TWI643847B - Novel benzoazepine derivatives and their medical uses - Google Patents

Abstract

An object of the present invention is to provide a compound having a V2 receptor agonistic action.

The pharmaceutical composition of the present invention contains a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient:

[wherein, R ¹ represents the following formula:

(wherein, A represents a lower alkyl group which may be substituted with a lower alkyl group; R ⁶ represents a hydrogen atom; and R ⁷ represents a hydroxyl group, an aromatic heterocyclic group which may be substituted by a lower alkyl group, or an amine methyl sulfonyl group or the like. And R ² represents a hydrogen atom or a lower alkyl group; R ³ represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms, or a halogen atom; R ⁴ represents a 5-membered aromatic monocyclic heterocyclic group, or 5 Non-aromatic monocyclic heterocyclic group or the like (wherein the heterocyclic group contains at least one nitrogen atom and may be substituted by a lower alkyl group); R ⁵ represents a lower alkyl group or a halogen atom or the like].

Description

Novel benzoazepine derivatives and their medical uses

The present invention relates to a novel benzoazepine derivative which is useful as a pharmaceutical and a medical use thereof. This compound has various medical uses as a V2 receptor agonist.

Arginine Vasopressin is a peptide containing nine amino acids that is biosynthesized in the hypothalamus and secreted from the posterior pituitary gland. The receptors for arginine superscriptin are classified into three subtypes: V1a, V1b and V2. V1a receptors are found in liver, muscle vascular cells, platelets, peripheral tissues and the central nervous system. V1b receptors are present in the central nervous system. In addition, another V2 receptor is present in the renal collecting duct cells. If ginsenoside is combined with the V2 receptor, it will promote the reabsorption of water in the renal collecting duct and reduce the amount of urine. Therefore, if the arginine vasopressin is insufficient, polyuria is exhibited, and the diseases caused thereby include central diabetes insipidus, nighttime enuresis in children, nocturnal urinary frequency, and overactive bladder. Therefore, V2 receptor agonists are useful as prophylactic or therapeutic agents for such diseases. Further, since the V2 receptor agonist has a blood factor VIII and a Wyberber's factor release action, it can be treated for a bleeding disease (hemophilia, Von Wylie disease, etc.).

Previously, as a V2 receptor agonist, it will act as a peptide of Desmopressin (removal of the amino group of cysteine at position 1 of arginine pressor and conversion of arginine at position 8) For d-type patients) for the treatment of central diabetes insipidus and nocturnal enuresis. However, the bioavailability of the desmopressin oral agent is very low, and a higher amount is required in order to obtain an effect. Further, the desmopressin preparation is relatively expensive, and the occurrence of side effects caused by the absorption deviation between individuals is worrying, and may not be satisfactory in terms of safety. therefore, It is expected to create medicines with higher bioavailability and less absorption deviation.

On the other hand, the metabolic reaction caused by cytochrome P-450 (CYP) plays a major role in the disappearance of the drug from the body. It can be considered that if the drug of the CYP metabolism of the same molecular species competes on its metabolic enzyme, it is subject to a certain Metabolic inhibition. If the CYP is inhibited, it may cause a change in the concentration of the drug in the blood and tissues, a change in the therapeutic effect, and a serious side effect. Therefore, it is desired to create a medicine which has low affinity for CYP and less concern for enzyme inhibition.

Benzene heterocyclic derivatives (Patent Documents 1 to 3), benzoazepine derivatives (Patent Documents 4 to 5), and guanamine have been reported as compounds having an vasopressin receptor agonistic effect. Derivatives (Patent Document 6) and benzodiazepine derivatives (Patent Document 7), as a compound having an angiogenic receptor antagonism, a substituted spirobenzoazinium derivative has been reported (Patent Document 8) However, such compounds are structurally different from the compounds of the invention having a carbonyl group on the carbon at the 4-position of the benzazepine.

[Previous Technical Literature] [Patent Literature]

Patent Document 1: International Publication No. 95/34540

Patent Document 2: Japanese Patent Laid-Open No. 09-221476

Patent Document 3: Japanese Patent Laid-Open Publication No. 2000-351768

Patent Document 4: International Publication No. 97/22591

Patent Document 5: Japanese Patent Laid-Open No. 11-60488

Patent Document 6: Japanese Patent Laid-Open No. 11-1456

Patent Document 7: International Publication No. 2006/104008

Patent Document 8: International Publication No. 2005/37795

An object of the present invention is to provide a compound having a V2 receptor agonistic effect, and A prophylactic or therapeutic agent based on V2 receptor agonism for central diabetes insipidus, nocturnal enuresis, nocturnal urinary frequency, overactive bladder, hemophilia, or Von Willebrand's disease is provided.

In view of the above, the present invention has been considered to be effective as a method for solving the above problems, and a compound having a new basic structure is effective, and efforts have been made to focus on the creation of a novel V2 receptor agonist. As a result, it has been found that the compound represented by the following formula (I) and a salt thereof have a very excellent V2 receptor agonistic effect, and thus the present invention has been completed.

That is, according to the present invention, there is provided a compound represented by the formula (I) or a pharmacologically acceptable salt thereof:

Wherein R ¹ represents a hydroxyl group, a lower alkoxy group, or the following formula:

(wherein A does not exist or represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; and R ⁷ represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic ring which may be substituted by a lower alkyl group; a non-aromatic heterocyclic group which may be substituted by a pendant oxy group, or an amine carbenyl group which may be substituted by a lower alkyl group; R ² represents a hydrogen atom or a lower alkyl group; and R ³ represents 1 to 3 fluorine atoms. An atom-substituted lower alkyl group or a halogen atom; R ⁴ represents a lower alkoxy group which may be substituted by a halogen atom, a 5-membered aromatic monocyclic heterocyclic group, or a 5-membered non-aromatic monocyclic heterocyclic group (wherein The heterocyclic group contains at least one nitrogen atom and may be substituted by a lower alkyl group; R ⁵ represents a hydrogen atom, a lower alkyl group, or a halogen atom], and these compounds are referred to as "this" in the following contents of the specification. Inventive compound". Hereinafter, various embodiments of the compounds of the present invention are listed.

An embodiment of the present invention is a compound wherein, in the above formula (I), R ¹ is a hydroxyl group, a lower alkoxy group, or the following formula:

[wherein A does not exist or represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; and R ⁷ represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic ring which may be substituted by a lower alkyl group; a non-aromatic heterocyclic group which may be substituted with a pendant oxy group, or an amine carbenyl group which may be substituted with a lower alkyl group; wherein A is a lower alkyl group which may be substituted by a lower alkyl group and R ⁶ and R ⁷ is a hydrogen atom, and A is absent and R ⁶ is a lower alkyl group and R ⁷ is a hydrogen atom.

Another embodiment of the present invention is a compound wherein, in the above formula (I), R ¹ is the following formula:

[wherein A does not exist or represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; and R ⁷ represents a hydrogen atom, a hydroxyl group, may be substituted by a lower alkyl group; Oxadiazolyl, may be substituted side group of pyrrolidinyl, or it may be substituted with 1 to 2 lower alkyl amine acyl; wherein, A is a lower alkyl group may be substituted by the lower alkylene group and R ^{6 is} And R ⁷ is a hydrogen atom, and A is absent and R ⁶ is a lower alkyl group and R ⁷ is a hydrogen atom.

A further embodiment of the present invention is a compound wherein, in the above formula (I), R ¹ is the following formula:

Wherein A represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom; and R ⁷ represents a hydroxyl group which may be substituted by a lower alkyl group; A oxazolyl group, or an amine carbenyl group].

According to still another embodiment of the present invention, in the above formula (I), R ⁴ is a lower alkoxy group which may be substituted by 1 to 3 fluorine atoms, and may be substituted by 1 to 4 lower alkyl groups. Pyrrolidinyl, pyrazolyl which may be substituted with 1 to 3 lower alkyl groups, or may be substituted by 1 to 2 lower alkyl groups Azolyl.

According to still another embodiment of the present invention, in the above formula (I), R ⁴ is any one selected from the group consisting of

[wherein R ⁸ represents a hydrogen atom or a lower alkyl group].

According to still another embodiment of the present invention, in the above formula (I), R ⁴ is any one selected from the group consisting of

[wherein R ⁸ represents a lower alkyl group].

A further embodiment of the present invention based compound, wherein in the above general formula (I), R ⁵ is a methyl group or a fluorine atom.

According to still another embodiment of the present invention, in the above formula (I), R ³ is a methyl group, a trifluoromethyl group or a chlorine atom.

A further embodiment of the present invention is a compound wherein, in the above formula (I), R ¹ is the following formula:

Wherein A represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom; and R ⁷ represents a hydroxyl group which may be substituted by a lower alkyl group; a oxadiazolyl or an aminomethylindenyl]; R ² is a hydrogen atom; R ³ is a methyl group, a trifluoromethyl group, or a chlorine atom; and R ⁴ is any one selected from the group consisting of

[wherein R ⁸ represents a lower alkyl group]; and R ⁵ is a methyl group or a fluorine atom.

Further, in the present invention, there is also provided a compound represented by the following formula (II) which is an intermediate of the compound of the present invention represented by the above formula (I).

[In the formula, R ² represents a hydrogen atom or a lower alkyl group; R ⁵ represents a hydrogen atom, a methyl group, an ethyl group, or a halogen atom; R ⁹ represents a hydrogen atom or a protective group of a carboxyl group; R ¹⁰ represents a hydrogen atom or a group of A protecting group; wherein, in the case where both R ² and R ⁵ are a hydrogen atom].

Further, the present invention also provides a pharmaceutical composition comprising the above-mentioned compound of the present invention as an active ingredient. That is, the pharmaceutical composition of the present invention can be used for preventing or treating a disease selected from the group consisting of central diabetes insipidus, nocturnal enuresis, nocturnal urinary frequency, overactive bladder, hemophilia, and Von Wylie disease.

The compound of the present invention has an excellent V2 receptor agonistic action as a preventive agent for diseases selected from the group consisting of central diabetes insipidus, nocturnal enuresis, nocturnal urinary frequency, overactive bladder, hemophilia, and Von Wylie disease. Or a therapeutic drug is more useful. Furthermore, the main compounds of the present invention selectively act on the V2 receptor, and have a lower inhibitory effect on the drug metabolizing enzymes CYP3A4 and CYP2C9 than the previously known compounds having a V2 receptor agonistic effect. Further, solubility, membrane permeability, and the like are excellent in terms of physical properties of pharmaceuticals, dynamics such as plasma clearance rate and volume of distribution, and thus are various side effects (effects on cytotoxicity, hERG or CYP) and pharmacodynamics. Excellent safety in terms of divergence Full and useful medicine.

Hereinafter, the compound of the present invention will be described.

The compound of the present invention is a compound represented by the above formula (I), and a compound of R ¹ , R ² , R ³ , R ⁴ and R ⁵ or a pharmacologically acceptable salt thereof is defined as follows.

R ¹ is a hydroxyl group, a lower alkoxy group, or the following formula:

[wherein A does not exist or represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; and R ⁷ represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic ring which may be substituted by a lower alkyl group; a group, a non-aromatic heterocyclic group which may be substituted with a pendant oxy group, or an amine carbenyl group which may be substituted with a lower alkyl group, wherein R ^{1 is} preferably a hydroxyl group, a lower alkoxy group, or Description: [Chemical 13]

[wherein A does not exist or represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; and R ⁷ represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic ring which may be substituted by a lower alkyl group; a non-aromatic heterocyclic group which may be substituted with a pendant oxy group, or an amine carbenyl group which may be substituted with a lower alkyl group; wherein A is a lower alkyl group which may be substituted by a lower alkyl group and R ⁶ and R ⁷ is a hydrogen atom, and A is absent and R ⁶ is a lower alkyl group and R ⁷ is a hydrogen atom, and particularly preferably the following formula:

[wherein A does not exist or represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; and R ⁷ represents a hydrogen atom, a hydroxyl group, may be substituted by a lower alkyl group; a oxadiazolyl group, a pyrrolidinyl group which may be substituted with a pendant oxy group, or an amine carbenyl group which may be substituted with 1 to 2 lower alkyl groups; wherein A is a lower alkyl group which may be substituted by a lower alkyl group and R ⁶ and R ⁷ are hydrogen atoms, and A is absent and R ⁶ is lower alkyl and R ⁷ is a hydrogen atom except the case], wherein, A is preferably a lower alkyl group may be substituted with a lower alkylene group of R ^{6 is} preferably a hydrogen atom, and R ^{7 is} preferably a hydroxyl group which may be substituted by a lower alkyl group. A oxazolyl group or an amine carbenyl group.

R ² is a hydrogen atom or a lower alkyl group, preferably a hydrogen atom. R ³ is a lower alkyl group or a halogen atom which may be substituted with 1 to 3 fluorine atoms, and among them, a methyl group, a trifluoromethyl group or a chlorine atom is preferred.

R ⁴ is a lower alkoxy group substituted by a halogen atom, a 5-membered aromatic monocyclic heterocyclic group, or a 5-membered non-aromatic monocyclic heterocyclic group (wherein the heterocyclic group contains at least one nitrogen atom) And can be substituted by a lower alkyl group). Among these, R ^{4 is} preferably a group selected from the group consisting of

Wherein R ⁸ represents a hydrogen atom or a lower alkyl group, and particularly preferably a group selected from the group consisting of

[wherein R ⁸ represents a lower alkyl group].

