JP2002241368A - New benzolactam derivative and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excellent neuropeptide Y(NPY) antagonist, i.e., an antifeeding agent, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris and an antihypertensive agent. SOLUTION: A compound represented by the formula (I) (R1 and R2 are each H, a halogen or the like; R3 is a lower alkyl which may have a substituent, an aryl lower alkyl which may have a substituent or the like; and R4 is NHCOR5, NHCONR9R10 or the like), a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutical composition containing the compound are provided. A method for suppressing feeding and a method for treating the myocardial infarction, angina pectoris and hypertension that are characterized by administering the compound are provided. A use of the compound for producing the pharmaceutical preparation for suppressing the feeding and treating the myocardial infarction, angina pectoris and hypertension is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a compound useful as a medicine and its use. Specifically, a novel benzolactam derivative having an anti-feeding action, an anti-myocardial infarction action, an anti-angina pectoris action, and an anti-hypertensive action, and an anti-feeding agent, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris containing the same, Agent.

[0002]

2. Description of the Related Art Neuropeptide Y (hereinafter abbreviated as NPY) is a peptide consisting of 36 amino acids. Are distributed in nerve fibers of the blood vessel wall present in the digestive tract and the like. One of the central actions of NPY is a feeding promoting action. It is known that administration of NPY into the ventricle of the rat and into the paraventricular nucleus of the hypothalamus stimulates eating behavior and increases the amount of mainly carbohydrate ingested. It also plays an important role in regulating the release of neurotransmitters, especially in the hypothalamus.

[0003] In peripheral tissues, NPY is secreted from nerve fibers together with noradrenaline and causes smooth muscle contraction of blood vessels and the like and myocardial contraction. Noradrenaline causes transient contractions, whereas NPY has a persistent contractile action. It is said to be involved in organ disorders. In addition, in depression, Alzheimer's dementia, Parkinson's disease, the amount of NPY in the cerebral spinal cord is reduced,
It is known that the amount of NPY is increased at the time of head trauma, and may be deeply involved in these diseases.

Compounds having a similar structure to the compounds of the present invention are described in JP-A-6-172316, JP-A-8-277271 and the like. These documents disclose that each compound has a growth hormone release promoting action and an angiotensin I converting enzyme inhibitory action, but does not mention NPY antagonistic action at all. Examples of the NPY antagonist include US Pat. No. 5,504,094, US Pat.
Various compounds have been reported, including benzothiophene derivatives, sulfonylquinoline derivatives, and benzylamine derivatives described in WO 96/14307, but all have completely different structures from the compound of the present invention.

[0005]

SUMMARY OF THE INVENTION The present invention provides an excellent NP
There is a need for the development of a Y antagonistic, ie, an excellent antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina, and a hypotensive agent.

[0006]

The present application provides a novel compound having an excellent NPY antagonism. Specifically, the present invention provides a compound of formula (I):

[0007]

Embedded image

(Wherein R ¹ and R ² are each independently hydrogen, halogen, hydroxy, nitro, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), carboxy) Is a lower alkoxycarbonyl which may have a substituent or a lower alkoxycarbonylamino which may have a substituent,

R ³ is I) lower alkyl optionally having substituent (s), except for unsubstituted methyl, wherein the substituent means (1) halogen,
(2) hydroxy, (3) lower alkoxy, (4) carboxy,
(5) cycloalkyl, (6) cycloalkenyl, (7) lower alkoxycarbonyl, (8) optionally substituted acyl, (9) amino, (10) nitro, (11) cyano, (12 ) -N
HC (= NR ¹⁸ ) NR ¹⁹ R ²⁰ (where R ¹⁸ , R ¹⁹ and R ²⁰ are each independently hydrogen, hydroxy or lower alkoxycarbonyl) or (13) carbamoyl optionally substituted by lower alkyl It is. ),

II) optionally substituted aryl-lower alkyl (where the substituent means (1) halogen, (2) hydroxy, (3) benzyloxy, (4) The group is lower alkoxycarbonyl, acyl, aryl, substituted amino or imino), lower alkyl optionally having (5) lower alkoxy optionally having substituent (s), (6) carboxy, (7 ) Lower alkoxycarbonyl,
(8) cyano, (9) nitro, (10) acyl, (11) optionally substituted amino (substituent means lower alkyl, optionally substituted aryl lower Alkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (but not acetyl),
Lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl, carbamoyl optionally having substituent (s), (12) -NHC (＝ R ¹⁶ ) R ¹⁷ (where R ¹⁶ is a substituent (wherein Is a lower alkoxycarbonyl or a cyano), which may have an imino or a lower alkylene which may have a substituent (where the substituent is cyano or nitro), and R ¹⁷ is a substituent (Where the substituent is lower alkoxycarbonyl or lower alkyl) optionally having amino,
Lower alkylthio or aryloxy) or
(13) heterocyclyl lower alkyl) or III)
Heterocyclyl lower alkyl optionally having substituent (s),

R ⁴ is I) NHCOR ⁵ [where R ⁵ is a lower alkyl optionally having substituent (s) wherein the substituent means (1) halogen, (2) hydroxy, (3)
Lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro, (10) cyano, (11) -NHC
(= NR ⁶ ) NR ⁷ R ^8, wherein R ⁶ is hydrogen or cyano, and R ⁷ and R ⁸ are each independently hydrogen, lower alkyl or nitro; or (12) i) benzyloxycarbonyl, ii) acyl (but not formyl), iii) lower alkylsulfonyl or iv) amino having any of carbamoyl which may have a substituent), aryl-lower alkyl which may have a substituent (Here, the substituent means halogen, hydroxy, lower alkyl,
Lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto,
Cyano or nitro), lower alkoxy optionally having substituent (s), aryl optionally having substituent (s), aryloxy optionally having substituent (s) or optionally having substituent (s) Good aryl lower alkoxy],

II) NHCONR ⁹ R ¹⁰ (where R ⁹ and R ¹⁰ are each independently hydrogen, hydroxy, halogen, acyl, optionally substituted lower alkyl, optionally substituted Good aryl lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl lower alkyl, optionally substituted cyclo Alkyl, arylsulfonyl which may have a substituent or amino which may have a substituent)

III) NHC (= NR ¹¹ ) NR ¹² R ¹³ (where R ¹¹ is hydrogen, hydroxy, lower alkyl optionally having substituent (s), aryl optionally having substituent (s), substituent) R ¹² and R ¹³ are each independently hydrogen, hydroxy, a lower alkyl optionally having substituent (s), A lower alkoxy which may have a substituent, an amino which may have a substituent, an aryl which may have a substituent, an aryl which may have a substituent, lower alkyl, An aryloxy optionally having a substituent, a heterocyclyl optionally having a substituent or a heterocyclyl lower alkyl optionally having a substituent, or R ¹² and R ¹³ together having a substituent. I To form a heterocyclyl)

IV) NHCSNR ¹⁴ R ¹⁵ (where R ¹⁴ and R ¹⁵ are each independently hydrogen, lower alkyl which may have a substituent, aryl which may have a substituent or a substituent V) lower alkyl optionally having substituent (s) or IV) acyl optionally having substituent (s), and X is CH
₂ , S or O, and n is 1 or 2.

When R ³ is lower alkyl which may have a substituent, R ⁴ is NHCONR ⁹ R ¹⁰ and R ⁹ and R ¹⁰ may each have a substituent. When not aryl, R ³ is an unsubstituted aryl lower alkyl, and R ⁴ is NHCOR ⁵ , R ⁵ is not an optionally substituted lower alkyl, and R ³ has a substituent. When optionally heterocyclyl lower alkyl, R ⁵ is NHCONR ⁹ R ¹⁰ . ) Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

The present invention also provides a medicine containing compound (I) as an active ingredient, more specifically, an NP antagonist, more specifically, an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and a hypotensive agent. I do. Further, the present invention provides a method for suppressing eating and a method for treating myocardial infarction, angina pectoris and hypertension, characterized by administering compound (I). In yet another aspect,
Provided is the use of the compound (I) for producing a medicament for suppressing eating and treating myocardial infarction, angina and hypertension.

In the present specification, “halogen” refers to
Includes fluorine, chlorine, bromine and iodine. "Lower alkyl" means straight-chain or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,
Neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n
-Nonyl and n-decyl and the like.

"Lower alkyl optionally having substituent (s)" means lower alkyl which may be substituted at any position with one or more substituents. The “lower alkyl optionally having substituent (s)” for R ³ does not include unsubstituted methyl, and examples of the substituent include (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) Carboxy, (5) cycloalkyl, (6) cycloalkenyl, (7) lower alkoxycarbonyl, (8) optionally substituted acyl, (9)
Amino, (10) nitro, (11) cyano, (12) -NHC (= N
R ¹⁸ ) NR ¹⁹ R ²⁰ (where R ¹⁸ , R ¹⁹ and R ²⁰ are each independently hydrogen, hydroxy or lower alkoxycarbonyl) or (13) carbamoyl optionally substituted with lower alkyl. Can be

When R ⁴ is “V) lower alkyl optionally having substituent (s)”, examples of the substituent of lower alkyl include halogen, hydroxy, lower alkoxy, acyl,
Carboxy, lower alkoxycarbonyl, cycloalkyl, nitro, cyano, optionally substituted amino (here, the substituent may be a lower alkyl, an optionally substituted aryl lower alkyl, And carbamoyl which may be present (here, the substituent is lower alkyl, aryl lower alkyl, etc.), carboxy, lower alkoxycarbonyl, aryl lower alkoxycarbonyl, etc.).

Examples of the substituent of "lower alkyl optionally having substituent (s)" for R ⁵ include (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, and (5) lower Alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro, (10) cyano, (1
^{1) -NHC (= NR 6)} NR 7 R 8 ( wherein R ⁶ is hydrogen or cyano, R ⁷ and R ⁸ are each independently hydrogen, lower alkyl or nitro) or (12) i) Benzyloxycarbonyl, ii) acyl (excluding formyl), iii) lower alkylsulfonyl or iv) amino having any of carbamoyl which may have a substituent.

Examples of other substituents of "lower alkyl which may have a substituent (s)" include, unless otherwise specified, halogen, hydroxy, lower alkoxy, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl , Amino, nitro, cyano and the like.

"Lower alkoxy", "lower alkoxycarbonyl" and "lower alkoxycarbonylamino"
Is the same as the above “lower alkyl”.
Examples of the substituent of "lower alkoxy optionally having substituent (s)", "lower alkoxycarbonyl optionally having substituent (s)" and "lower alkoxycarbonylamino optionally having substituent (s)" , Halogen, lower alkoxy, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, amino, nitro and cyano.

"Aryl" refers to phenyl, naphthyl,
Includes anthracenyl, indenyl, phenanthrenyl and the like. "Aryl optionally having substituent (s)"
It means a group which may have one or more substituents at any position of the aryl.

Examples of the substituent of the "aryl which may have a substituent" for R ⁹ and R ¹⁰ include halogen, hydroxy, lower alkyl which may have a substituent and a substituent. Lower alkoxy, acyl, carboxy, lower alkoxycarbonyl optionally having substituent (s), sulfate residue (OSO ₃ H or a metal salt thereof), tetrahydropyranyloxy, sulfamoyl,
Nitro, cyano, amino which may have a substituent, aryl which may have a substituent (lower alkyl, halogen or hydroxy), and which may have a substituent (lower alkyl, halogen or hydroxy) Good aryl lower alkyl, aryl lower alkoxy optionally having a substituent (lower alkyl, halogen or hydroxy) and heterocyclyl optionally having a substituent (lower alkyl, halogen or hydroxy) and the like are mentioned.

Unless otherwise specified, other substituents of the “aryl which may have a substituent” include, for example, halogen, hydroxy, lower alkyl, lower alkoxy,
Examples include carboxy, lower alkoxycarbonyl, cycloalkyl, cycloalkenyl, acyl, amino, nitro, cyano, aryl and the like.

The lower alkyl portion and the aryl portion of "aryl lower alkyl" are the same as the above "lower alkyl" and "aryl", respectively. "Aryl lower alkyl optionally having substituent (s)" means aryl lower alkyl which may be substituted at one or more substituents at any position of the lower alkyl moiety or the aryl moiety.
As the substituent, unless otherwise specified, halogen,
Examples include hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, cycloalkyl, cycloalkenyl, amino, nitro and cyano.

The substituent of the "aryl lower alkyl optionally having substituent (s)" for R ³ includes (1) halogen, (2)
Hydroxy, (3) benzyloxy, (4) a lower alkyl optionally having a substituent (where the substituent is lower alkoxycarbonyl, acyl, aryl, substituted amino or imino), (5) a substituent Lower alkoxy optionally having, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10) acyl, (11) amino optionally having a substituent (Here, the substituent means lower alkyl, aryl lower alkyl which may have a substituent, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl , carbamoyl which may have a substituent), (12) -NHC (= R 16) R 17 ( lower a is a substituent wherein R ¹⁶ is a substituent (here Job Shi is a carbonyl or cyano and is) substituents which may be imino or a substituent (here have a cyano or substituted lower alkylene optionally having a a) nitro, R ¹⁷ is a substituent ( Here, the substituent is an amino, lower alkylthio or aryloxy optionally having lower alkoxycarbonyl or lower alkyl) or (13) heterocyclyl lower alkyl.

The aryl part of “aryloxy” has the same meaning as the above “aryl”, and “aryloxy which may have a substituent” means that the aryl has one or more substituents at any position. Means that you may. Examples of the substituent include halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, nitro, cyano and the like.

The aryl portion and the lower alkyl portion of "aryl lower alkoxy" are the same as the above "aryl" and "lower alkyl", respectively. “Aryl lower alkoxy optionally having substituent (s)” means that the aryl or lower alkyl moiety may have one or more substituents at any position, and the substituent may be halogen. , Hydroxy, lower alkoxy, aryl lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, amino, nitro, cyano and the like.

"Heterocyclyl" refers to O, S and N
Means a heterocyclyl having one or more heteroatoms arbitrarily selected from a ring, specifically, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolinyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, Monocyclic heterocyclyls such as thiazolyl, thiadiazolyl, furyl, thienyl, ethyleneoxydinyl, dioxanyl, thiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, morpholinyl, benzazepine and the like , Indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolini , Naphthyridinyl, quinoxalinyl, pteridinyl, chromanyl, chromenyl, benzisoxazolyl, benzoxazolyl, Kisajiazoriru,
Includes fused ring heterocyclyls such as benzisothiazolyl, benzthiazolyl, benzthiadiazolyl, benzofuryl, benzothienyl, benzpiperazinyl, benzpiperidinyl, phthalimide and the like.

Examples of the substituent of the "heterocyclyl optionally having substituent (s)" include lower alkyl, halogen, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, aryl, and substituents (halogen, hydroxy, lower alkoxycarbonyl). Aryl optionally substituted with amino), heterocyclyl, carbamoyl, cyano, nitro,
Examples include arylsulfonyl and oxo which may have a substituent (lower alkyl, halogen or hydroxy), and the substituent may be present at one or more arbitrary positions.

The heterocyclyl portion and the lower alkyl portion of "heterocyclyl lower alkyl" are the same as the above "heterocyclyl" and "lower alkyl". "Heterocyclyl lower alkyl optionally having substituent (s)" means heterocyclyl lower alkyl which may have one or more substituents at any position of heterocyclyl and lower alkyl. Examples of the substituent include the above-mentioned "heterocyclyl optionally having substituent (s)" and the substituent of "lower alkyl optionally having substituent (s)".

The term "amino optionally having substituent (s)" includes substituted and unsubstituted amino, and may have one or two substituents. Examples of the substituent include, unless otherwise specified, hydroxy, lower alkyl optionally having a substituent, aryl optionally having a substituent, aryl optionally having a substituent Lower alkyl and the like. "Acyl" means acyl having 1 to 10 carbon atoms, formyl, acetyl, propionyl,
Butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl and crotonoyl, cyclohexanecarbonyl,
Includes aliphatic acyl or aroyl such as benzoyl. Examples of the substituent of the "optionally substituted acyl" include halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, optionally substituted amino, nitro, cyano , Aryl, lower arylalkyl, heterocyclyl and the like. "Carbamoyl optionally having substituent (s)" includes substituted and unsubstituted carbamoyl, wherein the substituent is hydroxy, lower alkyl, cycloalkyl, aryl, or aryl lower optionally having substituent (s). Alkyl and the like.

"Cycloalkyl" is a carbon ring having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl, bicyclodecyl and the like. "Cycloalkyl optionally having substituent (s)"
And the substituents are hydroxy, halogen, lower alkyl, lower alkoxycarbonyl, lower alkoxy, aryl,
Heterocyclyl and the like may be mentioned, and one or more arbitrary positions may be substituted with these substituents.

In the present specification, the term "compound (I)" also includes pharmaceutically acceptable salts of each compound. “Pharmaceutically acceptable salts” include, for example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid Salts of organic acids such as sodium, maleic acid and succinic acid; salts of organic bases such as ammonium, trimethylammonium and triethylammonium; salts of alkali metals such as sodium and potassium or salts of alkaline earth metals such as calcium and magnesium. Can be mentioned.

The compound (I) of the present invention includes a hydrate thereof, and one molecule of the compound (I) may be bound to an arbitrary number of water molecules. Further, the compound of the present invention can exist as an optical isomer, and the present invention includes each of these optically active substances and a racemic mixture thereof.

The compounds (I) all have an antifeeding action, a therapeutic action for myocardial infarction, a therapeutic action for angina, and a hypotensive action. Among them, the following compounds are particularly preferred. In the formula (I),

1) a compound wherein R ¹ and R ² are each independently hydrogen, hydroxy or a lower alkoxy which may have a substituent (hereinafter abbreviated as R12-1);
More preferably, each independently hydrogen or lower alkoxy (hereinafter abbreviated as R12-2),
Compounds that are particularly preferably both hydrogen (hereinafter abbreviated as R12-3),

2) aryl lower alkyl in which R ³ may have a substituent (wherein the substituent means (1) halogen, (2)
Hydroxy, (3) benzyloxy, (4) optionally substituted lower alkyl (where the substituent is lower alkyloxycarbonyl, acyl, aryl, substituted amino or imino), (5) substituted Lower alkoxy optionally having a group, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10) acyl, (11) may have a substituent Amino (where the substituent means a lower alkyl, an optionally substituted aryl lower alkyl, a heterocyclyl lower alkyl, a heterocyclylcarbonyl, an acyl (excluding acetyl), a lower alkoxycarbonyl, an arylalkoxycarbonyl, a lower alkyl have a sulfonyl or substituent is carbamoyl), (12) -NHC (= R 16) R 17 ( wherein R ¹⁶ is a substituent (here location A lower alkoxycarbonyl or cyano and is) good imino or substituted group which may have a (cyano or lower alkylene which may have a nitro and a) the wherein the substituents and radical, R
¹⁷ is a substituent (here, the substituent is lower alkoxycarbonyl or lower alkyl) which may have an amino, lower alkylthio or aryloxy, or (13) heterocyclyl lower alkyl. Hereinafter, R ³ is R3-1).

Preferably, the aryl-lower alkyl substituent is (2) hydroxy, (3) benzyloxy, or (11) optionally substituted amino (substituent means lower alkyl, substituent Aryl lower alkyl which may have,
Heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl or carbamoyl optionally having substituent (s) or (12) '-NHC (= R ^{16 '} ) R ^17'
Wherein R ^{16 ′} is imino optionally substituted with tert-butoxycarbonyl and R ^{17 ′} is amino optionally substituted with tert-butoxycarbonyl (hereinafter R ³ is R3 -2).

More preferably, the substituent of the aryl lower alkyl is an amino which may have a substituent (here, the substituent is carbamoyl or tert-butoxycarbonyl which may have a substituent). Yes (hereinafter R ³
Is an amino which may have a substituent (lower alkylcarbamoyl or tert-butoxycarbonyl) (hereinafter, R ³ is a substituent). R3
-4), particularly preferably the aryl-lower alkyl substituent is an unsubstituted amino, NHCON
A compound which is H-iso-Pr, NHCONH-tert-Bu or NHBoc (hereinafter, R ³ is abbreviated as R 3-5);

3) R ⁴ is I) NHCOR ^{5 ′} [where R ^{5 ′} is lower alkyl which may have a substituent (where the substituent is (1) halogen, (2) hydroxy, (3 )
Lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro, (10) cyano, (11) -NHC
(= NR ⁶ ) NR ⁷ R ^8, wherein R ⁶ is hydrogen or cyano, and R ⁷ and R ⁸ are each independently hydrogen, lower alkyl or nitro; or (12) i) benzyloxycarbonyl, ii) acyl (but not formyl), ii
i) a lower alkylsulfonyl or iv) an amino having either an optionally substituted carbamoyl), a lower alkoxy, an aryloxy or an aryllower alkoxy],

II) NHCONR ⁹ 'R ¹⁰ ' (where R ⁹ 'and R ¹⁰ ' are each independently hydrogen, acyl, lower alkyl which may have a substituent, Good aryl lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, heterocyclyl lower alkyl, cycloalkyl, arylsulfonyl or optionally substituted amino),

III) NHC (= NR ^{11 '} ) NR ^12' R
^{13 ′} (where R ^{11 ′} is hydrogen, lower alkyl which may have a substituent or aryl which may have a substituent, and R ^{12 ′} and R ^{13 ′} each independently represent hydrogen, Hydroxy, optionally substituted lower alkyl, amino or heterocyclyl) or

IV) NHCSNR ^{14 ′} R ^{15 ′} (where R ^{14 ′}
And R ^{15 ′} are each independently hydrogen, an aryl which may have a substituent or an aryl-lower alkyl which may have a substituent (hereinafter, when R ⁴ is R4-1) Abbreviated) compounds,

Preferably, I) NHCOR ^{5 ″} (where R ^{5 ″} is —NHC (= N
R ⁶ ) lower alkyl optionally substituted with NR ⁷ R ⁸ , wherein R ⁶ is hydrogen or cyano, and R ⁷ and R ⁸
Are each independently hydrogen, lower alkyl or nitro), aryloxy or aryl-lower alkoxy),

II) NHCONR ^{9 ″} R ^{10 ″} (where R ^{9 ″}
And R ^{10 ″} are each independently (1) hydrogen, (2) lower alkyl optionally substituted with hydroxy, (3) aryl optionally having substituent (s) wherein the substituent is halogen,
Carboxy, tetrazolyl, sulfate residue (OSO
₃ H or a metal salt thereof), pyridyl, hydroxy, tetrahydropyranyloxy, benzyloxy, optionally substituted lower alkoxy optionally substituted with halogen, sulfamoyl, nitro or lower alkyl amino), (4) cycloalkyl, (5 Optionally substituted heterocyclyl (substituent means lower alkyl, lower alkoxy, hydroxy, toluenesulfonyl; tert-butoxycarbonylamino or aryl-lower alkyl optionally substituted by amino; or carbamoyl) A) or (6) amino optionally substituted with aryl),

III) NHC (= NR ^{11 ″} ) NR ^{12 ″} R
^{13 ″} (where R ^{11 ″} is hydrogen, lower alkyl or phenyl optionally having hydroxy, and R ^{12 ″} and R ^{13 ″} each independently have hydrogen or a substituent. Or IV) NHCSNR ^{14 ″} R ^{15 ″} where R ^{14 ″} and R
^{15 ″} is each independently hydrogen, aryl or aryl-lower alkyl) (hereinafter R ⁴ is abbreviated as R4-2),

More preferably, II) NHCONR ^{9 ′ ″} R ^{10 ′ ″} (where R ^{9 ′ ″} and R
^{One of 10 '''} is hydrogen and the other is (1) lower alkyl,
(2) phenyl optionally substituted with halogen, hydroxy, nitro or lower alkylamino or (3) heterocyclyl), III) NHC (= NR ^{11 ″} ) NR ^{12 ″} R ^{13 ″} (Where R ^{11 ′ ″} is phenyl optionally having hydroxy, and one of R ^{12 ′ ″} and R ^{13 ′ ″} is hydrogen and the other has hydrogen or hydroxy. good lower alkyl) or ^{IV) NHCSNR 14 '''R}15''' ( wherein R ^{14 '''and} R ^15''' is one of hydrogen, is the other is phenyl or benzyl) A compound (hereinafter abbreviated as R ⁴ to R 4-3),

Particularly preferably, NHCONHMe, NHC
_{ONHPh, NHCONHC 6 H 4 -p-} OH or NH
CONHC a ₆ H ₄ -p-F (hereinafter R ⁴ is referred to as a R4-4) compound,

4) a compound wherein X is CH ₂ 5) a compound wherein n is 1 6) R ¹ and R ² are R12-1 and R ³ is R3-1
Wherein R ¹ and R ² are each R 12-
1, a compound in which R ³ is R3-2, more preferably a compound in which R ¹ and R ² are R12-2, and a compound in which R ³ is R3-3, more preferably a compound in which R ¹ and R ² are R12-
2, wherein R ³ is R 3-4, most preferably R ¹ and R ² are R 12-3 and R ³ is R 3-5;

7) R ¹ and R ² are R12-1;
⁴ is R4-1, more preferably R ¹ and R
² is R12-1, a compound wherein R ⁴ is R4-2, more preferably R ¹ and R ² are R12-2, R ⁴
Compounds There is R4-3, and most preferably R ¹ and R ²
Is a compound wherein R is R12-3 and R ⁴ is R4-4;

8) R ¹ and R ² are R12-1 and X
Compounds There is a CH _2, more preferably R ¹ and R ² are R12-2, compounds wherein X is CH _2, 9) R ³ is R3-1, compounds wherein R ⁴ is R4-1 A compound wherein R ³ is R3-1 and R ⁴ is R4-2, a compound wherein R ³ is R3-2 and R ⁴ is R4-2, R ³ is R3-2; compounds wherein R ⁴ is R4-3, R ³ is R3-2, compounds wherein R ⁴ is R4-4, R ³ is R3-3, compounds wherein R ⁴ is R4-2, R ³ There is R3-3, compounds wherein R ⁴ is R4-3, R ³ is R3-3, compounds wherein R ⁴ is R4-4, R ³ is R3-4, R ⁴ is R4- 2, a compound wherein R ³ is R 3-4 and R ⁴ is R 4-3, more preferably R ³ is R 3-4 and R ⁴ is R 4
-4 it is compound, and most preferably R ³ is R 35, compounds wherein R ⁴ is R 45,

10) A compound wherein R ³ is R3-1 and X is CH ₂ , preferably R ³ is R3-2 and X is C
A compound which is H ₂ , a compound wherein R ³ is R 3-3 and a compound wherein X is CH ₂ , more preferably R ³ is R 3-4,
A compound wherein X is CH ₂ , most preferably R ³ is R 3-5
, And the compound X is CH _2, 11) R ⁴ is R4-1, compound X is CH _2,
Preferably, compounds wherein R ⁴ is R 4-2 and X is CH ₂ , more preferably R ⁴ is R ⁴ -3 and X is CH ₂
And most preferably R ⁴ is R 4-4,
A compound wherein X is CH ₂ ,

12) R ¹ and R ² are R12-1;
A compound wherein R ³ is R3-1 and R ⁴ is R4-1, preferably R ¹ and R ² are R12-1, and R ³ is R3
Is -1, the compound R4 is R4-2, R ¹ and R ² are R12-1, R ³ is R3-1, compounds wherein R ⁴ is R4-3, R ¹ and R ² There are R12-2, R ³ is R3-1, compounds in which R ⁴ is R4-4,

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-2 and R ⁴ is R4-1, R ¹ and R ² are R12-1 and R ³ is R3 -2 and R ⁴
Is a compound wherein R is R4-2, a compound wherein R ¹ and R ² are R12-1, R ³ is R3-2, and R ⁴ is R4-3, R ¹ and R ² are R12-2 , R ³ is R3-2
Wherein R ⁴ is R 4-4,

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-3 and R ⁴ is R4-1, R ¹ and R ² are R12-1 and R ³ is R3 -3 and R ⁴
Is a compound wherein R ¹ is R4-2, R ¹ and R ² are R 12-2, R ³ is R 3-3 and R ⁴ is R 4-3, R ¹ and R ² are R 12-2 , R ³ is R3-3
Wherein R ⁴ is R 4-4,

[0058] R ¹ and R ² are R12-1, R ³ is R3-4, compounds wherein R ⁴ is R4-1, R ¹ and R ² are R12-1, R ³ is R3 -4 and R ⁴
Is a compound wherein R ¹ is R4-2, R ¹ and R ² are R 12-2, R ³ is R 3-4 and R ⁴ is R 4-3, R ¹ and R ² are R 12-2 , R ³ is R3-4
Wherein R ⁴ is R 4-4,

[0059] R ¹ and R ² are R12-2, R ³ is R 35, compounds wherein R ⁴ is R4-1, R ¹ and R ² are R12-2, R ³ is R3 -5 and R ⁴
Is R4-2, more preferably R ¹ and R ²
There is R12-2, R ³ is R3-5, R ⁴ is R4
-3 it is compound, and most preferably R ¹ and R ² R1
2-3, a compound wherein R ³ is R 3-5 and R ⁴ is R 4-4;

13) R ¹ and R ² are R12-1;
A compound wherein R ³ is R3-1 and X is CH ₂ , R ¹ and R ² are R12-1, R ³ is R3-2, X
Is CH ₂ , preferably R ¹ and R ² are R ¹
Is 2-2, R ³ is R3-3, compound X is CH _2, more preferably R ¹ and R ² are R12-2, R ³ is R3-4, X is CH _2, compound, most preferably R ¹ and R ² are R12-3, R ³ is R 35, compound X is CH _2,

14) R ¹ and R ² are R12-1,
R ⁴ is R4-1, compound X is CH _2, preferably R ¹ and R ² are R12-1, R ⁴ is R4-2
Wherein X is CH ₂ , more preferably R ¹ and R ² are R 12-2, R ⁴ is R 4-3, X
Compounds There is a CH _2, most preferably R ¹ and R ² are R12-3, R ⁴ is R4-4, compound X is CH _2,

15) R ³ is R3-1 and R ⁴ is R4-
1, X is CH ₂ , preferably R ³ is R
3-2, R ⁴ is R4-1 and X is CH ₂ , R ³ is R 3-3, R ⁴ is R 4-1;
A compound wherein X is CH ₂ , a compound wherein R ³ is R 3-4, a compound wherein R ⁴ is R 4-1 and X is CH ₂ , and a compound wherein R ³ is R 3-
Is 5, R ⁴ is R4-1, compound X is CH _2, R ³ is R3-1, R ⁴ is R4-2, compound X is CH _2, R ³ is is R3-2, R ⁴ is R4
-2, a compound wherein X is CH ₂ , a compound wherein R ³ is R 3-3, R ⁴ is R 4-2 and X is CH ₂ ,
R ³ is R3-4, R ⁴ is R4-2, X is CH
₂ , R ³ is R 3-5, and R ⁴ is R 4-2
Wherein X is CH ₂ ,

A compound wherein R ³ is R3-1, R ⁴ is R4-3 and X is CH ₂ , R ³ is R 3-2,
⁴ is R4-3, X is CH ₂ , R ³ is R
3-3, wherein R ⁴ is R 4-3 and X is CH ₂ , R ³ is R ^3-4 , R ⁴ is R 4-3,
A compound wherein X is CH ₂ , a compound wherein R ³ is R 3-5, a compound wherein R ⁴ is R 4-3 and X is CH ₂ , and a compound wherein R ³ is R 3-
Is 1, R ⁴ is R4-4, compound X is CH _2, R ³ is R3-2, R ⁴ is R4-4, compound X is CH _2, R ³ is is R3-3, R ⁴ is R4
-4, X is CH ₂ , more preferably R ³ is R 3-4, R ⁴ is R 4-4 and X is CH
₂ , most preferably R ³ is R 3-5,
A compound wherein R ⁴ is R 4-4 and X is CH ₂ ;

16) R ¹ and R ² are R12-1,
A compound wherein R ³ is R3-1 and R ⁴ is R4-1, preferably R ¹ and R ² are R12-1, and R ³ is R3
-2 and R ⁴ is R4-1, R ¹ and R
² is R12-1, R ³ is R3-3, R ⁴ is R
A compound which is 4-1; R ¹ and R ² are R12-2; R ³ is R3-4; and R ⁴ is R4-1; R ¹ and R ² are R12-2; R ³ is R3-5
And R ⁴ is R4-1,

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-1 and R ⁴ is R4-2, R ¹ and R ² are R12-1 and R ³ is R3 -2 and R ⁴
Is a compound wherein R is R4-2, R ¹ and R ² are R12-1, R ³ is R3-3 and R ⁴ is R4-2, R ¹ and R ² are R12-2 , R ³ is R3-4
Wherein R ⁴ is R4-2, R ¹ and R ² are R12-2, R ³ is R3-5, and R ⁴ is R4-
A compound that is 2,

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-1 and R ⁴ is R4-3, R ¹ and R ² are R12-1 and R ³ is R3 -2 and R ⁴
Is a compound wherein R ¹ is R 4-3, a compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3 and R ⁴ is R 4-3, R ¹ and R ² are R 12-2 , R ³ is R3-4
Wherein R ⁴ is R 4-3, R ¹ and R ² are R 12-2, R ³ is R 3-5, and R ⁴ is R 4-
A compound that is 3,

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-1 and R ⁴ is R4-4, R ¹ and R ² are R12-1 and R ³ is R3 -2 and R ⁴
Is R4-4, a compound wherein R ¹ and R ² are R12-2, R ³ is R3-3, and R ⁴ is R4-4, more preferably R ¹ and R ² are R12- 2 and
R ³ is R3-4, compounds in which R ⁴ is R4-4, most preferably R ¹ and R ² are R12-3, R ³ is R 35, R ⁴ is in R4-4 A compound,

17) R ¹ and R ² are R12-1;
R ³ is R3-1, R ⁴ is R4-1, X is CH
_2, compound, preferably R ¹ and R ² R12-1
In and, R ³ is R3-2, R ⁴ is R4-1,
A compound wherein X is CH ₂ , R ¹ and R ² are R 12-1, R ³ is R 3-3, R ⁴ is R 4-1 and X
Compounds There is CH _2, R ¹ and R ² are R12-2, R ³ is R3-4, R ⁴ is R4-1, compounds wherein X is CH _2, R ¹ and R ² There are R12-2, R ³ is R 35, R ⁴ is R4-1, compound X is CH _2,

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-1, R ⁴ is R4-2 and X is CH ₂ , wherein R ¹ and R ² are R 12-1 And R ³ is R
3-2, R ⁴ is R 4-2, X is CH ₂ , R ¹ and R ² are R 12-1 and R ³ is R ³
Is -3, R ⁴ is R4-2, compounds wherein X is CH _2, R ¹ and R ² are R12-2, R ³ is R3-
Is 4, R ⁴ is R4-2, compounds wherein X is CH _2, R ¹ and R ² are R12-2, R ³ is R3-5
A compound wherein R ⁴ is R 4-2 and X is CH ₂ ;

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-1, R ⁴ is R4-3 and X is CH ₂ , wherein R ¹ and R ² are R 12-1 And R ³ is R
3-2, R ⁴ is R 4-3, X is CH ₂ , R ¹ and R ² are R 12-2, R ³ is R ³
-3, R ⁴ is R 4-3, X is CH ₂ , R ¹ and R ² are R 12-2 and R ³ is R 3-
4, R ⁴ is R 4-3, X is CH ₂ , R ¹ and R ² are R 12-2, R ³ is R 3-5
Wherein R ⁴ is R 4-3 and X is CH ₂ ;

A compound wherein R ¹ and R ² are R12-1, R ³ is R3-1, R ⁴ is R4-4 and X is CH ₂ , wherein R ¹ and R ² are R12-1 And R ³ is R
3-2, R ⁴ is R 4-4, X is CH ₂ , R ¹ and R ² are R 12-2, R ³ is R ³
-3, R ⁴ is R 4-4 and X is CH ₂ , more preferably R ¹ and R ² are R 12-2, R ³ is R ^3-4 , R ⁴ is R 4 -4 and X is CH ₂ , most preferably R ¹ and R ² are R
12-3, R ³ is R 3-5, R ⁴ is R 4-4
Wherein X is CH ₂ . Hereinafter, a method for producing the compound (I) of the present invention will be described.

