) obtained in (2)
1N sodium hydroxide (5 ml) was added to a solution of 5 g) in tetrahydrofuran (5 ml) and methanol (10 ml), and the mixture was stirred at 60 ° C. for 30 minutes. The reaction solution was concentrated, acidified with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-fluorobenzyl)
-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.24 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.445 (9H, s), 2.853 (1H, dd, J =
5.2, 18.6Hz), 3.06-3.24 (2H, m), 4.311 (2H, d, J = 6.0H
z), 4.45 (1H, dd, J = 4.8,7.7Hz), 4.908 (1H, d, J = 14.6H
z), 5.342 (1H, d, J = 14.6Hz), 5.407 (1H, s), 6.525 (1H,
s), 6.83-7.52 (10H, m), (4) The compound (0.2 g) obtained in (3) and 2-fluorobenzylamine (52 mg) were dissolved in N, N-dimethylformamide (6 ml). While stirring under ice-cooling, diethyl cyanophosphate (65 mg) and triethylamine (5 mg) were added.
0 mg). After the reaction solution was stirred at room temperature for 20 minutes, it was added to ice water and extracted with ethyl acetate (40 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-
(Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-
(Fluorobenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.2 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.447 (9H, s), 2.694 (1H, dd, J =
6.0, 14.5Hz), 2.927 (1H, dd, J = 7.4, 14.5Hz), 4.281 (2
H, d, J = 5.8Hz), 4.37-4.62 (3H, m), 4.798 (1H, d, J = 14.6H
z), 5.334 (1H.s), 5.395 (1H, d, J = 14.6Hz), 6.16-6.26 (1
H, m), 6.499 (1H, d, J = 2.2Hz), 6.93-7.42 (14H, m).

Example 192 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(4-fluorobenzyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide.hydrochloride The compound (0.16 g) obtained in Example 191 was dissolved in 4N hydrogen chloride (ethyl acetate solution) (3 ml), and 1. 5
Stirred for hours. The reaction solution was distilled off, and the title compound (0.13 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 2.711 (1H, dd, J
= 6.0, 14.6 Hz), 2.927 (1H, d
d, J = 7.2, 14.6 Hz), 3.851 (2
H, br), 4.34-4.62 (3H, m),
4.783 (1H, d, J = 14.6 Hz), 5.3
35 (1H, s), 5.398 (1H, d, J = 14.
6.Hz), 6.35-6.46 (1H, m), 6.
515 (1H, d, J = 2.4 Hz), 6.86-
7.38 (14H, m).

Example 193 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -3-chloro-1- [3- (4-hydroxyphenyl) propyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzo Oxazepine-3-acetamide (1) 4-hydroxyphenylpropionic acid (3.0
g), benzyl bromide (7.7 g), potassium carbonate (7.5 g)
g) and a mixture of N, N-dimethylformamide (30 ml) was stirred at 60 ° C. for 3 hours. The reaction solution was washed with water (200m
l) and extracted with ethyl acetate (150 ml). The organic layer was washed with 5% potassium hydrogen sulfate, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and a solution of the residue in tetrahydrofuran (20 ml) was added to a solution of lithium aluminum hydride (1.05 g) in tetrahydrofuran (50 ml).
l) The suspension was added dropwise with stirring. The reaction solution was heated under reflux for 30 minutes, cooled to 0 ° C., decomposed with water (1 ml) and 1 N sodium hydroxide (3 ml), and the insoluble matter was filtered. After the filtrate was distilled off, 4-benzyloxyphenylpropanol (4.05 g) was obtained as colorless crystals from the residue. NMR (CDCl ₃ ) δ: 1.78-1.95 (2H, m), 2.657 (2H, t,
J = 8.2Hz), 3.63-3.73 (2H, m), 5.044 (2H, s), 6.78-7.48
(9H, m). (2) A solution of oxalyl chloride (1.15 g) in methylene chloride (20 ml) was cooled to -78 ° C, and dimethyl sulfoxide (1.42 g) was added. To this solution was added dropwise a solution of the compound obtained in (1) (2.0 g) in methylene chloride (10 ml). Then, triethylamine (4.17 g) was added, and the mixture was stirred at room temperature for 40 minutes, and then water (50 ml) was added. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 4-benzyloxyphenylpropionaldehyde (1.1 g) as a colorless oil. NMR (CDCl ₃ ) δ: 2.72-2.98 (4H,
m), 5.04 (2H, s), 6.88-7.48.
(9H, m), 9.812 (1H, br).

(3) 2-amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.7 g) obtained in Example (1) and (2) The obtained 4-benzyloxyphenylpropionaldehyde (0.51 g) was dissolved in methanol (20 ml), and acetic acid (0.14 g) and sodium cyanoborohydride (0.15 g) were added.
For 50 minutes. Water (80 ml) and ethyl acetate (100 ml) were added to the reaction solution and extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2- [3- (4-benzyloxyphenyl) propyl] amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (1.05 g) was obtained as a colorless oil. Was done. NMR (CDCl ₃ ) δ: 1.443 (9H, s), 1.72-1.78 (2H,
m), 2.473 (2H, t, J = 7.6Hz), 3.004 (2H, t, J = 7.4Hz), 4.23-
4.36 (2H, m), 4.38-4.86 (1H, m), 5.033 (2H, s), 5.738 (1
H, s), 6.516 (1H, d, J = 8.8Hz), 6.82-7.47 (15H, m). (4) To a solution of the compound obtained in (3) (1.05 g) in ethyl acetate (20 ml) 1N sodium hydroxide (10
ml) and stirred at room temperature, fumaric acid monoethyl ester (0.31 g) was added. After stirring for 20 minutes, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was treated with ethanol (20
ml), add potassium carbonate (0.8 g) and add
Stirred at 30 ° C. for 30 minutes. The reaction solution was ethyl acetate (50 ml)
, Washed with water and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 3,5-cis and 3,5-trans-1.
-[3- (4-benzyloxyphenyl) propyl]-
5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.1 g) ) Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.258 (3H, t, J = 7.2 Hz), 1.432 (9
H, s), 1.85-2.27 (3H, m), 2.55-3.15 (4H, m), 3.55-3.75 (2
H, m), 4.13 (2H, q, J = 7.2Hz), 4.05-4.65 (3H, m), 5.041 (3
/ 2H, s), 5.052 (1 / 2H, s), 5.753 (2 / 3H, s), 5.835 (1 / 3H,
s), 6.581 (2 / 3H, d, J = 2.4 Hz), 6.84-7.48 (15 1 / 3H, m). (5) The compound (1.1 g) obtained in (4) was treated with tetrahydrofuran (10 ml). And methanol (15 ml), 1N sodium hydroxide (6 ml) was added, and the mixture was stirred at 60 ° C. for 30 minutes. The reaction solution was concentrated, acidified with a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate (60 ml). The organic layer is washed with water, dried over anhydrous sodium sulfate,
Distilled off. The residue was purified by silica gel column chromatography to give 3,5-cis and 3,5-trans-1-.
"3- (4-benzyloxyphenyl) propyl] -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5
5g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.427 (9H, s), 1.88-2.27 (2H,
m), 2.627 (3 / 2H, t, J = 7.4Hz), 2.77-3.17 (5 / 2H, m), 3.48
-3.73 (1H, m), 4.03-4.12 (1 / 3H, m), 4.23-4.45 (11 / 3H,
m), 5.037 (4 / 3H, s), 5.049 (1 / 3H, m), 5.768 (2 / 3H, s),
5.856 (1 / 3H, s), 6.58 (1H, br), 6.85-7.48 (15 1 / 3H, m).

(6) Compound (0.5) obtained in (5)
g) and 2-fluorobenzylamine (0.11 g) with N,
After dissolving in N-dimethylformamide (10 ml), stirring at 0 ° C., diethyl cyanophosphate (0.14 g) and triethylamine (0.13 g) were added. After stirring the reaction solution at room temperature for 30 minutes, ice water and ethyl acetate (60 ml) were used.
And extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 3,5-trans-N-
(2-Fluorobenzyl) -1- [3- (4-benzyloxyphenyl) propyl] -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.24 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.435 (9H, s),
1.85-2.05 (2H, m), 2.57-2.7
6 (3H, m), 2.898 (1H, dd, J = 7.
2, 14.4 Hz), 3.53-3.75 (1H,
m), 4.02-4.58 (6H, m), 4.73
-4.88 (1H, m), 5.043 (2H, s),
5.732 (1H, s), 6.23-6.32 (1
H, m), 6.566 (1H, d, J = 2.4H
z), 6.86-7.47 (19H, m). (7) To a solution of the compound (0.43 g) obtained in (6) in ethyl acetate (12 ml) and methanol (3 ml) was added 10% palladium carbon (80 mg), and the mixture was stirred in a hydrogen stream for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated.
0 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is the title compound. 3,5-trans-
N- (2-fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-
1- [3- (4-hydroxyphenyl) propyl] -2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.34 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.437 (9H, s), 1.83-2.06 (2H,
m), 2.55-3.60 (4H, m), 3.52-3.75 (1H, m), 4.279 (2H, d, J
= 6.2Hz), 4.36-4.62 (4H, m), 4.75-4.95 (1H, m), 5.702 (1
H, s), 6.23-6.38 (1H, m), 6.553 (1H, d, J = 2.4Hz), 6.68-
7.47 (14H, m).

Example 194 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
[3- (4-Hydroxyphenyl) propyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide.hydrochloride Compound obtained in Example 193 ( To 0.3 g) was added 4N hydrogen chloride (ethyl acetate solution) (4 ml), and the mixture was stirred for 1.5 hours. The reaction solution was distilled off, and the title compound (0.24 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.82-2.02 (2H, m), 2.577 (2H, t,
J = 7.4Hz), 2.692 (1H, dd, J = 6.2, 14.6Hz), 2.833 (1H, dd,
J = 6.8, 14.6Hz), 3.262 (2H, br), 3.42-3.72 (1H, m), 3.8
52 (2H, s), 4.22-4.58 (4H, m), 5.69 (1H, s), 6.52 (1H, m),
6.558 (1H, d, J = 2.2Hz), 6.62-7.48 (14H, m).

Example 195 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7- [3- (4
-Hydroxyphenyl) propyloxy] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) (4-Benzyloxyphenyl) propanol (1.5 g) was dissolved in toluene (30 ml) and thionyl chloride (0.88 g) was dissolved.
And pyridine (0.1 ml) were added, and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was cooled, decomposed by adding saturated sodium hydrogen carbonate, and extracted with ethyl acetate (40 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 3- (4-benzyloxyphenyl) propyl chloride (1.3 g) was obtained as colorless crystals. Melting point: 34-35 ° C NMR (CDCl ₃ ) δ: 1.97-2.13 (2H, m), 2.723 (2H, t,
J = 7.6Hz), 3.516 (2H, t, J = 6.4Hz), 5.047 (2H, s), 6.87-
7.47 (9H, m). (2) Compound (70 mg) obtained in (1) and Example 1
3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5 obtained in Step 65
(3-tert-butoxycarbonylaminomethylphenyl) -7-hydroxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.15 g), potassium carbonate (50 mg) and N,
A solution of N-dimethylformamide (6 ml) was added at 70 DEG C. for 3 hours.
Stirred for hours. The reaction solution was added to water and ethyl acetate (40 m
Extracted in l). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-N- (2
-Fluorobenzyl) -7- [3- (4-benzyloxyphenyl) propyl] oxy-1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -2-oxo-1, 2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.17 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.417 (9H, s),
1.85-2.06 (2H, m), 2.58-2.7
7 (3H, m), 2.938 (1H, dd, J = 7.
4, 14.3 Hz), 3.65-3.82 (2H,
m), 4.157 (2H, d, J = 7.0 Hz),
4.35-4.76 (4H, m), 4.818 (1
H, d, J = 14.2 Hz), 5.033 (2H,
s), 5.319 (1H, s), 5.466 (1
H, d, J = 14.2 Hz), 6.022 (1H,
d, J = 2.8 Hz), 6.34-6.43 (1H,
m), 6.85-7.62 (28H, m). (3) 10% of a solution of the compound obtained in (2) (0.17 g) in ethyl acetate (5 ml) and methanol (10 ml) was added.
% Palladium carbon (80 mg) was added and the mixture was stirred in a hydrogen stream for 5 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was dissolved by adding ethyl acetate (40 ml), washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the title compound (0.11 g) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 1.456 (9H, s), 1.83-2.12 (2H,
m), 2.52-2.97 (4H, m), 3.48-3.63 (2H, m), 4.02-4.22 (2
H, m), 4.36-4.56 (3H, m), 4.783 (1H, d, J = 14.4Hz), 5.272
(1H, s), 5.475 (1H, d, J = 14.4Hz), 5.777 (1H, d, J = 3.0Hz),
6.25-6.42 (1H, m), 6.65-7.60 (23H, m).

Example 196 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7- [3- (4-hydroxyphenyl) propyl] -2-oxo-1,2,3,5-tetrahydro-
4,1-Benzoxazepine-3-acetamide hydrochloride To the compound (80 mg) obtained in Example 195 was added 4N hydrogen chloride (ethyl acetate solution) (2 ml), and the mixture was stirred for 2 hours. The reaction solution was distilled off, and the title compound (72 mg) was obtained from the residue.
Was obtained as a colorless title crystalline solid. NMR (CDCl ₃ ) δ: 1.83-2.02 (2H, m), 2.618 (2H, t,
J = 7.0Hz), 2.745 (1H, dd, J = 6.2,14.4Hz), 2.909 (1H, dd,
J = 6.8, 14.4Hz), 3.41 (2H, br), 3.636 (2H, t, J = 5.8Hz),
3.741 (2H, br), 4.28-4.62 (3H, m), 4.771 (1H, d, J = 14.4H
z), 5.269 (1H, s), 5.475 (1H, d, J = 14.4Hz), 5.827 (1H, d, J
= 2.8Hz), 6.48-6.72 (3H, m), 6.78-7.62 (21H, m).

Example 197 3,5-trans-N- (2-fluorobenzyl) -1
-(4-acetylaminobenzyl) -5- [3-[(1
-Tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide (1) 2-amino-α- obtained in Example 92
[3 ′-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -5-chloro-benzyl alcohol (2.0 g) and 4-nitrobenzaldehyde (0.85 g) were dissolved in methanol (30 ml), and acetic acid (0.35 g) and sodium cyanoborohydride were dissolved. (0.3
5 g) and stirred at 60 ° C. for 1.5 hours. The reaction solution was concentrated, and water (80 ml) and ethyl acetate (100 ml) were added to the residue.
And extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 5-chloro-2- (4-nitrobenzylamino) -α- [3 ′-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl]- Benzyl alcohol (2.2 g) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.341 (9H, br), 1.599 (6H, s),
2.67 (1H, br), 4.385 (2H, d, J = 3.4Hz), 4.97 (1H, br), 5.2
3 (1H, m), 5.826 (1H, s), 6.333 (1H, d, J = 8.8Hz), 6.90-7.
60 (8H, m), 8.085 (2H, d, J = 8.6Hz). (2) Dissolve the compound (2.2g) obtained in (1) in ethyl acetate (30ml) and add 1N sodium hydroxide. (2
0 ml) and the mixture was stirred at room temperature while adding fumaric acid chloride to monoethyl ester (0.7 g). Reaction solution is 10
After stirring for minutes, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (30 ml), and sodium carbonate (1.2 g) was added.
Was added and stirred at 60 ° C. for 2 hours. The reaction solution was diluted with ethyl acetate (80 ml), washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 3,5-trans-5.
-[3-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -7-chloro-1- (4
-Nitrobenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.9 g) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.262 (3H, t, J =
7.2 Hz), 1.284 (9H, br), 1.5
13 (3H, s), 1.562 (3H, s), 2.
77 (1H, dd, J = 5.0, 16.4 Hz),
3.16 (1H, dd, J = 9.2, 16.4H
z), 4.14 (2H, q, J = 7.2 Hz),
4.53 (1H, dd, J = 4.6, 6.5 Hz),
4.80-5.50 (4H, m), 6.62 (1
H, d, J = 2.2 Hz), 7.0-7.60 (8
H, m), 8.27 (2H, d, J = 8.6 Hz).

(3) Compound (0.9) obtained in (2)
g) was dissolved in ethyl acetate (15 ml), 10% palladium on carbon (0.1 g) was added, and the mixture was stirred in a hydrogen stream for 3 hours. The reaction was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-aminobenzyl) -5- [3- [1-
tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetic acid ethyl ester (0.5 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.245 (3H, t, J = 7.2 Hz), 1.29 (9
H, br), 2.73 (1H, dd, J = 5.6,16.7Hz), 3.12 (1H, dd, J = 8.
2, 16.7Hz), 4.14 (1H, q, J = 7.2Hz), 4.30-4.45 (2H, m),
5.0-5.20 (1H, m), 5.683 (1H, d, J = 14.0Hz), 6.45-6.70 (4
H, m), 6.95-7.50 (8H, m). (4) The compound (0.5 g) obtained in (3) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml), and 1N sodium hydroxide ( 6 ml) and stirred at 60 ° C. for 40 minutes. The reaction solution was concentrated, and water (20 m
After l) was added and neutralized with 10% potassium hydrogen sulfate, the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is N, N
-Dissolved in dimethylformamide (8 ml), 2-fluorobenzylamine (0.11 g) was added, and while stirring at 0 ° C, diethyl cyanophosphate (0.14 g) and triethylamine (0.1 g) were added. The reaction was allowed to proceed at room temperature for 20 minutes.
After stirring for minutes, the mixture was diluted with ethyl acetate (50 ml), washed with water, and dried over anhydrous sodium sulfate. Evaporate the solvent,
The residue was purified by silica gel column chromatography and 3,5-trans-N- (2-fluorobenzyl)
-1- (4-aminobenzyl) -5- [3-[(1-te
rt-butoxycarbonylamino-1-methyl) ethyl]
Phenyl] -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide (0.27 g) was obtained as colorless crystals. Melting point: 165-167 ° C NMR (CDCl ₃ ) δ: 0.95-1.65 (15H, m), 2.68 (1H, d
d, J = 6.4, 14.4Hz), 2.89 (1H, dd, J = 7.0, 14.4Hz), 4.250
-4.65 (4H, m), 4.95-5.15 (1H, m), 5.665 (1H, d, J = 14.0H
z), 5.73-5.95 (1H, m), 6.35-6.70 (4H, m), 6.90-7.45 (12
(H, m). (5) The compound (0.25 g) obtained in (4) was dissolved in methylene chloride (10 ml), and acetic anhydride (0.2 ml) and triethylamine (0.2 ml) were added. The reaction solution was stirred at room temperature for 30 minutes, then concentrated, and the residue was purified with ethyl acetate (3.
0 ml), washed with a 5% aqueous solution of potassium hydrogen sulfate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. Evaporate the solvent,
The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-
Fluorobenzyl) -1- (4-acetylaminobenzyl) -5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -7-chloro-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.26 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 0.95-1.52 (15H, m), 2.170 (3H,
m), 2.68 (1H, dd, J = 6.2,14.5Hz), 2.89 (1H, dd, J = 6.8,1
4.5Hz), 4.25-4.70 (4H, m), 5.152 (1H, s), 5.45-5.95 (2
H, m), 6.268 (1H, m), 6.489 (1H, s), 6.90-7.55 (14H, m).

Example 198 3,5-trans-N- (2-fluorobenzyl) -1
-(4-acetylaminobenzyl) -5- [3-[(1
-Amino-1-methyl) ethyl] phenyl] -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide hydrochloride The compound (0.22 g) obtained in Example 197 was dissolved in methanol (1 ml), and 4N hydrogen chloride (ethyl acetate solution) (5 ml) was added thereto for 40 minutes. Stirred. The reaction solution was distilled off, and the residue was methanol (10 ml) and ethyl acetate (20 ml).
ml) was added and evaporated again. The title compound (0.2 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.439 (3H, s),
1.458 (3H, s), 2.71 (1H, dd, J
= 5.8, 14.5 Hz), 2.91 (1H, d
d, J = 7.2, 14.5 Hz), 4.34-4.
60 (3H, m), 4.681 (1H, d, J = 1
4.4Hz), 5.226 (1H, s), 5.43
5 (1H, d, J = 14.4 Hz), 6.413 (1
H, m), 6.495 (1H, d, J = 2.2H
z), 6.95-7.52 (14H, m), 7.9
35 (1H, br).

Example 199 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- [3-[(1-tert
-Butoxycarbonylamino-1-methyl) ethyl] phenyl] -2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide (1) N, O-dimethylhydroxylamine (102.
5 g) was dissolved in 90% ethanol (400 ml), triethylamine (106 g) and isatoic anhydride (74 g) were added, and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated, saturated saline was added to the residue, and the mixture was extracted with ethyl acetate (500 ml). The organic layer is washed with water, dried over anhydrous sodium sulfate,
Distilled off. From the residue, N-methyl-N-methyloxy-2-aminobenzamide (81 g) was obtained as a yellow oil. This compound (6.8 g) and 1-[(tert-butoxycarbonylamino-1-methyl) ethyl] -3-bromobenzene (10 g) were added to tetrahydrofuran (200 m 2).
l), cooled to -80 ° C or lower, and stirred.
n-Butyllithium (1.6 mol / L) (128 ml) was added dropwise over 1.5 hours. Water (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2-amino-3 '-(1-tert-butoxycarbonylamino-
1-Methyl) ethyl-benzophenone (2.2 g) was obtained as a yellow oil. NMR (CDCl ₃ ) δ: 1.364 (9H, s), 1.642 (6H, s), 4.
85-5.03 (1H, m), 6.075 (2H, br), 6.55-6.77 (2H, m), 7.22
-7.72 (4H, m). (2) Dissolve the compound (2.1 g) obtained in (1) in methanol (30 ml), add sodium borohydride (0.4 g) and stir at room temperature for 30 minutes. did. The reaction solution was concentrated, water (50 ml) was added, and ethyl acetate (60 ml) was added.
Extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 2-amino-α- [3-[(1-
[tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] benzyl alcohol (2.0 g) was obtained as a pale yellow oil. NMR (CDCl ₃ ) δ: 1.35 (9H, br), 1.610 (6H, s), 2.
55-2.73 (1H, m), 3.96 (2H, br), 4.84-5.03 (1H, m), 5.859
(1H, s), 6.63-7.57 (8H, m),

(3) Compound (1.2) obtained in (2)
g) and 4-phenylbenzaldehyde (0.64 g) were dissolved in methanol (20 ml), acetic acid (0.24 g) and sodium cyanoborohydride (0.25 g) were added, and the mixture was stirred at 60 ° C for 30 minutes. The reaction solution was concentrated, and water (30
ml) and ethyl acetate (50 ml). The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2- (4-biphenylmethyl) amino-
α- [3-[(1-tert-butoxycarbonylamino-
1-Methyl) ethyl] phenyl] benzyl alcohol (1.5 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.34 (9H, br), 1.556 (3H, s), 1.
583 (3H, s), 2.38-2.57 (1H, m), 4.345 (2H, s), 4.83-5.17
(2H, m), 5.921 (1H, s), 6.63-6.56 (2H, m), 6.95-7.72 (15
(H, m). (4) The compound (1.5 g) obtained in (3) was dissolved in ethyl acetate (20 ml), and 1N sodium hydroxide (1 ml) was added.
0 ml) and stirring at room temperature, monoethyl fumarate chloride (0.39 g) was added. Reaction solution is 10
After stirring for minutes, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (30 ml), potassium carbonate (1.0 g) was added, and the mixture was stirred at 60 ° C for 1.5 hours. Concentrate the reaction,
Water (50 ml) and ethyl acetate (60 ml) were added to the residue for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-biphenylmethyl) -5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl]- 2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.12 g)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.247 (3H, t, J = 7.0Hz), 1.24-
1.43 (12H, m), 1.523 (3H, s), 2.773 (1H, dd, J = 5.4,16.6H
z), 3.144 (1H, dd.J = 8.4, 16.6Hz), 4.142 (1H, q, J = 7.0H
z), 4.498 (1H, dd, J = 5.4,8.4Hz), 4.63-4.75 (1H, m), 4.
934 (1H, d, J = 14.8Hz), 5.359 (1H, s), 5.495 (1H, d, J = 14.8
Hz), 6.572 (1H, d, J = 7.4Hz), 6.97-7.66 (16H, m).

(5) The compound (1.0) obtained in (4)
5 g) was dissolved in tetrahydrofuran (10 ml) and methanol (10 ml), and 1N sodium hydroxide (8 ml).
Was added and stirred at 60 ° C. for 40 minutes. Concentrate the reaction,
Water (20 ml) was added, the mixture was neutralized with a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography,
5-trans-1- (4-biphenylmethyl) -5
[3-[(1-tert-butoxycarbonylamino-1-
Methyl) ethyl] phenyl] -2-oxo-1,2,3,
5-Tetrahydro-4,1-benzoxazepine-3-acetic acid (0.9 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.428 (9H, br), 1.534 (6H, s),
2.88-3.25 (2H, m), 4.72-5.08 (2H, m), 5.33-5.62 (2H, m),
6.551 (1H, d, J = 8.2 Hz), 6.83-7.65 (16H, m). (6) The compound (0.9 g) obtained in (5) and 2-fluorobenzylamine (0.22 g) were converted to N , N-dimethylformamide (10 ml), diethyl cyanophosphate (0.28 g) and then triethylamine (0.21 g) were added with stirring at 0 ° C. The reaction was allowed to proceed at room temperature for 20 minutes.
After stirring for minutes, water (40 ml) was added and ethyl acetate (6 ml) was added.
0 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5.
-Trans-N- (2-fluorobenzyl) -1- (4
-Biphenylmethyl) -5- [3- [1-tert-butoxycarbonyl-1-methyl) ethyl] phenyl] -2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.75 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.294 (3H, s),
1.311 (9H, br), 1.579 (3H,
s), 2.720 (1H, dd, J = 5.8, 1
4.2Hz), 2.951 (1H, dd, J = 7.
2, 14.2 Hz), 4.38-4.73 (3H,
m), 4.877 (1H, d, J = 14.2 Hz),
5.325 (1H, s), 5.507 (1H, d,
J = 14.2 Hz), 6.32-6.42 (1H,
m), 6.555 (1H, d, J = 7.8 Hz),
6.94-7.63 (20H, m).

Example 200 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-amino-1-methyl) ethyl] phenyl] -1- (4-biphenylmethyl) -2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 4N hydrogen chloride (ethyl acetate solution) (6 ml) was added to the compound (0.7 g) obtained in Example 199. ) Was added and stirred for 2 hours. The reaction mixture was concentrated, ethyl acetate (20 ml) was added to the residue, and the mixture was concentrated again. From the residue, the title compound (0.56
g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.379 (3H, s), 1.392 (3H, s),
2.746 (1H, dd, J = 5.8, 14.3Hz), 2.963 (1H, dd, J = 7.4, 14.
3Hz), 4.37-4.58 (3H, s), 4.977 (1H, d, J = 14.6Hz), 5.420
(1H, d, J = 14.6Hz), 5.484 (1H, s), 6.504 (1H, t, J = 5.6Hz),
6.565 (1H, d, J = 7.6Hz), 6.95-7.58 (20H, m).