R ⁵ is a hydrogen atom, a lower alkyl group or a halogen atom, and among them, a methyl group or a fluorine atom is preferred.

More preferably, the compound of the present invention is in the formula (I), and R ¹ is the following formula:

Wherein A represents a lower alkyl group which may be substituted by a lower alkyl group, R ⁶ represents a hydrogen atom, and R ⁷ represents a hydroxyl group which may be substituted by a lower alkyl group. A oxazolyl group or an amine carbenyl group; R ² is a hydrogen atom; R ³ is a methyl group, a trifluoromethyl group, or a chlorine atom; and R ⁴ is a group selected from the group consisting of

[wherein R ⁸ represents a lower alkyl group]; and R ⁵ is a methyl group or a fluorine atom.

Furthermore, in the present specification, the definition is as follows.

The "lower alkoxy group" means -O-(C1 to C3 alkyl group), and examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, and an isopropoxy group.

The "lower alkyl group" means a linear alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, and a n-propyl group.

The "lower alkylene group" means a linear alkyl group having 1 to 3 carbon atoms, and examples thereof include a methylene group, an ethylidene group, and an extended propyl group.

The "aromatic heterocyclic group" means a monocyclic to tricyclic aromatic ring group containing at least one hetero atom such as nitrogen, oxygen or sulfur, and examples thereof include a pyridyl group, a thienyl group, a furyl group, and a pyridyl group. Base Base, thiazolyl, pyrimidinyl, pyrazolyl, pyrrolyl, Azolyl, Diazolyl, isothiazolyl, iso An azolyl group, an imidazolyl group, a quinolyl group, a quinazolinyl group, a fluorenyl group, an acridinyl group or the like.

The "non-aromatic heterocyclic group" means a non-aromatic ring group which may have an unsaturated bond locally and contains at least one hetero atom such as nitrogen, oxygen or sulfur, and examples thereof include a pyrrolidinyl group. Piperidinyl, hydrazinyl, Olinyl, thio Olinyl group, piperazine Pyrazole group Base, fluorenyl, 1,2-dihydroisoquinolinyl, 1,2,3,4-tetrahydroquin Orolinic group and the like.

The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine. child.

The "5-membered aromatic or non-aromatic monocyclic heterocyclic group" means a monocyclic group which may have an unsaturated bond and contains at least one hetero atom such as nitrogen, oxygen or sulfur, and examples thereof include pyrrolidinyl and thiophene. Base, furanyl, pyrazolyl, Azolyl, Diazolyl, imidazolyl and the like.

The "pharmacologically acceptable salt" means a salt which retains the biological effectiveness and characteristics of the compound represented by the general formula (I) and which has no adverse biological or other conditions. Such pharmacologically acceptable salts are included within the scope of the invention. The pharmacologically acceptable salt may, for example, be a salt with an amino acid (for example, a salt with an amino acid or a arginine), an alkali metal addition salt (for example, a salt with sodium or potassium), or an alkaline earth metal. Addition salts (eg, salts with calcium, magnesium, etc.), organic amine addition salts (eg, with diethylamine, diethanolamine, piperidine) A salt such as a salt), an inorganic acid addition salt (for example, a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or the like), an organic acid addition salt (for example, a salt with formic acid, acetic acid, trifluoroacetic acid, or the like). The formation reaction of the addition salts can be carried out according to a usual method.

When converted to the above formula (I) by a reaction caused by an enzyme or gastric acid or the like under physiological conditions in vivo, such compounds are included in the scope of the present invention. For example, when R ¹ of the compound represented by the formula (I) is a hydroxyl group and a carboxyl group is formed, esterification of the carboxyl group (for example, ethylation, carboxylmethylation, and pivaloxymethylation) may be mentioned. Or the like, or a compound obtained by amidination (for example, methyl amide or the like). Further, when the group represented by R ¹ has a hydroxyl group, examples thereof include deuteration (for example, acetylation, propylation, or tert-butylcarbonylation) and alkoxycarbonylation (for example, A). A compound obtained by oxycarbonylation, ethoxycarbonylation, ortho-butoxycarbonylation, or amber.

Next, a compound which is an intermediate of the compound of the present invention will be described.

[Chemistry 19]

The intermediate compound of the compound of the present invention is a compound represented by the above formula (II), wherein R ² is a hydrogen atom or a lower alkyl group, R ⁵ is a hydrogen atom, a methyl group, an ethyl group or a halogen atom, and R ⁹ is a hydrogen atom. A protecting group for an atom or a carboxyl group, and R ¹⁰ is a protecting group for a hydrogen atom or an amine group (except where R ² and R ⁵ are each a hydrogen atom).

Here, the "protecting group for a carboxyl group" is a group which is generally known as a protecting group for a carboxyl group in organic synthesis, and examples thereof include (1) a linear or branched chain lower alkyl group having 1 to 4 carbon atoms. (eg methyl, ethyl, isopropyl, tert-butyl), (2) halogenated lower alkyl (eg 2-iodethane, 2,2,2-trichloroethyl), (3) Lower alkoxymethyl (eg methoxymethyl, ethoxymethyl, isobutoxymethyl), (4) lower aliphatic methoxymethyl (eg, butoxymethyl, pentylene)醯oxymethyl), (5) 1-lower alkoxycarbonyloxyethyl (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl), (6) aryl An alkyl group (e.g., benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl), (7) diphenylmethyl, and (8) anthracenyl.

Further, the "protecting group for an amine group" means a group which is generally known as a protecting group for an amine group in organic synthesis, and is exemplified by: (1) a substituted or unsubstituted lower alkyl fluorenyl group (for example, a fluorenyl group) , ethyl hydrazino, chloroethyl fluorenyl, dichloroethyl fluorenyl, propyl fluorenyl, phenylethyl fluorenyl, phenoxyethyl hydrazino, thienyl ethenyl), (2) substituted or unsubstituted Lower alkoxycarbonyl (eg benzyloxycarbonyl, tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), (3) substituted or unsubstituted lower alkyl (eg methyl, tert-butyl, 2,2,2-trichloroethyl, trityl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl, pentyloxy) And (4) a substituted alkyl group (for example, a trimethyldecyl group, a tert-butyldimethylsilyl group), and (5) a substituted or unsubstituted benzylidene group (example) Such as benzylidene, arylene, p-nitrobenzylidene, m-chlorobenzylidene, 3,5-di(t-butyl)-4-hydroxybenzylidene, 3,5-di (Third butyl) benzylidene) and the like.

In the case where one or more asymmetric carbons are present in the compound of the present invention, the present invention also encompasses any of the compounds based on the asymmetric carbon isomers and any combination thereof. Further, in the case where the compound of the present invention is geometrically or tautomeric, the present invention also encompasses any of its geometric isomers or tautomers. Further, the compound of the present invention also contains a solvate of a solvent which is acceptable to a pharmaceutical such as water, ethanol or isopropyl alcohol.

The compound of the present invention, that is, the compound represented by the formula (I) can be produced by a method in which the method described in the following Reaction Scheme I, the method described in the examples, or a known method is combined.

[Reaction step formula I]

Wherein R ² represents a hydrogen atom or a lower alkyl group; R ³ represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms, or a halogen atom; and R ⁴ represents a lower alkoxy group which may be substituted by a halogen atom, 5 An aromatic monocyclic heterocyclic group or a 5-membered non-aromatic monocyclic heterocyclic group (wherein the heterocyclic group contains at least one nitrogen atom and may be substituted by a lower alkyl group); R ⁵ represents a hydrogen atom a lower alkyl group or a halogen atom; A is absent or represents a lower alkyl group which may be substituted by a lower alkyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; R ⁷ represents a hydrogen atom, a hydroxyl group, may be substituted by a lower alkyl group An aromatic heterocyclic group, a non-aromatic heterocyclic group which may be substituted with a pendant oxy group, or an amine carbenyl group which may be substituted with a lower alkyl group; R ⁹ represents a protecting group of a carboxyl group]

[Step I-1]

Using a compound represented by the formula (III) in a suitable solvent (for example, toluene, dichloromethane, etc.) in the presence or absence of an additive (for example, N,N-dimethylformamide, etc.) The chemical (for example, sulfoxide, chloroform, etc.) is used as a ruthenium chloride, and the compound represented by the formula (IIa) is used in a suitable solvent (for example, toluene, dichloromethane, tetrahydrofuran, acetonitrile, etc.). A base (e.g., triethylamine, N,N-diethylaniline, pyridine, etc.) is reacted, whereby a compound represented by the formula (IV) is obtained. The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. Further, the compound represented by the formula (III) and the formula (IIa) may be obtained as a commercially available product, and may be produced by the following reaction procedures of the formulae II to IV.

[Step I-2]

The protecting group R ⁹ of the compound represented by the formula (IV) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby a compound represented by the formula (V) is obtained.

[Step I-3]

The compound represented by the formula (V) and the compound represented by the formula (VI) are contained in a suitable solvent (for example, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, etc.) in an additive (for example). A condensing agent (for example, 1-ethyl-3-(3-dimethyl) in the presence or absence of diisopropylethylamine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc.) The aminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, and the like are reacted to obtain a compound represented by the formula (I). The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hour. Further, the compound represented by the formula (VI) may be obtained in the form of a commercially available product, and may be produced by a known method.

The compound represented by the formula (III) used as a starting material in the reaction step of the formula I can be produced by the method shown in the following reaction schemes II and III, the method described in the reference example, or a known method.

[Reaction step formula II]

Wherein R ³ represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms, or a halogen atom; R ⁸ represents a lower alkyl group; R ¹¹ represents a protecting group of a carboxyl group; and X represents a halogen atom, trifluoromethanesulfonic acid Ester, mesylate, etc.

[Step II-1]

The compound represented by the formula (VII) and the compound represented by the formula (VIII) are used in a suitable solvent (for example, N,N-dimethylformamide, dimethyl azine, N-methyl-2- In the pyrrolidinone or the like, a reaction is carried out using a base (for example, potassium carbonate, sodium carbonate or the like) to obtain a compound represented by the formula (IX). The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. Further, the compounds represented by the general formulae (VII) and (VIII) are commercially available, and can be produced by a known method.

[Step II-2]

The protecting group R ¹¹ of the compound represented by the formula (IX) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby the compound represented by the formula (IIIa) is obtained.

[Reaction step formula III]

Wherein R ³ represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms, or a halogen atom; R ⁸ represents a lower alkyl group; R ¹¹ represents a protecting group of a carboxyl group; and R ¹² represents a deprotection energy and R ¹¹ a protecting group for distinguishing a carboxyl group; X represents a leaving group such as a halogen atom, a trifluoromethanesulfonate or a mesylate;

[Step III-1]

The compound represented by the formula (X) is used in a suitable solvent (for example, toluene, dichloromethane, etc.) in the presence or absence of an additive (for example, N,N-dimethylformamide, etc.). a chemical (such as sulfoxide, chloroform, etc.) to form a ruthenium chloride, and an alcohol (such as methanol, ethanol, isopropanol, benzyl alcohol, etc.) in a suitable solvent (such as toluene, dichloromethane, In the tetrahydrofuran, acetonitrile or the like, a reaction is carried out using a base (for example, triethylamine, N,N-diethylaniline, pyridine or the like) to obtain a compound represented by the formula (XI). The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. Further, the compound represented by the formula (X) can be obtained as a commercially available product, or can be produced by a known method.

[Step III-2]

The compound represented by the formula (XI) is used in a suitable solvent (for example, dimethyl hydrazine, N,N-dimethylformamide, methanol, ethanol, etc.) in additives (for example, 1,3-bis(triphenylphosphino)propane, 1,1'-bis(diphenylphosphino)di In the presence or absence of ferrocene or the like, in a carbon monoxide environment, a base (for example, triethylamine, diisopropylethylamine, cesium carbonate, etc.) and a palladium catalyst (for example, palladium acetate, palladium chloride, or the like) are used. The reaction is carried out by chlorinating [1,1'-bis(diphenylphosphino)ferrocene]palladium, tetrakis(triphenylphosphine)palladium or the like, whereby a compound represented by the formula (XII) can be obtained. The reaction temperature is from 40 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[Step III-3]

The protecting group R ¹² of the compound represented by the formula (XII) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby a compound represented by the formula (XIII) can be obtained.

[Step III-4]

The compound represented by the formula (XIII) and the compound represented by the formula (XIV) are dissolved in a suitable solvent (for example, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, etc.) in the additive (two A condensing agent (for example, 1-ethyl-3-(3-dimethylamine) in the presence or absence of isopropylethylamine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc.) The propyl group carbodiimide hydrochloride, dicyclohexylcarbodiimide or the like is reacted, whereby a compound represented by the formula (XV) can be obtained. The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. Further, the compound represented by the formula (XIV) may be obtained in the form of a commercially available product, and may be produced by a known method.

[Step III-5]

The compound represented by the formula (XV) is used in an appropriate solvent (for example, dichloromethane, tetrahydrofuran, etc.) in the presence or absence of an additive (dimethyl sulfoxide) using an oxidizing agent (for example, Dess-Martin reagent) The pyridine-sulfur trioxide complex or the like is reacted to obtain a compound represented by the formula (XVI). The reaction temperature is from 0 ° C to room temperature, and the reaction time is from 30 minutes to 48 hours.