R ⁴ = NHCOR ⁵ , NHCONR ⁹ R ¹⁰ ,
NHC (= NR ¹¹ ) NR ¹² R ¹³ , NHCSNR ¹⁴ R ¹⁵
If

[0073]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , X and n
Is the same as defined above. [First step] First, compound a is reduced to obtain compound b. The reduction reaction uses, for example, palladium-carbon, triphenylphosphine-water, tin (II) chloride, lithium aluminum hydride, etc., and alcohols such as methanol and ethanol, tetrahydrofuran and the like as solvents. What is necessary is just to make it react under the conditions which do not impair other functional groups.

Compound a can be obtained from Med. Chem. , 2
8 , 1511 (1985); Chem. Soc. 1969 , 2176
A compound synthesized by a conventional method according to the method described in (1) may be used. Compound b is described in the literature (J. Org. Chem.
50 , 3408 (1985), WO9404211, C
hem. Pharm. Bull. , 34 , 1128 (1
986)) may be used.
m. Pharm. Bull. , 34 (3) 1128-1
147 (1986). Therefore, if these known compounds b are used as starting materials, the first step of the reduction reaction is unnecessary, and it is possible to start directly from the next second step.

[Second Step] Next, a substituent R ⁴ corresponding to compound b is introduced to obtain compound c. When R ⁴ is NHCOR ⁵ , an acetic acid derivative (for example, guanidinoacetic acid, (1-trityl-1H-imidazol-4-yl) acetic acid, N-Cbz-β-alanine, etc.) corresponding to the target compound is added to compound b. The target compound can be produced by a reaction and a coupling reaction. DC as coupling reagent
C (dicyclohexylcarbodiimide), WSCD (1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) or DPPA (diphenylphosphoryl azide) or the like, and using tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, or the like as a solvent, preferably under ice-cooling to room temperature. May be reacted for several tens of hours under ice cooling. If necessary, triethylamine, dimethylaminopyridine or the like may be used as a catalyst, and the reaction may be performed in the presence of 1-hydroxybenzotriazole.

Further, an amide compound is produced according to a conventional method using a general acylating agent (for example, acid chloride such as acetyl chloride and propionyl chloride, acid anhydride such as acetic anhydride, active ester, etc.) corresponding to the target compound. can do. Furthermore, an alkyl carbamate compound group can also be obtained by reacting compound b with a chlorocarbonate (eg, alkyl chlorocarbonate, arylalkyl chlorocarbonate, etc.). In this case, the reaction may be carried out using ethyl acetate, dioxane, acetonitrile or the like as a solvent in the presence of a base such as potassium carbonate, sodium hydroxide or triethylamine.

When the substituent R ⁴ is NHCONR ⁹ R ¹⁰ , the compound b is converted to an isocyanate compound having a substituent corresponding to the target compound (for example, lower alkyl isocyanate, aryl isocyanate, etc.). ) To give compound c. Using acetonitrile, dimethylformamide, methylene chloride, tetrahydrofuran, etc. as a solvent,
If necessary, the reaction may be carried out using triethylamine as a catalyst under ice-cooling to warming, preferably at about room temperature for several tens minutes to several days. Further, after reacting the compound b and a phenyl carbonate compound having a substituent corresponding to the target compound in a solvent such as dimethylformamide and acetonitrile for several hours to several tens of hours under ice cooling to heating. The target compound can also be obtained by reacting with an amino having a substituent corresponding to the target compound. If necessary, the reaction can be favorably carried out by using triethylamine as a catalyst.

Further, after reacting compound b with carbonyldiimidazole, phosgene, phenyl chlorocarbonate or the like, an amino compound (for example, aniline which may have a substituent, (Aminobenzothiazole, lower alkylamine, etc., which may be present, can also be used to obtain the desired compound.) The reaction may be carried out by using acetonitrile, tetrahydrofuran or the like as a solvent and, if necessary, using triethylamine as a catalyst under ice-cooling to heating, preferably at about room temperature for several tens to several tens of hours.

When R ⁴ is NHCSNR ¹⁴ R ¹⁵ , compound b and an isothiocyanate compound having a substituent corresponding to the target compound can be obtained by cooling a mixture of ice and heating using acetonitrile, dimethylformamide, tetrahydrofuran or the like as a solvent. The reaction may be carried out at room temperature, preferably around room temperature, for several hours to several tens of hours. Further, the compound b, thiocarbonyldiimidazole and an amino compound having a substituent corresponding to the target compound are reacted in a solvent such as acetonitrile or tetrahydrofuran at -80 ° C to room temperature for several minutes to several hours. To obtain the desired compound.

When R ⁴ is NHC (＝ NR ¹¹ ) NR ¹² R ¹³ , for example, the compound obtained by the above-mentioned method wherein R ⁴ is thioureide and methyl iodide are mixed in a solvent such as acetonitrile with ice cooling to room temperature. Below, preferably around a few minutes at room temperature
Let react for several hours. The thus obtained thiomethyl compound and the amine compound corresponding to the target compound were converted into methanol,
Using ethanol or the like as a solvent at room temperature to under heating, preferably 5
The target compound may be obtained by reacting at about 0 to 80 ° C. for several tens of minutes to several hours. Compound b and a hydrogen iodide salt of a methylisothiourea compound (for example, 3- (thiazole-2-
Il) methylisothiourea, 3-phenylmethylisothiourea, etc.) in an alcohol for several tens of hours to several days under reflux with heating to obtain the desired compound.

[0082] When an amino group and R ⁴ in the compound b, first introducing a group R ⁴ 'convertible to R ^4, oxidation at an appropriate stage, reduction, alkylation, hydrolysis, acylation, amidation, The compound may be converted to R ⁴ by a known reaction such as halogenation or sulfonylation. For example, when R ⁴ ′ has hydroxy as a substituent and the substituent of R ⁴ is a sulfate residue, the compound having R ⁴ ′ is dissolved in a solvent such as pyridine.
A sulfur trioxide pyridine complex is added and the mixture is stirred at 0 ° C. to under heating for several tens hours to several days. If necessary, the compound is further dissolved in a solution of sodium hydroxide, potassium hydroxide or the like to obtain a compound in which R ⁴ is a sulfate ester residue (OSO ₃ H or a metal salt thereof).

R ⁴ ′ has hydroxy as a substituent,
When the target substituent of R ⁴ is an alkoxyalkyl which may be substituted, potassium carbonate and an alkyl halide corresponding to the target compound are added in a solvent such as acetone, and the mixture is heated for several hours to several days. Is obtained. R ⁴ ′ has nitroguanidino as a substituent,
When the target substituent of R ⁴ is guanidino, R ⁴ ′
Can be reduced by a conventional method using a reducing agent such as palladium-carbon in a solvent such as acetic acid / methanol.
^The target compound in which ⁴ is guanidino is obtained.

When R ⁴ ′ has acetylthio as a substituent and the desired substituent of R ⁴ is mercapto,
By reacting the compound having R ⁴ ′ in a solvent such as degassed ethanol and degassed aqueous sodium hydroxide solution at 0 ° C. to heating under heating for several tens minutes to several tens of hours, the desired compound having R ⁴ is obtained. can get.

[0085] R ⁴ 'is has a terminal amino, when end of R ⁴ of interest is an amide, R ^4' in the compound having the compound and coupling with a carboxylic acid corresponding to the desired compound The compound having the desired R ⁴ can be obtained by reacting the reagent with dry tetrahydrofuran or the like as a solvent under ice cooling to room temperature for several hours to several tens of hours. If necessary, triethylamine, dimethylaminopyridine or the like may be used as a catalyst, and the reaction may be performed in the presence of 1-hydroxybenzotriazole. Further, a compound having R ⁴ ′ and a substituted isocyanate corresponding to the target compound may be reacted in a solvent such as dimethylformamide or tetrahydrofuran at 0 ° C. to room temperature for several tens minutes to several hours,
The acylation may be carried out using a commonly used acylating agent such as acetyl chloride.

When the terminal of R ⁴ ′ is amino and the terminal of R ⁴ is lower alkylsulfonyl, a lower alkylsulfonyl chloride corresponding to the target compound is added to a solution of the compound having R ⁴ ′ in tetrahydrofuran, dimethylformamide or the like. Of tetrahydrofuran, dimethylformamide, and the like, and the mixture is reacted under ice cooling to room temperature for several minutes to several hours to obtain the desired compound having R ⁴ .

When the terminal of R ⁴ ′ is amino and the terminal of R ⁴ is guanidino which may be substituted, a compound having R ⁴ ′ and a phenylisourea compound which may have a substituent ( For example, N-cyano-N-methyl-O-phenylisourea) is reacted in an alcohol such as ethanol or propanol at room temperature to 130 ° C. for several tens of hours to several days to obtain the desired compound. If necessary, the reaction can suitably proceed if triethylamine is used.

[Third Step] Finally, compound c is subjected to a substitution reaction of R ³ to obtain compound (I). Compound c and a halogen derivative having a substituent corresponding to the target compound (for example, lower alkyl halide, aryl halide, aryl lower alkyl halide, heterocyclyl lower alkyl halide, etc.) are subjected to N-alkylation reaction to give compound (I ) To manufacture. The N-alkylation is carried out in the presence of a base such as potassium carbonate-potassium iodide, sodium hydride, potassium hydroxide-n-tetrabutylammonium halide, potassium salt of tert-butanol, etc., and using tetrahydrofuran, dioxane, diethyl ether, dimethyl as a solvent. The reaction may be carried out using formamide or the like under ice-cooling to room temperature, preferably around room temperature for tens of minutes to tens of hours.

[0089] When introducing a substituent R ^3, first introducing a group R ³ 'convertible to R ^3, oxidation at an appropriate stage, reduction, alkylation, hydrolysis, acylation, amidation, halogenation,
It may be converted to R ³ by a known reaction such as sulfonylation. For example, when the terminal of R ³ ′ is amino and the target R ³ has a sulfonamide bond, the compound having R ³ ′ and the sulfonyl chloride derivative having the target substituent can be converted into a solvent such as tetrahydrofuran or benzene. During,
The reaction is carried out at −80 ° C. to 0 ° C. for several minutes to several hours in the presence of a catalyst such as triethylamine and dimethylaminopyridine to obtain a mono- or di-substituted sulfonamide.

[0090] Also, R ³ 'is end amino, when end of R ³ of interest is guanidino, in a solvent such as dimethylformamide, under ice-cooling - room temperature, R ³ preferably at about room temperature' And an amidine compound are reacted for several hours to several days to produce a guanidine compound. As the amidine compound, pyrazolylamidines (for example, N, N′-bis-amidinopyrazole, N, N
N'-bis-Cbz methylthioamidine) and nitroguanidines (eg, methylthionitroamidine).

When the terminal of R ³ ′ is cyano and the terminal of the intended substituent R ³ is amidino, alcohol is first added under an acid catalyst such as hydrochloric acid to obtain an imidate compound. Next, the desired compound is obtained by reacting with an amino compound such as ammonium chloride for several hours at room temperature to 100 ° C. using ethanol or the like as a solvent.

A ureide compound or a thioureide compound can also be obtained by reacting a compound in which the terminal of R ³ 'is amino with isocyanate or isothiocyanate. When the terminal of R ³ ′ is amino and the desired substituent R ³ is cyanoguanidino or nitroamidino, phenoxy is reacted by reacting diphenylcyanocarboimidate, 1,1-dimercapto-2-nitroethane, or the like. Compound and thiomethyl compound are synthesized. Then, the desired compound is obtained by reacting with an amino compound having a desired substituent in a solvent such as methanol at room temperature to heating.

R ⁴ = lower alkyl optionally having substituent (s)
In case of kill

[0094]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , X and n
Has the same meaning as described above, and Hal represents halogen. Med. Chem. , 28 , 1511 (19
The known compound d described in 85) is reacted with a cyano compound to obtain a compound e. Examples of the cyano compound include sodium cyanide, potassium cyanide, and copper cyanide.
Next, the compound e is subjected to a reaction such as hydrolysis and reduction by a conventional method, followed by a conversion reaction to R ^{4 in} the same manner as described above to obtain a compound c. Finally, the compound (I) is obtained by subjecting R ^{3 to} a substitution reaction in the same manner as described above.

The compound (I) can be produced by the above-mentioned method, but it is also possible to produce the compound (I) by replacing the respective steps according to the reaction. For example, it can be obtained by first subjecting compound a or compound e to the same substitution reaction of R ³ as described above, followed by reduction, and finally to the same conversion reaction to R ⁴ as described above.

Incidentally, with respect to a compound having a substituent (eg, hydroxy, amino, etc.) which hinders the reaction, the group is protected with an appropriate protecting group in advance, and the acid treatment is performed at an appropriate stage. The protecting group may be removed by a conventional method such as

Examples of the hydroxy-protecting group include lower alkyl, aralkyl (benzyl and the like), trialkylsilyl (tert-butyldimethylsilyl and the like), alkoxyalkyl (methoxymethyl and the like), tetrahydropyranyl, acyl (acetyl and the like), Alkylsulfonyl (methanesulfonyl, trifluoromethanesulfonyl, etc.) and the like.

Examples of the protecting group for amino include lower alkoxycarbonyl (such as tert-butylcarbonyl), aralkyloxycarbonyl (such as benzyloxycarbonyl), and amides (such as phthalimide).

The compound (I) of the present invention exhibits a strong NPY antagonistic effect and can be administered as a medicament to animals including humans. The compound of the present invention as an NPY antagonist is applicable as an antifeedant, and is useful for treating and / or preventing obesity, binge eating and anorexia associated with NPY. In addition, cardiovascular diseases such as myocardial infarction, angina, congestive heart failure, hypertension, arrhythmia, arteriosclerosis, organ circulatory failure based on vasospasm, bronchial asthma, diabetes, schizophrenia, depression, Alzheimer's dementia , Parkinson's disease,
It can also be used for the treatment and / or prevention of sleep disorders, gastrointestinal motility disorders, sexual dysfunction, inflammation, respiratory diseases, hormonal abnormalities, and the like.

When the compound (I) of the present invention is administered as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, or a hypotensive agent,
It can be administered either orally or parenterally. Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccals or sublinguals according to a conventional method. For parenteral administration, any commonly used dosage form, such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbents, and inhalants, can be suitably administered. In particular, oral administration is preferred.

An effective amount of the compound (I) of the present invention may be supplemented with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like which are suitable for the dosage form. To make a pharmaceutical preparation. In the case of an injection, a preparation may be prepared by sterilizing with an appropriate carrier.

Specifically, lactose, sucrose,
Examples of binders such as glucose, starch, calcium carbonate or crystalline cellulose include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose,
Disintegrants such as gelatin or polyvinylpyrrolidone; carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate; dispersants such as talc, magnesium stearate or macrogol; And the like. As a suppository base, cocoa butter, macrogol, methyl cellulose or the like can be used. In the case of preparing a liquid or emulsion or suspension injection, a solubilizing agent, a suspending agent, an emulsifier, a stabilizing agent, a preservative, an isotonic agent, etc. which are usually used are appropriately added. In the case of oral administration, a flavoring agent, a fragrance and the like may be added.

The dose of the compound (I) of the present invention as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, or a hypotensive agent depends on the age, weight, type and degree of disease, administration route and the like of the patient. Although it is desirable to set after taking into account, when administered orally to an adult, it is usually 0.05 to 100 mg / kg / day,
Preferably it is in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the administration route, but is usually 0.005 to 10 mg / kg / day, preferably within the range of 0.01 to 1 mg / kg / day. This may be administered once to several times a day. Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples do not limit the present invention.

[0105]

EXAMPLES The meanings of the abbreviations used in the examples are as follows. Bn benzyl Boc tert-butoxycarbonyl Bu butyl Cbz benzyloxycarbonyl c-Pr cyclopropyl Et ethyl i-Pr isopropyl Me methyl Ms methanesulfonyl n-Pr n-propyl Ph phenyl t-Bu tert-butyl Tet tetrasulfonyl Ts toluene Phenylmethyl THP tetrahydropyranyl DME 1,2-dimethoxyethane DMF N, N-dimethylformamide DMSO dimethylsulfoxide TBS tert-butyldimethylsilyl

Example 1 1- (3- (tert-butoki)
(Cicarbonylamino) benzyl) -3- (3-methyl
Raid) -2,3,4,5-tetrahydro-1H-1-
Synthesis of benzazepin-2-one (I-1)

[0107]

Embedded image

(First Step) 3- (3-Methylureido) -2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Compound 2) Methyl isocyanate was added under ice cooling. Literature (J. Org.
Chem. , 50 , 3408 (1985)), and then added dropwise to a solution of compound 1 (9.08 mmol) in dimethylformamide (20.0 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was poured into ice water, the resulting precipitate was filtered, and the residue was washed with a 10% aqueous sodium hydroxide solution, washed with water and dried to obtain the title compound.

Yield 68.9% mp. 256-260 ° C
(Decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.85 (1 H, m),
2.32 (1H, m), 2.50 (3H, s), 2.60-
2.73 (2H, m), 4.08 (1H, m), 5.98
(1H, dd, J = 4.5 Hz, 8.6 Hz), 6.10
(1H, d, J = 8.1 Hz), 7.12 (1H, td, J =
1.5 Hz, 7.5 Hz), 7.23-7.30 (2
H, m), 9.78 (1H, brs) IRνmax (KBr): 3393, 3319, 317
4,3140,3085,2939,2853,168
6,1658,1634,1561Cm ^-1 Elemental analysis: (C ₁₂ H ₁₅ N ₃ as O ₂₎ Found: C, 61.52; H, 6.56 ; N, 18.06 Calcd: C, 61 .79; H, 6.48; N, 18.01

(Second Step) Compound (I-1)

[0111]

Embedded image

Under ice-cooling, potassium hydroxide powder (0.6
13 mmol) of compound 2 (0.429) obtained in the first step
mmol), tetra-n-butylammonium bromide and meta- (tert-butoxycarbonylamino) benzyl bromide in dimethylformamide solution (5.0 ml), and the mixture was stirred at room temperature for 2 hours. Pour the reaction mixture into ice water,
Extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. Silica gel chromatography (ethyl acetate / n-hexane = 3
0/1) to give the title compound. The meta- (tert-butoxycarbonylamino) benzyl bromide used was synthesized by a conventional method using 3-aminobenzyl alcohol.

Yield 68.9% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s),
2.00 (1H, m), 2.30-2.90 (3H, m),
2.53 (3H, s), 4.62 (1H, m), 4.68
(1H, d, J = 16.2 Hz), 5.38 (1H, d, J =
16.0 Hz), 6.19 (1 H, m), 6.86 (1
H, d, J = 7.8 Hz), 7.06 (1H, d, J = 8.0)
Hz), 7.10-7.30 (5H, m), 7.47 (1
H, brs), 7.68 (1H, d, J = 7.8 Hz) IRνmax (Nujol): 3325, 1724, 1
624, 1549 cm ^-1 Elemental analysis: (C ₂₄ H ₃₀ N ₄ O ₄ .
0.2 C ₆ H ₆ ) Found: C, 66.31; H, 6.97; N, 12.15 Calculated: C, 66.65; H, 6.92; N, 12.34

The compounds of Examples 2 to 11 were synthesized in the same manner as in Example 1. Example 2 1- (tert-butoxycarbonylmethyl)
) -3- (3-Methylureido) -2,3,4,5-
Tetrahydro-1H-1-benzazepin-2-one
Synthesis yield of (I-2) 98.0% mp. 229-230 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s),
2.00 (1H, m), 2.60 (2H, m), 2.74
(3H, d, J = 4.8 Hz), 3.35 (1H, m),
4.21 (1H, d, J = 16.8 Hz), 4.45 (1
H, m), 4.48 (1H, m), 4.69 (1H, d, J =
17.1 Hz), 5.59 (1H, d, J = 6.6H)
z), 7.12 (1H, d, J = 8.4 Hz), 7.19
-7.29 (3H, m) IR max (KBr): 3417, 3300, 298
2,2938,1735,1688,1644,160
0,1550 cm ^-1 Elemental analysis: (as C ₁₈ H ₂₅ N ₃ O ₄ .1.0 H ₂ O) Actual: C, 58.86; H, 7.18; N, 11.52 Calculated: C H, 7.44; N, 11.51.

Example 3 1- (tert-butyl carbamo)
Ylcarbonylmethyl) -3- (3-methylureido)
-2,3,4,5-tetrahydro-1H-1-benzoa
Synthesis yield of Zepin-2-one (I-3) 93.6% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.19 (9H, s),
2.14-2.31 (1H, m), 1.78-1.89
(1H, m), 2.50-2.58 (4H, m), 3.17
-3.28 (1H, m), 4.05-4.15 (1H,
m), 4.19 (1H, d, J = 15.9 Hz), 4.43
(1H, d, J = 16.2 Hz), 5.95-6.00
(1H, m), 6.14 (1H, d, J = 8.1 Hz),
7.17-7.35 (3H, m) IR max (KBr): 3375, 3285, 296
1,934,1665,1642,1602,155
6 cm ^-1 elemental analysis: (as C ₁₈ H ₂₆ N ₄ O ₃ .0.15 CHCl ₃ ) Found: C, 59.77; H, 7.25; N, 15.52 Calculated: C, 59. 83; H, 7.23; N, 15.38

[0116]Example 4 3- (3-methylureido)-
1-((1-naphthyl) methyl) -2,3,4,5-te
Trahydro-1H-1-benzazepin-2-one (I
Synthesis of -4) 82.5% yield amorphous¹ H-NMR (CDCl_Three) Δ: 1.87 (1H, m),
2.34 (1H, m), 2.51 (2H, m), 2.71
(3H, d, J = 5.1 Hz), 4.39 (1H, m),
4.54 (1H, m), 5.35 (1H, d, J = 15.3)
Hz), 5.49 (1H, d, J = 8.1 Hz), 5.7
3 (1H, d, J = 15.3 Hz), 7.06-8.09
(11H, m) IRνmax (KBr): 3412, 3368, 294
3,1635,1600,1546cm^-1 Elemental analysis: (C_{twenty three}H_{twenty three}N_ThreeO_Two. 0.15H_TwoFound: C, 73.41; H, 6.34; N, 11.17 Calculated: C, 73.44; H, 6.24; N, 11.17

Example 5 1- (4- (tert-butyl)
Benzyl) -3- (3-methylureido) -2,
3,4,5-tetrahydro-1H-1-benzazepine
-2-one (I-5) synthesis yield 92.5% mp. 247-249 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.28 (9H, s),
1.98 (1H, m), 2.44-2.60 (3H, m),
2.68 (3H, d, J = 4.5 Hz), 4.48 (1H,
brs), 4.91 (1H, d, J = 14.7 Hz),
5.09 (1H, d, J = 15.0 Hz), 5.55 (1
H, brs), 7.12-7.30 (8H, m) IRνm
ax (KBr): 3400, 3317, 2960, 16
89, 1635, 1599, 1550 cm ^-1 Elemental analysis: (as C ₂₃ H ₂₉ N ₃ O ₂ ) Found: C, 72.69; H, 7.76; N, 11.04 Calculated: C, 72 .79; H, 7.70; N, 11.07

Example 6 3- (3-methylureido)-
1- (2-quinolylmethyl) -2,3,4,5-tetra
Hydro-1H-1-benzazepin-2-one (I-
62.5% Synthesis yield of 6) Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.93-2.03 (1
H, m), 2.57-2.68 (5H, m), 3.14-
3.27 (1H, m), 4.47 (1H, brs), 4.
53-4.62 (1H, m), 5.27 (1H, d, J = 1
5.9 Hz), 5.40 (1H, d, J = 15.9H)
z), 5.51 (1H, brs), 7.12-7.23
(4H, m), 7.46 (1H, d, J = 8.4Hz),
7.51 (1H, t, J = 8.1 Hz), 7.68 (1H,
td, J = 1.5, 8.1 Hz), 7.79 (1H, d, J =
7.5 Hz), 7.99 (1H, d, J = 8.4 Hz),
8.13 (1H, d, J = 8.4 Hz) IRνmax (KBr): 3377, 3058, 293
2,2865,1642,1600,1505Cm ^-1 Elemental _{analysis: (C 22 H 23 N 4} O 3 .0.15C 6 H 14 .0.3H 2
H) 6.30; N, 13.94 Calculated: C, 69.85; H, 6.58; N, 14.23.

Example 7 1- (bis (4-fluorophene)
Nil) methyl-3- (3-methylureido) -2,3
4,5-tetrahydro-1H-1-benzazepine-2
-On (I-7) synthesis yield 72.3% mp. 235-238 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.83-1.91 (1
H, m), 2.39-2.48 (3H, m), 2.70 (3
H, d, J = 5.1 Hz), 4.37 (1H, m), 4.4
8-4.56 (1H, m), 5.36 (1H, d, J = 8.
5.86 Hz (2H, t, J = 8.7 Hz),
95 (1H, d, J = 7.5 Hz), 7.03-7.11
(7H, m), 7.28-7.32 (2H, m) IR max (KBr): 3416, 3295, 165
1,1604,1556,1508Cm ^-1 Elemental _{analysis: (C 25 H 23 N 3} O 2 F 2 as) Found: C, 69.00; H, 5.58 ; N, 9.80;
F, 8.73 Calculated: C, 68.95; H, 5.32; N, 9.65;
F, 8.45

Example 8 1- (4-benzyloxyben)
Jill) -3- (3-methylureido) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one
Synthesis yield of (I-8) 98.4% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.85 (1 H, m),
2.49 (3H, m), 2.71 (3H, d, J = 5.7H
z), 4.44 (1H, m), 4.73 (1H, d, J = 1)
4.7 Hz), 5.01 (2H, s), 5.11 (1H,
d, J = 14.4 Hz), 5.47 (1H, brs),
6.85 (2H, d, J = 8.7 Hz), 7.11-7.
41 (11H, m) IRνmax (KBr): 3370, 2945, 286
4,1642,1604,1564,1511Cm ^-1 Elemental _{analysis: (C 26 H 27 N 3} O 3 .0.2C 6 H 14 .0.1H 2 O
Found) C, 72.83; H, 6.94; N, 9.35 Calculated: C, 72.83; H, 6.74; N, 9.37.

Example 9 3- (3-methylureido)-
1-phthalimidomethyl-2,3,4,5-tetrahydride
B-1H-1-Benzazepin-2-one (I-9)
Synthesis yield 6.1% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.89-2.03 (1
H, m), 2.43-2.79 (3H, m), 2.75 (3
H, d, J = 4.6 Hz), 4.36-4.49 (1H,
m), 4.42 (1H, d, J = 13.6 Hz), 4.62
(1H, brs), 5.61 (2H, t, J = 8.0H)
z), 6.33 (1H, d, J = 13.6 Hz), 7.1
3-7.45 (4H, m), 7.67-7.81 (4H,
m) IRνmax (KBr): 3423, 3313, 293
0, 1780, 1724, 1677, 1651, 160
4,1541 cm ^-1 [M + H] ⁺ = 393

Example 10 1- (3-N- (benzylo)
(Xycarbonyl) aminobenzyl) -3- (3-methyl
Ureido) -2,3,4,5-tetrahydro-1H-1
Synthesis yield of -benzoazepin -2-one (I-10) 79.8% mp. 106-110 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.96 (1H, m),
2.40-2.60 (5H, m), 2.74 (1H, m),
4.56 (1H, m), 4.76 (1H, d, J = 16.2)
Hz), 5.16 (2H, d, J = 2.4 Hz), 5.2
7 (1H, d, J = 15.6 Hz), 6.89 (1H, d, J
= 7.5 Hz), 7.07 (1H, d, J = 7.8H)
z), 7.14-7.52 (11H, m) IR max (KBr): 3387, 2951, 173
3,1646,1613,1600,1553Cm ^-1 Elemental _{analysis: (C 31 H 42 N 4} O 6 .0.15C 6 H 14 .0.15H
₂ O as) Found: C, 67.87; H, 6.42 ; N, 11.32 Calcd: C, 67.77; H, 6.34 ; N, 11.33

Example 11 3- (3-methylureido)
-1-((3-neopentylcarbonylamino) benzyl
Ru) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis yield of zoazepin-2-one (I-11) 66.1% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.06 (9H, s),
1.95-2.05 (1H, m), 2.19 (2H, d, J
= 3.6 Hz), 2.40-2.53 (4H, m), 2.
61-2.67 (1H, m), 2.78-2.90 (1
H, m), 4.54-4.66 (2H, m), 4.86 (1
H, brs), 5.46 (1H, d, J = 16.2 Hz),
6.06 (1H, brs), 6.94 (1H, d, J = 7.
8 Hz), 7.05 (1H, d, J = 7.5 Hz), 7.
13-7.25 (3H, m), 7.29 (1H, t, J =
7.8 Hz), 7.96 (1H, d, J = 7.5 Hz),
8.09 (1H, m) IRνmax (KBr): 3384, 2867, 165
3,1600,1552 cm ^-1 elemental analysis: (as C ₂₅ H ₃₂ N ₄ O ₃ .0.2 H ₂ O) actual: C, 68.36; H, 7.61; N, 12.65 calculated : C, 68.22; H, 7.42; N, 12.73

Example 12 3- (3-methylureido)
-1- (2- (ortho-methylphenyl-2-oxo)
Ethyl) -2,3,4,5-tetrahydro-1H-1-
Synthesis of benzazepin-2-one (I-12) Example 1 Compound 2 obtained in the first step (0.343 mmol)
l), ortho-methylbenzoylmethyl bromide (0.1.
412 mmol), potassium carbonate (0.411 mmol
l), dimethylformamide (5.0 ml) was added to potassium iodide (0.034 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. After washing with water three times and drying (anhydrous magnesium sulfate), the solvent was distilled off. Silica gel chromatography of the residue (chloroform / methanol = 40/1)
To give the title compound.

