Cyclic amine derivative

Abstract

The present invention addresses the problem of providing a novel cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof, and a medicine containing the compound as an active ingredient.　The cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof according to the present invention has both an antagonistic effect on histamine and an antagonistic effect on leukotrienes, and is therefore very useful as an active ingredient of a pharmaceutical composition such as a prophylactic and / or therapeutic agent for a wide range of allergic diseases.

Description

Cyclic amine derivatives

[0001] This invention relates to novel cyclic amine derivatives or pharmaceutically acceptable salts or hydrates thereof. Furthermore, this invention relates to pharmaceuticals such as anti-allergic drugs containing such compounds (in this application, the term "compound" may include its pharmaceutically acceptable salts or hydrates) as an active ingredient.

[0002] Histamine is a representative chemical mediator (inflammatory mediator) that induces allergic reactions. When allergy-causing substances enter the body, histamine is released from cells such as mast cells and basophils. The released histamine binds to histamine type 1 receptor (H1 receptor) proteins, exerting pharmacological effects such as blood pressure reduction, increased vascular permeability, smooth muscle contraction, vasodilation, and increased glandular secretion, and is involved in the manifestation of allergic reactions and inflammation. Therefore, many drugs that suppress histamine release or inhibit its binding to receptors (antihistamines) are commercially available and are used for many allergic diseases, such as allergic rhinitis, hay fever, urticaria, and atopic dermatitis.

[0003] As mentioned above, antihistamines are widely used to treat allergic diseases, but it has been found that they are not very effective for severe allergic diseases such as asthma. Furthermore, while antihistamines are highly effective against sneezing and runny nose, which are symptoms of allergic rhinitis, they are not very effective against nasal congestion. Therefore, in cases of allergic rhinitis accompanied by nasal congestion, it is currently recommended to use antihistamines in combination with other medications.

[0004] On the other hand, leukotrienes released from mast cells and eosinophils are inflammatory mediators that have physiological effects such as bronchial stenosis, excessive mucosal secretion, and pulmonary edema. Antileukotriene drugs, which are receptor antagonists of these leukotrienes, are prescribed to suppress inflammation in bronchial asthma through bronchodilation and to improve nasal congestion in allergic rhinitis.

[0005] As mentioned above, the diseases and symptoms affected by allergic diseases vary depending on the causative substance (inflammatory mediator) that triggers them. Furthermore, the causative substance differs from person to person, and multiple causative substances are often involved simultaneously, making it generally difficult to identify the causative substance. Therefore, when using anti-allergic drugs such as antihistamines and anti-leukotriene drugs to prevent or treat allergic diseases, drugs that exert multiple anti-allergic effects are expected to be more effective in preventing and treating a wider range of allergic diseases than drugs that have a single effect. Accordingly, compounds that possess both antagonistic effects against histamine and leukotrienes, which have been proven effective against various allergic diseases, can be active ingredients in drugs that are useful as preventive and / or therapeutic agents for a wide range of allergic diseases.

[0006] Conventionally, research has been conducted to search for compounds that possess both antihistamine and anti-leukotriene activity. For example, Patent Document 1 discloses a heterocyclic condensed benzothiazine derivative as a preventive and therapeutic agent for diseases involving histamine, leukotrienes, etc., although it is structurally different from the compound of the present invention. However, there have been no reports to date of an anti-allergic agent possessing both antihistamine and anti-leukotriene activity being marketed as a pharmaceutical product. Patients and medical professionals are seeking anti-allergic drugs with diverse and broad-ranging therapeutic effects. The inventors of the present invention have diligently researched compounds possessing both antihistamine and anti-leukotriene activity, aiming to develop a drug that is effective for all symptoms of allergic rhinitis, including nasal congestion, in addition to allergic dermatitis, hay fever, and urticaria, and is also effective for bronchial asthma, making it excellent for the prevention and / or treatment of a wide range of allergic diseases. As a result, they have discovered the cyclic amine derivative of the present invention that possesses both activity.

[0007] International Publication No. 99 / 43683

[0008] The present invention aims to provide novel cyclic amine derivatives or pharmaceutically acceptable salts or hydrates thereof (hereinafter sometimes referred to as "the compounds of the present invention"), more specifically, compounds that possess both antihistamine and anti-leukotriene activity and are useful as active ingredients in preventive and / or therapeutic agents for a wide range of allergic diseases such as asthma, allergic rhinitis, allergic dermatitis, and urticaria, as well as pharmaceuticals containing such compounds as active ingredients.

[0009] As a result of diligent research to solve the above problems, the present inventors have discovered that cyclic amine derivatives represented by the following general formula (I), or pharmaceutically acceptable salts or hydrates thereof, possess excellent antihistamine, anti-leukotriene, and anti-allergic effects, and are useful compounds as active ingredients in pharmaceuticals such as preventive and / or therapeutic agents for allergic diseases, thus completing the present invention.

[0010] The cyclic amine derivatives of the present invention, or their pharmaceutically acceptable salts or hydrates, exhibit inhibitory activity on the binding of human histamine H1 receptors and human leukotriene receptors. Furthermore, in histamine and leukotriene-induced increased skin vascular permeability experiments conducted on animals such as rats and guinea pigs after oral administration, they showed antihistamine and anti-leukotriene activity. Therefore, the compounds of the present invention are useful as active ingredients in pharmaceuticals such as preventive and / or therapeutic agents for a wide range of allergic diseases, including bronchial asthma, allergic rhinitis, urticaria, allergic dermatitis, atopic dermatitis, and hay fever. For example, in allergic rhinitis, they possess desirable properties as anti-allergic agents, being effective against all symptoms of sneezing, runny nose, and nasal congestion, thus demonstrating high utility.

[0011] The present invention relates to a cyclic amine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt or hydrate thereof, which is useful as a pharmaceutical such as an anti-allergic agent, and to a pharmaceutical containing at least one of the cyclic amine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt or hydrate thereof. [In the formula, R 1 is hydrogen or -R 6 -CO-R 7 Represents R 6represents a single bond, an optionally deuterated alkyl, -S-alkyl-, -S-methylcycloalkylmethyl- or -O-alkyl-, R 7 represents an amino, hydroxy or alkoxy optionally substituted with hydroxyalkyl; R 2 represents hydrogen, halogen, carboxy, carboxymethylsulfanyl or carboxyalkyl; ring W represents piperidyl, azaspiroheptyl or azetidyl; R 3 represents pyridyl, phenyl optionally substituted with one or two halogens or thienyl optionally substituted with alkyl; R 4 represents -O-CH2-, -CH2-O-CH2- or -CH=CH-; R 5 represents a substituent selected from the following (a) to (e); (a) quinolyl optionally substituted with 1 to 4 halogens, (b) benzothiazolyl optionally substituted with one or two halogens, (c) thiazolyl optionally substituted with a substituent selected from (1) phenyl optionally substituted with halogen, (2) alkyl or (3) cycloalkyl, (d) quinoxalyl, (e) tetrahydroquinolyl, A represents carbon or oxygen; X and Y each represent either -CH- and -S- or -CH- and -CH=CH-; and n represents an integer from 1 to 3; provided that when R 1 represents hydrogen, R 2 represents carboxy, carboxymethylsulfanyl or carboxyalkyl; R 1 is -R 6 -CO-R 7 represents, R 2 represents hydrogen or halogen. ]]

[0012] In the general formula (I) above, alkyl (including the "alkyl" in hydroxyalkyl and carboxyalkyl in the substituents) is a linear or branched alkyl group, preferably a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl. Alkoxy is a linear or branched alkoxy group, preferably a linear or branched alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy. Cycloalkyl is a saturated monocyclic hydrocarbon group, preferably a cyclic alkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Halogen is an element in group 17 of the periodic table, preferably fluorine, chlorine, bromine, iodine, etc.

[0013] The general method for producing the compounds of the present invention is shown below. However, it is obvious that those skilled in the art can make appropriate modifications to the method according to the chemical structure of a particular compound during its production. (Note that in the general formula below, Me represents methyl, and Het represents a heterocycle.)

[0014] Compounds of general formula (I) can be obtained by the ester hydrolysis reaction of compounds of general formula (II). The ester hydrolysis reaction is carried out by dissolving the compound of general formula (II) in a mixed solvent of water and an organic solvent miscible with water, such as methanol, ethanol, tetrahydrofuran (THF), or dioxane, and using 1 to several moles equivalent of sodium hydroxide, potassium hydroxide, or lithium hydroxide as a reaction reagent, at a suitable temperature between 0°C and the boiling point of the solvent for several hours to several days.

[0015] Compounds of general formula (II) can be obtained by a reductive alkylation reaction of the free form or hydrochloride salt of compound (III) with compound (IV). In a solvent inert to reducing agents such as methylene chloride, chloroform, dichloroethane (DCE), THF, or dioxane, and especially in the case of the hydrochloride salt of compound (III), the compounds of general formula (III) and general formula (IV) are treated with a reducing agent for several hours to several days at a suitable temperature between 0°C and the boiling point of the solvent, in the presence of a base such as triethylamine (TEA) or diisopropylethylamine in the presence of 1 molar equivalent or more. Sodium borohydride, sodium triacetoxyborate, sodium cyanoborohydride, etc. can be used as reducing agents. Compounds of general formula (II) can also be obtained by alkylating compound (III) with compound (IV'). In general formula (IV'), Q is a halogen group such as chlorine, bromine, or iodine, or a leaving group such as a methanesulfonic acid ester group or a p-toluenesulfonic acid ester group. The compound of general formula (II) can be obtained by treating the compound of general formula (III) and the compound of general formula (IV') in a solvent such as methylene chloride, chloroform, DCE, THF, dioxane, acetone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or ethanol in the presence of a base such as TEA, diisopropylethylamine, potassium carbonate, sodium carbonate, or cesium carbonate in an amount of 1 molar equivalent or more, at a suitable temperature between 0°C and the boiling point of the solvent for several hours to several days.

[0016] Compounds of general formula (III) can be obtained by deprotecting compounds of general formula (V). When T is a t-butyl group, the compound of general formula (V) is dissolved in a solvent such as methylene chloride, chloroform, DCE, or dioxane, and treated with an organic solvent solution of hydrogen chloride, an acetic acid solution of hydrogen bromide, etc., at a suitable temperature between -10°C and the boiling point of the solvent for several hours to several days to obtain the compound of general formula (III). When T is a 2,2,2-trichloroethyl group, the compound of general formula (V) is dissolved in acetic acid, zinc is added, and the resulting compound is treated at a suitable temperature between 0°C and the boiling point of the solvent for several hours to several days. The resulting compound is then neutralized, and hydrogen chloride is added to obtain the compound of general formula (III).

[0017] A compound of general formula (VI), in which ring W is piperidine, can be treated with 2,2,2-trichloroethyl chloroformate in toluene in the presence of potassium carbonate for several hours to several days at a suitable temperature between 0°C and the boiling point of the solvent to obtain a compound of general formula (V), in which T is a 2,2,2-trichloroethyl group.

[0018] Compounds of general formula (V), where T is a t-butyl group, can be obtained by the McMurry reaction of the compound of general formula (VII) with 1-(t-butoxycarbonyl)-4-piperidone, 1-(t-butoxycarbonyl)-3-azetidinone, or 1-(t-butoxycarbonyl)-2-azaspiro[3.3]-6-heptanone. Compounds of general formula (III) can be obtained by adding a THF solution of the compound of general formula (VII) and 1-(t-butoxycarbonyl)-4-piperidone, 1-(t-butoxycarbonyl)-3-azetidinone, or 1-(t-butoxycarbonyl)-2-azaspiro[3.3]-6-heptanone to a reaction mixture prepared from zinc and titanium tetrachloride in anhydrous THF, and treating the mixture for several hours to several days at a suitable temperature between 0°C and the boiling point of the solvent. Furthermore, the compound of general formula (III) can be treated with di-t-butyl dicarbonate to obtain the compound of general formula (V) in which T is a t-butyl group.

[0019] The compound of general formula (VI) in which the ring W is piperidine can be obtained by the dehydration reaction of the compound of general formula (VIII). The compound of general formula (VIII) is dissolved in a solvent such as methylene chloride, chloroform, DCE, ethyl acetate, dioxane, acetic acid, etc., and an organic solvent (dioxane, ethyl acetate, ether, THF, ethanol, etc.) or trifluoroacetic acid in which hydrogen chloride is dissolved is added, and it is treated at a suitable temperature between 0 °C and the boiling point of the solvent for several hours to several days. After distilling off the solvent, it is neutralized with potassium carbonate, sodium carbonate, etc. to obtain the compound of general formula (VI). The compound of general formula (VIII) can be obtained by the reaction of 4-chloro-1-methylpiperidine with a Grignard reagent prepared from magnesium and a tricyclic ketone represented by general formula (VII).

[0020] The compound of general formula (VII) can be synthesized by an intramolecular Friedel-Crafts reaction or the like of the compound of general formula (IX). For example, the intramolecular Friedel-Crafts reaction can be carried out as a carboxylic acid or after converting it to an acid chloride or a mixed acid anhydride, and if necessary, in the presence of a Lewis acid such as polyphosphoric acid, aluminum chloride, titanium chloride, tin chloride, BF3·OEt2 (boron trifluoride-diethyl ether complex), etc., using a solvent such as THF, dichloromethane (DCM), chloroform, DCE, carbon disulfide, nitrobenzene, etc. appropriately, at an optimum temperature between the melting point of the solvent and 300 °C. After the reaction, when the reaction mixture is treated with water, a carboxylic acid in which R 7 is a hydroxyl group is obtained, and when it is treated with methanol, R 7 is a methoxy group and a methyl ester form is obtained, and when it is treated with ethanol, R 7 is an ethoxy group and an ethyl ester form is obtained.

[0021] The compound of general formula (IX) is first prepared by halogenating the methyl group of the compound of formula (X) to synthesize a compound of general formula (XI). The compound of general formula (X) and N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) are dissolved in a solvent such as methylene chloride, chloroform, carbon tetrachloride, DCE, ethyl acetate, etc., and a small amount of azobisisobutyronitrile (AIBN) or benzoyl peroxide (BPO) is added as a reaction initiator, and the reaction is carried out at a temperature from 50 °C to the boiling point of the solvent for several hours to several days to obtain a compound of general formula (XI). In a solvent such as DMF, DMSO, acetone, acetonitrile, THF, dioxane, etc., a compound of general formula (XI) and a compound of formula (XII) are reacted in the presence of a basic substance such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, TEA, diisopropylethylamine, etc. to synthesize a compound of general formula (XIII) which is a diester. The compound of general formula (XIII) is reacted in a solvent such as ethanol, methanol, THF, dioxane, etc. using 1 to several molar equivalents of sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. as reaction reagents at a suitable temperature between 0 °C and the boiling point of the solvent for several hours to several days to synthesize a compound of general formula (IX).

[0022] The compound of general formula (IV) can be obtained, for example, as described in JP-A-10-109982, by reacting a substituted quinazidine (XIV) having a substituent with isophthalaldehyde or terephthalaldehyde in a solvent such as heptane, hexane, benzene, toluene or xylene in the presence of acetic anhydride at a temperature from room temperature to the boiling point of the solvent for several hours to several days.

[0023] Furthermore, the compound of general formula (IV) can also be obtained by dissolving substituted quinaldine (XIV) and NBS in a solvent such as methylene chloride, chloroform, carbon tetrachloride, DCE, or ethyl acetate, adding a small amount of AIBN or BPO as a reaction initiator, and reacting the mixture at a temperature from 50°C to the boiling point of the solvent for several hours to several days to obtain the compound of general formula (XV). Alternatively, the compound of general formula (XV) can be obtained by reacting it with 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, or 4-hydroxybenzaldehyde in a solvent such as DMF, DMSO, acetone, acetonitrile, THF, or dioxane, in the presence of a basic substance such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, TEA, or diisopropylethylamine.

[0024] The compound represented by the general formula (I) above includes, if pharmaceutically acceptable salts or cocrystals exist, various salts or cocrystals thereof, such as addition salts or cocrystals with acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, besilicic acid, L-mandelic acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, etc., or salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, or metals such as aluminum, or salts with bases such as choline, ammonia, and organic amines. These salts can be produced from the free compounds by known methods or can be converted between them. Furthermore, if the cyclic amine derivatives of this application exist in the form of stereoisomers such as cis-trans isomers, optical isomers, conformational isomers, or solvates such as hydrates, or metal complex compounds, then any of these stereoisomers, solvates, and complex compounds are included.

[0025] Examples of compounds of the present invention represented by general formula (I) are shown below. In the following examples and other descriptions, the following compound numbers may be used for each compound. • 2-{11-[1-({3-[(E)-2-(5-chloro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 1] • 2-{11-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]methyl}-4-piperidylidene)-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 2] • 2-{11-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 3] • 4-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyrate [Compound 4] • 4-{10-[1-({3-[(E)-2-(5-chloro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyrate [Compound 5] • 4-{10-[1-({3-[(4-cyclopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]4H-thieno[3,2-c][1]benzooxepin-8-yl}butyrate Compound 6] • 3-{10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 7] • 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 8] • 3-{10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid d [compound 9] ・3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [compound 10] ・2-{11-[1-(2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 11] • 3-{10-[1-({3-[(4-cyclobutylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 12] • 3-{10-[1-({3-[(4-cyclobutylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 13] • 3-{10-[1-({3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 14] • 3-[10-[1-({3-[(7-chloro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionic acid [Compound 15] • 3-{10-[1-({3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 16] • 3-{10-[1-({3-[(E)-2-(4-cyclobutylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 17] 3-{10-[1-(2-{3-[(7-chloro-2-quinolyl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid) [Compound 18] ・3-(10-{1-[(3-{[4-(4-chlorophenyl)thiazole-2-yl]methoxy}phenyl)methyl]-4-piperidylidene}-4H-thieno[3,2-c][1]benzooxepin-8-yl)propionic acid [Compound 19] ・3-{10-[1-({3-[(4-phenylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 20],

[0026] • 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl propionate [Compound 21] • 2-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 22] • 2-({10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [Compound 23] • 3-{10-[1-({3-[(E)-2-(5,6,7,8-tetrahydroquinoline-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 24] • 2-({10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [Compound 25] • 2-({10-[1-({3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [compound 26] • 2-[10-[1-[[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]methyl]-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]acetic acid [compound 27] • 2-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}acetic acid [compound 28]・2-{10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}acetic acid [compound 29] ・3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}propionic acid [compound 30] ・3-{10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}propionic acid [compound 31] • 4-{10-[1-({3-[(E)-2-(4-cyclobutylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyrate [Compound 32] • 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 33] • 2-{10-[1-(2-{3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 34] • 2-({10-[1-(2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [compound 35] • 2-({10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)propionic acid [compound 36] • 2-{10-[1-({3-[(E)-2-(4-cyclohexylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 37] • 2-({10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)propionic acid [compound 38] ・2-({10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)propionic acid [compound 39] ・2-({10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)propionic acid [compound 40],

[0027] • 2-({10-[1-(2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)propionic acid [Compound 41] • 2-({10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}oxy)acetic acid [Compound 42] • 2-({10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}oxy)acetic acid [compound 43] • 2-({10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [compound 44] • 3-({10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)propionic acid [Compound 45] • 10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-carboxylic acid [Compound 46] • 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 47] • 2-{10-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid compound 48] • 2-{10-[1-({3-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidyline]-4H-thieno[3,2-c][1]benzoxepin-8-yl}acetic acid [compound 49] ・2-{10-[1-({2-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzoxepin-8-yl}acetic acid [compound 50] ・2-{10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzoxepin-8-yl}acetic acid [compound 51] • 2-[10-[1-[[4-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl]methyl]-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]acetic acid [compound 52] • 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [compound 53] • 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 54] • 2-({10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [compound 55] • 2-({10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [compound 56] • 3-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [compound 57] • 2-[1-({10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanylmethyl)cyclopropyl]acetic acid [compound 58] ・2-[1-({10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanylmethyl)cyclopropyl]acetic acid [compound 59] ・2-{10-[1-({4-[(5-fluoro-1,3-benzothiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 60],