[Step III-6]

The compound represented by the formula (XVI) is used in a suitable solvent (for example, dichloromethane, acetonitrile, etc.) in the presence of an additive (triphenylphosphine) using a chlorinating agent (for example, hexachloroethane, 1,2- Dibromo-1,1,2,2-tetrachloroethane, etc.) and a base (for example, diisopropylethylamine, pyridine, triethylamine, etc.) are reacted, thereby obtaining a compound represented by the formula (XVII) . The reaction temperature is from 0 ° C to room temperature, and the reaction time is from 30 minutes to 5 hours.

[Step III-7]

The protecting group R ¹¹ of the compound represented by the formula (XVII) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby the compound represented by the formula (IIIb) is obtained.

In the reaction step, the compound represented by the formula (IIa) used as a starting material in the formula I can be used by combining the method shown in the following Reaction Schemes IV to VI, the method described in the Reference Example, or a known method. And manufacturing.

[Reaction step formula IV]

Wherein R ² represents a hydrogen atom or a lower alkyl group; R ⁵ represents a lower alkyl group or a halogen atom; R ⁹ represents a protecting group of a carboxyl group; R ¹⁰ represents a protecting group of a nitrogen atom; and R ¹³ represents a cyano group or a carboxylic acid derivative. (eg methyl ester, ethyl ester, etc.)

[Step IV-1]

The compound represented by the formula (VIII) is obtained by protecting the nitrogen atom of (2-aminophenyl)methanol with R ¹⁰ by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)". . Further, (2-aminophenyl)methanol can be obtained in the form of a commercially available product.

[Step IV-2]

The compound represented by the formula (XVIII) is reacted with manganese (IV) oxide in a suitable solvent (for example, dichloromethane, chloroform, acetone, tetrahydrofuran, etc.) to obtain a compound represented by the formula (XIX). The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[Step IV-3]

The compound represented by the formula (XIX) and the compound represented by the formula (XX) are used in a suitable solvent (for example, N,N-dimethylformamide, dimethylhydrazine, etc.), such as carbonic acid. The reaction is carried out by potassium, sodium hydride or the like, whereby a compound represented by the formula (XXI) can be obtained. The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. Further, the compound represented by the formula (XX) can be produced by the method of the following reaction step of the formula VII.

[Step IV-4]

The compound represented by the formula (XXI) is used in a suitable solvent (for example, diethyl carbonate, ethanol, etc.) in the presence or absence of an additive (for example, sodium bromide, lithium bromide, sodium iodide, etc.). For example, sodium ethoxide, potassium t-butoxide or the like is reacted, whereby a compound represented by the formula (XXII) can be obtained.

[Step IV-5]

The compound represented by the formula (XXII) is placed in a suitable solvent (for example, acetic acid, water, etc.) The reaction is carried out using an acid such as sulfuric acid, hydrochloric acid or the like, whereby a compound represented by the formula (XXIII) can be obtained. The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 12 hours to 7 days.

[Step IV-6]

The compound represented by the formula (XXIV) is obtained by protecting the carboxyl group of the compound represented by the formula (XXIII) with R ⁹ by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)".

[Step IV-7]

The nitrogen atom of the compound represented by the general formula (XXIV) is protected by R ¹⁰ by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby a compound represented by the general formula (XXV) is obtained. .

[Step IV-8]

The compound represented by the formula (XXV) is used in a suitable solvent (for example, methanol, ethanol, 1,4-two) The compound represented by the formula (XXVI) is obtained by reacting with a palladium catalyst (for example, palladium carbon, Pearlman catalyst, etc.) in a hydrogen atmosphere in a hydrogen atmosphere. The reaction temperature is from room temperature to 60 ° C, and the reaction time is from 1 hour to 48 hours.

[Step IV-9]

The compound represented by the formula (XXVI) and an electrophilic agent (for example, methyl iodide, methyl bromide, ethyl iodide, N-fluorobenzenesulfonimide, etc.) are dissolved in a suitable solvent (for example, tetrahydrofuran, diethyl ether, etc.) The reaction is carried out using a base (for example, lithium diisopropylamide, n-butyllithium, tert-butyllithium or the like), whereby a compound represented by the formula (XXVII) can be obtained. The reaction temperature is -78 ° C to 0 ° C, and the reaction time is 30 minutes to 24 hours.

[Step IV-10]

The protecting group R ¹⁰ of the compound represented by the formula (XXVII) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby the compound represented by the formula (IIa) is obtained.

[Reaction step formula V]

Wherein R ⁵ represents a lower alkyl group or a halogen atom; R ⁹ represents a protecting group of a carboxyl group; and R ¹⁰ represents a protecting group of a nitrogen atom]

[Step V-1]

Protection of nitrogen of 3,4-dihydro-1H-benzo[b]azepine-5(2H)-one with R ¹⁰ by reference to the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)" An atom, thereby obtaining a compound represented by the formula (XXVIII). Further, 3,4-dihydro-1H-benzo[b]azepine-5(2H)-one can be obtained in the form of a commercially available product.

[Step V-2]

The compound represented by the formula (XXVIII) is reacted in a suitable solvent (for example, dimethyl carbonate, diethyl carbonate or the like) using a base (for example, sodium methoxide, sodium ethoxide or the like), whereby a compound of the formula (XXIX) can be obtained. The compound represented. The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 5 hours.

[Step V-3]

The compound represented by the formula (XXIX) and an electrophilic agent (for example, methyl iodide, methyl bromide, ethyl iodide, N-fluorobenzenesulfonimide, etc.) are dissolved in a suitable solvent (for example, tetrahydrofuran, acetone, ethanol). The reaction is carried out by using a base (for example, potassium carbonate, cesium carbonate, sodium hydride or the like) to obtain a compound represented by the formula (XXX). The reaction temperature is from 0 ° C to the boiling of the solvent The reaction time is from 30 minutes to 48 hours.

[Step V-4]

The compound represented by the formula (XXX) and a reducing agent (for example, triethyl decane, etc.) are used in an appropriate solvent (for example, dichloromethane, tetrahydrofuran, etc.) using an acid (for example, trifluoroacetic acid, methanesulfonic acid, trifluorination). The reaction is carried out by using a borodiethyl ether complex or the like, whereby a compound represented by the formula (XXXI) can be obtained. The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[Step V-5]

The protecting group R ¹⁰ of the compound represented by the formula (XXXI) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby the compound represented by the formula (IIb) is obtained.

[Reaction step formula VI]

Wherein R ⁵ represents a hydrogen atom, a lower alkyl group or a halogen atom; R ⁹ represents a protecting group of a carboxyl group; R ¹⁰ represents a protecting group of a nitrogen atom; and R ¹⁴ and R ¹⁵ represent mutually different alkyl groups which may be substituted. Base, or substituted aryl]

[Step VI-1]

The protecting group R ⁹ of the compound represented by the formula (XXXI) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby a compound represented by the formula (XXXII) can be obtained.

[Step VI-2]

The compound represented by the formula (XXXII) and the compound represented by the formula (XXXIII) are dissolved in a suitable solvent (for example, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, etc.) in the additive (two The use of a condensing agent (1-ethyl-3-(3-dimethylamino) in the presence or absence of isopropylethylamine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc.) The propyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, and the like are reacted, whereby a compound represented by the formula (XXXIV) can be obtained. The reaction temperature is from 0 ° C to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[Step VI-3]

The compound represented by the formula (XXXIV) is reacted with an acid (for example, sulfuric acid, hydrochloric acid, or the like) in a suitable solvent (for example, methanol, ethanol, benzyl alcohol, or the like) to obtain a compound represented by the formula (XXXV). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 72 hours.

[Step VI-4]

The protecting group R ¹⁰ of the compound represented by the formula (XXXV) is removed by the method described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)", whereby the compound represented by the formula (IIc) is obtained.

The compound represented by the formula (XX) used in the reaction step IV can be produced by combining the method shown in the following Reaction Scheme VII, the method described in the Reference Example, or a known method.

[Reaction step formula VII]

[Chem. 26]

Wherein R ² represents a hydrogen atom or a lower alkyl group; R ¹³ represents a cyano group or a carboxylic acid derivative (e.g., methyl ester, ethyl ester, etc.); and X represents a halogen atom, a trifluoromethanesulfonate, a mesylate Equivalent

[Step VII-1]

The compound represented by the formula (XXXVI) is used in a suitable solvent (for example, N,N-dimethylformamide, dimethylhydrazine, acetonitrile, etc.) in an additive (for example, tetrabutylammonium bromide, iodine) The compound represented by the formula (XXXVII) is obtained by reacting with a cyanating agent (for example, sodium cyanide, potassium cyanide or the like) in the presence or absence of sodium, 18-crown-6-ether or the like. The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 24 hours.

[Step VII-2]

The compound represented by the formula (XXXVII) and a nucleophilic agent (for example, sulfinium chloride, methanesulfonium chloride, trifluoromethanesulfonyl anhydride or the like) are dissolved in a suitable solvent (for example, dichloromethane, toluene, etc.). The reaction is carried out using a base (e.g., triethylamine, diisopropylethylamine, pyridine, etc.), whereby a compound represented by the formula (XX) can be obtained. The reaction temperature is from 0 ° C to room temperature, and the reaction time is from 30 minutes to 24 hours.

Further, a compound which is used as a starting material, an intermediate, or a reagent necessary for the production of the compound of the present invention can be obtained in the form of a commercially available product, and can also be produced by referring to a known method.

The substituents (for example, a hydroxyl group, an amine group, a carboxyl group, and the like) contained in the compound of the present invention and the compound used for the production of the compound have the following conditions: in terms of compound production, it is effective in the stage of the raw material or the intermediate. An appropriate protecting group is introduced into the substituent, and the protecting group described in "Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)" can be appropriately selected as needed.

In order to use the compound of the present invention and a compound for producing the compound from a reaction liquid Isolation, purification, and the usual methods can be used. For example, solvent extraction, ion exchange resin, column chromatography using silica gel or alumina as a carrier, high performance liquid chromatography (HPLC) separation, thin layer chromatography, resin removal, recrystallization, etc., can be used. The separation and purification methods can be carried out singly or in combination. Isolation and purification can be carried out in each reaction or after completion of several reactions.

In the case where the compound in the present specification has an asymmetric carbon and an optical isomer is present, the optical isomer can be isolated by the following method: a conventional optical separation method of a racemic compound, for example, in the usual manner The crystallization of the recrystallized form of the optically active compound is carried out by recrystallization, or by a reaction with a generally optically active compound in the form of a non-image isomer. Further, each optical isomer may be isolated by high performance liquid chromatography (HPLC) separation using an optically active substance separation column.

The compound of the present invention thus produced functions as a V2 receptor agonist, and thus can be used as a medicine for preventing or treating central diabetes insipidus, nocturnal enuresis, nocturnal urinary frequency, overactive bladder, hemophilia, or Von Wylie disease. combination. Further, since the main compound of the compound of the present invention selectively acts on the V2 receptor, it is advantageous from the viewpoint of side effects. Further, the compound of the present invention has a lower inhibitory effect on the drug-metabolizing enzymes CYP3A4 and CYP2C9 than the previously known compound having a V2 receptor agonistic action, and further, solubility, membrane permeability, and the like as physical properties of the pharmaceutical or Dynamic aspects such as plasma clearance and volume distribution are also excellent in nature and therefore safe to use.

In the case of the administration form in the case of using the compound of the present invention as a medicine, various administration forms described in the "Japanese Pharmacopoeia" preparations can be selected according to the purpose. For example, when it is formed into a tablet form, it is usually only necessary to select a component which can be orally ingested in the field. For example, excipients such as lactose, crystalline cellulose, white sugar, and potassium phosphate are compatible therewith. Further, various additives commonly used in the field of usual preparations such as a binder, a disintegrant, a lubricant, and an anti-agglomeration agent may be formulated as needed.

The amount of the compound of the present invention contained as an active ingredient in the preparation of the present invention is not particularly limited, and can be appropriately selected from a wide range. The dosage of the compound of the present invention is appropriately determined depending on the usage, the age, sex and other conditions of the patient, and the degree of the disease. In the case of oral administration, the amount of the compound of the present invention is about 1 μg per 1 kg of body weight. Preferably, it is about 100 μg to 20 mg, more preferably about 50 μg to 5 mg, and it can be appropriately administered in one to four times in one day. However, the dosage and the number of administrations are determined in view of the extent of the symptoms to be treated, the choice of the compound to be administered, and the relevant conditions of the selected route of administration, and thus the above-mentioned dosage range and number of times do not limit the present invention. range.

[Examples]

Hereinafter, the contents of the present invention will be described in more detail by way of examples, reference examples, and pharmacological test examples. However, the technical scope of the present invention is not limited to the description.

The nuclear magnetic resonance ( ¹ H-NMR) spectrum in the following examples and reference examples uses tetramethyl decane as a standard substance, and the chemical shift value is described in δ value (ppm). The split pattern is a single peak with "s", a double peak with "d", a triplet with "t", a quadruple peak with "q", a five-fold peak with "quin", and a "m" with "m" Multiple peaks, with "br" indicating a broad peak. Mass spectrometry was performed by electrospray free (ESI). In the table, "Me" represents a methyl group, and "Et" represents an ethyl group.

[Reference Example 1] (S)methyl-2-methyl-4-(3-methylpyrrolidin-1-yl)benzoate

Methyl 4-fluoro-2-methylbenzoate (970 mg) was dissolved in N-methyl-2-pyrrolidone (20 mL), and (S)-3- was added in the presence of potassium carbonate (2.39 g) Methylpyrrolidine hydrochloride (772 mg) was stirred at 120 ° C for 6 hours. The reaction solution was returned to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjj .

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.88 (d, J = 8.0 Hz, 1H), 6.34-6.30 (m, 2H), 3.82 (s, 3H), 3.51-3.47 (m, 1H), 3.45- 3.39 (m, 1H), 3.36-3.29 (m, 1H), 2.92-2.88 (m, 1H), 2.59 (s, 3H), 2.45-2.32 (m, 1H), 2.17-2.10 (m, 1H), 1.68-1.58 (m, 1H), 1.13 (d, J = 8.0 Hz, 3H).

ESI/MS (m/z) 234 (M+H) ⁺ .

[Reference Example 2] (S)-2-methyl-4-(3-methylpyrrolidin-1-yl)benzoic acid

Methyl (S)-2-methyl-4-(3-methylpyrrolidin-1-yl)benzoate (710 mg) was dissolved in methanol (7 mL), water (6 mL), lithium hydroxide monohydrate After the product (383 mg), it was stirred at 60 ° C for 6 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added, and the mixture was acidified with 5% aqueous citric acid, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.

^{1 H-NMR (400MHz, CDCl} 3) δ 12.36 (brs, 1H), 8.00 (d, J = 8.0Hz, 1H), 6.36 (d, J = 8.0Hz, 1H), 6.31 (s, 1H), 3.51 -3.48(m,1H), 3.47-3.41(m,1H), 3.37-3.31(m,1H),2.93-2.89(m,1H),2.62(s,3H),2.42-2.35(m,1H) , 2.18-2.10 (m, 1H), 1.68-1.59 (m, 1H), 1.13 (d, J = 8.0 Hz, 3H).

ESI/MS (m/z) 220 (M+H) ⁺ , 218 (MH) ^- .

[Reference Example 3] Benzyl 4-bromo-2-methylbenzoate

4-bromo-2-methylbenzoic acid (2.15 g) was dissolved in sulfinium chloride (5.0 mL) and N,N-dimethylformamide (100 μL), and stirred at 50 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was applied to dichloromethane. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained was purified (yield: hexane/ethyl acetate = 1/0-6/1) to give the title compound (2.65 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 8.4 Hz, 1H), 7.47-7.30 (m, 7H), 5.33 (s, 2H), 2.58 (s, 3H).

[Reference Example 4] Methyl 4-[(benzyloxy)carbonyl]-3-methylbenzoate

Benzyl 4-bromo-2-methylbenzoate (4.86 g) was dissolved in a mixed solvent of dimethyl hydrazine (48 mL) and methanol (48 mL), and palladium acetate (358 mg), 1,3-bis ( After diphenylphosphine)propane (657 mg) and diisopropylethylamine (5.4 mL) were replaced with carbon monoxide and stirred at 60 ° C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified from mjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 8.1 Hz, 1H), 7.94-7.90 (m, 1H), 7.78 (dd, J = 8.1, 1.7 Hz, 1H), 7.49-7.43 ( m, 2H), 7.43-7.33 (m, 3H), 5.36 (s, 2H), 3.93 (s, 3H), 2.63 (s, 3H).

ESI/MS (m/z) 285 (M+H) ⁺ .

[Reference Example 5] 4-[(benzyloxy)carbonyl]-3-methylbenzoic acid

Methyl 4-[(benzyloxy)carbonyl]-3-methylbenzoate (3.03 g) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and water (30 mL), and lithium hydroxide monohydrate (671 mg) was added. Stir at room temperature for 2 hours. After adding 1 M hydrochloric acid to the reaction liquid to adjust to acidity, it was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated.

¹ H-NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.90-7.77 (m, 2H), 7.53-7.30 (m, 5H), 5.35 (s) , 2H), 2.55 (s, 3H).

ESI/MS (m/z) 269 (MH) ^- .

[Reference Example 6] Benzyl 4-[(1-hydroxypropan-2-yl)aminemethanyl]-2-methylbenzoate

4-[(Benzyloxy)carbonyl]-3-methylbenzoic acid (1.24 g) was dissolved in N,N-dimethylformamide (23 mL). Dimethylaminopropyl)carbodiimide hydrochloride (1.76 g), 1-hydroxybenzotriazole (1.41 g), diisopropylethylamine (3.1 mL) and DL-2-amino group 1-propanol (730 μL) was stirred at 40 ° C overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.90 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.48-7.29 (m, 5H) , 6.71 (brs, 1H), 5.32 (s, 2H), 4.31-4.15 (m, 1H), 3.73 (dd, J = 11.1, 3.7 Hz, 1H), 3.61 (dd, J = 11.1, 5.5 Hz, 1H) ), 3.37 (brs, 1H), 2.56 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H).

ESI / MS (m / z) 328 (M + H) +, 326 (MH) -.

[Reference Example 7] Benzyl 2-methyl-4-[(1-o-oxypropan-2-yl)aminemethanyl]benzoate

Benzyl 4-[(1-hydroxypropan-2-yl)amine-carbamoyl]-2-methylbenzoate (1.07 g) was dissolved in dichloromethane (16 mL) and was added at 0 ° C. After the Martin reagent (2.08 g), it was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was applied to dichloromethane. The organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified, mjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ 9.64 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 7.66-7.59 (m, 1H), 7.48-7.31 ( m, 5H), 7.01 (brs, 1H), 5.35 (s, 2H), 4.79-4.62 (m, 1H), 2.63 (s, 3H), 1.49 (d, J = 7.4 Hz, 3H).

ESI/MS (m/z) 326 (M+H) ⁺ , 324 (MH) ^- .

[Reference Example 8] 2-methyl-4-(4-methyl Benzyl-2-yl)benzoic acid benzyl ester

Triphenylphosphine (2.05 g) and hexachloroethane (1.85 g) were dissolved in acetonitrile (18 mL), and 2-methyl-4-[(1-trioxypropan-2-yl)aminecarboxamide was added. A solution of benzyl benzoate (846 mg) in acetonitrile (8 mL) was stirred at room temperature for 10 min. Pyridine (1.3 mL) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified, mjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ 8.02 (d, J = 8.2 Hz, 1H), 7.95-7.90 (m, 1H), 7.89-7.82 (m, 1H), 7.50-7.30 (m, 6H), 5.36 (s, 2H), 2.66 (s, 3H), 2.26 (d, J = 1.2 Hz, 3H).

ESI/MS (m/z) 308 (M+H) ⁺ .

[Reference Example 9] 2-methyl-4-(4-methyl Zin-2-yl)benzoic acid

2-methyl-4-(4-methyl Benzyl-2-yl)benzoic acid benzyl ester (69.0 mg) was dissolved in methanol (8 mL), and 1M aqueous sodium hydroxide (4 mL) was added and stirred at 50 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was evaporated to ethylamine.

¹ H-NMR (400 MHz, DMSO) δ 7.97 (q, J = 1.2 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.90-7.86 (m, 1H), 7.86-7.79 (m, 1H) ), 2.59 (s, 3H), 2.18 (d, J = 1.2 Hz, 3H).

ESI/MS (m/z) 218 (M+H) ⁺ , 216 (MH) ^- .

[Reference Example 10] Ethyl 1-toluenesulfonyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate

(2-Aminophenyl)methanol (13.4 g) was dissolved in chloroform (400 mL) and cooled to 0 °C. Pyridine (11 mL) and p-toluenesulfonium chloride (24.8 g) were added, and stirred at room temperature for 17 hours. The reaction solution was diluted with water, and 6 M hydrochloric acid was added thereto to adjust to acidity, followed by extraction with chloroform. The organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give N-[2-(hydroxymethyl)phenyl]-4-methylbenzenesulfonamide.

The above N-[2-(hydroxymethyl)phenyl]-4-methylbenzenesulfonamide (32.0 g) was dissolved in acetone (480 mL), and manganese (IV) oxide (75.0 g) was added thereto for 24 hours. Heat to reflux. After filtering the reaction solution, it was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was diluted with water and ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, whereby N-(2-carbamidophenyl)-4-methylbenzenesulfonamide was obtained.

The above N-(2-formylphenyl)-4-methylbenzenesulfonamide (24.0 g) was dissolved in N,N-dimethylformamide (300 mL), and ethyl bromobutyrate was added ( 36.4 g) and potassium carbonate (36.1 g) were stirred at 80 ° C for 36 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 4-[N-(2-carbamidophenyl)-4-methylphenylsulfonamide]butyrate.

The above 4-[N-(2-carbamidophenyl)-4-methylphenylsulfonamide] ethyl butyrate was dissolved in diethyl carbonate (480 mL), and a 20% sodium ethoxide-ethanol solution was added. (43.1 g), stirred at room temperature for 4 hours. The reaction solution was diluted with water, and 6 M hydrochloric acid was added thereto to adjust to acidity, followed by extraction with ethyl acetate. After washing the organic phase with saturated brine, it is treated with anhydrous sodium sulfate. Drying. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate / hexane = 1/10 - 1/4). The title compound (18.2 g) was obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ 6.97-6.87 (m, 1H), 6.61-6.53 (m, 1H), 6.48 (d, J = 7.9Hz, 1H), 3.86 (s, 1H), 3.14- 3.00 (m, 2H), 2.86-2.76 (m, 2H), 1.86-1.74 (m, 2H), 1.69-1.60 (m, 2H).

[Reference Example 11] Methyl 2,3-dihydro-1H-benzo[b]azepine-4-carboxylate

Ethyl 1-toluenesulfonyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (18.2 g) was dissolved in acetic acid (180 mL), sulfuric acid (90 mL) and water (9 mL), stirred at 90 ° C for 36 hours. The reaction solution was cooled to 0 ° C and diluted with dichloromethane and water. 5 M sodium hydroxide was added to the mixed solution, and after neutralization, extraction was carried out with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, whereby 2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid was obtained.

The 2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid was dissolved in methanol (180 mL), and sulfuric acid (10 mL) was added dropwise at room temperature, followed by heating under reflux for 17 hours. The residue obtained by concentrating the reaction liquid under reduced pressure was diluted with water, and then 5 M sodium hydroxide was added thereto, followed by neutralization, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate/hexane = 1/10-1/4) to obtain a yellow-white solid. The title compound (8.30 g).

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.65 (s, 1H), 7.29-7.23 (m, 1H), 7.13-7.06 (m, 1H), 6.78-6.72 (m, 1H), 6.63-6.57 (m) , 1H), 4.55 (s, 1H), 3.80 (s, 3H), 3.42-3.34 (m, 2H), 2.89-2.83 (m, 2H).

[Reference Example 12] 1-toluenesulfonyl-3,4-dihydro-1H-benzo[b]azepine-5(2H)-one

3,4-Dihydro-1H-benzo[b]azepine-5(2H)-one (10.0 g) was dissolved in pyridine (30 mL), and p-toluenesulfonyl chloride (13.6 g) was added in an ice bath. Stir at room temperature for 12 hours. Water (60 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 40 minutes. The obtained crystals were collected by filtration, washed with water, and dried to give the title compound (18.9 g) as pale yellow white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.71 (ddd, J = 7.8, 1.7, 0.4 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.55-7.46 (m, 2H), 7.41 7.35 (m, 1H), 7.23-7.30 (m, 2H), 3.86 (t, J = 6.6 Hz, 2H), 2.45-2.39 (m, 5H), 2.00-1.91 (m, 2H).

ESI/MS (m/z) 316 (M+H) ⁺ .

[Reference Example 13] Methyl 5-oxo-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate

1-Toluenesulfonyl-3,4-dihydro-1H-benzo[b]azepine-5(2H)-one (47.3 g) was dissolved in dimethyl carbonate (300 mL) at room temperature Sodium methoxide (48.6 g) was added and stirred at 70 ° C for 40 minutes. Thereafter, the mixture was cooled to room temperature, and the reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Methanol was added to the residue obtained, and the crystals thus obtained were filtered to give the title compound (43.8 g).

^{1 H-NMR (400MHz, CDCl} 3) δ 11.9 (brs, 1H), 7.81-7.10 (m, 8H), 4.10 (t, J = 6.4Hz, 2H), 3.75-3.69 (m, 3H), 2.57- 2.17 (m, 5H).

[Reference Example 14] Methyl 4-methyl-5-oxo-l-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

Dissolve methyl 5-oxo-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (100 mg) in acetone (2 mL) Potassium carbonate (74.1 mg) and methane iodide (33 μL) were added thereto, and the mixture was heated under reflux for 1.5 hours. Add water to the reaction solution and extract with ethyl acetate After washing, it was washed with saturated brine and dried over anhydrous sodium sulfate. After the reaction mixture was concentrated under reduced pressure, m.jjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.55 (d, J = 8.4 Hz, 2H), 7.46-7.31 (m, 4H), 7.28-7.21 (m, 2H), 4.08-3.99 (m, 1H), 3.87-3.77 (m, 1H), 3.61 (s, 3H), 2.47-2.31 (m, 4H), 1.89-1.78 (m, 1H), 1.31 (s, 3H).

ESI/MS (m/z) 388 (M+H) ⁺ .

Here, "racemic" is as shown in the following formula, for example.

It is represented as a racemic compound in the case of a quaternary carbon atom when the quaternary carbon atom is an asymmetric carbon. Further, the compound and the following compound obtained by using a racemic starting material in the same manner as the quaternary carbon atom at the 4-position are referred to as (racemic) at the end of the nomenclature.