Yield 79.0% Amorphous ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.07 (1
H, m), 2.41 (3H, m), 2.41-2.70 (3
H, m), 2.70 (3H, s), 3.45 (2H, m),
4.50 (1H, brs), 4.86 (1H, d, J = 1
9.2 Hz), 5.42 (1H, d, J = 19.4H)
z), 6.00 (1H, brs), 7.13-7.45
(6H, m), 7.70 (1H, d, 7.2 Hz) IRνmax (KBr): 3413, 3298, 169
8,1681, 1638, 1602 cm ^-1 Elemental analysis: (as C ₂₁ H ₂₃ N ₃ O ₃ ) Actual: C, 68.82; H, 6.41; N, 11.60 Calculated: C, 69 .02; H, 6.34; N, 11.50

Example 13 3- (3-methylureido)
-1- (2-Meta-nitrophenyl-2-oxoethyl
Ru) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis of zoazepin-2-one (I-13) The title compound was obtained in the same manner as in Example 12. Yield 11.8% Amorphous ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.97-
2.18 (2H, m), 2.53-2.73 (1H, m),
2.71 (3H, m), 3.42-3.60 (1H, m),
4.48-4.57 (1H, m), 4.54 (1H, d, J
= 17.4 Hz), 5.08 (1H, d, J = 17.4H)
z), 7.14-7.28 (4H, m), 7.73 (1
H, t, J = 8.0 Hz), 8.31 (1H, d, J = 7.8)
Hz), 8.47 (1H, d, J = 7.8 Hz), 8.8
1 (1H, s) IRνmax (KBr): 3424, 3323, 171
0,1677,1642,1615,1602,153
0 cm ^-1 elemental analysis: (C ₂₀ H ₂₀ N ₄ O ₅ .0.1CHCl ₃ .0.1H
₂ O as) Found: C, 58.86; H, 5.10 ; N, 13.78 Calcd: C, 58.86; H, 4.99 ; N, 13.66

Example 14 1- (Diphenylmethyl)-
3- (3-methylureido) -2,3,4,5-tetra
Hydro-1H-1-benzazepin-2-one (I-1)
Compound 2 obtained in the first step of Example 1 at 0 ° C. in a synthetic nitrogen stream of 4)
(0.214 mmol) of dimethylformamide (3.
Sodium hydride was added to the solution, and the mixture was stirred for 15 minutes.
l) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. Wash 3 times,
After drying (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (ethyl acetate / n-hexane = 10/1) to obtain the title compound.

Yield: 86.6% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.85-1.93 (1
H, m), 2.36-2.55 (3H, m), 2.60 (3
H, m), 4.52-4.60 (1H, m), 4.56 (1
H, brs), 5.70 (1H, brs), 7.00-
7.17 (10H, m), 7.31-7.38 (5H, m) IRνmax (CDCl ₃ ): 3448, 3398, 2
992, 2942, 1727, 1647, 1600, 1
540 cm ^-1 Elemental _{analysis: (C 25 H 25 N 3} O 2 .0.15C 6 H 14 .0.3H 2
Found: C, 74.60; H, 6.87; N, 9.91 Calculated: C, 74.45; H, 6.68; N, 10.06

Example 15 1- (4-hydroxybenzyl)
) -3- (3-Methylureido) -2,3,4,5-
Tetrahydro-1H-1-benzazepin-2-one
10% palladium-carbon (15 mg) was added to a methanol solution of the synthetic compound (I-8) (0.128 mmol) of (I-15), and the mixture was stirred in a hydrogen atmosphere for 3 hours. Evaporation gave quantitatively the title compound.

Mp. 262 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.92 (1 H, m),
2.37 (3H, m), 3.32 (3H, m), 4.25
(1H, m), 4.53 (1H, d, J = 14.4 Hz),
5.30 (1H, d, J = 14.4 Hz), 6.62 (2
H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6)
Hz), 7.19 (1H, dd, J = 1.6 Hz, 7.8)
Hz), 7.35 (2H, m) IRνmax (KBr): 3414, 3295, 294
7,1669,1632,1601,1593,156
1,1516 cm ^-1 Elemental analysis: (As C ₁₉ H ₂₁ N ₃ O ₃ .0.15 H ₂ O) Found: C, 66.65; H, 6.26; N, 12.45 Calculated: C , 66.70; H, 6.28; N, 12.28.

Example 16 3- (3- (4-benzylo)
Xy) phenylureido) -1- (3-amino-propyl
Ru) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis of zoazepin-2-one (I-16) (first step) 3- (3- (4-benzyloxy) phenylureido) -2,3,4,5-tetrahydro-1H
-1-Benzazepin-2-one (compound 3)

[0132]

Embedded image

To a solution of para-benzyloxyaniline hydrochloride (2.12 mmol) and carbonyldiimidazole (2.12 mmol) in dimethylformamide (6.0 ml) were added triethylamine (0.3 ml) under ice-cooling.
After l) was added dropwise, the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was added with compound 1 (1.99 mmol) under ice cooling.
Was added and stirred at room temperature for 18 hours. The reaction mixture was poured into ice water, the resulting precipitate was filtered, and the residue was purified by silica gel chromatography (chloroform / acetone = 20/1) to obtain the title compound.

Yield 42.7% mp. 189-191 ° C. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.00 (1
H, m), 2.63-2.75 (2H, m), 2.91 (1
H, m), 4.50 (1H, m), 5.02 (1H, s), 6.90
(1H, d, J = 9.0 Hz), 7.00 (1H, dd, J =
1.8 Hz, 7.8 Hz), 7.17-7.43 (9
H, m) IRνmax (KBr): 3323,3061,167
3,1602,1585,1560,1510Cm ^-1 Elemental analysis: (C ₂₄ as H ₂₃ N ₃ O ₃₎ Found: C, 71.55; H, 5.91 ; N, 10.69 Calculated: C, H, 5.77; N, 10.47.

(Second step) 3- (3- (4-benzyloxy) phenylureido) -1- (3-phthalimidopropyl) -2,3,4,5-tetrahydro-1H-1
-Benzazepin-2-one (compound 4)

[0136]

Embedded image

In a nitrogen stream at 0 ° C., sodium hydride (0.748 mmol) was added to a dimethylformamide solution (5.0 ml) of compound 3 (0.665 mmol) obtained in the first step.
l) was added and the mixture was stirred at that temperature for 1 hour, and then N- (3
-Bromopropyl) phthalimide (0.778 mmol
l) was added in 30 minutes. After stirring at room temperature for 1 hour, the temperature was returned to 0 ° C. and sodium hydride (0.325 mmol) was added.
N- (3-bromopropyl) phthalimide (0.398
mmol) and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 56/1).

Yield 80.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.87-1.99 (3
H, m), 2.54-2.66 (2H, m), 2.92 (3
H, m), 3.54 (1H, m), 3.64 (2H, t, J =
7.5 Hz), 4.39 (1H, m), 5.00 (2H,
s), 6.87 (2H, d, J = 8.1 Hz), 7.12-
7.43 (11H, m), 7.67 (2H, m), 7.78
(2H, m) IRνmax (KBr): 3376, 2940, 177
1,1712,1649,1601,1546,150
9 cm ^-1 elemental analysis: (C ₃₅ H ₃₂ N ₄ O ₅ .0.1 C ₆ H ₁₄ .0.3 H ₂ O
As) Found: C, 71.03; H, 5.85; N, 9.13 Calculated: C, 70.95; H, 5.69; N, 9.30

(Third Step) Compound (I-16)

[0140]

Embedded image

Hydrazine monohydrate (80 mg) was added to a solution of compound 4 (0.51 mmol) obtained in the second step in ethanol (10.0 ml), and the mixture was stirred at 110 ° C. for 3 hours. After cooling, water was added to the reaction mixture to form ethyl acetate.
Extracted twice with methanol. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 10 / 1-5 / 1) to give the title compound.

Yield 72.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.70 (2H, m),
1.90 (2H, m), 2.50-2.77 (6H, m),
3.57 (1H, m), 4.28 (1H, m), 4.43
(1H, m), 5.00 (2H, s), 6.17 (1H, b
rs), 6.87 (2H, d, J = 9.0 Hz), 7.1
6-7.43 (12H, m) IRνmax (KBr): 3398, 3061, 303
3,2932,2862,1648,1601,155
11,509 cm ^-1 elemental analysis: (C ₂₇ H ₃₀ N ₄ O ₃ .0.2 C ₆ H ₁₄ .1 .3 H ₂ O
Found) C, 67.82; H, 7.39; N, 11.59 Calculated: C, 67.85; H, 7.15; N, 11.22.

Example 17 3- (3- (4-benzylo)
Xy) phenylureido) -1- (3-N ', N''-
(Di-tert-butoxycarbonyl) guanidinopro
Pill) -2,3,4,5-tetrahydro-1H-1-be
Synthesis of nzoazepin-2-one (I-17)

[0144]

Embedded image

Compound (I-16) (0.22 mmol)
And literature (Tetrahedron. Lett., 34 ,
3389 (1993). )) Described compound N, N'-bis-
A solution of Boc-amidinopyrazole (0.243 mmol) in dimethylformamide (3.0 ml) was stirred at room temperature for 1 week. The solvent was distilled off, and the residue was subjected to silica gel chromatography (chloroform / methanol = 150 /
Purification by 1) gave the title compound.

Yield 64.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s),
1.49 (9H, s), 1.82 (2H, m), 2.56-
2.65 (2H, m), 2.83 (1H, m), 3.35-
3.63 (3H, m), 4.30 (1H, m), 4.43
(1H, m), 5.02 (2H, s), 6.00 (1H, b
rs), 6.69 (1H, brs), 6.89 (2H,
d, J = 8.6 Hz), 7.15-7.44 (11H,
m), 8.40 (1H, m), 11.45 (1H, brs) IRνmax (KBr): 3324, 2982, 171
7,1634,1511Cm ^-1 Elemental _{analysis: (C 38 H 48 N 6} O 7 .0.15C 6 H 14 .0.5H 2
Found: C, 64.85; H, 7.20; N, 11.85 Calculated: C, 64.64; H, 7.13; N, 11.64

Example 18 1- (3-N ′, N ″-(di
-Tert-butoxycarbonyl) guanidinopropyl
Ru) -3- (3- (4-hydroxy) phenylurei
Do) -2,3,4,5-tetrahydro-1H-1-ben
10% palladium-carbon (34 mg) was added to a solution of a compound (I-17) (0.13 mmol) of zoazepin-2-one (I-18) (0.13 mmol) in methanol and ethanol (1: 1). 0.0kg / c
After stirring at a pressure of m ² for 18 hours, the catalyst was filtered and the solvent was distilled off to give the title compound.

Yield: 88.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s),
1.85 (3H, m), 2.62 (2H, m), 2.83
(1H, m), 2.82 (1H, m), 3.39 (2H,
m), 3.56 (1H, m), 4.32 (2H, m), 5.
91 (1H, d, J = 7.8 Hz), 6.56 (1H,
s), 6.69 (2H, d, J = 8.6 Hz), 7.04
(1H, d, J = 8.6 Hz), 7.19-7.30 (4
H, m), 8.38 (1H, brs), 11.43 (1H,
brs) IRνmax (KBr): 3324, 2982, 293
4,1717,1639,1511 cm ^-1 [M + H] ⁺ = 611

Example 19 1- (3-guanidinopropyl
Ru) -3- (3- (4-hydroxy) phenylurei
D) -2,3,4,5-tetrahydro-1H- [1]
The compound (I-18) (0.09 mmol) of nzazepin-2-one (I-19 ) was added to
After adding a total of 5.0 ml of an N-hydrogen chloride / ethyl acetate solution and stirring at room temperature for 6 days, the solvent was distilled off to obtain the title compound.

Quantitative powder ¹ H-NMR (CDCl ₃ ) δ: 1.89 (2H, m),
2.02 (1H, m), 2.43 (1H, m), 2.66-
2.85 (2H, m), 3.22 (2H, t, J = 6.8H)
z), 3.80 (1H, m), 4.12 (1H, m), 4.
25 (1H, m), 6.68 (2H, d, J = 9.0H
z), 7.08 (2H, d, J = 8.6 Hz), 7.35
(2H, m) IRνmax (KBr): 3377,1653,160
0, 1559, 1516 cm ^-1 Elemental analysis: (C ₂₁ H ₂₇ N ₆ O ₃ Cl.2.5 HCl.0.4
Na ₂ SO ₄ . (As 0.6 H ₂ O) Found: C, 44.31; H, 5.26; N, 14.7.
6; Cl, 15.37 Calculated: C, 44.23; H, 5.43; N, 14.7.
4: Cl, 15.54

Example 20 3- (3- (4-benzylo)
Xy) phenylureido) -1- (3-aminobenzyl)
Ru) -2,3,4,5-tetrahydro-1H-1-ben
N-Alkylation was carried out from Compound 3 (0.5 mmol) of zoazepin-2-one (I-20) in the same manner as in the second step of Example 1. Then, under ice cooling,
It was dissolved in a 4N hydrogen chloride / ethyl acetate solution (4.0 ml) and stirred at room temperature for 18 hours. After adjusting the pH to 10 with a 10% aqueous solution of Na ₂ CO _{3 and} extracting twice with ethyl acetate, the organic layer was washed with water and dried (anhydrous magnesium sulfate), and then the solvent was distilled off. Silica gel chromatography (ethyl acetate /
Purification by n-hexane = 3/7) gave the title compound.

Yield: 78.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.96 (2H, m),
2.47-2.70 (3H, m), 3.61 (2H, br)
s), 4.60 (1H, m), 4.87 (1H, d, J = 1
5.6 Hz), 4.99 (2H, s), 5.04 (1H,
d, J = 15.6 Hz), 6.98-7.07 (2H,
m), 7.18 (3H, m), 7.36 (9H, m)

Example 21 3- (3- (4-benzylo)
Xy) phenylureido) -1- (3-N ', N''-
(Di-tert-butoxycarbonyl) guanidinoben
Jill) -2,3,4,5-tetrahydro-1H-1-be
Example 1 From Synthetic Compound (I-20) (0.36 mmol) of Nzoazepin-2-one (I-21)
The title compound was obtained in the same manner as in 7.

Yield 17.4% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.51 (18H, s),
1.94 (1H, m), 2.45-2.62 (3H, m),
4.50 (1H, m), 4.84 (1H, d, J = 15.3)
Hz), 5.03 (2H, s), 5.18 (1H, d, J =
15.3 Hz), 5.83 (1H, brs), 6.41
(2H, s), 6.93 (3H, t, J = 9.0 Hz),
7.15-7.44 (14H, m), 7.61-7.67
(1H, m) IRνmax (KBr): 3392, 2978, 293
2, 1719, 1642, 1548, 1509 cm ^-1 Elemental analysis: (as C ₃₂ H ₂₈ N ₆ O ₃ .0.1 C ₆ H ₁₄ ) Found: C, 67.78; H, 6.70; 11.32 Calculated: C, 67.55; H, 6.57; N, 11.09.

Example 22 1- (3-N ′, N ″-(di
-Tert-butoxycarbonyl) guanidinobenzi
Ru) -3- (3- (4-hydroxy) phenylurei
Do) -2,3,4,5-tetrahydro-1H-1-ben
Example 18 from synthetic compound (I-21) (0.1 mmol) of zoazepin-2-one (I-22)
The title compound was obtained in the same manner as in.

Yield 47.0% mp. 300 ° C. or higher ¹ H-NMR (CDCl ₃ ) δ: 1.50 (18H, s),
1.95 (1H, m), 2.46-2.65 (3H, m),
4.54 (1H, m), 4.86 (1H, d, J = 15.3)
Hz), 5.14 (1H, d, J = 14.4 Hz), 6.
02 (1H, brs), 6.63 (3H, m), 6.95
(3H, m), 7.18 (5H, m), 7.58 (1H, d,
J = 8.4 Hz) IRνmax (KBr): 3384, 2978, 293
4,1719,1644,1559,1514Cm ^-1 Elemental _{analysis: (C 35 H 42 N 6} O7.0.3H 2 O as) Found: C, 63.20; H, 6.64 ; N, 12. 81 Calculated: C, 63.30; H, 6.47; N, 12.65.

Example 23 1- (3-Guanidinobenzy)
Ru) -3- (3- (4-hydroxy) phenylurei
Do) -2,3,4,5-tetrahydro-1H-1-ben
The synthesized compound (I-22) (0.061 mmol) of zuazepin-2-one (I-23 ) was cooled under ice-cooling.
It was dissolved in a 4N hydrogen chloride / ethyl acetate solution (2.5 ml) and stirred at room temperature for 36 hours. The resulting precipitate was dried to give the title compound.

Yield: 84.8% Amorphous ¹ H-NMR (CD ₃ OD) δ: 2.00 (1 H, m),
2.43 (1H, m), 2.62-2.69 (2H, m),
4.37 (1H, m), 5.11 (2H, s), 6.68
(2H, d, J = 8.7 Hz), 7.08 (2H, d, J =
8.7 Hz), 7.16-7.38 (7H, m), 7.4
0 (1H, t, J = 7.5 Hz) IRνmax (KBr): 3309, 2954, 165
3,1600,1558,1513Cm ^-1 Elemental _{analysis: (C 25 H 26 N 6} O 3 .1.1HCl.0.5Et
OAc. 0.75H ₂ O as) Found: C, 58.30; H, 5.95 ; N, 14.9
7; Cl, 6.78 Calculated: C, 58.12; H, 5.92; N, 15.0
6; Cl, 6.79

Example 24 1- (3-cyanobenzyl)
-3- (3-phenylureido) -2,3,4,5-te
Trahydro-1H-1-benzazepin-2-one (I
Synthesis of -24)

[0160]

Embedded image

(First Step) 3-azido-1- (3-cyanobenzyl) -2,3,4,5-tetrahydro-1H
-1-benzazepin-2-one (compound 6) Reference (J. Med. Chem., 28 , 1511 (19)
85). )) And N-alkylation according to the method of the second step in Example 1 using compound 5 (1.98 mmol) and meta-cyanobenzyl bromide to give the title compound.

Yield 98.7% mp. 90-91 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.29-2.59 (4
H, m), 3.76 (3H, m), 4.82 (1H, d, J =
15.0 Hz), 5.30 (1H, d, J = 14.8H)
z), 7.17-7.57 (8H, m) IR max (KBr): 3435, 2958, 223
0,2098,1664,1601Cm ^-1 Elemental analysis: (C ₁₈ H ₁₅ as N5O) Found: C, 68.15; H, 4.96 ; N, 22.02 Calcd: C, 68.13; H, 4.96; N, 22.07

(Second Step) 3-Amino-1- (3-cyanobenzyl) -2,3,4,5-tetrahydro-1H
-1-Benzazepin-2-one (compound 7)

[0164]

Embedded image

The compound 6 obtained in the first step (1.76 mmol)
l) and a solution of triphenylphosphine (1.94 mmol) in tetrahydrofuran were stirred at room temperature for 18 hours. After water was added to the reaction mixture and the mixture was refluxed for 2 hours, tetrahydrofuran was distilled off and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. Purification by silica gel chromatography (chloroform / methanol = 1/4) gave the title compound quantitatively.

¹ H-NMR (CDCl ₃ ) δ: 1.86
(1H, m), 2.29-2.48 (3H, m), 3.43
(1H, m), 4.85 (1H, d, J = 15.0 Hz),
5.26 (1H, d, J = 14.7 Hz), 7.18 (3
H, m), 7.28 (1H, m), 7.39 (1H, m),
7.53 (3H, m) IR max (KBr): 2948, 2228, 165
8,1599cm ^-1

(Third Step) Compound (I-24)

[0168]

Embedded image

Under ice-cooling, phenyl isocyanate was added to the second
After dropwise adding the compound 7 (0.602 mmol) obtained in the step to a dimethylformamide solution (4.0 ml), the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. Silica gel chromatography (ether / n-hexane = 3 / 2-2)
/ 1) to give the title compound.

Yield: 82.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.92 (1 H, m),
2.43-2.59 (3H, m), 4.57 (1H, m),
4.89 (1H, d, J = 14.8 Hz), 5.20 (1
H, d, J = 15.4 Hz), 6.18 (1H, brs),
6.97-7.54 (14H, m) IR max (KBr): 3359, 3058, 295
2,2929,2860,2229,1648,160
0.1550 cm ^-1 elemental analysis: (C ₂₅ H ₂₂ N ₄ O ₂ .0.3 C ₆ H ₁₄ .1 .2 H ₂ O
N) 12.23 Calculated: C, 70.29; H, 6.29; N, 12.23

Example 25 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3-phenyi
Ruureido) -2,3,4,5-tetrahydro-1H-
Synthesis of 1-benzazepin-2-one (I-25) (first step) 3-azido-1- (3- (tert-butoxycarbonylamino) benzyl) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one (Compound 8) Compound 5 (4.94 mmol) was N-alkylated by the method of the second step in Example 1 to obtain the title compound.

Yield: 79.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
2.24-2.70 (4H, m), 3.76 (1H, t, J
= 9.0 Hz), 4.85 (1H, d, J = 14.7H)
z), 5.17 (1H, d, J = 14.7 Hz), 6.4
3 (1H, s), 6.86 (1H, d, J = 7.5 Hz),
7.16-7.41 (7H, m)

(Second Step) Compound (I-25) The compound 8 (9.47 mmol) obtained in the first step was reduced in the same manner as in Example 15 to obtain an amine compound (Compound 9). Example 24 The title compound was obtained in the same manner as in the third step.

Yield 69.6% mp. 139 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.99 (1H, m), 2.59 (2H, m), 2.80
(1H, m), 4.65 (1H, m), 4.79 (1H, d, J
= 15.6 Hz), 5.35 (1H, d, J = 15.6H)
z), 6.54 (1H, brs), 6.80-7.03
(8H, m), 7.35 (1H, brs), 7.62 (1
(H, brd, J = 7.8 Hz) IRνmax (KBr): 3358, 3057, 297
6,2931,1725,1649,1600,154
8 cm ^-1 Elemental analysis: (as C ₂₉ H ₃₂ N ₄ O ₄ .0.1 H ₂ O) Found: C, 69.77; H, 6.89; N, 10.83 Calculated: C, 69 .69; H, 6.71; N, 10.87

Example 26 1- (2- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3-phenyi
Ruureido) -2,3,4,5-tetrahydro-1H-
Synthesis of 1-benzazepin-2-one (I-26) (first step) 3-azido-1- (2- (tert-butoxycarbonylamino) benzyl) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one (compound 10) The same as in the second step of Example 1 using compound 5 (4.94 mmol) and ortho-Boc-aminobenzyl bromide (5.93 mmol). The title compound was obtained by the method.

Yield 53.9% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.57 (9H, s),
1.90-2.44 (4H, m), 3.66 (1H, m),
4.56 (1H, d, J = 14.7 Hz), 5.47 (1
H, d, J = 15.6 Hz), 5.17 (1H, d, J = 1)
4.7 Hz), 6.70 (1H, dd, J = 1.8 Hz,
7.8Hz), 6.77 (1H, td, J = 1.2Hz,
7.2 Hz), 7.14 (1H, dd, J = 1.5 Hz,
7.5Hz), 7.19-7.40 (5H, m), 7.9
5 (1H, d, J = 8.7 Hz), 8.56 (1H, s) IRνmax (KBr): 3288, 2977, 293
1,107,1727,1658,1592,153
6 cm ^-1 Elemental analysis: (as C ₂₂ H ₂₅ N ₅ O ₃ .0.7 H ₂ O) Found: C, 62.97; H, 6.12; N, 16.49 Calculated: C, 62 .90; H, 6.33; N, 16.67

(Step 2) Compound (I-26) The title compound was obtained from compound 10 (0.315 mmol) obtained in Step 1 in the same manner as in Example 25, Step 2.

Yield 53.9% powder mp. 235 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s),
1.73 (1H, m), 2.05-2.53 (3H, m),
4.45 (1H, m), 4.49 (1H, d, J = 14.6)
Hz), 5.42 (1H, d, J = 14.4 Hz), 6.
17 (1H, brs), 6.66 (1H, dd, J = 1.
6 Hz, 7.4 Hz), 6.78 (1H, td, J = 1.2)
Hz, 7.4 Hz), 6.99-7.36 (13H,
m), 7.80 (1H, d, J = 7.8 Hz), 8.73
(1H, brs) IRνmax (KBr): 3347, 3302, 311
6, 1715, 1645, 1601, 1560 cm ^-1 Elemental analysis: (as C ₂₉ H ₃₂ N ₄ O ₄ .0.1 H ₂ O) Found: C, 69.53; H, 6.78; N, 11 .24 Calculated: C, 69.33; H, 6.46; N, 11.15

Example 27 1- (3-Amidinobenzy)
) -3- (3-phenylureido) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one
Synthesized compound (I-24) (0.317 mmol) of hydrochloride (I-27) was dried with ethanol (0.5 ml) and dried chloroform (1).
0.0ml) and saturated with hydrogen chloride gas while stirring under ice-cooling. The mixture was alkalified with a 10N sodium hydroxide solution and separated. The chloroform layer was washed with water, washed with an aqueous solution of potassium carbonate, and the solvent was distilled off. Ammonium chloride (0.375 mmol) and 75% ethanol (10.0 ml) were added to the residue, and the mixture was heated with stirring at 70 ° C. for 4 hours, and then stirred at room temperature for 16 hours. Evaporate the ethanol,
A precipitate formed by adding 10% hydrochloric acid and ethyl acetate was filtered, washed with ethyl acetate and dried to obtain the title compound.

Yield 31.4% Amorphous ¹ H-NMR (CD ₃ OD) δ: 2.08 (1 H, m),
2.45 (1H, m), 2.70 (2H, m), 4.37
(1H, m), 4.96 (1H, d, J = 15.9 Hz),
5.36 (1H, d, J = 16.2 Hz), 7.00 (1
H, m), 7.04-7.32 (10H, m), 7.54-
7.79 (3H, m), 8.67 (1H, s), 9.25
(1H, s) IRνmax (KBr): 3301,3074,286
4,1663,1599,1551Cm ^-1 Elemental _{analysis: (C 25 H 25 N 5} O 2 .HCl.0.1C4H10.
(As 0.6 H ₂ O) Found: C, 63.20; H, 6.64; N, 12.8.
1; Cl, 7.35 Calculated: C, 63.27; H, 5.89; N, 14.5.
2: Cl, 7.35

Example 28 3- (3-benzylurei)
De) -1- (3- (tert-butoxycarbonylamido)
No) benzyl) -2,3,4,5-tetrahydro-1H
Example 25 Synthesis of 1-benzazepin-2-one (I-28) Example 25 From the compound obtained in the first step, Example 24
The title compound was obtained in the same manner as in the third step.

Yield 98.8% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s),
1.71 (1H, m), 1.92 (1H, m), 2.48
(2H, m), 2.68 (1H, m), 4.08 (1H,
m), 4.38 (1H, dd, J = 6.4, 15.0H)
z), 4.67 (1H, d, J = 16.2 Hz), 5.2
0 (1H, d, J = 15.6 Hz), 5.42 (1H, br
s), 6.10 (1H, brs), 6.80 (1H, d, J
= 7.8 Hz), 7.05 (1H, d, J = 7.5H)
z), 7.12-7.21 (10H, m), 7.58 (1
H, brd, J = 7.8 Hz) IRνmax (KBr): 3384, 2975, 172
5,1642,1603,1548Cm ^-1 Elemental analysis: (C ₃₀ H ₃₄ N ₄ as O ₄₎ Found: C, 69.93; H, 6.88 ; N, 10.77 Calcd: C, 70 .02; H, 6.66; N, 10.89

Example 29 3- (3- (4-benzylo)
Xy) phenylureido) -1- (3- (tert-butyl)
Toxylcarbonylamino) benzyl) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one
Synthesis of (I-29) Example 25 Using compound 9 obtained in the second step, Example 16
The title compound was obtained in the same manner as in the first step.

Yield 80.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
1.96 (1H, m), 2.49-2.63 (2H, m),
2.75 (1H, m), 4.62 (1H, m), 4.80
(1H, d, J = 15.9 Hz), 4.94 (2H, s),
5.29 (1H, d, J = 14.7 Hz), 6.38 (1
H, brs), 6.68 (2H, dd, J = 1.8 Hz,
8.7 Hz), 6.88 (3H, m), 7.12-7.3
9 (13H, m), 7.57 (1H, brd, J = 8.7H
z) IRνmax (KBr): 3373, 2975, 293
1,1725,1646,1604,1547,151
0 cm ^-1 Elemental analysis: (as C ₂₆ H ₂₇ N ₃ O ₃ ) Found: C, 71.10; H, 6.58; N, 9.03 Calculated: C, 71.27; H, 6 .31; N, 9.23

Example 30 3- (3- (4-hydroxy)
B) phenylureido) -1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -2,3,4,5-
Tetrahydro-1H-1-benzazepin-2-one
10% palladium-carbon (18 mg) was added to a methanol solution of the synthetic compound (I-29) (0.211 mmol) of (I-30), and the mixture was stirred in a hydrogen atmosphere for 3 hours. Then, the catalyst was filtered, and the solvent was removed. Evaporation gave the title compound.

Yield 94.5% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s),
1.98 (1H, m), 2.54 (3H, m), 4.54
(1H, m), 4.87 (1H, d, J = 15.6 Hz),
5.02 (1H, d, J = 15.6 Hz), 6.38 (1
H, d, J = 7.8 Hz), 6.46 (1H, d, J = 15.
6Hz), 6.80 (3H, m), 6.91 (1H, m),
7.34 (1H, d, J = 8.6 Hz), 7.47-7.
54 (1H, m), 7.04-7.54 (7H, m) IRνmax (KBr): 3361,974,293
1,1646, 1605, 1545, 1513 cm ^-1 Elemental analysis: (C ₂₉ H ₃₂ N ₄ O ₅ .0.15 C ₆ H ₁₄ .0.1H ₂
H) 6.75; N, 10.51 Calculated: C, 67.59; H, 6.51; N, 10.54

Example 31 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (4-
Sulfonyloxy) phenylureido) -2,3,4
5-tetrahydro-1H-1-benzazepin-2-o
To a pyridine solution of a synthetic compound (I-30) (0.211 mmol) of sodium salt (I-31) was added sulfur trioxide pyridine complex (0.97 mmol), the mixture was stirred at room temperature for 110 hours, and then concentrated. Water was added and filtered. 0.1N-sodium hydroxide solution (3.
5 ml), washed with chloroform, and extracted twice with 1-butanol. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off to obtain the title compound.

Yield 50.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
2.00 (1H, m), 2.36-2.69 (3H, m),
4.35 (1H, m), 4.82 (1H, d, J = 15.4)
Hz), 5.27 (1H, d, J = 14.8 Hz), 6.
84 (1H, brd, J = 7.4 Hz), 7.08-7.
35 (11H, m) IRνmax (KBr): 3388, 2977, 293
3,1654, 1604, 1548, 1506 cm ^-1 Elemental analysis: (as C ₂₉ H ₃₁ N ₄ O ₈ Na.2.2H ₂ O) Found: C, 52.79; H, 5.35; 8.49;
S, 5.26 Calculated: C, 52.91; H, 5.42; N, 8.51;
S, 4.87

Example 32 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (4-
(1H-tetrazol-5-yl)) phenylurei
Do) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis of zoazepin-2-one (I-32) EP-508796-A1 from 4-amino- (1-1H-tetrazol-5-yl) benzene (0.174 mmol) synthesized according to the method of EP-508796-A1.
The corresponding isocyanate was synthesized according to the method described in (1). The compound 9 obtained in the second step of Example 25 (0.157m
mol), a saturated aqueous solution of sodium carbonate and water were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. After washing the organic layer twice with water and drying (anhydrous magnesium sulfate),
The solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 8/1) to obtain the title compound.