[0028] • 2-{10-[1-({4-[(E)-2-(5-fluoro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 61] • 2-{10-[1-({6-[(7-fluoro-2-quinolyl)methoxy]-3-pyridyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 62] • 2-{10-[1-({4-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 63] • 2-{10-[1-({4-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 64] • 2-{10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno-[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 65] • 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 66] • 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 67] • 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-2,6-difluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 68] • 2-{10-[1-({4-[2-(5,6,7,8-tetrafluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 69] • 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-2-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 70] ・2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-3-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 71] ・2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-3,5-difluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 72] • 2-{10-[1-({4-[2-(5,6,7-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 73] • 2-{11-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 74] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl [Compound 75] • 2-{10-[1-({4-[2-(6,7,8-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 76] • 2-{10-[1-(2-{4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 77] • 2-{10-[1-({4-[2-(7,8-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 78]・2-{10-[1-({4-[2-(5,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 79] ・3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [compound 80],

[0029] • 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyrate [Compound 81] • 2-{10-[1-({4-[(5,6-difluoro-1,3-benzothiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 82] • 2-{10-[1-({5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 83] • 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 84] • 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 85] • 2-{10-[1-({4-[(E)-2-(5-fluoro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 86] • 2-{10-[1-({4-[2-(5,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 87] • 2-{10-[1-({4-[2-(7,8-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 88] • 2-{10-[1-({4-[2-(5,6,7-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 89] ・2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 90] ・2-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]-3-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 91] • 2-{10-[1-({4-[(5,6,7,8-tetrafluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 92] • 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-3-methyl-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 93] • 2-{10-[1-({5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 94] • 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-3-methyl-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 95] • 2-{10-[1-({5-[(6,7-difluoro-2-quinolyl)methoxymethyl]-2-thienyl}methyl-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 96] • 2-{10-[2-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-2-azaspiro[3,3]heptan-6-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 97] • 2-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 98] ・3-{2-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6-thiatricyclo[8.4.0.03,7]tetradeca-1(10),3(7),4,11,13-pentaen-5-yl}propionic acid [compound 99] ・1-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenylmethyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-carboxylic acid [compound 100],

[0030] • 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 101] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 102] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetate hemifumarate [Compound 102 fumarate] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetate monomalonate [Compound 102 malonate] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetate 2 / 3 tartrate [Compound 102, tartrate] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetate dibesylate [Compound 102, besylate] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sodium acetate [Compound 102, sodium salt] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}choline acetate [Compound 102, choline salt] • 2-{11-[1-({3-[(E)-2-(6,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 103]• 2-{10-[1-({3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 104] • 2-{11-[1-({3-[(E)-2-(5,6,7-trichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 105] • 2-({10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}sulfanyl)acetic acid [compound 106] • 2-{10-[1-({3-[(E)-2-quinoxaline-2-ylvinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 107] • 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 108] • 2-{11-[1-({3-[(E)-2-(7-fluoro-6-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid compound 109] • 2-{11-[1-({3-[(E)-2-(7-fluoro-6-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 110] • 2-{11-[1-({3-[(E)-2-(8-fluoro-7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 111] • 2-{11-[1-({4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 112]• 2-{11-[1-({4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 113] • 2-{11-[1-({3-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 114] • 2-{11-[1-({2-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 115] • 2-({11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sulfanyl)acetic acid [compound 116] • 3-{2-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4-thiatricycyclo[8.4.0.03,7]tetradeca-1(10),3(7),5,11,13-pentaen-5-yl}propionic acid [compound 117] • 2-({11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sulfanyl)acetic acid [Compound 118] • 3-}2-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4-thiatricycyclo[8.4.0.03,7]tetradeca-1(10),3(7),5,11,13-pentaen-5-yl}propionic acid [Compound 119] 2-{11-[1-({3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 120]

[0031] • 2-{11-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 121] • 2-{11-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 122] • 2-{10-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 123] • 2-{10-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 124] • 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [compound 125] • 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 126] • 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 127] • 2-({11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sulfanyl)acetic acid [compound 128] • 3-{2-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4-thiatricyclo[8.4.0.03,7]tetradeca-1(10),3(7),5,11,13-Pentaen-5-yl}propionic acid [Compound 129] ・2-({11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-yl}sulfanyl)acetic acid [Compound 130] ・2-({11-[1-({3-[(E)-2-(6-chloro-7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-yl}sulfanyl)acetic acid [Compound 131] • 2-{10-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [compound 132] • 2-({11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}sulfanyl)acetic acid [compound 133] • 2-({11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}sulfanyl)acetic acid [compound 134] • 2-{11-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 135] • 2-{11-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 136] • 2-({11-[1-({4-[(5,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sulfanyl)acetic acid [compound 137] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [compound 138] ・2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [compound 139] ・2-({11-[1-({3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sulfanyl)acetic acid [compound 140],

[0032] • 2-({11-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sulfanyl)acetic acid [compound 141] • 2-({11-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}sulfanyl)acetic acid [compound 142] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [Compound 143] • 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [Compound 144] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}-N-(2-hydroxyethyl) Acetamide [Compound 145] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetamide [Compound 146] • 3-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}propionic acid [Compound 147] • 3-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}propionic acid [Compound 148] • 2-{11-[1-({3-[(E)-2-(5,6-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetate hydrochloride [Compound 149] • 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid-d2 [compound 150] ・2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid-d2 [compound 151] ・2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid-d2 [compound 152] • 2-{11-[1-({3-[(E)-2-(6,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 153] • 2-{11-[1-({3-[(E)-2-(8-fluoro-7-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 154] • 2-{9-chloro-11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 155] • 2-{9-chloro-11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 156] • 2-{9-fluoro-11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 157] • 2-{9-fluoro-11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 158] ・2-{9-fluoro-11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [compound 159] ・4-{10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyric acid [compound 160],

[0033] Preferred embodiments of the present invention are shown below: (1) A cyclic amine derivative represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof. (2) The cyclic amine derivative described in (1) above, or a pharmaceutically acceptable salt or hydrate thereof, wherein ring W is azetidyl. (3) R 3 (1) or (2) above, a cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof, wherein R is a phenyl which may be substituted with one or two halogens. (4) R 4 (5) R 5 (1) to (4) above, a cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof, wherein A is a quinolyl which may be substituted with 1 to 4 halogens. (6) A cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof, wherein A is oxygen. (7) A cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof, wherein one of X and Y is -CH- and the other is -CH=CH-, wherein X and Y are either -CH- or -CH=CH-, wherein n is 1, wherein a cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof, wherein n is 1. (9) R 1 ga-R 6 -CO-R 7(10)R 6 It is an alkyl which may be deuterated, and R 7 (9) above, a cyclic amine derivative or a pharmaceutically acceptable salt or hydrate thereof, wherein the hydroxyl group may be substituted with an alkyl group. (11)R 2 (12)R 2 (13) A cyclic amine derivative according to any one of (1) to (8) above, wherein is a carboxyalkyl group, or a pharmaceutically acceptable salt or hydrate thereof. (14) A pharmaceutically acceptable amine derivative according to any one of (1) to (12) above, and a pharmaceutically acceptable salt or hydrate thereof. (15) A pharmaceutically acceptable amine derivative according to any one of (1) to (12) above, and a pharmaceutically acceptable salt or hydrate thereof. (16) A pharmaceutically acceptable amine derivative according to (14) above, wherein the allergic disease is a disease involving histamine and leukotrienes. (17) A pharmaceutically acceptable amine derivative according to (14) or (15) above, wherein the allergic disease is bronchial asthma, allergic rhinitis, urticaria, allergic dermatitis, atopic dermatitis, or hay fever.

[0034] (17) A cyclic amine derivative according to any one of (1) to (12) above, or a pharmaceutically acceptable salt or hydrate thereof, for use in the prevention and / or treatment of allergic diseases. (18) A cyclic amine derivative according to (17) above, or a pharmaceutically acceptable salt or hydrate thereof, for which the allergic disease is a disease involving histamine and leukotrienes. (19) A cyclic amine derivative according to (17) or (18) above, or a pharmaceutically acceptable salt or hydrate thereof, for which the allergic disease is bronchial asthma, allergic rhinitis, urticaria, allergic dermatitis, atopic dermatitis, or hay fever. (20) A method for the prevention and / or treatment of allergic diseases, comprising administering at least one effective amount of a cyclic amine derivative according to any one of (1) to (12) above, and a pharmaceutically acceptable salt or hydrate thereof, to a subject in need. (21) The method according to (20) above, for which the allergic disease is a disease involving histamine and leukotrienes. (22) The method according to (20) or (21) above, wherein the allergic disease is bronchial asthma, allergic rhinitis, urticaria, allergic dermatitis, atopic dermatitis, or hay fever. (23) The use of at least one of the cyclic amine derivatives and pharmaceutically acceptable salts and hydrates thereof according to any of (1) to (12) above in the manufacture of a medicament for the prevention and / or treatment of an allergic disease. (24) The use of at least one of the cyclic amine derivatives and pharmaceutically acceptable salts and hydrates thereof according to (23) above, wherein the allergic disease is a disease involving histamine and leukotrienes. (25) The use of at least one of the cyclic amine derivatives and pharmaceutically acceptable salts and hydrates thereof according to (23) or (24) above, wherein the allergic disease is bronchial asthma, allergic rhinitis, urticaria, allergic dermatitis, atopic dermatitis, or hay fever.

[0035] The compound of the present invention can be used to form pharmaceutical compositions by combining various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, and diluents as needed, depending on the dosage form. For oral administration, it can be prepared in dosage forms such as tablets, capsules, powders, granules, liquids, syrups, and sublingual preparations. Furthermore, depending on the type of disease and the patient, it can be formulated into other dosage forms optimal for treatment, such as injections, suppositories, inhalants, aerosols, eye drops, nasal sprays, ointments, creams, and other topical preparations. In formulation, the compound of the present invention may be used in the form of its pharmaceutically acceptable salt or hydrate, and can be used alone or in appropriate combinations. It may also be used as a compound with other pharmaceutically active ingredients.

[0036] When preparing an oral formulation, additives may include, for example, conventional excipients such as lactose, mannitol, corn starch, and potato starch; binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, and gelatin; disintegrants such as corn starch, potato starch, and potassium carboxymethylcellulose; lubricants such as talc and magnesium stearate; and other fillers, wetting agents, buffers, preservatives, and fragrances, which can be combined as appropriate. Flavorings and fragrances may also be added.

[0037] When preparing a liquid, emulsion, suspension, or viscous injectable or ophthalmic preparation, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, viscosity enhancers, etc., may be added as appropriate, and sterilization is usually performed.

[0038] The desirable dosage of the compound of the present invention may vary depending on the recipient (patient's age, weight, etc.), the type and severity of the disease, the dosage form, the method of administration, the duration of administration, etc. However, to obtain the desired effect, generally, adults can be orally administered 0.5 to 1000 mg, preferably 1 to 500 mg, of the compound of the present invention in one to several divided doses per day. In the case of parenteral administration, the daily dose should be at a dose level of 1 / 3 to 1 / 10 of each of the above doses, and can usually be administered in one to several divided doses per day.

[0039] The present invention will now be specifically described with reference to examples, but the present invention is not limited thereto. Furthermore, for the starting material compounds, compounds other than those produced in the following examples (Examples 1, 2, 35, 61, 76, 79, 81, 95, 96, 101, 102, 109, 120, 123, 127, 130, 138, 143, 146, 155, 159, and 163-167) were either produced using the same methods as in these examples, or commercially available compounds were used.

[0040] The melting point was measured using a Yamato MP-21 melting point analyzer after placing the sample in a glass capillary. No thermometer correction was performed. MS spectra were measured using a Smart Flash MS system (Yamazen Corporation). ¹H-NMR spectra were measured using an AVANCE III 500 nuclear magnetic resonance spectrometer (Bruker). When measured in deuterated organic solvents, the chemical shift value was expressed in ppm relative to tetramethylsilane (TMS) (δ = 0 ppm), which was added as an internal standard. When measured in heavy water, the water peak was used as the internal standard at 4.67 ppm. Silica gel column chromatography was performed using silica gel PSQ 100B or NH-DM1020 (Fuji Silysia Chemical). Thin-layer chromatography was performed using Silica gel F254 (Merck, No. 5715) or TLC plate NH (Fuji Silysia Chemical), and detection was performed using a UV lamp and a 5% phosphomolybdate-ethanol chromogenic reagent.

[0041] Example 1 (1) Preparation of 3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]benzaldehyde 6,7-difluoro-2-methylquinoline (3.0 g, 16.7 mmol), isophthalaldehyde (4.5 g, 33.5 mmol), and acetic anhydride (6.1 mL, 63.9 mmol) were added to m-xylene (50 mL) and stirred at 160°C for 48 hours. After cooling, water (150 mL) was added and stirred for 30 minutes. The precipitated crystals were filtered off, washed sequentially with water and ether, and then dried under reduced pressure on phosphorus pentoxide at 50°C to obtain the title compound (2.9 g, 59%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.62 (d, J = 16.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.93-8.01 (m, 3H), 8.04-8.09 (m, 2H), 8.28 (s, 1H), 8.41 (d, J = 8.7 Hz, 1H), 10.08 (s, 1H). MS (EI) m / z: 296 [M+H]+.

[0042] (2) Preparation of 3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]benzaldehyde 7-chloro-6-fluoro-2-methylquinoline (1.0 g, 5.1 mmol), isophthalaldehyde (2.1 g, 15.3 mmol), and acetic anhydride (1.0 mL, 10.5 mmol) were stirred in m-xylene (50 mL) at 160°C for 48 hours. After cooling, water (25 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (0.8 g, 50%) as an oil. 1H-NMR (DMSO-d6) δ: 7.62 (d, J = 16.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.95-8.05 (m, 3H), 8.09 (d, J = 7.4 MS (EI) m / z: 312 [M+H]+.

[0043] (3) Preparation of 3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]benzaldehyde 5,6,7-trifluoro-2-methylquinoline (3.0 g, 15.2 mmol), isophthalaldehyde (4.1 g, 30.4 mmol), and acetic anhydride (3.3 mL, 45.6 mmol) were stirred in m-xylene (100 mL) at 160°C for 48 hours. After cooling, water (200 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.2 g, 26%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.64-7.70 (m, 2H), 7.90-7.94 (m, 2H), 7.99-8.05 (m, 2H), 8.10 (d, J = 7.7 Hz, 1H), 8.30 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 10.08 (s, 1H). MS (EI) m / z: 314 [M+H]+.

[0044] (4) Preparation of 3-[(E)-2-Quinoxaline-2-ylvinyl]benzaldehyde 2-methylquinoxaline (3.0 g, 20.8 mmol), isophthalaldehyde (5.6 g, 41.6 mmol), and acetic anhydride (4.5 mL, 62.4 mmol) were stirred in m-xylene (50 mL) at 160°C for 24 hours. After cooling, water (200 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 3:1) to obtain the title compound (1.3 g, 24%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.69-7.76 (m, 2H), 7.81-7.84 (m, 1H), 7.88 (t, J = 6.9 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 8.08-8.14 (m, 4H), 8.33 (s, 1H), 9.31 (s, 1H), 10.09 (s, 1H). MS (EI) m / z: 261 [M+H]+.

[0045] (5) Preparation of 3-[(E)-2-(4-cyclohexylthiazole-2-yl)vinyl]benzaldehyde 3.5 g, 19.3 mmol of 4-cyclohexyl-2-methylthiazole, 5.2 g, 38.6 mmol of isophthalaldehyde, and 5.5 mL, 57.6 mmol of acetic anhydride were stirred in 100 mL of m-xylene at 160°C for 48 hours. After cooling, 60 mL of water was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (2.1 g, 37%) as an oil. 1H-NMR (DMSO-d6) δ: 1.22-1.48 (m, 5H), 1.69-1.80 (m, 3H), 1.99-2.01 (m, 2H), 2.70-2.75 (m, 1H), 7.27 (s, 1H), 7.52-7.64 (m, MS (EI) m / z: 298 [M+H]+.

[0046] (6) Preparation of 4-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]benzaldehyde 2-ethenyl-6,7-difluoroquinoline (2.0 g, 10.5 mmol), 4-bromobenzaldehyde (2.0 g, 10.9 mmol), palladium(II) acetate (0.5 g, 2.1 mmol), tri(o-tolyl)phosphine (2.6 g, 8.4 mmol) and TEA (8.0 mL, 57.4 mmol) were stirred in super-dehydrated acetonitrile (100 mL) under an argon atmosphere at 60°C for 48 hours. After cooling, water (50 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.0 g, 32%) as a hygroscopic solid. MS (EI) m / z: 296 [M+H]+.

[0047] (7) Preparation of 4-[(E)-2-(5-fluoro-1,3-benzothiazole-2-yl)vinyl]benzaldehyde 5-fluoro-2-methyl-1,3-benzothiazole (2.5 g, 14.9 mmol), terephthalaldehyde (4.0 g, 29.9 mmol), and acetic anhydride (3.0 mL, 31.4 mmol) were stirred in m-xylene (50 mL) at 160°C for 48 hours. After cooling, water (50 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (2.8 g, 66%) as a hygroscopic solid. MS (EI) m / z: 284 [M+H]+.

[0048] (8) Preparation of 4-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]benzaldehyde 4-isopropyl-2-methylthiazole (4.3 g, 30.3 mmol), terephthalaldehyde (8.1 g, 60.6 mmol), and acetic anhydride (9.2 mL, 96.3 mmol) were stirred in m-xylene (50 mL) at 160°C for 48 hours. After cooling, water (50 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (0.4 g, 5%) as an oil. MS (EI) m / z: 258 [M+H]+.

[0049] (9) Preparation of 3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]benzaldehyde 4-isopropyl-2-methylthiazole (4.6 g, 32.4 mmol), isophthalaldehyde (8.7 g, 65.1 mmol), and acetic anhydride (9.2 mL, 96.3 mmol) were stirred in m-xylene (100 mL) at 160°C for 48 hours. After cooling, water (150 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 3:1) to obtain the title compound (3.3 g, 39%) as an oil. MS (EI) m / z: 258 [M+H]+.

[0050] (10) Preparation of 3-[(E)-2-(4-cyclobutylthiazole-2-yl)vinyl]benzaldehyde 4-cyclobutyl-2-methylthiazole (3.3 g, 21.7 mmol), isophthalaldehyde (5.8 g, 43.1 mmol), and acetic anhydride (6.1 mL, 63.9 mmol) were added to m-xylene (70 mL) and stirred at 160°C for 48 hours. After cooling, water (150 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 3:1) to obtain the title compound (2.2 g, 38%) as an oil. 1H-NMR (DMSO-d6) δ: 2.13-2.33 (m, 6H), 3.62-3.69 (m, 1H), 7.34 (s, 1H), 7.54-7.66 (m, 3H), 7.86 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.26 (s, 1H), 10.04 (s, 1H). MS (EI) m / z: 270 [M+H]+.