[Example 1] 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic)

Methyl 4-methyl-5-oxo-l-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic) : 74.0 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (29 μL), triethyl decane (120 μL), methanesulfonic acid (19 μL), and boron trifluoride diethyl ether were added in an ice bath. The mixture (36 μL) was stirred in this state for 30 minutes and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and then washed with water and brine, and dried over anhydrous sodium sulfate. Decompress the reaction solution After concentrating, the obtained residue was purified (jjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.33 - 7.06 (m, 6H), 4.14 - 3.37 (m, 5H), 2.69 (d, J = 13.8 Hz, 1H), 2.53-2.37 (m, 4H), 2.21-2.09 (m, 1H), 1.83-1.54 (m, 1H), 1.12 (brs, 3H).

ESI/MS (m/z) 374 (M+H) ⁺ .

[Embodiment 2] 4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic)

Dissolving methyl 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic: 434 mg) in methanol Magnesium (283 mg) was added to (12 mL), and the mixture was stirred at 60 ° C for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.09 (dd, J = 7.4, 1.6 Hz, 1H), 7.04 (td, J = 7.4, 1.6 Hz, 1H), 6.81 (td, J = 7.4, 1.2 Hz, 1H), 6.67 (dd, J=7.4, 1.2 Hz, 1H), 3.71 (brs, 1H), 3.62 (s, 3H), 3.18-3.05 (m, 3H), 2.79 (d, J = 13.7 Hz, 1H) ), 2.26 (dddd, J = 13.9, 7.0, 2.6, 1.1 Hz, 1H), 1.70 (ddd, J = 13.9, 9.1, 3.2 Hz, 1H), 1.24 (s, 3H).

ESI/MS (m/z) 220 (M+H) ⁺ .

[Example 3] 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic)

Methyl 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic: 4.82 g) was dissolved in 1M sodium hydroxide (37 mL) was added to a mixed solvent of tetrahydrofuran (35 mL) and methanol (35 mL), and the mixture was stirred at 50 ° C for 11 hours. Decompress the reaction solution After concentration, water was added to the obtained residue, and extracted with ethyl acetate. After 6 M hydrochloric acid was added to the aqueous phase to adjust the acidity, the mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.27-7.12 (m, 6H), 3.98-3.49 (m, 2H), 2.71 (d, J = 14.0 Hz, 1H), 2.49 (d, J = 14.0 Hz, 1H), 2.43 (s, 3H), 2.19-2.13 (m, 1H), 1.78-1.71 (m, 1H), 1.16 (brs, 3H).

ESI/MS (m/z) 360 (M+H) ⁺ , 358 (MH) ^- .

[Reference Example 15] N-[(R)-2-hydroxy-1-phenylethyl]-4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]nitrogen呯-4-carbamamine (chiral A) [Reference Example 16] N-[(R)-2-hydroxy-1-phenylethyl]-4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]nitrogen呯-4-carbamamine (chiral B)

Dissolving 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic: 1.00 g) in N, Add 1-hydroxybenzotriazole (563 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to N-dimethylformamide (20 mL) Salt (800 mg) and (R)-(-)-2-phenylglycolamine (572 mg) were stirred at room temperature for 3 hours. After adding water and extracting with ethyl acetate, the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by chromatography (hexane/ethyl acetate = 1/1) to afford the title compound as a colorless oil. (Chiral A): 526 mg, Reference Example 16 (chiral B): 629 mg].

Reference Example 15 (Chiral A): ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.3 Hz, 2H), 7.32-7.23 (m, 9H), 7.17 (td, J = 7.4, 1.4) Hz, 1H), 7.09 (dd, J = 7.4, 1.4 Hz, 1H), 6.96 (brs, 1H), 6.16 (d, J = 6.9 Hz, 1H), 4.94 - 4.90 (m, 1H), 3.88-3.74 (m,1H), 3.81 (dd, J=5.3, 5.3 Hz, 2H), 3.63-3.49 (m, 1H), 2.64 (d, J = 14.3 Hz, 1H), 2.52 (d, J = 14.3 Hz, 1H), 2.40 (s, 3H), 2.29-2.23 (m, 1H), 1.72-1.65 (m, 1H), 1.12 (brs, 3H).

ESI/MS (m/z) 479 (M+H) ⁺ , 477 (MH) ^- .

Reference Example 16 (Chiral B): ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.37-7.20 (m, 9H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (dd, J=7.0, 1.8 Hz, 1H), 6.16 (d, J=6.9 Hz, 1H), 4.96-4.92 (m, 1H), 3.78-3.74 (m, 4H), 2.64 (d) , J = 14.1 Hz, 1H), 2.59 - 2.53 (m, 1H), 2.42 (s, 3H), 2.27 - 2.22 (m, 1H), 1.70 - 1.62 (m, 1H), 1.11 (brs, 3H).

ESI / MS (m / z) 479 (M + H) +, 477 (MH) -.

Here, "chiral A" is as shown in the following formula, for example.

It is a highly polar isomer which is optically active in the case of a quaternary carbon atom when the quaternary carbon atom is an asymmetric carbon. Further, the compound and the following compound obtained by using a highly polar isomer which is optically active as a quaternary carbon atom as a raw material are referred to as "chiral A" at the end of the nomenclature.

Here, "chiral B" is as shown in the following formula, for example, [Chem. 29]

It is a low polar isomer which is optically active in the case of a quaternary carbon atom when the quaternary carbon atom is an asymmetric carbon. Further, the compound and the following compound obtained by using a low polar isomer which is optically active as a quaternary carbon atom as a raw material are referred to as "chiral B" at the end of the nomenclature.

[Example 4] 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A)

Making N-[(R)-2-hydroxy-1-phenylethyl]-4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b] Nitrozine-4-carbamide (chiral A: 526 mg) was dissolved in methanol (11 mL), concentrated sulfuric acid (2.2 mL) was added, and the mixture was stirred at 80 ° C for 11 hours. The reaction solution was concentrated under reduced pressure, and water was evaporated. The organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.28-7.25 (m, 2H), 7.23 - 7.14 (m, 3H), 7.12-7.08 (m, 1H), 4.00-3.87 (m, 1H), 3.64-3.48 (m, 1H), 3.53 (s, 3H), 2.69 (d, J = 13.8 Hz, 1H), 2.47 (d, J = 13.8 Hz, 1H), 2.43 (s, 3H), 2.18-2.13 (m, 1H), 1.76-1.70 (m, 1H), 1.12 (brs, 3H).

ESI/MS (m/z) 374 (M+H) ⁺ .

[Example 5] 4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A)

Use 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A) instead of 4-methyl 1-methyl-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic), which was carried out in the same manner as in Example 2. The reaction is carried out to thereby obtain the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.09 (dd, J = 7.4, 1.4 Hz, 1H), 7.04 (td, J = 7.4, 1.4 Hz, 1H), 6.81 (td, J = 7.4, 1.4 Hz, 1H), 6.67 (dd, J=7.4, 1.4 Hz, 1H), 3.71 (brs, 1H), 3.62 (s, 3H), 3.18-3.05 (m, 3H), 2.79 (d, J = 13.7 Hz, 1H) ), 2.26 (dddd, J = 13.9, 7.0, 2.6, 1.1 Hz, 1H), 1.70 (ddd, J = 13.9, 9.1, 3.2 Hz, 1H), 1.24 (s, 3H).

ESI/MS (m/z) 220 (M+H) ⁺ .

[Reference Example 17] Ethyl 1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

Ethyl 1-toluenesulfonyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (631 mg) was dissolved in ethanol (8 mL), and 10% palladium carbon (63.0 mg) was added. The mixture was stirred at 50 ° C for 14.5 hours under a hydrogen atmosphere. The title compound (634 mg) was obtained as a white solid.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.66-7.58 (m, 2H), 7.31-7.23 (m, 3H), 7.22-7.12 (m, 3H), 4.20-3.96 (m, 2H), 3.65-3.38 (m, 1H), 2.75-2.57 (m, 2H), 2.55-2.45 (m, 1H), 2.42 (s, 3H), 2.15 - 1.96 (m, 3H), 1.19 (t, J = 7.1 Hz, 3H) ).

[Embodiment 6] Ethyl 4-fluoro-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

Ethyl 1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic: 1.00 g) was dissolved in tetrahydrofuran (25 mL) , cooled to -78 ° C. After a 2 M solution of lithium diisopropylamide-tetrahydrofuran (1.7 mL) was added dropwise at -78 ° C, the mixture was stirred for 30 minutes. N-fluorobenzenesulfonimide (1.27g) in tetrahydrofuran solution (10mL) was added dropwise at the same temperature, and stirred 10 After a minute, the temperature was raised to -40 ° C and further stirred for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and then purified, mjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ 7.66-7.61 (m, 2H), 7.31-7.19 (m, 5H), 7.16-7.11 (m, 1H), 4.25-4.16 (m, 2H), 3.63-3.41 (m, 1H), 3.01-2.80 (m, 2H), 2.56-2.37 (m, 4H), 2.15-2.03 (m, 2H), 1.30-1.25 (m, 3H).

ESI/MS (m/z) 392 (M+H) ⁺ .

[Embodiment 7] Methyl 4-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

Use 4-fluoro-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (racemic) instead of 4-methyl- Methyl 1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic), which was reacted in the same manner as in Example 2. Thereby, the title compound is obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.65-7.60 (m, 2H), 6.88 (td, J = 7.9,1.2Hz, 1H), 6.78 (dd, J = 7.9,1.2Hz, 1H), 3.82 ( s, 3H), 3.45-3.06 (m, 4H), 2.28-2.46 (m, 1H), 2.24-2.11 (m, 1H).

ESI/MS (m/z) 224 (M+H) ⁺ .

[Embodiment 8] 4-fluoro-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic)

Use 4-fluoro-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (racemic) instead of 4-methyl- Methyl 1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic), which was reacted in the same manner as in Example 3. Thereby, the title compound is obtained.

1H-NMR (400MHz, CDCl ₃ ) δ 7.63 (d, J = 8.3 Hz, 2H), 7.32-7.21 (m, 5H), 7.17-7.12 (m, 1H), 4.23 (d, J = 13.7 Hz, 1H) ), 3.55-3.42 (m, 1H), 3.05-2.87 (m, 2H), 2.63-2.39 (m, 4H), 2.16-2.09 (m, 1H).

ESI/MS (m/z) 364 (M+H) ⁺ .

[Reference Example 18] 4-fluoro-N-[(R)-2-hydroxy-1-phenylethyl]-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine -4-carboxamide (chiral A) [Reference Example 19] 4-fluoro-N-[(R)-2-hydroxy-1-phenylethyl]-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine -4-carboxamide (chiral B)

4-Fluoro-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic) was used instead of 4-methyl-1- Tosylsulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic) was reacted in the same manner as in Reference Examples 15 and 16. This gave the title compound [Reference Example 18 (chiral A), Reference Example 19 (chiral B)].

Reference Example 18 (Chiral A): ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.3 Hz, 2H), 7.46-7.17 (m, 10H), 7.07-7.02 (m, 1H), 7.01-6.94(m,1H),5.07-5.01(m,1H), 4.35(d,J=14.8Hz,1H),3.92-3.86(m,2H),3.48-3.36(m,1H),2.91- 2.73 (m, 1H), 2.69-2.47 (m, 3H), 2.39 (s, 3H), 2.08-1.92 (m, 1H).

ESI/MS (m/z) 483 (M+H) ⁺ .

Reference Example 19 (Chiral B): ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, J = 8.3 Hz, 2H), 7.44 (dd, J = 7.8, 1.4 Hz, 1H), 7.39 - 7.21. m, 9H), 7.12 (dd, J = 7.4, 1.5 Hz, 1H), 7.00-6.97 (m, 1H), 5.06-5.02 (m, 1H), 4.32 (dt, J = 14.8, 4.0 Hz, 1H) , 3.92-3.89 (m, 2H), 3.39 (dd, J = 13.8, 13.8 Hz, 1H), 2.91-2.72 (m, 2H), 2.58-2.41 (m, 1H), 2.41 (s, 3H), 2.03 (dd, J = 6.6, 5.8 Hz, 1H), 1.94-1.87 (m, 1H).

ESI/MS (m/z) 483 (M+H) ⁺ .

[Embodiment 9] 4-fluoro-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A)

4-Fluoro-N-[(R)-2-hydroxy-1-phenylethyl]-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]nitrogen呯-4-carbamide (chiral A) in place of N-[(R)-2-hydroxy-1-phenylethyl]-4-methyl-1-toluenesulfonyl-2,3,4, 5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (chiral A) was reacted in the same manner as in Example 4 to give the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.3 Hz, 2H), 7.31-7.19 (m, 5H), 7.13 (dd, J = 5.1, 2.5 Hz, 1H), 4.25-4.07 ( m, 1H), 3.77 (s, 3H), 3.61-3.42 (m, 1H), 3.09-2.80 (m, 2H), 2.57-2.39 (m, 4H), 2.15-2.04 (m, 1H).

ESI/MS (m/z) 378 (M+H) ⁺ .

[Embodiment 10] 4-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A)

Use 4-fluoro-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A) instead of 4-methyl- Methyl 1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic), which was reacted in the same manner as in Example 2. Thereby, the title compound is obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.65-7.60 (m, 2H), 6.88 (td, J = 7.9,1.2Hz, 1H), 6.78 (dd, J = 7.9,1.2Hz, 1H), 3.82 ( s, 3H), 3.45-3.06 (m, 4H), 2.28-2.46 (m, 1H), 2.24-2.11 (m, 1H).