Yield 42.8% Amorphous ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 1.37 (9
H, s), 2.05 (1H, m), 2.68-2.78 (2
H, m), 2.90 (1H, m), 4.59 (1H, m),
4.69 (1H, d, J = 16.2 Hz), 5.57 (2
H, m), 6.76 (2H, brs), 7.01 (1H, b
rd, J = 7.2 Hz), 7.18-7.33 (9H,
m), 7.59 (1H, s), 8.06 (1H, brs) IRνmax (KBr): 3384, 2977, 293
0,1647,1601,1541Cm ^-1 Elemental _{analysis: (C 30 H 32 N 8} O 4 .0.2C 6 H 14 .0.6H 2 O
Found) C, 62.57; H, 6.04; N, 18.69 Calculated: C, 62.80; H, 6.08; N, 18.78.

Example 33 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (4-
(3-chloropropoxy)) phenylureido) -2,
3,4,5-tetrahydro-1H-1-benzazepine
To an acetone solution of a compound (I-30) (0.137 mmol) of -2-one (I-33), potassium carbonate (0.137 mmol) and 1-bromo-3-chloropropane (0.27 mmol) were added to obtain a solution. After heating under reflux for 1 hour, 1-bromo-3-chloropropane (0.27 mmol) was added, and the mixture was further heated under reflux for 24 hours, and then the solvent was distilled off. The residue was subjected to silica gel chromatography (chloroform / methanol = 50 /
Purification according to 1) gave quantitatively the title compound.

Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.96 (1H, m), 2.19 (2H, m), 2.52-
2.64 (2H, m), 2.78 (1H, m), 3.73
(2H, t, J = 6.4 Hz), 4.02 (2H, d, J =
5.9 Hz), 4.60 (2H, m), 4.85 (1H,
d, J = 16.2 Hz), 5.22 (1H, d, J = 16.0 Hz).
2 Hz), 5.17 (1H, s), 6.55 (1H, d
d, J = 1.5 Hz, 9.0 Hz), 6.80 (1H,
s), 6.87 (2H, d, J = 8.7 Hz), 6.95
(2H, dd, J = 1.8 Hz, 9.0 Hz), 7.12
−7.25 (5H, m), 7.55 (1H, brd, J =
6.9 Hz), IRνmax (KBr): 3382, 2972, 293
2,1724,1651,1604,1543,151
1 cm ^-1 Elemental analysis: (as C ₃₂ H ₃₇ N ₄ O ₅ Cl. 0.2 H ₂ O) Found: C, 64.42; H, 6.40; N, 9.61;
Cl, 5.69 Calculated: C, 64.41; H, 6.32; N, 9.39;
Cl, 5.94

Example 34 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (3-
Tetrahydropyran-2-yloxy) phenylurei
Do) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis of zoazepin-2-one (I-34)
meta- (tetrahydropyran-2-yl) aniline obtained by protecting with a z group, followed by protecting a hydroxyl group with a tetrahydropyranyl group and then removing the Cbz group, and a compound obtained in the second step of Example 25 The title compound was obtained by the method of Example 32 using Compound 9.

Yield: 78.8% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s),
1.54-1.68 (4H, m), 1.80-1.97
(3H, m), 2.63 (3H, m), 3.58 (1H,
m), 3.88 (1H, m), 4.59 (1H, m), 5.
02 (2H, s), 5.05 (1H, s), 5.40 (1
H, m), 6.71-6.89 (4H, m), 7.79-
7.48 (1H, m) IR max (KBr): 3378, 2944, 286
8,1725,1654,1602,1544Cm ^-1 Elemental _{analysis: (C 34 H 40 N 4} O 6 .0.6H as ₂ O) Found: C, 66.52; H, 6.79 ; N, 9 .16 calc: C, 66.78; H, 6.75; N, 9.31.

Example 35 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (3-
(Hydroxy) phenylureido) -2,3,4,5-te
Trahydro-1H-1-benzazepin-2-one (I
To a solution of the synthetic compound (I-34) (0.165 mmol) of -35) in methanol (2.5 ml) was added para-toluenesulfonic acid monohydrate (0.012 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was made alkaline with a saturated aqueous solution of sodium carbonate and extracted twice with ethyl acetate. Wash the organic layer with water,
After drying (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 40/1) to obtain the title compound.

Yield 44.6% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.59 (9H, s),
2.02 (1H, m), 2.50-2.91 (3H, m),
4.59 (3H, m), 6.30 (1H, d, J = 9.4H)
z), 6.71 (3H, m), 6.93 (1H, brd, J
= 7.8 Hz), 7.05 (1H, brs), 7.17
−7.39 (6H, m), 7.51 (1H, d, J = 8.2)
Hz), IRνmax (KBr): 3387, 2976, 164
8,1603,1548Cm ^-1 Elemental _{analysis: (C 29 H 32 N 4} O 5 .0.3H 2 O as) Found: C, 66.69; H, 6.44 ; N, 10.81 Calculated : C, 66.73; H, 6.29; N, 10.73

Example 36 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (2-
(Hydroxy) phenylureido) -2,3,4,5-te
Trahydro-1H-1-benzazepin-2-one (I
-36) (first step) 1- (3- (tert-butoxycarbonylamino) benzyl) -3- (3- (2-tert-
Butyldimethylsilyloxy) phenylureido) -2,
3,4,5-Tetrahydro-1H-1-benzazepin-2-one (Compound 11) After protecting the hydroxyl group of ortho-nitrophenol with a tert-butyldimethylsilyl group by a conventional method, the nitro group is reduced. The resulting compound (2- (tert-butyldimethylsilyloxy) aniline; 0.174 mmol
l) and the compound 9 obtained in the second step of Example 25 (0.262
The title compound was obtained in the same manner as in Example 32 using the above compound (mmol).

Yield 70.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.22 (6H, s),
1.01 (9H, s), 1.96 (1H, m), 2.45-
2.65 (3H, m), 4.54 (1H, m), 5.01
(2H, s), 6.68-6.92 (6H, m), 7.10
−7.26 (6H, m), 7.44 (1H, brd, J =
4.0 Hz), 7.82 (1 H, m) IR max (KBr): 3415, 2954, 293
0,2899,1728,1655,1599,152
8 cm ^-1 Elemental analysis: (as C ₃₅ H ₄₆ N ₄ O ₅ Si) Found: C, 66.75; H, 7.63; N, 8.71 Calculated: C, 66.64; H, 7.35; N, 8.88

(Second Step) Compound (I-36) A solution of the compound (0.127 mmol) obtained in the first step in tetrahydrofuran (2.0 ml) was added under ice-cooling to tetrahydrofuran (tetra-n-butylammonium fluoride). 1.0 ml) solution was added dropwise, and after 5 minutes, the mixture was returned to room temperature and stirred for 1 hour. Ice water and a saturated aqueous solution of sodium carbonate were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. After washing with water and drying (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 50/1) to obtain the title compound.

Yield: 82.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s),
2.00 (1H, m), 2.51-2.77 (3H, m),
4.56 (1H, m), 5.31 (2H, d, J = 15.4)
Hz), 6.62 (1H, m), 6.85 (4H, m),
7.08-7.23 (6H, m), 7.54-7.63
(2H, m) IRνmax (KBr): 3384, 2976, 293
1,1726,1647,1602,1542Cm ^-1 Elemental _{analysis: (C 29 H 32 N 4} O 5 .0.1C 6 H 14 .0.3H 2 O
Found) C, 67.11; H, 6.75; N, 10.75 Calculated: C, 67.00; H, 6.46; N, 10.56.

Example 37 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (pyri
Zin-3-yl) ureido) -2,3,4,5-tetra
Hydro-1H-1-benzazepin-2-one (I-3
The title compound was obtained by the method of Example 32 using 3-amino-pyridine (0.289 mmol) and compound 9 (0.262 mmol) obtained in the second step of Example 25.

Yield 25.9% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.97 (1H, m), 2.53-2.62 (2H, m),
2.74 (1H, m), 4.60 (1H, m), 4.90
(1H, d, J = 15.6 Hz), 5.23 (1H, d, J =
15.3 Hz), 6.54 (1H, d, J = 7.5H)
z), 6.87 (1H, d, J = 7.5 Hz), 6.97
(1H, m), 7.11 (1H, brs), 7.23 (5
H, m), 7.50 (2H, d, J = 8.4 Hz), 7.6
4 (1H, brs), 8.10 (1H, d, J = 3.9H)
z), 8.29 (1H, brs) IRνmax (KBr): 3365, 3058, 297
6,2932,1656,1606,1548Cm ^-1 Elemental _{analysis: (C 28 H 31 N 5} O 4 .0.5H 2 O as) Found: C, 66.16; H, 6.49 ; N, 13 .53 calc: C, 65.87; H, 6.32; N, 13.72

Example 38 3- (3-((5-tert)
-Butyl) isoxazol-3-yl) ureido) -1
-(3- (tert-butoxycarbonylamino) ben
Jill) -2,3,4,5-tetrahydro-1H-1-be
Synthesis of nzoazepin-2-one (I-38): Using 3-amino-5-tert-butyl-isoxazole (0.29 mmol) and compound 9 (0.262 mmol) obtained in the second step of Example 25. The title compound was obtained by the method of Example 32.

Yield 60.4% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.29 (9H, s),
1.48 (9H, s), 2.02 (1H, m), 2.46-
2.64 (3H, m), 4.54 (1H, m), 4.92
(1H, d, J = 14.7 Hz), 5.19 (1H, d, J =
14.7 Hz), 6.10 (1 H, s), 6.72 (1
H, s), 6.83 (1H, d, J = 7.8 Hz), 7.1
4-7.26 (6H, m), 7.48 (1H, d, J = 7.
2Hz), 7.54 (1H, brs), 8.17 (1H,
brs) IRνmax (KBr): 3331, 297, 293
3, 1664, 1610, 1542 cm ^-1 Elemental analysis: (as C ₃₀ H ₃₇ N ₅ O ₅ .0.1 H ₂ O) Found: C, 65.58; H, 6.85; N, 12.86 Calculated: C, 65.58; H, 6.82; N, 12.75.

Example 39 3- (3- (benzothiazole)
Ru-6-yl) ureido) -1- (3- (tert-
Toxylcarbonylamino) benzyl) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one
Synthesis of (I-39) 6-aminobenzothiazole (0.300 mmol) obtained by reducing 6-nitrobenzothiazole by a conventional method.
l) and the compound 9 obtained in the second step of Example 25 (0.262
The title compound was obtained in the same manner as in Example 32 using the above compound (mmol).

Yield 50.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s),
2.03 (1H, m), 2.60 (1H, m), 2.70
(1H, m), 2.86 (1H, m), 4.76 (1H, d,
J = 15.9 Hz), 5.48 (1H, d, J = 15.9H)
z), 6.81 (1H, d, J = 11.1 Hz), 6.8
9 (1H, d, J = 8.4 Hz), 6.99 (1H, d, J =
8.4 Hz), 7.02 (1H, s), 7.19-7.3
5 (6H, m), 7.53 (1H, d, J = 9.0 Hz),
7.58 (1H, d, J = 7.8 Hz), 7.71 (1H,
s), 8.61 (1H, s) IR max (KBr): 3358, 2977, 293
0,2930,1653,1602,1550,152
1 cm ^-1 Elemental analysis: (as C ₃₀ H ₃₁ N ₅ O ₄ S. 0.4 H ₂ O) Found: C, 63.82; H, 5.85; N, 12.3
6; S, 5.74 Calculated: C, 63.79; H, 5.67; N, 12.4
0; S, 5.68

Example 40 3- (3- (benzotriazo)
Yl-5-yl) ureido) -1- (3- (tert-
Butoxycarbonylamino) benzyl) -2,3,4
5-tetrahydro-1H-1-benzazepin-2-o
Synthetically conventional methods emission (I-40) obtained by reducing 5-nitro-benzotriazole 6-amino-benzotriazole (0.261Mm
ol) and compound 9 obtained in the second step of Example 25 (0.25
The title compound was obtained by the method of Example 32 using 2 mmol).

Yield 41.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.20 (9H, d, J =
7.5 Hz), 2.11 (1H, m), 2.52-2.6
6 (2H, m), 2.81 (1H, m), 4.66 (1H,
m), 4.85 (1H, brs), 5.35 (1H, br)
s), 6.63 (1H, brs), 6.94 (2H, d, J
= 15.9 Hz), 7.01 (1H, brs), 7.2
2 (2H, m) 7.42 (2H, s), 7.51 (1H, b
r, s), 8.65 (2H, s), IR max (KBr): 3360, 2975, 293
0, 1654, 1603, 1576, 1536 cm ^-1 Elemental analysis: (C ₂₉ H ₃₁ N ₇ O ₄ .0.1 C ₆ H ₁₄ .0.4 H ₂ O
Found) C, 63.87; H, 6.21; N, 17.67 Calculated: C, 63.79; H, 6.00; N, 17.58

Example 41 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (1-
Para-tosyl-1H-benzimidazol-5-yl)
Ureido) -2,3,4,5-tetrahydro-1H-1
-Synthesis literature of benzazepin-2-one (I-41) (Roczniki Chem., 38 , 1073)
(1964). 1) -para-tosyl-5-nitrobenzimidazole was reduced to give 1-para-tosyl-5-aminobenzimidazole. Using this compound (0.720 mmol) and compound 9 (0.655 mmol) obtained in the second step of Example 25, the title compound was obtained by the method of Example 32.

Yield 41.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.93 (1H, m), 2.36 (3H, s), 2.45-
2.69 (3H, m), 4.57 (1H, m), 4.96
(1H, d, J = 7.8 Hz), 5.06 (2H, d, J =
7.6 Hz), 6.30 (1H, m), 6.63 (1H,
s), 6.82 (1H, d, J = 7.8 Hz), 7.82
(1H, d, J = 8.6 Hz), 7.14-7.30 (1
0H, m), 7.45-7.58 (1H, m), 8.31
(1H, s) IRνmax (KBr): 3393, 3087, 297
5,2930,1719,1655,1599,154
3 cm ^-1 Elemental analysis: (as C ₃₇ H ₃₈ N ₆ O ₆ S. 0.4 H ₂ O) Found: C, 63.37; H, 5.72; N, 11.99 Calculated: C, H, 5.57; N, 11.97.

Example 42 3- (3- (benzimidazo)
Yl-5-yl) ureido) -1- (3- (tert-
Butoxycarbonylamino) benzyl) -2,3,4
5-tetrahydro-1H-1-benzazepin-2-o
In methanol (2.0 ml) solution of Compound (I-41) (0.115mmol) of the emission (I-42), was added dropwise 10% potassium hydroxide / methanol (2.0 ml), and stirred for 30 minutes. 1
Neutralized with 0% hydrochloric acid and extracted twice with ethyl acetate. After washing with water and drying (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 10/1) to obtain the title compound.

Yield 64.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s),
2.01 (1H, m), 2.49-2.61 (2H, m),
2.77 (1H, m), 4.60 (1H, m), 4.77
(1H, m), 5.28 (1H, brs), 6.69 (1
H, brs), 6.88 (2H, brd, J = 8.4H)
z), 7.10-7.26 (8H, m), 7.34 (1
H, s), 7.47 (1H, m), 7.67-7.81 (1
H, m) IRνmax (KBr): 3387, 2977, 293
3,1654,1602,1549Cm ^-1 Elemental _{analysis: (C 30 H 32 N 6} O 4 .1.2H 2 as O) Found: C, 64.03; H, 6.00 ; N, 15.02 Calculated: C, 64.09; H, 6.17; N, 14.95.

Example 43 3- (3- (2-((4-B
Benzyloxy) phenyl) ethyl) ureido) -1-
(3- (tert-butoxycarbonylamino) benzyl
Ru) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis of zoazepin-2-one (I-43) from 3- (4-benzyloxy) propionic acid (J. Chem. Soc., Perkin Tran)
s. 12185 (1988). Example 2) with isocyanate compound (0.187 mmol) obtained according to the method of Example 2.
5 The title compound was obtained by the method of Example 32 from compound 9 (0.170 mmol) obtained in the second step.

Yield: 82.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s),
1.93 (1H, m), 2.41-2.60 (4H, m),
2.72 (1H, m), 3.19 (1H, m), 3.35
(1H, m), 4.55 (1H, m), 4.72 (1H, d,
J = 15.9 Hz), 4.95 (1H, brs), 5.0
0 (2H, s), 5.11 (1H, d, J = 15.6H)
z), 5.88 (1H, brs), 6.81-6.89
(3H, m), 6.99-7.43 (14H, m), 7.5
8 (1H, brd, J = 8.4 Hz) IRνmax (KBr): 3384, 2974, 293
1,1724,1644,1606,1548,151
2 cm ^-1 Elemental analysis: (as C ₃₈ H ₄₃ N ₄ O ₅ ) Actual: C, 71.51; H, 6.98; N, 8.80 Calculated: C, 71.79; H, 6 .82; N, 8.81

Example 44 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (2-
((4-hydroxy) phenyl) ethyl) ureido)-
2,3,4,5-tetrahydro-1H-1-benzoase
The title compound was obtained by the method of Example 30 using a synthetic compound (I-43; 0.10 mmol) of pin-2-one (I-44) .

Yield 77.0% mp. 128 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.26 (1 H, t, J =
7.2 Hz), 1.44 (9H, s), 1.91 (1H,
m), 2.51 (4H, m), 2.66 (1H, m), 3.
24 (2H, m), 4.52 (1H, m), 4.76 (1
H, d, J = 15.6 Hz), 5.09 (1H, d, J = 1)
5.6 Hz), 5.19 (1H, brs), 6.06
(1H, brs), 6.64 (2H, d, J = 8.1H)
z), 6.83 (3H, t, J = 7.8 Hz), 7.11
(1H, t, J = 7.8 Hz), 7.13-7.19 (6
H, m), 7.46 (1H, d, J = 7.8 Hz) IRνmax (KBr): 3338, 2974, 293
1,1724,1644,1608,1548,151
7 cm ^-1 elemental analysis value: (C ₃₁ H ₃₇ N ₄ O ₅ .0.1 C ₆ H ₁₄ .0.3 H ₂ O
Found) C, 67.73; H, 6.95; N, 9.87 Calculated: C, 67.84; H, 6.99; N, 10.01.

Example 45 1,3-bis- (1- (3-
(Tert-butoxycarbonylamino) benzyl)-
2-oxo-2,3,4,5-tetrahydro-1H-be
Nzo [b] azepin-3-yl) urea (I-45)
Synthesis Example 25 Compound 9 obtained in the second step (0.472 mmol
l) and the isocyanate obtained by the method of Example 32,
The title compound was obtained.

Yield 18.6% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.45 (18H, s),
1.91 (2H, m), 2.31-2.61 (6H, m),
4.37 (2H, m), 4.84 (2H, d, J = 14.8)
Hz), 5.16 (2H, d, J = 15.2 Hz), 6.
15 (2H, brs), 6.75 (2H, d, J = 7.6H)
z), 6.97-7.16 (14H, m), 7.52 (2
(H, brd, J = 7.8 Hz) IRνmax (KBr): 3397, 2931, 172
5,1655,1603,1541Cm ^-1 Elemental _{analysis: (C 45 H 52 N 6} O 7 .0.1C 6 H 14 .0.8H 2 O
Found) C, 67.34; H, 6.85; N, 10.12 Calculated: C, 67.45; H, 6.83; N, 10.35.

Example 46 1- (3- (tert-buto)
Xycarbonylamino) benzyl) -3-((4-cal
Boxy) phenylureido) -2,3,4,5-tetra
Hydro-1H-1-benzazepin-2-one (I-4
Compound 9 obtained in the second step of Synthesis Example 25 (0.183 mol)
l) and references (J. Chem. Soc., Chem. Co.).
mmun. , 82 (1973). )) Was added dropwise to a solution of 4-phenoxycarbonylaminobenzoic acid (0.195 mmol) described in the above) in dimethylformamide (3.0 ml), and the mixture was stirred at room temperature for 18 hours. Ice water and 10% hydrochloric acid were poured into the reaction mixture, and the resulting precipitate was collected by filtration. The residue was subjected to silica gel chromatography (chloroform / methanol = 20/1).
To give the title compound.

Yield 46.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.45 (18H, s),
1.91 (2H, m), 2.31-2.61 (6H, m),
4.37 (2H, m), 4.84 (2H, d, J = 14.8)
Hz), 5.16 (2H, d, J = 15.2 Hz), 6.
15 (2H, brs), 6.75 (2H, d, J = 7.6H)
z), 6.97-7.16 (14H, m), 7.52 (2
(H, brd, J = 7.8 Hz) IRνmax (KBr): 3397, 2931, 172
5,1655,1603,1541Cm ^-1 Elemental _{analysis: (C 45 H 52 N 6} O 7 .0.1C 6 H 14 .0.8H 2 O
Found) C, 67.34; H, 6.85; N, 10.12 Calculated: C, 67.45; H, 6.83; N, 10.35.

Example 47 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3-dimethyl)
Ruureido) -2,3,4,5-tetrahydro-1H-
Synthesis of 1-benzoazepin-2-one (I-47)

[0222]

Embedded image

Example 25 Compound 9 obtained in the second step (0.
To a solution of 524 mol) in acetonitrile (6.0 ml) was added carbonyldiimidazole (1.05 mmol), and the mixture was stirred at room temperature for 1 hour. Ice water was poured into the reaction mixture, and the solvent was distilled off. After extracting twice with ethyl acetate, the organic layer was washed with water and dried (anhydrous magnesium sulfate), and then the solvent was distilled off. A 1M-dimethylamine / tetrahydrofuran solution (0.25 m) was added to the obtained residue (0.251 mmol).
l) was added and the mixture was stirred at room temperature for 18 hours. Acidified with 10% hydrochloric acid and extracted twice with ethyl acetate. After washing with water and drying (anhydrous magnesium sulfate), the solvent was distilled off to obtain the title compound.

Yield 46.2% mp. 197-199 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
2.00 (1H, m), 2.48-2.58 (2H, m),
2.73 (1H, m), 4.53 (1H, m), 4.83
(1H, d, J = 15.3 Hz), 5.19 (1H, d, J =
15.6 Hz), 6.85 (1H, d, J = 7.8H)
z), 6.99 (1H, s), 7.07-7.27 (7
H, m), 7.37 (1H, brd, J = 7.5 Hz) IRνmax (KBr): 3421, 3310, 297
4,2937,1728,1664,1635,160
3,1541Cm ^-1 Elemental _{analysis: (C 25 H 32 N 4} O 4 .0.
3H ₂ O As) Found: C, 65.57; H, 7.17 ; N, 12.25 Calcd: C, 65.57; H, 7.18 ; N, 12.23

Example 48 1- (3-aminobenzyl)
-3- (3-phenylureido) -2,3,4,5-te
Trahydro-1H-1-benzazepin-2-one (I
-48) The title compound was obtained from the synthetic compound (I-25) (0.640 mmol) in the same manner as in Example 23.

Quantitative amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.95 (1 H, m),
2.47-2.68 (3H, m), 4.63 (1H, m),
4.88 (1H, d, J = 15.3 Hz), 5.04 (1
H, d, J = 15.3 Hz), 6.54 (3H, m), 6.
64 (1H, s), 6.90 (1H, m), 7.02 (1
H, t, J = 7.8 Hz), 7.08-7.27 (8H,
m), 7.54 (1H, brs) IRνmax (KBr): 3358, 3058, 294
9,2196,1635,1599,1550cm ^-1

Example 49 1- (3- (methanesulfonate)
Ruminyl) benzyl) -3- (phenylureido)-
2,3,4,5-tetrahydro-1H-1-benzoase
Pin-2-one (I-49) and 1- (3- (bisme
Tansulfonylamino) benzyl) -3- (phenylphenyl)
Raid) -2,3,4,5-tetrahydro-1H-1-
Synthesis of Benzozepin-2-one (I-50)

[0228]

Embedded image

Compound (I-48) (0.199 mmol
0.1 ml of triethylamine was added dropwise to a solution of 1) in dry tetrahydrofuran (3.0 ml), and a solution of methanesulfonyl chloride (0.199 mmol) in tetrahydrofuran (0.31 ml) was added dropwise at -65 ° C.
The mixture was stirred for 0 minutes and heated to -30 ° C. After stirring for 30 minutes, water was added, the mixture was returned to room temperature, acidified with 10% hydrochloric acid, and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was subjected to silica gel chromatography (chloroform / acetone = 8/1).
-5/1) to give the title compound.

(I-49): Yield 57.6% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 2.00 (1H, m),
2.52-2.76 (3H, m), 2.70 (3H, s),
4.63 (1H, brs), 4.83 (1H, d, J = 1
5.6 Hz), 4.83 (1H, d, J = 15.6H)
z), 5.28 (1H, d, J = 15.3 Hz), 6.3
5 (1H, brs), 6.86-7.28 (12H,
m), 7.47 (1H, m), 7.61 (1H, m) IRνmax (KBr): 3384, 2952, 293
0, 1648, 1599, 1547 cm ^-1 Elemental analysis: (C ₂₅ H ₂₇ N ₄ O ₄ S. 0.1 C ₆ H ₁₄ .1.0 H ₂
Found) C, 62.00; H, 5.78; N, 11.4.
4: S, 6.26 Calculated: C, 61.84; H, 5.96; N, 11.2
7; S, 6.45

(I-50): Yield 33.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.88 (1H, m),
2.35-2.55 (3H, m), 3.26 (6H, S),
4.55 (1H, m), 4.82 (1H, d, J = 15.0)
Hz), 5.31 (1H, d, J = 14.4 Hz), 6.
20 (1H, brs), 7.20 (1H, m), 7.17
−7.35 (14H, m) IRνmax (KBr): 3396, 3034, 293
1,1655,1600,1545Cm ^-1 Elementary _{analysis: (C26H 29 N 4 O 6} S 2 .0.2C 6 H 14 .1.0H
₂ O as) Found: C, 55.34; H, 5.47 ; N, 9.48;
S, 10.61 Calculated: C, 55.10; H, 6.21; N, 9.45;
S, 17.67

Example 50 1- (3- (isopropyls)
Ruphonylamino) benzyl) -3- (phenylurei)
Do) -2,3,4,5-tetrahydro-1H-1-ben
0.1 ml of triethylamine and dimethylaminopyridine (0.042 mm) were added to a solution of a compound (I-48) (0.349 mmol) of zoazepin-2-one (I-51) in dry tetrahydrofuran (3.0 ml).
ol) and isopropylsulfonyl chloride to give 4
After heating under reflux for an hour, the mixture was cooled, added with water, made acidic with 10% hydrochloric acid, and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off.
The residue was subjected to silica gel chromatography (chloroform /
Purification by acetone = 15/2) gave the title compound.

Yield 4.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.22-1.30 (6
H, m), 1.94 (1H, m), 2.53-2.65 (3
H, m), 4.53 (1H, m), 4.60 (1H, m),
4.96 (1H, d, J = 15.2 Hz), 5.09 (1
H, d, J = 15.2 Hz), 6.17 (1H, brs),
6.91 (2H, t, J = 7.0 Hz), 7.15-7.
26 (11H, m), 7.63 (1H, m) IRνmax (KBr): 3380, 1645, 159
8,1545 cm ^-1 [M + H] ⁺ = 508

Example 51 1- (3- (3-cyano-2)
-Phenylisoureido) benzyl) -3- (phenyl
Ureido) -2,3,4,5-tetrahydro-1H-1
-Synthesis of benzazepin-2-one (I-52)

[0235]

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Compound (I-48) (0.498 mmol)
l) in dry tetrahydrofuran (3.0 ml) was added to diphenylcyanocarboimidate (J. Heteroc).
ycl. Chem. 19 , 1205 (1982)) (0.546 mmol), and the mixture was stirred at 50 ° C. for 5 days, then cooled and the solvent was distilled off. Silica gel chromatography of the residue (chloroform / acetone = 6/1)
To give the title compound.

Yield: 95.1% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.89 (1 H, m),
2.32-2.61 (1H, m), 4.53 (1H, m),
4.63 (2H, s), 6.43 (1H, d, J = 7.8H)
z), 6.85-7.48 (11H, m), 7.72 (1
H, s), 9.50 (1H, brs) IR νmax (KBr): 3361, 6058, 295
2,2196,1636,1599,1549Cm ^-1 Elemental _{analysis: (C 32 H 28 N 6} O 3 .0.25CHCl 3 .0.
25C ₆ H ₁₄ . 0.75H ₂ O as) Found: C, 66.51; H, 5.48 ; N, 13.90 Calcd: C, 66.50; H, 5.50 ; N, 13.79

Example 52 1- (3- (1-methylthio)
-2-nitro-ethenylamino) benzyl) -3- (f
Enylureido) -2,3,4,5-tetrahydro-1
Synthesis of H-1-benzazepin-2-one (I-53) A solution of compound (I-48) (0.623 mmol) in dry tetrahydrofuran (7.0 ml) was mixed with 1,1-dimercapto-2-nitroethane (Chem. Ber. 100 ,
599 (1967)) (0.763 mmol), and the mixture was stirred at 70 ° C. for 5 days and at 80 ° C. for 2 days, then cooled and the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / acetone = 10/1) to obtain the title compound.

Yield 84.7% mp. 125-127 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.94 (1 H, m),
2.27 (3H, s), 2.48-2.59 (3H, m),
4.57 (1H, m), 4.90 (1H, d, J = 14.4)
Hz), 5.15 (2H, d, J = 15.3 Hz), 6.
19 (1H, brs), 6.63 (1H, s), 7.00
(1H, brs), 7.17-7.34 (12H, m),
11.77 (1H, s) IRνmax (KBr): 3352, 3144, 305
6,2929,1655,1599,1550Cm ^-1 Elemental _{analysis: (C 27 H 27 N 5} O 4 as S) Found: C, 62.76; H, 5.28 ; N, 13.7
3: S, 5.96 Calculated: C, 62.65; H, 5.28; N, 13.5.
3: S, 6.20

Example 53 1- (3- (N′-cyano-)
N ''-methyl) guanidinobenzyl) -3- (phenyl
Ruureido) -2,3,4,5-tetrahydro-1H-
Synthesis of 1-benzazepin-2-one (I-54)

[0241]

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Compound (I-52) (0.127 mmol
l) to a methanol (2.0 ml) solution was added with a 40% methylamine / methanol solution (2.5 ml).
After stirring for 8 hours, the mixture was concentrated. The residue was purified by PTLC (chloroform / methanol = 20/1) to obtain the title compound.

Yield 60.6% mp. 234-236 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.03 (1H, m),
2.51-2.66 (3H, m), 2.77 (3H, d, J
= 4.8 Hz), 4.53 (1H, m), 4.61 (2
H, s), 4.82 (1H, brs), 6.64 (1H,
d, J = 7.8 Hz), 6.92 (2H, t, J = 8.7H)
z), 7.03 (1H, d, J = 7.8 Hz), 7.14
-7.29 (10H, m), 7.86 (1H, s), 8.2
6 (1H, s) IRνmax (KBr): 3339,2953,217
1,1654,1600,1556 cm ^-1 Elemental analysis: (C ₂₇ H ₂₇ N ₇ O ₂ .0.1 C ₃ H ₈ O.0.2 H ₂ O
Found) C, 66.76; H, 5.79; N, 19.78 Calculated: C, 66.91; H, 5.98; N, 19.96.

Example 54 1- (3- (1-methylamido)
No-2-nitroethenyl) aminobenzyl) -3- (f
Enylureido) -2,3,4,5-tetrahydro-1
Synthesis of H-1-benzoazepin-2-one (I-55) A 40% methylamine / methanol solution (3.0 ml) was added to a methanol (2.0 ml) solution of compound (I-53) (0.17 mmol). After stirring at room temperature for 18 hours, the mixture was stirred at 60 ° C. for 6 hours and concentrated. The residue was subjected to silica gel chromatography (chloroform / acetone = 2 /
Purification according to 1) gave the title compound.

Yield 41.0% mp. 235 ° C. (decomposition) ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.00 (1
H, m), 2.55 (1H, m), 2.60 (1H, d, J =
3.6 Hz), 2.81 (2H, m), 4.49 (1H,
m), 4.82 (1H, brs), 5.19 (1H, br)
s), 6.97 (1H, d, J = 6.6 Hz), 7.08
-7.34 (13H, m) IRνmax (KBr): 3324, 3134, 306
7,2952,1698,1647,1600,155
2 cm ^-1 elemental analysis: (as C ₂₇ H ₂₈ N ₆ O ₄ .1.2 H ₂ O) Found: C, 61.93; H, 5.63; N, 16.09 Calculated: C, 62 .10; H, 5.87; N, 16.09

Example 55 1- (3- (N′-cyano-)
N ''-(1-ethylpropyl) guanidino) benzyl
) -3- (phenylthioureido) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one
Synthesis of (I-56) (First Step) 3-Amino-1- (3- (N′-cyano-N ″-(1-ethylpropyl) guanidino) benzyl) -2,3,4,5- Tetrahydro-1H-1-benzazepin-2-one (compound 12)

[0247]

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Compound (I-52) (0.147 mmol)
3-aminopentane (10.0 ml) was added to 1), sealed, stirred at 115 ° C. for 15 hours, and concentrated. The residue was purified by silica gel chromatography (chloroform / methanol = 25/2) to obtain the title compound.