[0051] (11) Preparation of 3-[(E)-2-(5,6,7,8-tetrahydroquinoline-2-yl)vinyl]benzaldehyde 2-methyl-5,6,7,8-tetrahydroquinoline (5.0 g, 33.9 mmol), isophthalaldehyde (9.1 g, 67.9 mmol), and acetic anhydride (9.6 mL, 100.5 mmol) were stirred in o-xylene (100 mL) at 160°C for 19 hours. After cooling, saturated potassium carbonate aqueous solution (150 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.3 g, 44%) as an oil. MS (EI) m / z: 264 [M+H]+.

[0052] (12) Preparation of 3-[(E)-2-(5-chloro-1,3-benzothiazole-2-yl)vinyl]benzaldehyde 5-chloro-2-methyl-1,3-benzothiazole (13.77 g, 75 mmol), isophthalaldehyde (20.12 g, 150 mmol), and acetic anhydride (21.5 mL, 225 mmol) were stirred in m-xylene (75 mL) at 160°C for 48 hours. After cooling, water (150 mL) was added and stirred for 30 minutes. The precipitated crystals were filtered off, washed sequentially with water and ether, and then dried under reduced pressure on phosphorus pentoxide at 50°C to obtain the title compound (10.57 g, 47%). Mp. 142-143℃. 1H-NMR (DMSO-d6) δ: 7.50-7.53 (m, 1H), 7.66-7.70 (m, 1H), 7.76-7.87 (m, 2H), 7.91-7.94 (m, 1H), 8.09 (d, J = 1.5 Hz, 1H), 8.13-8.19 (m, 2H), 8.34 (s, 1H), 10.07 (s, 1H). MS (EI) m / z: 298 [MH]+

[0053] (13) Preparation of 3-[(E)-2-(6,7-dichloro-2-quinolyl)vinyl]benzaldehyde 6,7-dichloro-2-methylquinoline (3.0 g, 13.7 mmol), isophthalaldehyde (3.7 g, 27.3 mmol), and acetic anhydride (3.0 mL, 41.1 mmol) were stirred in m-xylene (40 mL) at 160°C for 48 hours. After cooling, water (200 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (3.0 g, 67%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.62 (d, J = 16.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.94-8.01 (m, 2H), 8.09 (d, J = 7.6 MS (EI) m / z: 329 [M+H]+.

[0054] (14) Preparation of 3-[(E)-2-(7-fluoro-6-chloro-2-quinolyl)vinyl]benzaldehyde 7-fluoro-6-chloro-2-methylquinoline (6.7 g, 34.3 mmol), isophthalaldehyde (13.8 g, 102.8 mmol), and acetic anhydride (7.0 mL, 102.8 mmol) were stirred in m-xylene (100 mL) at 160°C for 48 hours. After cooling, water (200 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.5 g, 14%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.61 (d, J = 16.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.93-7.99 (m, 3H), 8.08 (d, J = 7.7 MS (EI) m / z: 312 [M+H]+.

[0055] (15) Preparation of 8-fluoro-7-chloro-2-methylquinoline A solution of 6-fluoro-5-chloroaniline (5.0 g, 34.3 mmol), p-chloranil (8.5 g, 34.6 mmol), and concentrated hydrochloric acid (10 mL) in 2-butanol (50 mL) was added dropwise over 5 minutes under heating reflux to a solution of crotonaldehyde (3.0 mL, 36.4 mmol) in 2-butanol (6 mL), followed by heating under reflux for a further 2 hours. After cooling, the solvent was removed under reduced pressure, and toluene (50 mL) was added to the residue to remove water as an azeotrope under reduced pressure. A mixed solvent of toluene (50 mL) and THF (50 mL) was added to the residue and stirred at room temperature for 30 minutes. The precipitated solid was filtered off, and the solid was washed with THF (100 mL). 100 mL of 10 w / v% potassium carbonate aqueous solution and 100 mL of ethyl acetate were added to the solid and stirred for 1 hour. After removing insoluble matter with Celite, the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH-DM1020, n-hexane) to obtain the title compound (2.3 g, 35%) as a hygroscopic solid. ¹H-NMR (DMSO-d6) δ: 2.71 (s, 3H), 7.56 (d, J = 8.5 Hz, 1H), 7.64-7.68 (m, 1H), 7.82 (d, J = 8.9 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H). MS (EI) m / z: 196 [M+H]+.

[0056] (16) Preparation of 3-[(E)-2-(8-fluoro-7-chloro-2-quinolyl)vinyl]benzaldehyde The compound obtained in Example 1 (15) (2.3 g, 12.0 mmol), isophthalaldehyde (4.8 g, 35.8 mmol), and acetic anhydride (3.0 mL, 44.0 mmol) were stirred in m-xylene (50 mL) at 160 °C for 72 hours. After cooling, water (200 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.3 g, 35%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.67-7.72 (m, 3H), 7.85-7.91 (m, 2H), 8.01 (d, J = 16.4 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 8.33 (s, 1H), 8.51 (d, J = 8.7 Hz, 1H), 10.09 (s, 1H).MS (EI) m / z: 312 [M+H]+.

[0057] (17) Preparation of 3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]benzaldehyde 5,7-dichloro-2-methylquinoline (3.9 g, 18.4 mmol), isophthalaldehyde (4.9 g, 36.8 mmol), and acetic anhydride (7.0 mL, 55.2 mmol) were stirred in m-xylene (50 mL) at 160°C for 72 hours. After cooling, water (200 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (2.5 g, 42%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.65-7.70 (m, 2H), 7.90-7.92 (m, 2H), 8.02 (d, J = 16.3 Hz, 1H), 8.06-8.11 (m, 3H), 8.30 (s, 1H), 8.57 (d, J = 8.9 Hz, 1H), 10.09 (s, 1H). MS (EI) m / z: 329 [M+H]+.

[0058] (18) Preparation of 3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]benzaldehyde 5,7-difluoro-2-methylquinoline (9.7 g, 54.1 mmol), isophthalaldehyde (14.5 g, 108.3 mmol), and acetic anhydride (22.0 mL, 173.5 mmol) were stirred in m-xylene (100 mL) at 160°C for 48 hours. After cooling, water (200 mL) was added and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (8.4 g, 53%) as a hygroscopic solid. 1H-NMR (DMSO-d6) δ: 7.55-7.59 (m, 1H), 7.64-7.70 (m, 3H), 7.91 (d, J = 7.6 Hz, 1H), 7.95-8.04 (m, 2H), 8.10 (d, J = 7.7 Hz, 1H), 8.30 (s, 1H), 8.51 (d, J = 8.7 Hz, 1H), 10.08 (s, 1H). MS (EI) m / z: 296 [M+H]+.

[0059] (19) Preparation of 3-[(E)-2-(5,6-difluoro-2-quinolyl)vinyl]benzaldehyde 5,6-difluoro-2-methylquinoline (15.1 g, 84.0 mmol) and isophthalaldehyde (16.1 g, 120.0 mmol) were dissolved in a mixed solvent of n-heptane (90 mL) and toluene (30 mL), and acetic anhydride (11.0 mL, 115.1 mmol) and acetic acid (2.0 mL) were added dropwise at 70°C. The mixture was stirred at 130°C for 24 hours. After cooling, the mixture was washed with a mixed solvent (n-hexane:toluene = 4:1, 50 mL), and the crystals were dissolved in ethyl acetate (150 mL) and insoluble matter was filtered off. The solvent was removed from the filtrate under reduced pressure, and the precipitated crystals were filtered and washed with methanol (50 mL) to obtain the title compound (11.43 g, 46%) as hygroscopic crystals. ¹H-NMR (DMSO-d6) δ: 7.63-7.69 (m, 2H), 7.88-7.92 (m, 3H), 7.99 (d, J = 16.5 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 7.7 Hz, 1H), 8.29 (s, 1H), 8.54 (d, J = 8.8 Hz, 1H), 10.08 (s, 1H).

[0060] (20) Preparation of (E)-3-[2-(7-fluoroquinoline-2-yl)vinyl]benzaldehyde The title compound was obtained from 7-fluoro-2-methylquinoline, isophthalaldehyde, acetic anhydride, and m-xylene in the same manner as the synthesis in Example 1 (1).

[0061] (21) Preparation of (E)-3-[2-(7-chloroquinoline-2-yl)vinyl]benzaldehyde The title compound was obtained from 7-chloro-2-methylquinoline, isophthalaldehyde, acetic anhydride, and m-xylene in the same manner as the synthesis in Example 1 (1).

[0062] (22) Preparation of (E)-3-[2-(7-chloro-8-fluoroquinoline-2-yl)vinyl]benzaldehyde The title compound was obtained from 7-chloro-8-fluoro-2-methylquinoline, isophthalaldehyde, acetic anhydride, and m-xylene in the same manner as the synthesis in Example 1 (1).

[0063] (23) Preparation of (E)-3-[2-(6,8-difluoroquinoline-2-yl)vinyl]benzaldehyde The title compound was obtained from 6,8-difluoro-2-methylquinoline, isophthalaldehyde, acetic anhydride, and m-xylene in the same manner as the synthesis in Example 1 (1).

[0064] (24-1) Preparation of 2-[(E)-2-(3-bromophenyl)vinyl]-7-chloroquinoline: A solution of 7-chloroquinaldine (8.88 g, 50 mmol), 3-bromobenzaldehyde (7.0 mL, 60 mmol), and acetic anhydride (14 mL, 150 mmol) in xylene (50 mL) was heated under reflux for 7 hours. After cooling, the precipitated crystals were filtered and washed with n-hexane to obtain the title compound (11.61 g, 67%). Maximum temperature: 126-128°C.

[0065] (24-2) Preparation of t-butyl 2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}acetate A solution of dicyclohexylamine (2.6 mL, 13 mmol) in toluene (30 mL) was added dropwise to a solution of n-butyllithium in n-hexane (1.6 mol / L, 8.2 mL, 13 mmol) at 0°C for 30 minutes. Then, a solution of t-butyl acetate (1.5 mL, 11 mmol) in toluene (15 mL) was added dropwise at the same temperature for 30 minutes. After stirring at room temperature for 30 minutes, bis(dibenzylideneacetone)palladium(0) (0.29 g, 0.5 mmol), a solution of the compound obtained in Example 1 (24-1) (3.45 g, 10 mmol) in toluene (150 mL), and tributylphosphine (10% n-hexane solution, 1.1 mL, 0.5 mmol) were added sequentially. After stirring at room temperature for 20 hours, the reaction solution was added to a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 9:1) to obtain the title compound (2.88 g, 76%) as crystals. Mp. 77-79℃ MS (EI) m / z: 380 [M+H]+.

[0066] (24-3) Preparation of 2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethanol A mixture of lithium aluminum hydride (LAH) (0.76 g, 20 mmol) and THF (30 mL) was added dropwise over 30 minutes under ice cooling to a solution of the compound obtained in Example 1 (24-2) (3.15 g, 8.3 mmol) in THF (50 mL). After stirring for another 30 minutes under ice cooling, ethyl acetate (40 mL) was added dropwise. After stirring at room temperature for 30 minutes, water and saturated aqueous ammonium chloride solution were added. Insoluble matter was filtered off using Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the title compound (1.35 g, 53%) as crystals. Mp. 141-143℃. MS (EI) m / z: 309 [M]+.

[0067] (24-4) Preparation of 2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}acetaldehyde In a solution of the compound obtained in Example 1 (24-3) (0.2 g, 0.65 mmol) in DCM (10 mL), a solution of Dess-Martin periodinane (DMP) (0.3 g, 0.68 mmol) in DCM (10 mL) was added dropwise over 10 minutes at room temperature. After adding ether (50 mL) to the reaction mixture, it was gradually added to a saturated sodium bicarbonate aqueous solution (50 mL) in which sodium thiosulfate (4.0 g) was dissolved. After stirring for about 10 minutes, the organic layer was separated and washed with saturated sodium bicarbonate aqueous solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (0.15 g, 75%) as a hygroscopic solid. MS (EI) m / z: 308 [M+H]+.

[0068] (25-1) Preparation of ethyl thiophene-2-carboxylate A solution of thiophene-2-carboxylic acid (25 g, 195 mmol) in ethanol (400 mL) was mixed with concentrated sulfuric acid (1.0 mL) and heated under reflux for 3 days. The solvent was removed under reduced pressure, and the resulting residue was dissolved in ethyl acetate (300 mL) and dried with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure. The compound was purified by silica gel column chromatography (n-hexane:ethyl acetate = 19:1) to obtain the title compound (27.68 g, 91%) as an oil.

[0069] (25-2) Preparation of Ethyl 5-Formylthiophene-2-carboxylate: The compound obtained in Example 1 (25-1) (22.90 g, 147 mmol) and hexamethylenetetramine (22.7 g, 162 mmol) were mixed in trifluoroacetic acid (TFA) (200 mL) and stirred at 100°C for 2 days. After removing the solvent under reduced pressure, the residue was dissolved in water (200 mL) and potassium carbonate was added until the pH was approximately 8. After extraction with ethyl acetate (100 mL x 3), the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate = 9:1) to obtain the title compound (22.94 g, 85%) as crystals. Mp. 56-57°C. MS (EI) m / z: 184[M]+.

[0070] (25-3) The compound obtained in Production Example 1 (25-2) of ethyl 5-(1,3-dioxolan-2-yl)thiophene-2-carboxylate (18.42 g, 100 mmol), ethylene glycol (28 mL, 500 mmol), and a toluene solution (400 mL) of p-toluenesulfonic acid monohydrate (1.0 g) were heated under reflux for 6 hours in a flask equipped with a Dean-Stark apparatus. After cooling, the solvent was removed under reduced pressure, and water was added to the resulting residue, which was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate = 4:1) to obtain the title compound (20.85 g, 91%) as an oil.

[0071] (25-4) Preparation of [5-(1,3-dioxolan-2-yl)-2-thienyl]methanol A mixture of LAH (14.0 g, 370 mmol) and anhydrous THF (200 mL) was added dropwise over 1 hour under ice cooling to a solution of the compound obtained in Example 1 (25-3) (44.23 g, 184 mmol) in THF (150 mL). After stirring at room temperature for 20 hours, ethyl acetate (100 mL) was added dropwise over 30 minutes under ice cooling. Water (100 mL) and 2 mol / L aqueous sodium hydroxide solution (100 mL) were added and stirred for 1 hour. After filtering off the gel-like substance using Celite, the organic solvent of the filtrate was removed under reduced pressure. The residue was extracted with ethyl acetate (100 mL x 3) and then washed with saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:2) to obtain the title compound (28.55 g, 83%) as an oil.

[0072] (25-5) Preparation of 5-(hydroxymethyl)thiophene-2-carboaldehyde. The compound obtained in Example 1 (25-4) (28.55 g, 153 mmol) was mixed with acetic acid (150 mL) and water (30 mL) and stirred at room temperature for 2 days. After removing the solvent under reduced pressure, water (100 mL) was added to the residue and the pH was adjusted to approximately 8 using potassium carbonate. After extraction with ethyl acetate (100 mL x 3), the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate = 4:1) to obtain the title compound (20.16 g, 93%) as an oil.

[0073] (25-6) The compound obtained in Example 1 (25-5) of 5-{[t-butyl(dimethyl)silyl]oxymethyl}thiophene-2-carboaldehyde (20.16 g, 142 mmol) and TEA (22 mL, 160 mmol) were added dropwise to a solution of t-butyldimethylsilyl chloride (TBDMS-Cl) (22.61 g, 150 mmol) in a solution of t-butyldimethylsilyl chloride (TBDMS-Cl) (50 mL) in TEA (22 mL, 160 mmol) in a solution of TEA (22 mL, 160 mmol) in the preparation of 5-{[t-butyl(dimethyl)silyl]oxymethyl}thiophene-2-carboaldehyde (25-6) in Example 1 (25-5) in a solution of TEA (2

[0074] (25-7) Preparation of t-butyl-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methoxy)dimethylsilane Under an argon atmosphere and ice-salt cooling, (7-fluoro-2-quinolyl)methyltriphenylphosphonium bromide (30.14 g, 60 mmol) was dispersed in anhydrous THF (200 mL), and n-BuLi (1.6 mol / L n-hexane solution) (41 mL, 66 mmol) was added dropwise over 30 minutes. The mixture was stirred for 30 minutes under ice-salt cooling and then for 30 minutes at room temperature, and then cooled again in an ice-salt bath. Solution of the compound obtained in Example 1 (25-6) (15.40 g, 60 mmol) in THF (80 mL) was added dropwise over 30 minutes, and then stirred at room temperature for 20 hours. The reaction mixture was added to saturated ammonium chloride aqueous solution (200 mL) and then extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:n-hexane = 1:1) to obtain the title compound (11.07 g, 47%) as crystals. Maximum temperature: 74-75°C.

[0075] (25-8) The compound obtained in Production Example 1 (25-7) of {5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methanol (11.07 g, 28 mmol) was stirred at room temperature for 20 hours in a mixed solvent of THF (70 mL), acetic acid (70 mL), and water (70 mL). The solvent was removed by distillation under reduced pressure, and water (100 mL) and potassium carbonate (20 g) were added to the resulting residue. The precipitated crystals were filtered and washed with water, then dried on phosphorus pentoxide under reduced pressure at 50°C for 24 hours to obtain the title compound (6.51 g, 81%). Mp. 183-185°C. MS (EI) m / z: 285[M]+.

[0076] (25-9) {5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]thiophene-2-carboaldehyde} A solution of the compound obtained in Example 1 (25-8) (1.0 g, 3.5 mmol) in DCM (30 mL) was added dropwise over 10 minutes at room temperature to a solution of DMP (1.5 g, 3.5 mmol) in DCM (10 mL). Mild reflux occurred, causing turbidity. After adding ether (50 mL) to the reaction mixture, it was gradually added to a saturated sodium bicarbonate aqueous solution (50 mL) in which sodium thiosulfate (4.0 g) was dissolved. After stirring for about 10 minutes, the organic layer was separated and washed with saturated sodium bicarbonate aqueous solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.0 g, quant.) as a hygroscopic solid. Note that "quant." is an abbreviation for "quantitative yield," indicating that the reaction proceeded quantitatively and achieved a near-perfect yield of almost 100%. MS (EI) m / z: 284 [M+H]+.

[0077] (26-1) Preparation of (6,7-difluoro-2-quinolyl)methyltriphenylphosphonium bromide: A solution of 2-(bromomethyl)-6,7-difluoroquinoline (1.66 g, 6.4 mmol) and triphenylphosphine (1.84 g, 7.0 mmol) in toluene (50 mL) was heated under reflux for 20 hours. The precipitated crystals were filtered to obtain the title compound (2.73 g, 81%). Mp. 250℃ (dec.).

[0078] (26-2) Preparation of t-butyl-({5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thienyl}methoxy)dimethylsilane Under an argon atmosphere and ice-salt cooling, the compound obtained in Example 1 (26-1) (2.73 g, 5.2 mmol) was dispersed in anhydrous THF (30 mL), and n-BuLi (1.6 mol / L n-hexane solution) (3.4 mL, 5.5 mmol) was added dropwise over 30 minutes. The mixture was stirred for 30 minutes under ice-salt cooling and then for 30 minutes at room temperature, and then cooled again in an ice-salt bath. The compound obtained in Example 1 (25-6) (1.28 g, 5 mmol) was added dropwise in THF (20 mL) solution over 30 minutes, and then stirred at room temperature for 20 hours. The reaction mixture was added to saturated ammonium chloride aqueous solution (50 mL), and then extracted with ethyl acetate (30 mL x 3). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:n-hexane = 1:1) to obtain the title compound (1.36 g, 65%) as crystals. Mp. 82-84℃. MS (EI) m / z: 418[M+H]+.