Example 201 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -7-chloro-1- (4
-Diethylamino) benzyl-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide (1) 2-amino-α- obtained in Example 92
[3 ′-[(1-tert-butoxycarbonylamino-1
-Methyl) ethyl] phenyl] -5-chloro-benzyl alcohol (0.9 g) and 4- (diethylamino) benzaldehyde (0.45 g) were dissolved in methanol (20 ml), and acetic acid (0.16 g) was added. While stirring at, sodium cyanoborohydride (0.17 g) was added. The reaction solution was stirred at 60 ° C. for 40 minutes, concentrated, and extracted by adding water (40 ml) and ethyl acetate (50 ml).
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethyl acetate (20 ml), 1N sodium hydroxide (12 ml) was added, and while stirring, fumaric acid monoethyl ester (0.26 g) was added.
After stirring the reaction solution for 20 minutes, the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (20 ml), potassium carbonate (0.4 g) was added, and the mixture was stirred at 60 ° C for 1.5 hours. The reaction was diluted with ethyl acetate (50 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography and 3,5-trans-5- [3-[(1-tert-butoxycarbonylamino-1-methyl) ethyl] phenyl] -1- (4-diethylamino) benzyl- 7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetic acid ethyl ester (0.32 g) was obtained as a yellow-green amorphous solid. NMR (CDCl ₃ ) δ: 1.08-1.47 (18H, m), 1.539 (3H,
s), 1.593 (3H, s), 2.753 (1H, dd, J = 5.4,16.5Hz), 3.106
(1H, dd, J = 8.0,16.5Hz), 3.333 (4H, q, J = 7.2Hz), 4.139
(2H, q, J = 7.2Hz), 4.420 (1H, dd, J = 5.6, 8.1Hz), 4.588 (1
(H, d, J = 14.2Hz), 4.83-4.93 (1H, m), 5.325 (1H, s), 5.467
(1H, d, J = 14.2Hz), 6.52-6.63 (3H, m), 6.84-7.52 (8H, m). (2) The compound (0.3g) obtained in (1) was treated with tetrahydrofuran ( 4 ml) and methanol (10 ml)
Add 1N sodium hydroxide (5 ml) and add 40 ml at 60 ° C.
Stirred for minutes. The reaction solution was concentrated, water (20 ml) was added,
Neutralize with 5% aqueous potassium hydrogen sulfate solution and add ethyl acetate (5%
0 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in N, N-dimethylformamide (6 ml), 2-fluorobenzylamine (40 mg) was added, and the mixture was stirred at 0 ° C. while stirring with diethyl cyanophosphate (60 mg) and triethylamine (50 mg).
Was added. The reaction solution was stirred at room temperature for 20 minutes, added to ice water and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -5- [3-[(1-tert-butoxycarbonylamino-1-methyl). Ethyl] phenyl] -7-chloro-1- (4-diethylamino) benzyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.21 g) Obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.129 (6H, t, J = 6.8Hz), 1.22-1.
43 (9H, m), 1.512 (3H, s), 2.692 (1H, dd, J = 6.0,14.5Hz),
2.925 (1H, dd, J = 7.2,14.5Hz), 3.327 (4H, q, J = 6.8Hz),
4.37-4.63 (4H, m), 4.83-4.93 (1H, m), 5.306 (1H, s), 5.4
39 (1H, d, J = 14.0Hz), 6.32-6.43 (1H, m), 6.47-7.25 (15H,
m),

Example 202 3,5-trans-N- (2-fluorobenzyl) -5
-[3-[(1-Amino-1-methyl) ethyl] phenyl] -7-chloro-1- (4-diethylamino) benzyl-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide dihydrochloride To the compound obtained in Example 201 (0.18 g) was added 4N hydrogen chloride (ethyl acetate solution) (3 ml), and the mixture was added at room temperature for 3 hours.
Stirred for 0 minutes. The reaction mixture was concentrated, ethyl acetate (20 ml) was added to the residue, and the mixture was concentrated again. The title compound (0.17 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.121 (6H, t, J = 7.0Hz), 1.469 (3
H, s), 1.490 (3H, s), 2.730 (1H, dd, J = 5.8,14.6Hz), 3.3
10 (4H, q, J = 7.0Hz), 4.35-4.53 (3H, m), 4.597 (1H, d, J = 1
4.2Hz), 5.359 (1H, s), 5.40 (1H, d, J = 14.2Hz), 6.45-6.6
2 (4H, m), 6.87-7.55 (12H, m).

Example 203 N- (2-Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethyl) phenyl-7-chloro-
2-oxo-1-[(3-phenyl) -2-propenyl] -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) Obtained in Example (1) The obtained 2-amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.6 g) and cinnamaldehyde (0.5 g) were dissolved in methanol (15 ml), and acetic acid was added. (0.11 g) and stirring at room temperature,
Sodium cyanoborohydride (0.12 g) was added. The reaction solution was stirred at 60 ° C. for 40 minutes, concentrated, and extracted by adding water (30 ml) and ethyl acetate (50 ml).
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and α- (3-tert-butoxycarbonylaminomethylphenyl) -5-chloro-2-[(3-phenyl)
-2-propenyl] amino-benzyl alcohol (0.
8g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.445 (9H, s), 3.83-3.89 (2H,
m), 4.291 (2H, d, J = 5.6Hz), 4.73-4.86 (1H, m), 5.823 (1H,
s), 6.08-6.47 (2H, m), 6.630 (1H, d, J = 8.6Hz), 6.990 (1
(H, d, J = 2.0Hz), 7.04-7.48 (10H, m). (2) The compound (0.8 g) obtained in (1) was dissolved in ethyl acetate (20 ml), and 1N sodium hydroxide was added. (1
0 ml) and monoethyl fumarate chloride (0.29 g) was added with stirring at room temperature. After stirring for 10 minutes, the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was ethanol (20 m
l), add potassium carbonate (0.7 g) and add 60 ° C
For 2 hours. The reaction solution was diluted with ethyl acetate (50 ml), washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 3,5-cis and 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- [ (3-phenyl) -2-
Propenyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.6 g) was obtained as an oily mixture. NMR (CDCl ₃ ) δ: 1.18-1.33 (3H, m), 1.447 (9H,
s), 2.62-3.23 (2H, m), 3.93-4.92 (8H, m), 5.760 (1 / 2H,
s), 5.866 (1 / 2H.s), 6.12-6.72 (2H, m), 6.95-7.63 (11H,
m). (3) The compound (0.6 g) obtained in (2) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml), and 1N sodium hydroxide (5 ml) was added.
For 40 minutes. The reaction was concentrated, diluted with water (10 ml), neutralized with 5% aqueous potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. Oily residue (0.3
g) was dissolved in N, N-dimethylformamide (6 ml), and 2-fluorobenzylamine (65 mg) was added.
While stirring at 0 ° C., diethyl cyanophosphate (85 mg)
And triethylamine (57 mg) were added. The reaction solution was stirred at room temperature for 20 minutes, diluted with ethyl acetate (30 ml), washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to give the title compound, N- (2-fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethyl) phenyl-7-chloro-2. -Oxo-1-[(3
-Phenyl) -2-propenyl] -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.22 g) as a colorless oil. NMR (CDCl ₃ ) δ: 1.419 (3.6H, s), 1.439 (5.4H,
s), 2.63-3.07 (2H, m), 3.959 (0.8H, d, J = 6.4Hz), 4.25
(1.2H, d, J = 5.6Hz), 4.33-4.92 (5.4H, m), 5.26-5.93 (0.6
H, m), 5.738 (0.6H, s), 5.857 (0.4H, s), 6.23-6.63 (3.6
H, m), 6.96-7.47 (15.4H, m).

Example 204 N- (2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2-oxo-1-[(3-
Phenyl) -2-propenyl] -1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 4N hydrogen chloride (acetic acid) was added to the compound (0.22 g) obtained in Example 203. (Ethyl solution) (3 ml) and stirred for 40 minutes. The reaction solution was distilled off, and the residue was treated with ethyl acetate (30%).
ml) was added and evaporated again. The title compound (0.21 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl3) δ: 2.165 (2H, br), 2.63-3.07 (2H,
m), 3.62-3.98 (2.6H, m), 4.33-4.83 (4H, m), 5.25-5.42
(0.4H, s), 5.746 (0.6H, s), 5.847 (0.4H, s), 6.23-6.63
(2.6H, m), 6.78-7.47 (15.4H, m).

Example 205 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethyl) phenyl-1- [2- (4-benzyloxycarbonylamino) phenylethyl] -7-chloro-2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-
3-acetamide (1) 4-aminophenethyl alcohol (3.5 g)
Was dissolved in ethyl acetate (60 ml), 1N sodium hydroxide (50 ml) was added, and carbobenzoxy chloride (4.5 g) was added with stirring at room temperature. After stirring for 30 minutes, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 4-benzyloxycarbonylaminophenethyl alcohol (4.5 g) was obtained as brown crystals (4.5 g). NMR (CDCl ₃ ) δ: 2.822 (2H, t, J = 6.6 Hz), 3.829 (2
(H, t, J = 6.6Hz), 5.199 (2H, s), 6.69 (1H, br), 7.13-7.44
(2) A solution of oxalyl chloride (1.29 g) in methylene chloride (40 ml) was cooled to -78 ° C, dimethyl sulfoxide (1.6 g) was added, and the mixture was stirred for 5 minutes. )
Methylene chloride (10m2) of the compound (2.5g) obtained in
l) The solution was added dropwise. Then triethylamine (6.4m
l) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 4-benzyloxycarbonylaminophenylacetaldehyde (0.5 g) as a colorless oil. NMR (CDCl ₃ ) δ: 3.62-3.68 (2H, m), 5.206 (2H,
s), 6.63-6.77 (1H, m), 7.13-7.45 (9H, m), 9.73 (1H, br). (3) 2-amino-5-chloro-α obtained in Example (1) -(3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.6 g) and (1)
4- (benzyloxycarbonylaminophenylacetaldehyde (0.5 g) obtained in
Acetic acid (0.11 g) and sodium cyanoborohydride (0.12 g), and the mixture was stirred at 60 ° C for 1 hour. The reaction solution was concentrated, and extracted by adding water (20 ml) and ethyl acetate (30 ml). The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2-
[2- (4-Benzyloxycarbonylamino) phenylethyl] -5-chloro-α- (3-tert-butoxycarbonylaminomethyl) phenyl-benzyl alcohol (0.8 g) was obtained. NMR (CDCl ₃ ) δ: 1.435 (9H, s),
2.73-2.83 (2H, m), 3.23-3.3
3 (2H, m), 4.255 (2H, d, J = 5.8
Hz), 5.194 (2H, s), 5.623 (1
H, s), 6.85-7.45 (11H, m).

(4) Compound (0.8) obtained in (3)
g) was dissolved in ethyl acetate (30 ml), 1N sodium hydroxide (10 ml) was added, and while stirring at room temperature, fumaric acid monoethyl ester (0.24 g) was added.
After stirring the reaction solution for 40 minutes, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml) and potassium carbonate (0.4) was added.
g) was added and the mixture was stirred at 60 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate (40 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 3,5-trans-5.
-(3-tert-butoxycarbonylaminomethylphenyl) -1- [2- (4-benzyloxycarbonylamino) phenylethyl] -7-chloro-2-oxo-1,
2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.25 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.232 (3H, t, J = 7.2 Hz), 2.723 (1
H, dd, J = 5.8, 16.6Hz), 2.83-3.16 (3H, m), 3.79-3.97 (1
H, m), 4.119 (2H, q, J = 7.2Hz), 4.255 (2H, d, J = 5.8Hz), 4.
355 (1H, dd, J = 6.0,7.7Hz), 4.68-4.87 (1H, m), 5.172 (3
H, s), 6.478 (1H, d, J = 2.4Hz), 6.910 (1H, s), 7.04-7.43
(5H, m). (5) The compound (0.25 g) obtained in (4) was dissolved in tetrahydrofuran (4 ml) and methanol (8 ml), and 1N sodium hydroxide (2 ml) was added thereto. Stirred for 20 minutes. The reaction solution was concentrated, neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in N, N-dimethylformamide (6 ml), and 2-fluorobenzylamine (42 mg) was added.
While stirring at ° C, diethyl cyanophosphate (55 mg) and triethylamine (36 mg) were added. The reaction was allowed to
After stirring for 0 minutes, the mixture was diluted with ethyl acetate (50 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -1- "2- (4-benzyloxycarbonylamino) phenylethyl] -7-chloro-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.2 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.419 (9H, s), 2.642 (1H, dd, J = 6.
2, 14.6Hz), 2.76-3.14 (3H, m), 3.73-4.58 (6H, m), 4.68
-4.92 (1H, m), 5.02-5.17 (1H, m), 5.128 (1H, s), 5.182 (2
H, s), 6.12-6.33 (1H, m), 6.463 (1H, d, J = 2.4Hz), 6.855
(1H, s), 6.96-7.43 (19H, m).

Example 206 3,5-trans-N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -1- [2- (4-benzyloxycarbonylamino) phenylethyl] -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide hydrochloride To the compound (45 mg) obtained in Example 205 was added 4N hydrogen chloride (ethyl acetate solution) (2 ml), and the mixture was stirred for 2 hours. The reaction mixture was evaporated, and ethyl acetate was added to the residue to give the title compound (31 mg) as colorless crystals. Melting point: 196-198 ° C NMR (CDCl ₃ ) δ: 2.65-3.55 (5H, m), 4.035 (2H, b
r), 4.23-4.45 (3H, m), 4.52-4.72 (1H, m), 5.142 (2H, s),
5.244 (1H, s), 6.366 (1H, d, J = 2.0Hz), 7.05-7.65 (19H,
m), 8.15-8.55 (3H, m), 9.700 (1H, s).

Example 207 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethyl) phenyl-7-chloro-1- (furan-2-yl) methyl-
1,2,3,5-tetrahydro-4,1-benzonzazepine-3-acetamide (1) 2-amino-5-chloro-α- (3- (tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) and furfural (0.15 g) were dissolved in methanol (15 ml), and acetic acid (0.1 g) and sodium cyanoborohydride (0.11 g) were added. And stirred at 60 ° C. for 40 minutes. The reaction mixture was concentrated, and water (30 ml) and ethyl acetate (50 ml) were added to the residue.
ml) and extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 5-chloro-2- (furan-2-yl-methyl) amino-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.6 g) was colorless. Obtained as an oil. NMR (CDCl ₃ ) δ: 1.451 (9H, s), 4.240 (2H, s), 4.
303 (2H, d, J = 6.2Hz), 4.73-4.92 (1H, m), 5.804 (1H, s),
6.04-6.08 (1H, m), 6.26-6.33 (1H, m), 6.652 (1H, d, J = 8.8
(Hz), 6.97-7.43 (7H, m). (2) The compound (0.6 g) obtained in (1) was dissolved in ethyl acetate (15 ml), and 1N sodium hydroxide (8 ml) was added.
ml) and the mixture was stirred while adding monoethyl ester of fumaric acid chloride (0.23 g). After stirring the reaction solution for 10 minutes, the organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in ethanol (20 ml), potassium carbonate (0.4 g) was added and the mixture was stirred at 60-70 ° C for 40 minutes. The reaction solution was diluted with ethyl acetate (50 ml), washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 3,5-trans-5-
(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (furan-2-yl) methyl-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.4 g)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.232 (3H, t, J = 7.2 Hz), 1.454 (9
H, s), 2.769 (1H, dd, J = 5.6,16.8Hz), 3.091 (1H, dd, J = 8.
0, 16.8Hz), 4.125 (2H, q, J = 7.2Hz), 4.328 (2H, d, J = 6.0H
z), 4.441 (1H.dd, J = 5.8,7.9Hz), 4.638 (1H, d, J = 15.4H
z), 5.411 (1H, d, J = 15.4Hz), 5.566 (1H, s), 6.27-6.36 (2
H, m), 6.537 (1H, s), 7.08-7.43 (7H, m). (3) The compound (0.4 g) obtained in (2) was dissolved in tetrahydrofuran (3 ml) and methanol (6 ml). ,
Add 1N sodium hydroxide (3 ml) and add
Stirred for minutes. The reaction solution was concentrated, neutralized with a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in N, N-dimethylformamide (6 ml), and 2-fluorobenzylamine (65 mg) was added thereto.
mg) and triethylamine (58 mg). After the reaction solution was stirred at room temperature for 20 minutes, water (30 ml) and ethyl acetate (40 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl)
-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (furan-2-yl) methyl-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide (0.15 g)
Was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.443 (9H, s), 2.699 (1H, dd, J =
6.2, 14.5Hz), 2.905 (1H, dd, J = 7.2,14.5Hz), 4.293 (2
H, d, J = 6.0Hz), 4.33-4.58 (3H, m), 4.796 (1H, d, J = 15.4H
z), 4.85-4.97 (1H, m), 5.393 (1H, d, J = 15.4Hz), 5.538 (1
H, s), 6.24-6.44 (3H, m), 6.516 (1H, s), 6.97-7.38 (11H,
m).

Example 208 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(Furan-2-yl) methyl-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide hydrochloride To the compound (0.12 g) obtained in Example 207 was added 4N hydrogen chloride (ethyl acetate solution) (2 ml), and the mixture was stirred for 2 hours. The reaction solution was distilled off, and the residue was treated with ethyl acetate (30 m
l) was added and evaporated again. From the residue, the title compound (0.
11 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.196 (2H, br), 2.712 (1H, dd, J =
6.0, 14.5Hz), 2.904 (1H, dd, J = 7.0, 14.5Hz), 3.859 (2
H, s), 4.33-4.58 (3H, m), 4.823 (1H, d, J = 15.4Hz), 5.361
(1H, d, J = 15.4Hz), 5.564 (1H, s), 6.25-6.57 (4H, m), 6.9
7-7.37 (11H, m).

Example 209 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-1- (thiazol-5-yl) methyl-4,1
-Benzoxazepine-3-acetamide (1) 2-amino-α- obtained in Example (1)
(3-tert-butoxycarbonylaminomethylphenyl) -5-chloro-benzyl alcohol (1 g) and thiazole-5-carboxaldehyde (0.34 g) were dissolved in methanol (10 ml), and acetic acid (0.33 g) and cyano were dissolved. Add sodium borohydride (0.21 g) and add 6
Stirred at 0 ° C. for 1 hour. The reaction solution was added to a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and α- (3-tert-butoxycarbonylaminomethylphenyl) -5-chloro-2- (thiazol-5-yl) methylamino-benzyl alcohol (1.22 g)
Was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.438 (9H, s), 4.273 (2H, d, J = 5.
4Hz), 4.456 (2H, s), 4.89-5.17 (2H, br), 5.773 (1H, s),
6.580 (1H, d, J = 8.4Hz), 7.01-7.36 (6H, m), 7.539 (1H, s),
8.624 (1H, s). (2) The compound (1.1 g) obtained in (1) was dissolved in ethyl acetate (20 ml), and sodium hydrogen carbonate (0.3) was dissolved.
g) was added and, while stirring at room temperature, monoethyl chloride fumarate (0.41 g) was added. The reaction solution was stirred for 1 hour, washed with water, dried over anhydrous sodium sulfate,
Distilled off. The residue was dissolved in ethanol (20 ml), potassium carbonate (0.24 g) was added, and the mixture was stirred at room temperature for 20 hours. Water (100 ml) and ethyl acetate (100 m
l) was added for extraction, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 3,5-cis and 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1,2. , 3,5-
Tetrahydro-2-oxo-1- (thiazol-5-yl) methyl-4,1-benzoxazepine-3-acetic acid ethyl ester (0.81 g) was obtained as a mixture of a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.249 (3H, t, J = 7.4Hz), 1.435,
1.449 (9H, each s), 2.767 (2 / 3H, dd, J = 5.4,16.8Hz),
2.877 (1 / 3H, dd, J = 6.2, 16.8Hz), 3.122 (2 / 3H, dd, J = 8.
4, 16.8Hz), 3.164 (1 / 3H, 1H, dd, J = 8.4,16.8Hz), 4.09-
4.32 (4H + 2 / 3H, m), 4.444 (2 / 3H, dd, J = 5.4,8.4Hz), 4.
540 (1 / 3H, dd, J = 6.2,8.4Hz), 4.80-4.90 (1H, br), 5.034
(2 / 3H, d, J = 15.4Hz), 5.401 (2 / 3H, s), 5.658 (2 / 3H, d, J =
15.4Hz), 5.855 (1 / 3H, s), 6.546 (2 / 3H, d, J = 2.2Hz), 6.
91-7.55 (6H + 1 / 3H, m), 7.777 (1H, s), 8.790 (1H, s).

(3) Compound (0.7) obtained in (2)
g) was dissolved in ethanol (7 ml), 1N sodium hydroxide (1.5 ml) was added, and the mixture was stirred at 60 ° C for 30 minutes. Water (100 ml) was added to the reaction solution, neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (100 ml × 2). The organic layer is washed with water, dried over anhydrous sodium sulfate,
Distilled off. From the residue, 3,5-cis and 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1,2,3,5-tetrahydro-2-oxo-1- (Thiazol-5-yl) methyl-
4,1-benzoxazepine-acetic acid (0.36 g) was obtained as a mixture of a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.441 (9H, s), 2.74-2.82 (4 / 3H,
m), 3.108 (2 / 3H, dd, J = 7.6, 16.2Hz), 4.25-4.48 (3H + 2
/ 3H, m), 5.05-5.15 (1H, br), 5.056 (2 / 3H, d, J = 16.2Hz),
5.416 (2 / 3H, s), 5.786 (2 / 3H, d, J = 16.2Hz), 5.722 (1 / 3H,
s), 6.54-7.52 (7H, m), 7.790 (1H, s), 8.655 (1H, br), 8.
788 (1H, s). (4) The compound (0.29 g) obtained in (3) and 2-
Fluorobenzylamine (67 mg) was dissolved in N, N-dimethylformamide (3 ml) and stirred at room temperature,
Diethyl cyanophosphate (96 mg) and triethylamine (74 mg) were added. The reaction solution was stirred for 10 minutes, diluted with ethyl acetate (50 ml), washed with a 5% aqueous solution of potassium hydrogen sulfate, washed with saturated sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography.
The title compound, 3,5-trans-N- (2-fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1,2,3,5-
Tetrahydro-1- (thiazol-5-yl) methyl-
2-oxo-4,1-benzoxazepine-3-acetamide (0.2 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.445 (9H, s), 2.696 (1H, dd, J =
5.8, 14.6Hz), 2.929 (1H, dd, J = 6.8, 14.6Hz), 4.283 (2
(H, d, J = 5.6Hz), 4.38-4.60 (3H, m), 4.85-4.95 (1H, br),
4.989 (1H, d, J = 15.2Hz), 5.372 (1H, s), 5.654 (1H, d, J = 1
5.2Hz), 6.20-6.30 (1H, br), 6.529 (1H, d, J = 1.8Hz), 6.9
5-7.43 (10H, m), 7.766 (1H, s), 8.773 (1H, s),

Example 210 3,5-trans-N- (2-fluorobenzyl) -5
-(3-aminomethylphenyl) -7-chloro-1,2,
3,5-tetrahydro-1- (thiazol-5-yl)
Methyl-2-oxo-4,1-benzoxazepine-3
-Acetamide oxalate To the compound (0.1 g) obtained in Example 209 was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, ethyl acetate (10 ml) was added to the residue to dissolve the residue, and oxalic acid (11 mg) in methanol (2 ml) was added to the solution.
l) The solution was added. The solvent was distilled off, and ether and hexane were added to the residue to precipitate the title compound (135 mg) as a non-crystalline solid. NMR (CD ₃ OD) δ: 2.72-2.95 (2H, m), 4.094 (2H,
s), 4.416 (2H, s), 4.46-4.53 (1H, m), 5.184 (1H, d, J = 15.
4Hz), 5.440 (1H, s), 5.724 (1H, d, J = 15.4Hz), 6.435 (1H,
d, J = 2.2Hz), 7.01-7.65 (6H, m), 7.821 (1H, s), 8.968 (1
H, s).

Example 211 N- (2-Fluorobenzyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3-dihydro-2-oxo-1H-1,4- Benzodiazepine-3-acetamide (1) Compound obtained in Example 97 (1) 5- (3
-Tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3-dihydro-2-oxo-1
To a solution of H-1,4-benzodiazepine-3-acetic acid methyl ester (0.6 g) in methanol (6 ml) was added a 1N aqueous sodium hydroxide solution (1.5 ml).
Stirred for hours. The reaction was diluted with water (50 ml), acidified and extracted twice with ethyl acetate (50 ml). The whole extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 5- (3-te
rt-butyloxycarbonylaminomethylphenyl)-
7-chloro-2,3-dihydro-2-oxo-1H-1,
4-benzodiazepine-3-acetic acid (0.64 g) was obtained as a colorless amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.10-3.49 (2
H, m), 4.11 (1H, t, J = 6.4Hz), 4.20-4.36 (2H, m), 4.90-5.
00 (1H, br), 7.16-7.49 (7H, m), 9.80 (1H, br). (2) The compound (0.57 g) obtained in (1) and 2-
To a solution of fluorobenzylamine (0.16 g) in dimethylformamide (5 ml) was added diethyl cyanophosphate (0.2).
2 g) and triethylamine (0.19 g) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was ethyl acetate (50 ml)
After washing with water, a 5% aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography [eluent: Ac
OEt-hexane (1: 1)] to give N- (2-fluorobenzyl) -5- (3-tert-
Butyloxycarbonylaminomethylphenyl) -7-
Chloro-2,3-dihydro-2-oxo-1H-1,4-
Benzodiazepine-3-acetamide (0.75 g) was obtained as an anhydrous amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.06 (1H, dd,
J = 6.6, 14.6Hz), 3.18 (1H, dd, J = 6.6, 14.6Hz), 4.16 (1
H, dd, J = 6.0,6.6Hz), 4.30 (2H, d, J = 6.0Hz), 4.47 (1H, d
d, J = 5.0, 15.4Hz), 4.61 (1H, dd, J = 6.6, 15.4Hz), 4.84-
4.96 (1H, br), 6.70-6.80 (1H, br), 7.00-7.41 (11H, m),
8.65-8.75 (1H, br).

Example 212 N- (2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetamide * Monohydrochloride Compound N- (2-fluorobenzyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3-dihydro- obtained in Example 211
A solution of 2-oxo-1H-1,4-benzodiazepine-3-acetamide (0.16 g) in trifluoroacetic acid (2
ml) was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). To this solution was added 4N hydrogen chloride in ethyl acetate (0.2 ml), and the solvent was distilled off under reduced pressure. The residue was treated with diethyl ether
After washing with hexane (1: 1), the product is filtered to give N
-(2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetamide monohydrochloride (0.1%). 13g) was obtained as a colorless amorphous solid. ¹ H-NMR (CD ₃ OD) δ: 3.29-3.32 (2H, m), 3.95-
4.01 (1H, m), 4.23 (2H, s), 4.49 (2H, s), 7.02-7.85 (11H,
m).

Example 213 (3,5-trans) -N- (2-fluorobenzyl)
-5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-3
-Acetamide Compound N- obtained in Example 211-
(2-fluorobenzyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-
Acetic acid (1 ml) and sodium cyanoborohydride (17 mg) were added to a solution of 2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-acetamide (0.1 g) in methanol (2 ml) at room temperature. Then, the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was diluted with ethyl acetate, washed with a 1N aqueous sodium hydroxide solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography [eluent: hexane-ethyl acetate (1: 1)].
(3,5-cis) -N- (2-fluorobenzyl) -5
-(3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-
2-oxo-1H-1,4-benzodiazepine-3-acetamide (0.08 g) and (3,5-trans)-
N- (2-fluorobenzyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo-1H-
1,4-benzodiazepine-3-acetamide (0.19
g) were each obtained as a colorless amorphous solid. 3,5-cis form: ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9
H, s), 2.62 (1H, dd, J = 7.0,15.0Hz), 2.77 (1H, dd, J = 4.8,
15.0Hz), 4.01 (1H, dd, J = 4.8, 7.0Hz), 4.22 (2H, d, J = 5.
0Hz), 4.46 (2H, d, J = 6.2Hz), 4.84-4.98 (1H, br), 5.19 (1
H, s), 6.55-6.65 (1H, br), 6.82-7.31 (11H, m), 7.55-7.6
5 (1H, br). Anal. Calcd for C ₃₀ H ₃₂ N ₄ O ₄ ClF + 0.3H ₂ O: C, 62.94;
H, 5.74; N, 9.79.Found: C, 62.87; H, 5.86; N, 9.6
7. 3,5-trans form: ¹ H-NMR (CDCl ₃ ) δ: 1.4
4 (9H, s), 2.56 (1H, dd, J = 6.4, 15.0Hz), 2.75 (1H, dd, J =
6.6, 15.0Hz), 3.82 (1H, dd, J = 6.4,6.6Hz), 4.30 (2H, d,
J = 6.2Hz), 4.46 (2H, d, J = 5.2Hz), 4.90-5.00 (1H, br), 5.
31 (1H, s), 6.62 (1H, s), 6.70-6.80 (1H, br), 6.94-7.38
(10H, m), 8.10-8.20 (1H, br).