Yield 70.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.86 (1H, td, J =
3.0 Hz, 7.5 Hz), 1.24 (1 H, t, J =
7.2 Hz), 1.37 (2H, m), 1.51 (2H,
m), 1.79 (4H, m), 2.34-2.57 (3H,
m), 3.43 (1H, m), 3.75 (1H, m), 4.
58 (1H, d, J = 8.4 Hz), 4.90 (1H, d, J
= 15.0 Hz), 5.16 (1H, t, J = 15.0H)
z), 7.09-7.37 (10H, m) IR max (KBr): 3421, 3360, 328
1,2963,2932,2874,2172,166
1,1584 cm ^-1 Elemental analysis: (C ₂₄ H ₃₀ N ₆ O. 0.4 C ₆ H ₁₄ .0.8 H ₂ O
Found) C, 68.06; H, 7.84; N, 18.15 Calculated: C, 68.00; H, 7.98; N, 17.89.

(Second step) Compound (I-56)

[0251]

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Compound 12 (0.053 mmol) was added under ice-cooling.
l) in acetonitrile (1.0 ml) was added to a solution of phenylisothiocyanate in acetonitrile (0.15 m
l) was added, and the mixture was stirred at room temperature for 18 hours, then at 60 ° C for 6 hours, and concentrated. The residue was purified by silica gel chromatography (chloroform / acetone = 15/2) to obtain the title compound.

Yield: 78.4% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.83 (6H, t, J =
7.2 Hz), 1.22-1.36 (3H, m), 1.4
9 (2H, m), 1.91 (1H, m), 2.54 (2H,
m), 2.89 (1H, m), 3.71 (1H, m), 4.
47 (1H, d, J = 6.3 Hz), 4.84 (1H, d, J
= 14.7 Hz), 5.01-5.10 (2H, m),
7.12-7.46 (14H, m), 8.02 (1H, b
rs) IRvmax (KBr): 3311, 3058, 296
4,2933,2172,1655,1587,156
0, 1526 cm ^-1 Elemental analysis: (as C ₂₇ H ₂₇ N ₅ O ₄ S. 1.0 H ₂ O) Found: C, 65.04; H, 5.53; N, 17.15 Calculated: C, 65.12; H, 6.40; N, 17.23

Example 56 1- (3- (1- (1-ethyl)
Rupropylamino) -2-nitroethenyl) aminoben
Jill) -3- (phenylthioureido) -2,3,4
5-tetrahydro-1H-1-benzazepin-2-o
Synthesis of (I-57) (First Step) 3-Amino-1- (3- (1- (1-ethylpropylamino) -2-nitroethenyl) aminobenzyl) -2,3,4,5-tetrahydro -1H-1-
Benzoazepin-2-one (Compound 13) The title compound was obtained from compound (I-55) (0.280 mmol) in the same manner as in Example 55, Step 1.

Yield 45.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.88 (6H, br
s), 1.30-1.94 (5H, m), 2.30-2.
50 (3H, m), 3.20 (1H, m), 3.43 (1
H, m), 4.60 (1H, m), 4.89 (1H, d, J =
14.4 Hz), 5.18 (1H, d, J = 14.8H)
z), 6.69 (1H, s), 7.06-7.38 (10
H, m) IRνmax (KBr): 3433,3258,304
9,2965,2934,2876,1663,160
7,1557 cm ^-1 Elemental analysis: (As C ₂₄ H ₃₁ N ₅ O ₃ .1.0 H ₂ O) Found: C, 63.28; H, 7.30; N, 15.37 Calculated: C H, 7.16; N, 15.38.

(Step 2) Compound (I-57) The title compound was obtained from compound 13 (0.107 mmol) obtained in Step 1 by the method of Example 55 Step 2.

Yield: 81.6% Amorphous ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (6H, t, J =
7.5 Hz), 1.45-1.67 (4H, m), 1.9
0-2.04 (1H, m), 2.48-2.60 (3H,
m), 3.73 (1H, brs), 4.90 (1H, m),
4.96 (1H, d, J = 15.0 Hz), 5.23 (1
H, d, J = 15.3 Hz), 5.94 (1H, brs),
7.08-7.40 (11H, m), 7.47 (1H, d,
J = 7.5 Hz), 7.92 (2H, d, J = 7.2H)
z), 9.11 (1H, brs), 9.81 (1H,
s), 10.21 (1H, brs) IRνmax (KBr): 3275, 3058, 296
4,29333,1660,1602,1550Cm ^-1 Elemental _{analysis: (C 31 H 36 N 6} O 3 S.0.3H 2 O as) Found: C, 64.31; H, 6.43 ; N, 14.6
5; S, 6.38 Calculated: C, 64.40; H, 6.38; N, 14.5.
1; S, 6.28

Example 57 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3-benzyl)
Ruthioureido) -2,3,4,5-tetrahydro-1
Synthesis of H-1-benzoazepin-2-one (I-58) Compound 9 (0.1) obtained in the second step of Example 25 was cooled with ice.
57 mmol) of dimethylformamide (1.0 ml)
A solution of phenylisothiocyanate in dimethylformamide (0.46 ml) was added to the solution, and the mixture was stirred at room temperature for 30 minutes, then at 60 ° C for 6 hours, and concentrated. The residue was purified by silica gel chromatography (chloroform / methanol = 50/1) to obtain the title compound.

Yield 92.9% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.89 (1H, s), 2.51-2.81 (3H, m),
4.43-4.52 (1H, m), 4.65 (1H, br)
s), 4.72 (1H, brs), 4.78 (1H, d, J
= 15.6 Hz), 5.12 (1H, d, J = 15.2H)
z), 6.77 (1H, brs), 6.85 (1H, d, J
= 7.8 Hz), 7.12-7.41 (12H, m) IR νmax (KBr): 3335, 3062, 603
1,975,2929,1725,1650,160
4,1535 cm ^-1 Elemental analysis: (as C ₃₀ H ₃₄ N ₄ O ₃ S) Found: C, 67.82; H, 6.62; N, 10.4
2: S, 6.19 Calculated: C, 67.90; H, 6.46; N, 10.5
6; S, 6.04

Example 58 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -7-methoxy-3
-(3-methylureido) -2,3,4,5-tetrahi
Dro-1H-1-benzazepin-2-one (I-5
Synthesis of 9) (first step) 3-azido-1- (3- (tert-butoxycarbonylamino) benzyl) -7-methoxy-
2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (compound 15)

[0261]

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Compound 14 described in WO9216,524
(0.157 mmol) to give the title compound in the same manner as in Example 12.

Yield: 79.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
2.16-2.69 (4H, m), 3.75 (1H, d
d, J = 7.6 Hz, 15.3 Hz), 3.79 (3H,
s), 4.76 (1H, d, J = 14.4 Hz), 5.15
(1H, d, J = 14.4 Hz), 6.44 (1H, br
s), 6.67 (1H, d, J = 2.8 Hz), 6.78.
(1H, dd, J = 3.0 Hz, 8.8 Hz), 6.86
(1H, td, J = 1.2Hz, 7.7Hz), 7.10
(1H, d, J = 8.8 Hz), 7.13 (1H, m),
7.17 (1H, t, J = 7.8 Hz), 7.40 (1H,
m) IRνmax (KBr): 3412, 2975, 293
3,2108,1726,1668,1610,153
9 cm ^-1 Elemental analysis: (as C ₂₃ H ₂₇ N ₅ O ₄ ) Found: C, 63.05; H, 6.33; N, 15.78 Calculated: C, 63.14; H, 6 .22; N, 16.01

(Second step) Compound (I-59)

[0265]

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From compound 15 obtained in the first step to Example 24
An amine compound was obtained in the same manner as in the second step. The amine compound (0.328 mmol) in methylene chloride (8.0 m
l) Add methyl isocyanate (0.613 mmol
1) methylene chloride (2.0 ml) solution was added dropwise,
Stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture was recrystallized from methylene chloride-ether and filtered to obtain 95 mg of the title compound. The mother liquor was purified by silica gel chromatography (ethyl acetate / methylene chloride = 7/3). To give 26 mg of the title compound (121 total).
mg).

Yield 78.6% mp. 209-210 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s),
1.94 (1H, dt, J = 7.4, 11.1 Hz);
36-2.82 (3H, m), 2.61 (3H, s), 3.
79 (3H, s), 4.55 (1H, m), 4.72 (1
H, brs), 4.76 (1H, d, J = 15.2 Hz),
5.18 (1H, d, J = 15.2 Hz), 5.95 (1
H, brs), 6.71 (1H, s), 6.73 (1H, d
d, J = 2.8 Hz, 8.6 Hz), 6.86 (1H, b
rd, J = 7.8 Hz), 7.00 (1H, dd, J =
1.8Hz, 7.2Hz), 7.13 (1H, m), 7.
17 (1H, brs), 7.23 (1H, t, J = 7.8 Hz), 7.5
9 (1H, brd, J = 7.8 Hz) IRνmax (KBr): 3403, 2967, 293
6,1726,1671,1641,1612,159
3,1549 cm ^-1 Elemental analysis: (As C ₂₅ H ₃₂ N ₄ O ₅ .0.2 H ₂ O) Found: C, 63.62; H, 6.97; N, 12.07 Calculated: C , 63.60; H, 6.92; N, 11.87.

Example 59 1- (3- (tert-buto)
Xycarbonylamino) benzyl) -3-((thiazo-
Ru-2yl) guanidino) -2,3,4,5-tetrahi
Dro-1H- [1] benzazepin-2-one (I-6
Synthesis of 0) (First Step) Hydrogen iodide of 3- (thiazol-2-yl) -2-methylisothiourea (Compound 17)

[0269]

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References (J. Prakt. Chem., 31)
3 , 1148 (1971). ) Described in Compound 16 (1.
To a suspension of 25 mmol) in ethanol (5.0 ml) was added methyl iodide (1.88 mmol), and the mixture was heated under reflux for 1 hour and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / n-hexane).
The title compound was obtained. Yield 88.8% ¹ H-NMR (CD ₃ OD) δ: 2.50 (3H, s),
6.84 (1H, d, J = 3.8 Hz), 7.38 (1H,
d, J = 4.0 Hz)

(Second Step) Compound (I-60)

[0272]

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Example 25 Compound 9 obtained in the second step (0.
786 mmol) and the compound 17 obtained in the first step (1.1
1 mmol), 2-propanol (12 ml) was added, the mixture was heated under reflux for 11 days, and then concentrated. The residue was purified by PTLC (chloroform / methanol = 5/1) to obtain the title compound.

Yield 4.0% mp. 124 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H, s),
2.01 (1H, m), 2.52-2.72 (3H, m),
2.77 (1H, m), 4.86 (1H, d, J = 15.3)
Hz), 5.13 (1H, d, J = 15.3 Hz), 5.
94 (1H, brs), 6.57 (1H, d, J = 3.9H)
z), 6.63 (1H, s), 6.89 (2H, d, J =
7.2 Hz), 6.96 (1H, brs), 7.14-
7.29 (7H, m), 7.37 (1H, d, J = 8.4H
z) IRνmax (KBr): 3398, 2976, 172
4,165,1612,1541 cm ^-1 Elemental analysis: (as C ₂₆ H ₃₀ N ₆ O ₃ S. 0.2H ₂ O) Found: C, 61.26; H, 6.18; 3
3: S, 6.38 Calculated: C, 61.20; H, 6.01; N, 16.4.
7; S, 6.28

Example 60 3-amino-5- (3- (t
tert-butoxycarbonylamino) benzyl) -2,
3,4,5-tetrahydro-1,5-benzothiazepine
Synthesis of 4-one (I-61) (first step) 3- (3-phenylureido) -2,
3,4,5-tetrahydro-1,5-benzothiazepin-4-one (compound 19)

[0276]

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Compound 18 described in WO9401421
(0.365 mmol) to give the title compound in the same manner as in the third step of Example 24.

Yield 65.6% mp. 233 ° C. (decomposition) ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.73 (3
H, brs), 2.95 (1H, t, J = 10.2 Hz),
3.85 (1H, dd, J = 6.6Hz, 11.0H
z), 4.69 (1H, m), 6.23 (1H, m), 6.
96-7.38 (10H, m), 7.65 (1H, d, J =
6.2 Hz) IRνmax (KBr): 3348, 3315, 326
0, 3190, 3041, 2961, 1676 cm ^-1 Elemental analysis: (C ₁₆ H ₁₅ N ₃ O ₂ S. 0.1 H ₂ O) Found: C, 61.16; H, 4.86; N, 13.4
1; S, 9.93 Calculated: C, 60.97; H, 4.86; N, 13.3.
3: S, 10.17

(Second Step) Compound (I-61)

[0280]

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The compound 19 obtained in the first step (0.239m
mol) in the same manner as in Example 1, Step 2, to give the title compound.

Yield 55.5% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
2.92 (1H, t, J = 11.5 Hz), 3.79 (1
H, dd, J = 6.8, 11.2 Hz), 4.79 (2
H, m), 4.89 (1H, d, J = 15.6 Hz), 5.
26 (1H, d, J = 16.2 Hz), 6.65 (2H, b
rs), 6.95 (2H, m), 7.08-7.26 (8
H, m), 7.30-7.45 (2H, m), 7.46 (1
(H, d, J = 7.8 Hz) IRνmax (KBr): 3373, 2976, 292
8,1652,1600,1549Cm ^-1 Elemental _{analysis: (C 26 H 34 N 4} O 6 S.0.1C 6 as H ₁₄₎ Found: C, 65.22; H, 6.14 ; N, 10 .6
9; S, 6.01 Calculated: C, 65.15; H, 6.00; N, 10.6
3: S, 6.08

Example 61 (S) -5- (3- (ter)
t-butoxycarbonylamino) benzyl) -3- (3
-Phenylureido) -2,3,4,5-tetrahydro
Of 1,5-benzothiazepin-4-one (I-62)
Synthesis (First Step) (S) -3-Amino-5- (3- (te
rt-butoxycarbonylamino) benzyl) -2,
3,4,5-tetrahydro-1,5- [5] benzothiazepin-4-one (compound 21)

[0284]

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References (Chem. Pharm. Bul)
l. , 34 , 1128 (1986). Compound 2 described in
After N-alkylation from 0 (0.43 mmol) in the same manner as in Example 12, deprotection was conducted in the same manner as in Example 3, Step 3, to obtain the title compound.

Yield 80.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.80 (2H, brs), 2.80-2.94 (1H,
m), 3.52-3.66 (2H, m), 5.06 (2H,
s), 6.47 (1 h, brs), 6.95 (1 H, d, J
= 7.4 Hz), 7.12 (6H, m), 7.58 (1
(H, dd, J = 1.6 Hz, 7.4 Hz) IRνmax (KBr): 3351, 2974, 292
7,1723,1662,1610,1544Cm ^-1 Elemental _{analysis: (C 26 H 34 N 4} O 6 S.0.2C 3 H 8 O.0.3H 2 O
Found) C, 62.62; H, 6.62; N, 10.2
5; S, 7.64 Calculated: C, 62.38; H, 6.63; N, 10.0
1; S, 7.57

(Step 2) Compound (I-62)

[0288]

Embedded image

The compound 21 obtained in the first step (0.133m
mol), to give the title compound in the same manner as in Example 24, Step 3.

Yield 94.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
2.91 (1H, t, J = 11.4 Hz), 3.82 (1
H, dd, J = 6.6, 11.4 Hz), 4.80 (2
H, m), 5.31 (1H, d, J = 15.9 Hz), 6.
60 (1H, brs), 6.68 (1H, s), 6.93
(1H, brs), 6.94 (2H, d, J = 7.5H)
z), 7.03 (2H, t, J = 7.5 Hz), 7.10
(1H, t, J = 6.9 Hz), 7.19-7.26 (4
H, m), 7.35 (1H, t, J = 6.6 Hz), 7.4
7 (1H, brd, J = 8.1 Hz), 7.64 (1H,
d, J = 7.2 Hz) IRνmax (KBr): 3377, 2976, 292
7,1652,1600Cm ^-1 Elemental _{analysis: (C 26 H 34 N 4} O 6 S.0.1C 6 as H ₁₄₎ Found: C, 65.19; H, 6.12 ; N, 10.7
1; S, 5.89 Calculated: C, 65.15; H, 6.00; N, 10.6
3: S, 6.08

Example 62 1- (3- (tert-butyl)
Ruacetylamino) benzyl) -3- (2- (N-nitro
Loganidino) acetylamino) -2,3,4,5-te
Trahydro-1H-1-benzazepin-2-one (I
-63) (First step) 3-Amino-1- (3- (tert-butylacetylamino) benzyl) -2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (compound 22) Compound 5 (0.717 mmol) was N-alkylated in the same manner as in Example 12, and then reduced in the manner of Example 15 to obtain the title compound.

Yield: 88.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s),
1.87 (1H, s), 2.07 (2H, brs), 2.
28-2.47 (2H, m), 2.58 (1H, m), 3.
45 (1H, m), 4.91 (1H, d, J = 14.7H)
z), 5.08 (1H, d, J = 14.7 Hz), 6.9
0 (1H, d, J = 8.1 Hz), 7.13-7.35
(7H, m), 7.56 (1H, d, J = 8.4 Hz) IRνmax (KBr): 3430, 3002, 295
2,2924,2858,1727,1660,159
8,1526 cm ^-1

(Second Step) Compound (I-63)

[0294]

Embedded image

The compound 22 obtained in the first step (0.630 m
mol), literature (Can. J. Chem., 36 , 14).
36 (1958)) (0.727 mm)
ol), WSCD (0.727 mmol) and 1-hydroxybenzotriazole (0.727 mmol) were added with dry tetrahydrofuran (8 ml), and triethylamine (0.5 ml) was added dropwise under ice-cooling, followed by stirring at room temperature for 18 hours. . The reaction mixture was poured into ice water, neutralized with 10% hydrochloric acid, and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / acetone = 2/1) to obtain the title compound.

Yield 27.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.01 (9H, s),
2.17 (2H, d, J = 3.0 Hz), 4.02 (2H, d, J = 3.0 Hz)
brs), 4.42 (1H, brs), 4.92 (2H,
brs), 6.78 (1H, brd, J = 5.0 Hz),
8.7 Hz), 7.08-7.37 (7H, m), 7.6
3 (1H, brs), 8.33 (1H, brs) IRνmax (KBr): 3326, 2954, 286
7, 1655, 1601, 1542 cm ^-1 elemental analysis: (C ₂₈ H ₃₃ N ₇ O ₅ .0.15 C ₆ H ₁₄ .0.5H ₂
Found: C, 59.35; H, 6.76; N, 17.91 Calculated: C, 59.23; H, 6.67; N, 17.97 [M + H] ⁺ = 479.

Example 63 1-((4-benzyloxy)
B) benzyl) -3- (2- (N-nitroguanidino)
(Acetylamino) -2,3,4,5-tetrahydro-1
Synthesis of H-1-benzazepin-2-one (I-64) (first step) 3-Amino-1-((4-benzyloxy) benzyl) -2,3,4,5-tetrahydro-1H
-1-benzazepin-2-one (compound 23) After N-alkylation from compound 5 (0.296 mmol) by the same method as in Example 12, reduction by the same method as in the second step of Example 24 was carried out. The title compound was obtained.

Yield 90.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.61 (2H, br)
s), 1.82 (1H, m), 2.24-2.48 (3
H, m), 3.37 (1H, m), 4.74 (1H, d, J =
14.4 Hz), 5.00 (2H, s), 5.26 (1
H, d, J = 14.4 Hz), 6.84 (2H, d, J = 8.
4Hz), 7.13-7.41 (11H, m) IRνmax (KBr): 3016, 3006, 165
4,1601,1508cm ^-1

(Step 2) Compound (I-64) The title compound was obtained from compound 23 (0.720 mmol) obtained in Step 1 by the same method as in Step 2 of Example 62.

Yield 20.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 2.03 (1 H, m),
2.42 (3H, m), 3.99 (2H, m), 4.36
(1H, m), 4.71 (1H, d, J = 14.4 Hz),
4.96 (1H, s), 5.18 (1H, d, J = 14.8)
Hz), 6.71 (2H, d, J = 7.0 Hz), 7.0
6-7.38 (11H, m), 7.74 (2H, brs) IRνmax (KBr): 3399, 3329, 164
8,1510 cm ^-1 Elemental analysis: (as C ₂₇ H ₂₈ N ₆ O ₅ ) Found: C, 63.75; H, 6.38; N, 14.74 Calculated: C, 63.77; H , 3.35; N, 14.87.

Example 64 1- (3- (tert-butyl)
Ruacetylamino) benzyl) -3-((2-guanidinium
No) acetylamino) -2,3,4,5-tetrahydro
Of -1H-1-benzazepin-2-one (I-65)
To a 10% acetic acid / methanol solution (4.4 ml) of the synthetic compound (I-63) (0.115 mmol) was added 10% palladium-carbon (16 mg), and the mixture was stirred in a hydrogen atmosphere for 13 hours. The solvent was distilled off. PTLC residue
(Chloroform / methanol / NH ₄ OH = 60/10 //
Purification in 1) gave the title compound.

Yield 36.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.05 (9H, s),
1.90 (3H, s), 2.20 (2H, s), 2.05-
2.76 (4H, m), 3.95 (2H, d, J = 2.0H)
z), 4.37 (1H, m), 4.81 (1H, d, J = 1
5.0 Hz), 5.31 (1H, d, J = 14.8H)
z), 6.96 (1H, d, J = 8.4 Hz), 7.14
-7.48 (9H, m) IR max (KBr): 3330, 2955, 165
7,1600,1551 cm ^-1 Elemental analysis: (C ₂₆ H ₂₇ N ₃ O ₃ .0.1 C ₆ H ₁₄ .0.3 CH
Cl ₃ . (As 1.8 H ₂ O) Found: C, 56.47; H, 6.79; N, 13.35 Calculated: C, 56.40; H, 7.09; N, 13.65

Example 65 1-((4-benzyloxy)
B) benzyl) -3-((2-guanidino) acetyla
Mino) -2,3,4,5-tetrahydro-1H-1-be
The title compound was obtained from the synthetic compound (I-64) ( 0.140 mmol) of nzazepin-2-one (I-66) in the same manner as in Example 64.

Yield 33.7% Amorphous ¹ H-NMR (CD ₃ OD) δ: 1.92 (3H, s),
2.02-2.51 (4H, m), 3.94 (1H, d, J
= 1.8 Hz), 4.33 (1H, dd, J = 7.6H)
z, 11.6 Hz), 4.67 (1H, d, J = 14.6)
Hz), 5.26 (1H, d, J = 14.4 Hz), 6.
63 (1H, d, J = 8.2 Hz), 7.01 (2H, d, J
= 8.6 Hz), 7.20 (2H, m), 7.36 (2
H, m) IRνmax (KBr): 3373, 1654, 160
1,1552,1515Cm ^-1 Elemental _{analysis: (C 20 H 23 N 5} O 3 .C 2 H 4 O 2 .1.3H 2 O as) Found: C, 56.88; H, 6.15 ; N, 15.10 Calculated: C, 56.84; H, 6.42; N, 15.06.

Example 25 The compounds of Examples 66 to 70 were obtained from the compound 9 obtained in the second step and various carboxylic acid compounds in the same manner as in the second step of Example 62.

Example 66 3- (2- (benzyloxy)
Carbonylaminoacetylamino) -1- (3- (te
rt-butoxycarbonylamino) benzyl) -2,
3,4,5-tetrahydro-1H-1-benzazepine
Synthesis yield of -2-one (I-67): 88.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
1.80-1.96 (1H, m), 2.45-2.67
(1H, m), 3.87 (2H, t, J = 5.2Hz),
4.46-4.58 (1H, m), 4.91 (1H, d, J
= 14.8 Hz), 5.06 (1H, d, J = 14.8H)
5. z), 5.13 (2H, s), 6.55 (1H, s),
82-6.94 (2H, m), 7.14-7.41 (12
H, m) IRνmax (KBr): 3018, 3008, 172
1,1654,1601,1520,1504Cm ^-1 Elemental _{analysis: (C 32 H 36 N 4} O 6 .0.4C 6 H 14 .0.2H 2 O
Found) C, 67.53; H, 7.01; N, 9.18 Calculated: C, 67.65; H, 6.93; N, 9.17

Example 67 3- (3- (benzyloxy)
Carbonylamino) propionylamino) -1- (3-
(Tert-butoxycarbonylamino) benzyl)-
2,3,4,5-tetrahydro-1H-1-benzoase
Synthesis yield of pin-2-one (I-68) 61.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
1.85-1.97 (1H, m), 2.39-2.67
(5H, m), 3.41-3.47 (2H, m), 4.47
-4.55 (1H, m), 4.96 (1H, t, J = 15.
0 Hz), 5.03 (1H, d, J = 15.3 Hz),
5.07 (2H, s), 5.48 (1H, m), 6.50
(1H, t, J = 7.5 Hz), 7.13-7.42 (1
2H, m) IRνmax (KBr): 3325, 2974, 165
2,1652,1603,1540Cm ^-1 Elemental _{analysis: (C 33 H 38 N 4} O 6 .0.05C 6 as H ₁₄₎ Found: C, 67.52; H, 6.88 ; N, 9. 32 Calculated: C, 67.47; H, 6.61; N, 9.45.

Example 68 3- (4- (benzyloxy)
Carbonylamino) butyrylamino) -1- (3- (t
tert-butoxycarbonylamino) benzyl) -2,
3,4,5-tetrahydro-1H-1-benzazepine
80.0% synthesis yield of 2-one (I-69) amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
1.78-1.98 (3H, m), 2.25 (2H, t, J
= 7.2 Hz), 2.44-2.72 (3H, m), 3.
19-3.25 (2H, m), 4.48-4.57 (1
H, m), 4.99 (2H, s), 5.08 (2H, s),
5.08 (2H, s), 6.60 (1H, brs), 6.
64 (1H, brs), 6.85 (1H, d, J = 7.8H)
z), 7.11-7.44 (12H, m) IRνmax (KBr): 3438, 3028, 301
0, 2978, 2932, 1720, 1649, 160
6,1522Cm ^-1 Elemental _{analysis: (C 34 H 40 N 4} O 6 .0.3C 6 H 14 .0.2H 2 O
Found) C, 68.30; H, 7.36; N, 8.66 Calculated: C, 68.23; H, 7.13; N, 8.89

Example 69 3- (5- (benzyloxy)
Carbonylamino) pentanoylamino) -1- (3-
(Tert-butoxycarbonylamino) benzyl)-
2,3,4,5-tetrahydro-1H-1-benzoase
Synthesis yield of pin-2-one (I-70) 93.3% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49-1.55 (1
1H, m), 1.62 (2H, m), 1.89 (1H, m),
2.20 (1H, t, J = 7.0 Hz), 2.44-.
2.70 (3H, m), 3.14-3.20 (2H, m),
4.48-4.56 (1H, m), 4.95 (1H, d, J
= 15.3 Hz), 5.03 (1H, d, J = 15.3H)
z), 5.08 (1H, s), 6.53 (1H, br)
s), 6.70 (1H, brs), 7.13-7.42
(12H, m) IRνmax (KBr): 3321, 933, 286
7,1701,1651,1603,1541Cm ^-1 Elemental _{analysis: (C 35 H 42 N 4} O 6 .0.2C 6 H 14 .0.1H 2 O
Found) C, 68.65; H, 7.40; N, 8.74 Calculated: C, 68.60; H, 7.16; N, 8.84

Example 70 3- (6- (benzyloxy)
Carbonylamino) hexanoylamino) -1- (3-
(Tert-butoxycarbonylamino) benzyl)-
2,3,4,5-tetrahydro-1H-1-benzoase
Synthesis yield of pin-2-one (I-71) 76.8% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.28-1.37 (2
H, m), 1.46-1.50 (11H, m), 1.57-
1.64 (2H, m), 1.84-1.93 (1H, m),
2.15-2.20 (2H, m), 2.44-2.66
(3H, m), 3.16 (2H, q, J = 6.6 Hz),
4.49-4.57 (1H, m), 4.91 (1H, d, J
= 14.7 Hz), 4.92 (1H, brs), 5.0
4 (1H, d, J = 14.7 Hz), 5.08 (2H,
s), 6.45 (1H, t, J = 7.2 Hz), 6.62.
(1H, brs), 6.83 (1H, d, J = 7.8H)
z), 7.12-7.42 (12H, m) IR max (KBr): 3323, 2933, 286
3,1704,1651,1603,1540Cm ^-1 Elemental _{analysis: (C 36 H 44 N 4} O 6 .0.25C 6 H 14 .0.1H 2
Found: C, 69.15; H, 7.61; N, 8.48 Calculated: C, 69.06; H, 7.37; N, 8.59.

Example 71 3- (2-acetylthio-3)
-Phenylpropionylamino) -1- (3- (ter
t-butoxycarbonylamino) benzyl) -2,3
4,5-tetrahydro-1H-1-benzazepine-2
Synthesis of -one (I-72)

[0312]

Embedded image

Example 25 Compound 9 obtained in the second step (0.
262 mmol) and the carboxylic acid compound (0.068 mmol) described in JP-A-7-165722 by the same method as in the second step of Example 62 to give the title compound.

Yield 29.9% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.26 (1 H, m),
1.49 (9H, s), 2.33 (3H, d, J = 8.4H
z), 2.38-2.70 (3H, m), 2.95 (1
H, m), 3.26 (1H, m), 4.20 (1H, m),
4.43 (1H, m), 4.89 (1H, d, J = 15.0)
Hz), 5.04 (1H, d, J = 15.3 Hz), 6.
16 (1H, brs), 6.83 (1H, m), 6.90
(1H, brd, J = 6.6 Hz), 7.07-7.24
(11H, m), 7.45 (1H, brd, J = 7.2H
z) IRνmax (KBr): 3351, 2975, 293
1,1726,1689,1658,1605,153
4cm ^-1

Example 72 3-acetylamino-1-
(3- (tert-butoxycarbonylamino) benzyl
Ru) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis of zoazepin-2-one (I-73) Compound 9 obtained in the second step of Example 25 (0.2
Triethylamine (0.1 ml) and acetyl chloride (0.703 mmol) were added to a solution of 20 mmol) in tetrahydrofuran (2.0 ml), and the mixture was stirred at room temperature for 15 hours. Water and 10% hydrochloric acid were added, and the mixture was extracted twice with ethyl acetate. did. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (ethyl acetate / n-hexane = 60/1) to obtain the title compound.

Yield 93.5% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.86-1.95 (1H, m), 1.98 (3H, s),
2.46-2.69 (3H, m), 4.48-4.57
(1H, m), 4.95 (1H, d, J = 14.7 Hz),
5.05 (1H, d, J = 15.3 Hz), 6.49 (2
H, m), 6.86 (1H, d, J = 7.8 Hz), 7.1
6-7.25 (5H, m), 7.38 (1H, d, J = 6.
9 Hz) IRνmax (KBr): 3319, 3074, 297
5,2931,2867,1725,1651,160
5,1544 cm ^-1 elemental analysis: (C ₂₉ H ₃₈ N ₄ O ₄ .0.2 C ₆ H ₁₄ .0.4 H ₂ O
Found) C, 67.53; H, 8.10; N, 10.84 Calculated: C, 67.57; H, 7.34; N, 9.38.

Example 73 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3-carbo
(Methoxyamino) -2,3,4,5-tetrahydro-1
Synthesis of H-1-benzazepin-2-one (I-74)

[0318]

Embedded image

Example 25 Compound 9 obtained in the second step (0.
131 mmol) in ethyl acetate (3.0 ml), potassium carbonate (0.39 mmol) and water (1.5 ml) were added, and under ice-cooling, methyl chlorocarbonate (0.39 mmol) was added.
l) was added and the mixture was stirred at room temperature for 15 hours, and then added with water and 10% hydrochloric acid, and extracted twice with ethyl acetate. Wash the organic layer with water,
After drying (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 40/1) to obtain the title compound.