[0079] (26-3) The compound obtained in Production Example 1 (26-2) of {5-[(E)-2-(6,7,-difluoro-2-quinolyl)vinyl]-2-thienyl}methanol (1.2 g, 2.9 mmol) was stirred at room temperature for 20 hours in a mixed solvent of THF (10 mL), acetic acid (10 mL), and water (10 mL). The solvent was removed by distillation under reduced pressure, and water (20 mL) and potassium carbonate (5 g) were added to the resulting residue. The precipitated crystals were filtered and washed with water, then dried on phosphorus pentoxide under reduced pressure at 50°C for 24 hours to obtain the title compound (0.84 g, 95%). Mp. 172-174°C. MS (EI) m / z: 303[M]+.

[0080] (26-4) To a solution of the compound obtained in Example 1 (26-3) of 5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]thiophene-2-carboaldehyde (0.7 g, 2.3 mmol) in DCM (30 mL), a solution of DMP (1.0 g, 2.4 mmol) in DCM (10 mL) was added dropwise over 10 minutes at room temperature. Mild reflux occurred and the solution became turbid. After adding ether (50 mL) to the reaction mixture, it was gradually added to a saturated sodium bicarbonate aqueous solution (50 mL) in which sodium thiosulfate (4.0 g) was dissolved. After stirring for about 10 minutes, the organic layer was separated and washed with saturated sodium bicarbonate aqueous solution and saturated brine. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (0.7 g, quant.) as a hygroscopic solid. MS (EI) m / z: 302 [M+H]+.

[0081] (27-1) Preparation of {5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thienyl}methanol Under an argon atmosphere and ice-salt cooling, (7-chloro-2-quinolyl)methyltriphenylphosphonium bromide (23.78 g, 45.8 mmol) was dispersed in anhydrous THF (200 mL), and n-BuLi (1.6 mol / L n-hexane solution) (32 mL, 51 mmol) was added dropwise over 30 minutes. The mixture was stirred for 30 minutes under ice-salt cooling and then for 30 minutes at room temperature, and then cooled again in an ice-salt bath. A solution of the compound obtained in Example 1 (25-6) (11.23 g, 43.8 mmol) in THF (80 mL) was added dropwise over 30 minutes, and then stirred at room temperature for 20 hours. The reaction mixture was added to water (500 mL) and then extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crystals of the title compound, which were then filtered. The filtrate was further purified by silica gel column chromatography (toluene:ethyl acetate = 4:1) to recover the title compound, which was then combined with the previously collected crystals to obtain the title compound (8.84 g, 67%). Mp. 155-157℃. MS (EI) m / z: 301[M]+.

[0082] (27-2) Preparation of 5-[(E)-2-(7-chloro-2-quinolyl)vinyl]thiophene-2-carboaldehyde. In a solution of the compound obtained in Example 1 (27-1) (1.4 g, 4.5 mmol) in DCM (30 mL), a solution of DMP (2.0 g, 4.7 mmol) in DCM (10 mL) was added dropwise over 10 minutes at room temperature. Mild reflux occurred and the solution became turbid. After adding ether (50 mL) to the reaction mixture, it was gradually added to a saturated sodium bicarbonate aqueous solution (50 mL) in which sodium thiosulfate (4.0 g) was dissolved. After stirring for about 10 minutes, the organic layer was separated and washed with saturated sodium bicarbonate aqueous solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.2 g, 85%) as a hygroscopic solid. MS (EI) m / z: 300 [M+H]+.

[0083] (28-1) Preparation of 1-bromo-3-methylbutan-2-one Under ice cooling, 3-methyl-2-butanone (9.8 mL, 92.0 mmol) was added to methanol (60 mL), and a solution of bromine (5.0 mL, 97.0 mmol) dissolved in methanol (15 mL) was added dropwise over 15 minutes at 0°C, stirring at 0°C for 1 hour and then at room temperature for 16 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue, which was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (12.1 g, 80%) as an oil. 1H-NMR (CDCl3) δ: 1.16 (d, J = 7.2 Hz, 6H), 2.90-3.05 (m, 1H), 3.98 (s, 2H).

[0084] (28-2) The compound obtained in Production Example 1 (28-1) of ethyl 4-isopropylthiazole-2-carboxylate (4.0 g, 24.2 mmol) was dissolved in ethanol (40 mL), ethyl thiooxamate (2.0 mg, 15.0 mmol) was added, and the mixture was heated under reflux at 80°C for 24 hours under an argon atmosphere. The solvent was removed under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (3.4 g, 70%) as an oil. 1H-NMR (DMSO-d6) δ: 1.24 (d, J = 7.0 Hz, 6H), 1.31 (t, J = 6.8 Hz, 3H), 3.01-3.17 (m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 7.71 (s, 1H).

[0085] (28-3) The compound obtained in Production Example 1 (28-2) of (4-isopropylthiazole-2-yl)methanol (3.4 g, 17.1 mmol) was dissolved in anhydrous THF (35 mL), LAH (1.0 g, 26.3 mmol) was added at -15°C, and the mixture was stirred at -15°C for 30 minutes. Water (1.0 mL), aqueous sodium hydroxide solution (15 w / v%) (3.0 mL), and ethyl acetate (70 mL) were added to the reaction solution and the mixture was stirred at room temperature for 10 minutes. The reaction solution was filtered, the filtrate was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (1.2 g, 45%) as an oil. 1H-NMR (CDCl3) δ: 1.27 (d, J = 6.8 Hz, 6H), 2.99-3.12 (m, 1H), 3.51-3.80 (brs, 1H), 4.90 (s, 2H), 6.83 (s, 1H).

[0086] (28-4) Preparation of (4-isopropylthiazole-2-yl)methylmethanesulfonate Under ice cooling, TEA (1.3 mL, 9.5 mmol) and the compound obtained in Example 1 (28-3) (1.2 g, 7.6 mmol) were added to DCM (65 mL). A solution of mesylchloride (0.6 mL, 8.0 mmol) in DCM (10 mL) was added dropwise, and the mixture was stirred for 30 minutes. The mixture was then stirred for another 30 minutes at room temperature, and the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting title compound was used directly in the next reaction.

[0087] (28-5) Preparation of 3-[(4-isopropylthiazole-2-yl)methoxy]benzaldehyde] Potassium carbonate (1.1 g, 38.0 mmol) and 3-hydroxybenzaldehyde (0.83 g, 6.8 mmol) were added to a 30 mL solution of the compound obtained in Example 1 (28-4) of 3-[(4-isopropylthiazole-2-yl)methoxy]benzaldehyde, and the mixture was stirred at room temperature for 24 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1) to obtain the title compound (1.0 g, 50%) as an oil. 1H-NMR (DMSO-d6) δ: 1.34 (d, J = 6.0 Hz, 6H), 3.10-3.15 (m, 1H), 5.40 (s, 2H), 6.92 (s, 1H), 7.29-7.53 (m, 4H), 9.98 (s, 1H).

[0088] (29-1) Preparation of 2-bromo-1-cyclopropylethanone: Under ice cooling, cyclopropyl methyl ketone (8.5 mL, 92.0 mmol) was added to methanol (60 mL). A solution of bromine (5.0 mL, 97.0 mmol) dissolved in methanol (15 mL) was added dropwise over 15 minutes at 0°C. The title compound (14.6 g, 98%) was obtained as an oily substance in the same manner as in the synthesis of Example 1 (28-1). ¹H-NMR (CDCl3) δ: 0.95-1.03 (m, 2H), 1.08-1.15 (m, 2H), 2.13-2.21 (m, 1H), 4.00 (s, 2H).

[0089] (29-2) Preparation of ethyl 4-cyclopropylthiazole-2-carboxylate: The compound obtained in Example 1 (29-1) (4.0 g, 24.2 mmol) was dissolved in ethanol (40 mL), ethyl thiooxamate (2.0 g, 15.0 mmol) was added, and the title compound (2.4 g, 50%) was obtained as an oil in the same manner as the synthesis in Example 1 (28-2). ¹H-NMR (DMSO-d6) δ: 0.80-0.84 (m, 2H), 0.92-0.97 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 2.13-2.20 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 7.70 (s, 1H).

[0090] (29-3) The compound obtained in Example 1 (29-2) of (4-cyclopropylthiazole-2-yl)methanol (2.4 g, 12.0 mmol) was dissolved in anhydrous THF (35 mL), and LAH (0.70 g, 18.4 mmol) was added at -15°C. The title compound (0.35 g, 18%) was obtained as an oil in the same manner as in the synthesis of Example 1 (28-3). ¹H-NMR (DMSO-d6) δ: 0.77-0.84 (m, 2H), 0.85-0.88 (m, 2H), 2.00-2.04 (m, 2H), 5.96 (t, J = 7.1 Hz, 1H), 7.15 (s, 1H).

[0091] (29-4) Preparation of (4-cyclopropylthiazole-2-yl)methylmethanesulfonate Under ice cooling, TEA (0.4 mL, 2.8 mmol) and the compound obtained in Example 1 (29-3) (0.35 g, 2.3 mmol) were added to DCM (20 mL), and a solution of mesylchloride (0.2 mL, 2.4 mmol) in DCM (2 mL) was added dropwise. The title compound obtained in the same manner as the synthesis in Example 1 (28-4) was used directly in the next reaction.

[0092] (29-5) Preparation of 3-[(4-cyclopropylthiazole-2-yl)methoxy]benzaldehyde To a solution of the compound obtained in Example 1 (29-4) in DMF (10 mL), potassium carbonate (0.30 g, 11.2 mmol) and 3-hydroxybenzaldehyde (0.25 g, 2.0 mmol) were added, and the title compound (0.15 g, 26%) was obtained as an oil in the same manner as the synthesis in Example 1 (28-5). 1H-NMR (DMSO-d6) δ: 0.80-0.83 (m, 2H), 0.89-0.92 (m, 2H), 1.17 (d, J = 6.0 Hz, 6H), 3.18-3.19 (m, 1H), 5.45 (s, 2H), 7.09 (s, 1H), 7.24-7.57 (m, 5H), 9.92 (s, 1H).

[0093] (30-1) Preparation of 2-bromo-1-cyclobutylethanone: Under ice cooling, methanol (100 mL) was mixed with 3-acetylcyclobutane (16.0 mL, 146.0 mmol), and bromine (8.0 mL, 155.0 mmol) was added dropwise over 15 minutes at 0°C. The title compound (17.9 g, 69%) was obtained as an oil in the same manner as in the synthesis of Example 1 (28-1). MS (EI) m / z: 178 [M+H]+.

[0094] (30-2) Preparation of Ethyl 4-Cyclobutylthiazole-2-carboxylate: The compound obtained in Example 1 (30-1) (5.0 g, 28.2 mmol) was dissolved in ethanol (70 mL), copper acetate (0.51 g, 2.8 mmol) and ethyl thioxamate (3.8 g, 28.2 mmol) were added, and the title compound (4.8 g, 81%) was obtained as an oily substance in the same manner as the synthesis in Example 1 (28-2). MS (EI) m / z: 212 [M+H]+.

[0095] (30-3) The compound obtained in Production Example 1 (30-2) of (4-cyclobutylthiazole-2-yl)methanol (3.2 g, 15.1 mmol) was dissolved in anhydrous THF (35 mL), and LAH (1.0 g, 26.3 mmol) was added at -15°C. The title compound (2.1 g, 54%) was obtained as an oil in the same manner as the synthesis in Example 1 (28-3). MS (EI) m / z: 170 [M+H]+.

[0096] (30-4) Preparation of (4-cyclobutylthiazole-2-yl)methylmethanesulfonate: Under ice cooling, TEA (1.3 mL, 9.5 mmol) and the compound obtained in Example 1 (30-3) (1.3 g, 7.6 mmol) were added to DCM (65 mL). A solution of mesylchloride (0.6 mL, 8.0 mmol) in DCM (10 mL) was added dropwise, and the title compound obtained in the same manner as in the synthesis of Example 1 (28-4) was used directly in the next reaction. MS (EI) m / z: 248 [M+H]+.

[0097] (30-5) Preparation of 3-[(4-cyclohexylthiazole-2-yl)methoxy]benzaldehyde: Potassium carbonate (1.1 g, 38.0 mmol) and 3-hydroxybenzaldehyde (0.83 g, 6.8 mmol) were added to a 30 mL solution of the compound obtained in Example 1 (30-4) in DMF, and the title compound (1.0 g, 50%) was obtained as an oil in the same manner as the synthesis in Example 1 (28-5). MS (EI) m / z: 274 [M+H]+.

[0098] (31-1) Preparation of ethyl 4-(4-chlorophenyl)thiazole-2-carboxylate: 4-chlorophenacyl bromide (10.0 g, 42.8 mmol) was dissolved in ethanol (70 mL), copper acetate (0.78 g, 4.3 mmol) and ethyl thioxamate (5.7 g, 42.8 mmol) were added, and the title compound (11.3 g, quant.) was obtained as a hygroscopic solid in the same manner as in the synthesis of Example 1 (30-2). MS (EI) m / z: 268 [M+H]+.

[0099] (31-2) The compound obtained in Example 1 (31-1) of preparation of [4-(4-chlorophenyl)thiazole-2-yl]methanol (11.3 g, 42.8 mmol) was dissolved in anhydrous THF (35 mL), LAH (2.4 g, 64.2 mmol) was added at -15°C, and the title compound (3.5 g, 36%) was obtained as a hygroscopic solid in the same manner as the synthesis in Example 1 (30-3). MS (EI) m / z: 226 [M+H]+.

[0100] (31-3) Preparation of [4-(4-chlorophenyl)thiazole-2-yl]methylmethanesulfonate: Under ice cooling, TEA (2.6 mL, 19.0 mmol) and the compound obtained in Example 1 (31-2) (3.5 g, 15.5 mmol) were added to DCM (130 mL). A solution of mesylchloride (1.2 mL, 16.0 mmol) in DCM (20 mL) was added dropwise, and the resulting title compound was used directly in the next reaction in the same manner as in the synthesis of Example 1 (30-4). MS (EI) m / z: 304 [M+H]+.

[0101] (31-4) Preparation of 3-{[4-(4-chlorophenyl)thiazole-2-yl]methoxy}benzaldehyde: Potassium carbonate (2.2 g, 76.0 mmol) and 3-hydroxybenzaldehyde (1.7 g, 13.6 mmol) were added to a 60 mL solution of the compound obtained in Example 1 (31-3) in DMF, and the title compound (2.3 g, 45%) was obtained as a hygroscopic solid in the same manner as the synthesis in Example 1 (30-5). MS (EI) m / z: 330 [M+H]+.

[0102] (32-1) Preparation of Ethyl 4-Phenylthiazole-2-carboxylate: Phenacyl bromide (23i) (10.0 g, 52.3 mmol) was dissolved in ethanol (100 mL), copper acetate (0.95 g, 5.3 mmol) and ethyl thioxamate (6.9 g, 52.3 mmol) were added, and the title compound (9.7 g, 80%) was obtained as a hygroscopic solid in the same manner as the synthesis in Example 1 (30-2). MS (EI) m / z: 234 [M+H]+.

[0103] (32-2) The compound obtained in Example 1 (32-1) of (4-phenylthiazole-2-yl)methanol (9.7 g, 47.1 mmol) was dissolved in anhydrous THF (35 mL), and LAH (3.0 g, 78.5 mmol) was added at -15°C. The title compound (6.4 g, 80%) was obtained as an oil in the same manner as in the synthesis of Example 1 (30-3). MS (EI) m / z: 192 [M+H]+.

[0104] (32-3) Preparation of (4-phenylthiazole-2-yl)methylmethanesulfonate: Under ice cooling, TEA (5.7 mL, 42.0 mmol) and the compound obtained in Example 1 (32-2) (6.4 g, 33.5 mmol) were added to DCM (260 mL). A solution of mesylchloride (2.7 mL, 35.0 mmol) in DCM (30 mL) was added dropwise, and the resulting title compound was used directly in the next reaction in the same manner as in the synthesis of Example 1 (30-4). MS (EI) m / z: 270 [M+H]+.

[0105] (32-4) Preparation of 3-[(4-phenylthiazole-2-yl)methoxy]benzaldehyde: Potassium carbonate (4.7 g, 162.0 mmol) and 3-hydroxybenzaldehyde (4.1 g, 33.5 mmol) were added to a 100 mL solution of the compound obtained in Example 1 (32-3) in DMF, and the title compound (5.2 g, 53%) was obtained as a hygroscopic solid in the same manner as the synthesis in Example 1 (30-5). MS (EI) m / z: 296 [M+H]+.

[0106] (33-1) The compound obtained in Production Example 1 (28-4) of 2-(bromomethyl)-4-isopropylthiazole (3.1 g, 13.3 mmol) was dissolved in acetone (50 mL), lithium bromide (3.5 g, 39.9 mmol) was added, and the mixture was heated under reflux at 60°C for 4 hours. The solvent was removed under reduced pressure, chloroform (100 mL) was added to the residue, and the mixture was filtered. The filtrate was washed with water and saturated saline solution, and then dried over anhydrous sodium sulfate. The oily residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (1.1 g, 38%) as an oil. MS (EI) m / z: 221 [M+H]+.

[0107] (33-2) Preparation of 2{3-[(4-isopropylthiazole-2-yl)methoxy]phenylacetaldehyde} In a 30 mL solution of the compound obtained in Example 1 (33-1) of 2{3-[(4-isopropylthiazole-2-yl)methoxy]phenylacetaldehyde}, potassium carbonate (1.1 g, 38.0 mmol) and 2-(3-hydroxyphenyl)acetaldehyde (0.76 g, 5.6 mmol) were added, and the mixture was heated under reflux at 60°C for 4 hours. The reaction solution was filtered, and the filtrate was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (1.5 g, quant.) as an oil. MS (EI) m / z: 276 [M+H]+.

[0108] (34-1) Preparation of 2-(bromomethyl)-7-chloroquinoline 7-chloroquinaldine (35.0 g, 197 mmol), NBS (38.6 g, 217 mmol), and AIBN (0.82 g, 5 mmol) were stirred in ethyl acetate (400 mL) at 70°C for 6 hours. After cooling, insoluble matter was filtered off, and the filtrate was sequentially washed with 1 mol / L hydrochloric acid, water, and saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was removed by distillation, and the resulting oily residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:toluene = 1:1) to obtain the title compound (21.04 g, 42%) as crystals. Mp. 105-107℃. 1H-NMR (CDCl3) δ: 4.69 (s, 2H), 7.51 (dd, J = 1.8, 8.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H).

[0109] (34-2) Preparation of 3-[(7-chloro-2-quinolyl)methoxy]benzaldehyde 3-hydroxybenzaldehyde (2.69 g, 22 mmol), potassium carbonate (6.91 g, 50 mmol), and the compound obtained in Example 1 (34-1) (5.13 g, 20 mmol) were stirred in DMF (50 mL) at room temperature for 20 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was crystallized from ether and petroleum ether to obtain the title compound (3.33 g, 56%). Mp. 110-111℃. 1H-NMR (DMSO-d6) δ: 5.47 (s, 2H), 7.40-7.45 (m, 1H), 7.53-7.59 (m, 3H), 7.65-7.68 (m, 1H), 7.73 (d, J = 8.5 Hz, 1H), 8.05-8.09 (m, 2H), 8.48 (d, J = 8.5 Hz, 1H), 9.98 (s, 1H). MS (EI) m / z: 297 [M]+.