ESI/MS (m/z) 224 (M+H) ⁺ .

[Example 11] Ethyl 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

The reaction was carried out in the same manner as in Example 6 using methylene iodide instead of N-fluorobenzenesulfonimide, whereby the title compound was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.31 - 7.08 (m, 6H), 4.08 - 3.86 (m, 3H), 3.71-3.41 (m, 1H), 2.67 (d, J = 13.9 Hz, 1H), 2.52-2.39 (m, 4H), 2.21-2.10 (m, 1H), 1.82-1.63 (m, 1H), 1.21-1.02 (m, 6H).

ESI/MS (m/z) 388 (M+H) ⁺ .

[Embodiment 12] Ethyl 4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

Use 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (racemic) instead of 4-methyl 1-methyl-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic), which was carried out in the same manner as in Example 2. The reaction is carried out to thereby obtain the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.12-7.06 (m, 1H), 7.03 (td, J = 7.5, 1.4 Hz, 1H), 6.81 (td, J = 7.5, 1.4 Hz, 1H), 6.67 ( Dd, J = 7.5, 1.4 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.71 (brs, 1H), 3.20-3.63 (m, 3H), 2.79 (d, J = 13.8 Hz, 1H) ), 2.31-2.22 (m, 1H), 1.74-1.64 (m, 1H), 1.24 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H).

ESI/MS (m/z) 234 (M+H) ⁺ .

[Reference Example 20] Methyl 1-(t-butoxycarbonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate

Methyl 2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (114 g) was dissolved in tetrahydrofuran (1.2 L), and 4-dimethylaminopyridine (6.85 g) was added. After dibutyl butyl carbonate (490 g), it was stirred at 80 ° C for 5 hours. Thereafter, 4-dimethylaminopyridine (68.5 g) and ditributyl dicarbonate (184 g) were further added, and the mixture was stirred at 80 ° C for 15 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate was added, and the organic phase was washed successively with 20% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate /hexane = 1 / 6) The residue was purified to give the title compound (141 g).

^{1 H-NMR (400MHz, CDCl} 3) δ 7.67 (s, 1H), 7.41-7.27 (m, 3H), 7.19 (t, J = 8.0Hz, 1H), 3.82 (s, 3H), 3.65 (s, 2H), 2.89 (t, J = 4.0 Hz, 2H), 1.47 (s, 9H).

ESI/MS (m/z) 304 (M+H) ⁺ .

[Reference Example 21] Methyl 1-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate

Substituting 1-(t-butoxycarbonyl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester for 1-toluenesulfonyl-2,3-dihydro- Ethyl 1H-benzo[b]azepine-4-carboxylate was reacted in the same manner as in Reference Example 17, whereby the title compound was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.26-7.12 (m, 4H), 4.45-4.25 (m, 1H), 3.69 (s, 3H), 3.00-2.10 (m, 4H), 2.10-2.00 (m) , 2H), 1.53-1.36 (m, 9H).

ESI / MS (m / z) 306 (M + H) +.

[Example 13] Methyl 1-(t-butoxycarbonyl)-4-ethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

Substituting 1-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester for 1-toluenesulfonyl-2,3 , 4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester, using ethyl iodide instead of N-fluorobenzenesulfonimide, using the same method as in Example 6 Thereby, the title compound is obtained.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.21-7.08 (m, 4H), 4.30 (s, 1H), 3.59 (s, 3H), 3.00-2.83 (m, 3H), 2.23-2.18 (m, 1H ), 1.69-1.37 (m, 12H), 0.85 (t, J = 8.0 Hz, 3H).

ESI/MS (m/z) 334 (M+H) ⁺ .

[Embodiment 14] 1-(T-butoxycarbonyl)-4-ethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic)

Replace with methyl 1-(t-butoxycarbonyl)-4-ethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic) 4-methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic), utilized in Example 3 The reaction was carried out in the same manner, whereby the title compound was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.26-7.10 (m, 4H), 4.29-2.83 (m, 4H), 2.20-2.16 (m, 1H), 1.68-1.37 (m, 12H), 0.91-0.87 (m, 3H).

ESI/MS (m/z) 320 (M+H) ⁺ , 318 (MH) ^- .

[Reference Example 22] 4-ethyl-4-{[(R)-2-hydroxy-1-phenylethyl]aminecarbamyl}-2,3,4,5-tetrahydro-1H-benzo[b]azepine 1-carboxylic acid tert-butyl ester (chiral A) [Reference Example 23] 4-ethyl-4-{[(R)-2-hydroxy-1-phenylethyl]aminecarbamyl}-2,3,4,5-tetrahydro-1H-benzo[b]azepine 1-carboxylic acid tert-butyl ester (chiral B)

Substituting 4-(t-butoxycarbonyl)-4-ethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic) for 4- Methyl-1-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic), using the same conditions as Reference Examples 15 and 16. The reaction was carried out, whereby the title compound was obtained [Reference Example 22 (chiral A), Reference Example 23 (chiral B)].

Reference Example 22 (Chiral A): ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.33-6.93 (m, 9H), 6.31 (s, 1H), 4.98 (s, 1H), 4.30-3.83 (m, 3H) ), 2.96-2.27 (m, 4H), 1.68-1.37 (m, 13H), 0.95-0.91 (m, 3H).

ESI/MS (m/z) 439 (M+H) ⁺ , 437 (MH) ^- .

Reference Example 23 (Chiral B): ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.35-7.14 (m, 9H), 6.25 (brs, 1H), 4.97-4.94 (m, 1H), 4.36-4.23 (m) , 1H), 3.77-3.70 (m, 2H), 3.00-2.95 (m, 2H), 2.38-2.20 (m, 2H), 1.71-1.53 (m, 3H), 1.37 (s, 9H), 0.86 (t , J = 7.7 Hz, 3H).

ESI/MS (m/z) 439 (M+H) ⁺ , 437 (MH) ^- .

[Example 15] 4-ethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A)

4-ethyl-4-{[(R)-2-hydroxy-1-phenylethyl]amine-carbamoyl}-2,3,4,5-tetrahydro-1H-benzo[b]nitrogen呯-1-carboxylic acid tert-butyl ester (chiral A) instead of N-[(R)-2-hydroxy-1-phenylethyl]-4-methyl-1-toluenesulfonyl-2,3 4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (chiral A) was reacted in the same manner as in Example 4 to give the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.09 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.80 (t, J = 8.0 Hz, 1H), 6.65 (d) , J=8.0Hz, 1H), 3.72(brs,1H), 3.61(s,3H),3.22-2.83(m,4H), 2.28-2.22(m,1H),1.76-1.51(m,3H), 0.85 (t, J = 8.0 Hz, 3H).

ESI/MS (m/z) 234 (M+H) ⁺ .

[Reference Example 24] (S)-3-cyano-2-methylpropyl mesylate

(R)-3-bromo-2-methyl-1-propanol (30.1 g) was dissolved in dimethyl hydrazine (130 mL), sodium cyanide (10.1 g) was added, and the mixture was stirred at 60 ° C for 1.5 hours. . Water was added to the reaction mixture, and extraction was carried out four times with dichloromethane. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (S)-4-hydroxy-3-methylbutyronitrile.

The above (S)-4-hydroxy-3-methylbutyronitrile was dissolved in dichloromethane (400 mL), and triethylamine (44 mL) and methanesulfonium chloride (18.4 mL) were added at 0 ° C. Stir at °C for 30 minutes. After adding 1 M hydrochloric acid to the reaction liquid to adjust to acidity, extraction was carried out with dichloromethane. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give titled as a colorless oil. Compound (29.9 g).

^{1 H-NMR (400MHz, CDCl} 3) δ 4.25 (dd, J = 10.3,4.7Hz, 1H), 4.08 (dd, J = 10.3,7.5Hz, 1H), 3.06 (s, 3H), 2.57-2.41 ( m, 2H), 2.41-2.25 (m, 1H), 1.18 (d, J = 6.9 Hz, 3H).

[Reference Example 25] (S)-N-(3-cyano-2-methylpropyl)-N-(2-methylnonylphenyl)-4-methylbenzenesulfonamide

Dissolving N-(2-formylphenyl)-4-methylbenzenesulfonamide (33.0 g) and (S)-3-cyano-2-methylpropyl methanesulfonate (23.3 g) Lithium bromide (15.6 g) and potassium carbonate (24.9 g) were added to N,N-dimethylformamide (480 mL), and stirred at 70 ° C for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by EtOAc EtOAc EtOAc EtOAc Compound (23.5 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.45-10.38 (m, 1H), 8.04 (dd, J = 7.1, 2.3 Hz, 1H), 7.56-7.45 (m, 2H), 7.43-7.39 (m, 2H) ), 7.28 (d, J = 8.3 Hz, 2H), 6.82 - 6.71 (m, 1H), 3.85-3.64 (m, 1H), 3.50 - 3.21 (m, 1H), 2.62 - 2.39 (m, 1H), 2.45 (s, 3H), 2.35 (dd, J = 6.4, 2.4 Hz, 1H), 2.13-1.95 (m, 1H), 1.20-1.04 (m, 3H).

ESI/MS (m/z) 357 (M+H) ⁺ .

[Reference Example 26] (S)-3-methyl-1-toluenesulfonyl-2,3-dihydro-1H-benzo[b]azepine-4-carbonitrile

Dissolving (S)-N-(3-cyano-2-methylpropyl)-N-(2-methylnonylphenyl)-4-methylbenzenesulfonamide (17.7 g) in diethyl carbonate A 20% sodium ethoxide-ethanol solution (24 mL) was added to the ester (830 mL), and stirred at room temperature for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane = 1/9-1/1) The residue thus obtained was purified to give the title compound (9.00 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.65 (dd, J = 8.0, 1.0 Hz, 1H), 7.46-7.33 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 (td, J = 7.5, 1.0 Hz, 1H), 7.21-7.18 (m, 3H), 6.71 (d, J = 1.8 Hz, 1H), 4.40 (dd, J = 13.5, 4.2 Hz, 1H), 3.23 - 3.01 (m) , 2H), 2.39 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H).

ESI/MS (m/z) 339 (M+H) ⁺ , 337 (MH) ^- .

[Reference Example 27] (S)-3-methyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester

Replacement of 1-toluenesulfonyl-2,3- using (S)-3-methyl-1-toluenesulfonyl-2,3-dihydro-1H-benzo[b]azepine-4-carbonitrile Ethyl dihydro-1H-benzo[b]azepine-4-carboxylate was reacted in the same manner as in Reference Example 11 to give the title compound.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.62 (s, 1H), 7.27 (dd, J = 7.8,1.6Hz, 1H), 7.11 (ddd, J = 8.3,7.2,1.6Hz, 1H), 6.73 ( Ddd, J=7.8, 7.2, 1.2 Hz, 1H), 6.69-6.61 (m, 1H), 4.57 (brs, 1H), 3.80 (s, 3H), 3.42-3.25 (m, 2H), 3.04 (d, J=12.8Hz, 1H), 1.15 (d, J=6.8Hz, 3H).

ESI/MS (m/z) 218 (M+H) ⁺ .

[Example 16] (3S)-1-(tert-butoxycarbonyl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester Spin)

Methyl (S)-3-methyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxylate (305 mg) was dissolved in tetrahydrofuran (3 mL). Butyl ester (1.1 mL) and 4-dimethylaminopyridine (305 mg) were heated to reflux for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate /hexane = 1/4 - 1/2) to obtain (3S)-1- (t-butoxycarbonyl)-3-methyl 2,3-dihydro-1H-benzo[b]azepine-4-carboxylate Methyl ester.

Dissolving the above methyl (3S)-1-(t-butoxycarbonyl)-3-methyl 2,3-dihydro-1H-benzo[b]azepine-4-carboxylate in ethanol (4 mL) Medium, 10% palladium on carbon (30.0 mg) was added. After replacing the inside of the reaction vessel with hydrogen, it was stirred at 50 ° C for 4 hours. After replacing the inside of the reaction vessel with argon gas, the reaction liquid was filtered through celite, and washed with ethyl acetate. After adding water to the filtrate and separating the layers, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.29-7.01 (m, 4H), 4.54-3.91 (m, 1H), 3.82-3.40 (m, 3H), 3.27-2.07 (m, 5H), 1.60-1.30 (m, 9H), 1.13 - 0.79 (m, 3H).

[Example 17] (3S)-1-(tert-butoxycarbonyl)-3,4-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic)

Methyl (3S)-1-(t-butoxycarbonyl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (251 mg Dissolved in tetrahydrofuran (5 mL) and cooled to -78 °C. Lithium diisopropylguanamine (1.8 M tetrahydrofuran solution) (870 μL) was added dropwise and stirred for 30 minutes. Methyl iodide (98 μL) was added and stirred at -40 ° C for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.25-7.04 (m, 4H), 4.22-4.04 (m, 1H), 3.74 (s, 3H), 3.23 (d, J = 13.2 Hz, 1H), 2.71 2.35 (m, 3H), 1.60-1.31 (m, 9H), 0.85-0.69 (m, 3H).

[Embodiment 18] (3S)-3,4-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic)

(3S)-1-(Tertibutoxycarbonyl)-3,4-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b] Methyl hydrazine-4-carboxylate (racemic: 219 mg) was dissolved in dichloromethane (4.4 mL), trifluoroacetic acid (730 μL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0 ° C and diluted with dichloromethane and water. 5 M sodium hydroxide was added to the mixed solution, and after neutralization, extraction was carried out with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (144 mg).