Yield 93.8% mp. 183-184 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
1.96 (1H, m), 2.46-2.69 (1H, m),
3.36 (1H, s), 4.32 (1H, m), 5.00
(2H, s), 5.66 (1H, brd, J = 7.8H
z), 6.66 (1H, s), 6.85 (1H, brd, J
= 7.5 Hz), 7.12-7.22 (2H, m), 7.
45 (1H, d, J = 8.4 Hz) IRνmax (KBr): 3347, 3386, 295
₃ , 1712, 1651, 1612, 1546 cm ^-1 Elemental analysis: (as C ₂₄ H ₂₉ N ₃ O ₅ .0.15 H ₂ O) Found: C, 65.19; H, 6.74; N, 9 .54 calc: C, 65.19; H, 6.68; N, 9.50

Example 74 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (2-merca
Pt-3-phenylpropionylamino) -2,3.
4,5-tetrahydro-1H-1-benzazepine-2
Synthetic compound (I-72) (0.068 mmol) of -one (I-75) was added to degassed ethanol (5.0 ml) and degassed 1N aqueous sodium hydroxide solution (0.4 ml), and the mixture was stirred at room temperature. For 6 hours. After neutralizing with 10% hydrochloric acid and concentrating, the resulting precipitate was collected by filtration and washed with n-hexane. Purification by PTLC (chloroform / acetone = 80/1) gave the title compound.

Yield: 59.2% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.63 (1H, m), 1.98 (1H, m), 2.40-
2.65 (3H, m), 3.09 (2H, m), 3.50
(1H, m), 4.44 (1H, m), 4.91 (1H, d
d, J = 4.2, 15.0 Hz), 5.06 (1H, d, J
= 15.0 Hz), 6.56 (1H, brs), 6.8
3 (1H, d, J = 7.8 Hz), 6.91 (1H, br
s), 7.12-7.27 (13H, m), 7.40 (1
(H, d, J = 8.1 Hz) IRνmax (KBr): 3324, 2977, 293
^1, 1725, 1652, 1604, 1533 cm ^-1 Elemental analysis: (C ₃₁ H ₃₅ N ₃ O ₄ S. 0.1 H ₂ O) Found: C, 67.44; H, 6.57; N, 7.67;
S, 5.88 Calculated: C, 67.34; H, 6.53; N, 7.60;
S, 5.80

Example 75 3- (3-acetylamino-
Propionylamino) -1- (3- (tert-butoki)
(Cyclocarbonylamino) benzyl) -2,3,4,5-te
Trahydro-1H-1-benzazepin-2-one (I
-76) (First Step) 3- (3-Amino-propionylamino) -1- (3- (tert-butoxycarbonylamino) benzyl) -2,3,4,5-tetrahydro-1H
-1-Benzazepin-2-one (compound 24) The title compound was obtained from compound (I-68) in the same manner as in Example 15.

Yield Quantitative amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s),
2.28-2.41 (4H, m), 2.70-2.75
(1H, m), 3.13-3.22 (1H, m), 3.38
(2H, m), 4.36-4.44 (1H, m), 4.50
(1H, d, J = 14.4 Hz), 5.16 (1H, d, J =
14.1 Hz), 6.50 (1H, d, J = 7.5H)
z), 6.88 (1H, d, J = 7.5 Hz), 7.07
−7.24 (7H, m), 7.65 (1H, d, J = 8.1)
Hz), 7.85 (1H, brs), 4.50 (1H,
d, J = 14.4 Hz), 8.48 (1H, d, J = 6.6)
Hz) IRνmax (KBr): 3254, 1721, 165
3,1609,1543Cm ^-1 Elemental _{analysis: (C 24 H 30 N 4} O 4 .0.25CHCl 3 .1.
0H ₂ O as) Found: C, 60.52; H, 7.09 ; N, 11.06 Calcd: C, 60.61; H, 6.90 ; N, 11.20

(Step 2) Compound (I-76) The title compound was obtained from the compound (0.177 mmol) obtained in Step 1 by the same method as in Step 2 of Example 62. Yield 65.6% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.63 (1H, m), 1.98 (1H, m), 2.40-
2.65 (3H, m), 3.09 (2H, m), 3.50
(1H, m), 4.44 (1H, m), 4.91 (1H, d
d, J = 4.2, 15.0 Hz), 5.06 (1H, d, J
= 15.0 Hz), 6.56 (1H, brs), 6.8
3 (1H, d, J = 7.8 Hz), 6.91 (1H, br
s), 7.12-7.27 (13H, m), 7.40 (1
(H, d, J = 8.1 Hz) IRνmax (KBr): 3324, 2977, 293
^1, 1725, 1652, 1604, 1533 cm ^-1 Elemental analysis: (C ₃₁ H ₃₅ N ₃ O ₄ S. 0.1 H ₂ O) Found: C, 67.44; H, 6.57; N, 7.67;
S, 5.88 Calculated: C, 67.34; H, 6.53; N, 7.60;
S, 5.80

Example 76 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (3-
Methanesulfonylamino) propionylamino) -2,
3,4,5-tetrahydro-1H-1-benzazepine
Synthesis of 2-one (I-77) Compound 24 obtained in the first step of Example 75 (0.
177 mmol) in tetrahydrofuran (2.0 ml)
A solution of mesyl chloride (0.21 mmol) in tetrahydrofuran (1.0 ml) was added to the solution, and the solution was heated at that temperature for 30 minutes.
Stirred for minutes. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was subjected to silica gel chromatography (chloroform / n-hexane = 10 /
Purification according to 1) gave the title compound.

Yield: 76.7% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.94-2.04 (1H, m), 2.43-2.58
(4H, m), 3.25-3.47 (2H, m), 4.47
-4.57 (1H, m), 4.95 (1H, d, J = 15.
0 Hz), 5.04 (1H, d, J = 15.0 Hz),
5.85 (1H, brt, J = 6.5 Hz), 6.71 (2
H, m), 6.84 (1H, d, J = 6.6 Hz), 7.1
4-7.29 (6H, m), 7.42 (1H, brd, J =
7.8 Hz) IRνmax (KBr): 3346, 2975, 293
1,1643,1603,1541Cm ^-1 Elemental _{analysis: (C 26 H 34 N 4} O 6 S.0.15C 6 H 14 .0.2C
HCl ₃ . (As 0.3 H ₂ O) Found: C, 56.81; H, 6.58; N, 9.56;
S, 5.66 Calculated: C, 56.82; H, 6.49; N, 9.78;
S, 5.60

Example 75 The compounds of Examples 77 to 80 were obtained from compound 24 obtained in the first step by using various substituted isocyanates in the same manner as in the third step of Example 24.

Example 77 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (3-
Methylureido) propionylamino) -2,3,4
5-tetrahydro-1H-1-benzazepin-2-o
Emissions synthesis yield 69.8% amorphous ¹ H-NMR (CDCl ₃₎ of (I-78) δ: 1.49 (9H, s),
1.91-2.07 (1H, m), 2.35-2.57
(4H, m), 2.67 (3H, d, J = 4.8 Hz),
2.66-2.74 (1H, m), 3.26-3.36
(1H, m), 3.51-3.61 (1H, m), 4.48
-4.56 (1H, m), 4.87 (1H, d, J = 15.
0 Hz), 5.11 (1H, d, J = 15.3 Hz),
6.85 (1H, d, J = 7.5 Hz), 6.98 (2H,
brs), 7.11-7.23 (6H, m), 7.43.
(1H, d, J = 8.1 Hz) IRνmax (KBr): 3392, 2932, 172
2,1648,1603,1547Cm ^-1 Elemental _{analysis: (C 27 H 35 N 5} O 5 .0.2C 6 H 14 .0.3H 2 O
As) Found: C, 63.70; H, 7.38; N, 13.03 Calculated: C, 63.72; H, 7.15; N, 13.18

Example 78 3- (3- (3-benzyl)
Reid) propionylamino) -1- (3- (tert)
-Butoxycarbonylamino) benzyl) -2,3.
4,5-tetrahydro-1H-1-benzazepine-2
-Yone (I-79) synthesis yield 77.5% mp. 108-120 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s),
1.92 (1H, m), 2.35-2.71 (5H, m),
3.31 (1H, m), 3.59 (1H, m), 4.33
(2H, d, J = 5.8Hz), 4.49 (1H, m),
4.86 (1H, d, J = 15.2 Hz), 5.09 (1
H, d, J = 15.6 Hz), 5.15 (1H, brs),
5.42 (1H, brt, J = 6.0 Hz), 6.60 (1
H, brs), 6.78-6.84 (2H, m), 7.1.
4-7.28 (10H, m) IR max (KBr): 3330, 2975, 293
0,1723,1648,1603,1546Cm ^-1 Elemental _{analysis: (C 33 H 39 N 5} O 5 .0.2C 6 H 14 .0.8H 2 O
Found) C, 66.57; H, 7.09; N, 11.18 Calculated: C, 66.54; H, 7.09; N, 11.34.

Example 79 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (3-
Propylureido) propionylamino) -2,3
4,5-tetrahydro-1H-1-benzazepine-2
Synthesis yield of -one (I-80) 79.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, t, J =
7.2 Hz), 1.43 (2H, q, J = 7.2 Hz),
1.49 (9H, s), 1.95 (1H, m), 2.35-
2.73 (5H, m), 3.01 (1H, d, J = 7.0H
z), 3.07 (1H, d, J = 6.8 Hz), 3.31
(1H, m), 3.53 (1H, m), 4.45-4.58
(1H, m), 4.88 (1H, d, J = 15.6 Hz),
5.10 (1H, d, J = 15.2 Hz), 5.36 (1
H, brs), 6.85 (1H, d, J = 7.4 Hz),
6.95 (1H, brs), 7.10-7.24 (6H,
m), 7.43 (1H, d, J = 8.2 Hz) IRνmax (KBr): 3337, 2963, 293
2,2872,1724,1648,1603,154
8 cm ^-1 elemental analysis value: (C ₂₉ H ₃₉ N ₅ O ₅ .0.1 C ₆ H ₁₄ .0.1 H ₂ O
Found) C, 64.82; H, 7.59; N, 12.78 Calculated: C, 64.78; H, 7.47; N, 12.78

Example 80 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (3-
(2-((4-benzyloxy) phenyl) ethyl) u
Reid) propionylamino) -2,3,4,5-tetra
Lahydro-1H-1-benzazepin-2-one (I-
81) Synthesis yield of 78.7% amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s),
1.96 (1H, m), 2.36 (2H, m), 2.47
(1H, d, J = 7.5 Hz), 2.53 (1H, d, J =
7.5Hz), 2.68 (3H, t, J = 6.9Hz),
3.32 (2H, m), 3.55 (1H, m), 4.51
(1H, m), 4.69 (1H, brs), 6.60 (1
H, brs), 6.81-6.88 (4H, m), 7.0.
6-7.43 (13H, m) IRνmax (KBr): 3386,2973,293
2,1723,1647,1607,1547,151
1 cm ^-1 Elemental analysis value: (as C ₄₁ H ₄₈ N ₅ O ₆ .0.1 C ₆ H ₁₄ ) Actual value: C, 69.76; H, 7.10; N, 9.71 Calculated value: 69.84; H, 6.94; N, 9.97.

Example 81 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3-((N
-Cyano-N'-methyl) guanidino) propionyla
Mino) -2,3,4,5-tetrahydro-1H-1-be
Synthesis of nzoazepin-2-one (I-82) (first step) N-cyano-N'-methyl-O-phenylisourea (compound 25) diphenylcyanocarboimidate (2.0 mmol)
A 40% methylamine / methanol solution (0.2 ml) was added to a methanol (10.0 ml) solution of
Stir for 5 hours. The reaction mixture was added with n-hexane, filtered and concentrated to obtain the title compound. Yield 63.9% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 3.08 (3H, d, J =
4.6Hz), 6.55 (1H, brs), 7.10
(1H, d, J = 7.8 Hz), 7.29-7.45 (3
H, m)

(Second Step) Compound (I-82) Example 75 Compound 24 obtained in the first step (0.124 mm
ol) to the compound 25 synthesized in the first step (0.371 m
mol) in 2-propanol, and triethylamine (0.05 ml) was added thereto, followed by stirring at 120 ° C for 5 days.
Concentrate and remove the residue by PTLC (chloroform / methanol = 10
/ 1) to give the title compound.

Yield 10.0% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.97-2.12 (1H, m), 2.32-2.76
(5H, m), 2.59 (3H, d, J = 4.6 Hz),
3.38-3.69 (2H, m), 4.45-4.59
(1H, m), 4.88 (1H, d, J = 15.2 Hz),
5.08 (1H, d, J = 15.2 Hz), 5.75 (1
H, brt, J = 6.0 Hz), 6.07 (1H, br
s), 6.84 (1H, d, J = 5.8 Hz), 6. . 8
6 (1H, brs), 7.09-7.28 (7H, m),
7.43 (1H, d, J = 8.1 Hz) IRνmax (KBr): 3422, 3002, 216
6,1721,1648,1596,1523 cm ^-1 [M + H] ⁺ = 534

Example 82 1- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (2-
(4-hydroxyphenyl) ethyl) ureido) prop
Onylamino) -2,3,4,5-tetrahydro-1H
The title compound was obtained from the compound (I-81) (0.072 mmol) of -1-benzazepin-2-one (I-83) in the same manner as in Example 15. Yield 99.1% amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
1.98 (1H, m), 2.25 (2H, m), 2.60
(5H, m), 3.35 (4H, m), 4.50 (1H,
m), 4.80 (1H, brs), 4.86 (1H, d, J
= 15.3 Hz), 5.08 (1H, d, J = 14.4H)
z), 5.41 (1H, brs), 6.65 (2H, d, J
= 8.1 Hz), 6.69 (1H, t, J = 7.5H)
z), 6.84 (1H, d, J = 7.5 Hz), 6.91
(2H, d, J = 8.7 Hz), 6.99 (1H, br
s), 7.09-7.24 (6H, m), 7.39 (1
(H, d, J = 8.1 Hz) IRνmax (KBr): 3338, 2931, 172
2,1647,1612,1547,1516Cm ^-1 Elemental _{analysis: (C 34 H 42 N 5} O 6 .0.6C 6 H 14 .1.2H 2 O
Found) C, 64.01; H, 7.30; N, 9.82 Calculated: C, 63.96; H, 7.54; N, 9.92

Example 83 5- (3- (tert-buto)
(Xycarbonylamino) benzyl) -3- (3- (ben
(Dyloxycarbonylamino) propionylamino)-
2,3,4,5-tetrahydro-1,5-benzothiaze
Synthesis of pin-4-one (I-84)

[0338]

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Example 61 Compound 21 obtained in the first step
(0.204 mmol) and N-Cbz-β-alanine (0.235 mmol) to give the title compound by the same method as in the second step of Example 62.

Yield 61.6% mp. 86 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s),
2.43 (2H, t, J = 5.5 Hz), 2.84 (1H,
t, J = 11.2 Hz), 3.44 (2H, m), 3.74
(1H, dd, J = 6.6, 11.0 Hz), 4.68
(1H, m), 4.97 (1H, d, J = 15.4Hz),
5.07 (2H, s), 5.09 (1H, d, J = 15.0)
Hz), 5.37 (1H, brs), 6.57-6.6.
9 (2H, m), 6.93 (1H, d, J = 7.6 Hz),
7.16-7.39 (1H, m), 7.59-7.63
(1H, m) IRνmax (KBr): 3322, 2975, 293
0,1722,1654,1610,1535Cm ^-1 Elemental _{analysis: (C 30 H 34 N 4} O 3 as S) Found: C, 63.69; H, 6.36 ; N, 9.26;
S, 5.30 Calculated: C, 63.65; H, 6.16; N, 9.11;
S, 5.21

Example 84 (R) -3- (3- (benzyl)
Ruoxycarbonylamino) -propionylamino)-
5- (3- (tert-butoxycarbonylamino) be
Ndyl) -2,3,4,5-tetrahydro-1,5-b
Synthesis of Nzooxaazepin -4-one (I-85) (First Step) (R) -3- (3- (benzyloxycarbonylamino) propionylamino) -2,3,4
5-tetrahydro-1,5-benzoxazepine-4
-One (compound 27)

[0342]

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References (Chem. Pram. Bul)
l. , 34, 1128 (1986). The compound 2 described in ())
The title compound was obtained from 6 (0.466 mmol) and N-Cbz-β-alanine (0.560 mmol) in the same manner as in the second step of Example 62.

Yield 61.6% mp. 178-179 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.52 (2H, t, J =
6.0 Hz), 3.47 (2H, q, J = 6.3 Hz),
4.17 (1H, t, J = 10.5Hz), 4.64-
4.69 (1H, m), 5.42 (1H, brt, J = 4.9)
Hz), 6.87 (1H, brd, J = 6.0 Hz),
6.99-7.21 (4H, m), 7.32 (5H, s),
8.06 (1H, s) IRνmax (KBr): 3315, 3247, 171
0, 1680, 1647, 1603 cm ^-1 Elemental analysis: (as C ₂₀ H ₂₁ N ₃ O ₅ ) Actual: C, 62.43; H, 5.58; N, 11.14 Calculated: C, 62 .65; H, 5.52; N, 10.96

(Second Step) Compound (I-85)

[0346]

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The compound 27 obtained in the first step (0.250 m
mol) and meta- (tert-butoxycarbonylamino) benzyl bromide (0.300 mmol) to give the title compound in the same manner as in Example 12.

Yield: 72.1% Amorphous ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s),
2.46 (2H, m), 3.45 (2H, q, J = 6.0H
z), 4.16 (0.5 H, d, J = 7.2 Hz);
20 (0.5 H, d, J = 6.9 Hz), 4.63 (0.
5H, d, J = 7.5 Hz), 4.66 (0.5H, d, J =
7.2Hz), 4.98 (1H, m), 5.05 (1H,
s), 5.07 (1H, s), 5.34 (1H, brs),
6.50 (1H, brs), 6.58 (1H, d, J = 7.
5 Hz), 6.89 (1H, d, J = 7.13-7.35)
(11H, m) IRνmax (KBr): 3326, 1707, 165
5,1610,1597, 1534cm ^-1 Elemental _{analysis: (C 32 H 36 N 4} O 7 .0.2C 6
H _14. 0.3H ₂ O as) Found: C, 65.15; H, 6.53 ; N, 9.19 Calculated: C, 65.23; H, 6.50 ; N, 9.17

Example 85 1- (3- (3-Isopropyl)
(Rureido) benzyl) -3- (N'-methyl-N ''
-4-hydroxyphenylguanidino) -2,3,4
5-tetrahydro-1H-1-benzazepin-2-o
( 1st step) 3-Azido-1- (3- (N'-isopropylureido) benzyl) -2,3,4,5-tetrahydro-1H-1-benzazepine-2 -One (compound 2
9)

[0350]

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Compound 5 (13.5 g) was suspended in 160 ml of tetrahydrofuran, and suspended under a nitrogen stream and ice cooling.
(3-isopropyl) ureidobenzyl bromide (compound 28; 20.8 g), n-tetrabutylammonium bromide (2.15 g), powdered potassium hydroxide (4.8)
1 g) were added sequentially and stirred vigorously. The mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into ethyl acetate and ice water, the ethyl acetate layer was washed with brine, dried, and dried under reduced pressure. The residue was purified by silica gel chromatography, and crystallized from ethyl acetate and hexane to give compound 29 (21). .0 g).

Mp. 99-103 ° C NMR (300 M) (CD ₃ OD) δ: 1.15 (6
H, d, J = 6.6), 2.20 (1H, m), 2.3
6 (1H, m), 2.56 (2H, m), 2.84 (2
H, m), 4.76 (1H, d, J = 14.7), 2.
84 (2H, m), 4.76 (1H, d, J = 14.
7), 5.33 (1H, d, J = 14.7), 6.80
(1H, d, J = 7.5), 7.11 (1H, t, J =
7.5), 7.20 (3H, m), 7.30 (3H,
m). Elemental analysis: (C ₂₁ H ₂₄ N ₆ O ₂ 0.1 CH ₃ CO ₂ C ₂
H as ₅₎ Found: C, 64.33; H, 6.29 ; N, 20.6
5 Calculated: C, 64.03; H, 6.24; N, 20.9
0

(Second step) 3-amino-1- (3- (3
-Isopropylureido) benzyl) -2,3,4,5
-Tetrahydro-1H-1-benzazepin-2-one (compound 30)

[0354]

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Compound 29 (20.5 g) and 10% palladium-carbon (2.0 g) were transferred into methanol (500 ml), subjected to catalytic reduction under atmospheric pressure, filtered, and the filtrate was dried under reduced pressure to remove bubbles. Compound 30 (18.3 g) was obtained.

NMR (300M) (CD ₃ OD) δ:
1.15 (6H, d, J = 6.6), 1.86 (1H,
m), 2.31 (1H, m), 2.40-2.65 (2
H, m), 3.36 (1H, dd, J = 7.5, 11.
7), 3.85 (1H, m), 4.82 (1H, d, J
= 14.7), 5.24 (1H, d, J = 14.7),
6.83 (1H, d, J = 7.5), 7.14 (1H,
t, J = 7.5), 7.2 (6H, m). Elemental analysis: (as C ₂₁ H ₂₆ N ₄ O ₂ 0.2 H ₂ O) Found: C, 68.09; H, 7.19; N, 15.1
4 Calculated: C, 68.16; H, 7.22; N, 15.2
0

(Third Step) 1- (3- (3-isopropylureido) benzyl) -3- (N ′-(4-methoxymethyloxyphenyl) thioureido) -2,3,4
5-tetrahydro-1H-1-benzazepin-2-one (Compound 32)

[0358]

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Compound 30 (1.22 g) was dissolved in 12 ml of acetonitrile, thiocarbonyldiimidazole (1.40 g) was added under cooling at −50 ° C., and the mixture was stirred for 10 minutes and further at room temperature for 10 minutes. Thereto was added para-methoxymethyloxyaniline (2.60 g), and the mixture was stirred for 1 hour. Ethyl acetate and water were added to the reaction solution, shaken, the ethyl acetate layer was dried, dried under reduced pressure, and then subjected to silica gel chromatography to obtain Compound 32 (3.50 g).

NMR (300M) (CD ₃ OD) δ:
1.14 (6H, d, J = 6.3), 1.95 (1H,
m), 2.5-2.7 (3H, m), 3.43 (3H,
s), 3.85 (1H, m), 4.83 (1H, d, 1
5.2), 5.00 (1H, dd, J = 6.0, 10.
0), 5.17 (2H, s), 5.21 (1H, d, J
= 15.2), 6.86 (1H, d, J = 7.0),
7.0-7.4 (11H, m)

(Fourth step) 3- (3- (4-hydroxyphenyl) thioureido) -1- (3- (3-isopropylureido) benzyl) -2,3,4,5-tetrahydro-1H-1- Benzoazepin-2-one (Compound 3
3)

[0362]

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Compound 32 obtained in the third step (2.50 g)
Was dissolved in 10 ml of methylene chloride, trifluoroacetic acid (5 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Toluene (5 ml) was added, and the mixture was dried under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate, dried, and dried under reduced pressure to give a foamy compound 33 (1.90 g).
I got NMR (300 M) (CD ₃ OD) δ: 1.13 (6
H, J = 6.3), 1.95 (1H, m), 2.5-
2.7 (3H, m), 3.85 (1H, m), 4.81
(1H, d, J = 14.7), 4.99 (1H, dd,
6.9, 10.8), 5.22 (1H, J = 14.
7), 6.81 (2H, d, J = 8.7), 6.83
(1H, d, J = 7.0), 7.10 (1H, m),
7.11 (2H, d, J = 8.7), 7.2-7.4
(6H, m).

(Fifth step) 3- (3- (4-hydroxyphenyl) -2-methylisothioureido) -1- (3
-(3-isopropylureido) benzyl) -2,3
4,5-tetrahydro-1H-1-benzoazepine-2
-One (compound 34)

[0365]

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Compound 33 (1.80 g) obtained above was dissolved in acetonitrile (30 ml), and methyl iodide (3 m
l) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was dried under reduced pressure, dissolved in ethyl acetate, and vigorously shaken with aqueous sodium carbonate. The ethyl acetate layer was dried and dried under reduced pressure to obtain a foamed compound 3.
4 (1.56 g) was obtained. NMR (300 M) (CD ₃ OD) δ: 1.14 (6
H, J = 6.3), 2.1 (1H, m), 2.31 (3
H, s), 2.5-2.7 (3H, m), 3.86 (1
H, m), 4.97 (1H, d, J = 15.0), 5.
11 (1H, d, J = 15.0), 6.5-6.7 (4
H, m), 6.89 (1H, d, J = 7.2), 7.0.
1 (1H, t, J = 7.8), 7.1-7.3 (6H,
m).

(Sixth Step) Compound (I-86)

[0368]

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Compound 34 (200 mg) obtained above was added to 20
% Methylamine in ethanol solution (2 ml),
After heating at 70 ° C. for 6 hours in a sealed tube, the mixture was dried under reduced pressure. The residue was eluted with butanol-acetic acid-water (5: 1: 1) using silica gel thin layer chromatography and eluted.
The mixture was shaken with aqueous sodium carbonate and the ethyl acetate layer was dried under reduced pressure to obtain a foamy compound (I-86) (52 mg).

(I-86) powder NMR (CD ₃ OD) δ: 1.13 (6H, dd, J =
6.3, 1.8), 2.05 (1H, m), 2.5-
2.7 (3H, m), 2.82 (3H, s), 3.83
(1H, m), 4.30 (1H, dd, J = 7.2, 1
0.0), 4.85 (1H, d, J = 15.0), 5.
20 (1H, d, J = 15.0), 6.63 (2H,
d, J = 8.7), 6.75 (2H, d, J = 8.
7), 6.80 (1H, t, J = 7.5), 7.07
(1H, t, J = 7.5), 7.2-7.4 (6H,
m) Elemental analysis: (as C ₂₉ H ₃₄ N ₆ O ₃ .0.5H ₂ O) Found: C, 66.22; H, 6.75; N, 15.7
7 Calculated: C, 66.52; H, 6.74; N, 16.0.
5

Reference Example 1 Synthesis of Compound 28 (First Step) 3- (3-Isopropylureido) benzyl alcohol (Compound 36)

[0372]

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3-Aminobenzyl alcohol (compound 3
5; 25 g) in 455 ml of acetonitrile,
Isopropyl isocyanate (22.0 ml) under ice-cooling
Of acetonitrile (60 ml) was added over 10 minutes. The mixture was further stirred at room temperature for 45 minutes and at 50 ° C for 2 hours 30 minutes. Ethyl acetate (300 ml) was added to the reaction solution,
It was left for 30 minutes. The precipitated crystals were collected by filtration to give Compound 36.
(35.3 g) was obtained. mp. 144-5 ° C NMR (300 M) (CD ₃ OD) δ: 1.17 (6
H, d, J = 6.6), 3.88 (1H, m, J = 6.
6), 4.55 (2H, s), 6.96 (1H, d, J
= 6.9), 7.24 (2H, m), 7.32 (1H,
s).

(Second Step) 3- (Methanesulfonyloxymethyl) -N- (isopropylaminocarbonyl) aniline (Compound 37)

[0375]

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Compound 36 (2.34 g) was dissolved in dimethylformamide (23 ml), and triethylamine (2.04 ml) and methanesulfonyl chloride (1.1 ml) were added under ice-cooling.
3 ml) and stirred for 1 hour. The reaction solution was transferred to a mixed solution of ethyl acetate and ice water. After shaking, the ethyl acetate layer was washed with water, dried, and the solvent was distilled off. The residue was crystallized from ether to obtain Compound 37 (2.66 g).

Mp. 115-118 ° C NMR (300 M) (CD ₃ OD) δ: 1.17 (6
H, d, J = 6.6), 3.03 (3H, s), 3.8
8 (1H, m, J = 6.6), 5.20 (2H, s),
7.04 (1H, m), 7.32 (2H, m), 7.5
0 (1H, m). Elemental analysis: (as C ₁₂ H ₁₈ N ₂ O ₄ S) Found: C, 50.14; H, 6.27; N, 9.6
9; S, 11.21 Calculated: C, 50.33; H, 6.34; N, 9.7
8; S, 11.20

(Third Step) Compound 28

[0379]

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Compound 37 (2.60 g) was dissolved in dimethylformamide (20 ml), lithium bromide (1.21 g) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and 20 minutes. After adding ethyl acetate and water to the reaction solution and shaking, the ethyl acetate layer was washed with water, dried and evaporated to dryness under reduced pressure. The residue was crystallized from ether to obtain Compound 28 (2.38 g).

Mp. 162-165 ° C NMR (300 M) (CD ₃ OD) δ: 1.17 (6
H, d, J = 6.6), 3.88 (1H, m, J = 6.
6), 4.50 (2H, s), 7.01 (1H, m),
7.23 (2H, m), 7.45 (1H, m). Elemental analysis: (C ₁₁ H ₁₅ N ₂ as OBr) Found: C, 48.72; H, 5.59 ; N, 10.3
6; Br, 29.18 Calculated: C, 48.73; H, 5.58; N, 10.3.
3; Br, 29.47

Example 86 1- (3- (3-Isopropyl)
Luureido) benzyl) -3- (3-phenylurei
Do) -2,3,4,5-tetrahydro-1H-1-ben
Synthesis of zoazepin-2-one (I-87)

[0383]

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Example 85 Compound 30 (1) obtained in the second step
Phenylisocyanate (50 mg) under ice-cooling.
Stirred for hours. Ether was added to the reaction solution, and the mixture was allowed to stand. The precipitated crystals were collected by filtration to obtain Compound (I-87) (97 mg).

(I-87) mp. 229-230 ° C NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.3), 2.00 (1H, m), 2.4-2.7 (3
H, m), 3.85 (1H, m), 4.36 (1H, d
d, J = 7.3, 11.3), 4.84 (1H, d, J)
= 15.0), 5.26 (1H, d, J = 15.0),
6.84 (1H, d, J = 7.8), 6.97 (1H,
t, J = 7.6), 7.1-7.4 (11H, m) Elemental analysis: (as C ₂₈ H ₃₁ N ₅ O ₃ ) Actual: C, 69.25; H, 6. 47; N, 14.4
0 Calculated: C, 69.26; H, 6.43; N, 14.4.
2

Example 87 1- (3- (3-Isopropyl)
Luureido) benzyl) -3- (3-benzothiazole
-6-yl) ureido) -2,3,4,5-tetrahydride
B-1H-1-Benzazepin-2-one (I-88)
Synthesis of (first step) 1-(3- (N'-isopropyl ureido) benzyl) -3- (imidazol-1-yl-carbonyl amino) -2,3,4,5-tetrahydro -1H-
1-benzoazepin-2-one (compound 38)

[0387]

Embedded image

Compound 30 (5.02 g) was dissolved in 55 ml of acetonitrile, and carbonyldiimidazole (2.67 g) was added under ice-cooling.
The reaction was carried out under stirring for minutes. The reaction solution was poured into water, extracted with ethyl acetate, dried, and dried under reduced pressure. The residue was subjected to silica gel chromatography to obtain a colorless foamy compound 38 (6.86 g).

NMR (300 M) (CD ₃ OD) δ:
1.15 (6H, d, J = 6.6), 2.42 (2H,
m), 2.53-2.77 (2H, m), 3.85 (1
H, m), 4.45 (1H, dd, J = 11.5, 8.
0), 4.87 (1H, d, J = 14.7), 5.24
(1H, d, J = 14.7), 6.85 (1H, d, J)
= 7.5), 7.04 (1H, m), 7.13 (1H,
t, J = 8.0), 7.19-7.42 (6H, m),
7.68 (1H, s), 8.30 (1H, s).

(Second Step) Compound (I-88)

[0391]

Embedded image

Compound 38 (205 mg) was dissolved in 1 ml of acetonitrile, and 6-aminobenzothiazole (2
64 mg) was added and reacted under boiling stirring for 1 hour and 30 minutes. The reaction solution was poured into diluted hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and dried under reduced pressure. The residue was purified using thin-layer silica gel chromatography, and further purified with ethyl acetate-methanol-e.
Crystallization from tell gave (I-88) (152 mg).