[0110] (35-1) Preparation of 2-(bromomethyl)-7-fluoroquinoline 7-fluoroquinaldine (32.24 g, 200 mmol), NBS (39.16 g, 220 mmol), and AIBN (0.82 g, 5 mmol) were treated in ethyl acetate (400 mL) in the same manner as in the synthesis of Example 1 (34-1). The crude product was purified by silica gel column chromatography (PSQ-100B, n-hexane:toluene = 1:1) to obtain the title compound (23.16 g, 48%) as crystals. Mp. 103-105℃. 1H-NMR (DMSO-d6) δ: 4.86 (s, 2H), 7.55-7.60 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 2.2, 10.5 Hz, 1H), 8.11 (dd, J = 6.4, 8.9 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H). MS (EI) m / z: 238 [M]+.

[0111] (35-2) Preparation of 3-[(7-fluoro-2-quinolyl)methoxy]benzaldehyde 3-hydroxybenzaldehyde (2.69 g, 22 mmol), potassium carbonate (6.91 g, 50 mmol), and the compound obtained in Example 1 (35-1) (5.13 g, 20 mmol) were stirred in DMF (50 mL) at room temperature for 20 hours. The reaction mixture was poured into water (200 mL), and the precipitated crystals were filtered off. The mixture was then dried under reduced pressure on phosphorus pentoxide at 50°C to obtain the title compound (4.67 g, 83%). Mp. 115-116℃. 1H-NMR (DMSO-d6) δ: 5.47 (s, 2H), 7.40-7.45 (m, 1H), 7.53-7.60 (m, 3H), 7.69 (d, J = 8.5 Hz, 1H), 7.77 (dd, J = 2.4, MS (EI) m / z: 297 [M]+.

[0112] (36) Preparation of 4-[(7-fluoro-2-quinolyl)methoxy]benzaldehyde 2-(bromomethyl)-7-fluoroquinoline bromide was prepared from 7-fluoro-2-methylquinoline (39.05 g, 240 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) according to a previously established method. A mixture of 2-(bromomethyl)-7-fluoroquinoline and 4-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (35-2) was used directly in the next reaction. MS (EI) m / z: 298 [M+H]+.

[0113] (37) Preparation of 2-[(7-fluoro-2-quinolyl)methoxy]benzaldehyde 2-(bromomethyl)-7-fluoroquinoline bromide was prepared from 7-fluoro-2-methylquinoline (39.05 g, 240 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) according to a previously established method. A mixture of 2-(bromomethyl)-7-fluoroquinoline and 2-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 298 [M+H]+.

[0114] (38-1) Preparation of Methyl 2-{3-[(7-chloro-2-quinolyl)methoxy]phenyl}acetate 2-(bromomethyl)-7-chloroquinoline (10.26 g, 40 mmol), 2-(3-hydroxymethyl)methyl acetate (7.31 g, 44 mmol), and potassium carbonate (13.82 g, 100 mmol) were added to DMF (80 mL) and stirred at room temperature for 24 hours. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (12.04 g, 88%) as crystals. Mp. 70-72℃.

[0115] (38-2) Preparation of 2-{3-[(7-chloro-2-quinolyl)methoxy]phenyl}ethanol Sodium borohydride (2.65 g, 70 mmol), lithium chloride (2.97 g, 70 mmol), and the compound obtained in Example 1 (38-1) (11.93 g, 35 mmol) were added to a mixed solvent of THF (100 mL) and ethanol (100 mL) and stirred at 50°C for 30 minutes. After adding ethanol (100 mL) to the reaction mixture, it was stirred for a further 24 hours at 50°C. After cooling, aqueous citric acid solution was added to the reaction mixture and stirred for 1 hour. After removing the organic solvent under reduced pressure, the mixture was extracted with ethyl acetate (50 mL x 3). The title compound (6.59 g, 60%) was purified by silica gel column chromatography (toluene:ethyl acetate = 4:1) to obtain the crystals. Mp. 149-150℃. MS (EI) m / z: 314 [M+H]+.

[0116] (38-3) Preparation of 2-{3-[(7-chloro-2-quinolyl)methoxy]phenyl}acetaldehyde In a solution of the compound obtained in Example 1 (38-2) (1.0 g, 3.3 mmol) in DCM (30 mL), a solution of DMP (1.5 g, 3.5 mmol) in DCM (10 mL) was added dropwise over 10 minutes at room temperature. Mild reflux occurred and the solution became turbid. After adding ether (50 mL) to the reaction mixture, it was gradually added to a saturated sodium bicarbonate aqueous solution (50 mL) in which sodium thiosulfate (4.0 g) was dissolved. After stirring for about 10 minutes, the organic layer was separated and washed with saturated sodium bicarbonate aqueous solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain the title compound (0.9 g, 89%) as a hygroscopic solid. MS (EI) m / z: 312 [M+H]+.

[0117] (39) Preparation of 4-[(6,7-difluoro-2-quinolyl)methoxy]benzaldehyde Bromide 2-(bromomethyl)-6,7-difluoroquinoline was prepared from 6,7-difluoro-2-methylquinoline (39.05 g, 218 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) according to a previously established method. A mixture of 2-(bromomethyl)-6,7-difluoroquinoline and 4-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours, and the title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 300 [M+H]+.

[0118] (40) Preparation of 4-[(6,7-difluoro-2-quinolyl)methoxy]-2,6-difluorobenzaldehyde Bromide 2-(bromomethyl)-6,7-difluoroquinoline was prepared from 6,7-difluoro-2-methylquinoline (39.05 g, 218 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) according to a previously established method. A mixture of 2-(bromomethyl)-6,7-difluoroquinoline and 4-hydroxy-2,6-difluorobenzaldehyde (1.7 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 336 [M+H]+.

[0119] (41) Preparation of 4-[(6,7-difluoro-2-quinolyl)methoxy]-2-fluorobenzaldehyde Bromide 2-(bromomethyl)-6,7-difluoroquinoline was prepared from 6,7-difluoro-2-methylquinoline (39.05 g, 218 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) according to the previously established method. A mixture of 2-(bromomethyl)-6,7-difluoroquinoline and 4-hydroxy-2-fluorobenzaldehyde (1.5 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 318 [M+H]+.

[0120] (42) Preparation of 4-[(6,7-difluoro-2-quinolyl)methoxy]-3-fluorobenzaldehyde Bromide 2-(bromomethyl)-6,7-difluoroquinoline was prepared from 6,7-difluoro-2-methylquinoline (39.05 g, 218 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) according to the previously established method. A mixture of 2-(bromomethyl)-6,7-difluoroquinoline and 4-hydroxy-3-fluorobenzaldehyde (1.5 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours, and the title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 318 [M+H]+.

[0121] (43) Preparation of 4-[(6,7-difluoro-2-quinolyl)methoxy]-3,5-difluorobenzaldehyde Bromide 2-(bromomethyl)-6,7-difluoroquinoline was prepared from 6,7-difluoro-2-methylquinoline (39.05 g, 218 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) according to a previously established method. A mixture of 2-(bromomethyl)-6,7-difluoroquinoline and 4-hydroxy-3,5-difluorobenzaldehyde (1.7 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 336 [M+H]+.

[0122] (44-1) Preparation of 5,6,7,8-tetrafluoro-2-methylquinoline A solution of 2,3,4,5-tetrafluoroaniline (5.0 g, 37.1 mmol), p-chloranil (9.0 g, 36.8 mmol), and concentrated hydrochloric acid (10 mL) in 2-butanol (60 mL) was added dropwise over 5 minutes under heating reflux to a solution of crotonaldehyde (3.1 mL, 37.5 mmol) in 2-butanol (5 mL), followed by heating under reflux for a further 2 hours. After cooling, the solvent was removed under reduced pressure, and toluene (100 mL) was added to the residue to remove water as an azeotropic mixture under reduced pressure. A mixed solvent of toluene (200 mL) and THF (50 mL) was added to the residue and stirred at room temperature for 30 minutes, and the precipitated solid was filtered off. 100 mL of 10 w / v% potassium carbonate aqueous solution and 100 mL of ethyl acetate were added to the solid and stirred for 1 hour. After removing insoluble matter with Celite, the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH-DM1020, n-hexane) to obtain the title compound (2.2 g, 27%) as a hygroscopic solid. MS (EI) m / z: 216 [M+H]+.

[0123] (44-2) Preparation of 4-[(5,6,7,8-tetrafluoro-2-quinolyl)methoxy]benzaldehyde Bromide 2-(bromomethyl)-5,6,7,8-tetrafluoroquinoline was prepared from 5,6,7,8-tetrafluoro-2-methylquinoline (2.2 g, 10.0 mmol), NBS (2.3 g, 12.8 mmol), and AIBN (0.01 g) according to a previously established method. A mixture of 2-(bromomethyl)-5,6,7,8-tetrafluoroquinoline and 4-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 336 [M+H]+.

[0124] (45-1) Preparation of 5,6,7-trifluoro-2-methylquinoline: 5,6,7-trifluoroaniline (5.0 g, 33.9 mmol), p-chloranil (8.4 g, 34.3 mmol), and concentrated hydrochloric acid (10 mL) in a solution of 2-butanol (60 mL) were added dropwise over 5 minutes under heating reflux to a solution of crotonaldehyde (2.9 mL, 34.3 mmol) in 2-butanol (5 mL). The title compound (1.5 g, 22%) was obtained as a hygroscopic solid in the same manner as in the synthesis of Example 1 (44-1). MS (EI) m / z: 198 [M+H]+.

[0125] (45-2) Preparation of 4-[(5,6,7-trifluoro-2-quinolyl)methoxy]benzaldehyde Bromide 2-(bromomethyl)-5,6,7-trifluoroquinoline was prepared from 5,6,7-trifluoro-2-methylquinoline (1.5 g, 7.5 mmol), NBS (1.6 g, 8.9 mmol), and AIBN (0.01 g) according to a previously established method. A mixture of 2-(bromomethyl)-5,6,7-trifluoroquinoline and 4-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 318 [M+H]+.

[0126] (46-1) Preparation of 6,7,8-trifluoro-2-methylquinoline: A solution of 6,7,8-trifluoroaniline (5.0 g, 33.9 mmol), p-chloranil (8.4 g, 34.3 mmol), and concentrated hydrochloric acid (10 mL) in 2-butanol (60 mL) was dropwise added over 5 minutes under heating reflux to a solution of crotonaldehyde (2.9 mL, 34.3 mmol) in 2-butanol (5 mL). The title compound (1.7 g, 25%) was obtained as a hygroscopic solid in the same manner as in the synthesis of Example 1 (44-1). MS (EI) m / z: 198 [M+H]+.

[0127] (46-2) Preparation of 4-[(6,7,8-trifluoro-2-quinolyl)methoxy]benzaldehyde Bromide 2-(bromomethyl)-6,7,8-trifluoroquinoline was prepared from 6,7,8-trifluoro-2-methylquinoline (1.7 g, 8.5 mmol), NBS (1.8 g, 10.1 mmol), and AIBN (0.01 g) according to a previously established method. A mixture of 2-(bromomethyl)-6,7,8-trifluoroquinoline and 4-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 318 [M+H]+.

[0128] (47-1) Preparation of 7,8-difluoro-2-methylquinoline: A solution of 7,8-difluoroaniline (5.0 g, 38.7 mmol), p-chloranil (9.4 g, 38.3 mmol), and concentrated hydrochloric acid (10 mL) in 2-butanol (60 mL) was dropwise added over 5 minutes under heating reflux to a solution of crotonaldehyde (3.2 mL, 39.1 mmol) in 2-butanol (5 mL). The title compound (2.7 g, 39%) was obtained as a hygroscopic solid in the same manner as in Example 1 (44-1). MS (EI) m / z: 180 [M+H]+.

[0129] (47-2) Preparation of 4-[(7,8-difluoro-2-quinolyl)methoxy]benzaldehyde Bromide 2-(bromomethyl)-7,8-difluoroquinoline was prepared from 7,8-difluoro-2-methylquinoline (2.7 g, 15.1 mmol), NBS (2.8 g, 15.7 mmol), and AIBN (0.01 g) according to a previously established method. A mixture of 2-(bromomethyl)-7,8-difluoroquinoline and 4-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 300 [M+H]+.

[0130] (48-1) Preparation of 5,7-difluoro-2-methylquinoline: A solution of 6,8-difluoroaniline (5.0 g, 38.7 mmol), p-chloranil (9.4 g, 38.3 mmol), and concentrated hydrochloric acid (10 mL) in 2-butanol (60 mL) was dropwise added over 5 minutes under heating reflux to a solution of crotonaldehyde (3.2 mL, 39.1 mmol) in 2-butanol (5 mL). The title compound (4.1 g, 59%) was obtained as a hygroscopic solid in the same manner as in the synthesis of Example 1 (44-1). MS (EI) m / z: 180 [M+H]+.

[0131] (48-2) Preparation of 4-[(5,7-difluoro-2-quinolyl)methoxy]benzaldehyde Bromide 2-(bromomethyl)-5,7-difluoroquinoline was prepared from 6,8-difluoro-2-methylquinoline (4.1 g, 22.8 mmol), NBS (4.3 g, 24.0 mmol), and AIBN (0.02 g) according to a previously established method. A mixture of 2-(bromomethyl)-5,7-difluoroquinoline and 4-hydroxybenzaldehyde (1.3 g, 10.7 mmol), potassium carbonate (3.4 g, 24.3 mmol), and DMF (50 mL) was stirred at room temperature for 24 hours. The title compound obtained in the same manner as in the synthesis of Example 1 (34-2) was used directly in the next reaction. MS (EI) m / z: 300 [M+H]+.

[0132] Example 2 (1) Preparation of 3-{[4-(2-methoxy-2-oxyethyl)phenoxy]methyl}thiophene-2-carboxylate methyl 3-methyl-2-thiophenecarboxylate (39.05 g, 250 mmol), NBS (50.0 g, 280 mmol), and AIBN (0.2 g) were heated under reflux in 1,2-dichloroethane (DCE, 300 mL) for 3 hours. After cooling, the mixture was washed with 10% aqueous potassium carbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting bromide was mixed with methyl 4-hydroxyphenylacetate (41.55 g, 250 mmol), potassium carbonate (69.11 g, 500 mmol), and DMF (250 mL) and stirred at room temperature for 24 hours. The reaction mixture was added to water (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the title compound (55.90 g, 70%) was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 4:1) to obtain crystals. Temperature: 62-64°C.

[0133] (2) Preparation of 3-{[4-(carboxymethyl)phenoxy]methyl}thiophene-2-carboxylic acid. A 2 mol / L aqueous sodium hydroxide solution (260 mL, 520 mmol as NaOH) was added to a methanol (1200 mL) solution of the compound obtained in Example 2 (1), and the mixture was heated under reflux for 24 hours. After cooling, the solvent was removed under reduced pressure, and the resulting residue was dissolved in water (500 mL). 2 mol / L hydrochloric acid (300 mL) was then added. The precipitated crystals were filtered, washed with water, and dried under reduced pressure on phosphorus pentoxide at 50°C to obtain the title compound (50.0 g, 99%). Mp. 212-215°C.

[0134] (3) Preparation of methyl 2-(10-oxo-4H-thieno[3,2-c][1]benzooxepin-8-yl)acetate. The compound obtained in Example 2 (2) (49.85 g, 170 mmol) and trifluoroacetic anhydride (55 mL, 383 mmol) were added to DCE (460 mL) and stirred at 60°C for 24 hours. After the reaction solution was allowed to cool, methanol (250 mL) was added and the mixture was heated under reflux for a further 24 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate (300 mL) and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The oily residue was crystallized from a 4:1 mixed solvent of n-hexane and ethyl acetate to obtain the title compound (47.76 g, 97%). Mp. 75-77°C. MS (EI) m / z: 288 [M]+.

[0135] (4) Preparation of methyl 2-[10-hydroxy-10-(1-methyl-4-piperidyl)-4H-thieno[3,2-c][1]benzooxepin-8-yl]acetate Magnesium (3.90 g, 160 mmol), 4-chloro-1-methylpiperidine (3.0 mL, 23 mmol), and 1,2-dibromoethane (0.2 mL) were added to THF (80 mL) and heated to 110°C to initiate the Grignard reaction. Under reflux, a THF solution of 4-chloro-1-methylpiperidine (19.0 mL, 137 mmol) was added dropwise over 1 hour, and the mixture was stirred at the same temperature for 24 hours. After cooling the reaction mixture in an ice-salt bath, a THF (160 mL) solution of the compound obtained in Example 2 (3) (23.1 g, 80 mmol) was gradually added dropwise over 1 hour. After stirring for another hour at the same temperature, saturated ammonium chloride aqueous solution (300 mL) was added and stirred at room temperature for 1 hour. Extraction with ethyl acetate, washing with water and saturated saline solution, and drying over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 9:1) to obtain the title compound (16.48 g, 53%) as crystals. Mp. 170℃ (dec.) .MS (EI) m / z: 388 [M+H]+.

[0136] (5) Preparation of methyl 2-[10-(1-methyl-4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]acetate. To a solution of the compound obtained in Example 2 (4) (21.70 g, 56 mmol) in DCM (350 mL), TFA (43 mL, 560 mmol) was added dropwise over 30 minutes under ice cooling, and the mixture was gradually returned to room temperature and stirred for 20 hours. The reaction mixture was cooled on ice, and an aqueous solution of potassium carbonate (83 g, 600 mmol) (400 mL) was added dropwise over 1 hour. After separating the organic layer, the aqueous layer was extracted with DCM (100 mL x 2). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 9:1) to obtain the title compound (19.96 g, 96%) as an oil. MS (EI) m / z: 370 [M+H]+.

[0137] (6) Preparation of 4-[8-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-c][1]benzooxepin-10-ylidene]piperidine-1-carboxylic acid 2,2,2-trichloroethyl. The compound obtained in Example 2 (5) (19.95 g, 54 mmol) was dissolved in toluene (150 mL) and potassium carbonate (0.7 g, 5 mmol) was added. Chloroformic acid 2,2,2-trichloroethyl (Troc-Cl, 9 mL, 65 mmol) was added dropwise at room temperature over 15 minutes. After heating under reflux for 24 hours, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with saturated aqueous ammonium chloride (100 mL), water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PSQ-100B, toluene:ethyl acetate = 9:1) to obtain the title compound (21.48 g, 75%) as an oil. MS (EI) m / z: 529 [M+H]+.

[0138] (7) Preparation of 2-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl acetate hydrochloride The compound obtained in Example 2 (6) (21.48 g, 40.6 mmol) was dissolved in acetic acid (250 mL), zinc powder (16.00 g, 244 mmol) was added, and the mixture was stirred at room temperature for 72 hours. Insoluble matter was filtered off, the mixture was washed with methanol, and the solvent was removed under reduced pressure. Water (200 mL) was added to the residue, and potassium carbonate (20 g) was gradually added. Ethyl acetate (150 mL) was added and the mixture was stirred for 1 hour, after which the insoluble matter was filtered off with Celite. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (NH-DM1020, chloroform). The resulting oily substance was dissolved in DCM (50 mL), and a 4 mol / L hydrogen chloride / dioxane solution (20 mL, 80 mmol as HCl) was added. After shaking for a while, the solvent was removed under reduced pressure, and the resulting oily residue was solidified from the ether to obtain the title compound (14.32 g, 90%) as a hygroscopic solid.