Example 214 (3,5-trans) -N- (2-fluorobenzyl)
-5- (3-Aminomethylphenyl) -7-chloro-
2,3,4,5-tetrahydro-2-oxo-1H-1,4
-Benzodiazepine-3-acetamide dihydrochloride Compound (3,5-trans) obtained in Example 213-
N- (2-fluorobenzyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo-1H-
1,4-benzodiazepine-3-acetamide (0.11
A solution of g) in trifluoroacetic acid (1 ml) was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). To this solution was added 4N hydrogen chloride in ethyl acetate (0.2 ml), and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether-hexane (1: 5) and collected by filtration to give (3,5-trans) -N
-(2-Fluorobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-
Acetamide dihydrochloride (97 mg) was obtained as a colorless amorphous solid. ¹ H-NMR (CD ₃ OD) δ: 2.92 (1 H, d
d, J = 4.0, 16.2 Hz), 3.17 (1
H, dd, J = 8.8, 16.2 Hz), 4.22
(2H, s), 4.38 (1H, dd, J = 4.0,
8.8 Hz), 4.42 (2H, s), 5.85
(1H s), 6.88 (1H, d, J = 2.2H)
z), 7.01-7.83 (10H, m).

Example 215 (3,5-trans) -N- (2-fluorobenzyl)
-1- (4-biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo-1H
-1,4-benzodiazepine-3-acetamide (1) Compound 1- (4-) obtained in Example 97 (2)
Biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3
Acetic acid (3 ml) and sodium cyanoborohydride (97 mg) were added to a methanol solution (6 ml) of -dihydro-2-oxo-1H-4,1-benzodiazepine-3-acetic acid methyl ester (0.66 g) at room temperature. And stirred at 60 ° C. for 2 hours. Dilute the reaction with ethyl acetate (100 ml)
Washed with 1N aqueous sodium hydroxide solution and saturated saline. After drying this over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give (3,5-trans) -1- (4-
Biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,
4,5-tetrahydro-2-oxo-1H-4,1-benzodiazepine-3-acetic acid methyl ester (0.65 g)
Was obtained as a colorless amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.43, 1.44 (total 9H, ea
ch s), 2.63 (1H, dd, J = 4.6,16.4Hz), 2.96 (1H, dd, J = 8.
6, 16.4Hz), 3.70 (3H, s), 3.79 (1H, dd, J = 4.6,8.6Hz),
4.20 (2H, d, J = 5.2Hz), 4.25-4.30 (1H, br), 4.70-4.80 (1
H, br), 4.82 (1H, s), 4.86 (1H, d, J = 14.4Hz), 5.46 (1H, d, J
= 14.4Hz), 6.49 (1H, s), 6.97-7.58 (15H, m). (2) 1N aqueous sodium hydroxide solution was added to a methanol solution (6ml) of the compound (0.6g) obtained in (1). (1.2 ml) and stirred at 60 ° C. for 1 hour. The reaction was diluted with water (50 ml), acidified and extracted twice with ethyl acetate (50 ml). The whole extract was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give (3,5-trans) -1- (4
-Biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -2,3,4,5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid (0.62 g) Was obtained as a colorless amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.32, 1.34 (total 9H, ea
ch s), 2.63 (1H, dd, J = 6.0,17.0Hz), 2.84 (1H, dd, J = 8.
4, 17.0Hz), 3.68 (1H, dd, J = 6.0,8.4Hz), 4.10 (2H, d, J =
5.2Hz), 4.15-4.20 (1H, br), 4.70 (1H, s), 4.72 (1H, d, J =
14.8Hz), 5.39 (1H, d, J = 14.8Hz), 6.40 (1H, s), 6.84-7.4
7 (15H, m). (3) Compound (3,5-trans) obtained in (2)
-1- (4-biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -2,3,
To a solution of 4,5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-acetic acid (0.53 g) and 2-fluorobenzylamine (0.11 g) in dimethylformamide (5 ml) was added diethyl cyanophosphate (5 ml). 0.15 g) and triethylamine (0.13 g) were added.
Stirred for minutes. The reaction solution was diluted with ethyl acetate (50 ml), washed with water, a 5% aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is separated and formed by silica gel column chromatography [eluent: hexane-ethyl acetate (3: 2)].
(3,5-trans) -N- (2-fluorobenzyl)
-1- (4-biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo-1H
-1,4-benzodiazepine-3-acetamide (0.4
8g) was obtained as a colorless amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.56 (1H, dd,
J = 5.4, 15.0Hz), 2.81 (1H, dd, J = 7.4, 15.0Hz), 3.82 (1
H, dd, J = 5.4, 7.4Hz), 4.16 (2H, d, J = 7.0Hz), 4.48 (2H, t,
J = 4.8Hz), 4.76 (1H, s), 4.77 (1H, d, J = 14.6Hz), 5.49 (1
(H, d, J = 14.6Hz), 6.46 (1H, s), 6.65-6.75 (1H, m), 6.89-
7.56 (19H, m).

Example 216 (3,5-trans) -N- (2-fluorobenzyl)
-5- (3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-
3-acetamide dihydrochloride Compound (3,5-trans)-obtained in Example 215
N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo A solution of -1H-1,4-benzodiazepine-3-acetamide (0.12 g) in trifluoroacetic acid (2 ml) was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). To this solution was added a 4N hydrogen chloride solution in ethyl acetate (0.
2 ml) was added and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol-diethyl ether (1:10) to give (3,5-trans) -N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -1-.
(4-biphenylmethyl) -7-chloro-2,3,4,5
-Tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-acetamide dihydrochloride (88 mg) was obtained as colorless powdery crystals. Melting point: 210-216 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.97 (1H, dd, J = 3.6,16.0H)
z), 3.28 (1H, dd, J = 9.4,16.0Hz), 4.06 (2H, s), 4.35 (1H,
dd, J = 3.6, 9.4Hz), 4.43-4.45 (2H, m), 4.98 (1H, d, J = 14.
6Hz), 5.12 (1H, s), 5.58 (1H, d, J = 14.6Hz), 6.77 (1H, d, J
= 2.2Hz), 7.00-7.73 (19H, m).

Example 217 (3,5-trans) -N- (2-fluorobenzyl)
-1- (4-biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-4-methyl-2,3,4,5-tetrahydro-2-
Oxo-1H-1,4-benzodiazepine-3-acetamide Compound (3,5-trans)-obtained in Example 215
N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-2,3,4,5-tetrahydro-2-oxo A mixture of -1H-1,4-benzodiazepine-3-acetamide (0.2 g), iodomethane (42 mg), potassium carbonate (46 mg) and dimethylformamide (2 ml) was stirred at 60 DEG C. for 2 hours. The reaction solution was diluted with ethyl acetate (50 ml), and water, 5%
The extract was washed with an aqueous solution of potassium hydrogen sulfate, an aqueous solution of saturated sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and generated by silica gel column chromatography [eluent: hexane-ethyl acetate (3: 2)] to give (3,5-
Trans) -N- (2-fluorobenzyl) -1- (4
-Biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-4-
Methyl-2,3,4,5-tetrahydro-2-oxo-1
H-1,4-benzodiazepine-3-acetamide (0.
21 g) was obtained as a colorless amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.14 (3H, s),
2.61 (1H, dd, J = 6.0, 15.2Hz), 2.87 (1H, dd, J = 8.4, 15.2H
z), 4.01 (1H, s), 4.07 (1H, dd, J = 6.0,8.4Hz), 4.14-4.2
5 (2H, m), 4.42 (1H, dd, J = 6.6, 15.4Hz), 4.52 (1H, dd, J =
6.6, 15.4Hz), 4.70-4.80 (1H, br), 4.84 (1H, d, J = 14.6H
z), 5.48 (1H, d, J = 14.6Hz), 6.39 (1H, s), 6.93-7.57 (20
H, m).

Example 218 (3,5-trans) -N- (2-fluorobenzyl)
-5- (3-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-4-methyl-2,3,4,
5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-acetamide dihydrochloride Compound (3,5-trans)-obtained in Example 217
(2-fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert-butyloxycarbonylaminomethylphenyl) -7-chloro-4-methyl-2,3,
A solution of 4,5-tetrahydro-2-oxo-1H-1,4-benzodiazepine-3-acetamide (0.1 g) in trifluoroacetic acid (1 ml) was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). To this solution was added 4N hydrogen chloride in ethyl acetate (0.2 ml), and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether-hexane (1: 1) and collected by filtration to give (3,5-trans) -N- (2-fluorobenzyl) -5- (3-aminomethylphenyl)-
1- (4-biphenylmethyl) -7-chloro-4-methyl-2,3,4,5-tetrahydro-2-oxo-1H-
1,4-Benzodiazepine-3-acetamide dihydrochloride (95 mg) was obtained as a colorless amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 2.15 (3H, s), 2.62 (1H, dd,
J = 6.2, 15.2Hz), 2.87 (1H, dd, J = 8.6, 15.2Hz), 3.77 (2
H, s), 4.03 (1H, s), 4.08 (1H, dd, J = 6.2, 8.6Hz), 4.36-
4.55 (2H, m), 4.83 (1H, d, J = 14.6Hz), 5.50 (1H, d, J = 14.6H
z), 6.41 (1H, s), 6.97-7.61 (19H, m).

Example 219 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-
1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamide (1) 2- (4-) obtained in (1) of Example (4)
Biphenylmethyl) amino-5-chloro-α- (3-te
rt-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) and thiomalic acid (0.14)
g) and p-toluenesulfonic acid (9 mg) were suspended in toluene (10 ml) and stirred at 80 ° C for 1 hour. The reaction was diluted with ethyl acetate (50 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was xylene (1
0 ml) and heated under reflux for 15 hours. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography, and 5- [3- (tert-butoxycarbonylaminomethyl) phenyl] -7-chloro-1,2,3,5-tetrahydro-2-oxo is obtained. -1- (4-phenylbenzyl)-
4,1-benzothiazepine-3-acetic acid (0.31 g) was obtained as a mixture of the cis-form and the trans-form. NMR (CDCl ₃ ) δ: 1.308, 1.338 (9H, each s), 2.3
6-2.50 (1H, m), 2.616 (1 / 2H, d, J = 15.8Hz), 3.03-3.27 (1
H, m), 3.57-3.72 (1H, m), 4.22-4.40 (2H, m), 4.655 (1/2
× 2H, s), 4.792 (1/2 × 1H, s), 4.981 (1/2 × 1H, s), 5.00-
5.10 (1H, br), 5.631 (1H, d, J = 14.0Hz), 6.55-7.53 (15H, br
m). (2) Dissolve the compound (5.0 g) obtained in (1) and 2-fluorobenzylamine (1.0 g) in N, N-dimethylformamide (50 ml) and stir at room temperature with cyanoline. Diethyl acid (1.4 g) and triethylamine (1.0 g) were added. After stirring the reaction for 10 minutes,
Dilute with ethyl acetate (200 ml), wash with 5% aqueous potassium hydrogen sulfate, saturated sodium hydrogen carbonate and water in that order,
It was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -5- (3-tert.
-Butoxycarbonylaminomethylphenyl) -7-chloro-1,2,3,5-tetrahydro-2-oxo-4,1-
Benzothiazepine-3-acetamide (1.7 g) was obtained as colorless crystals. Melting point: 123-125 ° C NMR (CDCl ₃ ) δ: 1.437 (9H, s), 2.353 (1H, dd, J =
4.0, 14.6Hz), 3.004 (1H, dd, J = 10.2, 14.6Hz), 3.849 (1
H, dd, J = 4.0, 10.2Hz), 4.372 (1H, d, J = 14.0Hz), 4.46-4.
52 (2H, m), 4.870 (2H, s), 4.912 (1H, s), 5.721 (1H, d, J = 1
4.0Hz), 6.18-6.25 (1H, br), 6.634 (1H, s), 6.69-6.73 (1
H, br), 6.94-7.60 (19H, m).

Example 220 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzothiazepine-3-acetamide hydrochloride To the compound (0.35 g) obtained in Example 219 was added trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 10 minutes.
The reaction solution was distilled off, and the residue was dissolved in ethyl acetate (30 ml), washed with 1N sodium hydroxide, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and 4
Add normal hydrogen chloride (ethyl acetate solution) to make the hydrochloride,
Colorless crystals (0.32 g) were obtained from ether and hexane. Melting point: 280-283 ° C NMR (CDCl ₃ ) δ: 2.355 (1H, dd, J = 3.2, 14.2 Hz),
3.004 (1H, dd, J = 9.8, 14.2Hz), 3.80-3.90 (1H, m), 4.331
(1H, dd, J = 6.2,13.4Hz), 4.381 (1H, s), 4.46-4.52 (2H,
m), 4.874 (2H, s), 5.762 (1H, dd, J = 5.0,13.4Hz), 6.15-
6.25 (1H, br), 6.66-7.59 (20H, m).

Example 221 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1,
2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamido-S-oxide The compound obtained in Example 219 (1.18 g) was dissolved in ethyl acetate (50 ml). m-chloroperbenzoic acid (0.
27 g) and stirred at 0 ° C. for 5 minutes. The reaction solution was diluted with ether acetate (50 ml), washed with an aqueous solution of sodium bisulfite, washed with 1N sodium hydroxide and water in that order,
Dry over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to separate the diastereomer of the title compound. The non-polar compound (0.3 g) was obtained as colorless crystals, and the polar substance (0.5
g) were each obtained as an amorphous solid. Non-polar isomer: Melting point: 214-215 ° C. NMR (CDCl ₃ ) δ: 1.431 (9H, s), 2.865 (1H, dd, J =
2.6, 15.0Hz), 3.369 (1H, dd, J = 11.4, 15.0Hz), 3.606
(1H, dd, J = 2.6, 11.4Hz), 4.02-4.08 (2H, m), 4.210 (1H,
s), 4.39-4.53 (3H, m), 4.61-4.70 (1H, br), 5.762 (1H, d,
J = 14.4Hz), 6.05-6.15 (1H, br), 6.75-7.56 (20H, m). Polar isomer: NMR (CDCl ₃ ) δ: 1.434 (9H, s), 2.773 (1H, dd, J =
5.0, 15.0Hz), 3.992 (1H, dd, J = 5.0,9.2Hz), 4.05-4.11
(2H, m), 4.46-4.52 (3H, m), 6.40-6.50 (1H, br), 6.70-7.
60 (20H, m).

Example 222 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamide S-oxide -Hydrochloride To the nonpolar isomer (0.1 g) obtained in Example 221 was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved by adding ethyl acetate (10 ml). 4N hydrogen chloride (ethyl acetate solution)
(0.1 ml) and concentrated again. The residue was treated with ether and ethanol to give the non-polar isomer of the title compound (9
1 mg) were obtained as colorless crystals. Melting point: 182-186 ° C NMR (CD ₃ OD) δ: 2.850 (1H, dd, J = 2.2,14.8Hz),
3.415 (1H, dd, J = 11.0, 14.8Hz), 3.560 (1H, dd, J = 2.2, 1
1.0Hz), 3.956 (2H, s), 4.34-4.52 (2H, m), 4.641 (1H, d, J
= 14.2Hz), 4.749 (1H, s), 5.723 (1H, d, J = 14.2Hz), 6.616
(1H, d, J = 8.0Hz), 6.982 (1H, d, J = 2.0Hz), 7.07-7.76 (19H,
m). The polar isomer (0.1 g) obtained in Example 221 was treated in the same manner to give the polar isomer of the title compound (63 mg) as colorless crystals. Melting point: 201-204 ° C NMR (CD ₃ OD) δ: 2.844 (1H, dd, J = 6.0, 16.2Hz),
3.200 (1H, dd, J = 9.6, 16.2Hz), 3.867 (1H, d, J = 13.0Hz),
3.962 (1H, d, J = 13.0Hz), 4.008 (1H, dd, J = 6.0,9.6Hz),
4.421 (2H, s), 4.652 (1H, d, J = 14.4Hz), 4.683 (1H, s), 5.
851 (1H, d, J = 14.4Hz), 6.810 (1H, br), 6.859 (1H, d, J = 2.0
Hz), 7.06-7.75 (19H, m).

Example 223 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-
1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamide S-dioxide 3,5-trans-N- (2
-Fluorobenzyl) 5- (3-tert-butoxycarbonylaminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-1,2,3,5-tetrahydro-2
-Oxo-4,1-benzothiazepine-3-acetamide (0.3 g) was dissolved in ethyl acetate (3 ml), m-chloroperbenzoic acid (0.14 g) was added, and the mixture was stirred at 0 ° C for 30 minutes. . The reaction solution was diluted with ethyl acetate (50 ml), washed successively with saturated sodium hydrogen sulfite, 1N sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate and hexane to give the title compound (0.18 g) as colorless crystals. NMR (CDCl ₃ ) δ: 1.432 (9H, s), 2.827 (1H, dd, J =
3.4, 15.8Hz), 3.331 (1H, dd, J = 10.2, 15.8Hz), 4.03-4.
06 (2H, m), 4.443 (1H, d, J = 13.6Hz), 4.48-4.62 (4H, m),
5.897 (1H, d, J = 13.6Hz), 6.15-6.25 (1H, br), 6.87-7.57
(21H, m).

Example 224 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamide S-dioxide -Hydrochloride To the compound (0.1 g) obtained in Example 223 was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction was concentrated and the residue was dissolved in ethyl acetate (5 ml),
4N hydrogen chloride (ethyl acetate solution) (0.1 ml) was added. The solvent was distilled off, and the obtained crystals were recrystallized from ethanol and ether to give the title compound (85 mg) as colorless crystals. NMR (CD ₃ OD) δ: 2.832 (1H, dd, J = 3.2,15.6Hz),
3.348 (1H, dd, J = 11.2, 15.6Hz), 3.863 (1H, d, J = 13.6H
z), 3.972 (1H, d, J = 13.6Hz), 4.378 (1H, d, J = 15.8Hz), 4.
487 (1H, d, J = 15.8Hz), 4.527 (1H, dd, J = 3.2, 11.2Hz), 4.
682 (1H, d, J = 14.2Hz), 4.733 (1H, s), 5.848 (1H, d, J = 14.2
Hz), 6.81-7.8 6 (21H, m).

Example 225 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -1- (3,4-dibenzyloxybenzyl) -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetamide (1) 3,4-dibenzyloxybenzaldehyde 3,4-dihydroxybenzaldehyde (5.0 g), benzyl bromide (14.8 g), potassium carbonate (13 g),
And a mixture of N, N-dimethylformamide (120 ml) was stirred at 60 ° C. for 2 hours. Add cold water (200
ml) and extracted with ethyl acetate (150 ml). The organic layer was washed with a 5% aqueous potassium hydrogen carbonate solution, washed with water, dried over anhydrous sodium sulfate, and evaporated. From the residue, 3,4-dibenzyloxybenzaldehyde (10.5)
g) was obtained as colorless crystals. Melting point: 87-88 ° C 2-amino-5-chloro- obtained in Example 1 (2).
α- (3-tert-Butoxycarbonylaminomethylphenyl) benzyl alcohol (0.6 g) and 3,4-dibenzyloxybenzaldehyde (0.55 g) were dissolved in methanol (20 ml), and acetic acid (0.12 g) was added. Sodium cyanoborohydride (0.13 g) was added and the mixture was stirred at 60 ° C for 1.5 hours. The reaction solution was concentrated, and water (50 m
l) and ethyl acetate (80 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
From the residue, 2- (3,4-dibenzyloxybenzyl) amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.83 g) was obtained as colorless crystals. Melting point: 118-120 ° C NMR (CDCl ₃ ) δ: 1.436 (9H, s), 4.125 (2H, s), 4.
267 (2H, d, J = 5.4Hz), 4.75-4.92 (1H, m), 5.071 (2H, s),
5.137 (2H, s), 5.741 (1H, s6.44-7.52 (10H, m).),

(2) 2- (3,4-) obtained in (1)
Dibenzyloxybenzyl) amino-5-chloro-α-
(3-tert-Butoxycarbonylaminomethylphenyl) benzyl alcohol (0.75 g) was dissolved in ethyl acetate (20 ml), and 1N sodium hydroxide (10 ml) was added.
l) was added and, with stirring, monoethyl fumarate chloride (0.19 g) was added. After stirring the reaction solution for 30 minutes, it was washed with water, dried over anhydrous sodium sulfate and evaporated. Ethanol (30 ml) was added to the residue to dissolve it,
Potassium carbonate (0.6 g) was added and the mixture was stirred at 60 ° C for 40 minutes. The reaction mixture was concentrated, and the residue was treated with ethyl acetate (50 ml).
And water (60 ml) were added for extraction. Wash the organic layer with water,
It was dried over anhydrous sodium sulfate and evaporated. The residue was separated and purified by silica gel column chromatography, and 3,5-cis-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-
1- (3,4-dibenzoyloxybenzoyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.15 g) as a colorless oil Was obtained. NMR (CDCl ₃ ) δ: 1.251 (3H, t, J = 7.2 Hz), 1.425 (9
H, s), 2.858 (1H, dd, J = 5.2,16.7Hz), 3.256 (1H, dd, J = 8.
6, 16.7Hz), 3.456 (1H, d, J = 15.8Hz), 4.04-4.37 (4H, m),
4.55-4.66 (2H, m), 4.88-5.06 (1H, m), 5.099 (2H, s),
5.855 (1H, s), 6.52-7.47 (20H, m). From the eluted part, 3,5-trans-5- (3
-tert-butoxycarbonylaminomethylphenyl)-
7-chloro-1- (3,4-dibenzyloxybenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetic acid ethyl ester (0.
6g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.259 (3H, t, J = 7.2 Hz), 1.443 (9
H, s), 2.760 (1H, dd, J = 5.2,16.7Hz), 3.147 (1H, dd, J = 8.
6, 16.7Hz), 4.124 (2H, q, J = 7.2Hz), 4.276 (2H, d, J = 6.2H
z), 4.454 (1H, dd, J = 5.0,8.7Hz), 4.897 (1H, d, J = 14.8H
z), 5.104 (2H, s), 5.148 (2H, s), 5.165 (1H, d, J = 14.8Hz),
5.366 (1H, s), 6.498 (1H, d, J = 2.2Hz), 6.68-7.47 (19H,
m).

(3) The trans form (0.6 g) obtained in (2) was dissolved in ethanol (15 ml), 1N sodium hydroxide (4 ml) was added, and the mixture was stirred at 60 ° C. for 50 minutes. The reaction solution was concentrated, neutralized with 5% potassium hydrogen sulfate, and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography,
5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (3,4-dibenzyloxybenzyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid (0.38 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.436 (9H, s), 2.75-3.25 (2H,
m), 4.275 (2H, d, J = 6.2Hz), 4.34-4.46 (1H, m), 4.794 (1H,
d, J = 14.6Hz), 4.87-5.05 (1H, m), 5.079 (2H, s), 5.141 (2
H, s), 5.244 (1H, d, J = 14.6Hz), 5.341 (1H, s), 6.488 (1H,
br), 6.68-7.47 (19H, m). (4) The compound (0.35 g) obtained in (3) and 2-
Dissolve fluorobenzylamine (68 mg) in N, N-dimethylformamide (8 ml) and stir at 0 ° C.
Diethyl cyanophosphate (90 mg) and triethylamine (60 mg) were added. After the reaction solution was stirred at room temperature for 30 minutes, water (60 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.36 g) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.433 (9H, s), 2.698 (1H, dd, J =
5.8, 14.6Hz), 4.236 (2H, d, J = 5.8Hz), 4.34-4.62 (3H,
m), 4.796 (1H, d, J = 14.6Hz), 4.83-4.97 (1H, m), 5.069 (2
H, s), 5.139 (2H, s), 5.221 (1H, d, J = 14.6Hz), 5.333 (1H,
s), 6.243 (1H, t, J = 6.0Hz), 6.482 (1H, d, J = 2.4Hz), 6.67
-7.47 (23H, m).

Example 226 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(3,4-dibenzyloxybenzyl) -2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride To the compound (50 mg) obtained in Example 225, 4N hydrochloric acid (ethyl acetate solution) (2 ml) was added. And stirred for 30 minutes. The reaction solution was concentrated, ethyl acetate (20 ml) was added to the residue, and the mixture was distilled again. From the residue, the title compound (40 mg)
Was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.348 (2H, br), 2.716 (1H, dd, J =
5.8, 14.6Hz), 2.933 (1H, dd, J = 7.2,14.6Hz), 3.802 (2
H, br), 4.33-4.58 (3H, m), 4.775 (1H, d, J = 14.6Hz), 5.055
(2H, s), 5.124 (2H, s), 5.234 (1H, d, J = 14.6Hz), 5.345 (1
H, s), 6.397 (1H, t, J = 5.8Hz), 6.495 (1H, d, J = 2.2Hz), 6.
68-7.47 (23H, m).

Example 227 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (3,4-dihydroxybenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1
-Benzoxazepine-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1-
(3,4-dibenzyloxybenzyl) -2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.26 g) was added to ethyl acetate (1
0 ml) and methanol (2 ml), 10% palladium on carbon (50 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 40 minutes. The reaction solution was filtered, the filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The title compound (0.2 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.438 (9H, br), 2.669 (1H, dd, J =
6.0, 14.4Hz), 2.880 (1H, dd, J = 7.2, 14.4Hz), 4.05-4.6
2 (5H, m), 4.92-5.25 (2H, m), 5.38-5.86 (1H, m), 6.28-7.
45 (14H, m).

Example 228 3,5-trans-N- (2-fluorobenzyl) -5
-(Aminomethylphenyl) -7-chloro-1- (3,
4-dihydroxybenzyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride To the compound (0.17 g) obtained in Example 227, 4N hydrogen chloride (ethyl acetate solution) (2 ml) was added, and the mixture was stirred for 30 minutes. did. The reaction solution was evaporated to give the title compound (0.16 g) as a colorless amorphous solid from the residue. NMR (D ₆ -DMSO) δ: 2.620 (1H, dd, J = 5.8, 15.2
Hz), 2.833 (1H, dd, J = 7.4, 15.2Hz), 3.92-4.45 (5H, m),
4.686 (1H, d, J = 14.4Hz), 5.339 (1H, d, J = 14.4Hz), 5.451 (1
H, s), 6.360 (1H, d, J = 2.0Hz), 6.42-7.72 (13H, m), 8.401
(2H, br), 8.549 (1H, br), 8.65-9.25 (1H, m).