(I-88) mp. _{236-238 ℃ NMR (DMSO-d 6} ): 1.07 (6H, d, J =
6.6), 1.96 (1H, m), 2.37 (1H,
m), 2.61 (2H, m), 3.72 (1H, m),
4.16-4.30 (1H, m), 4.77 (1H,
d, J = 15.0), 5.28 (1H, d, J = 15.
0), 5.92 (1H, d, J = 7.8), 6.66
(1H, d, J = 8.1), 6.73 (1H, d, J =
7.5), 7.09 (1H, t, J = 8.0), 7.1
6-7.39 (6H, m), 7.44 (1H, d, J =
8.1), 7.91 (1H, d, J = 8.7), 8.2
4 (1H, s), 8.25 (1H, s), 9.05 (1
H, s), 9.16 (1H, s). Elemental analysis: (C ₂₉
H ₃₀ N ₆ O ₃ S. Found) C, 64.19; H, 5.57; N, 15.4.
9; S, 5.91 Calculated: C, 64.05; H, 5.68; N, 15.2
8; S, 5.80 Mass: m / z [M + H] ⁺ 543

Example 88 1- (3-tert-butoki)
(Cicarbonylamino) benzyl) -3- (3-phenyl
Guanidino) -2,3,4,5-tetrahydro-1H-
Synthesis of 1-benzoazepin-2-one (I-89) (first step) S-methylphenylisothiourea hydroiodide (compound 40)

[0395]

Embedded image

Compound 39 (1.50 g) was suspended in 10 ml of acetonitrile, and methyl iodide (1.25 m
l) was added and reacted under boiling for 1 hour. After cooling on ice, the precipitated crystals were collected by filtration and subjected to S-methylhydroiodide (compound 4).
0; 2.31 g). NMR (200M) (DMS
O) δ: 2.69 (3H, s), 7.3-7.6 (5
H, m).

(Second step) Compound (I-89)

[0398]

Embedded image

Example 25 Compound 9 (38) obtained in the first step
2 mg) and the compound 40 obtained in the first step (294 m
g) was transferred into 1 ml of ethanol and heated in a sealed tube at 100 ° C. for 5 hours. After drying under reduced pressure, ethyl acetate and sodium carbonate water were added to the residue, and the mixture was vigorously shaken. The ethyl acetate layer was washed with water, dried and dried under reduced pressure. The residue was washed with ether, purified by thin-layer silica gel chromatography using acetonitrile-methanol, and crystallized from ether to obtain the title compound (72 mg).

(I-89) mp. 132-135 ° C NMR (CD ₃ OD) δ: 1.49 (9H, s);
00 (1H, m), 2.56 (2H, m), 2.69
(1H, m), 4.45 (1H, dd, J = 7.8, 1
2.3), 4.95 (1H, d, J = 15.3), 5.
15 (1H, d, J = 15.3), 6.85 (1H,
d, J = 8.0), 6.9-7.1 (5H, m), 7.
1-7.4 (7H, m) Elemental _{analysis:. (C 29 H 33 N} 5 O 3 .0.5 (C 2 H 5) 2
Found: C, 69.25; H, 7.10; N, 12.9.
5 Calculated: C, 69.38; H, 7.14; N, 13.0.
5

Example 89 1- (3- (3-Isopropyl)
Luureido) benzyl) -3- (3-phenylthiouree
Id) -2,3,4,5-tetrahydro-1H-1-be
Synthesis of nzoazepin-2-one (I-90)

[0402]

Embedded image

Example 85 Compound 30 (3
00 mg) was dissolved in 1 ml of acetonitrile, and phenylisothiocyanate (135 mg) was added under ice-cooling.
The mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to give Compound (I-90) (360 mg).

(I-90) mp. 195-197 ° C NMR (CD ₃ OD) δ: 1.15 (6H, d, J =
6.3), 1.95 (1H, m), s), 2.5-2.
7 (3H, m), 3.86 (1H, m), 4.88 (1
H, d, J = 15.0), 5.03 (1H, dd, J =
7.2, 10.1), 5.17 (1H, d, J = 15.
0), 6.86 (1H, d, J = 7.5), 7.13
(1H, t, J = 8.1), 7.2-7.4 (11H,
m). Elemental analysis: (as C ₂₈ H ₃₁ N ₅ O ₂ S.) Found: C, 67.01; H, 6.32; N, 13.9.
4: S, 6.48 Calculated: C, 65.18; H, 6.18; N, 14.6.
2; S, 6.39

Example 90 1- (3- (3-Isopropyl)
Luureido) benzyl) -3- (N'-phenyl-
N ''-methylguanidino) -2,3,4,5-tetra
Hydro-1H-1-benzazepin-2-one (I-9
Synthesis of 1) (first step) 1- (3- (3-isopropylureido)
(Benzyl) -3- (S-methyl-3-phenylisothioureido) -2,3,4,5-tetrahydro-1H-1
-Benzazepin-2-one (compound 41)

[0406]

Embedded image

Compound (I-90; 300 mg) was added in an amount of 3 ml.
Suspended in acetonitrile of methyl iodide (0.3m
l) was added and stirred for 1 hour. After drying under reduced pressure, ethyl acetate and sodium carbonate water were added to the residue, and the mixture was vigorously shaken. The ethyl acetate layer was washed with water, dried and dried under reduced pressure to obtain a foamed compound (Compound 41; 290 mg). Was. NMR (300 M) (CD ₃ OD) δ: 1.15 (6
H, d, J = 6.6), 2.13 (1H, m), 2.3
0 (3H, s), 2.4-2.7 (3H, m), 3.8
5 (1H, m), 4.51 (1H, dd, J = 7.0,
10.2), 4.97 (1H, d, J = 15.0),
5.08 (1H, d, J = 15.0), 6.73 (2
H, d, J = 7.5), 5.9-7.0 (3H, m),
7.1-7.3 (8H, m).

(Second Step) Compound (I-91)

[0409]

Embedded image

To compound 41 (230 mg) was added 1 ml of 40%
A methylamine methanol solution was added, and the mixture was heated at 80 ° C. for 4 hours in a sealed tube. After drying under reduced pressure, the residue was acetonitrile-
Purification by thin layer silica gel chromatography using methanol-acetic acid (3: 1: 0.2) afforded the title compound (14) as a powder.
0 mg).

(I-91) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.3), 1.98 (1H, m), 2.4-2.7 (3
H, m), 2.73 (3H, s), 3.83 (1H,
m), 4.30 (1H, dd, J = 7.2, 10.
4), 4.88 (1H, d, J = 15.3), 5.14
(1H, d, J = 15.0), 6.83 (3H, m),
6.91 (1H, t, J = 7.5), 7.03 (1H,
t, J = 7.5), 7.1-7.4 (8H, m) Elemental _{analysis: (C 28 H 32 N 6} O 2 .0.3H 2 O as) Found: C, 69.36 H, 6.99; N, 16.4
1 Calculated: C, 69.11; H, 6.92; N, 16.6.
7

Example 91 1- (3- (3-tert-
Butylureido) benzyl) -3- (3-phenyluree
Id) -2,3,4,5-tetrahydro-1H-1-be
Synthesis of nzoazepin-2-one (I-92) (first step) 1- (3-aminobenzyl) -3-azido-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Compound 42)

[0413]

Embedded image

Example 25 Compound 8 obtained in the first step (1.
50 g) was dissolved in 10 ml of methylene chloride, trifluoroacetic acid (5 ml) was added thereto under ice cooling, and the mixture was stirred for 4 hours.
The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate, dried, and evaporated to dryness under reduced pressure to obtain 1.21 g of Compound 42 as a foam. NMR (300 M) (CDCl ₃ ) δ: 2.3 (2H,
m), 2.6 (2H, m), 2.85 (2H, br)
s), 3.74 (1H, dd, J = 7.8, 10.
5), 4.80 (1H, d, 14.4), 5.10 (1
H, d, J = 14.4), 6.54 (2H, m), 6.
64 (1H, s), 7.02 (1H, t, J = 7.
8), 7.1-7.3 (4H, m).

(Second Step) 3-Azido-1- (3-
(3-tert-butylureido) benzyl) -2,
3,4,5-tetrahydro-1H-1-benzazepin-2-one (compound 43)

[0416]

Embedded image

Compound 42 (1.20 g) was dissolved in 10 ml of acetonitrile, and 1.4 ml of tert.
-Butyl isocyanate was added and stirred overnight. The residue was subjected to silica gel chromatography using toluene-ethyl acetate to obtain 1.29 g of a crystalline compound 43. _{NMR (300M) CDCl 3: 1.35} (9H,
s), 2.3 (2H, m), 2.6 (2H, m), 3.
75 (1H, dd, J = 7.8, 11.0), 4.87
(1H, d, 14.7), 4.90 (1H, brs),
5.05 (1H, d, J = 14.7), 6.66 (1
H, s), 6.76 (1H, d, J = 7.5), 7.1
-7.5 (7H, m)

(Third step) 3-amino-1- (3-
(3-tert-butylureido) benzyl) -2,
3,4,5-tetrahydro-1H-1-benzazepin-2-one (compound 44)

[0419]

Embedded image

Compound 43 (1.10 g) was dissolved in 20 ml of methanol, and 10% palladium-carbon (300 m
g) was added, and catalytic reduction was performed under normal pressure. After filtration, the filtrate was dried under reduced pressure to obtain 1.00 g of Compound 44. _{NMR (300M) CDCl 3: -2.5} (2H,
m), 2.6 (1H, m), 3.43 (1H, dd, J
= 7.5, 11.1), 4.83 (1H, d, 14.
7), 5.05 (1H, d, J = 14.7), 5.18
(1H, s), 6.78 (1H, d, J = 7.3),
6.83 (1H, s), 7.0-7.5 (7H, m)

(Fourth Step) Compound (I-92)

[0422]

Embedded image

The compound (I-) was obtained in the same manner as in Example 86.
92) was obtained. mp. 203-205 ° C NMR (CD ₃ OD) δ: 1.33 (9H, s);
00 (1H, m), 2.4-2.7 (3H, m), 4.
36 (1H, dd, J = 7.2, 9.8), 4.84
(1H, d, J = 14.7), 5.25 (1H, d, J)
= 14.7), 6.83 (1H, d, J = 7.0),
6.96 (1H, t, J = 7.2), 7.1-7.4
(7H, m). Elemental analysis: (as C ₂₉ H ₃₃ N ₅ O ₃ ) Actual: C, 69.44; H, 6.68; N, 13.8
7 Calculated: C, 69.72; H, 6.66; N, 14.0.
2

Examples 92 to 158 Synthesis of other compounds
Formed following the same manner were synthesized other compounds. The compounds synthesized and physical properties are shown below.

[0425]

[Table 1]

[0426]

[Table 2]

[0427]

[Table 3]

[0428]

[Table 4]

[0429]

[Table 5]

[0430]

[Table 6]

[0431]

[Table 7]

[0432]

[Table 8]

[0433]

[Table 9]

[0434]

[Table 10]

[0435]

[Table 11]

[0436]

[Table 12]

[0437]

[Table 13]

(I-93) mp. 209-211 ° C. NMR (CDCl ₃ ): 0.95 (3H, d, J = 6.
3), 1.01 (3H, d, J = 6.3), 1.48
(9H, s), 1.95 (1H, m), 2.50 (1
H, m), 2.76 (2H, m), 3.79 (1H, d
q, J = 6.3, 14.4), 4.57 (1H, m),
4.70 (1H, brs), 4.73 (1H, d, J =
15.9), 5.31 (1H, d, J = 15.9),
5.64 (1H, d, J = 8.1), 6.86 (1H,
d, J = 7.5), 7.06 (1H, d, J = 8.
1), 7.2 (7H, m), 7.62 (1H, d, J =
8.1). Elemental analysis: (as C ₂₆ H ₃₄ N ₄ O ₄ ) Found: C, 66.91; H, 7.40; N, 12.0
1 Calculated: C, 66.93; H, 7.34; N, 12.0
1

(I-94) mp. _{202-205 ℃ NMR (CDCl 3):} 1.24 (9H, s), 1.4
9 (9H, s), 1.93 (1H, m), 2.5 (2
H, m), 2.7 (1H, m), 4.52 (1H,
m), 4.65 (1H, s), 4.74 (1H, d, J
= 15.9), 5.29 (1H, d, J = 15.9),
5.35 (1H, d, J = 8.1), 6.85 (1H,
d, J = 7.5), 6.96 (1H, s), 7.06
(1H, d, J = 7.5), 7.2 (9H, m), 7.
59 (1H, d, J = 7.5). Elemental analysis: (as C ₂₇ H ₃₆ N ₄ O ₄ ) Actual: C, 67.35; H, 7.73; N, 11.4
9 Calculated: C, 67.48; H, 7.55; N, 11.6.
6

(I-95) powder NMR (CD ₃ OD) δ: 1.48 (9H, s), 4.
3 (1H, m), 4.55 (1H, m), 4.89 (1
H, dd, J = 7.8, 11.4), 4.97 (1H,
d, J = 15.9), 5.24 (1H, d, J = 15.
9), 6.9 (2H, m), 7.1-7.4 (11H,
m) Elemental analysis: (as C ₂₈ H ₃₀ N ₄ O ₅ .0.5H ₂ O) Found: C, 65.87; H, 6.10; N, 10.8
8 Calculated: C, 65.74; H, 6.11; N, 10.9
5 Mass: m / z [M + H] ⁺ 503

(I-96) NMR (CD ₃ OD) δ: 1.49 (9H, s), 2.
03 (1H, m), 2.55 (2H, m), 2.67
(1H, m), 4.36 (1H, dd, J = 6.9, 1
0.2), 4.83 (1H, d, J = 14.7), 5.
28 (1H, d, J = 14.7), 6.85 (1H,
d, J = 7.5), 7.12 (1H, t, J = 7.
7), 7.2-7.4 (6H, m), 7.47 (2H,
d, J = 9.7), 7.74 (2H, d, J = 10.
1). Elemental _{analysis: (C 29 H 33 N 5} O 6 as S ₁₎ Found: C, 60.02; H, 5.85 ; N, 11.8
9; S, 5.35 Calculated: C, 60.09; H, 5.74; N, 12.0
8; S, 5.53

(I-97) mp. _{198-201 ℃ NMR (CDCl 3):} 0.85-1.35 (4H,
m), 1.49 (9H, s), 1.50-2.00 (7
H, m), 2.40-2.80 (3H, m), 3.4
(1H, m), 4.55 (1H, dd, J = 7.5, 1
1.1), 4.79 (1H, d, J = 15.3), 5.
25 (1H, d, J = 15.3), 5.60 (1H, b
rs), 6.86 (1H, d, J = 8.1), 7.00
(1H, s), 7.09-7.40 (7H, m), 7.
57 (1H, d, J = 7.5). Elemental analysis: (as C ₂₉ H ₃₈ N ₄ O ₄ ) Actual: C, 68.54; H, 7.65; N, 11.0
1 Calculated: C, 68.75; H, 7.56; N, 11.0
6

(I-98) mp. 168-170 ° C NMR (CDCl ₃ ): 1.49 (9H, s), 2.1
1 (1H, m), 2.56 (2H, m), 2.70 (1
H, m), 4.50 (1H, dd, J = 7.2, 9.
0), 4.82 (1H, d, J = 15.0), 5.31
(1H, d, J = 15.0), 6.86 (1H, d, J)
= 9.0), 7.04 (1H, t, J = 5.1), 7.
13 (1H, t, J = 9.0), 7.1-7.40 (6
H, m), 8.56 (2H, d, J = 5.1). Elemental analysis: (as C ₂₇ H ₃₀ N ₆ O ₄ .0.2H ₂ O) Found: C, 63.99; H, 6.10; N, 16.7
2 Calculated: C, 64.07; H, 6.05; N, 16.6.
0

(I-99) mp. 205-208 ° C NMR (CDCl ₃ ): 1.50 (9H, s), 2.1
(1H, m), 2.48-2.75 (3H, m), 4.
55 (1H, m), 4.92 (1H, d, J = 15.
0), 5.15 (1H, d, J = 15.0), 6.50
(1H, s), 6.88 (1H, d, J = 7.8),
7.2 (6H, m), 7.4 (3H, m), 7.55
(1H, m), 7.87 (2H, d, J = 8.4),
8.69 (1H, s), 9.44 (1H, d, J = 7.
2). Elemental analysis: (as C ₃₀ H ₃₂ N ₄ O ₅ ) Actual: C, 67.93; H, 6.21; N, 10.6
7 Calculated: C, 68.17; H, 6.10; N, 10.6
0

(I-100) powder NMR (CDCl ₃ ): 1.48 (9H, s), 1.9
0 (1H, m), 2.50 (3H, m), 4.40 (1
H, m), 4.96 (1H, d, J = 15.2), 5.
11 (1H, d, J = 15.2), 6.71 (1H,
s), 6.80 (1H, d, J = 7.8), 7.13-
7.58 (10H, m), 7.93 (2H, m), 8.
60 (1H, s). Elemental analysis: (C ₂₉ H ₃₂ N ₄ O ₆ S ₁ .0.3AcOE
t. 0.7 H ₂ O as) Found: C, 59.92; H, 5.96 ; N, 9.3
1; S, 5.23 Calculated: C, 60.05; H, 5.99; N, 9.2
4: S, 5.29

(I-101) powder NMR (CD ₃ OD) δ: 2.0 (1H, m), 2.3
8-2.74 (3H, m), 3.44 (4H, m),
3.66 (4H, m), 4.36 (1H, dd, J =
7.5, 11.4), 4.90 (1H, d, J = 15.
0), 5.21 (1H, d, J = 15.0), 6.9
(2H, m), 7.15-7.36 ( 11H, m) Elemental _{analysis: (C 29 H 31 N 5} O 4 .0.4Et 2 O.0.
5H ₂ O as) Found: C, 66.47; H, 6.38 ; N, 12.4
7 Calculated: C, 66.55; H, 6.57; N, 12.6.
8 Mass: m / z [M + H] ⁺ 514

(I-102) powder NMR (CD ₃ OD) δ: 1.38 (9H, S);
95 (1H, m), 2.4-2.6 (3H, m), 3.
12 (3H, s), 4.37 (1H, dd, J = 7.
2,9.7), 4.90 (1H, d, J = 15.0),
5.27 (1H, d, J = 15.0), 6.94 (1
H, t, J = 7.2), 7.1-7.4 (13H,
m). Elemental analysis: (as C ₃₀ H ₃₄ N ₄ O ₄ .0.2 H ₂ O) Found: C, 69.62; H, 6.70; N, 10.6
3 Calculated: C, 69.53; H, 6.69; N, 10.8
1

(I-103) mp. 210-215 ° C NMR (CD ₃ OD) δ: 2.01 (1H, m);
4-2.6 (2H, m), 2.65 (1H, m), 4.
36 (1H, dd, J = 7.4, 11.7), 4.83
(1H, d, J = 14.7), 5.28 (1H, d, J
= 14.7), 6.87 (1H, d, J = 6.3),
6.96 (1H, t, J = 6.6), 7.14 (1H,
t, J = 7.0), 7.1-7.4 (10H, m). Elemental analysis: (as C ₂₅ H ₂₅ N ₅ O ₃ S ₁ ) Actual: C, 67.66; H, 5.77; N, 15.6
3 Calculated: C, 67.71; H, 5.68; N, 15.7.
9

(I-104) mp. 238-239 ° C NMR (CD ₃ OD-CDCl ₃ ) δ: 2.05 (1H,
m), 2.5-2.8 (3H, m), 2.76 (3H,
s), 4.42 (1H, dd, J = 7.5, 11.
4), 4.93 (1H, d, J = 15.0), 5.15
(1H, d, J = 15.0), 6.86 (1H, d, J)
= 7.6), 6.96 (1H, t, J = 7.6), 7.
1-7.4 (11H, m). Elemental analysis: (as C ₂₆ H ₂₇ N ₅ O ₃ ) Actual: C, 67.99; H, 6.01; N, 15.1
6 Calculated: C, 68.25; H, 5.95; N, 15.3.
1

(I-105) mp. > 230 ° C NMR (CD ₃ OD) δ: 0.5 (2H, m), 0.7
3 (2H, m), 2.0 (1H, m), 2.4-2.8
(2H, m), 4.52 (1H, dd, J = 7.5, 1
1.7), 4.74 (1H, d, J = 15.3), 5.
26 (1H, d, J = 15.3), 6.82 (1H,
d, J = 8.1), 6.96-7.03 (2H, m),
7.1-7.3 (9H, m), 7.65 (1H, d, J
= 8.1). Elemental analysis: (as C ₂₈ H ₂₉ N ₅ O ₃ .0.5H ₂ O) Found: C, 68.35; H, 6.08; N, 14.0
7 Calculated: C, 68.27; H, 6.14; N, 14.2
2 Mass: m / z [M + H] ⁺ 484

(I-106) mp. 180-183 ° C NMR (CD ₃ OD) δ: 1.33 (9H, s);
95 (1H, m), 2.33 (1H, m), 2.55
(2H, m), 2.65 (3H, s), 4.29 (1
H, dd, J = 7.5, 10.0), 4.85 (1H,
d, J = 15.0), 5.18 (1H, d, J = 15.
0), 6.81 (1H, d, J = 7.8), 7.1-
7.4 (7H, m). Elemental analysis: (C ₂₄ H ₃₁ N ₅ O ₃ .
0.4. Found: AcOEt) Found: C, 65.07; H, 7.29; N, 14.9.
6 Calculated: C, 65.07; H, 7.29; N, 14.8.
1

(I-107) powder NMR (CD ₃ OD) δ: 0.93 (3H, t, J =
6.6), 1.11 (3H, d, J = 6.6), 1.4
6 (2H, dq, J = 6.6, 6.6), 2.0 (1
H, m), 2.38-2.72 (3H, m), 3.66.
(1H, m), 4.36 (1H, dd, J = 7.5, 1
1.8), 4.83 (1H, d, J = 14.7), 5.
26 (1H, d, J = 14.7), 6.84 (1H,
d, J = 7.5), 6.95 (1H, m), 7.1-
7.4 (11H, m). Elemental analysis: (as C ₂₉ H ₃₃ N ₅ O ₃ .0.2H ₂ O) Found: C, 69.07; H, 6.64; N, 13.8
0 Calculated: C, 69.21; H, 6.69; N, 13.9.
1 Mass: m / z [M + H] ⁺ 500

(I-108) mp. 157-160 ° C NMR (CD ₃ OD) δ: 2.04 (1H, m);
50 (2H, m), 2.70 (1H, m), 4.38
(1H, dd, J = 7.5, 11.5), 4.88 (1
H, d, J = 15.0), 5.28 (1H, d, J = 1)
5.0), 6.9-7.1 (3H, d, m), 7.1-
7.5 (15H, m) elemental analysis: (C ₃₁ H ₂₉ N ₅ O ₃ .
Found) C, 71.67; H, 5.71; N, 13.4.
8 Calculated: C, 71.66; H, 5.63; N, 13.4.
8

(I-109) mp. 237-239.
5 ° C. NMR (CD ₃ OD-DMSO-d ₆ ) δ: 1.13 (6
H, d, J = 6.6), 3.82 (1H, m), 4.3
0 (1H, m), 4.55 (1H, m), 4.84 (1
H, dd, J = 7.8, 11.4), 4.93 (1H,
d, J = 15.9), 5.29 (1H, d, J = 15.
9), 6.85 (1H, d, J = 7.8), 6.97
(1H, t, J = 7.2), 7.1-7.5 (11H,
m). Elemental analysis: (as C ₂₈ H ₃₂ N ₆ O ₃ .0.3 H ₂ O) Found: C, 65.81; H, 5.97; N, 14.2
7 Calculated: C, 65.97; H, 6.05; N, 14.2.
1 Mass: m / z [M + H] ⁺ 488

(I-110) mp. 241-244 ° C NMR (DMSO-d ₆ ) δ: 1.06 (6H, d, J
= 6.6), 1.3 (1H, m), 1.75 (2H, b
rs. ), 2.0 (2H, m), 2.5 (2H, m),
3.7 (1H, m), 3.8 (1H, m), 4.55
(1H, d, J = 14.4), 5.19 (1H, d, J
= 14.4), 5.91 (1H, d, J = 7.5),
6.58 (2H, d, J = 8.1), 6.66 (1H,
d, J = 7.2), 6.87 (1H, t, J = 7.
2), 7.05-7.35 (11H, m), 8.24
(1H, s), 8.71 (1H, s). Elemental analysis: (as C ₂₉ H ₃₃ N ₅ O ₃ .0.8 H ₂ O) Found: C, 67.77; H, 6.62; N, 13.6.
1 Calculated: C, 67.76; H, 6.78; N, 13.6.
2 Mass: m / z [M + H] ⁺ 500

(I-111) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.3), 2.00 (1H, m), 2.4-2.6 (2
H, m), 2.65 (1H, m), 3.84 (1H,
m), 4.35 (1H, m), 4.85 (1H, d, J
= 15.0), 5.22 (1H, d, J = 15.0),
6.68 (2H, d, J = 8.0), 6.84 (1H,
d, J = 7.8), 7.07 (1H, d, J = 8.
0), 7.1-7.4 (8H, m). Elemental analysis: (as C ₂₈ H ₃₁ N ₅ O ₄ .0.7H ₂ O) Found: C, 65.71; H, 6.39; N, 13.3.
4 Calculated: C, 65.40; H, 6.35; N, 13.6.
2

(I-112) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.6), 2.0 (1H, m), 2.4-2.7 (3
H, m), 3.85 (1H, m), 4.35 (1H, d
d, J = 7.2, 11.1), 4.83 (1H, d, J)
= 14.7), 5.28 (1H, d, J = 14.7),
6.84 (2H, d, J = 7.8), 7.12 (1H,
t, J = 7.8), 7.2-7.4 (7H, m), 7.
53 (2H, d, J = 9.3), 8.11 (2H, d,
J = 9.3). Elemental analysis: (as C ₂₈ H ₃₀ N ₆ O ₅ .0.5H ₂ O) Found: C, 62.31; H, 5.92; N, 15.7
4 Calculated: C, 62.33; H, 5.79; N, 15.5
7 Mass: m / z [M + H] ⁺ 531

(I-113) mp. 210-216 ° C NMR (DMSO-d ₆ ) δ: 1.07 (6H, d, J
= 6.6), 1.9 (1H, m), 2.3 (1H,
m), 2.45-2.7 (2H, m), 2.79 (6
H, s), 3.7 (1H, m), 4.2 (1H, m),
4.74 (1H, d, J = 15.0), 5.26 (1
H, d, J = 15.0), 5.92 (1H, d, J =
7.5), 6.33 (1H, d, J = 8.1), 6.6
3 (2H, d, J = 9.0), 6.71 (1H, d, J
= 7.5), 7.07 (1H, t, J = 7.5), 7.
13 (2H, d, J = 9.0), 7.25 (4H,
m), 7.32 (1H, dt, J = 2.5, 7.5),
7.420 (1H, d, J = 7.5), 8.25 (1
H, s), 8.37 (1H, s). Elemental analysis: (as C ₃₀ H ₃₆ N ₆ O ₃ .0.5SiO ₂ ) Found: C, 64.47; H, 6.61; N, 14.9
1 Calculated: C, 64.50; H, 6.49; N, 15.0
4 Mass: m / z [M + H] ⁺ 529

(I-114) mp. 233-237 ° C NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.6), 2.00 (1H, m), 2.34-2.74
(3H, m), 3.85 (1H, m), 4.35 (1
H, dd, J = 7.8, 11.7), 4.83 (1H,
d, J = 14.7), 5.25 (1H, d, J = 14.0).
7), 6.84 (1H, d, J = 7.8), 6.95
(2H, t, J = 9.0), 7.12 (1H, t, J =
7.8), 7.16-7.38 (8H, m). Elemental analysis: (as C ₂₈ H ₃₀ N ₅ O ₃ F) Found: C, 66.78; H, 6.01; N, 13.9
1; F, 3.77 Calculated: C, 66.81; H, 6.01; N, 13.8.
4: F, 3.79

(I-115) powder NMR (DMSO-d ₆ ) δ: 1.07 (6H, d, J
= 6.6), 1.94 (1H, m), 2.38 (1H,
m), 2.60 (2H, m), 3.72 (1H, m),
4.21 (1H, m), 4.74 (1H, d, J = 1
5), 5.30 (1H, d, J = 15), 5.90 (1
H, d, J = 7.5), 6.72 (1H, d, J = 7.
5), 7.01 (1H, d, J = 3.6), 7.06
(1H, m), 7.08 (1H, t, J = 7.8),
7.16-7.38 (5H, m), 7.30 (1H,
d, J = 3.6), 7.45 (1H, d, J = 8.
1), 8.25 (1H, brs), 10.57 (1H,
brs). Elemental analysis: (as C ₂₅ H ₂₈ N ₆ O ₃ S) Found: C, 60.96; H, 5.73; N, 17.0
6; S, 6.51 Calculated: C, 60.97; H, 5.97; N, 16.7.
7; S, 6.61

(I-116) mp. 228-232 ° C NMR (DMSO-d ₆ ) δ: 1.07 (6H, d, J
= 6.3), 2.00 (1H, m), 2.34 (1H,
m), 2.59 (2H, m), 3.74 (1H, m),
3.77 (3H, s), 4.20 (1H, m), 4.7
5 (1H, d, J = 15.3), 5.27 (1H, d,
J = 15), 5.91 (1H, d, J = 7.8), 6.
55 (1H, d, J = 7.8), 6.72 (2H,
m), 7.08 (1H, t, J = 7.5), 7.22
(4H, m), 7.33 (1H, m), 7.43 (1
H, d, J = 7.8), 7.70 (1H), 8.09
(1H, d, J = 3), 8.24 (1H, s), 8.6
9 (1H, s). Elemental analysis: (as C ₂₈ H ₃₂ N ₆ O ₄ ) Actual: C, 65.10; H, 6.24; N, 16.2
7 Calculated: C, 65.13; H, 6.30; N, 16.1
2.