[0139] Example 3 (1) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.55 g, 1.4 mmol of the compound obtained in Example 2 (7), 0.44 g, 1.5 mmol of the compound obtained in Example 1 (1), 0.45 g, 2.1 mmol of sodium triacetoxyborohydride, and 0.3 mL, 1.8 mmol of TEA were added to DCM (30 mL) and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.74 g, 83%) as an oil. (2) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 33] The compound obtained in Example 3 (1) (0.74 g, 1.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.6 mL, as NaOH) was added at room temperature. The mixture was stirred at room temperature for 24 hours, and then the solvent was removed by distilling off under reduced pressure. Water (10 mL) was added to the resulting residue, and the pH was adjusted to approximately 6 with 1 mol / L hydrochloric acid. The precipitated crystals were filtered and thoroughly washed with water, then dried under reduced pressure at 50°C on phosphorus pentoxide to obtain compound 33 (0.30 g, 41%) as crystals.

[0140] Example 4 (1) Preparation of 2-[10-[1-[[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]methyl]-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl acetate 0.55 g, 1.4 mmol of the compound obtained in Example 2 (7), 3-[(E)-2-(7-chloro-2-quinolyl)vinyl]benzaldehyde (0.68 g, 1.5 mmol), sodium triacetoxyburohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 1.7 mmol) were added to DCM (30 mL), and the title compound (0.77 g, 86%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-[10-[1-[[3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]methyl]-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]acetic acid [Compound 27] The compound obtained in Example 3 (1) (0.77 g, 1.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.6 mL, as NaOH) was added at room temperature. Compound 27 (0.45 g, 60%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0141] Example 5 (1) Preparation of 2-{10-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.50 g, 1.3 mmol of the compound obtained in Example 2 (7), 3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]benzaldehyde (0.42 g, 1.4 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 1.7 mmol) were added to DCM (30 mL), and the title compound (0.45 g, 54%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 48] The compound obtained in Example 5 (1) (0.45 g, 0.7 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) was added at room temperature, and Compound 48 (0.30 g, 68%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0142] Example 6 (1) Preparation of 2-{10-[1-({3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (30 mL), the compound obtained in Example 2 (7) (0.63 g, 1.6 mmol), the compound obtained in Example 1 (3) (0.50 g, 1.6 mmol), sodium triacetoxyborohydride (0.51 g, 2.4 mmol), and TEA (0.3 mL, 1.8 mmol) were added, and the title compound (0.83 g, 80%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 104] The compound obtained in Example 6 (1) (0.83 g, 1.3 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.65 mL, 1.3 mmol as NaOH) at room temperature was added, and compound 104 (0.42 g, 51%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0143] Example 6a (1) Preparation of 2-{10-[1-({3-[(E)-2-quinoxaline-2-ylvinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (30 mL), the compound obtained in Example 2 (7) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (4) (0.33 g, 1.3 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.22 mL, 1.3 mmol) were added, and the title compound (0.54 g, 73%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-quinoxaline-2-ylvinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 107] The compound obtained in Example 6a (1) (0.54 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.45 mL, as 0.9 mmol of NaOH) was added at room temperature. Compound 107 (0.46 g, 88%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0144] Example 7 (1) Preparation of 2-{10-[1-({3-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidiline]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.50 g, 1.3 mmol of the compound obtained in Example 2 (7), 3-[(7-fluoro-2-quinolyl)methoxy]benzaldehyde (0.40 g, 1.4 mmol), sodium triacetoxyburohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (50 mL), and the title compound (0.70 g, 88%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidiline]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 49] The compound obtained in Example 7 (1) (0.70 g, 1.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as NaOH) was added at room temperature. Compound 49 (0.4 g, 59%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0145] Example 8 (1) Preparation of 2-{10-[1-({2-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.50 g, 1.3 mmol of the compound obtained in Example 2 (7), 0.40 g, 1.4 mmol of the compound obtained in Example 1 (37), 0.41 g, 1.9 mmol of sodium triacetoxyborohydride, and 0.2 mL, 1.2 mmol of TEA were added to DCM (50 mL), and the title compound (0.90 g, quant.) was obtained as an oil in the same manner as the synthesis of the compound in Example 3 (1). (2) Preparation of 2-{10-[1-({2-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 50] The compound obtained in Example 8 (1) (0.90 g, 1.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 50 (0.4 g, 55%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0146] Example 9 (1) Preparation of 2-{10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidiline]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.50 g, 1.3 mmol of the compound obtained in Example 2 (7), 0.40 g, 1.4 mmol of the compound obtained in Example 1 (36), 0.41 g, 1.9 mmol of sodium triacetoxyborohydride, and 0.2 mL, 1.2 mmol of TEA were added to DCM (50 mL), and the title compound (0.90 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 51] The compound obtained in Example 9 (1) (0.90 g, 1.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 51 (0.2 g, 30%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0147] Example 10 (1) Preparation of 2-[10-[1-[[4-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl]methyl]-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.25 g, 0.6 mmol), the compound obtained in Example 1 (6) (0.20 g, 0.7 mmol), sodium triacetoxyborohydride (0.20 g, 1.0 mmol), and TEA (0.1 mL, 0.6 mmol) were added, and the title compound (0.15 g, 37%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-[10-[1-[[4-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl]methyl]-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]acetic acid [Compound 52] The compound obtained in Example 10 (1) (0.15 g, 0.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.05 mL, as 0.3 mmol of NaOH) was added at room temperature. Compound 52 (0.16 g, quant.) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0148] Example 11 (1) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (39) (0.41 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.60 g, 73%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 54] The compound obtained in Example 11 (1) (0.60 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 54 (0.4 g, 60%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0149] Example 12 (1) Preparation of 2-{10-[1-({6-[(7-fluoro-2-quinolyl)methoxy]-3-pyridyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.50 g, 1.3 mmol of the compound obtained in Example 2 (7), 6-[(7-fluoro-2-quinolyl)methoxy]-3-pyridinecarboxaldehyde (0.38 g, 1.4 mmol), sodium triacetoxyburohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (50 mL), and the title compound (0.30 g, 38%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({6-[(7-fluoro-2-quinolyl)methoxy]-3-pyridyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 62] The compound obtained in Example 12 (1) (0.30 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 62 (0.12 g, 41%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0150] Example 13 (1) Preparation of 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.50 g, 1.3 mmol), 5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thiophenecarboxaldehyde (0.38 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.57 g, 72%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 67] The compound obtained in Example 13 (1) (0.57 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 67 (0.2 g, 39%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0151] Example 14 (1) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-2,6-difluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (40) (0.41 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.30 g, 35%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-2,6-difluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 68] The compound obtained in Example 14 (1) (0.30 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 68 (0.2 g, 51%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0152] Example 15 (1) Preparation of 2-{10-[1-({4-[2-(5,6,7,8-tetrafluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (44-2) (0.50 g, 1.5 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.3 mL, 1.8 mmol) were added, and the title compound (0.60 g, 69%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(5,6,7,8-tetrafluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 69] The compound obtained in Example 15 (1) (0.60 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 0.9 mmol of NaOH) was added at room temperature. Compound 69 (0.3 g, 55%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0153] Example 16 (1) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-2-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.23 g, 0.6 mmol), the compound obtained in Example 1 (41) (0.20 g, 0.6 mmol), sodium triacetoxyborohydride (0.19 g, 0.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.30 g, 76%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-2-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 70] The compound obtained in Example 16 (1) (0.30 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 70 (0.2 g, 68%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0154] Example 17 (1) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-3-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.42 g, 1.1 mmol), the compound obtained in Example 1 (42) (0.36 g, 1.1 mmol), sodium triacetoxyborohydride (0.34 g, 1.6 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.72 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-3-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 71] The compound obtained in Example 17 (1) (0.72 g, 1.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 71 (0.6 g, 85%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0155] Example 18 (1) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-3,5-difluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.17 g, 0.4 mmol of the compound obtained in Example 2(7), 4-[(6,7-difluoro-2-quinolyl)methoxy]-3,5-difluorobenzaldehyde (0.15 g, 0.5 mmol), sodium triacetoxyburohydride (0.13 g, 0.6 mmol), and TEA (0.1 mL, 0.6 mmol) were added to DCM (30 mL), and the title compound (0.20 g, 71%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]-3,5-difluorophenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 72] The compound obtained in Example 18 (1) (0.20 g, 0.3 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.05 mL, as 0.3 mmol of NaOH) was added at room temperature. Compound 72 (0.2 g, 81%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0156] Example 19 (1) Preparation of 2-{10-[1-({4-[2-(5,6,7-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (30 mL), the compound obtained in Example 2 (7) (0.12 g, 0.3 mmol), the compound obtained in Example 1 (45-2) (0.10 g, 0.3 mmol), sodium triacetoxyborohydride (0.10 g, 0.5 mmol), and TEA (0.1 mL, 0.6 mmol) were added, and the title compound (0.13 g, 62%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(5,6,7-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 73] The compound obtained in Example 19 (1) (0.13 g, 0.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.05 mL, as 0.3 mmol of NaOH) was added at room temperature. Compound 73 (0.1 g, quant.) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0157] Example 20 (1) Preparation of 2-{10-[1-({4-[2-(6,7,8-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (46-2) (0.42 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.38 g, 45%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(6,7,8-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 76] The compound obtained in Example 20 (1) (0.38 g, 0.6 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 76 (0.3 g, 81%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0158] Example 21 (1) Preparation of methyl 2-(10-{1-[2-(4-hydroxyphenyl)ethyl]-4-piperidylidene}-4H-thieno[3,2-c][1]benzooxepin-8-yl)acetate. Add the compound obtained in Example 2(7) (0.50 g, 1.3 mmol), 2-(4-hydroxyphenyl)acetaldehyde (0.42 g, 1.4 mmol), sodium triacetoxyburohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) to DCM (50 mL), and the title compound (0.37 g, 61%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-(2-{4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To 50 mL of DMF, the compound obtained in Example 21(1) (0.37 g, 0.8 mmol), 2-(bromomethyl)-6,7-difluoroquinoline (0.21 g, 0.8 mmol), and potassium carbonate (0.29 g, 2.1 mmol) were added, and the title compound (0.32 g, 63%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (3) Preparation of 2-{10-[1-(2-{4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 77] The compound obtained in Example 21(2) (0.32 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 77 (0.3 g, 86%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0159] Example 22 (1) Preparation of 2-{10-[1-({4-[2-(7,8-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.42 g, 1.1 mmol), the compound obtained in Example 1 (47-2) (0.34 g, 1.1 mmol), sodium triacetoxyborohydride (0.34 g, 1.6 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.52 g, 75%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(7,8-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 78] The compound obtained in Example 22 (1) (0.52 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 78 (0.4 g, 85%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0160] Example 23 (1) 2-{10-[1-({4-[2-(5,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate DCM (50 mL) was mixed with the compound obtained in Example 2(7) (0.42 g, 1.1 mmol), the compound obtained in Example 1(48-2) (0.34 g, 1.1 mmol), sodium triacetoxyborohydride (0.34 g, 1.6 mmol), and TEA (0.2 mL, 1.2 mmol). The title compound (0.52 g, 75%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({4-[2-(5,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 79] The compound obtained in Example 23 (1) (0.52 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 79 (0.4 g, 87%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0161] Example 24 (1) Preparation of 2-{10-[1-({5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.35 g, 0.9 mmol of the compound obtained in Example 2(7), 5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thiophenecarboxaldehyde (0.28 g, 0.9 mmol), sodium triacetoxyborohydride (0.28 g, 1.3 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (50 mL), and the title compound (0.56 g, 98%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 83] The compound obtained in Example 24 (1) (0.56 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 83 (0.5 g, 91%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0162] Example 25 (1) Preparation of 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.50 g, 1.3 mmol of the compound obtained in Example 2(7), 0.40 g, 1.3 mmol of 5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thiophenecarboxaldehyde, 0.41 g, 1.9 mmol of sodium triacetoxyborohydride, and 0.2 mL, 1.2 mmol of TEA were added to DCM (50 mL), and the title compound (0.67 g, 82%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 84] The compound obtained in Example 25 (1) (0.67 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 84 (0.6 g, 85%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0163] Example 26 (1) Preparation of 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-3-methyl-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2(7) (0.50 g, 1.3 mmol), 5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-3-methyl-2-thiophenecarboxaldehyde (0.40 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.33 g, 40%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-3-methyl-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 93] The compound obtained in Example 26 (1) (0.33 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 93 (0.09 g, 28%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0164] Example 27 (1) Preparation of 2-{10-[1-({4-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 2 (7) (0.43 g, 1.1 mmol), the compound obtained in Example 1 (8) (0.30 g, 1.2 mmol), sodium triacetoxyborohydride (0.35 g, 1.7 mmol), and TEA (0.3 mL, 1.8 mmol) were added, and the title compound (0.20 g, 31%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 63] The compound obtained in Example 27(1) (0.20 g, 0.3 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 0.4 mmol of NaOH) was added at room temperature, and Compound 63 (0.13 g, 66%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0165] Example 28 (1) 2-{10-[1-({4-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate DCM (40 mL) was mixed with the compound obtained in Example 2(7) (0.31 g, 0.8 mmol), [4-(4-isopropylthiazole-2-yl)methoxy]benzaldehyde (0.22 g, 0.8 mmol), sodium triacetoxyborohydride (0.25 g, 1.2 mmol), and TEA (0.2 mL, 1.2 mmol) to obtain the title compound (0.22 g, 46%) as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({4-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 64] The compound obtained in Example 28 (1) (0.22 g, 0.4 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 0.4 mmol of NaOH) was added at room temperature, and Compound 64 (0.10 g, 47%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0166] Example 29 (1) Preparation of 2-{10-[1-({4-[(5,6-difluoro-1,3-benzothiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.35 g, 0.9 mmol of the compound obtained in Example 2(7), 4-[(5,6-difluoro-1,3-benzothiazole-2-yl)methoxy]benzaldehyde (0.29 g, 0.9 mmol), sodium triacetoxyburohydride (0.29 g, 1.3 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (40 mL), and the title compound (0.27 g, 45%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({4-[(5,6-difluoro-1,3-benzothiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 82] The compound obtained in Example 29 (1) (0.27 g, 0.4 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 0.4 mmol of NaOH) was added at room temperature, and Compound 82 (0.20 g, 79%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0167] Example 30 (1) Preparation of 2-{10-[1-({3-[(E)-2-(4-cyclohexylthiazol-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.55 g, 1.4 mmol of the compound obtained in Example 2 (7), 0.44 g, 1.5 mmol of the compound obtained in Example 1 (5), 0.45 g, 2.1 mmol of sodium triacetoxyborohydride, and 0.3 mL, 1.8 mmol of TEA were added to DCM (50 mL), and the title compound (0.90 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(4-cyclohexylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 37] The compound obtained in Example 30 (1) (0.90 g, 1.4 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.7 mL, as NaOH) was added at room temperature. Compound 37 (0.70 g, 80%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0168] Example 31 (1) 2-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate DCM (30 mL) was mixed with the compound obtained in Example 2 (7) (0.71 g, 1.8 mmol), the compound obtained in Example 1 (28-5) (0.50 g, 1.9 mmol), sodium triacetoxyborohydride (0.57 g, 2.7 mmol), and TEA (0.3 mL, 1.8 mmol) to obtain the title compound (0.60 g, 55%) as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 22] The compound obtained in Example 31(1) (0.60 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature. Compound 22 (0.36 g, 62%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0169] Example 32 (1) 2-{10-[1-(2-{3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate DCM (30 mL) was mixed with the compound obtained in Example 2 (7) (0.55 g, 1.4 mmol), 2-{3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}acetaldehyde (0.41 g, 1.5 mmol), sodium triacetoxyburohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 1.7 mmol) to obtain the title compound (0.87 g, quant.) as an oily substance in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-(2-{3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 34] The compound obtained in Example 32 (1) (0.87 g, 1.4 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.7 mL, as 1.4 mmol of NaOH) was added at room temperature. Compound 34 (0.47 g, 55%) was obtained as a 0.6-hydrate crystal in the same manner as the synthesis in Example 3 (2).

[0170] Example 33 (1) Preparation of 2-{10-[1-({4-[(5-fluoro-1,3-benzothiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.39 g, 1.0 mmol, 4-[(5-fluoro-1,3-benzothiazole-2-yl)methoxy]benzaldehyde (0.30 g, 1.0 mmol), sodium triacetoxybrohydride (0.31 g, 1.5 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (30 mL), and the title compound (0.47 g, 76%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({4-[(5-fluoro-1,3-benzothiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 60] The compound obtained in Example 33(1) (0.47 g, 0.7 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) was added at room temperature. Compound 60 (0.15 g, 33%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0171] Example 34 (1) Preparation of 2-{10-[1-({4-[(E)-2-(5-fluoro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate 0.50 g, 1.3 mmol of the compound obtained in Example 2(7), 0.38 g, 1.4 mmol of the compound obtained in Example 1(7), 0.41 g, 1.9 mmol of sodium triacetoxyborohydride, and 0.2 mL, 1.2 mmol of TEA were added to DCM (30 mL), and the title compound (0.79 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{10-[1-({4-[(E)-2-(5-fluoro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 61] The compound obtained in Example 34(1) (0.79 g, 1.3 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.7 mL, as 1.4 mmol of NaOH) was added at room temperature. Compound 61 (0.26 g, 33%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0172] Example 35 (1) Preparation of 2-{[4-(2-methoxy-2-oxoethyl)phenoxy]methyl}thiophene-3-carboxylate methyl 2-methyl-3-thiophencarboxylic acid (35.70 g, 250 mmol), potassium bicarbonate (50 g, 500 mmol), and methyl iodide (31 mL, 500 mmol) were stirred in DMF (200 mL) at room temperature for 20 hours. The reaction mixture was added to water (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting methyl 2-methyl-3-thiophenecarboxylate was dissolved in DCE (400 mL), NBS (46.27 g, 260 mmol) and AIBN (0.2 g) were added, and the mixture was heated under reflux for 3 hours. After cooling, the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. Methyl 2-(bromomethyl)-3-thiophenecarboxylate, obtained by distillation under reduced pressure, was dissolved in DMF (400 mL). Methyl 4-hydroxyphenylacetate (31.12 g, 233 mmol) and potassium carbonate (69.1 g, 500 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was added to water (800 mL) and extracted with ethyl acetate (150 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distillation under reduced pressure was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (43.41 g, 54%) as crystals. Maximum temperature: 75-76°C.

[0173] (2) Preparation of 2-{[4-(carboxymethyl)phenoxy]methyl}thiophene-3-carboxylic acid: To a methanol (1000 mL) solution of the compound obtained in Example 35 (1) (43.41 g, 135 mmol), a sodium hydroxide (16.4 g, 410 mmol) solution in water (200 mL) was added, and the mixture was heated under reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure, and water (1000 mL) and 6 mol / L hydrochloric acid (100 mL) were added to the resulting residue. The precipitated crystals were filtered and washed with water, then dried on phosphorus pentoxide under reduced pressure at 50°C for 24 hours to obtain the title compound (35.81 g, 91%). Mp. 200-202°C.

[0174] (3) Preparation of methyl 2-(10-oxo-4H-thieno[2,3-c][1]benzooxepin-8-yl)acetate. The compound obtained in Example 35(2) (44.4 g, 155 mmol), trifluoroacetic anhydride (TFAA, 55 mL, 390 mmol), and DCE (500 mL) were mixed and stirred at 60°C for 20 hours. Methanol (250 mL) was added, and the mixture was heated under reflux for a further 24 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) and then crystallized with petroleum ether to obtain the title compound (34.74 g, 78%). Mp. 61-62°C. MS (EI) m / z: 288[M]+.