Example 229 3,5-trans-N- (2-fluorobenzyl) -5
-(4-tert-butoxycarbonylaminomethylphenyl) -1- (4-benzyloxybenzyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide (1) 2-amino-5 obtained in Example 81 (3)
-Chloro-α- (4-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (1.0 g) and 4
-Benzyloxybenzaldehyde (0.65 g) is dissolved in methanol (20 ml), and acetic acid (0.2 g) and sodium cyanoborohydride (0.2 g) are added thereto.
For 50 minutes. The reaction solution was concentrated, and water (50
ml) and ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
The residue was purified by silica gel column chromatography to give 2- (4-benzyloxybenzyl) amino-5-
Chloro-α- (4-tert-butoxycarbonylamino)
Benzyl alcohol (1.05 g) was obtained as colorless crystals. NMR (CDCl ₃ ) δ: 1.450 (9H.s), 4.164 (2H, s), 4.
317 (2H, d, J = 5.4Hz), 4.88-4.92 (1H, m), 5.046 (2H, s),
5.797 (1H, s), 6.538 (1H, d, J-8.6Hz), 6.83-7.47 (15H,
m). (2) The compound (0.9 g) obtained in (1) was dissolved in ethyl acetate (30 ml), and 1N sodium hydroxide (1
0 ml) and stirring, and monoethyl fumarate chloride (0.29 g) was added. After stirring the reaction solution for 30 minutes, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. Ethanol (20m
l), add potassium carbonate (0.7 g) and add 60 ° C
For 40 minutes. The reaction solution was concentrated, and ethyl acetate (5
0 ml) and water (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml) and potassium carbonate (0.1 ml).
7 g) and stirred at 60 ° C. for 40 minutes. The reaction solution was concentrated and extracted by adding water (60 ml) and ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-cis-1- (4-benzyloxybenzyl) -5- (4-
tert-butoxycarbonylaminomethylphenyl) -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepine-3-acetic acid ethyl ester (0.2 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.261 (3H, t, J = 7.2 Hz), 1.439 (9
H, s), 2.872 (1H, dd, J = 7.8,16.7Hz), 3.188 (1H, dd, J = 7.
8, 16.7Hz), 3.722 (1H, d, J = 16.0Hz), 4.14 (2H, q, J = 7.2H
z), 4.55-4.73 (2H, m), 4.77-4.92 (1H, m), 5.03 (2H, s),
5.870 (1H, s), 6.78-7.47 (16H, m). From the part eluted later, 3,5-trans-1- (4
-Benzyloxybenzyl) -5- (4-tert-butoxycarbinylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.85 g)
Was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.245 (3H, t, J = 7.2 Hz), 1.466 (9
H, s), 2.758 (1H, dd, J = 5.6,16.8Hz), 3.102 (1H, dd, J = 8.
2, 16.8Hz), 4.124 (2H, q, J = 7.2Hz), 4.336 (2H, d, J = 6.0H
z), 4.450 (1H, dd, J = 5.6,8.2Hz), 4.745 (1H, d, J = 14.6H
z), 4.83-4.96 (1H, m), 5.044 (2H, s), 5.365 (1H, s), 5.4
30 (1H, d, J = 14.6Hz), 6.508 (1H, d, J = 1.8Hz), 6.84-7.47 (1
5H, m).

(3) 3,5-trans-1- (4-benzyloxybenzyl) -5- (4) obtained in (2)
-Tert-butoxycarbonylaminomethylphenyl)-
7-Chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.85 g) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml). 1N sodium hydroxide (3 ml) was added, and the mixture was stirred at 60 ° C for 50 minutes. The reaction was diluted with water (80 ml), neutralized with 5% potassium bicarbonate and extracted with ethyl acetate (60 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 3,5.
-Trans-1- (4-benzyloxybenzyl) -5
-(4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5
5g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.462 (9H, s), 2.831 (1H, dd, J =
5.0, 16.7Hz), 3.147 (1H, dd, J = 8.0,16.7Hz), 4.333 (2
H, d, J = 5.6Hz), 4.412 (1H, dd, J = 5.2, 8.0Hz), 4.776 (1H,
d, J = 14.6Hz), 4.83-4.98 (1H, m), 5.037 (2H, s), 5.373 (1
H, s), 5.405 (1H, d, J = 14.6Hz), 6.518 (1H, d, J = 2.0Hz),
6.83-7.47 (15H, m). (4) Compound (0.55 g) obtained in (3) and 2-
Fluorobenzylamine (0.13 g) was dissolved in N, N-dimethylformamide (10 ml), and diethyl cyanophosphate (0.16 g) and triethylamine (0.11 g) were added with stirring at 0 ° C. After the reaction solution was stirred at room temperature for 30 minutes, water (50 ml) and ethyl acetate (80 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-
Trans-N- (2-fluorobenzyl) -1- (4-
Benzyloxybenzyl) -5- (4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.55 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.472 (9H, s), 2.694 (1H, dd, J =
6.4, 14.5Hz), 2.897 (1H, dd, J = 7.0, 14.5Hz), 4.333 (2
H, d, J = 6.0Hz), 4.38-4.62 (2H, m), 4.691 (1H, d, J = 14.6H
z), 5.036 (2H, s), 5.332 (1H, s), 5.436 (1H, d, J = 14.6H
z), 6.23-6.35 (1H, m), 6.481 (1H, d, J = 2.0Hz), 6.83-7.47
(19H, m).

Example 230 3,5-trans-N- (2-fluorobenzyl) -5
-(4-aminomethylphenyl) -1- (4-benzyloxybenzyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-
3-acetamide hydrochloride 3,5-trans-N- (2
-Fluorobenzyl) -1- (4-benzyloxybenzyl) -5- (4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide (50 mg) was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride (ethyl acetate solution) (2 ml) was added, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated, ethyl acetate (20 ml) was added to the residue, and the mixture was distilled off again. The title compound (38 mg) was obtained as a colorless amorphous solid from the residue. NMR (CDCl ₃ ) δ: 2.677 (1H, dd, J = 6.0,14.5Hz),
2.894 (1H, dd, J = 7.2,14.5Hz), 3.35-4.05 (4H, m), 4.32-
4.58 (3H, m), 4.722 (1H, d, J = 14.8Hz), 5.019 (2H, s), 5.3
47 (1H, d, J = 14.8Hz), 5.354 (1H, s), 6.478 (1H, d, J = 2.2H
z), 6.62-6.63 (1H, m), 6.83-7.45 (19H, m).

Example 231 3,5-trans-N- (2-fluorobenzyl) -5
-(4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4-hydroxybenzyl)-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) -1- (4-benzyloxybenzyl) -5- (4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide (0.45 g) was dissolved in ethyl acetate (20 ml) and methanol (5 ml), 10% palladium on carbon (0.1 g) was added, and the mixture was stirred under a hydrogen atmosphere for 50 minutes. The reaction solution was filtered, the filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, the title compound (0.
36 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.465 (9H, s), 2.732 (1H, dd, J =
6.4, 14.6Hz), 2.878 (1H, dd, J = 6.8,14.6Hz), 4.296 (2
(H, d, J = 5.8Hz), 4.33-4.67 (4H, m), 4.85-5.03 (1H, m), 5.
263 (1H, s), 5.403 (1H, d, J = 14.4Hz), 6.445 (1H, d, J = 2.2H
z), 6.48-6.76 (1H, m), 6.63-7.37 (19H, m).

Example 232 3,5-trans-N- (2-fluorobenzyl) -5
-(4-aminomethylphenyl) -7-chloro-1-
(4-hydroxybenzyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide.hydrochloride 3,5-trans-N- (2
-Fluorobenzyl) -5- (4-tert-butoxycarbonylaminomethylphenyl) -7-chloro-1- (4
-Hydroxybenzyl) -2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide (0.16 g) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride (ethyl acetate solution) (3 ml) was added, and the mixture was stirred for 30 minutes. The reaction was concentrated and the residue was treated with ether to give the title compound (0.14 g) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.734 (1H, dd, J = 6.2,14.8Hz),
2.889 (1H, dd, J = 7.0, 14.8Hz), 3.93 (2H, br), 4.32-4.50
(3H, m), 4.639 (1H, d, J = 14.4Hz), 5.325 (1H, s), 5.434 (1
(H, d, J = 14.4Hz), 6.448 (1H, s), 6.78-7.62 (14H, m).

Example 233 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (5-tert-butoxycarbonylaminomethyl-2-methoxyphenyl)-
7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) 4-tert-butoxycarbonylaminomethyl-
2-bromoanisole 3-bromo-4-methoxybenzaldehyde (5.0
g) was dissolved in methanol (100 ml), sodium borohydride (0.5 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and water (100 ml) and ethyl acetate (1
5 ml) and extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in toluene (8
0 ml), thionyl chloride (2.8 g) and pyridine (0.5 ml) were added, and the mixture was stirred at room temperature for 40 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to decompose it, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was dissolved in N, N-dimethylformamide (50 ml) and potassium phthalimide (5.2
g) was added and the mixture was stirred at 80 ° C for 1 hour. Cooling water was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (150 ml) and tetrahydrofuran (20 ml), saturated hydrazine (2 ml) was added, and the mixture was stirred at 80 ° C for 2 hours. The insoluble material was filtered off, the filtrate was concentrated, and ethyl acetate (150 ml) and a saturated aqueous solution of sodium hydrogen carbonate (200 ml) were added to the residue, followed by shaking. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethyl acetate (60 ml) and tetrahydrofuran (20 ml) and di-tert-carbonate was added.
-Butyl (4.6 g) was added and stirred for 40 minutes. The reaction solution was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is purified by silica gel chromatography,
4-tert-butoxycarbonylaminomethyl-2-bromoanisole (5.7 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.460 (9H, s), 3.885 (3H, s), 4.
227 (2H, d, J = 6.0Hz), 4.70-4.93 (1H, m), 6.853 (1H, d, J =
8.4Hz), 7.198 (1H, dd, J = 2.0,8.4Hz), 7.472 (1H, d, J = 2.
0Hz).

(2) 2-amino-4-chloro-5'-t
ert-Butoxycarbonylaminomethyl-2′-methoxybenzophenone 4-tert-butoxycarbonylaminomethyl-2-bromoanisole (5.5 g) obtained with (1) and N-methyl-N-methyloxy-2- Amino-4-chlorobenzamide (4.09 g) was added to tetrahydrofuran (120 m
The solution dissolved in l) is cooled to -78 ° C, and n-butyllithium (1.6 mol / L, hexane solution) is stirred while stirring.
(57 ml) was added dropwise over 40 minutes. Add water (150
ml) and ethyl acetate (200 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2-amino-4-chloro-5'-tert-butoxycarbonylaminomethyl-2'-methoxybenzophenone (5.5 g) as a yellow oil. NMR (CDCl ₃ ) δ: 1.448 (9H, s), 3.762 (3H, s), 4.
280 (2H, d, J = 6.0Hz), 4.78-4.93 (1H, m), 6.421 (2H, br),
6.62-7.43 (6H, m). (3) Dissolve the compound (5.5 g) obtained in (2) in methanol (60 ml), and add sodium borohydride (1.5 g) with stirring at room temperature. Was. The reaction solution was concentrated, and extracted by adding ethyl acetate (80 ml) and water (100 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2-amino-5-chloro-
α- (5-tert-butoxycarbonylaminomethyl-2
-Methoxy) benzyl alcohol (5.6 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.438 (9H, s), 3.857 (3H, s), 4.
217 (2H, d, J = 5.8Hz), 4.73-4.92 (1H, m), 5.981 (1H, s),
6.607 (1H, d, J = 8.4Hz), 6.85-7.33 (5H, m).

(4) Compound (2.5) obtained in (3)
g) and 4-phenylbenzaldehyde (1.2 g) were dissolved in methanol (40 ml) and stirred with acetic acid (0.2 g).
45 g) and sodium cyanoborohydride (0.48)
g) was added. After stirring the reaction solution at 60 ° C. for 30 minutes,
The mixture was concentrated, and extracted by adding water (100 ml) and ethyl acetate (120 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2- (4-biphenylmethyl) -5-chloro-α- (5-tert-butoxycarbonylamino-2-methoxy) benzyl alcohol (3.3 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.426 (9H, s), 3.732 (3H, s), 4.
210 (2H, d, J = 5.8Hz), 4.35 (2H, s), 4.65-4.85 (1H, m), 6.
035 (1H, s), 6.701 (1H, d, J = 8.6Hz), 6.84-7.63 (14H, m). (5) The compound (3.3g) obtained in (4) was treated with ethyl acetate (30ml). Dissolved in 1N sodium hydroxide (2
0 ml) and stirring, and monoethyl fumarate chloride (1.05 g) was added. After stirring the reaction solution for 20 minutes, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. Ethanol (80m
l), add potassium carbonate (3.5 g) and add
For 1.5 hours. The reaction solution was concentrated, and extracted by adding ethyl acetate (100 ml) and water (80 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
The residue was purified by silica gel column chromatography and 3,5-trans-1- (4-biphenylmethyl)
-5- (5-tert-butoxycarbonylaminomethyl-
2-methoxyphenyl) -7-chloro-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (3.5 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.260 (3H, t, J = 7.4Hz), 1.466 (9
H, s), 2.805 (1H, dd, J = 5.2,16.6Hz), 3.173 (1H, dd, J = 8.
6, 16.6Hz), 3.397 (3H, s), 4.160 (2H, q, J = 7.4Hz), 4.29
8 (2H, d, J = 5.6Hz), 4.507 (1H, dd, J = 5.2,8.6Hz), 4.72-
4.92 (1H, m), 4.965 (1H, d, J = 15.0Hz), 5.505 (1H, d, J = 15.
0Hz), 5.911 (1H, s), 6.546 (1H, s), 6.752 (1H, d, J = 8.4H
z), 7.23-7.63 (13H, m).

(6) Compound (3.3) obtained in (5)
g) in tetrahydrofuran (30 ml) and methanol (5
0 ml), 1N sodium hydroxide (20 ml) was added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction solution was concentrated, diluted with water (100 ml), neutralized with a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-biphenylmethyl) -5- (5-tert-butoxycarbonylaminomethyl-2-methoxyphenyl) -7-chloro-2- Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (1.7 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.446 (9H, s), 2.84-3.23 (2H,
m), 3.404 (3H, s), 4.283 (2H, d, J = 5.6Hz), 4.43-4.85 (2
H, m), 4.941 (1H, d, J = 15.0Hz), 5.517 (1H, d, J = 15.0Hz),
5.914 (1H, s), 6.544 (1H, s), 6.741 (1H, d, J = 8.4Hz), 7.1
3-7.58 (13H, m). (7) The compound (0.3 g) obtained in (6) and 2-fluorobenzylamine (68 mg) were dissolved in N, N-dimethylformamide (10 ml), and the solution was dissolved at 0 ° C. While stirring with
Diethyl cyanophosphate (90 mg) and triethylamine (80 mg) were added. After the reaction solution was stirred at room temperature for 20 minutes, ice water and ethyl acetate (50 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2
-Fluorobenzyl) -1- (4-biphenylmethyl)
-5- (5-tert-butoxycarbonylaminomethyl-
2-methoxyphenyl) -7-chloro-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetamide (0.21 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.454 (9H, s), 2.738 (1H, dd, J =
5.4, 14.4Hz), 2.994 (1H, dd, J = 7.8,14.4Hz), 3.380 (3
H, s), 4.244 (2H, d, J = 6.0Hz), 4.37-4.65 (3H, m), 4.73-
4.85 (1H, m), 4.903 (1H, d, J = 15.2Hz), 5.517 (1H, d, J = 15.
2Hz), 5.891 (1H, s), 6.28-6.42 (1H, m), 6.542 (1H, d, J = 1.
8Hz), 6.750 (1H, d, J = 8.6Hz), 6.96-7.58 (17H, m).

Example 234 3,5-trans-N- (2-fluorobenzyl) -5
-(5-aminomethyl-2-methoxyphenyl) -1-
(4-biphenylmethyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 3,5-trans-N- (2
-Fluorobenzyl) -1- (4-biphenylmethyl)
-5- (5-tert-butoxycarbonylaminomethyl-
2-methoxyphenyl) -7-chloro-2-oxo-
To 1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.16 g) was added 4N hydrogen chloride (ethyl acetate solution) (2 ml), and the mixture was stirred for 30 minutes. The reaction solution was concentrated, and ethyl acetate (30 ml) was added to the residue, followed by evaporation. From the residue, the title compound (0.14 g)
Was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.765 (1H, dd, J = 5.6,14.4Hz),
2.991 (1H, dd, J = 7.6,14.4Hz), 3.391 (3H, s), 3.62-4.05
(2H, m), 4.38-4.62 (3H, m), 4.900 (1H, d, J = 15.2Hz), 5.5
16 (1H, d, J = 15.2Hz), 5.909 (1H, s), 6.45-6.63 (2H, m),
6.752 (1H, d, J = 8.4Hz), 6.92-7.62 (17H, m).

Example 235 3,5-trans-N- (2-fluorobenzyl) -1
-(2-benzyloxybenzyl) -5- (3-tert-
(Butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide (1) 2-amino-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) obtained in Example 1 (2) And 2-benzyloxybenzaldehyde (0.7 g) were dissolved in methanol (20 ml), acetic acid (0.15 g) and sodium cyanoborohydride (0.16 g) were added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction solution was concentrated, and water (50 m
l) and ethyl acetate (60 ml) were added for extraction. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2- (2-benzyloxybenzylamino)
-5-chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (1.05
g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.441 (9H, s), 4.248 (2H, d, J = 5.
8Hz), 4.328 (2H, br), 5.061 (2H, s), 5.749 (1H, s), 6.55
4 (1H, d, J = 8.8Hz), 6.82-7.52 (14H, m). (2) Dissolve the compound (1.05g) obtained in (1) in ethyl acetate (40ml) and add 1N water Sodium oxide (20 ml) was added, and a solution of monoethyl fumarate chloride (0.33 g) in ethyl acetate (2 ml) was added dropwise with stirring. After stirring the reaction solution for 20 minutes, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (30 ml), potassium carbonate (0.7 g) was added, and the mixture was stirred at 60 ° C for 1.5 hours. The reaction mixture was concentrated, and ethyl acetate (50 ml) and water (50 ml) were added.
ml) and extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-cis-1- (2-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7 was eluted from the previously eluted portion. -Chloro-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.15 g) was obtained as a colorless oil> NMR (CDCl ₃ ) δ: 1.233 (3H, t, J = 7.2 Hz), 1.422 (9
H, s), 2.862 (1H, dd, J = 5.8,16.6Hz), 3,199 (1H, dd, J = 8.
0, 16.6Hz), 3.958 (1H, d, J = 16.6Hz), 4.03-4.22 (4H, m),
4.456 (1H, d, J = 16.6Hz), 4.666 (1H, dd, J = 5.8,8.0Hz),
4.72-4.88 (1H, m), 4.942 (2H, s), 5.876 (1H, s), 6.82-7.4
5 (16H, m). From the part eluted later, 3,5-trans-1- (2
-Benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (0.45 g)
Was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.240 (3H, t, J = 7.2 Hz), 1.423 (9
H, s), 2.749 (1H, dd, J = 5.2,16.7Hz), 3.109 (1H, dd, J = 8.
2, 16.7Hz), 4.132 (2H, q, J = 7.2Hz), 4.311 (2H, d, J = 6.0H
z), 4.481 (1H, dd, J = 5.4,8.4Hz), 4.73-4.85 (1H, m), 4.
899 (1H, d, J = 11.4Hz), 5.021 (1H, d, J = 11.4Hz), 5.178 (1
H, d, J = 15.0Hz), 5.289 (1H, d, J = 15.0Hz), 5.583 (1H, s),
6.465 (1H, d, J = 2.2Hz), 7.83-7.48 (15H, m).

(3) A mixture (0.7 g) of the 3,5-cis form and 3,5-trans form obtained in (2) was dissolved in tetrahydrofuran (5 ml) and ethanol (10 ml). Normal sodium hydroxide (3 ml) was added and the mixture was stirred at 60 ° C. for 30 minutes. The reaction was concentrated, diluted with water (20 ml), acidified with 5% aqueous potassium hydrogen sulfate and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue,
5-cis and 3,5-trans-1- (2-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid (0.62 g) was obtained as a mixture of a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.412 (9 × 1 / 5H, s), 1.454 (9 ×
4 / 5H, s), 2.75-3.26 (2H, m), 3.85-4.63 (4H, m), 4.75-
5.36 (4H, m), 5.597 (4 / 5H, s), 5.894 (1 / 5H, s), 6.466 (1
/ 5H, br), 6.75-7.45 (151 / 5H, m). (4) The compound (0.6 g) obtained in (3) and 2-fluorobenzylamine (0.14 g) were converted to N, N-dimethyl. Dissolve in formamide (8 ml) and stir at 0 ° C.
Diethyl cyanophosphate (0.18 g) and triethylamine (0.12 g) were added. After the reaction solution was stirred at room temperature for 30 minutes, water (40 ml) and ethyl acetate (50 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -1- (2-benzyloxybenzyl) -5- (3-tert-butoxycarbonyl) (Aminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.5 g) was obtained as a colorless amorphous solid. . NMR (CDCl ₃ ) δ: 1.450 (9H, s), 2.680 (1H.dd, J =
5.8, 14.2Hz), 2.912 (1H, dd, J = 7.21, 14.2Hz), 4.278 (2
(H, d, J = 6.0Hz), 4.32-4.61 (3H, m), 4.73-5.36 (5H, m), 5.
552 (1H, s), 6.23-6.38 (1H, m), 6.442 (1H, d, J = 2.4Hz),
6.88-7.43 (19H, m). Melting point: 173-174 ° C

Example 236 3,5-trans-N- (2-fluorobenzyl) -4
-(3-Aminomethylphenyl) -1- (2-bedyloxybenzyl) -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide hydrochloride 3,5-trans-N- (2
-Fluorobenzyl) -1- (2-benzyloxybenzyl) -5- (tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide (0.1 g) was added with 4 N hydrogen chloride (ethyl acetate solution) (3 ml) and stirred for 40 minutes. The reaction solution was concentrated, and ethyl acetate (30 ml) was added to the residue, followed by evaporation. The title compound (92 mg) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.701 (1H, dd, J = 5.8,14.4Hz),
2.918 (1H, dd, J = 7.2,14.4Hz), 3.846 (2H, br), 4.33-4.6
2 (3H, m), 4.899 (1H, d, J = 11.6Hz), 5.016 (1H, d, J = 11.6H
z), 5.154 (1H, d, J = 15.4Hz), 5.276 (1H, d, J = 15.4Hz), 5.
584 (1H, s), 6.385 (1H, m), 6.473 (1H, d, J = 2.2Hz), 6.82-
7.45 (19H, m).

Example 237 3,5-trans-N- (2-fluorobenzyl) -5
-(Tert-butoxycarbonylaminomethylphenyl)
-7-chloro-1- (2-hydroxybenzyl) -2-
Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-N- (2
-Fluorobenzyl) -1- (2-benzyloxybenzyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide (0.45 g) was dissolved in ethyl acetate (20 ml) and methanol (5 ml), 10% palladium on carbon (0.15 g) was added, and the mixture was stirred under a hydrogen atmosphere for 1.5 hours. The reaction solution was filtered, the filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The title compound (0.32 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.448 (9H, s), 2.677 (1H, dd, J =
6.0, 14.6Hz), 2.919 (1H, dd, J = 7.6,14.6Hz), 4.244 (2H,
d, J = 5.6Hz), 4.34-4.85 (5H, m), 5.070 (2 / 3H, s), 5.115
(1 / 3H, s), 5.496 (2 / 3H, s), 5.569 (1 / 3H, s), 6.12-6.26
(1H, m), 6.46-7.55 (15H, m).

Example 238 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-1-
(2-Hydroxybenzyl) -2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride 4N hydrogen chloride (ethyl acetate solution) was added to the compound (0.28 g) obtained in Example 237.
(4 ml) and stirred for 40 minutes. The reaction solution was concentrated, and ethyl acetate (30 ml) was added to the residue, followed by evaporation. The title compound (0.18 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.62-2.98 (2H, m), 3.72-3.95 (2
H, m), 4.25-4.66 (4H, m), 5.231 (1H, s), 5.47-5.62 (1H,
m), 6.32-6.44 (1H, m), 6.48-7.55 (15H, m).

Example 239 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -5- (N-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -7-chloro-2-oxo-1,2,3,
5-tetrahydro-4,1-benzoxazepine-3-
Acetamide (1) N-tert-butoxycarbonyl-5-bromo-
1,2,3,4-tetrahydroisoquinoline (0.9 g),
A solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (0.68 g) in tetrahydrofuran (15 ml) was cooled to -78 ° C, and stirred with n-butyllithium (1.6). Mol, hexane solution) (9 ml) was added dropwise over 30 minutes. Water (50
ml), and the mixture was decomposed and extracted with ethyl acetate (80 ml). The organic layer is washed with water, dried over anhydrous sodium sulfate,
Distilled off. The residue was purified by silica gel column chromatography to give 2- (N-tert-butoxycarbonyl-
1,2,3,4-tetrahydroisoquinolin-5-yl)
Carbonyl-4-chloro-aniline (0.26 g) was obtained as yellow crystals. Melting point: 159-160 ° C NMR (CDCl ₃ ) δ: 1.490 (9H, s), 2.730 (2H, t, J = 5.
8Hz), 3.593 (2H, t, J = 6.0Hz), 4.648 (2H, s), 6.425 (2H, b
r), 6.685 (1H, d, J = 8.8 Hz), 7.08-7.32 (5H, m). (2) The compound (0.24 g) obtained in (1) was dissolved in methanol (8 ml) and stirred. While adding sodium borohydride (0.05 g). After the reaction solution was stirred for 20 minutes, it was concentrated, and ethyl acetate (20 ml) and water (30 ml) were added.
l) was added and extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. From the residue, 2-amino-5-chloro-α- (N-tert-butoxycarbonyl-
1,2,3,4-tetrahydroisoquinolin-5-yl)
Benzyl alcohol (0.22 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.476 (9H, s), 2.46-2.93 (2H,
m), 3.57 (2H, t, J = 5.8Hz), 3.85-4.20 (2H, m), 4.606 (2H,
s), 5.955 (1H, s), 6.60-7.42 (6H, m).

(3) Compound (0.2) obtained in (2)
2g) and 4-phenylbenzaldehyde (0.13)
g) in methanol (10 ml) was added to acetic acid (0.05 g) and sodium cyanoborohydride (0.0 g).
5 g) and stirred at 60 ° C. for 30 minutes. The reaction solution was diluted with water (30 ml) and extracted with ethyl acetate (40 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give 2- (4-biphenylmethylamino)
-5-chloro-α- (N-tert-butoxycarbonyl-
1,2,3,4-tetrahydroisoquinolin-5-yl)
Benzyl alcohol (0.26 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.466 (9H, s), 2.45-2.92 (2H,
m), 3.40-3.70 (2H, m), 4.387 (2H, br), 4.610 (2H, s), 5.
0-5.2 (1H, m), 6.004 (1H, s), 6.629 (1H, d, J = 8.6Hz), 6.73
5 (1H, d, J = 2.4 Hz), 7.05-7.65 (13H, m). (4) The compound (0.26 g) obtained in (3) was dissolved in ethyl acetate (10 ml), and 1N water was added. Sodium oxide (3 ml) was added, and while stirring, monoethyl fumarate chloride (0.095 mg) was added. After stirring the reaction solution for 20 minutes, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. Residue is ethanol (1
Potassium carbonate (0.2 g) was added to the solution dissolved in 2 ml) and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was concentrated, and extracted by adding water (20 ml) and ethyl acetate (30 ml).
The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-biphenylmethyl) -5- (N-tert-butoxycarbonyl-1,2,
3,4-tetrahydroisoquinolin-5-yl) -7-
Chloro-2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetic acid ethyl ester (0.28 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.268 (3H, t, J = 7.2 Hz), 1.316 (9
H, br), 2.50-3.50 (4H, m), 2.83 (1H, dd, J = 5.4,16.7Hz),
4.17 (2H, q, J = 7.2Hz), 4.341 (1H, d, J = 17.0Hz), 4.48 (1H
H, dd, J = 5.4, 8.0Hz), 4.592 (1H, d, J = 17.0Hz), 4.75 (1H,
m), 5.545 (1H, s), 5.62-5.85 (1H, m), 6.462 (1H, s), 7.0-
7.7 (14H, m).