(I-117) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.3), 2.06 (1H, m), 2.44-2.77
(3H, m), 3.85 (1H, m), 4.46 (1
H, dd, J = 7.0, 11.5), 4.82 (1H,
d, J = 14.4), 5.29 (1H, d, J = 14.0).
4), 6.84 (1H, d, J = 7.5), 7.17
(5H, m), 7.34 (3H, m), 8.10 (1
H, dd, J = 2.4, 8.7), 8.77 (1H,
d, J = 2.1). Mass: m / z [M + H] ⁺ 530

(I-118) mp. 197-199 ° C NMR (DMSO-d ₆ ) δ: 1.06 (6H, d, J
= 6.3), 1.96 (1H, m), 2.30-2.6.
9 (2H, m), 3.71 (1H, m), 4.21 (1
H, m), 4.73 (1H, d, J = 14.7), 5.
29 (1H, d, J = 15.3), 5.90 (1H,
d, J = 7.8), 6.71 (1H, d, J = 7.
5), 7.09 (2H, m), 7.23 (4H, m),
7.34 (1H, m), 7.44 (1H, d, J = 7.
8), 8.24 (1H, s), 8.98 (1H, s),
10.99 (1H, brs). Elemental analysis: (as C ₂₄ H ₂₇ N ₇ O ₃ S. 0.2 Et ₂ O) Found: C, 58.59; H, 5.75; N, 19.2
8; S, 6.31 Calculated: C, 58.66; H, 5.69; N, 19.3
6; S, 6.28 Mass: m / z [M + H] ⁺ 494

(I-119) powder NMR (DMSO-d ₆ ) δ: 1.07 (6H, d, J
= 6.3), 1.99 (1H, m), 2.34-2.7.
2 (3H, m), 3.71 (1H, m), 4.25 (1
H, m), 4.76 (1H, d, J = 15.3), 5.
31 (1H, d, J = 15), 5.91 (1H, d, J)
= 7.8), 6.73 (1H, d, J = 7.5), 7.
09 (1H, t, J = 8), 7.16-7.41 (8
H, m), 7.46 (1H, d, J = 7.50), 7.
63 (1H, d, J = 7.8), 7.86 (1H, d,
J = 7.5), 8.26 (1H, s), 10.82 (1
H, brs). Elemental analysis: (as C ₂₉ H ₃₀ N ₆ O ₃ S. 0.3 H ₂ O) Found: C, 63.55; H, 5.63; N, 15.3
3: S, 5.85 Calculated: C, 63.68; H, 5.74; N, 15.0.
4: S, 5.98 Mass: m / z [M + H] ⁺ 543

(I-120) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.6), 2.00 (1H, m), 2.35-2.74
(3H, m), 3.85 (1H, m) 4.35 (1H,
dd, J = 7.8, 11.4), 4.81 (1H, d,
J = 14.7), 5.29 (1H, d, J = 14.0).
7), 6.84 (1H, d, J = 7.5), 7.12
(1H, t, J = 7.8), 7.16-7.42 (8
H, m), 8.24 (2H, d, J = 6.6). Elemental analysis: (C ₂₇ H ₃₀ N ₆ O ₃ .0.3 MeOH 0.0.
Found: 1H ₂ O) Found: C, 65.84; H, 6.36; N, 16.8.
8 Calculated: C, 66.11; H, 6.40; N, 16.5.
5 Mass: m / z [M + H] ⁺ 487

(I-121) mp. 171-174 ° C NMR (DMSO-d ₆ ) δ: 1.07 (6H, d, J
= 6.3), 1.96 (1H, m), 2.32-2.7.
0 (3H, m), 3.72 (1H, m), 4.27 (1
H, m), 4.74 (1H, d, J = 14.7), 5.
29 (1H, d, J = 15.0), 5.91 (1H,
d, J = 7.5), 6.72 (1H, d, J = 7.5)
0), 7.08 (1H, t, J = 7.5), 7.23
(4H, m), 7.34 (1H, dt, J = 1.8,
7.5), 7.45 (1H, d, J = 7.5), 8.0
3 (1H, d, J = 7.8), 8.18 (1H, d, J
= 2.4), 8.25 (2H, m), 8.81 (1H,
d, J = 1.5), 9.62 (1H, s). Elemental analysis: (as C ₂₆ H ₂₉ N ₇ O ₃ .0.3 H ₂ O) Found: C, 63.35; H, 6.05; N, 19.8
9 Calculated: C, 63.48; H, 6.98; N, 19.7.
7 Mass: m / z [M + H] ⁺ 488

(I-122) mp. 168-172 ° C NMR (DMSO-d ₆ ) δ: 1.17 (6H, d, J
= 6.3), 1.04 (4H, m), 1.23-1.4.
6 (3H, m), 1.56 (1H, m), 1.83 (1
H, m), 1.96 (1H, brs), 2.22 (2
H, m), 2.52 (2H, m), 3.30 (1H,
m), 3.72 (1H, m), 4.12 (1H, m),
4.71 (1H, d, J = 14.1), 5.26 (1
H, dd, J = 15.0, 7.0), 5.90 (1H,
d, J = 7.8), 5.98 (1H, dd, J = 3.
9, 8.1), 6.13 (1H, m), 6.70 (1
H, d, J = 7.5), 7.06 (1H, t, J = 7.
8), 7.24 (5H, m), 7.40 (1H, m),
8.22 (1H, s). Elemental analysis: (as C ₂₉ H ₃₇ N ₅ O ₃ .0.3 H ₂ O) Found: C, 68.43; H, 7.44; N, 13.7
6 Calculated: C, 68.52; H, 7.69; N, 13.7
4 Mass: m / z [M + H] ⁺ 504

(I-123) mp. 200-203 ° C NMR (CD ₃ OD) δ: 1.13 (6H, dd, J =
3.3, 6.6), 2.05 (1H, m), 2.38-
2.75 (3H, m), 3.84 (1H, m), 4.4
1 (1H, dd, J = 7.5, 11.4), 4.83
(1H, d, J = 14.7), 5.28 (1H, d, J
= 14.7), 6.86 (1H, d, J = 7.8),
7.13 (1H, t, J = 8.0), 7.23 (3H,
m), 7.35 (3H, m), 7.42 (1H, dd,
J = 4.0, 8.0), 7.60 (1H, dd, J =
2.4, 9.0), 7.88 (1H, d, J = 9.
0), 7.99 (1H, d, J = 2.4), 8.16
(1H, m), 8.65 (1H, dd, J = 1.5,
4.5). Elemental analysis: (as C ₃₁ H ₃₂ N ₆ O ₃ ) Actual: C, 69.38; H, 6.01; N, 15.6
6 Calculated: C, 69.12; H, 6.01; N, 15.5.
8

(I-124) powder NMR (DMSO-d ₆ ) δ: 1.07 (6H, d, J
= 6.3), 2.31 (2H, m), 2.62 (2H,
m), 3.72 (1H, m), 4.24 (1H, m),
4.77 (1H, d, J = 15.3), 5.26 (1
H, d, J = 15.3), 5.30 (2H, d, J =
1.8), 5.93 (1H, d, J = 7.5), 6.3
5 (2H, brs), 6.72 (1H, d, J = 7.
5), 7.08 (1H, t, J = 8.0), 7.17−
7.38 (5H, m), 7.33 (1H, d, J = 2.
1), 7.44 (1H, d, J = 7.8), 8.03
(1H, d, J = 7.8), 8.25 (1H, br
s). Elemental analysis: (as C ₂₅ H ₂₉ N ₇ O ₃ .0.4H ₂ O) Found: C, 62.20; H, 6.22; N, 20.3
1 Calculated: C, 62.36; H, 6.23; N, 20.1
6 Mass: m / z [M + H] ⁺ 476

(I-125) mp. 203-207 ° C NMR (DMSO-d ₆ ) δ: 1.07 (6H, d, J
= 6.3), 1.93 (1H, m), 2.30 (1H,
m), 2.46-2.38 (2H, m), 3.72 (1
H, m), 4.15 (1H, m), 4.74 (1H,
d, J = 15.3), 5.27 (1H, d, J = 15.
3), 5.91 (1H, d, J = 7.8), 6.28
(1H, d, J = 9.6), 6.47 (1H, d, J =
7.8), 6.71 (1H, d, J = 7.5), 7.0
7 (1H, t, J = 8.0), 7.14-7.36 (6
H, m), 7.42 (1H, d, J = 7.8), 7.4
8 (1H, d, J = 2.7), 8.24 (1H, s),
8.29 (1H, s), 11.16 (1H, brs). Elemental analysis: (as C ₂₇ H ₃₀ N ₆ O ₄ .0.3 H ₂ O) Found: C, 63.84; H, 6.07; N, 16.5
4 Calculated: C, 62.89; H, 6.02; N, 16.4
6 Mass: m / z [M + H] ⁺ 503

(I-126) powder NMR (CD ₃ OD) δ: 1.15 (6H, d, J =
6.3), 1.93 (1H, m), 2.32 (1H,
m), 2.5-2.7 (2H, m), 3.19 (2H,
m), 3.53 (2H, m), 3.85 (1H, m),
4.29 (1H, dd, J = 7.7, 11.5);
85 (1H, d, J = 14.7), 5.20 (1H,
d, J = 14.7), 6.83 (1H, d, J = 7.
8), 7.1-7.4 (7H, m ) Elemental _{analysis: (C 24 H 31 N 5} O 4 .0.4H 2 O as) Found: C, 62.73; H, 6.93 N, 15.0
0 Calculated: C, 62.56; H, 6.96; N, 15.2
0

(I-127) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.6), 2.0 (1H, m), 2.4-2.7 (3
H, m), 3.84 (1H, m), 4.35 (1H, d
d, J = 8.1, 11.7), 4.82 (1H, d, J)
= 15.0), 5.22 (1H, d, J = 15.0),
6.88 (4H, m), 7.1-7.4 (9H, m). Elemental analysis: (C ₂₈ H ₃₂ N ₆ O ₃ .0.25Et ₂ O.
0.4 H ₂ O as) Found: C, 66.25; H, 6.66 ; N, 15.9
2 Calculated: C, 66.18; H, 6.76; N, 15.9.
7 Mass: m / z [M + H] ⁺ 501

(I-128) mp. 168-171 ° C NMR (CD ₃ OD) δ: 1.14 (6H, s);
1 (1H, m), 2.3 (1H, m), 2.5 (2H,
m), 3.84 (1H, m), 4.16 (1H, dd,
J = 7.5, 11.7), 4.83 (1H, d, J = 1)
5.0), 5.04 (2H, s), 5.23 (1H,
d, J = 15.0), 6.83 (1H, d, J = 7.
8), 7.1-7.4 (12H, m). Elemental analysis: (C ₂₉ H ₃₂ N ₄ O ₄ .0.4CH ₃ CO ₂ Et
Found) C, 68.69; H, 6.56; N, 10.5
5 Calculated: C, 68.59; H, 6.62; N, 10.4
6

(I-129) mp. 158-164 ° C NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.6), 2.15 (1H, m), 2.40 (1H,
m), 2.60 (2H, m), 3.84 (1H, m),
4.20 (1H, dd, J = 7.5, 11.4);
87 (1H, d, J = 15.0), 5.23 (1H,
d, J = 15.0), 6.84 (1H, d, J = 7.
2), 7.10-7.40 (12H, m). Elemental analysis: (as C ₂₉ H ₃₀ N ₄ O ₄ ) Actual: C, 68.90; H, 6.23; N, 11.5
6 Calculated: C, 69.12; H, 6.21; N, 11.5
1 Massm / z [M + H] +487

(I-130) powder NMR (CD ₃ OD) δ: 1.49 (9H, s), 2.
14 (1H, m), 2.54 (2H, m), 2.67
(1H, m), 2.81 (3H, s), 4.22 (1
H, dd, J = 7.5, 12.5), 4.90 (1H,
d, J = 14.6), 5.35 (1H, d, J = 14.0).
6), 6.81 (1H, d, J = 7.5), 7.11
(1H, t, J = 7.2), 7.3 (3H, m), 7.
4 (3H, m) Elemental _{analysis: (C 24 H 31 N 5} O 3 .2H 2 O as) Found: C, 60.54; H, 7.22 ; N, 14.8
9 Calculated: C, 60.87; H, 7.45; N, 14.7.
9

(I-131) mp. 180-183 ° C NMR (CD ₃ OD) δ: 1.48 (9H, s);
05 (1H, m), 2.5-2.8 (3H, m), 4.
35 (1H, m), 4.84 (1H, d, J = 14.
8), 5.30 (1H, d, J = 14.8), 6.8
(3H, m), 7.0-7.4 ( 9H, m) Elemental _{analysis: (C 29 H 33 N 5} O 4 ..0.2CH 3 CO 2 C
₂ H ₅ . (As 2.6 H ₂ O) Found: C, 61.69; H, 6.49; N, 12.0
1 Calculated: C, 61.65; H, 6.93; N, 11.9.
8 Massm / z [M + H] ⁺ 516

(I-132) powder NMR (CD ₃ OD) δ: 1.48 (9H, s), 2.
07 (1H, m), 2.55 (2H, m), 2.69
(1H, m), 4.20 (1H, dd, J = 7.5, 1
2.5), 4.78 (1H, d, J = 11.4), 5.
35 (1H, d, J = 11.4), 6.83 (1H,
d, J = 7.6), 7.11 (1H, t, J = 8.
1), 7.2-7.3 (3H, m), 7.3-7.5
(3H, m) Elemental _{analysis: (C 23 H 29 N 5} O 3 .3H 2 O as) Found: C, 60.30; H, 6.99 ; N, 15.2
4 Calculated: C, 60.11; H, 7.24; N, 15.2
4

(I-133) powder NMR (CD ₃ OD) δ: 1.48 (9H, s), 2.
2 (1H, m), 2.4-2.8 (3H, m), 2.9
2 (3H, m), 4.31 (1H, dd, J = 7.6,
11.4), 4.84 (1H, d, J = 14.8),
5.23 (1H, d, J = 14.8), 6.8 (2H,
d, J = 7.4), 7.0-7.4 (12H, m). Elemental _{analysis: (C 30 H 35 N 5} O 3 ..2.3H 2 O as) Found: C, 64.92; H, 7.19 ; N, 12.6
2 Calculated: C, 64.92; H, 6.79; N, 12.8.
0 Massm / z [M + H] ⁺ 514

(I-134) powder NMR (CD ₃ OD) δ: 1.49 (9H, s), 2.
05 (1H, m), 2.6 (3H, m), 4.41 (1
H, dd, J = 7.2, 11.1), 4.90 (1H,
d, J = 15.0), 5.20 (1H, d, J = 15.
0), 6.87 (1H, d, J = 7.5), 6.94
(2H, d, J = 7.5), 7.0-7.35 (10
H, m). Massm / z [M + H] ⁺ 515

(I-135) powder NMR (CD ₃ OD) δ: 1.98 (1H, m);
3-2.7 (3H, m), 3.66 (3H, s), 4.
10 (1H, m), 4.85 (1H, d, J = 15.
0), 5.07 (1H, d, J = 15.0), 6.8-
7.4 (13H, m) Elemental _{analysis: (C 30 H 35 N 5} O 4 .. As) Found: C, 67.84; H, 6.71 ; N, 13.0
4 Calculated: C, 68.03; H, 6.66; N, 13.2
2

(I-136) mp. _{150-153 ℃ NMR (CDCl 3) δ} : 1.50 (9H, s), 1.
95 (1H, m), 2.5-2.8 (3H, m), 4.
30 (2H, m), 4.70 (1H, d, J = 20.
0), 5.32 (1H, d, J = 20.0), 6.8-
7.4 (13H, m) Elemental _{analysis: (C 29 H 33 N 5} O 4 ..0.2 (C 2 H 5) 2
Found: O, C, 67.84; H, 6.65; N, 13.2.
0 Calculated: C, 67.65; H, 6.63; N, 13.0.
0 Massm / z [M + H] ⁺ 516

(I-137) powder NMR (CD ₃ OD) δ: 1.49 (9H, s), 1.
95 (1H, m), 2.15 (1H, m), 2.34
(1H, m), 2.52 (1H, m), 2.89 (6
H, s), 3.99 (1H, dd, J = 7.5, 11.
5), 4.77 (1H, d, J = 15.0), 5.09
(1H, d, J = 15.0), 6.61 (2H, d, J
= 7.2), 6.69 (2H, d, J = 7.2), 6.
77 (1H, d, J = 7.2), 6.9-7.3 (9
H, m) Elemental analysis: (as C ₂₉ H ₃₃ N ₅ O ₄ ... 0.2 H ₂ O) Found: C, 70.03; H, 7.12; N, 13.0
0 Calculated: C, 70.09; H, 7.10; N, 13.1
8

(I-138) powder NMR (CD ₃ OD) δ: 1.47 (9H, s), 1.
94 (1H, m), 2.10 (1H, m), 2.38
(1H, m), 2.50 (1H, m), 3.15 (4
H, m), 3.55 (4H, m), 3.97 (1H, d
d, J = 7.5, 10.5), 4.78 (1H, d, J)
= 14.5), 5.10 (1H, d, J = 14.5),
6.69 (2H, d, J = 6.9), 6.78 (1H,
d, J = 6.9), 6.72 (1H, t, J = 7.
0), 7.0-7.3 (9H, m ) Elemental _{analysis: (C 33 H 39 N 6} O 4 .0.5H 2 as O) Found: C, 68.63; H, 7.04 N, 11.7
5 Calculated: C, 68.49; H, 6.97; N, 12.0
0

(I-139) powder NMR (CD ₃ OD) δ: 1.49 (9H, s), 4.
3 (1H, m), 4.6 (1H, m), 5.00 (1
H, dd, J = 7.2, 11.4), 5.02 (1H,
d, J = 15.9), 5.19 (1H, d, J = 15.
9), 6.8-7.4 (13H, m ) Elemental _{analysis: (C 28 H 31 N 5} O 4 .0.1CH 3 OH.
(As 0.4 H ₂ O) Found: C, 66.21; H, 6.32; N, 13.4.
0 Calculated: C, 65.92; H, 6.34; N, 13.6.
8 Massm / z [M + H] ⁺ 502

(I-140) powder NMR (CD ₃ OD) δ: 2.03 (1H, m), 2.
55 (2H, m), 2.70 (1H, m), 4.46
(1H, dd, J = 6.9, 11.1), 4.98 (1
H, d, J = 15.0), 5.18 (1H, d, J = 1)
5.0), 6.9-7.4 (18H, m ) Elemental _{analysis: (C 31 H 31 N 6} O 2 ..0.5H 2 O.0.
₅ (C ₂ H 5) as a ₂ O) Found: C, 70.29; H, 6.24 ; N, 14.9
9 Calculated: C, 70.07; H, 6.59; N, 14.8.
6

(I-141) mp. 163-165 ° C NMR (CD ₃ OD) δ: 2.00 (1H, m);
15 (1H, m), 2.37 (1H, m), 2.55
(1H, m), 2.94 (6H, s), 2.98 (6
H, s), 3.98 (1H, dd, J = 7.8, 11.
4), 4.78 (1H, d, J = 15.0), 5.10
(1H, d, J = 15.0), 6.66 (2H, d, J
= 7.8), 6.79 (2H, m), 7.0-7.3.
(9H, m) Elemental analysis: (as C ₂₉ H ₃₄ N ₆ O ₂ ) Actual: C, 69.72; H, 6.91; N, 16.5
8 Calculated: C, 69.86; H, 6.87; N, 16.8.
5 Massm / z [M + H] ⁺ 499

(I-142) powder NMR (CD ₃ OD) δ: 2.00 (1H, m);
10 (1H, m), 2.40 (1H, m), 2.50
(1H, m), 3.30 (2H, m), 3.46 (2
H, t, J = 4.8), 3.61 (2H, m), 3.6.
7 (2H, t, J = 5.4), 3.96 (1H, dd,
J = 7.5, 11.5), 4.80 (1H, d, J = 1)
4.7), 5.12 (1H, d, J = 14.7), 6.
72 (2H, d, J = 7.4), 6.84 (1H,
m), 7.0-7.3 (9H, m) Massm / z [M + H] ⁺ 583

(I-143) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.6), 1.17 (6H, d, J = 6.6), 2.0
8 (1H, m), 2.4-2.7 (3H, m), 3.8
5 (2H, m), 4.30 (1H, dd, J = 7.5,
10.5), 4.81 (1H, d, J = 14.7),
5.20 (1H, d, J = 14.7), 6.68 (2
H, d, J = 8.7), 6.80 (2H, d, J = 7.
0), 7.06 (1H, t, J = 7.2), 7.1-
7.3 (6H, m) Elemental analysis: (as C ₃₁ H ₃₈ N ₆ O ₃ .H ₂ O) Found: C, 66.12; H, 7.12; N, 14.9
9 Calculated: C, 66.41; H, 7.12; N, 14.5.
8 Massm / z [M + H] ⁺ 543

(I-144) powder NMR (CD ₃ OD) δ: 1.13 (6H, dd, J =
6.3, 2.1), 2.05 (1H, m), 2.5-
2.7 (3H, m), 3.83 (1H, 7tet, J =
6.3), 4.37 (1H, dd, J = 6.9, 10.
5), 4.87 (1H, d, J = 14.8), 5.23
(1H, d, J = 15.0), 6.67 (2H, d, J
= 6.3)), 6.81 (2H, d, J = 6.3),
6.82 (1H, t, J = 7.8), 7.08 (1H,
t, J = 7.8), 7.2-7.4 (6H, m) Elemental analysis: (as C ₂₈ H ₃₂ N ₆ O ₃ ... 0.5H ₂ O) Actual: C, 65. 94; H, 6.65; N, 16.3
9 Calculated: C, 65.99; H, 6.53; N, 16.4
9

(I-145) powder NMR (CD ₃ OD) δ: 1.14 (6H, dd, J =
6.3, 1.8), 2.05 (1H, m), 2.4-
2.7 (3H, m), 3.32 (2H, m), 3.64
(2H, m), 3.83 (1H, m), 4.32 (1
H, dd, J = 6.9, 9.0), 4.88 (1H,
d, J = 15.0), 5.17 (1H, d, J = 8.
7), 6.65 (2H, d, J = 8.7), 6.76
(2H, d, J = 8.7), 6.80 (1H, m),
7.0-7.4 (7H, m) Elemental _{analysis: (C 30 H 36 N 6} O 4 .H 2 as O) Found: C, 64.14; H, 6.72 ; N, 14. 6
7 Calculated: C, 64.04; H, 6.81; N, 16.9.
4 Massm / z [M + H] ⁺ 545

(I-146) powder NMR (CD ₃ OD) δ: 1.14 (6H, d, J =
6.6), 1.40 (1H, m), 1.80 (1H,
m), 2.45 (1H, m), 3.84 (1H, m),
3.96 (1H, dd, J = 1.8, 7.5), 4.6
2 (1H, d, J = 14.1), 5.13 (1H, d,
J = 14.1), 6.74 (1H, d, J = 7.8),
6.9-7.35 (12H, m) Elemental _{analysis: (C 30 H 36 N 6} O 2 .1.5H 2 O as) Found: C, 66.58; H, 6.95 ; N, 15.2
7 Calculated: C, 66.77; H, 7.28; N, 15.5.
7 Massm / z [M + H] ⁺ 513

Test Example 1 Inhibition of NPYY1 receptor
Using the SK-N-MC cells cultured, the cells were incubated with ¹²⁵ I-labeled peptide YY (about 50,000 cpm) at 37 ° C. for 1 hour in the presence or absence of the compound (I) of the present invention. After the reaction was completed, the ¹²⁵ I-labeled peptide YY bound to the cells was separated using a glass fiber filter paper, and the radioactivity was measured using a gamma counter. Specific binding was determined by subtracting non-specific binding obtained under conditions containing 10 ^-7 M non-radioactive NPY. The IC ₅₀ value was calculated as the concentration of the compound (I) of the present invention which inhibits the specific binding of ¹²⁵ I-labeled peptide YY to cells by 50%.

The results are shown below.

[0494]

[Table 14]

Formulation Example 1 Tablet Compound of the present invention 15 mg Starch 15 mg Lactose 15 mg Crystalline cellulose 19 mg Polyvinyl alcohol 3 mg Distilled water 30 ml Calcium stearate 3 mg Components other than calcium stearate are uniformly mixed, crushed, granulated and dried. And granules of an appropriate size. Next, calcium stearate was added and compression molded to obtain tablets.

[0496]

As is clear from the above test examples, the compounds of the present invention show strong NPY antagonistic activity. Therefore, the compound of the present invention is very useful as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina, and an antihypertensive agent.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/55 AED A61K 31/55 AED C07D 267/14 C07D 267/14 281/10 281/10 C 281/18 281 / 18 401/06 223 401/06 223 401/12 223 401/12 223 403/06 209 403/06 209 403/12 223 403/12 223 413/12 223 413/12 223 417/12 223 417/12 223 / / C07D 225/06 C07D 225/06 267/22 267/22 C07M 7:00 C07M 7:00 F term (reference) 4C034 EC05 4C036 AB03 AB05 AB09 AB10 AB14 AB17 AB20 4C056 AA03 AB01 AC03 AD03 AE03 FA02 FB11 FC04 4C033A BB09 CC19 CC22 CC26 CC29 CC34 CC42 CC51 CC61 CC62 CC67 DD07 DD12 DD14 DD19 EE01 4C086 AA01 AA02 AA03 BC32 BC33 BC36 BC38 BC39 BC41 BC42 BC46 BC48 BC50 BC52 BC64 BC65 BC67 BC68 BC69 BC70 BC71 BC73 BC75 BC76 BC02 GA85 BC82 GA GA07 GA09 GA10 GA12 MA01 MA04 NA14 ZA02 ZA05 ZA12 ZA16 ZA18 ZA36 ZA38 ZA40 ZA42 ZA45 ZA59 ZA66 ZA70 ZA81 ZB11 ZC03 ZC21 ZC35 ZC42

Claims (10)

[Claims] 1. A compound of formula (I): (Wherein R ¹ and R ² are each independently hydrogen, halogen,
Hydroxy, nitro, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), carboxy, lower alkoxycarbonyl optionally having substituent (s) or having substituent (s) R ³ is I) lower alkyl optionally having a substituent (however, excluding unsubstituted methyl, wherein the substituent is (1)
Halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) cycloalkyl, (6) cycloalkenyl,
(7) lower alkoxycarbonyl, (8) optionally substituted acyl, (9) amino, (10) nitro, (11) cyano,
^{(12) -NHC (= NR 18} ) NR 19 R 20 ( wherein R ^18, R
¹⁹ and R ²⁰ are each independently hydrogen, hydroxy or lower alkoxycarbonyl) or (13) carbamoyl optionally substituted with lower alkyl. ), II) optionally substituted aryl-lower alkyl (where the substituents are (1) halogen, (2) hydroxy,
(3) benzyloxy, (4) lower alkyl optionally having a substituent (where the substituent is lower alkoxycarbonyl, acyl, aryl, substituted amino or imino), (5) having a substituent Optionally lower alkoxy, (6)
Carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10) acyl, (11) optionally substituted amino (substituent means lower alkyl, substituent Aryl lower alkyl which may have, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl, carbamoyl which may have a substituent), (12) —NHC (＝ R ¹⁶ ) R ¹⁷ (where R ¹⁶ is a substituent, wherein the substituent is lower alkoxycarbonyl or cyano) or an imino or a substituent (here, substituted R ¹⁷ is a lower alkylene which may have a cyano or nitro group, and R ¹⁷ is a substituent (where the substituent is a lower alkoxycarbonyl group). Amino optionally having a carbonyl or a lower alkyl),
Lower alkylthio or aryloxy) or
(13) heterocyclyl lower alkyl) or III) optionally substituted heterocyclyl lower alkyl, wherein R ⁴ is I) NHCOR ⁵ [where R ⁵ is lower optionally substituted] Alkyl (where the substituents are (1) halogen, (2) hydroxy, (3)
Lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro, (10) cyano, (11)-
NHC (= NR ⁶ ) NR ⁷ R ⁸ wherein R ⁶ is hydrogen or cyano, and R ⁷ and R ⁸ are each independently hydrogen, lower alkyl or nitro; or (12) i) benzyloxycarbonyl Ii) acyl (but not formyl), iii) lower alkylsulfonyl or iv) amino having any of carbamoyl which may have a substituent), and aryl which may have a substituent Alkyl (where the substituent is halogen, hydroxy, lower alkyl,
Lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto,
Cyano or nitro), lower alkoxy optionally having substituent (s), aryl optionally having substituent (s), aryloxy optionally having substituent (s) or having substituent (s) A good aryl-lower alkoxy], II) NHCONR ⁹ R ¹⁰ wherein R ⁹ and R ¹⁰ are each independently hydrogen, hydroxy, halogen, acyl, lower alkyl which may have a substituent, Optionally substituted aryl lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl lower alkyl, substituted Cycloalkyl which may be optionally substituted, arylsulfonyl which may have a substituent or amino which may have a substituent) III) NHC (= NR ¹¹ ) NR ¹² R ¹³ (where R ¹¹ is hydrogen, hydroxy, lower alkyl optionally having substituent (s), aryl optionally having substituent (s), aryl lower alkyl which may have substituent (s) or substituent (s) R ¹² and R ¹³ are each independently hydrogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), substituent Optionally substituted amino, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, substituted An optionally substituted heterocyclyl or an optionally substituted heterocyclyl lower alkyl, or R ¹² and R ¹³ together form an optionally substituted heterocyclyl), IV) NHCSNR ¹⁴ R ¹⁵ (where R ¹⁴ and R ¹⁵ are each independently hydrogen, lower alkyl optionally having substituents, aryl optionally having substituents or aryl having substituents V) lower alkyl optionally having substituent (s) or VI) acyl optionally having substituent (s), and X is CH
₂ , S or O, and n is 1 or 2. However, when R ³ is lower alkyl which may have a substituent, R ⁴ is NHCONR ⁹ R ¹⁰ , and R ⁹ and R ¹⁰ are each not an aryl which may have a substituent. , R ³ is unsubstituted aryl lower alkyl, and R ⁴
Is NHCOR ⁵ , R ⁵ is not lower alkyl optionally having substituent (s), and when R ³ is heterocyclyl lower alkyl optionally having substituent (s), R ⁵ is NHC ⁵
ONR ⁹ R ¹⁰ . Or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 2. A method according to claim 1, wherein R ³ is an optionally substituted aryl-lower alkyl, and the substituent is (2) hydroxy, (3) benzyloxy, or (11) Good amino (where the substituent means a lower alkyl, an optionally substituted aryl lower alkyl, a heterocyclyl lower alkyl, a heterocyclylcarbonyl, an acyl (excluding acetyl), a lower alkoxycarbonyl, an arylalkoxycarbonyl, a lower Alkylsulfonyl, carbamoyl optionally having substituent (s) or (12) ′-NHC (＝ R ^{16 ′} ) R ^{17 ′} (where R ^{16 ′} may be substituted with tert-butoxycarbonyl And R ^{17 ′} is an amino optionally substituted with tert-butoxycarbonyl). Acceptable salts or hydrates thereof. 3. R ⁴ is I) NHCOR ^{5 ′} wherein R ^{5 ′} is a lower alkyl optionally having substituent (s) wherein the substituent is (1) halogen, (2)
Hydroxy, (3) lower alkoxy, (4) carboxy, (5)
Lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro, (10) cyano,
(11) -NHC (= NR ⁶ ) NR ⁷ R ⁸ (where R ⁶ is hydrogen or cyano, and R ⁷ and R ⁸ are each independently hydrogen, lower alkyl or nitro) or (12) i ) Benzyloxycarbonyl, ii) acyl (excluding formyl), iii) lower alkylsulfonyl or iv) amino having any of carbamoyl which may have a substituent), lower alkoxy, aryloxy or aryl II) NHCONR ⁹ 'R ¹⁰ ' (where R ⁹ 'and R ¹⁰ ' are each independently hydrogen, acyl, lower alkyl which may have a substituent, or a substituent Optionally substituted aryl lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, heterocyclyl lower alkyl, cycloalkyl, aryl III) NHC (= NR ^{11 ′} ) NR ^{12 ′} R ^{13 ′} (where R ^{11 ′} is hydrogen, lower alkyl optionally substituted or substituted) R ^{12 ′} and R ^{13 ′} are each independently hydrogen, hydroxy, optionally substituted lower alkyl, amino or heterocyclyl) or IV) NHCSNR ^{14 ′} R ^{15 ′} (where R ^{14 ′} and R ^{15 ′} are each independently hydrogen, optionally substituted aryl or optionally substituted aryl-lower alkyl) A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 4. R ¹ and R ² are each independently hydrogen, hydroxy or lower alkoxy optionally having substituent (s), and R ³ is aryl optionally having substituent (s). Lower alkyl (where the substituent is (1) halogen, (2) hydroxy, (3) benzyloxy, (4) lower alkyl which may have a substituent (where the substituent is lower alkoxycarbonyl , Acyl, aryl, substituted amino or imino), (5) optionally substituted lower alkoxy, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10 ) Acyl, (11) amino which may have a substituent (here, the substituent means lower alkyl, optionally substituted aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl, acyl (however, Acetyl is excluded K),
Lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl, or carbamoyl which may have a substituent), (12) -NHC (= R ¹⁶ ) R ¹⁷ (where R ¹⁶ is a substituent (here, substituted) a lower alkoxycarbonyl or cyano and is) good imino or substituted group which may have a (cyano or substituted lower alkylene which may have a nitro and a) the wherein the substituents and radicals, R ¹⁷ is A substituent (where the substituent is a lower alkoxycarbonyl or a lower alkyl), which may have an amino, a lower alkylthio or an aryloxy, or (13) a heterocyclyl lower alkyl;
And R ⁴ is I) NHCOR ^{5 ′} [where R ^{5 ′} is lower alkyl which may have a substituent (where the substituent is (1) halogen, (2) hydroxy, (3)
Lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro, (10) cyano, (11) -NHC (= NR ⁶ ) NR ⁷ R ⁸ (where R ⁶ is hydrogen or cyano, R ⁷ and R ⁸ are each independently hydrogen,
(12) i) benzyloxycarbonyl, ii) acyl (but not formyl), iii) lower alkylsulfonyl or iv) carbamoyl optionally having substituent (s). Amino), lower alkoxy, aryloxy or aryl-lower alkoxy], II) NHCONR ⁹ 'R ¹⁰ ', wherein R ⁹ 'and R ¹⁰ ' each independently have a hydrogen, an acyl or a substituent. Optionally substituted lower alkyl, optionally substituted aryl lower alkyl, optionally substituted aryl, optionally substituted heterocyclyl, heterocyclyl lower alkyl, cycloalkyl, aryl Sulfonyl or optionally substituted amino), III) NHC (= NR ¹¹ ) NR ^{12 '} R ^13' (where R ^{1 1 ′} is hydrogen, lower alkyl which may have a substituent or aryl which may have a substituent, and R ^{12 ′} and R ^{13 ′} each independently have hydrogen, hydroxy, or a substituent. Or optionally) lower alkyl, amino or heterocyclyl) or IV) NHCSNR ^{14 ′} R ^{15 ′} (where R ^{14 ′} and R ^{15 ′} are each independently hydrogen or an optionally substituted aryl) Or an optionally substituted aryl lower alkyl), or a pharmaceutically acceptable salt thereof or a hydrate thereof. 5. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. 6. A neuropeptide Y antagonist comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. 7. An antifeedant comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. 8. A therapeutic agent for myocardial infarction comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. 9. A therapeutic agent for angina pectoris comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. 10. An antihypertensive comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.