[0175] (4) Preparation of 4-[8-(2-methoxy-2-oxoethyl)-4H-thieno[2,3-c][1]benzooxepin-10-ylidene]piperidine-1-carboxylic acid t-butyl Under an argon atmosphere, zinc powder (17.3 g, 262 mmol) was added to anhydrous THF (150 mL), and titanium tetrachloride (25 g, 131 mmol) was added dropwise over 1 hour under ice-salt cooling. After heating under reflux for 2 hours, it was allowed to cool, and the compound obtained in Example 35(3) (9.23 g, 32 mmol) and a solution of 1-Boc-4-piperidone (Boc:t-butoxycarbonyl, 6.38 g, 32 mmol) in anhydrous THF (80 mL) were added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to an ice-cooled aqueous solution of potassium carbonate (83 g, 600 mmol) (300 mL), followed by the addition of ethyl acetate (100 mL). The mixture was stirred under ice for 2 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (180 mL) and TEA (4.9 mL, 35 mmol) was added. After adding a solution of (Boc)2O (7.64 g, 35 mmol) in DCM (50 mL) under ice, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (13.94 g, 96%) as an oil. MS (EI) m / z: 455[M]+.

[0176] (5) Preparation of 2-[10-(4-piperidylidene)-4H-thieno[2,3-c][1]benzooxepin-8-yl]methyl acetate hydrochloride. The compound obtained in Example 35(4) (13.94 g, 30 mmol) was added dropwise to a 150 mL solution of DCM (4) with 75 mL of 4 mol / L hydrogen chloride-dioxane solution (300 mmol as HCl) over 30 minutes under ice cooling. The mixture was stirred at room temperature for 4 hours, after which the solvent was removed under reduced pressure. The resulting oily residue was crystallized from ether to obtain the title compound (8.47 g, 72%). Mp. 215℃ (dec.). MS (EI) m / z: 356[M+H]+.

[0177] Example 36 (1) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 35 (5) (0.24 g, 0.6 mmol), the compound obtained in Example 1 (1) (0.19 g, 0.6 mmol), sodium triacetoxyborohydride (0.19 g, 0.9 mmol), and TEA (0.1 mL, 0.6 mmol) were added, and the title compound (0.25 g, 65%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 47] The compound obtained in Example 36 (1) (0.25 g, 0.4 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 0.4 mmol of NaOH) was added at room temperature, and Compound 47 (0.2 g, 63%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0178] Example 37 (1) Preparation of 2-{10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (36) (0.44 g, 1.5 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.88 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(7-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 65] The compound obtained in Example 37(1) (0.88 g, 1.4 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.7 mL, 1.4 mmol as NaOH) was added at room temperature, and Compound 65 (0.7 g, 82%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0179] Example 38 (1) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (39) (0.45 g, 1.5 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.60 g, 72%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 66] The compound obtained in Example 38 (1) (0.60 g, 0.9 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.45 mL, as 0.9 mmol of NaOH) was added at room temperature, and Compound 66 (0.3 g, 53%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0180] Example 39 (1) Preparation of 2-{10-[1-({4-[2-(5,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (48-2) (0.44 g, 1.5 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.20 g, 24%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(5,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 87] The compound obtained in Example 39 (1) (0.20 g, 0.3 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.15 mL, 0.3 mmol as NaOH) was added at room temperature, and Compound 87 (0.15 g, 77%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0181] Example 40 (1) Preparation of 2-{10-[1-({4-[2-(7,8-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (47-2) (0.45 g, 1.5 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.70 g, 84%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(7,8-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 88] The compound obtained in Example 40 (1) (0.70 g, 1.1 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.15 mL, 0.3 mmol as NaOH) was added at room temperature, and Compound 88 (0.55 g, 81%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0182] Example 41 (1) Preparation of 2-{10-[1-({4-[2-(5,6,7-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (25 mL), the compound obtained in Example 35 (5) (0.28 g, 0.7 mmol), the compound obtained in Example 1 (45-2) (0.26 g, 0.8 mmol), sodium triacetoxyborohydride (0.23 g, 1.1 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.22 g, 47%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[2-(5,6,7-trifluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 89] The compound obtained in Example 41 (1) (0.22 g, 0.3 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.15 mL, 0.3 mmol as NaOH) was added at room temperature, and compound 89 (0.16 g, 75%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0183] Example 42 (1) Preparation of 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To 25 mL of DCM, the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), 5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thiophenecarboxaldehyde (0.43 g, 1.5 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.17 g, 21%) was obtained as an oil in the same manner as in the synthesis of Example 3 (1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 90] The compound obtained in Example 42 (1) (0.17 g, 0.3 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.15 mL, 0.3 mmol as NaOH) was added at room temperature, and Compound 90 (0.14 g, 75%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0184] Example 43 (1) Preparation of 2-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]-3-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To 25 mL of DCM, the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (42) (0.43 g, 1.4 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.36 g, 43%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]-3-fluorophenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 91] The compound obtained in Example 43 (1) (0.36 g, 0.6 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.30 mL, 0.6 mmol as NaOH) was added at room temperature, and Compound 91 (0.30 g, 85%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0185] Example 44 (1) Preparation of 2-{10-[1-({4-[(5,6,7,8-tetrafluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To 25 mL of DCM, the compound obtained in Example 35 (5) (0.23 g, 0.6 mmol), the compound obtained in Example 1 (44-2) (0.23 g, 0.7 mmol), sodium triacetoxyborohydride (0.19 g, 0.9 mmol), and TEA (0.1 mL, 0.6 mmol) were added, and the title compound (0.24 g, 60%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[(5,6,7,8-tetrafluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 92] The compound obtained in Example 44 (1) (0.24 g, 0.3 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.15 mL, 0.3 mmol as NaOH) was added at room temperature, and Compound 92 (0.03 g, 13%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0186] Example 45 (1) Preparation of 2-{10-[1-({5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To 25 mL of DCM, the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), 5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thiophenecarboxaldehyde (0.45 g, 1.5 mmol), sodium triacetoxyburohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.52 g, 63%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 94] The compound obtained in Example 45 (1) (0.52 g, 0.8 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.45 mL, as 0.9 mmol of NaOH) was added at room temperature, and Compound 94 (0.24 g, 48%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0187] Example 46 (1) Preparation of 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-3-methyl-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To 25 mL of DCM, the compound obtained in Example 35 (5) (0.50 g, 1.3 mmol), 5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-3-methyl-2-thiophenecarboxaldehyde (0.40 g, 1.4 mmol), sodium triacetoxyburohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.82 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(7-fluoro-2-quinolyl)vinyl]-3-methyl-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid (compound 95) The compound obtained in Example 46 (1) (0.82 g, 1.3 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.75 mL, 1.5 mmol as NaOH) was added at room temperature, and compound 95 (0.20 g, 25%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0188] Example 47 (1) Preparation of 2-{10-[1-({5-[(6,7-difluoro-2-quinolyl)methoxymethyl]-2-thienyl}methyl-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate} 0.14 g, 0.4 mmol, 5-[(6,7-difluoro-2-quinolyl)methoxymethyl]-2-thiophenecarboxaldehyde (0.13 g, 0.4 mmol), sodium triacetoxyburohydride (0.11 g, 0.5 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (25 mL), and the title compound (0.14 g, 60%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({5-[(6,7-difluoro-2-quinolyl)methoxymethyl]-2-thienyl}methyl-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 96] The compound obtained in Example 47 (1) (0.14 g, 0.2 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.15 mL, as 0.3 mmol of NaOH) was added at room temperature, and Compound 96 (0.09 g, 67%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0189] Example 48 (1) Preparation of 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 35 (5) (0.50 g, 1.4 mmol), 5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thiophenecarboxaldehyde (0.44 g, 1.5 mmol), sodium triacetoxyborohydride (0.44 g, 2.1 mmol), and TEA (0.3 mL, 1.8 mmol) were added, and the title compound (0.70 g, 79%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({5-[(E)-2-(7-chloro-2-quinolyl)vinyl]-2-thienyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 85] The compound obtained in Example 48 (1) (0.70 g, 1.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.6 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 85 (0.53 g, 77%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0190] Example 49 (1) Preparation of 2-{10-[1-({4-[(E)-2-(5-fluoro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 35 (5) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (7) (0.42 g, 1.5 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 1.8 mmol) were added, and the title compound (0.56 g, 64%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[(E)-2-(5-fluoro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 86] The compound obtained in Example 49 (1) (0.56 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and Compound 86 (0.53 g, 97%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0191] Example 50 (1) Preparation of methyl 3-{10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate To 30 mL of DCM, add 0.30 g, 1.1 mmol of methyl hydrochloride 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate, 0.44 g, 1.1 mmol of 3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]benzaldehyde, 0.34 g, 1.6 mmol of sodium triacetoxyborohydride, and 0.2 mL, 1.3 mmol of TEA, and proceed in the same manner as in the synthesis of Example 3 (1) to produce the title compound (0.20 (2) Preparation of 3-{10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 9] The compound obtained in Example 50 (1) (0.20 g, 0.3 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 0.4 mmol of NaOH) was added at room temperature, and Compound 9 (0.14 g, 70%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0192] Example 51 (1) Preparation of 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate methyl [compound 21] 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate methyl hydrochloride (0.28 g, 1.1 mmol), the compound obtained in Example 1 (28-5) (0.44 g, 1.1 mmol), sodium triacetoxyborohydride (0.34 g, 1.6 mmol), and TEA (0.2 mL, 1.3 mmol) were added to DCM (30 mL) and compound 21 (0.48 g, 72%) was obtained as a hygroscopic solid in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 10] The compound obtained in Example 51 (1) (0.48 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) was added at room temperature, and Compound 10 (0.43 g, 92%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0193] Example 52 (1) Preparation of methyl 3-{10-[1-({3-[(4-cyclobutylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate To 30 mL of DCM, add 0.48 g, 1.2 mmol of 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate methyl hydrochloride, 0.90 g, 2.8 mmol of 3-[(4-cyclobutylthiazole-2-yl)methoxy]benzaldehyde, 0.38 g, 1.8 mmol of sodium triacetoxyborohydride, and 0.2 mL, 1.3 mmol of TEA, and proceed in the same manner as in the synthesis of Example 3 (1) to produce the title compound (0.70 (2) Compound 13 was obtained as an oily substance (0.70 g, 1.1 mmol) obtained in Example 52 (1) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.6 mL, as NaOH) was added at room temperature, and compound 13 (0.30 g, 79%) was obtained as crystals in the same manner as in the synthesis of Example 3 (2).

[0194] Example 53 (1) Preparation of methyl 3-[10-[1-({3-[(7-chloro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate methyl hydrochloride (0.47 g, 1.2 mmol), the compound obtained in Example 1 (34-2) (0.35 g, 1.2 mmol), sodium triacetoxyborohydride (0.37 g, 1.8 mmol), and TEA (0.2 mL, 1.3 mmol) were added to DCM (30 mL), and the title compound (0.40 g, 52%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-[10-[1-({3-[(7-chloro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionic acid [Compound 15] The compound obtained in Example 53 (1) (0.40 g, 0.6 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.3 mL, as 0.6 mmol of NaOH) was added at room temperature, and Compound 15 (0.29 g, 75%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0195] Example 54 (1) Preparation of 3-{10-[1-({3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate methyl hydrochloride (0.50 g, 1.2 mmol), the compound obtained in Example 1(9) (0.32 g, 1.2 mmol), sodium triacetoxyborohydride (0.39 g, 1.9 mmol), and TEA (0.2 mL, 1.3 mmol) were added to DCM (30 mL) and the title compound (0.50 g, 67%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 3-{10-[1-({3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 16] The compound obtained in Example 54 (1) (0.50 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) was added at room temperature, and Compound 16 (0.33 g, 67%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0196] Example 55 (1) Preparation of 3-{10-[1-({3-[(E)-2-(4-cyclobutylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate methyl hydrochloride (0.50 g, 1.2 mmol), the compound obtained in Example 1 (10) (0.49 g, 1.9 mmol), sodium triacetoxyborohydride (0.39 g, 1.9 mmol), and TEA (0.2 mL, 1.3 mmol) were added to DCM (30 mL) and the title compound (0.40 g, 52%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(E)-2-(4-cyclobutylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 17] The compound obtained in Example 55(1) (0.40 g, 0.6 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.3 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 17 (0.20 g, 53%) was obtained as a 2.5-hydrate crystal in the same manner as the synthesis in Example 3(2).

[0197] Example 56 (1) Preparation of methyl 3-{10-[1-(2-{3-[(7-chloro-2-quinolyl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate To 30 mL of DCM, add 0.65 g, 1.6 mmol of methyl hydrochloride 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate, 1.00 g, 3.2 mmol of acetaldehyde, 0.51 g, 2.4 mmol of sodium triacetoxyburohydride, and 0.3 mL, 1.7 mmol of TEA, and proceed in the same manner as in Example 3(1) to produce the title compound (0.66 (2) Preparation of 3-{10-[1-(2-{3-[(7-chloro-2-quinolyl)methoxy]phenyl}ethyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 18] The compound obtained in Example 56 (1) (0.66 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and compound 18 (0.47 g, 73%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0198] Example 57 (1) Preparation of methyl 3-(10-{1-[(3-{[4-(4-chlorophenyl)thiazole-2-yl]methoxy}phenyl)methyl]-4-piperidylidene}-4H-thieno[3,2-c][1]benzooxepin-8-yl)propionate 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate methyl hydrochloride (0.50 g, 1.2 mmol), the compound obtained in Example 1 (31-4) (0.41 g, 1.2 mmol), sodium triacetoxyborohydride (0.39 g, 1.9 mmol), and TEA (0.3 mL, 1.7 mmol) were added to DCM (30 mL) and the title compound (0.59 g, 71%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-(10-{1-[(3-{[4-(4-chlorophenyl)thiazole-2-yl]methoxy}phenyl)methyl]-4-piperidylidene}-4H-thieno[3,2-c][1]benzooxepin-8-yl)propionic acid [Compound 19] The compound obtained in Example 57 (1) (0.59 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and Compound 19 (0.41 g, 70%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0199] Example 58 (1) Preparation of 3-{10-[1-({3-[(4-phenylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate methyl hydrochloride (0.50 g, 1.2 mmol), the compound obtained in Example 1 (32-4) (0.38 g, 1.3 mmol), sodium triacetoxyborohydride (0.39 g, 1.9 mmol), and TEA (0.3 mL, 1.7 mmol) were added to DCM (30 mL) and the title compound (0.50 g, 63%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(4-phenylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 20] The compound obtained in Example 58 (1) (0.50 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) was added at room temperature, and Compound 20 (0.36 g, 73%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0200] Example 59 (1) Preparation of methyl 3-{10-[1-({3-[(E)-2-(5,6,7,8-tetrahydroquinoline-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionate 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate methyl hydrochloride (0.40 g, 1.0 mmol), compound obtained in Example 1 (11) (0.28 g, 1.0 mmol), sodium triacetoxyborohydride (0.31 g, 1.5 mmol), and TEA (0.3 mL, 1.7 mmol) were added to DCM (30 mL), and the title compound (0.40 (2) Preparation of 3-{10-[1-({3-[(E)-2-(5,6,7,8-tetrahydroquinoline-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 24] The compound obtained in Example 59 (1) (0.40 g, 0.7 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) was added at room temperature, and Compound 24 (0.21 g, 54%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0201] Example 60 (1) Preparation of 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl]propionate methyl hydrochloride (0.50 g, 1.2 mmol), the compound obtained in Example 1 (1) (0.42 g, 1.4 mmol), sodium triacetoxyborohydride (0.42 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (50 mL), and the title compound (0.77 g, 96%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}propionic acid [Compound 80] The compound obtained in Example 60 (1) (0.77 g, 1.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature, and Compound 80 (0.5 g, 64%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0202] Example 61 (1) Preparation of t-butyl 4-(4H-thieno[3,2-c][1]benzooxepin-10-ylidene)piperidine-1-carboxylic acid Under an argon atmosphere, zinc powder (9.4 g, 144 mmol) was added to anhydrous THF (100 mL), and titanium(IV) chloride (8.1 mL, 272 mmol) was added dropwise at 0°C. After heating under reflux for 2 hours, a THF solution (40 mL) of 4H-thieno[3,2-c][1]benzooxepin-10-one (3.9 g, 18.0 mmol) and 1-(t-butoxycarbonyl)-4-piperidone (3.6 g, 18.0 mmol) was added dropwise at room temperature. After heating under reflux for 2 hours, saturated potassium carbonate aqueous solution (100 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain an oily substance, which was dissolved in DCM (120 mL). TEA (6.5 mL, 47 mmol) was added, and then a solution of (Boc)2O (6.6 g, 30 mmol) in DCM (70 mL) was added dropwise at room temperature. After stirring for 48 hours, the reaction mixture was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (4.4 g, 71%) as an oily substance.

[0203] (2) The compound obtained in Production Example 61(1) of t-butyl (2.0 g, 5.2 mmol), palladium acetate (0.17 g, 0.5 mmol), copper acetate (0.19 g, 0.5 mmol), and ethyl acrylate (0.6 mL, 5.2 mmol) were mixed in acetonitrile (100 mL) and stirred at 80°C for 2 days under an oxygen atmosphere. The reaction mixture was added to saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated ammonium chloride aqueous solution, water, and saturated brine, and then dried over anhydrous sodium sulfate. The oily residue obtained by distillation under reduced solvent pressure was purified by silica gel column chromatography (PSQ-100B, n-hexane:ethyl acetate = 5:1) to obtain the title compound (0.35 g, 18%) as an oil. ¹H-NMR (DMSO-d6) δ: 1.43 (s, 9H), 2.51-4.20 (m, 14H), 4.83-5.45 (m, 2H), 6.16-7.70 (m, 7H). MS (EI) m / z: 482[M+H]+.

[0204] (3) The compound obtained in Production Example 61(2) of 4-[2-(3-ethoxy-3-oxopropyl)-4H-thieno[3,2-c][1]benzooxepin-10-ylidene]piperidine-1-carboxylic acid t-butyl (0.35 g, 0.7 mmol) was dissolved in acetic acid (50 mL), Pd(OH)2-C (70 mg) was added, and the mixture was stirred at 60°C under a hydrogen atmosphere for 24 hours. After filtering off the catalyst, the solvent was removed by distillation under reduced pressure to obtain the title compound (0.32 g, 91%) as an oil. 1H-NMR (DMSO-d6) δ: 1.41 (s, 9H), 2.00-4.07 (m, 18H), 4.72-5.36 (m, 2H), 6.54-7.28 (m, 5H). MS (EI) m / z: 484[M+H]+.

[0205] (4) Preparation of 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-2-yl]propionate ethyl hydrochloride. The compound obtained in Example 61 (3) (0.32 g, 0.7 mmol) was dissolved in ethyl acetate (10 mL), and a 4 mol / L hydrogen chloride / ethyl acetate solution (1.2 mL, 4.8 mmol as HCl) was added at room temperature. After stirring for 24 hours, the solvent was removed under reduced pressure to obtain the title compound (0.28 g, quant.) as an oily substance. ¹H-NMR (DMSO-d6) δ: 2.61-4.16 (m, 18H), 4.74-5.38 (m, 2H), 6.57-7.30 (m, 5H). MS (EI) m / z: 389[M+H]+.