(5) Compound (0.2) obtained in (4)
8 g) of tetrahydrofuran (5 ml) and methanol (10
ml) solution, 1N sodium hydroxide (3 ml) was added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction was concentrated, diluted with water (10 ml), neutralized with 5% potassium bisulfate,
Extracted with ethyl acetate (30 ml). Wash the organic layer with water,
It was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-trans-1- (4-biphenylmethyl) -5- (N-te
rt-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -7-chloro-2-oxo-
1,2,3,5-Tetrahydro-4,1-benzoxazepine-3-acetic acid (0.2 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.375 (9H, br), 2.80-3.40 (4H,
m), 2.88 (1H, dd, J = 5.2,16.8Hz), 3.18 (1H, dd, J = 8.0,1
6.8Hz), 4.341 (1H, d, J = 16.8Hz), 4.44 (1H, dd, J = 5.4, 7.
996), 4.596 (1H, d, J = 16.8Hz), 4.66-4.90 (1H, m), 5.550
(1H, s), 5.62-5.82 (1H, m), 6.475 (1H, s), 7.0-7.65 (1
4H, m). (6) The compound (0.15 g) obtained in (5) and 2-
Fluorobenzylamine (0.035 g) was dissolved in N, N-dimethylformamide (5 ml) and diethyl cyanophosphate (0.045 g) followed by triethylamine (0.05 g).
05g) was added. After stirring the reaction solution for 30 minutes, water (2
0 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2
-Fluorobenzyl) -1- (4-biphenylmethyl)
-5- (N-tert-butoxycarbonyl-1,2,3,4
-Tetrahydroisoquinolin-5-yl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.16 g) was obtained as colorless crystals. Was. NMR (CDCl ₃ ) δ: 1.369 (9H, br), 2.55-3.40 (2H,
m), 2.75 (1H, dd, J = 6.0,14.6Hz), 2.96 (1H, dd, J = 7.0,1
4.6Hz), 4.25-4.85 (6H, m), 5.20 (1H, s), 5.55-5.80 (1H,
m), 6.256 (1H, br), 6.43 (1H, br), 6.95-7.65 (18H, m). Melting point: 125-127 ° C

Example 240 3,5-trans-N- (2-fluorobenzyl) -1
-(4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-5- (1,2,3,5-tetrahydroisoquinolin-5-yl) -4,1-benzo Oxazepine-3-acetamide hydrochloride The 3,5-trans-N- (2
-Fluorobenzyl) -1- (4-biphenylmethyl)
-5- (N-tert-butoxycarbonyl-1,2,3,4
-Tetrahydroisoquinolin-5-yl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (0.13 g) in 4N hydrogen chloride ( (Ethyl acetate solution) (3 ml) and 2
Stirred for hours. The reaction solution was concentrated, and ethyl acetate (3
0 ml) was added and evaporated. From the residue, the title compound (0.
1g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.10-1.17 (2H, m), 2.508 (2H, t,
J = 6.0Hz), 2.74 (1H, dd, J = 6.2,14.4Hz), 2.96 (1H, dd, J =
7.0, 14.4Hz), 3.882 (2H, s), 4.35-4.70 (4H, m), 5.446 (1
H, s), 5.828 (1H, d, J = 14.4Hz), 6.15-6.35 (1H, m), 6.464
(1H, d, J = 1.6Hz), 6.92-7.60 (18H, m). Melting point (free): 184-185 ℃

Example 241 3,5-trans-N-isopropyl-1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-1- obtained in Example 4 (2)
(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-
N, N-dimethylformamide (3m3) of oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.11 g) and isopropylamine (15 mg)
l) While stirring the solution at 0 ° C., diethyl cyanophosphate (35 mg) and triethylamine (22 mg) were added. After the reaction solution was stirred at room temperature for 20 minutes, water (20 ml) was added, and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.12 g) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.126 (3H, d, J = 4.2 Hz), 1.158 (3
H, d, J = 4.2Hz), 1.439 (9H, s), 2.621 (1H, dd, J = 6.0, 14.0
Hz), 2.842 (1H, dd, J = 7.4, 14.0Hz), 4.221 (2H, d, J = 5.4H
z), 4.525 (1H, dd, J = 6.2,7.3Hz), 4.65-4.85 (1H, m), 4.
936 (1H, d, J = 14.8Hz), 5.378 (1H, s), 5.413 (1H, d, J = 14.
8Hz), 6.495 (1H, d, J = 2.0Hz), 6.95-7.62 (15H, m).

Example 242 3,5-trans-N-isopropyl-1- (3-aminomethylphenyl) -1- (4-biphenylmethyl)-
7-Chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide.hydrochloride 4N hydrogen chloride (90 mg) of the compound obtained in Example 241 (90 mg) After stirring the solution (ethyl acetate solution) (2 ml) for 30 minutes, the mixture was concentrated, and ethyl acetate (10 ml) was added to the residue, followed by concentration again. The title compound (72 mg) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.125 (3H, d, J = 4.0 Hz), 1.158 (3
H, d, J = 4.0Hz), 2.631 (1H, dd, J = 6.2, 14.2Hz), 2.836 (1
H, dd, J = 7.6, 14.2Hz), 3.798 (2H, br), 4.526 (1H, dd, J =
6.6, 6.6Hz), 4.905 (1H, d, J = 14.6Hz), 5.383 (1H, s), 5.
440 (1H, d, J = 14.6Hz), 5.683 (1H, d, J = 8.0Hz), 6.515 (1H,
d, J = 1.8Hz), 6.88-7.63 (15H, M).

Example 243 N- [3,5-trans-1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2, 3,5-
Tetrahydro-4,1-benzoxazepine-3-acetyl] -pyrrolidine 3,5- obtained in Example 4 (2)
Trans-1- (4-biphenylmethyl) -5- (3-
tert-butoxycarbonylaminomethylphenyl) -7
-Chloro-2-oxo-1,2,3,5-tetrahydro-
While stirring a solution of 4,1-benzoxazepine-3-acetic acid (0.11 g) and pyrrolidine (15 mg) in N, N-dimethylformamide (4 ml) at 0 ° C., diethyl cyanophosphate (35 mg) and triethylamine (35 mg) were added. 30 mg) was added. After the reaction solution was stirred at room temperature for 20 minutes, water (20 ml) was added.
And ethyl acetate (30 ml) were added for extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (0.15 g) as a colorless oil. NMR (CDCl ₃ ) δ: 1.435 (9H, s), 1.65-2.08 (4H, m), 2.692
(1H, dd, J = 4.6, 16.0Hz), 3.05-3.65 (6H, m), 4.225 (2H,
d, J = 6.0Hz), 4.635 (1H, dd, J = 4.6,8.7Hz), 4.68-4.83 (1
H, m), 4.892 (1H, d, J = 14.6Hz), 5.371 (1H, s), 5.491 (1H,
d, J = 14.6Hz), 6.485 (1H, s), 6.88-7.63 (15H, m).

Example 244 N- [3,5-trans-5- (3-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-
2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl] -pyrrolidine hydrochloride 4N hydrogen chloride of the compound (0.15 g) obtained in Example 243 (Ethyl acetate solution) (2 ml) The solution was stirred for 30 minutes, concentrated, ethyl acetate (20 ml) was added to the residue, and the residue was distilled off again. The title compound (65 mg) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.76-2.05 (4H, m), 2.706 (1H, d
d, J = 4.8, 15.7Hz), 3.139 (1H, dd, J = 8.6, 15.7Hz), 3.3
3-3.63 (4H, m), 3.791 (2H, br), 4.640 (1H, dd, J = 4.8,
8.8Hz), 4.866 (1H, d, J = 14.6Hz), 5.379 (1H, s), 5.513 (1
(H, d, J = 14.6Hz), 6.511 (1H, br), 6.93-7.63 (15H, m).

Example 245 3,5-trans-N- (2-methoxyphenyl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-1- obtained in Example 4 (2)
(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-
2-anisidine (0.118) was added to a solution of oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.3 g) in N, N-dimethylformamide (3 ml).
g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (91 mg) and 4-dimethylaminopyridine (58 mg) were added, and the mixture was stirred for 12 hours.
The reaction solution was diluted with ethyl acetate (30 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The title compound (0.29 g) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.89 (1H, dd, J = 6.
8, 14.8Hz), 3.12 (1H, dd, J = 6.8,14.6Hz), 3.76 (3H, s),
4.16 (2H, d, J = 5.2Hz), 4.57 (1H, d, J = 6.8Hz), 4.68 (1H, b
r), 4.91 (1H, d, J = 14.6Hz), 5.43 (1H, s), 5.48 (1H, d, J = 1
4.6Hz), 6.49 (1H, d, J = 1.6Hz), 6.83-7.59 (18H, m), 8.21
(1H, s), 8.36 (1H, dd, J = 1.8,7.6Hz),

Example 246 3,5-trans-N- (2-methoxyphenyl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-
Tetrahydro-4,1-benzoxazepine-3-acetamide To a solution of the compound obtained in Example 245 (0.219 g) in ethyl acetate (1 ml) was added 4N hydrogen chloride (ethyl acetate solution) (1 ml). Stir for 1 hour. The reaction solution was concentrated, and the residue was precipitated by adding ether to give the title compound (0.172 g) as a colorless amorphous solid. NMR (DMSO-D ₆ ) δ: 2.89 (1H, dd, J = 7.4,15.4H
z), 3.16 (1H, dd, J = 7.4,15.4Hz), 3.80 (3H, s), 4.07 (2H,
s), 4.55 (1H, t, J = 7.4Hz), 5.14 (1H, d, J = 15.6Hz), 5.40
(1H, d, J = 15.6Hz), 5.62 (1H, s), 6.43 (1H, d, J = 2.0Hz),
6.88-7.71 (18H, m), 7.95 (1H, d, J = 7.8Hz), 8.30 (3H, br),
9.33 (1H, s).

Example 247 3,5-trans-N-cyclohexyl-1- (4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-1- obtained in Example 4 (2)
(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-
N, N-dimethylformamide (3 g) of oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.3 g) and cyclohexylamine (0.12 g)
1) -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (91 mg) and 4-dimethylaminopyridine (58 mg) were added to the solution, and the mixture was stirred for 12 hours. The reaction solution was diluted by adding ethyl acetate (20 ml),
It was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound (34 mg) as a colorless oil. NMR (CDCl ₃ ) δ: 1.06-1.37 (5H, m), 1.44 (9H, m),
1.62-1.94 (4H, m), 2.62 (1H, dd, J = 6.0, 14.0Hz), 2.84
(1H, dd, J = 7.6,14.0Hz), 3.65-3.72 (1H, m), 4.21 (2H, d,
J = 5.6Hz), 4.51 (1H, dd., J = 6.0, 7.6Hz), 4.74 (1H, br),
4.91 (1H, d, J = 14.8Hz), 5.37 (1H, s), 5.41 (1H, d, J = 14.8H
z), 5.37 (1H, s), 5.41 (1H, d, J = 14.8Hz), 5.70 (1H, d, J =
7.6Hz), 6.49 (1H, d, J = 1.8Hz), 6.97-7.60 (15H, m).

Example 248 3,5-trans-N-cyclohexyl-5- (3-aminomethylphenyl) -1- (4-biphenylmethyl)
-7-chloro-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide hydrochloride To a solution of the compound obtained in Example 247 (34 mg) in ethyl acetate (1 ml) was added A 4N hydrogen chloride (ethyl acetate) solution (1 ml) was added, and the mixture was stirred for 1 hour. The reaction solution was concentrated and the residue was treated with ether to give the title compound (28 mg) as a colorless amorphous solid. _{NMR (DMSO-D 6) δ} : 1.07-1.31 (6H, m), 1.43-
1.78 (4H, m), 2.56 (1H, dd, J = 6.6,15.4Hz), 2.72 (1H, dd,
J = 6.6, 15.4Hz), 3.45-3.51 (1H, m), 4.00-4.09 (2H, m),
4.44 (1H, t, J = 6.6Hz), 5.10 (1H, d, J = 8.0,15.4Hz), 5.37
(1H, d, J = 15.4Hz), 5.56 (1H, s), 6.39 (1H, d, J = 1.8Hz), 7.
11 (1H, d, J = 7.4Hz), 7.38-7.69 (13H, m), 7.89 (1H, d, J = 7.
6Hz), 8.30 (3H, br).

Example 249 3,5-trans-N- (thiazol-2-yl) -1
-(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2
-Oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide 3,5-trans-1- obtained in Example 4 (2)
(4-biphenylmethyl) -5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-
N, N-dimethylformamide (2m) of oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.2 g) and 2-aminothiazole (63 mg)
l) 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (73 mg) and 4-dimethylaminopyridine (40 mg) were added to the solution. After stirring the reaction solution for 12 hours, it was diluted with ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The title compound (144 mg) was obtained from the residue as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.42 (9H, s), 3.02-3.23 (2H, m),
4.22 (2H, br), 4.60 (1H, t, J = 6.6Hz), 4.90 (1H, d, J = 14.6
Hz), 5.22 (1H, br), 5.42 (1H, s), 5.50 (1H, d, J = 14.6Hz),
6.52 (1H, s), 6.85 (1H, br), 6.95 (1H, d, J = 3.2Hz), 7.09
(1H, s), 7.25-7.59 (14H, m), 11.19 (1H, s).

Example 250 3,5-trans-N- (thiazol-2-yl) -5
-(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide / hydrochloric acid Salt 4N hydrogen chloride (ethyl acetate solution) was added to a solution of the compound (144 mg) obtained in Example 249 in ethyl acetate (1 ml).
(1 ml) was added and stirred for 1 hour. The reaction was concentrated and the residue was treated with ether to give the title compound (120 mg) as a colorless amorphous solid. _{NMR (DMSO-D 6) δ} : 2.97 (1H, d
d, J = 5.4, 16.6 Hz), 3.17 (1
H, dd, J = 8.0, 16.6 Hz), 4.01
(2H, d, J = 5.8 Hz), 4.58 (1H, d
d, J = 5.4, 8.0 Hz), 5.14 (1H,
d, J = 15.8 Hz), 5.62 (1H, s),
6.43 (1H, d, J = 1.8 Hz), 7.12
(1H, d, J = 7.2 Hz), 7.24 (1H,
d, J = 3.6 Hz), 7.44-7.80 (15
H, m), 8.41 (3H, br).

Example 251 3,5-trans-N- (2-fluorobenzyl) -5
-(3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-1- (4-trifluoromethylbenzyl)-
4,1-benzoxazepine-3-acetamide (1) 2-amino-5- obtained in Example 1 (2)
Chloro-α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.5 g) and 4-
Acetic acid (0.1 g) and sodium cyanoborohydride (0.17 g) were added to a solution of trifluoromethylbenzaldehyde (0.28 g) in methanol (20 ml) to give a solution of 60%.
Stirred at 40 ° C. for 40 minutes. The reaction solution was concentrated, and extracted by adding ethyl acetate (30 ml) and water (20 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography,
5-Chloro-2- (4-trifluoromethylbenzylamino) -α- (3-tert-butoxycarbonylaminomethylphenyl) benzyl alcohol (0.6 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.426 (9H, s), 2.848 (1H, d, J = 3.
6Hz), 4.18-4.37 (4H, m), 4.767 (1H, d, J = 5.6Hz), 4.83-4.
94 (1H, m), 5.15-5.25 (1H, m), 5.825 (1H, d, J = 3.0Hz), 6.
419 (1H, d, J = 8.6 Hz), 6.98-7.76 (10H, m). (2) 1N hydroxide was added to a solution of the compound (0.6 g) obtained in (1) in ethyl acetate (15 ml). Sodium (5m
l) was added thereto, and a solution of monoethyl chloride fumarate (0.21 g) in ethyl acetate (2 ml) was added dropwise with stirring at room temperature. After stirring the reaction solution for 20 minutes, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (20 ml), potassium carbonate (0.3 g) was added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction was diluted with water (50 ml), washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography, and 3,5-cis-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2 , 3,5-Tetrahydro-1- (4-trifluoromethylbenzyl) -4,1-benzoxazepine-
3-Acetic acid ethyl ester (0.12 g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.267 (3H, t, J = 7.2 Hz), 1.429 (9
H, s), 2.871 (1H, dd, J = 5.4,16.8Hz), 3.250 (1H, dd, J = 8.
4, 16.8Hz), 3.790 (1H, d, J = 16.2Hz), 4.05-4.35 (2H, m),
4.56-4.72 (2H, m), 4.75-5.02 (1H, m), 5.896 (1H, s), 6.
88-7.58 (11H, m). From the part eluted next, 3,5-trans-5- (3
-Tert-butoxycarbonylaminomethylphenyl)-
7-chloro-2-oxo-1,2,3,5-tetrahydro-1- (4-trifluoromethylbenzyl) -4,1-
Benzoxazepine-3-acetic acid ethyl ester (0.3
6g) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.259 (3H, t, J = 7.2 Hz), 1.437 (9
H, s), 2.768 (1H, dd, J = 5.0,16.9Hz), 3.154 (1H, dd, J = 8.
8, 16.9Hz), 4.14 (2H, q, J = 7.2Hz), 4.306 (2H, d, J = 5.8H
z), 4.512 (1H, dd, J = 5.0,8.8Hz), 5.109 (1H, d, J = 15.2H
z), 5.294 (1H, d, J = 15.2Hz), 5.416 (1H, s), 6.546 (1H, d,
J = 2.2Hz), 6.97-7.68 (10H, m).

(3) A mixture of the trans-isomer and the cis-isomer obtained in (2) (0.42 g) in tetrahydrofuran (5 m
l) and methanol (10 ml) solution, 1N sodium hydroxide (3 ml) was added, and the mixture was stirred at 60 ° C for 40 minutes. The reaction was diluted with water (20 ml), neutralized with 5% aqueous potassium hydrogen sulfate, and extracted with ethyl acetate (40 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated.
The residue was purified by silica gel column chromatography and 3,5-trans-5- (3-tert-butoxycarbonylaminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4 , 1-benzoxazepine-3-acetic acid (0.12 g) was obtained as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 1.499 (9H, s), 2.854 (1H, dd, J =
4.8, 17.0Hz), 3.05-3.32 (1H, m), 4.309 (2H, d, J = 5.6H
z), 4.43-4.56 (1H, m), 4.95-5.03 (1H, m), 5.04-5.42 (2
H, m), 5.453 (1H, s), 6.548 (1H, br), 6.85-7.66 (10H, m). (4) The compound (0.16 g) obtained in (3) and 2-
While stirring a solution of fluorobenzylamine (38 mg) in N, N-dimethylformamide (4 ml) at 0 ° C., diethyl cyanophosphate (40 mg) and triethylamine (35 mg) were added.
mg) was added. The reaction solution was stirred at room temperature for 20 minutes, diluted with ethyl acetate (20 ml), washed with a 5% aqueous potassium hydrogen sulfate solution, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give the title compound, 3,5-trans-N- (2-fluorobenzyl) -5- (3-tert-butylcarbonylphenyl) -7-chloro-2-oxo. −
1,2,3,5-tetrahydro-1- (4-trifluoromethylbenzyl) -4,1-benzoxazepine-3-
Acetamide (0.11 g) was obtained as colorless crystals. NMR (CDCl ₃ ) δ: 1.446 (9H, s), 2.708 (1H, dd, J =
5.6, 14.6Hz), 4.277 (2H, d, J = 5.8Hz), 4.37-4.62 (3H,
m), 4.75-4.93 (1H, m), 5.027 (1H, d, J = 14.8Hz), 5.335 (1
(H, d, J = 14.8Hz), 5.372 (1H, s), 6.14-6.27 (1H, m), 6.524
(1H, d, J = 2.2Hz), 6.93-7.65 (14H, m). Melting point: 100-101 ° C

Example 252 3,5-trans-N- (2-fluorobenzyl) -5
-(3-Aminomethylphenyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-1- (4-trifluorobenzyl) -4,1-benzoxazepine-3-
Acetamide hydrochloride To the compound (70 mg) obtained in Example 251 was added a 4N hydrogen chloride (ethyl acetate) solution (2 ml), and the mixture was stirred for 30 minutes. The reaction solution was concentrated, and ethyl acetate (20 m
l) was added and evaporated. The residue was treated with ether to give the title compound (70 mg) as a colorless amorphous solid. NMR (CDCl ₃ ) δ: 2.45-2.65 (2H, m), 2.728 (1H, d
d, J = 5.6, 14.7Hz), 3.851 (2H, br), 4.33-4.62 (3H, m),
4.995 (1H, d, J = 15.8Hz), 5.339 (1H, d, J = 15.8Hz), 5.362
(1H, s), 6.37-6.47 (1H, m), 6.526 (1H, d, J = 2.4Hz), 6.85
-7.63 (14H, m).

The pharmacological action of the compound of the present invention will be specifically described below, but it should not be construed that the invention is limited thereto. Genetic manipulation using E. coli is described in Molecular Cloning (Molecular Cloning, T. Mariatis et al.), 198
The method described in the ninth edition was followed. (1) Cloning of Human Somatostatin Receptor Protein Subtype 1 (SSTR1) DNA Nucleotide sequence of a known human SSTR1 cDNA [Proc. Natl. Acad. Sci. ., US
A), Vol. 89, pp. 251-255, 1992], DNA oligomers S1-1 and S1-2 were synthesized. The sequence of S1-1 was 5′-GGTCGACCTCA
GCTAGGATGTTCCCCAATG-3 ′ (SEQ ID NO: 1), and the sequence of S1-2 is 5′-GGTC
GACCCGGGCTCAGAGCGTCGTGAT-
3 ′ (SEQ ID NO: 2). As a template, human chromosomal DNA (Clontech, Catalog No. CL6550)
-1) was used. To 0.5 ng of the DNA was added 25 pmol of each of the above DNA oligomers, and a polymerase chain reaction was carried out using 2.5 units of Pfu DNA polymerase (Stratagene). The composition of the reaction solution is the Pf
The instructions attached to the uDNA polymerase were followed. The reaction conditions were repeated at 35 cycles of 94 ° C. for 1 minute, 63 ° C. for 1 minute, and 75 ° C. for 2 minutes.
When the reaction solution was subjected to 1% agarose gel electrophoresis, a DNA fragment of a target size (about 1.2 kb) was specifically amplified. The DNA fragment was recovered from an agarose gel according to a conventional method, and pUC1 cleaved at the HincII site.
18 and transformed into competent cells, Escherichia coli JM109. A transformant having a plasmid containing the DNA fragment was selected, and an automatic nucleotide sequence analyzer ALF D using a fluorescent dye was selected.
Insert DNA with NA sequencer (Pharmacia)
When the nucleotide sequence of the fragment was confirmed, the amino acid sequence predicted from the nucleotide sequence completely matched the sequence described in the above-mentioned literature. (2) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 1 (SSTR1) DNA pAKKO-111 was used as an expression vector in CHO (Chinese hamster ovary) cells. pAK
KO-111 was constructed as follows. JP-A-5-076
No. 385, pTB1417 to Hind II
A 1.4 kb DNA fragment containing the SRα promoter and the polyA addition signal was obtained by I and Cla I treatment. Also, pTB348 [Biochemical and Biophysical Research Communications (Biochem. Biophys. Res. C)
ommun. ), 128, 256-264, 1985.
4.5 kb DNA containing the dihydrofolate reductase (DHFR) gene by treatment with Cal I and Sal I
A fragment was obtained. The ends of these DNA fragments were made blunt by treatment with T4 polymerase and ligated with T4 ligase to construct a pAKKO-111 plasmid. Next, 5 μg of the plasmid having the human SSTR1 DNA fragment obtained in the above (1) was digested with a restriction enzyme SalI, and then subjected to 1% agarose gel electrophoresis.
A 1.2 kb DNA fragment encoding STR1 was recovered. And, the expression vector pAKKO-111
(5.5 kb) 1 μg was digested with SalI, and
A cloning site for inserting the TR1 DNA fragment was created. The expression vector fragment and 1.2 kb DNA
The fragments were ligated using T4 DNA ligase, the reaction solution was introduced into Escherichia coli JM109 by the calcium chloride method, and the expression plasmid pA1 in which the human SSTR1 DNA fragment was inserted in the forward direction with respect to the promoter from the transformants.
11-SSTR1 was obtained. This transformant is designated as Escherichia coli JM109 / pA-1-11-SSTR1.

(3) CHO (dh) of human somatostatin receptor protein subtype 1 (SSTR1) DNA
Introduction and expression into fr ⁻ ) cells CHO (dhfr ⁻ ) cells 1 × 10 ⁶ cells were collected at a diameter of 8 cm.
Ham F containing 10% fetal bovine serum using a Petri dish
The cells were cultured for 24 hours in 12 medium, and the cells were added to the human SSTR1 cDNA expression plasmid 1 pA-
10 μg of 1-11-SSTR1 was added to the calcium phosphate method (Cellfect Transfection Kit; Pharmacia).
a)). Twenty-four hours after the introduction, the medium was changed to DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies with this medium (that is, DHFR + cells) were selected. Further, the selected cells were cloned from a single cell by the limiting dilution method, and the somatostatin protein activity was measured by the following method. Human SSTR cDNA
The expression cell line was added to a measurement buffer [50 mM Tris-HCl, 1
mM EDTA, 5 mM magnesium chloride, 0.1%
BSA, 0.2 mg / ml bacitracin, 10 μg
/ Ml leupeptin, 1 μg / ml pepstatin,
200 units / ml of aprotinin (pH 7.
5)] and increase the cell number to 2 × 10 ⁴ per 200 μl.
Adjusted to individual. Dispense 200 μl into tubes and add 5 nM
[ ¹²⁵ I] -Somatostatin-14 (2000 Ci / m
mol, Amersham) and add 2 μl.
Incubation was performed at 5 ° C for 60 minutes. In addition, a tube to which 2 μl of somatostatin-14 (10 ⁻⁴ M) was added was also incubated to measure the amount of non-specific binding (NSB). Washing buffer [50 mM Tris-HCl, 1 mM EDTA, 5 mM magnesium chloride (p
H7.5)] (1.5 ml), filtered through GF / F glass fiber filter paper (Whatman), and further buffered with the same buffer (1.
5 ml). [ ¹²⁵ I] of the filter paper was measured with a γ-counter. Thus, a cell line having high somatostatin binding property, SSTR1-8-3, was selected.

(4) Cloning of Human Somatostatin Receptor Protein Subtype 2 (SSTR2) DNA The nucleotide sequence of a known human SSTR2 cDNA [Proceding of the National Academy of Science USA (Proc. Natl. Acad.Sci., US
A), Vol. 89, pp. 251-255, 1992] to synthesize DNA oligomers PT-1 and PT-2. The sequence of PT-1 is 5'-GGTCGACACCA
TGGACATGGCGGATGAG-3 ′ (SEQ ID NO: 3), and the sequence of PT-2 is 5′-GGTCG
ACAGTTCAGACTACTGGTTTGG-3 '
(SEQ ID NO: 4). Human pituitary cDNA (Clontech, catalog number 7173-1) was used as a template. To 1 ng of the cDNA, 25 pmol of each of the DNA oligomers was added, and a polymerase chain reaction was carried out using 2.5 units of Taq DNA polymerase (Takara Shuzo Co., Ltd.). The composition of the reaction solution was in accordance with the instructions attached to the Taq DNA polymerase. Reaction conditions are 94 ° C
For 30 seconds, at 52 ° C. for 20 seconds, and at 72 ° C. for 60 seconds.
As a cycle, 30 cycles were repeated. Reaction solution 1
When electrophoresed on a% agarose gel, a DNA fragment of the target size (about 1.1 kb) was specifically amplified. The DNA fragment was recovered from an agarose gel according to a conventional method, and pUC118 cleaved at a Hinc II site.
And transformed into competent cells, Escherichia coli JM109. The D
Two transformants (No. 5 and No. 7) having the plasmid containing the NA fragment were selected, and the base of the inserted DNA fragment was selected using an automatic base sequence analyzer 373A DNA sequencer (manufactured by Applied Biosystems) using a fluorescent dye. After confirming the sequence, it was confirmed that the sequence between SalI and BstPI of No. 5 strain was 77
No. 1 point mutation was confirmed in the sequence of the 0 base fragment.
One point mutation was confirmed in the sequence of the 360 base fragment between BstPI and SalI of the strain. So, No.5 strain of Bs
tPI-SalI fragment and BstPI-Sal of No. 7 strain
The remaining fragment except for I was purified by agarose electrophoresis, and a plasmid was constructed by connecting these fragments by a ligation reaction. When the nucleotide sequence of the DNA fragment inserted into this plasmid was confirmed, it completely matched the sequence described in the above-mentioned literature.