ESI/MS (m/z) 234 (M+H) ⁺ .

[Embodiment 19] (3S)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester

Methyl (3S)-1-(t-butoxycarbonyl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (outside The racemic: 913 mg) was dissolved in dichloromethane (9 mL), trifluoroacetic acid (3 mL), and stirred at room temperature for 1 hour. The reaction solution was cooled to 0 ° C and diluted with dichloromethane and water. 5 M sodium hydroxide was added to the mixed solution, and after neutralization, extraction was carried out with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (560 mg).

ESI/MS (m/z) 220 (M+H) ⁺ .

[Example 20] Methyl (3R)-4-fluoro-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic)

Methyl (3S)-1-(t-butoxycarbonyl)-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (outside Racemic: 571 mg) was dissolved in tetrahydrofuran (7 mL) and cooled to -78. After a 2 M lithium diisopropylamide-tetrahydrofuran solution (1.8 mL) was added dropwise at -78 ° C, the mixture was stirred for 30 minutes. A tetrahydrofuran solution (2 mL) of N-fluorobenzenesulfonimide (1.13 g) was added dropwise at the same temperature, and the mixture was stirred for 10 minutes, then warmed to -40 ° C, and then stirred for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/4). Thereby, (3R)-1-(t-butoxycarbonyl)-4-fluoro-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine- Methyl 4-carboxylate (racemic: 463 mg).

The above (3R)-1-(t-butoxycarbonyl)-4-fluoro-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate The acid methyl ester (racemic: 456 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0 ° C and diluted with dichloromethane and water. 5 M sodium hydroxide was added to the mixed solution, and after neutralization, extraction was carried out with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (259 mg).

ESI/MS (m/z) 238 (M+H) ⁺ .

[Example 21] 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzene And [b]methyl hydrazine-4-carboxylate (racemic)

2-Methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoic acid (507 mg) was suspended in sulfinium chloride (5 mL) and stirred at 50 ° C for 30 minutes. The liquid was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (8 mL), and methyl 4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate was added (external After the racemic solution of 466 mg) and pyridine (430 μL) in dichloromethane (2 mL), the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by EtOAc (hexane/ethyl acetate = 2 / 1-1 / 1) to afford the title compound as a yellow oil. (848 mg).

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.84-7.42 (m, 2H), 7.16-5.56 (m, 6H), 6.27-6.19 (m, 1H), 4.85-4.61 (m, 1H), 3.79-3.44 (m, 4H), 3.13-2.80 (m, 3H), 2.53-2.29 (m, 6H), 1.99-1.93 (m, 1H), 1.43 (brs, 2H), 1.06 (brs, 1H).

ESI/MS (m/z) 418 (M+H) ⁺ .

[Example 22] 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzene And [b]azepine-4-carboxylic acid (racemic)

4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2(3,4,5-tetrahydro-1H- Methyl benzo[b]azepine-4-carboxylate (racemic: 848 mg) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), and 5 M sodium hydroxide (2 mL) was added at 50 ° C After stirring for 3.5 hours, the reaction liquid was concentrated under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After 6M hydrochloric acid was added to the aqueous phase to adjust to acidity, extraction was carried out with dichloromethane to sat. The organic phase was washed with water and dried over anhydrous sodium sulfate.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.84-7.45 (m, 2H), 7.21-6.55 (m, 6H), 6.27-6.20 (m, 1H), 4.87-4.61 (m, 1H), 3.75-2.82 (m, 4H), 2.53-2.28 (m, 6H), 2.01-1.95 (m, 1H), 1.50 (brs, 2H), 1.10 (brs, 1H).

ESI/MS (m/z) 404 (M+H) ⁺ , 402 (MH) ^- .

[Example 23] N-(2-Amino-2-oxoethyl)-N,4-dimethyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl) Benzamethylene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (racemic)

4-Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H- Benzo[b]azepine-4-carboxylic acid (racemic: 20.0 mg) was dissolved in dichloromethane (1.5 mL), and 1-hydroxybenzotriazole (13.4 mg), 1-ethyl-3 was added. -(3-Dimethylaminopropyl)carbodiimide hydrochloride (19.0 mg) and N-methylglycineamine hydrochloride (12.4 mg) were stirred at room temperature for 17.5 hours. After adding water and extracting with dichloromethane, the organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure using a thin layer of silica gel chromatography (chloroform / The residue obtained was purified to give the title compound (yield: 2.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.84-7.44 (m, 2H), 7.19-6.76 (m, 4H), 7.11 (dd, J = 8.2, 2.0 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 6.27-6.19 (m, 1H), 5.56 (brs, 1H), 5.33 (brs, 1H), 4.96-4.82 (m, 1H), 4.56-4.49 (m, 1H), 4.18-3.94 ( m, 2H), 3.61-3.15 (m, 5H), 2.93-2.88 (m, 1H), 2.52-2.33 (m, 6H), 1.95-1.89 (m, 1H), 1.56 (brs, 2H), 1.26 ( Brs, 1H).

ESI/MS (m/z) 474 (M+H) ⁺ , 472 (MH) ^- .

The compound was synthesized according to the following reaction formula by the method of Example 21. The synthesized compounds and data are shown in Tables 1 and 2.

[Example 44] 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzene And [b]azepine-4-carboxylic acid (chiral A)

4-Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H- Methyl benzo[b]azepine-4-carboxylate (chiral A) in place of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl) Methylbenzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic) was reacted in the same manner as in Example 22, Thereby the title compound was obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.84-7.45 (m, 2H), 7.21-6.55 (m, 6H), 6.27-6.20 (m, 1H), 4.87-4.61 (m, 1H), 3.75-2.82 (m, 4H), 2.53-2.28 (m, 6H), 2.01-1.95 (m, 1H), 1.50 (brs, 2H), 1.10 (brs, 1H).

ESI/MS (m/z) 404 (M+H) ⁺ , 402 (MH) ^- .

[Example 45] 4-methyl-1-[2-methyl-4-(pyrrolidin-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine- 4-carboxylic acid (chiral A)

4-Methyl-1-[2-methyl-4-(pyrrolidin-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine Methyl 4-carboxylate (chiral A) in place of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2 Methyl 3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic) was obtained by the same procedure as in Example 22 to give the title compound.

ESI/MS (m/z) 393 (M+H) ⁺ , 391 (MH) ^- .

[Example 46] 4-methyl-1-[2-methyl-4-(4-methyl) Zin-2-yl)benzhydryl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic)

Using 4-methyl-1-[2-methyl-4(4-methyl) Ethyl-2-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester (racemic) instead of 4-methyl- 1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]nitrogen Methyl hydrazine-4-carboxylate (racemic) was reacted in the same manner as in Example 22 to give the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.78 (s, 1H), 7.50-7.37 (m, 2H), 7.22-6.80 (m, 4H), 6.62-6.57 (m, 1H), 4.86-4.61 (m) , 1H), 3.49-3.47 (m, 1H), 3.29-2.83 (m, 2H), 2.53 (s, 3H), 2.34-2.27 (m, 1H), 2.20 (d, J = 1.2 Hz, 2H), 2.10 (s, 1H), 2.02-1.96 (m, 1H), 1.50 (brs, 2H), 1.10 (brs, 1H).

ESI/MS (m/z) 405 (M+H) ⁺ , 403 (MH) ^- .

[Example 47] 1-[2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-4-methyl-2,3,4,5-tetrahydro-1H-benzo [b]azepine-4-carboxylic acid (chiral A)

1-[2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)benzimidyl]-4-methyl-2,3,4,5- Methyl tetrahydro-1H-benzo[b]azepine-4-carboxylate (chiral A) in place of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazole) 1-methyl)benzimidyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic), using the same as Example 22 The method is carried out to thereby obtain the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.84-7.70 (m, 1H), 7.64-7.60 (m, 1H), 7.52-6.83 (m, 6H), 6.30-6.21 (m, 1H), 4.80-4.59 (m, 1H), 3.51-2.77 (m, 3H), 2.47-1.95 (m, 5H), 1.62-1.07 (m, 3H).

ESI/MS (m/z) 424 (M+H) ⁺ , 422 (MH) ^- .

[Example 48] 1-[2-chloro-4-(3-fluoropropoxy)benzylidene]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4 -carboxylic acid (racemic)

1-[2-Chloro-4-(3-fluoropropoxy)benzylidenyl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine- 4-carboxylic acid ethyl ester (racemic) in place of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2, Methyl 3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic) was reacted in the same manner as in Example 22 to give the title compound.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.38-6.78 (m, 6H), 6.54 (d, J = 8.5Hz, 1H), 4.83-4.51 (m, 3H), 4.16-3.97 (m, 2H), 3.76-3.48(m,1H), 3.28-2.77(m,2H),2.44-2.21(m,1H), 2.13(quin,J=5.9Hz,1H),2.07(quin,J=5.9Hz,1H) , 2.02-1.95 (m, 1H), 1.47 (brs, 2H), 1.08 (brs, 1H).

ESI/MS (m/z) 420 (M+H) ⁺ , 419 (MH) ^- .

[Example 49] 1-[2-chloro-4-(pyrrolidin-1-yl)benzylidene)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4 -carboxylic acid (racemic)

1-[2-Chloro-4-(pyrrolidin-1-yl)benzylidene]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine- Methyl 4-carboxylate (racemic) instead of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2, Methyl 3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate The reaction was carried out in the same manner as in Example 22 to give the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.19 (d, J = 7.3 Hz, 1H), 7.07 - 6.92 (m, 2H), 6.85 - 6.81 (m, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 6.11 (dd, J = 8.5, 2.3 Hz, 1H), 4.84 - 4.78 (m, 1H), 4.63-4.57 (m, 1H), 3.52-3.49 (m, 1H), 3.18-3.15 (m, 4H), 3.10-3.08 (m, 1H), 2.41-2.23 (m, 2H), 1.95 (ddd, J = 6.6, 3.3, 3.3 Hz, 4H), 1.46 (brs, 2H), 1.09 (brs, 1H).

ESI/MS (m/z) 413 (M+H) ⁺ , 411 (MH) ^- .

[Example 50] 1-(2-chloro-4-propoxybenzhydryl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (outside Racem

1-(2-Chloro-4-propoxybenzhydryl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid A Ester (racemic) instead of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzhydryl]-2,3,4,5 -Methyltetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic), the reaction was carried out in the same manner as in Example 22 to give the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.20 (d, J = 7.5 Hz, 1H), 7.13 - 6.81 (m, 4H), 6.77 (d, J = 2.5 Hz, 1H), 6.53 (dd, J = 8.5, 2.5 Hz, 1H), 4.82-4.58 (m, 1H), 3.80 (t, J = 6.6 Hz, 2H), 3.50 (d, J = 13.7 Hz, 1H), 3.27-3.04 (m, 2H), 2.45-2.24 (m, 1H), 2.02-1.94 (m, 1H), 1.73 (sext, J = 7.2 Hz, 2H), 1.47 (brs, 2H), 1.08 (brs, 1H), 0.98 (t, J = 7.2 Hz, 3H).

ESI/MS (m/z) 402 (M+H) ⁺ , 400 (MH) ^- .

[Example 51] 1-[2-chloro-4-( Zin-2-yl)benzylidene]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic)

Use 1-[2-chloro-4-( Methyl oxazol-2-yl)benzylidene]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic) 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzene And [b]methyl azide-4-carboxylate (racemic) was reacted in the same manner as in Example 22 to give the title compound.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.95 (brs, 1H), 7.71-7.68 (m, 1H), 7.68 (s, 1H), 7.22 (s, 1H), 7.22-7.00 (m, 3H), 6.98-6.89 (m, 2H), 4.83-4.62 (m, 1H), 3.54-3.50 (m, 1H), 3.31-3.08 (m, 2H), 2.49-2.29 (m, 1H), 2.06-1.98 (m , 1H), 1.49 (brs, 2H), 1.09 (brs, 1H).

ESI/MS (m/z) 411 (M+H) ⁺ , 409 (MH) ^- .

[Example 52] 1-[2-Chloro-4-(1H-pyrazol-1-yl)benzylidenyl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine 4-carboxylic acid (racemic)

1-[2-Chloro-4-(1H-pyrazol-1-yl)benzylidenyl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[b]nitrogen Methyl 呯-4-carboxylate (racemic) instead of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]- Methyl 2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic) was reacted in the same manner as in Example 22 to give the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.67-7.65 (m, 1H), 7.38-7.34 (m, 1H), 7.21-6.86 (m, 5H), 6.44 (dd, J = 2.5, 1.7 Hz, 1), 4.84 - 4.61 (m, 1H), 3.53 - 3.50 (m, 1H), 3.32-3.07 (m, 2H), 2.48-2.24 (m, 1H), 2.05-1.98 (m, 1H), 1.49 (brs, 2H), 1.09 (brs, 1H).

ESI/MS (m/z) 410 (M+H) ⁺ , 408 (MH) ^- .