(5) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 2 (SSTR2) DNA As an expression vector in CHO (Chinese hamster ovary) cells, pAKKO-111 described in (2) above was used.
Was used. The human SSTR2cD obtained in the above (4)
5 μg of the plasmid having the NA fragment was digested with the restriction enzyme SalI.
After 1% agarose gel electrophoresis, a 1.1 kb DNA fragment encoding human SSTR2 was recovered. And the expression vector pAKKO-11
1 (5.5 kb) 1 μg was digested with SalI
A cloning site for inserting the STR2 DNA fragment was created. The expression vector fragment and 1.1 kb DN
The A fragment was ligated using T4 DNA ligase, and the reaction mixture was introduced into E. coli JM109 by the calcium chloride method.
C01 was obtained. This transformant is designated as Escherichia coli JM109 / pAC01. (6) human somatostatin receptor protein subtype 2 (SSTR2) DNA of CHO (dhfr ^-) Transfer and Expression CHO into cells (dhfr ^-) cells 1X10 ⁶ cells, diameter 8cm
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in a 12-medium medium, these cells were added to the human SSTR2 cDNA expression plasmid pAC0 obtained in (5) above.
1, 10 μg of calcium phosphate method (Cell Phect Trans
fection Kit; Pharmacia). Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Furthermore, the selected cells were cloned from a single cell by the limiting dilution method, and a cell line highly expressing human SSTR2, SSTR2
-HS5-9 was selected.

(7) Cloning of Human Somatostatin Receptor Protein Subtype 3 (SSTR3) DNA The base sequence of a known human SSTR3 cDNA [Molecular Endocrinol.
2136-2142, 1992].
Oligomers, S3-1 and S3-2, were synthesized. S3-
The sequence of 1 is 5'-GGTCGACCTCCAACCAT
GGACATGCTTCATC-3 '(SEQ ID NO: 5)
And the sequence of S3-2 is 5′-GGTCCGACTT.
TCCCCAGGCCCCTACAGGGTA-3 ′ (SEQ ID NO: 6). As a template, human chromosomal DNA
(Clontech, catalog number CL6550-1) was used. To 0.5 ng of the DNA, 25 pmol of each of the DNA oligomers was added, and a polymerase chain reaction was performed using 2.5 units of Pfu DNA polymerase (Stratagene). The reaction solution composition followed the instructions attached to Pfu DNA polymerase. The reaction conditions are 9
One cycle of 4 ° C. for 1 minute, 63 ° C. for 1 minute, and 75 ° C. for 2 minutes was repeated for 35 cycles. 1% reaction solution
Electrophoresis on an agarose gel revealed that a DNA fragment of the target size (about 1.3 kb) was specifically amplified. The amino acid sequence predicted from the nucleotide sequence completely matched the sequence described in the literature. (8) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 3 (SSTR3) DNA pAKKO-111 described in (2) above was used as an expression vector in CHO cells. Plasmid 5 μl containing the human SSTR3 DNA fragment obtained in (7) above
g was digested with the restriction enzyme SalI, followed by 1% agarose gel electrophoresis to encode human SSTR3.
A 3 kb DNA fragment was recovered. Then, 1 μg of the expression vector pAKKO-111 (5.5 kb) was added to Sa.
After digestion with I1, a cloning site for inserting the human SSTR3 DNA fragment was created. The expression vector and a 1.3 kb DNA fragment were ligated using T4 DNA ligase, and the reaction solution was subjected to a calcium chloride method using Escherichia coli JM.
109, and human / SSTR3
An expression plasmid pA1-11-SSTR3 in which the DNA fragment was inserted in the forward direction with respect to the promoter was obtained. This transformant was transformed into Escherichia col
i) Displayed as JM109 / pA-1-11-SSTR3.

(9) CHO (dh) of human somatostatin receptor protein subtype 3 (SSTR3) DNA
Introduction and expression into fr ⁻ ) cells 1 × 10 ⁶ CHO (dhfr ⁻ ) cells were transferred to an 8 cm diameter.
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in 12 medium, the cells were added to the human SSTR3 DNA expression plasmid pA-1 obtained in (5) above.
10 μg of 11-SSTR3 was introduced by the calcium phosphate method. Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Furthermore, the selected cells were cloned from a single cell by the limiting dilution method, and the somatostatin receptor protein expression ability of these cells was measured by the binding assay described in (3) above. Thus, a cell line with high somatostatin binding activity, SSTR3-15-
19 was selected. (10) Cloning of Human Somatostatin Receptor Protein Subtype 4 (SSTR4) DNA Known nucleotide sequence of human SSTR4 DNA [Proceding of the National Academy of Science USA (Proc. Natl. Acad. Sci., US
A), Vol. 90, pp. 4196-4200, 1993], DNA oligomers S4-1 and S4-2 were synthesized. The sequence of S4-1 is 5'-GGCTCGAGT
CACCATGAGCGCCCCCCTCG-3 ′ (SEQ ID NO: 7), and the sequence of S4-2 is 5′-GGGC
TCGAGCTCTCCAGAAGGTGGGTGG-
3 ′ (SEQ ID NO: 8). As a template, human chromosomal DNA (Clontech, Catalog No. CL6550)
-1) was used. To 0.5 ng of the DNA, 25 pmol of each of the DNA oligomers was added, and a polymerase chain reaction was performed using 2.5 units of Pfu DNA polymerase (Stratagene). The composition of the reaction solution is PfuD
The instructions attached to the NA polymerase were followed. The reaction conditions were repeated for 35 cycles, each cycle consisting of 94 ° C. for 1 minute, 66 ° C. for 1 minute, and 75 ° C. for 2 minutes. When the reaction solution was subjected to 1% agarose gel electrophoresis, a DNA fragment of a target size (about 1.2 kb) was specifically amplified. When the nucleotide sequence of the DNA fragment was confirmed by the method described in the above (1), the amino acid sequence predicted from the nucleotide sequence was completely identical to the sequence described in the literature.

(11) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 4 (SSTR4) DNA The pAKKO-111 described in (2) above was used as an expression vector in CHO cells. Plasmid 5 having the human SSTR4 DNA fragment obtained in (10) above
After digesting μg with the restriction enzyme Xhol, 1% agarose gel electrophoresis was performed to recover a 1.2 kb DNA fragment encoding human SSTR4. Then, 1 μg of the above-described expression vector pAKKO-111 (5.5 kb) was digested with SalI to prepare a cloning site for inserting a human SSTR4 DNA fragment. The expression vector fragment and the 1.2 kb DNA fragment were ligated using T4 DNA ligase, and the reaction mixture was introduced into Escherichia coli JM109 by the calcium chloride method.
An expression plasmid pA1-11-SSTR4 in which the STR4 DNA fragment was inserted in the forward direction with respect to the promoter was obtained. This transformant was transformed into Escheric
hia coli) JM109 / pA-1-11-SSTR4. (12) human somatostatin receptor protein subtype 4 (SSTR4) DNA of CHO (dhfr ^-) Transfer and Expression CHO into cells (dhfr ^-) cells 1X10 ⁶ cells, diameter 8cm
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in a 12-medium medium, the human SSTR4 DNA expression plasmid pA-1 obtained in the above (8) was added to the cells.
11-SSTR4, 10 μg was introduced by the calcium phosphate method. Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Furthermore, the selected cells were cloned from a single cell by the limiting dilution method, and the somatostatin receptor protein expression ability of these cells was measured by the binding assay described in (3) above. Thus, a cell line with high somatostatin binding activity, SSTR4-1-2,
Was selected.

(13) Cloning of Human Somatostatin Receptor Protein Subtype (SSTR5) DNA Base sequence of known human SSTR5 cDNA [Biochem.
Biophys. Res. Commun., 195, 844-852.
P. 1993], a DNA oligomer, S5-
1 and S5-2 were synthesized. The sequence of S5-1 is 5′-
GGTCGACCACCCATGGAGCCCCTGTTT
CCC-3 ′ (SEQ ID NO: 9), and the sequence of S5-2 is 5′-CCGTCGACACTCTCACAGCT.
TGCTGG-3 ′ (SEQ ID NO: 10). As a template, human chromosomal DNA (Clontech, catalog number CL6550-1) was used. 0.5 ng of the DNA
25 pmol of each of the DNA oligomers was added to
1. Pfu DNA polymerase (Stratagene Co., Ltd.)
The polymerase chain reaction was performed using 5 units. The reaction solution composition followed the instructions attached to Pfu DNA polymerase. The reaction conditions were repeated for 35 cycles, each cycle consisting of 94 ° C. for 1 minute, 66 ° C. for 1 minute, and 75 ° C. for 2 minutes. When the reaction solution was subjected to electrophoresis on a 1% agarose gel, DNA of a target size (about 1.1 kb) was obtained.
The fragment was specifically amplified. When the nucleotide sequence of the DNA fragment was confirmed by the method described in the above (1), the amino acid sequence predicted from the nucleotide sequence was completely identical to the sequence described in the literature.

(14) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 5 (SSTR5) DNA The pAKKO-111 described in (2) above was used as an expression vector in CHO cells. Plasmid 5 having the human SSTR5 DNA fragment obtained in (13) above
After digesting μg with the restriction enzyme SalI, 1% agarose gel electrophoresis was performed to recover a 1.1 kb DNA fragment encoding human SSTR5. Then, 1 μg of the above-mentioned expression vector pAKKO-111 (5.5 kb) was digested with SalI to prepare a cloning site for inserting a human SSTR5 DNA fragment. The expression vector fragment and the 1.1 kb DNA fragment were ligated using T4 DNA ligase, and the reaction mixture was introduced into Escherichia coli JM109 by the calcium chloride method.
An expression plasmid pA1-11-SSTR5 in which the STR5 DNA fragment was inserted in the forward direction with respect to the promoter was obtained. This transformant was transformed into Escheric
hia coli) JM109 / pA-1-11-SSTR5.

(15) CHO (d) of human somatostatin receptor protein subtype 5 (SSTR5) DNA
hfr ^-) Transfer and Expression CHO into cells (dhfr ^-) cells 1X10 ⁶ cells, diameter 8cm
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in 12 medium, the human SSTR5 cDNA expression plasmid pA-
5-11 μS of 1-11-SSTR was introduced by the calcium phosphate method. Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Furthermore, the selected cells were cloned from a single cell by the limiting dilution method, and the somatostatin receptor protein expression ability of these cells was measured by the binding assay described in (3) above. Thus, a cell line with high somatostatin binding activity, SSTR5-32-
4 was selected.

Experimental Example 1 Preparation of CHO Cell Membrane Fraction Containing Human Somatostatin Receptor Human somatostatin receptor expressing CHO cell line, SS
TR1-8-3, SSTR2-HS5-9, SSTR3
-15-19, SSTR4-1-2, or SSTR
5-32-4 (10 ⁹⁾ was centrifuged and resuspended in phosphate was added 5 mM EDTA buffered saline (PBS-EDTA). A cell homogenate buffer (10 mM NaHCO ₃ , 5 mM EDTA, pH =
7.5) was added, and the mixture was homogenized using a Polytron homogenizer. The supernatant obtained by centrifugation at 400 × g for 15 minutes was further centrifuged at 100,000 × g for 1 hour,
A precipitate of the membrane fraction was obtained. The precipitate is washed with 2 ml of assay buffer (25 ml of Tris-HCl, 1 ml of EDTA, 0.1 ml
1% BSA (bovine serum albumin), 0.25 ml PM
SF, 1 μg / ml pepstatin, 20 μg / ml leupeptin, 10 μg / ml phosphoramidone, pH = 7.
5) and centrifuged at 100,000 × g for 1 hour. The membrane fraction recovered as a precipitate was resuspended in 20 ml of assay buffer, aliquoted, stored at -80 ° C, and thawed at each use.

Experimental Example 2 Measurement of ¹²⁵ I-Somatostatin Binding Inhibition Rate The membrane fraction prepared in Example 1 was diluted with an assay buffer to 3 μg / ml, and 173 μl was dispensed into tubes. 2 μl of compound dissolved in DMSO and 200 pM
Of radiolabeled somatostatin ( ¹²⁵ I-somatostatin: Amersham) was added simultaneously. To determine maximum binding, 2 μl of DMSO and 200 μl
A reaction solution was prepared by adding 25 μl of M ¹²⁵ I-somatostatin. Also, to measure non-specific binding,
2 μl of 100 μM somatostatin dissolved in DMSO
And a reaction mixture containing 25 μl of 200 pM ¹²⁵ I-somatostatin. After reacting at 25 ° C. for 60 minutes, the reaction solution was subjected to suction filtration using a polyethylene imine-treated Whatman glass filter (GF-B). After filtration, it remained on the filter paper using a γ-counter.
The radioactivity of ¹²⁵ I-somatostatin was measured. Formula PBM = (B-NSB) / (B O -NSB) × 100 (PBM: Percent Maximum Binding, B: radioactivity when compound was added, B _O: maximum binding radioactivity, NS
B: non-specific binding radioactivity) was calculated to determine the binding rate (%) of each test substance. The binding ratio was determined by changing the concentration of the test substance, and the concentration (IC ₅₀ value) of the test substance that inhibited 50% binding was calculated from the Hill plot. [Table 5] shows the reactivity (IC ₅₀ value, μM) of each compound examined by the above method for each human somatostatin receptor.

[Table 5]

Experimental Example 3 Inhibitory Effect on Forskolin-Stimulated cAMP Accumulation in CHO Cells Expressing Human Somatostatin Receptor In order to measure the amount of intracellular adenosine 3 ', 5'-1 phosphate (cAMP) accumulation, refer to Reference Examples 2-3 and The human somatostatin receptor-expressing cell lines described in Example 3-3, Reference Example 4-3 and Reference Example 5-3, respectively, SSTR2-HS5
-9, SSTR3-15-19, SSTR4-1-2,
And SSTR5-32-4 were grown to confluence in 24-well plates. The cells were added to 1 ml of medium A
[Dulbecco's modified Eagle's medium (DMEM), 20 mM
2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid (HEPES) (pH 7.
5), washed twice with 0.2% bovine serum albumin, 0.2 mM 3-isobutyl-1-methylxanthine (IBMX)], and then 400 μl of medium A was added to each well and incubated at 37 ° C. for 1 hour. . 50 μl of a solution of the compound of Example 5 and Example 102 (diluted in medium A to 10 times the final concentration) and 50 μl of forskolin solution (10 μM final concentration) were added to each well. 3
Incubated for 0 minutes. After washing the cells twice with 1 ml of medium A, 500 μl of medium A and 100 μl of 20%
A perchloric acid aqueous solution was added to each well, and the cells were lysed by allowing them to stand at 4 ° C. for 20 minutes. The lysate was transferred to an Eppendorf tube, centrifuged (15,000 rpm, 10 minutes), and 500 μl of the supernatant was transferred to another Eppendorf tube, and 60 mM HEP containing 1.5 M potassium chloride was added.
Neutralized with an aqueous ES solution. CAM contained in this extract
The amount of P was measured using a kit (cAMP EIA system) manufactured by Amersham. These results (ED ₅₀ value,
nM) is shown in [Table 6].

[Table 6] From the above results, it was clarified that the compound of Example 5 and the compound of Example 102 had an agonistic effect on human somatostatin receptor.

Experimental Example 4 Inhibition of secretion of growth hormone (GH) by primary cultured cells of rat anterior pituitary gland Forty Wistar rats (8-week-old, male) were decapitated under anesthesia, and the anterior pituitary gland was excised from buffer A. [137 mM
Sodium chloride, 5 mM potassium chloride, 0.7 mM disodium hydrogen phosphate, 25 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid (HEPES) (pH 7.3), 50 μg / ml gentamicin sulfate ], And washed once with buffer A. This was divided into four portions with scissors and further washed twice, and the pituitary gland was treated with 30 ml of enzyme solution I [0.4% collagenase A (Boehringer Mannheim), 0.4% bovine serum albumin, 10 μg / ml deoxygenase. Incubation was carried out at 37 ° C. for 1 hour with shaking in ribonuclease I (Sigma), buffer A containing 0.2% glucose. The tissue fragments are dispersed with a Komagome pipette and centrifuged (4
80 × g, 6 minutes), and the supernatant was removed. 30 ml of precipitate
Was suspended in an enzyme solution II [buffer A containing 0.25% pancreatin (Sigma)], and incubated at 37 ° C. for 8 minutes with shaking. After adding 2 ml of fetal calf serum and centrifuging again (480 × g, 6 minutes), the supernatant was removed. 10 ml of medium I [10% fetal serum, 20 mM HEPES (pH 7.3), 50 U / ml
Dulbecco's modified Eagle's medium (DMEM) containing penicillin G and 50 μg / ml streptomycin] was added, and the mixture was suspended and filtered using a nylon mesh. After washing twice more with 10 ml of the medium I, the number of cells was counted, and the cells were suspended in the medium I to 1.5 × 10 ⁵ cells / ml.
Dispense 1 ml of the cell suspension into each well of a 24-well plate,
37 ° C. in 5% CO ₂ -95% air in a carbon dioxide gas culture medium
For 3 days. The cells were washed twice with 1 ml of medium II (medium I containing 0.2% bovine serum albumin instead of 10% fetal bovine serum), and then 1 ml of medium II was added and cultured for 1 hour. The culture supernatant was removed and 0.8 ml of medium I was removed.
I was added to each well of a 24-well plate. Somatostatin-1 diluted with medium II to 10 times the final concentration
4 (SS-14) or the compound of Example 5 or Example 10
0.1 ml of compound 2 and 0.1 ml of 10 nM growth hormone releasing hormone (GHRH) were added. After culturing at 37 ° C. for 3 hours, 0.6 ml of the culture supernatant was collected, and 1000 × g, 8
The supernatant was collected by centrifugation for minutes. The concentration of GH in the supernatant was determined by radioimmunoassay (RIA) manufactured by Amersham.
The measurement was performed using the kit. The amount of GH secreted by the primary cultured cells of the rat anterior pituitary gland decreased depending on the concentration of the added compound of Example 5 and the compound of Example 102. The ED ₅₀ value at that time was determined to be 8 nM for the compound of Example 5 and 10 nM for the compound of Example 102. From the above results, it was clarified that the compound of Example 5 and the compound of Example 102 had an effect of suppressing GH secretion from primary cultured cells of rat anterior pituitary.

Experimental Example 5 GH Secretion Inhibition Test Using SD Rats Male SD rats (11 weeks old) were treated with a compound administration group (n =
5) and a control group (n = 4). A 3 mg / kg / 5 ml compound of Example 5 was used as a 0.5% methylcellulose physiological saline solution in the compound administration group, and 5 ml / kg in the control group.
0.5% methylcellulose saline was administered intraperitoneally. Four hours after the administration, whole blood was collected by decapitation under anesthesia, centrifuged at 4 ° C and 2500 rpm for 30 minutes, and 1 ml of the obtained plasma was dispensed and stored at -20 ° C. GH concentrations in plasma were measured by RIA using the rat GH [ ¹²⁵ I] assay system (Amersham). The results are shown in [Table 7].

[Table 7] In the compound-administered group of Example 5, the plasma GH concentration was significantly reduced (p <0.05), which revealed that the compound of Example 5 had GH secretion inhibitory activity in rats.

Experimental Example 6 Insulin secretion inhibition test using SD rats In order to examine the inhibitory effect of the compound of Example 5 on insulin secretion after glucose stimulation, glucose and Example 5 were tested.
And then blood was collected over time,
Insulin concentration in plasma was measured by IA. Male S
D-type rats (8-week-old, n = 3) were weighed and 50 mg /
Anesthetized by intraperitoneal administration of kg pentobarbital. 50 mg of 30 mg EDTA as anticoagulant
300 μl of Trasilol (Bayer) at 000 unit / ml
And 3 μl was previously dispensed into an Eppendorf tube for blood collection. After fixing the rat in the rat fixation device, the neck was opened, and 100 μl of blood was collected from one jugular vein using a 25-G injection needle. In the control administration group [glucose (-)], 5% propylene glycol, 30%
Hydroxypropyl-β-cyclodextrin (hydrox
ypropyl-β-cyclodextrin), and the control group [glycose (+)] was 300 mg / kg / ml in 5% propylene glycol and 30% hydroxypropyl-β-cyclodextrin. What melt | dissolved glucose was used so that it might become. On the other hand, [Compound (+)] for the compound administration group contained 300 mg / kg / ml glucose and 0.003, 0.03, 5% propylene glycol, 30% hydroxypropyl-β-cyclodextrin in physiological saline. The compound of Example 5 was dissolved at 0.3 or 3 mg / kg / ml. From the jugular vein on the side not used for blood collection, only glucose and the compound or glucose prepared as described above were intravenously injected, and 1, 2, 4, 6, 8,
Ten minutes later, 100 μl of blood was collected. After blood collection,
After centrifugation at 10,000 rpm for 15 minutes at 4 ° C., the supernatant was stored at −20 ° C. Measurement of plasma insulin concentration was performed by RIA using rat insulin [ ¹²⁵ I] assay system (Amersham). The 25-fold diluted rat plasma was dispensed into two tubes, each containing 50 μl of each sample, and 50 μl of the primary antibody and 50 μl of [ ¹²⁵ I] rat insulin were added and stirred. After standing for 4 times at room temperature together with the dilution series of standard rat insulin that was subjected to the same operation, 125 μl of the secondary antibody was added.
Stir at room temperature for 10 minutes, then 4 ° C, 300
Centrifuge at 0 rpm for 10 minutes, decant the supernatant,
Water droplets remaining on the inner wall of the tube were removed with a cotton swab and counted with a gamma counter. Although plasma insulin concentration is increased by glucose administration, co-administration of the compound with glucose suppresses the increase in insulin concentration in a dose-dependent manner, and the dose of 50% inhibition may be about 0.03 mg / kg. I understand. From the above results, it was revealed that the compound of Example 5 had an action of suppressing rat insulin secretion.

[0332]

The compound (I) of the present invention or a salt thereof has an excellent somatostatin receptor agonizing action and low toxicity, and thus can be a safe preventive / therapeutic drug for diseases associated with this action. .

[0333]

[Sequence list]

 SEQ ID NO: 1 Sequence length: 30 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGTCGACCTC AGCTAGGATG TTCCCCAATG 30

SEQ ID NO: 2 Sequence length: 28 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGTCGACCCG GGCTCAGAGC GTCGTGAT 28

SEQ ID NO: 3 Sequence length: 28 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGTCGACACC ATGGACATGG CGGATGAG 28

SEQ ID NO: 4 Sequence length: 26 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGTCGACAGT TCAGATACTG GTTTGG 26

SEQ ID NO: 5 Sequence length: 30 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGTCGACCTC AACCATGGAC ATGCTTCATC 30

SEQ ID NO: 6 Sequence length: 29 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGTCGACTTT CCCCAGGCCC CTACAGGTA 2
9

SEQ ID NO: 7 Sequence length: 28 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGCTCGAGTC ACCATGAGCG CCCCCTCG 28

SEQ ID NO: 8 Sequence length: 27 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGGCTCGAGC TCCTCAGAAG GTGGTGG 27

SEQ ID NO: 9 Sequence length: 28 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: GGTCGACCAC CATGGAGCCC CTGTTCCC 28

SEQ ID NO: 10 Sequence length: 26 Sequence type: nucleic acid Number of strands: single-stranded Topology: linear Sequence type: other nucleic acid (synthetic DNA) Sequence: CCGTCGACAC TCTCACAGCT TGCTGG 26

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 413/04 333 C07D 413/04 333 413/06 209 413/06 209 211 211 213 213 307 307 307 333 333

Claims (35)

[Claims] 1. A compound of the general formula Or S (O) n (n represents 0, 1 or 2)
Is shown. Or a salt thereof. 2. The ring A is halogen, C is_1-6Alkyl, halogen
No-C_1-6Alkyl, phenyl, benzyl, C_1-6Arco
Xy, halogeno-C_1-6Alkoxy, phenoxy, C
_7-14Aralkyloxy, formyloxy, C_1-6Archi
Ru-carbonyloxy, C_1-6Alkylthio, halogeno
-C_1-6Alkylthio, hydroxy, mercapto, shea
No, nitro, carboxy, formyl, C_1-6Alkyl-
Carbonyl, benzoyl, C_1-6Alkoxy-carboni
Phenoxycarbonyl, amino, mono- or di-C
_1-6Alkylamino, formylamino, C_1-6Alkyl-
Carbonylamino, carbamoyl, mono- or di-C
_1-6Alkyl-carbamoyl, sulfo, C_1-6Alkyls
Ruphonyl, benzoyl-C_1-6Alkoxy, hydroxy
-C_1-6Alkoxy, C_1-6Alkoxy-carbonyl-C
_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6Alkoki
Si, imidazol-1-yl-C_1-6Alkoxy, C
_7-14Aralkyloxy-carbonyl-C_1-6Alkoki
Si, hydroxyphenyl-C_1-6Alkoxy, C_7-14A
Aralkyloxy-carbonyl, mono- or di-C_1-6Al
Killamino-C_1-6Alkoxy and mono- or di-C_1-6A
1 to 1 selected from alkylamino-carbonyloxy
C optionally having 4 substituents_6-14Aromatic hydrocarbon
Nitrogen, oxygen and sulfur atoms other than carbon and carbon atoms
5 having 1 to 4 heteroatoms selected from
6-membered monocyclic aromatic heterocycle or benzene ring and 5 or 6
Or tricyclic ring formed by condensing a membered monocyclic aromatic heterocycle
A condensed aromatic fused heterocyclic ring, wherein ring B is halogen, C_1-6Alkyl, halogeno-C_1-6Al
Kill, phenyl, benzyl, C_1-6Alkoxy, halogen
No-C_1-6Alkoxy, phenoxy, C_7-14Aralkyl
Oxy, formyloxy, C_1-6Alkyl-carbonyl
Oxy, C_1-6Alkylthio, halogeno-C_1-6Alkyl
Thio, hydroxy, mercapto, cyano, nitro, cal
Boxy, formyl, C_1-6Alkyl-carbonyl, ben
Zoil, C_1-6Alkoxy-carbonyl, phenoxyca
Rubonyl, amino, mono- or di-C_1-6Alkylam
No, formylamino, C_1-6Alkyl-carbonylamido
No, carbamoyl, mono- or di-C_1-6Alkyl-ka
Rubamoyl, Sulfo, C_1-6Alkylsulfonyl, ben
Zoyl-C_1-6Alkoxy, hydroxy-C_1-6Alkoki
Si, C_1-6Alkoxy-carbonyl-C_1-6Alkoxy,
C_3-14Cycloalkyl-C_1-6Alkoxy, imidazo
Ru-1-yl-C_1-6Alkoxy, C_7-14Aralquilo
Xy-carbonyl-C_1-6Alkoxy, hydroxyfe
Nil-C_1-6Alkoxy and C_7-14Aralkyloxy-
Having 1 to 4 substituents selected from carbonyl
May be C_6-14In addition to aromatic hydrocarbons and carbon atoms
1 to 1 selected from a nitrogen atom, an oxygen atom and a sulfur atom
5- or 6-membered monocyclic aromatic heterocycle having 4 heteroatoms
Ring or benzene ring and 5- or 6-membered monocyclic aromatic heterocycle
Is fused to form a fused bicyclic or tricyclic aromatic heterocyclic ring, or ring B is R^TwoAnd halogen, C_1-6Alkyl,
Halogeno-C_1-6Alkyl, phenyl, benzyl, C_1-6
Alkoxy, halogeno-C_1-6Alkoxy, phenoki
Si, C_7-14Aralkyloxy, formyloxy, C_1-6
Alkyl-carbonyloxy, C_1-6Alkylthio, ha
Logeno-C_1-6Alkylthio, hydroxy, mercap
G, cyano, nitro, carboxy, formyl, C_1-6A
Alkyl-carbonyl, benzoyl, C_1-6Alkoxy-
Carbonyl, phenoxycarbonyl, amino, mono- or
Is Di-C_1-6Alkylamino, formylamino, C_1-6A
Alkyl-carbonylamino, carbamoyl, mono- or
Di-C_1-6Alkyl-carbamoyl, sulfo, C_1-6Al
Killsulfonyl, benzoyl-C_1-6Alkoxy, hide
Roxy-C_1-6Alkoxy, C_1-6Alkoxy-carboni
Le-C_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6A
Lucoxy, imidazol-1-yl-C_1-6Alkoki
Si, C_7-14Aralkyloxy-carbonyl-C_1-6Al
Coxy, hydroxyphenyl-C_1-6Alkoxy and C
_7-14No one selected from aralkyloxy-carbonyl
A nitrogen atom, an oxygen atom which may have 4 substituents
1 to 3 heteroatoms selected from the group consisting of a hydrogen atom and a sulfur atom
5- or 6-membered monocyclic non-aromatic heterocycle having benzene and benzene
Bicyclic non-aromatic fused nitrogen-containing heterocyclic ring formed by condensing rings
Z may be a halogen, C may form a ring_1-6Alkyl, halogeno-C_1-6Al
Kill, phenyl, benzyl, C_1-6Alkoxy, halogen
No-C_1-6Alkoxy, phenoxy, C_7-14Aralkyl
Oxy, formyloxy, C_1-6Alkyl-carbonyl
Oxy, C_1-6Alkylthio, halogeno-C_1-6Alkyl
Thio, hydroxy, mercapto, cyano, nitro, cal
Boxy, formyl, C_1-6Alkyl-carbonyl, ben
Zoil, C_1-6Alkoxy-carbonyl, phenoxyca
Rubonyl, amino, mono- or di-C_1-6Alkylam
No, formylamino, C_1-6Alkyl-carbonylamido
No, carbamoyl, mono- or di-C_1-6Alkyl-ka
Rubamoyl, Sulfo, C_1-6Alkylsulfonyl, ben
Zoyl-C_1-6Alkoxy, hydroxy-C_1-6Alkoki
Si, C_1-6Alkoxy-carbonyl-C_1-6Alkoxy,
C_3-14Cycloalkyl-C_1-6Alkoxy, imidazo
Ru-1-yl-C_1-6Alkoxy, C_7-14Aralquilo
Xy-carbonyl-C_1-6Alkoxy, hydroxyfe
Nil-C_1-6Alkoxy, C_7-14Aralkyloxy-ca
1 to 5 selected from rubonyl, oxo and thioxo
C optionally having two substituents_3-14Cycloalkyl
Group, C_3-14Cycloalkenyl group, C_3-14Cycloalkadi
Enyl group, indanyl group or C_6-14Aryl group, carbon source
Other than nitrogen, nitrogen, oxygen and sulfur
5- or 6-membered monocyclic ring having 1 to 4 heteroatoms
Aromatic or non-aromatic heterocycle, or benzene ring and 5 or 6
Or tricyclic ring formed by condensing a membered monocyclic aromatic heterocycle
Formula aromatic fused heterocycle or partially reduced form thereof, or
(1) halogen, (2) nitro, (3) cyano, (4) imino, (5)
(i) C optionally substituted with 1 to 5 halogens
_1-6Alkyl, phenyl, benzyl, formyl, C_1-6A
Alkyl-carbonyl, benzoyl, C_1-6Alkoxy-
Carbonyl, C_7-14Aralkyloxy-carbonyl,
Ruho, C_1-6Alkylsulfonyl and C_1-6Alkylam
Having one or two substituents selected from no-carbonyl
Amino, (ii) pyrrolidinyl, (iii) piperi
Jill, (iv) morpholinyl, (v) thiomorpholinyl, (vi)
4-methylpiperidyl, (vii) 4-phenylpiperidi
(Viii) 4-benzyloxycarbonylpiperidyl,
(6) (i) halogen, hydroxy, C_1-6Alkoxy, phor
Mill, C_1-6Alkyl-carbonyl, carboxy, C_1-6
Alkoxy-carbonyl, amino, mono- or di-C
_1-6Alkylamino, pyrrolidinyl, piperidyl, mol
Folinyl, thiomorpholinyl, 4-methylpiperidyl,
4-phenylpiperidyl, carbamoyl, mono- or di-
-C_1-6Alkylcarbamoyl, phenoxy, mono- or
Is Di-C_1-6Alkyl-carbamoyloxy, formyl
Amino, C_1-6Alkyl-carbonylamino, formyl
Oxy and C_1-6Selected from alkyl-carbonyloxy
C may have 1 to 3 substituents_1-6A
Alkyl, (ii) halogen, hydroxy, C_1-6Alkoki
Shi, Formyl, C_1-6Alkyl-carbonyl, carboxy
Si, C_1-6Alkoxy-carbonyl, amino, mono- or
Is Di-C_1-6Alkylamino, pyrrolidinyl, piperidi
, Morpholinyl, thiomorpholinyl, 4-methylpipe
Lysyl, 4-phenylpiperidyl, carbamoyl, mono
-Or di-C_1-6Alkylcarbamoyl, phenoxy,
Mono- or di-C_1-6Alkyl-carbamoyloxy,
Formylamino, C_1-6Alkyl-carbonylamino,
Formyloxy, C_1-6Alkyl-carbonyloxy,
C_1-6Alkyl and halogeno-C_1-6Selected from alkyl
C which may have 1 to 5 substituents_6-10Ants
(Iii) halogen, hydroxy, C_1-6Alkoxy,
Holmill, C_1-6Alkyl-carbonyl, carboxy,
C_1-6Alkoxy-carbonyl, amino, mono- or di-
-C_1-6Alkylamino, pyrrolidinyl, piperidyl,
Morpholinyl, thiomorpholinyl, 4-methylpiperidi
, 4-phenylpiperidyl, carbamoyl, mono- or
Is Di-C_1-6Alkyl carbamoyl, phenoxy, mono
-Or di-C_1-6Alkyl-carbamoyloxy, phor
Milamino, C_1-6Alkyl-carbonylamino, phor
Miloxy, C_1-6Alkyl-carbonyloxy, C_1-6
Alkyl and halogeno-C_1-61 selected from alkyl
C to C 5 optionally having 5 substituents_7-14Aralki
And (iv) halogen, hydroxy, C_1-6Alkoxy,
Holmill, C_1-6Alkyl-carbonyl, carboxy,
C_1-6Alkoxy-carbonyl, amino, mono- or di-
-C_1-6Alkylamino, pyrrolidinyl, piperidyl,
Morpholinyl, thiomorpholinyl, 4-methylpiperidi
, 4-phenylpiperidyl, carbamoyl, mono- or
Is Di-C_1-6Alkyl-carbamoyl, phenoxy, mo
No- or di-C_1-6Alkyl-carbamoyloxy, e
Lumilamino, C_1-6Alkyl-carbonylamino, e
Lumiloxy and C_1-6Alkyl-carbonyloxy
And optionally one or three substituents selected from
Lumil, C_1-6Alkyl-carbonyl, benzoyl, C
_1-6Alkoxy-carbonyl, benzyloxycarboni
Le, C_1-6Alkylsulfonyl, carbamoyl, mono-
Or di-C_1-6Selected from alkyl-carbamoyl
Hydroxy optionally having substituent (s), (7) C_1-6Archi
Benzyl or mono- or di-C_1-6Alkylamino
Optionally substituted carboxy, (8) C_3-6Cycloa
Lucil, (9) C_3-6Cycloalkenyl, (10) halogen, C
_1-6Alkyl, halogeno-C_1-6Alkyl, phenyl, benzo
Ngil, C_1-6Alkoxy, halogeno-C_1-6Alkoki
Si, phenoxy, C_{7- 14}Aralkyloxy, formylo
Kissi, C_1-6Alkyl-carbonyloxy, C_1-6Archi
Lucio, halogeno-C_1-6Alkylthio, hydroxy,
Mercapto, cyano, nitro, carboxy, formyl,
C_1-6Alkyl-carbonyl, benzoyl, C_1-6Arco
Xy-carbonyl, phenoxycarbonyl, amino,
No- or di-C_1-6Alkylamino, formylamino,
C_1-6Alkyl-carbonylamino, carbamoyl, molybdenum
No- or di-C_1-6Alkyl-carbamoyl, sulfo,
C_1-6Alkylsulfonyl, benzoyl-C_1-6Alkoki
Si, hydroxy-C_1-6Alkoxy, C_1-6Alkoxy-
Carbonyl-C_1-6Alkoxy, C_3-14Cycloalkyl
-C_1-6Alkoxy, imidazol-1-yl-C_1-6A
Lucoxy, C_7-14Aralkyloxy-carbonyl-C
_1-6Alkoxy, hydroxyphenyl-C_1-6Alkoxy
And C_7-14Selected from aralkyloxy-carbonyl
A carbon atom or less, which may have 1 to 4 substituents
In addition, one selected from nitrogen atom, oxygen atom and sulfur atom
5- or 6-membered monocyclic heterocycle having 4 heteroatoms
Or a benzene ring and a 5- or 6-membered monocyclic heterocyclic ring condensed
The formed bi- or tricyclic fused heterocycle, (11) oxo and (1
2) having 1 to 5 substituents selected from pyrrolidinyl
C that may be_1-10Alkyl group, C_2-10Alkenyl group
Or C_2-10Alkynyl group, R¹Is a hydrogen atom, (1) halogen, (2) nitro, (3) shea
No, (4) imino, (5) (i) substituted with 1 to 5 halogens
C that may be_1-6Alkyl, phenyl, benzyl
Le, Formyl, C_1-6Alkyl-carbonyl, benzoy
Le, C_1-6Alkoxy-carbonyl, C_7-14Aralkyl
Oxy-carbonyl, sulfo, C_1-6Alkylsulfoni
And C_1-6Selected from alkylamino-carbonyl
Amino optionally having one or two substituents, (ii)
Loridinyl, (iii) piperidyl, (iv) morpholinyl, (v)
Thiomorpholinyl, (vi) 4-methylpiperidyl, (vii)
4-phenylpiperidyl, (viii) 4-benzyloxyca
Rubonyl piperidyl, (6) (i) halogen, hydroxy, C
_1-6Alkoxy, formyl, C_1-6Alkyl-carboni
Le, carboxy, C_1-6Alkoxy-carbonyl, amine
No, mono- or di-C_1-6Alkylamino, pyrrolidini
, Piperidyl, morpholinyl, thiomorpholinyl, 4
-Methylpiperidyl, 4-phenylpiperidyl, carb
Moyl, mono- or di-C_1-6Alkyl-carbamoy
Phenoxy, mono- or di-C_1-6Alkyl-cal
Bamoyloxy, formylamino, C_1-6Alkyl-ka
Rubonylamino, formyloxy and C_1-6Alkyl-
1 to 3 substituents selected from carbonyloxy
C that you may have_1-6Alkyl, (ii) halogen, hydr
Roxy, C_1-6Alkoxy, formyl, C_1-6Alkyl-
Carbonyl, carboxy, C_1-6Alkoxy-carboni
, Amino, mono- or di-C_1-6Alkylamino, pi
Loridinyl, piperidyl, morpholinyl, thiomorpholin
Nyl, 4-methylpiperidyl, 4-phenylpiperidi
Carbamoyl, mono- or di-C_1-6Alkyl-ka
Rubamoyl, phenoxy, mono- or di-C_1-6Archi
Ru-carbamoyloxy, formylamino, C_1-6Al
Kill-carbonylamino, formyloxy, C_1-6Al
Kill-carbonyloxy, C_1-6Alkyl and halogeno
-C_1-61 to 3 substituents selected from alkyl
C that you may have_6-10Aryl, (iii) halogen, ar
Droxy, C_1-6Alkoxy, formyl, C_1-6Alkyl
-Carbonyl, carboxy, C_1-6Alkoxy-carbo
Nil, amino, mono- or di-C_1-6Alkylamino,
Pyrrolidinyl, piperidyl, morpholinyl, thiomorpho
Linyl, 4-methylpiperidyl, 4-phenylpiperidi
Carbamoyl, mono- or di-C_1-6Alkyl-ka
Rubamoyl, phenoxy, mono- or di-C_1-6Archi
Ru-carbamoyloxy, formylamino, C_1-6Al
Kill-carbonylamino, formyloxy, C_1-6Al
Kill-carbonyloxy, C_1-6Alkyl and halogeno
-C_1-61 to 5 substituents selected from alkyl
C that you may have_7-14Aralkyl and (iv) halogen,
Hydroxy, C_1-6Alkoxy, formyl, C_1-6Archi
Ru-carbonyl, carboxy, C_1-6Alkoxy-cal
Bonyl, amino, mono- or di-C_1-6Alkylam
, Pyrrolidinyl, piperidyl, morpholinyl, thiomo
Rufolinyl, 4-methylpiperidyl, 4-phenylpipe
Lysyl, carbamoyl, mono- or di-C_1-6Alkyl
Carbamoyl, phenoxy, mono- or di-C_1-6A
Alkyl-carbamoyloxy, formylamino, C_1-6
Alkyl-carbonylamino, formyloxy and C
_1-61 to 1 selected from alkyl-carbonyloxy
Formyl optionally having three substituents, C_1-6Al
Kill-carbonyl, benzoyl, C_1-6Alkoxy-ka
Rubonyl, benzyloxycarbonyl, C_1-6Alkyl
Sulfonyl, carbamoyl or mono- or di-C_1-6A
Alkyl-carbamoyl, having a substituent selected from
Hydroxy, (7) C_1-6Alkyl, benzyl or
Mono- or di-C_1-6Substituted with alkylamino
Good carboxy, (8) C_3-6Cycloalkyl, (9) C_3-6
Cycloalkenyl, (10) halogen, C_1-6Alkyl, ha
Logeno-C_1-6Alkyl, phenyl, benzyl, C_1-6A
Lucoxy, halogeno-C_1-6Alkoxy, phenoxy,
C_7-14Aralkyloxy, formyloxy, C_1-6Al
Kill-carbonyloxy, C_1-6Alkylthio, halogen
No-C_1-6Alkylthio, hydroxy, mercapto,
Ano, nitro, carboxy, formyl, C_1-6Alkyl
-Carbonyl, benzoyl, C_1-6Alkoxy-carbo
Nil, phenoxycarbonyl, amino, mono- or di-
C_1-6Alkylamino, formylamino, C_1-6Alkyl
-Carbonylamino, carbamoyl, mono- or di-C
_1-6Alkyl-carbamoyl, sulfo, C_1-6Alkyls
Ruphonyl, benzoyl-C_1-6Alkoxy, hydroxy
-C_1-6Alkoxy, C_1-6Alkoxy-carbonyl-C
_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6Alkoki
Si, imidazol-1-yl-C_1-6Alkoxy, C
_7-14Aralkyloxy-carbonyl-C_1-6Alkoki
Si, hydroxyphenyl-C_1-6Alkoxy and C_7-14
1 to 4 selected from aralkyloxy-carbonyl
Nitrogen atom other than the carbon atom which may have
One to four selected from oxygen, oxygen and sulfur
A 5- or 6-membered monocyclic aromatic heterocycle having a heteroatom or
A benzene ring and a 5- or 6-membered monocyclic aromatic heterocycle are fused
Selected from bi- or tricyclic fused aromatic heterocycles formed by
C which may have 1 to 5 substituents_1-10A
Alkyl group, C_2-10Alkenyl group, C_2-10Alkynyl group,
C_3-10Cycloalkyl group, C_3-10Cycloalkenyl group,
C_5-10Cycloalkadienyl group, C_6-14Aryl group or
C_7-14Aralkyl groups and, in addition to these substituents,
_6-14Aryl group or C_7-14The aralkyl group is C_1-6Archi
Le, halogeno-C_1-6Alkyl and halogen, C_1-6Al
Kill, halogeno-C_1-6Alkyl, C_1-6Alkoxy, C
_7-14Aralkyloxy, hydroxy, amino, mono- or
Is Di-C_1-6Alkylamino, carboxy, C_1-6Archi
Le-carbonyl, C_1-6Alkoxy-carbonyl, nitro
Having 1 to 5 substituents selected from b and cyano
May be C_6-141 to 5 selected from aryl
Or a halogen, C_1-6
Alkyl, halogeno-C_1-6Alkyl, phenyl, ben
Jill, C_1-6Alkoxy, halogeno-C_1-6Alkoxy,
Phenoxy, C_7-14Aralkyloxy, formyloxy
Si, C_1-6Alkyl-carbonyloxy, C_1-6Alkyl
Thio, halogeno-C_1-6Alkylthio, hydroxy,
Lcapto, cyano, nitro, carboxy, formyl, C
_1-6Alkyl-carbonyl, benzoyl, C_1-6Alkoki
C-carbonyl, phenoxycarbonyl, amino, mono
-Or di-C_1-6Alkylamino, formylamino, C
_1-6Alkyl-carbonylamino, carbamoyl, mono
-Or di-C_1-6Alkyl-carbamoyl, sulfo, C
_1-6Alkylsulfonyl, benzoyl-C_1-6Alkoki
Si, hydroxy-C_1-6Alkoxy, C_1-6Alkoxy-
Carbonyl-C_1-6Alkoxy, C_3-14Cycloalkyl
-C_1-6Alkoxy, imidazol-1-yl-C_1-6A
Lucoxy, C_7-14Aralkyloxy-carbonyl-C
_1-6Alkoxy, hydroxyphenyl-C_1-6Alkoxy
And C_7-14Selected from aralkyloxy-carbonyl
Other than carbon atoms optionally having 1 to 4 substituents
At least one selected from nitrogen, oxygen and sulfur
A 5- or 6-membered monocyclic heterocycle having 4 heteroatoms or
Is a condensed form of a benzene ring and a 5- or 6-membered monocyclic heterocycle.
A bi- or tricyclic fused heterocycle formed^TwoIs (A) an unsubstituted amino group, (B) (1) halogen,
(2) nitro, (3) cyano, (4) imino, (5) (i) 1 to 5
C optionally substituted with two halogens_1-6Alkyl,
Phenyl, benzyl, formyl, C_1-6Alkyl-cal
Bonyl, benzoyl, C_1-6Alkoxy-carbonyl,
C_7-14Aralkyloxy-carbonyl, sulfo, C_1-6
Alkylsulfonyl and C_1-6Alkylamino-carbo
May have one or two substituents selected from nyl
Amino, (ii) pyrrolidinyl, (iii) piperidyl, (iv)
Morpholinyl, (v) thio-morpholinyl, (vi) 4-methyl
Lupiperidyl, (vii) 4-phenylpiperidyl, (viii)
4-benzyloxycarbonylpiperidyl, (6) (i) halo
Gen, hydroxy, C_1-6Alkoxy, formyl, C_1-6
Alkyl-carbonyl, carboxy, C_1-6Alkoxy
-Carbonyl, amino, mono- or di-C_1-6Alkyl
Amino, pyrrolidinyl, piperidyl, morpholinyl, thi
Omorpholinyl, 4-methylpiperidyl, 4-phenyl
Piperidyl, carbamoyl, mono- or di-C_1-6Al
Quilcarbamoyl, phenoxy, mono- or di-C_1-6
Alkyl-carbamoyloxy, formylamino, C
_1-6Alkyl-carbonylamino, formyloxy and
C_1-6No one selected from alkyl-carbonyloxy
C optionally having three substituents_1-6Alkyl, (i
i) halogen, hydroxy, C_1-6Alkoxy, holmi
Le, C_1-6Alkyl-carbonyl, carboxy, C_1-6A
Lucoxy-carbonyl, amino, mono- or di-C_1-6
Alkylamino, pyrrolidinyl, piperidyl, morpholy
Nil, thiomorpholinyl, 4-methylpiperidyl, 4-
Phenylpiperidyl, carbamoyl, mono- or di-C
_1-6Alkyl-carbamoyl, phenoxy, mono- or
Di-C_1-6Alkyl-carbamoyloxy, formylua
Mino, C_1-6Alkyl-carbonylamino, formylo
Kissi, C_1-6Alkyl-carbonyloxy, C_1-6Archi
And halogeno-C_1-61 to 1 selected from alkyl
C optionally having three substituents_6-10Aryl, (ii
i) halogen, hydroxy, C_1-6Alkoxy, holmi
Le, C_1-6Alkyl-carbonyl, carboxy, C_1-6A
Lucoxy-carbonyl, amino, mono- or di-C_1-6
Alkylamino, pyrrolidinyl, piperidyl, morpholy
Nil, thiomorpholinyl, 4-methylpiperidyl, 4-
Phenylpiperidyl, carbamoyl, mono- or di-C
_1-6Alkyl-carbamoyl, phenoxy, mono- or
Di-C_1-6Alkyl-carbamoyloxy, formylua
Mino, C_1-6Alkyl-carbonylamino, formylo
Kissi, C_1-6Alkyl-carbonyloxy, C_1-6Archi
And halogeno-C_1-61 to 1 selected from alkyl
C optionally having 5 substituents_7-14Aralkyl and
(iv) halogen, hydroxy, C_1-6Alkoxy, holmi
Le, C_1-6Alkyl-carbonyl, carboxy, C_1-6A
Lucoxy-carbonyl, amino, mono- or di-C_1-6
Alkylamino, pyrrolidinyl, piperidyl, morpholy
Nil, thiomorpholinyl, 4-methylpiperidyl, 4-
Phenylpiperidyl, carbamoyl, mono- or di-C
_1-6Alkyl-carbamoyl, phenoxy, mono- or
Di-C_1-6Alkyl-carbamoyloxy, formylua
Mino, C_1-6Alkyl-carbonylamino, formylo
Kishi and C_1-6Selected from alkyl-carbonyloxy
Formyl optionally having 1 to 3 substituents,
C_1-6Alkyl-carbonyl, benzoyl, C_1-6Arco
Xy-carbonyl, benzyloxycarbonyl, C_1-6
Alkylsulfonyl, carbamoyl or mono- or di-
C_1-6Having a substituent selected from alkylamino
Hydroxy, (7) C_1-6Alkyl, benzyl or
Mono- or di-C_1-6Substituted with alkylamino
Good carboxy, (8) C_3-6Cycloalkyl, (9) C_3-6
Cycloalkenyl, (10) halogen, C_1-6Alkyl, ha
Logeno-C_1-6Alkyl, phenyl, benzyl, C_1-6A
Lucoxy, halogeno-C_1-6Alkoxy, phenoxy,
C_7-14Aralkyloxy, formyloxy, C_1-6Al
Kill-carbonyloxy, C_1-6Alkylthio, halogen
No-C_1-6Alkylthio, hydroxy, mercapto,
Ano, nitro, carboxy, formyl, C_1-6Alkyl
-Carbonyl, benzoyl, C_1-6Alkoxy-carbo
Nil, phenoxycarbonyl, amino, mono- or di-
C_1-6Alkylamino, formylamino, C_1-6Alkyl
-Carbonylamino, carbamoyl, mono- or di-C
_1-6Alkyl-carbamoyl, sulfo, C_1-6Alkyls
Ruphonyl, benzoyl-C_1-6Alkoxy, hydroxy
-C_1-6Alkoxy, C_1-6Alkoxy-carbonyl-C
_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6Alkoki
Si, imidazol-1-yl-C_1-6Alkoxy, C
_7-14Aralkyloxy-carbonyl-C_1-6Alkoki
Si, hydroxyphenyl-C_1-6Alkoxy and C_7-14
1 to 4 selected from aralkyloxy-carbonyl
Nitrogen atom other than the carbon atom which may have
One to four selected from oxygen, oxygen and sulfur
A 5- or 6-membered monocyclic aromatic heterocycle having a heteroatom or
A benzene ring and a 5- or 6-membered monocyclic aromatic heterocycle are fused
Selected from bi- or tricyclic fused aromatic heterocycles formed by
C which may have 1 to 5 substituents_1-10A
Alkyl group, C_2-10Alkenyl group, C_2-10Alkynyl group,
C_3-10Cycloalkyl group, C_3-10Cycloalkenyl group,
C_5-10Cycloalkadienyl group, C_6-14Aryl group or
C_7-14Aralkyl groups and, in addition to these substituents,
_6-14Aryl group or C_7-14The aralkyl group is C_1-6Archi
Le, halogeno-C_1-6Alkyl and halogen, C_1-6Al
Kill, halogeno-C_1-6Alkyl, C_1-6Alkoxy, C
_7-14Aralkyloxy, hydroxy, amino, mono- or
Is Di-C_1-6Alkylamino, carboxy, C_1-6Archi
Le-carbonyl, C_1-6Alkoxy-carbonyl, nitro
Having 1 to 5 substituents selected from b and cyano
May be C_6-141 to 5 selected from aryl
Or a halogen, C _1-6
Alkyl, halogeno-C_1-6Alkyl, phenyl, ben
Jill, C_1-6Alkoxy, halogeno-C_1-6Alkoxy,
Phenoxy, C_7-14Aralkyloxy, formyloxy
Si, C_1-6Alkyl-carbonyloxy, C_1-6Alkyl
Thio, halogeno-C_1-6Alkylthio, hydroxy,
Lcapto, cyano, nitro, carboxy, formyl, C
_1-6Alkyl-carbonyl, benzoyl, C_1-6Alkoki
C-carbonyl, phenoxy, amino, mono- or di-
C_1-6Alkylamino, formylamino, C_1-6Alkyl
-Carbonylamino, carbamoyl, mono- or di-C
_1-6Alkyl-carbamoyl, sulfo, C_1-6Alkyls
Ruphonyl, benzoyl-C_1-6Alkoxy, hydroxy
-C_1-6Alkoxy, C_1-6Alkoxy-carbonyl-C
_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6Alkoki
Si, imidazol-1-yl-C_1-6Alkoxy, C
_7-14Aralkyloxy-carbonyl-C_1-6Alkoki
Si, hydroxyphenyl-C_1-6Alkoxy and C_7-14
1 to 4 selected from aralkyloxy-carbonyl
Nitrogen atom other than the carbon atom which may have
One to four selected from oxygen, oxygen and sulfur
5- or 6-membered monocyclic heterocycles or benzes having heteroatoms
Formed by the condensation of a ring and a 5- or 6-membered monocyclic heterocycle
2- or 3-cyclic fused heterocycle and halogen, hydroxy,
C_1-6Alkoxy, formyl, C_1-6Alkyl-carboni
Le, carboxy, C_1-6Alkoxy-carbonyl, amine
No, mono- or di-C_1-6Alkylamino, pyrrolidini
, Piperidyl, morpholinyl, thiomorpholinyl, 4
-Methylpiperidyl, 4-phenylpiperidyl, carb
Moyl, mono- or di-C_1-6Alkyl-carbamoy
Phenoxy, mono- or di-C_1-6Alkyl-cal
Bamoyloxy, formylamino, C_1-6Alkyl-ka
Rubonylamino, formyloxy and C_1-6Alkyl-
1 to 3 substituents selected from carbonyloxy
Formyl, C_1-6Alkyl-carboni
Benzoyl, C_1-6Alkoxy-carbonyl, C