[Example 53] 4-methyl-1-[4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzylidene]-2,3,4,5-tetrahydro -1H-benzo[b]azepine-4-carboxylic acid (chiral A)

4-Methyl-1-[4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzylidene]-2,3,4,5-tetra Hydrogen-1H-benzo[b]azepine-4-carboxylic acid methyl ester (chiral A) in place of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazole- 1-yl)benzhydryl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4- The methyl carboxylate (chiral A) was reacted in the same manner as in Example 22 to give the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ 8.07-7.90 (m, 1H), 7.76-7.75 (m, 1H), 7.61-7.48 (m, 1H), 7.37-6.87 (m, 4H), 6.79-6.72 (m, 1H), 6.33-6.24 (m, 1H), 4.81-4.60 (m, 1H), 3.47-2.82 (m, 3H), 2.39-1.97 (m, 5H), 1.64-1.09 (m, 3H) .

ESI/MS (m/z) 458 (M+H) ⁺ , 456 (MH) ^- .

[Example 54] 4-fluoro-1-[2-methyl-4-(pyrrolidin-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4 -carboxylic acid (chiral A)

4-Fluoro-1-[2-methyl-4-(pyrrolidin-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine- Methyl 4-carboxylate (chiral A) replaces 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2, Methyl 3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (racemic) was reacted in the same manner as in Example 22 to give the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.24-7.16 (m, 1H), 7.14 - 6.94 (m, 2H), 6.76-6.47 (m, 2H), 6.37-6.23 (m, 1H), 6.09-5.94 (m, 1H), 5.03-4.82 (m, 1H), 3.78-2.86 (m, 7H), 2.71-2.38 (m, 4H), 2.29-2.13 (m, 1H), 2.09-1.84 (m, 4H) .

ESI/MS (m/z) 397 (M+H) ⁺ .

[Example 55] (3S)-3,4-Dimethyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzimidyl]-2,3,4,5 -tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemic)

Using (3S)-3,4-dimethyl-1-[2-methyl-4-(3-methyl-1H-pyrazolo-1-yl)benzylidene]-2,3,4 ,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic) instead of 4-methyl-1-[2-methyl-4-(3-methyl-1H) -pyrazol-1-yl)benzimidyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic), utilized and implemented In the same manner as in Example 22, the reaction was carried out. The title compound was obtained.

ESI/MS (m/z) 418 (M+H) ⁺ , 416 (MH) ^- .

[Example 56] (3S)-1-[2-chloro-4-(pyrrolidin-1-yl)benzylidenyl]-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b] Azaindole-4-carboxylic acid (racemic)

Using (3S)-1-[2-chloro-4-(pyrrolidin-1-yl)benzylidenyl]-3-methyl-2,3,4,5-tetrahydro-1H-benzo[b Methyl hydrazine-4-carboxylate (racemic) instead of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene ]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic), the reaction was carried out in the same manner as in Example 22, whereby the title was obtained. Compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.18 (d, J = 7.3 Hz, 1H), 7.08-6.93 (m, 2H), 6.90-6.72 (m, 2H), 6.38-6.36 (m, 1H), 6.15-6.09(m,1H), 6.15-6.09(m,1H), 4.96(d,J=12.0Hz,1H), 3.40-3.29(m,1H),3.18-3.15(m,4H),2.96- 2.90 (m, 1H), 2.50-2.42 (m, 2H), 2.23-2.17 (m, 1H), 1.97-1.93 (m, 4H), 1.7-1.04 (m, 3H).

ESI/MS (m/z) 413 (M+H) ⁺ , 411 (MH) ^- .

[Example 57] (3R)-1-[2-chloro-4-(pyrrolidin-1-yl)benzylidene]-4-fluoro-3-methyl-2,3,4,5-tetrahydro-1H-benzene And [b]azepine-4-carboxylic acid (racemic)

Using (3R)-1-[2-chloro-4-(pyrrolidin-1-yl)benzylidene]-4-fluoro-3-methyl-2,3,4,5-tetrahydro-1H- Methyl benzo[b]azepine-4-carboxylate (racemic) instead of 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl) Methylbenzylidene]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid methyl ester (racemic) was reacted in the same manner as in Example 22, Thereby the title compound was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.14 (d, J = 7.0 Hz, 1H), 7.09-7.02 (m, 2H), 6.88 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 6.12 (dd, J = 8.4, 2.2 Hz, 1H), 4.81-4.77 (m, 1H), 3.71 (dd, J = 44.3, 14.7) Hz, 1H), 3.20-3.14 (m, 5H), 2.89-2.74 (m, 2H), 1.95 (ddd, J = 6.7, 3.6, 3.6 Hz, 4H), 1.06 (d, J = 6.2 Hz, 3H) .

ESI/MS (m/z) 431 (M+H) ⁺ , 429 (MH) ^- .

The compound was synthesized according to the following reaction formula by the method of Example 22. The synthesized compounds and data are shown in Table 3.

The compound was synthesized according to the following reaction formula by the method of Example 23. The synthesized compounds are shown in Tables 4 to 6, and the data are shown in Tables 7 to 9.

[Table 4]

Pharmacological test (1) Production of human V2 receptor expressing cells

Inserting a DNA fragment containing a human V2 receptor coding region into a vertebrate cell In the expression vector. The gene is introduced into animal cells to express human V2 receptor on the cell surface. The expression vector can express the neo gene functioning as a G418 resistance marker, and thus the human V2 receptor stably expressing cells can be selectively obtained by culturing in a medium containing G418.

(2) cAMP production test in V2 receptor-expressing cells

The human V2 receptor-expressing cells prepared by the above method were recovered, and after resuspending in a culture buffer (F-12 medium, 20 mM HEPES), 5 μl of the cells were dispensed to 384 wells at a density of 15,000 cells/well. In the board. Add 5 μl (10 μl/well) of compound solution diluted in assay buffer (F-12 medium, 20 mM HEPES, 1 mM IBMX) or 8-AVP ((Arg ⁸ )-vasopressin) solution to each well (final Concentration: 15,000 cells/well, 500 μM IBMX, 1% dimethylammonium). After incubation at room temperature for 30 minutes, the amount of cAMP production was measured according to the stated protocol using a commercially available HTRF cAMP kit (Cisbio). Excel Fit was used to determine the EC ₅₀ and Emax values of the test compounds. The Emax value of the test compound was calculated by setting the maximum reaction of 8-AVP to 100%, and based on the concentration-response curve of the test compound, the value showing the reaction of 50% was taken as the EC ₅₀ value, and the obtained EC ₅₀ was obtained. The Emax values are shown in Table 10.

As a result, it was found that all of the compounds of the examples subjected to this test had V2 receptor agonist activity.

(3) Rat PK (pharmacokinetics, pharmacokinetics) test

As experimental animals, male Sprague-Dawely (Crj: CD (SD) IGS: Charles River Laboratories Japan Co., Ltd.) rats of 7 to 8 weeks old were used. Rats used a hunger strike overnight. After the test compound was dissolved in DMSO, PEG (polyethylene glycol) and physiological saline were added to prepare at a concentration of 0.5 mg/mL (20/20/60, v/v/v) to 0.5 mg/ The amount of kg is administered to the tail vein. Blood was collected from the jugular vein by a heparin-treated syringe over a period of 6 to 8 hours after the administration, and the blood taken was centrifuged to obtain plasma. The concentration of the drug in the plasma was determined using LC/MS/MS. The sample for LC/MS/MS measurement was obtained by adding an internal standard substance and acetonitrile to plasma and removing the supernatant from the protein. PK parameters were analyzed using a non-compartmental model. The clearance rate (CL _p ) was calculated by dividing the AUC _0-∞ by the amount of administration. The distribution volume (Vd _ss ) is calculated by multiplying CL _p by the average residence time (MRT). The obtained CLp and Vd _{ss are} shown in Table 11.

As a result, it was found that all the compounds of the examples subjected to this test had good plasma clearance and distribution volume, and were excellent in dynamics.

Further, the comparative compound 1 is a compound of Example 4 described in International Publication No. 2006/104008 (Compound: N-(2-hydroxyethyl)-(R)-1-(2-chloro- 4-pyrazol-1-ylbenzimidyl)-3-methyl-1,2,3,5-tetrahydrobenzo[e]-1,4-diazepine-4-carboxamide).

(4) Cytochrome P450 (3A4) enzyme inhibition test

Using a 96-well plate, the midazolam (2.5 μM) as a substrate, the test compound (0.21 to 50 μM), and the human liver microsomal protein concentration of 0.1 mg protein/mL were contained in 1.55 mM NADP ⁺ , 3.3 mM glucose-6-phosphate, 3.3mM MgCl ₂ and 0.4Units / ml glucose-6-phosphate dehydrogenase 0.1M phosphate buffer (pH value = 7.4) of the total amount of 500μl as a reaction solution. Incubate at 37 ° C for 10 minutes, add 4 times the amount of cold acetonitrile, and stop the reaction. Thereafter, centrifugation (5000 g × 10 minutes × 4 ° C) was carried out, and the supernatant was taken, and the amount of metabolite produced was measured by LC/MS/MS. The inhibition rate of each concentration was calculated with respect to the value containing no test compound, and the concentration point of the test compound which inhibited the production amount of 50% of the metabolite was determined. The IC ₅₀ was determined using the concentrations of these two test compounds and the inhibition rate. The IC ₅₀ values obtained are shown in Table 12.

(5) Cytochrome P450 (2C9) enzyme inhibition test

Using a 96-well plate, sulfaphenazole (10 μM), test compound (0.21 to 50 μM), human liver microsomal protein concentration 0.1 mg protein/mL as a substrate, containing 1.55 mM NADP ⁺ , 3.3 mM glucose - As a reaction liquid, a total amount of 500 μl of a 0.1 M phosphate buffer (pH = 7.4) of 6-phosphate, 3.3 mM MgCl ₂ and 0.4 Units/ml glucose-6-phosphate dehydrogenase was used. Incubate at 37 ° C for 10 minutes, add 4 times the amount of cold acetonitrile, and stop the reaction. Thereafter, centrifugation (5000 g × 10 minutes × 4 ° C) was carried out, and the supernatant was taken, and the amount of metabolite produced was measured by LC/MS/MS. The inhibition rate of each concentration was calculated with respect to the value containing no test compound, and the concentration point of the test compound which inhibited the production amount of 50% of the metabolite was determined. The IC ₅₀ was determined using the concentrations and inhibition rates of the two test compounds. The IC ₅₀ values obtained are shown in Table 12.

As a result, it was found that all the compounds of the examples subjected to this test showed a low inhibitory effect on the drug metabolizing enzymes CYP3A4 and CYP2C9.

Further, the comparative compound 2 is a compound of Example 32 described in International Publication No. 97/22591 (Compound: 2-[(5R)-1-(2-chloro-4-pyrrolidine-1-) Benzomethylene)-2,3,4,5-tetrahydrobenzoazin-5-yl]-N-isopropylacetamide).

[Industrial availability]

The compound of the present invention has a V2 receptor agonistic action and is therefore useful as a preventive or therapeutic agent for central diabetes insipidus, nocturnal enuresis, nocturnal urinary frequency, overactive bladder, hemophilia, or Von Wylie disease.

Claims (8)

a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, [wherein, R ¹ represents the following formula: (wherein A represents a linear alkyl group having 1 to 3 carbon atoms which may be substituted by a linear alkyl group having 1 to 3 carbon atoms; R ⁶ represents a hydrogen atom; R ⁷ represents a hydroxyl group, or Can be substituted by a linear alkyl group containing 1 to 3 carbon atoms Razolyl); R ² represents a hydrogen atom; R ³ represents a linear alkyl group having 1 to 3 carbon atoms which may be substituted by 1 to 3 fluorine atoms, or a halogen atom; and R ⁴ represents an acceptable 1~ 1 to 4 substituted pyrrolidinyl groups of a linear alkyl group of 3 carbon atoms, or 1 to 3 substituted pyrazolyl groups which may be substituted with a linear alkyl group of 1 to 3 carbon atoms; R ⁵ A hydrogen atom, a linear alkyl group having 1 to 3 carbon atoms, or a halogen atom]. The compound of claim 1, wherein R ⁴ is any one selected from the group consisting of: [wherein R ⁸ represents a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms]. The compound of claim 2, wherein R ⁴ is as follows: [wherein R ⁸ represents a linear alkyl group having 1 to 3 carbon atoms]. The compound of claim 1, wherein in the above formula (I), R ⁵ is a methyl group or a fluorine atom. The compound of claim 1, wherein in the above formula (I), R ³ is a methyl group, a trifluoromethyl group, or a chlorine atom. The compound of claim 1, wherein in the above formula (I), R ¹ is the following formula: Wherein A represents a linear alkyl group having 1 to 3 carbon atoms which may be substituted by a linear alkyl group having 1 to 3 carbon atoms; R ⁶ represents a hydrogen atom; R ⁷ represents a hydroxyl group, or Can be substituted by a linear alkyl group containing 1 to 3 carbon atoms Razolyl]; R ² is a hydrogen atom; R ³ is a methyl group, a trifluoromethyl group, or a chlorine atom; and R ⁴ is a formula: [Chem. 6] [wherein R ⁸ represents a linear alkyl group having 1 to 3 carbon atoms]; and R ⁵ is a methyl group or a fluorine atom. A pharmaceutical composition containing the compound according to any one of claims 1 to 6 as an active ingredient. Use of a compound according to any one of claims 1 to 6 for the manufacture of a preventive or therapeutic agent selected from the group consisting of central diabetes insipidus, nocturnal enuresis, nocturnal urinary frequency, overactive bladder, hemophilia, and Medicine for diseases in the group consisting of Von Wylie disease.