_7-14Aralkyloxy-carbonyl, piperidine-4-
Ilcarbonyl, C_1-6Alkylsulfonyl, carbamo
Il or mono- or di-C_1-6Alkyl-carbamoy
Even if it has one or two substituents selected from
Good amino group, or (C) halogen, C_1-6Alkyl,
Halogeno-C_1-6Alkyl, phenyl, benzyl, C_1-6
Alkoxy, halogeno-C_1-6Alkoxy, phenoki
Si, C_{7- 14}Aralkyloxy, formyloxy, C_1-6
Alkyl-carbonyloxy, C_1-6Alkylthio, ha
Logeno-C_1-6Alkylthio, hydroxy, mercap
G, cyano, nitro, carboxy, formyl, C_1-6A
Alkyl-carbonyl, benzoyl, C_1-6Alkoxy-
Carbonyl, phenoxycarbonyl, amino, mono- or
Is Di-C_1-6Alkylamino, formylamino, C_1-6A
Alkyl-carbonylamino, carbamoyl, mono- or
Di-C_1-6Alkyl-carbamoyl, sulfo, C_1-6Al
Killsulfonyl, benzoyl-C_1-6Alkoxy, hide
Roxy-C_1-6Alkoxy, C_1-6Alkoxy-carboni
Le-C_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6A
Lucoxy, imidazol-1-yl-C_1-6Alkoki
Si, C_7-14Aralkyloxy-carbonyl-C_1-6Al
Coxy, hydroxyphenyl-C_1-6Alkoxy and C
_7-14No one selected from aralkyloxy-carbonyl
Nitrogen other than the carbon atom which may have four substituents
1 to 4 atoms selected from atoms, oxygen atoms and sulfur atoms
A 5- or 7-membered nitrogen-containing heterocyclic group having a hetero atom of
Or a 7-membered nitrogen-containing heterocyclic ring condensed with benzene or pyridine
D is a bond or C_3-6Cycloalkylene or phenylene
And C_1-6Alkyl, halogeno-
C_1-61 selected from alkyl, phenyl and benzyl
C to C 3 optionally having 3 substituents_1-10Archire
Group, E is a bond, -CON (R^a)-, -N (R^a) CO-, -N
(R^b) CON (R^c)-, -N (R^d) COO-, -N (R^e) S
O_Two-, -COO-, -N (R^f)-, -O-, -S-,-
SO-, -SO_Two-,(R^a, R^b, R^c, R^d, R^eAnd R^fAre each a hydrogen atom
Or (1) halogen, (2) nitro, (3) cyano, (4) imino,
(5) (i) optionally substituted with 1 to 5 halogens
C_1-6Alkyl, phenyl, benzyl, formyl, C_1-6
Alkyl-carbonyl, benzoyl, C_1-6Alkoxy
-Carbonyl, C_7-14Aralkyloxy-carbonyl,
Sulfo, C_1-6Alkylsulfonyl and C_1-6Alkyria
Having one or two substituents selected from mino-carbonyl
Amino, (ii) pyrrolidinyl, (iii) pipet
Lysyl, (iv) morpholinyl, (v) thiomorpholinyl, (v
i) 4-methylpiperidyl, (vii) 4-phenylpiperidi
(Viii) 4-benzyloxycarbonylpiperidyl,
(6) (i) halogen, hydroxy, C_1-6Alkoxy, phor
Mill, C_1-6Alkyl-carbonyl, carboxy, C_1-6
Alkoxy-carbonyl, amino, mono- or di-C
_1-6Alkylamino, pyrrolidinyl, piperidyl, mol
Folinyl, thiomorpholinyl, 4-methylpiperidyl,
4-phenylpiperidyl, carbamoyl, mono- or di-
-C_1-6Alkyl-carbamoyl, phenoxy, mono-
Or di-C_1-6Alkyl-carbamoyloxy, holmi
Luamino, C_1-6Alkyl-carbonylamino, holmi
Roxy and C_1-6Select from alkyl-carbonyloxy
C 1 to 3 which may have 1 to 3 substituents_1-6
Alkyl, (ii) halogen, hydroxy, C_1-6Alkoki
Shi, Formyl, C_1-6Alkyl-carbonyl, carboxy
Si, C_1-6Alkoxy-carbonyl, amino, mono- or
Is Di-C_1-6Alkylamino, pyrrolidinyl, piperidi
, Morpholinyl, thiomorpholinyl, 4-methylpipe
Lysyl, 4-phenylpiperidyl, carbamoyl, mono
-Or di-C_1-6Alkyl-carbamoyl, phenoxy
Si, mono- or di-C_1-6Alkyl-carbamoyloxy
Si, formylamino, C_1-6Alkyl-carbonylamido
No, formyloxy, C_1-6Alkyl-carbonyloxy
Si, C_1-6Alkyl and halogeno-C_1-6Select from alkyl
C 1 to 3 which may have 1 to 3 substituents_6-10
Aryl, (iii) halogen, hydroxy, C_1-6Alkoki
Shi, Formyl, C_1-6Alkyl-carbonyl, carboxy
Si, C_1-6Alkoxy-carbonyl, amino, mono- or
Is Di-C_1-6Alkylamino, pyrrolidinyl, piperidi
, Morpholinyl, thiomorpholinyl, 4-methylpipe
Lysyl, 4-phenylpiperidyl, carbamoyl, mono
-Or di-C_1-6Alkyl-carbamoyl, phenoxy
Si, mono- or di-C_1-6Alkyl-carbamoyloxy
Si, formylamino, C_1-6Alkyl-carbonylamido
No, formyloxy, C_1-6Alkyl-carbonyloxy
Si, C_1-6Alkyl and halogeno-C_1-6Select from alkyl
C 1 to 5 which may have 1 to 5 substituents_7-14
Aralkyl and (iv) halogen, hydroxy, C_1-6Al
Coxy, formyl, C_1-6Alkyl-carbonyl, cal
Boxy, C_1-6Alkoxy-carbonyl, amino, mono
-Or di-C_1-6Alkylamino, pyrrolidinyl, pipet
Lysyl, morpholinyl, thiomorpholinyl, 4-methyl
Piperidyl, 4-phenylpiperidyl, carbamoyl,
Mono- or di-C_1-6Alkyl-carbamoyl, pheno
Xy, mono- or di-C_1-6Alkyl-carbamoylo
Kishi, formylamino, C_1-6Alkyl-carbonyla
Mino, formyloxy and C_1-6Alkyl-carbonyl
Having one to three substituents selected from oxy,
Good formyl, C_1-6Alkyl-carbonyl, benzo
Il, C_1-6Alkoxy-carbonyl, benzyloxy
Si, C_1-6Alkylsulfonyl, carbamoyl or mono
-Or di-C_1-6Alkyl-carbamoyl, selected from
Optionally substituted hydroxy, (7) C_1-6Al
Kill, benzyl or mono- or di-C_1-6Alkylam
Carboxy optionally substituted with_3-6Cyclo
Alkyl, (9) C_3-6Cycloalkenyl, (10) halogen,
C_1-6Alkyl, halogeno-C_1-6Alkyl, phenyl,
Benzyl, C_1-6Alkoxy, halogeno-C_1-6Alkoki
Si, phenoxy, C_7-14Aralkyloxy, formylo
Kissi, C_1-6Alkyl-carbonyloxy, C_1-6Archi
Lucio, halogeno-C_1-6Alkylthio, hydroxy,
Mercapto, cyano, nitro, carboxy, formyl,
C_1-6Alkyl-carbonyl, benzoyl, C_1-6Arco
Xy-carbonyl, phenoxycarbonyl, amino,
No- or di-C_1-6Alkylamino, formylamino,
C_1-6Alkyl-carbonylamino, carbamoyl, molybdenum
No- or di-C_1-6Alkyl-carbamoyl, sulfo,
C_1-6Alkylsulfonyl, benzoyl-C_1-6Alkoki
Si, hydroxy-C_1-6Alkoxy, C_1-6Alkoxy-
Carbonyl-C_1-6Alkoxy, C_3-14Cycloalkyl
-C_1-6Alkoxy, imidazol-1-yl-C_1-6A
Lucoxy, C_7-14Aralkyloxy-carbonyl-C
_1-6Alkoxy, hydroxyphenyl-C_1-6Alkoxy
And C_7-14Selected from aralkyloxy-carbonyl
Other than carbon atoms optionally having 1 to 4 substituents
At least one selected from nitrogen, oxygen and sulfur
5- or 6-membered monocyclic aromatic compound having 4 heteroatoms
Prime ring or benzene ring and 5- or 6-membered monocyclic aromatic heterocycle
Is formed by condensing a bicyclic or tricyclic fused aromatic heterocyclic ring,
May have 1 to 5 substituents selected from
C_1-10Alkyl group, C_2-10Alkenyl group, C_2-10Archi
Nyl group, C_3-10Cycloalkyl group, C_3-10Cycloalkene
Nyl group, C_5-10Cycloalkadienyl group, C_6-14Ally
Group or C_7-14In addition to aralkyl groups and their substituents
C_6-14Aryl group or C_7-14The aralkyl group is C_1-6
Alkyl, halogeno-C_1-6Alkyl and halogen, C
_1-6Alkyl, halogeno-C_1-6Alkyl, C_1-6Arco
Kissi, C_7-14Aralkyloxy, hydroxy, amino,
Mono- or di-C_1-6Alkylamino, carboxy, C
_1-6Alkyl-carbonyl, C_1-6Alkoxy-carboni
1 to 5 substitutions selected from le, nitro and cyano
C optionally having a group_6-14One selected from aryl
G may have 5 substituents, G is a bond, or C_3-6Cycloalkylene or phenyle
And may contain C_1-6Alkyl, halogeno-
C_1-61 selected from alkyl, phenyl and benzyl
C to C 3 optionally having 3 substituents_1-10Archire
L is -O- or -S-, C_3-6Cycloalkylene or
May be via enylene, C_1-6Alkyl, halogen
No-C_1-6Selected from alkyl, phenyl and benzyl
C which may have 1 to 3 substituents_1-10Al
A xylene group, X is two hydrogen atoms, oxygen atoms or sulfur atoms,−N (R^Four) − (R^FourIs a hydrogen atom, (1) halogen, (2)
Toro, (3) cyano, (4) imino, (5) (i) one to five ha
C optionally substituted with a logen_1-6Alkyl, phenyl
Benzyl, formyl, C_1-6Alkyl-carboni
Benzoyl, C_1-6Alkoxy-carbonyl, C
_7-14Aralkyloxy-carbonyl, sulfo, C_1-6A
Rukylsulfonyl and C_1-6Alkylamino-carboni
May have one or two substituents selected from
Amino, (ii) pyrrolidinyl, (iii) piperidyl, (iv)
Rufolinyl, (v) thiomorpholinyl, (vi) 4-methylpi
Peridyl, (vii) 4-phenylpiperidyl, (vii) 4-
Benzyloxycarbonylpiperidyl, (6) (i) halogen,
Hydroxy, C_1-6Alkoxy, formyl, C_1-6Archi
Ru-carbonyl, carboxy, C_1-6Alkoxy-cal
Bonyl, amino, mono- or di-C_1-6Alkylam
, Pyrrolidinyl, piperidyl, morpholinyl, thiomo
Rufolinyl, 4-methylpiperidyl, 4-phenylpipe
Lysyl, carbamoyl, mono- or di-C_1-6Alkyl
Carbamoyl, phenoxy, mono- or di-C_1-6Al
Kill-carbamoyloxy, formylamino, C_1-6A
Alkyl-amino, formyloxy and C_1-6Alkyl-
1 to 3 substituents selected from carbonyloxy
C that you may have_1-6Alkyl, (ii) halogen, hydr
Roxy, C_1-6Alkoxy, formyl, C_1-6Alkyl-
Carbonyl, carboxy, C_1-6Alkoxy-carboni
, Amino, mono- or di-C_1-6Alkylamino, pi
Loridinyl, piperidyl, morpholinyl, thiomorpholin
Nyl, 4-methylpiperidyl, 4-phenylpiperidi
Carbamoyl, mono- or di-C_1-6Alkyl-ka
Rubamoyl, phenoxy, mono- or di-C_1-6Archi
Ru-carbamoyloxy, formylamino, C_1-6Al
Kill-carbonylamino, formyloxy, C_1-6Al
Kill-carbonyloxy, C_1-6Alkyl and halogeno
-C_1-61 to 3 substituents selected from alkyl
C that you may have_6-10Aryl, (iii) halogen, ar
Droxy, C_1-6Alkoxy, formyl, C_1-6Alkyl
-Carbonyl, carboxy, C_1-6Alkoxy-carbo
Nil, amino, mono- or di-C_1-6Alkylamino,
Pyrrolidinyl, piperidyl, morpholinyl, thiomorpho
Linyl, 4-methylpiperidyl, 4-phenylpiperidi
Carbamoyl, mono- or di-C_1-6Alkyl-ka
Rubamoyl, phenoxy, mono- or di-C_1-6Archi
Ru-carbamoyloxy, formylamino, C_1-6Al
Kill-carbonylamino, formyloxy, C_1-6Al
Kill-carbonyloxy, C_1-6Alkyl and halogeno
-C_1-61 to 5 substituents selected from alkyl
C that you may have_7-14Aralkyl and (iv) halogen,
Hydroxy, C_1-6Alkoxy, formyl, C_1-6Archi
Ru-carbonyl, carboxy, C_1-6Alkoxy-cal
Bonyl, amino, mono- or di-C_1-6Alkylam
, Pyrrolidinyl, piperidyl, morpholinyl, thiomo
Rufolinyl, 4-methylpiperidyl, 4-phenylpipe
Lysyl, carbamoyl, mono- or di-C_1-6Alkyl
Carbamoyl, phenoxy, mono- or di-C_1-6A
Alkyl-carbamoyloxy, formylamino, C_1-6
Alkyl-carbonylamino, formyloxy and C
_1-61 to 1 selected from alkyl-carbonyloxy
Formyl optionally having three substituents, C_1-6Al
Kill-carbonyl, benzoyl, C_1-6Alkoxy-ka
Rubonyl, benzyloxy, C_1-6Alkylsulfoni
Carbamoyl or mono- or di-C_1-6Alkyl-
Carbamoyl, which may have a substituent selected from
Hydroxy, (7) C_1-6Alkyl, benzyl or mono- or
Is Di-C_1-6A group that may be substituted with alkylamino
Ruboxi, (8) C_3-6Cycloalkyl, (9) C_3-6Cycloa
Lucenyl, (10) halogen, C_1-6Alkyl, halogeno-
C_1-6Alkyl, phenyl, benzyl, C_1-6Alkoki
Si, halogeno-C_1-6Alkoxy, phenoxy, C_7-14
Aralkyloxy, formyloxy, C_1-6Alkyl-
Carbonyloxy, C_1-6Alkylthio, halogeno-C
_1-6Alkylthio, hydroxy, mercapto, cyano,
Nitro, carboxy, formyl, C_1-6Alkyl-cal
Bonyl, benzoyl, C_1-6Alkoxy-carbonyl,
Phenoxycarbonyl, amino, mono- or di-C_1-6
Alkylamino, formylamino, C_1-6Alkyl-ka
Rubonylamino, carbamoyl, mono- or di-C_1-6
Alkyl-carbamoyl, sulfo, C_1-6Alkylsul
Honyl, benzoyl-C_1-6Alkoxy, hydroxy-
C_1-6Alkoxy, C_1-6Alkoxy-carbonyl-C
_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6Alkoki
Si, imidazol-1-yl-C_1-6Alkoxy, C
_7-14Aralkyloxy-carbonyl-C_1-6Alkoki
Si, hydroxyphenyl-C_1-6Alkoxy and C_7-14
1 to 4 selected from aralkyloxy-carbonyl
Nitrogen atom other than the carbon atom which may have
One to four selected from oxygen, oxygen and sulfur
A 5- or 6-membered monocyclic aromatic heterocycle having a heteroatom or
A benzene ring and a 5- or 6-membered monocyclic aromatic heterocycle are fused
Selected from bi- or tri-cyclic fused aromatic heterocycles formed by
C which may have 1 to 5 substituents_1-10Al
Kill group, C_2-10Alkenyl group, C_2-10Alkynyl group, C
_3-10Cycloalkyl group, C_3-10Cycloalkenyl group, C
_5-10Cycloalkadienyl group, C_6-14Aryl group or C
_7-14Aralkyl groups and, in addition to these substituents,_6-14
Aryl group or C_7-14The aralkyl group is C_1-6Alkyl,
Halogeno-C_1-6Alkyl and halogen, C_1-6Archi
Le, halogeno-C_1-6Alkyl, C_1-6Alkoxy, C
_7-14Aralkyloxy, hydroxy, amino, mono- or
Is Di-C_1-6Alkylamino, carboxy, C_1-6Archi
Le-carbonyl, C_1-6Alkoxy-carbonyl, nitro
Having 1 to 5 substituents selected from b and cyano
May be C_6-141 to 5 selected from aryl
Or a halogen, hydroxy
Si, C_1-6Alkoxy, formyl, C_1-6Alkyl-cal
Bonyl, carboxy, C_1-6Alkoxy-carbonyl,
Amino, mono- or di-C_1-6Alkylamino, pylori
Zinyl, piperidyl, morpholinyl, thiomorpholini
4-methylpiperidyl, 4-phenylpiperidyl,
Carbamoyl, mono- or di-C_1-6Alkyl-carba
Moyl, phenoxy, mono- or di-C_1-6Alkyl-
Carbamoyloxy, formylamino, C_1-6Alkyl
-Carbonylamino, formyloxy and C_1-6Archi
1 to 3 substitutions selected from ru-carbonyloxy
Optionally formyl, C_1-6Alkyl-cal
Bonyl, benzoyl, C_1-6Alkoxy-carbonyl,
Benzyloxycarbonyl, C_1-6Alkylsulfoni
Carbamoyl or mono- or di-C_1-6Alkyl-
Carbamoyl) or S (O)_n(N is 0, 1 or 2)
A compound according to claim 1. 3. Z is a cyclic group which may have a substituent, G
Represents a divalent hydrocarbon group which may have a substituent,
And B ring compound according to claim 1, wherein not form a non-aromatic fused nitrogen-containing heterocyclic ring and R ^2. (4) ^{-N (R 4) - (R} 4 is a hydrogen atom, have a substituent showing a substituted hydrocarbon group or an acyl group) compound according to Claim 1. (5) 6. The compound according to claim 1, wherein ring B is a benzene ring which may have a substituent. 7. The compound according to claim 1, wherein ring B is an aromatic heterocyclic ring which may have a substituent. 8. The compound according to claim 1, wherein the ring B is a benzene ring or a thiophene ring. 9. The compound according to claim 1, wherein ring A is a benzene ring which may have a substituent. 10. The ring A is halogen, hydroxy or C _1-6.
The compound according to claim 1, which is a benzene ring optionally substituted with alkoxy. 11. The compound according to claim 1, wherein R ¹ is a hydrocarbon group which may have a substituent. (12) R ¹ is (1) hydroxy, (2) phenyl or
(3) C _1-6 alkyl - according to claim 1, which is a carbonyl or C _1-6 alkylsulfonyl and alkylsulfonyl substituted with may be substituted with also an amino C _1-6 alkyl or C _7-14 aralkyl group Compound. 13. The compound according to claim 1, wherein X is an oxygen atom. 14. The compound according to claim 1, wherein Y is an oxygen atom. 15. L may have a substituent, and-
The compound according to claim 1, which is a divalent hydrocarbon group optionally containing O- or -S-. 16. The method according to claim 1, wherein L is a C _1-6 alkylene group.
A compound as described. 17. The compound according to claim 1, wherein Z is a phenyl group which may have a substituent. 18. The compound according to claim 1, wherein Z is a phenyl group substituted with halogen. 19. The compound according to claim 1, wherein D is a divalent hydrocarbon group which may have a substituent. 20. The method according to claim 1, wherein D is a C _1-6 alkylene group.
A compound as described. 21. The compound according to claim 1, wherein E is -CON (Ra)-(Ra represents a hydrogen atom or a hydrocarbon group which may have a substituent). 22. The compound according to claim 1, wherein E is -CONH-. 23. The method according to claim 1, wherein G is a C _1-6 alkylene group.
A compound as described. 24. The method according to claim 1, wherein R ² is an unsubstituted amino group.
A compound as described. 25. The compound according to claim 1, wherein the ring formed by combining ring B and R ² is a tetrahydroisoquinoline ring. 26. A benzene ring in which ring A may have a substituent; and ring B has a substituent. 27. The ring A is halogen, hydroxy or C _1-6.
A benzene ring optionally substituted with alkoxy, a benzene ring in ring B, a phenyl group in which Z is substituted with halogen, and R ¹ is (1) hydroxy, (2) phenyl or (3) C _1-6 alkyl-carbonyl or C _1-6 compound of claim 1, wherein substituted alkylsulfonyl substituted with also an amino is also C _1-6 alkyl or C _7-14 aralkyl group. (28) a benzene ring in which ring A may have a substituent; and ring B has a substituent. 29. The ring A is halogen, hydroxy or C _1-6.
A benzene ring optionally substituted with alkoxy, a thiophene ring in ring B, a phenyl group in which Z is substituted with halogen, and R ¹ is (1) hydroxy, (2) phenyl or (3) C _1-6 alkyl-carbonyl or C _1-6 alkylsulfonyl optionally substituted with amino which may be substituted with alkylsulfonyl C _1-6
The compound according to claim 1, which is an alkyl or C _7-14 aralkyl group. 30. A ring is halogen, hydroxy, C_1-6A
Lucoxy, halogeno-C_1-6Alkoxy, C_7-14Aral
Killoxy, benzoyl-C_1-6Alkoxy, hydroxy
Sea C_1-6Alkoxy, C_1-6Alkoxy-carbonyl-
C_1-6Alkoxy, C_3-14Cycloalkyl-C_1-6Arco
Xy, imidazol-1-yl-C_1-6Alkoxy, C
_7-14Aralkyloxy-carbonyl-C_1-6Alkoxy
Or hydroxyphenyl-C_1-6Substituted with alkoxy
Optionally a benzene ring, and B ring is C_1-6Benze optionally substituted with alkoxy
Ring or thiophene ring, Z is halogen, formyl, halogeno-C_1-6Alkyl,
C_1-6Alkoxy, C_1-6Alkyl-carbonyl, oxo
And 1 to 3 substituents selected from pyrrolidinyl and
C that you may have_6-14Aryl, C_3-10Cycloalkyl
, Piperidyl, thienyl, furyl, pyridyl, thiazo
Ril, indolyl or C_1-6Alkyl group, D is C_1-6An alkylene group, G may contain a bond, or phenylene,
C optionally substituted with phenyl_1-6Alkylene
Group, R¹Is a hydrogen atom, (1) halogen, (2) nitro, (3) C_1-6A
C optionally substituted by alkyl-carbonyl_1-6Al
Kill, benzoyloxycarbonyl and C_1-6Alkyl
Having one or two substituents selected from sulfonyl
Amino, (4) (i) hydroxy, C_1-6Alkyl-
Carbonyl, carboxy or C_1-6Alkoxy-carbo
C optionally substituted with nyl_1-6Alkyl, (ii) hydrid
Phenyl optionally substituted with roxy, (iii) benzo
Yl or (iv) mono- or di-C_1-6Alkylamino-ka
Hydroxy optionally substituted with rubonyl, (5) C_3-6
Cycloalkyl, (6) hydroxy or halogeno-C_1-6A
Phenyl or (7) thienyl optionally substituted with
, Furyl, thiazolyl, indolyl or benzyloxy
C optionally substituted with cyclocarbonylpiperidyl_1-6
Alkyl group, C_2-6Alkenyl group, C_6-14Aryl group
Is C_7-14Aralkyl group, R^TwoIs (1) unsubstituted amino group, (2) piperidyl group or (3)
(i) benzyl, (ii) amino or phenyl substituted
May be C_1-6Alkyl, (iii) mono- or di-C _1-6A
Alkyl-carbamoyl, (iv) C_1-6Alkoxy-carbo
Nil, (v) C_1-6Alkyl-sulfonyl, (vi) piperidyl
Substituted by carbonyl and (vii) halogen or amino
May be C_1-61 selected from alkyl-carbonyl
Or an amino group which may have two substituents, E is a bond, -CON (R^a)-, -N (R^a) CO-, -N
(R^b) CON (R^c)-, -COO-,(R^a, R^bAnd R^cIs a hydrogen atom or C_1-6Archi
L), L may be via —O—, and C_1-6With alkyl
Optionally substituted C_1-6An alkylene group, X is an oxygen atom,−N (R^Four)-(R^FourIs a hydrogen atom or C_1-6Alkyl group),
And B ring is R^TwoRing formed by bonding with
The compound according to claim 1, which is a soquinoline ring. 31. 3,5-trans-N- (2-fluorobenzyl) -5- (3-aminomethylphenyl) -1- (4-
(Biphenylmethyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide or a salt thereof, (3S, 5S) -N- (2-fluorobenzyl) -5- (3-
(Aminomethylphenyl) -7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-
Benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5
(3-Aminomethylphenyl) -1- [2- (4-biphenyl) ethyl] -7-chloro-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5
(4-aminomethylphenyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof 3,5-trans-N- (2-fluorobenzyl) -5
(2-aminomethylthiophen-5-yl) -1- (4-
(Biphenylmethyl) -7-chloro-2-oxo-1,2,
3,5-tetrahydro-4,1-benzoxazepine-3
-Acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5-
[3-[(1-amino-1-methyl) ethyl] phenyl] -1
-(4-biphenylmethyl) -7-chloro-2-oxo-
1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -7-chloro-1- (4-
(Hydroxybenzyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -1 −
(4-acetylaminobenzyl) -5- (3-aminomethylphenyl) -7-chloro-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5
(3-aminomethylphenyl) -7-chloro-1- (4-
(Methanesulfonylaminobenzyl) -2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5-
(3-aminomethylphenyl) -1- (4-biphenylmethyl) -2-oxo-1,2,3,5-tetrahydro-4,
1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5-
(3-aminomethylphenyl) -1- (4-hydroxybenzyl) -7-methyloxy-2-oxo-1,2,3,5
-Tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5
[4-[(1-amino-1-methyl) ethyl] phenyl]
-1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans- N- (2-fluorobenzyl) -5
(3-Aminomethylphenyl) -7-chloro-1- [2-
(4-hydroxyphenyl) ethyl] -2-oxo-1,
2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, 3,5-trans-N- (2-fluorobenzyl) -5-
(3-Aminomethylphenyl) -1- (4-biphenylmethyl) -7-hydroxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof Or 3,5-trans-N- (2-fluorobenzyl) -1- (4-biphenylmethyl) -7-chloro-2-oxo-1,2,3,5-tetrahydro-5
The compound according to claim 1, which is (1,2,3,4-tetrahydroisoquinolin-5-yl) -4,1-benzoxazepine-3-acetamide or a salt thereof. 32. A compound of the general formula [The symbols in the formula are as defined in claim 1. Or a salt thereof, and a compound represented by the general formula: [The symbols in the formula are as defined in claim 1. A compound represented by the following general formula: [The symbols in the formula are as defined in claim 1. Or a salt thereof. [33] a medicine comprising the compound of the above [1]; 34. The medicament according to claim 33, which is a somatostatin receptor agonist. 35. The medicament according to claim 33, which is an agent for preventing or treating diabetes, obesity, diabetic complications or intractable diarrhea.