[0206] Example 62 (1) Preparation of 3-{10-[1-({3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionate ethyl The compound obtained in Example 61 (4) (0.56 g, 1.3 mmol), 3-[(4-cyclobutylthiazole-2-yl)methoxy]benzaldehyde (0.34 g, 1.3 mmol), sodium triacetoxyburohydride (0.42 g, 1.9 mmol), and TEA (0.2 mL, 1.3 mmol) were added to DCM (30 mL), and the title compound (0.63 g, 76%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(E)-2-(4-isopropylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 14] The compound obtained in Example 62 (1) (0.63 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and Compound 14 (0.36 g, 60%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0207] Example 63 (1) Preparation of 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionate ethyl Compound obtained in Example 61 (4) (0.42 g, 1.0 mmol), Compound obtained in Example 1 (28-5) (0.56 g, 2.1 mmol), Sodium triacetoxyborohydride (0.31 g, 1.5 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (30 mL), and the title compound (0.63 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 8] The compound obtained in Example 63 (1) (0.63 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as NaOH) was added at room temperature. Compound 8 (0.29 g, 48%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0208] Example 64 (1) Preparation of 3-{10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionate ethyl Compound obtained in Example 61 (4) (0.30 g, 0.7 mmol), 3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]benzaldehyde (0.18 g, 0.7 mmol), sodium triacetoxyburohydride (0.21 g, 1.0 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (30 mL), and the title compound (0.29 g, 68%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 7] The compound obtained in Example 64 (1) (0.29 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and Compound 7 (0.22 g, 70%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0209] Example 65 (1) Preparation of 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionate ethyl compound To DCM (50 mL), the compound obtained in Example 61 (4) (0.50 g, 1.2 mmol), the compound obtained in Example 1 (1) (0.37 g, 1.3 mmol), sodium triacetoxyborohydride (0.38 g, 1.8 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.30 g, 38%) was obtained as an oil in the same manner as the synthesis in Example 8. (2) Preparation of 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 53] The compound obtained in Example 65 (1) (0.30 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 53 (0.3 g, 91%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0210] Example 66 (1) Preparation of 3-{10-[1-({3-[(4-cyclobutylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionate ethyl compound The compound obtained in Example 61 (4) (0.50 g, 1.2 mmol), 3-[(4-cyclobutylthiazole-2-yl)methoxy]benzaldehyde (0.72 g, 2.6 mmol), sodium triacetoxyburohydride (0.38 g, 1.8 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (30 mL), and the title compound (0.40 g, 52%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(4-cyclobutylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 12] The compound obtained in Example 66(1) (0.40 g, 0.6 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.3 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 12 (0.17 g, 44%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0211] Example 67 (1) Preparation of 3-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionate ethyl compound The compound obtained in Example 61 (4) (0.50 g, 1.2 mmol), the compound obtained in Example 1 (39) (0.38 g, 1.3 mmol), sodium triacetoxyborohydride (0.38 g, 1.8 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (50 mL), and the title compound (0.30 g, 38%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-2-yl}propionic acid [Compound 57] The compound obtained in Example 67 (1) (0.30 g, 0.5 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.3 mL, as 0.6 mmol of NaOH) was added at room temperature, and compound 57 (0.11 g, 38%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0212] Example 67a (1) Preparation of 2-{11-[1-({3-[(E)-2-(5-chloro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}ethyl acetate To DCM (30 mL), the compound obtained in Example 102 (0.48 g, 1.3 mmol), the compound obtained in Example 1(12) (0.40 g, 1.3 mmol), sodium triacetoxyborohydride (0.42 g, 2.0 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.68 g, 78%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(5-chloro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 1] The compound obtained in Example 67a (1) (0.68 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as NaOH) was added at room temperature, and Compound 1 (0.60 g, 93%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0213] Example 68 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]methyl}-4-piperidylidene)-6H-benzo[c][1]benzooxepin-2-yl}ethyl acetate To DCM (30 mL), the compound obtained in Example 102 (0.49 g, 1.3 mmol), 3-[(E)-2-(7-chloro-2-quinolyl)vinyl]benzaldehyde (0.39 mg, 1.3 mmol), sodium triacetoxyburohydride (0.42 g, 2.0 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.42 g, 49%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl]methyl}-4-piperidylidene)-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 2] The compound obtained in Example 68 (1) (0.42 g, 0.7 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature. Compound 2 (0.37 g, 92%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0214] Example 69 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}ethyl acetate To DCM (30 mL), the compound obtained in Example 102 (0.49 g, 1.3 mmol), 3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]benzaldehyde (0.37 g, 1.3 mmol), sodium triacetoxyburohydride (0.42 g, 2.0 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.52 g, 62%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 3] The compound obtained in Example 69 (1) (0.52 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature. Compound 3 (0.43 g, 87%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0215] Example 70 (1) Preparation of 2-{11-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}ethyl acetate Add the compound obtained in Example 102 (0.50 g, 1.3 mmol), the compound obtained in Example 1 (39) (0.41 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) to DCM (30 mL), and proceed in the same manner as the synthesis in Example 3 (1) to obtain the title compound (0.58 g, 71%) as an oil. (2) Preparation of 2-{11-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 74] The compound obtained in Example 70 (1) (0.58 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature. Compound 74 (0.43 g, 76%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0216] Example 71 (1) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}ethyl acetate To DCM (30 mL), the compound obtained in Example 102 (0.50 g, 1.3 mmol), the compound obtained in Example 1(1) (0.41 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.43 g, 53%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl [Compound 75] The compound obtained in Example 71(1) (0.43 g, 0.7 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) at room temperature was added, and compound 75 (0.33 g, 79%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0217] Example 72 (1) Preparation of 2-{11-[1-(2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}ethyl acetate To DCM (30 mL), the compound obtained in Example 102 (0.50 g, 1.3 mmol), the compound obtained in Example 1 (24-4) (0.42 g, 1.4 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.4 mL, 1.8 mmol) were added, and the title compound (0.66 g, 80%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-(2-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 11] The compound obtained in Example 72 (1) (0.66 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and compound 11 (0.36 g, 95%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0218] Example 73 (1) Preparation of 2-{11-[1-({4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To 50 mL of DCM and 5 mL of TEA, add (0.67 g, 1.7 mmol) of 4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]benzaldehyde (0.82 g, 2.6 mmol) and sodium triacetoxyborohydride (0.55 g, 2.6 mmol) obtained in Example 101 (2), and stir at room temperature for 48 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue and extracted with DCM (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.68 g, 61%) as an oil. (2) Preparation of 2-{11-[1-({4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 112] The compound obtained in Example 73 (1) (0.68 g, 1.06 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.53 mL, as NaOH) was added at room temperature, and compound 112 (0.63 g, 94%) was obtained as crystals in the same manner as in the synthesis of Example 3 (2).

[0219] Example 74 (1) Preparation of 2-{11-[1-({3-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate DCM (50 mL) and TEA (3 mL) were combined with 3-[(7-chloro-6-fluoro-2-quinolyl)methoxy]benzaldehyde (0.50 g, 1.6 mmol) and sodium triacetoxyborohydride (0.34 g, 1.6 mmol) obtained in Example 101 (2), and the title compound (0.33 g, 46%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 114] The compound obtained in Example 74 (1) (0.33 g, 0.51 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.26 mL, as 0.52 mmol of NaOH) was added at room temperature. Compound 114 (0.20 g, 63%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0220] Example 75 (1) Preparation of 2-{11-[1-({2-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate 50 mL of DCM and 3 mL of TEA were mixed with 0.41 g, 1.1 mmol of the compound obtained in Example 101 (2), 2-[(7-chloro-6-fluoro-2-quinolyl)methoxy]benzaldehyde (0.50 g, 1.6 mmol), and sodium triacetoxyborohydride (0.34 g, 1.6 mmol) and stirred at room temperature for 24 hours. The title compound (0.20 g, 29%) was obtained as an oil in the same manner as in the synthesis of Example 3 (1). (2) Preparation of 2-{11-[1-({2-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 115] The compound obtained in Example 75 (1) (0.20 g, 0.32 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.16 mL, as 0.32 mmol of NaOH) was added at room temperature. Compound 115 (0.14 g, 72%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0221] Example 76 (1) Preparation of 4-[9-(2-methoxy-2-oxo-ethyl)-6H-benzo[c][1]benzooxepin-11-ylidene]piperidine-1-carboxylic acid t-butyl Under an argon atmosphere, zinc powder (17.1 g, 262 mmol) was added to anhydrous THF (150 mL), and titanium tetrachloride (25 g, 131 mmol) was added dropwise over 30 minutes under ice-salt cooling. After heating under reflux for 2 hours, it was allowed to cool, and a solution of 2-(11-oxo-6H-benzo[c][1]benzooxepin-9-yl)acetate (11.3 g, 40.0 mmol) and 1-Boc-4-piperidone (8.0 g, 40.0 mmol) in anhydrous THF (100 mL) was added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to an ice-cooled aqueous solution of potassium carbonate (83 g, 600 mmol) (300 mL), followed by the addition of ethyl acetate (100 mL). The mixture was stirred under ice for 3 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (200 mL) and TEA (7.0 mL, 50 mmol) was added. After adding a solution of (Boc)2O (10.9 g, 50 mmol) in DCM (50 mL) under ice, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:methyl acetate = 9:1) to obtain the title compound (15.16 g, 87%) as an oil. (2) Preparation of 2-[11-(4-piperidylidene)-6H-benzo[c][1]benzooxepin-9-yl]methyl acetate hydrochloride. The compound obtained in Example 76 (1) (15.16 g, 34.9 mmol) was added dropwise to a solution of DCM (300 mL) with a 4 mol / L hydrogen chloride / dioxane solution (88 mL, 352 mmol as HCl) over 30 minutes under ice cooling. After stirring at room temperature for 20 hours, the solvent was removed under reduced pressure and the mixture was solidified with ether to obtain the title compound (10.2 g, 76%) as a hygroscopic solid.

[0222] Example 77 (1) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-yl}methyl acetate To DCM (50 mL) and TEA (3 mL), the compound obtained in Example 76 (2) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (1) (0.38 g, 1.3 mmol), and sodium triacetoxyborohydride (0.41 g, 1.9 mmol) were added and stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.25 g, 31%) as an oil. (2) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperizylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [Compound 138] The compound obtained in Example 77 (1) (0.25 g, 0.40 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.20 mL, as NaOH) was added at room temperature, and Compound 138 (0.23 g, 93%) was obtained as crystals in the same manner as in the synthesis of Example 3 (2).

[0223] Example 78 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-yl}methyl acetate 50 mL of DCM and 3 mL of TEA were mixed with the compound obtained in Example 76 (2) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (18) (0.38 g, 1.3 mmol), and sodium triacetoxyborohydride (0.41 g, 1.9 mmol). The title compound (0.45 g, 55%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [Compound 139] The compound obtained in Example 78 (1) (0.45 g, 0.71 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.36 mL, 0.72 mmol as NaOH) was added at room temperature. Compound 139 (0.38 g, 87%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0224] Example 79 (1) Preparation of 6-[8-(2-methoxy-2-oxoethyl)-4H-thieno[2,3-c][1]benzooxepin-10-ylidene]-2-azaspiro[3.3]heptane-2-carboxylic acid t-butyl Under an argon atmosphere, zinc powder (7.6 g, 116 mmol) was added to anhydrous THF (50 mL), and titanium tetrachloride (11 g, 58 mmol) was added dropwise over 1 hour under ice-salt cooling. After heating under reflux for 2 hours, the mixture was allowed to cool, and a solution of methyl 2-(10-oxo-4H-thieno[2,3-c][1]benzooxepin-8-yl)acetate (4.10 g, 14 mmol) and t-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid (3.00 g, 14 mmol) in anhydrous THF (20 mL) was added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to an ice-cooled aqueous solution of potassium carbonate (37 g, 266 mmol) (130 mL), and then ethyl acetate (40 mL) was added. The mixture was stirred under ice for 2 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (80 mL) and TEA (2.2 mL, 15 mmol) was added. After adding a solution of (Boc)2O (3.38 g, 15 mmol) in DCM (20 mL) under ice cooling, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (3.60 g, 54%) as an oil. (2) Preparation of 2-[10-(2-azaspiro[3,3]heptan-6-ylidene)-4H-thieno[2,3-c][1]benzooxepin-8-yl]methyl acetate hydrochloride. The compound obtained in Example 79 (1) (3.60 g, 7.67 mmol) was added dropwise to a 50 mL solution of DCM (20 mL, 80 mmol as HCl) over 30 minutes under ice cooling. After stirring at room temperature for 4 hours, the solvent was removed by distillation under reduced pressure.The resulting oily residue was solidified from ether to obtain the title compound (2.45 g, 79%) as a hygroscopic solid.

[0225] Example 80 (1) Preparation of 2-{10-[2-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-2-azaspiro[3.3]heptan-6-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (25 mL), the compound obtained in Example 79 (2) (0.48 g, 1.2 mmol), the compound obtained in Example 1 (39) (0.39 g, 1.3 mmol), sodium triacetoxyborohydride (0.38 g, 1.8 mmol), and TEA (0.2 mL, 1.2 mmol) were added, and the title compound (0.18 g, 23%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[2-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)-2-azaspiro[3.3]heptan-6-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 97] The compound obtained in Example 80 (1) (0.18 g, 0.3 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.15 mL, as 0.3 mmol of NaOH) was added at room temperature, and Compound 97 (0.09 g, 51%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0226] Example 81 (1) Preparation of 3-[8-(2-methoxy-2-oxoethyl)-4H-thieno[2,3-c][1]benzooxepin-10-ylidene]azetidine-1-carboxylic acid t-butyl Under an argon atmosphere, zinc powder (5.6 g, 85 mmol) was added to anhydrous THF (50 mL), and titanium tetrachloride (8.1 g, 43 mmol) was added dropwise over 1 hour under ice-salt cooling. After heating under reflux for 2 hours, it was allowed to cool, and a solution of 2-(10-oxo-4H-thieno[2,3-c][1]benzooxepin-8-yl)methyl acetate (3.00 g, 10 mmol) and 1-Boc-3-azetidinone (1.80 g, 10 mmol) in anhydrous THF (20 mL) was added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to an ice-cooled aqueous solution of potassium carbonate (27 g, 195 mmol) (90 mL), followed by the addition of ethyl acetate (40 mL). The mixture was stirred under ice for 2 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (50 mL) and TEA (1.6 mL, 11 mmol) was added. After adding a solution of (Boc)2O (2.48 g, 11 mmol) in DCM (20 mL) under ice, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (1.10 g, 25%) as an oil. (2) Preparation of 2-[10-(azetidine-3-ylidene)-4H-thieno[2,3-c][1]benzooxepin-8-yl]methyl acetate hydrochloride. The compound obtained in Example 81 (1) (1.10 g, 2.60 mmol) was added dropwise to a 20 mL solution of DCM (2) with a 4 mol / L hydrogen chloride-dioxane solution (7.0 mL, 28 mmol as HCl) over 30 minutes under ice cooling. After stirring at room temperature for 4 hours, the solvent was removed under reduced pressure. The resulting oily residue was solidified from ether to obtain the title compound (0.73 g, 86%) as a hygroscopic solid.

[0227] Example 82 (1) Preparation of 2-{10-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To 25 mL of DCM, add the compound obtained in Example 81 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (17) (0.45 g, 1.4 mmol), sodium triacetoxyborohydride (0.44 g, 2.1 mmol), and TEA (0.3 mL, 1.8 mmol), and the title compound (0.65 g, 74%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 124] The compound obtained in Example 82 (1) (0.65 g, 1.0 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.50 mL, as 1.0 mmol of NaOH) was added at room temperature. Compound 124 (0.55 g, 87%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0228] Example 83 (1) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To DCM (25 mL), the compound obtained in Example 81 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (1) (0.41 g, 1.4 mmol), sodium triacetoxyborohydride (0.44 g, 2.1 mmol), and TEA (0.3 mL, 1.8 mmol) were added, and the title compound (0.50 g, 60%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 126] The compound obtained in Example 83 (1) (0.50 g, 0.82 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.41 mL, 0.82 mmol as NaOH) was added at room temperature. Compound 126 (0.44 g, 90%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0229] Example 84 (1) Preparation of 2-{10-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}methyl acetate To 25 mL of DCM, add the compound obtained in Example 81 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (2) (0.43 g, 1.4 mmol), sodium triacetoxyborohydride (0.44 g, 2.1 mmol), and TEA (0.3 mL, 1.8 mmol), and the title compound (0.39 g, 46%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 132] The compound obtained in Example 84 (1) (0.39 g, 0.63 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.32 mL, 0.64 mmol as NaOH) was added at room temperature. Compound 132 (0.29 g, 76%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0230] Example 85 (1) Preparation of 2-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetate methyl The compound obtained in Example 81 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (39) (0.45 g, 1.5 mmol), sodium triacetoxyborohydride (0.44 g, 2.1 mmol), and TEA (0.3 mL, 1.8 mmol) were added to DCM (25 mL), and the title compound (0.22 g, 26%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({4-[(6,7-difluoro-2-quinolyl)methoxy]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[2,3-c][1]benzooxepin-8-yl}acetic acid [Compound 98] The compound obtained in Example 85 (1) (0.22 g, 0.4 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.30 mL, as 0.6 mmol of NaOH) was added at room temperature. Compound 98 (0.20 g, 94%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0231] Example 86 (1) Preparation of 3-[8-(2-methoxy-2-oxo-ethyl)-4H-thieno[3,2-c][1]benzooxepin-10-ylidene]azetidine-1-carboxylic acid t-butyl Under an argon atmosphere, zinc powder (34.6 g, 524 mmol) was added to anhydrous THF (300 mL), and titanium tetrachloride (50 g, 262 mmol) was added dropwise over 1 hour under ice-salt cooling. After heating under reflux for 2 hours, it was allowed to cool, and a solution of 2-(10-oxo-4H-thieno[3,2-c][1]benzooxepin-8-yl)methyl acetate (17.87 g, 62.0 mmol) and 1-Boc-3-azetidinone (10.6 g, 62.0 mmol) in anhydrous THF (150 mL) was added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to an ice-cooled aqueous solution of potassium carbonate (166 g, 1200 mmol) (600 mL), followed by the addition of ethyl acetate (200 mL). The mixture was stirred under ice for 3 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (250 mL) and TEA (11.0 mL, 77 mmol) was added. After adding a solution of (Boc)2O (15.3 g, 70 mmol) in DCM (50 mL) under ice, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:methyl acetate = 19:1) to obtain the title compound (17.91 g, 68%) as an oil. (2) Preparation of 2-[10-(azetidine-3-ylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl acetate hydrochloride. The compound obtained in Example 86 (1) (17.91 g, 42.0 mmol) was added dropwise to a solution of DCM (200 mL) with a 4 mol / L hydrogen chloride / dioxane solution (100 mL, 400 mmol as HCl) over 30 minutes under ice cooling. After stirring at room temperature for 20 hours, the solvent was removed under reduced pressure and the mixture was solidified with ether to obtain the title compound (11.64 g, 76%) as a hygroscopic solid.

[0232] Example 87 (1) Preparation of 2-{10-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (40 mL) and TEA (1 mL), the compound obtained in Example 86 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (17) (0.45 g, 1.4 mmol), and sodium triacetoxyborohydride (0.44 g, 2.1 mmol) were added and stirred at room temperature for 48 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue and extracted with DCM (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.45 g, 51%) as an oil. (2) Preparation of 2-{10-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 123] The compound obtained in Example 87(1) (0.45 g, 0.70 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.35 mL, 0.70 mmol as NaOH) was added at room temperature, and Compound 123 (0.34 g, 78%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0233] Example 88 (1) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl acetate To DCM (40 mL) and TEA (1 mL), the compound obtained in Example 86 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (1) (0.41 g, 1.4 mmol), and sodium triacetoxyborohydride (0.44 g, 2.1 mmol) were added and stirred at room temperature for 72 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue and extracted with DCM (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.46 g, 55%) as an oil. (2) Preparation of 2-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}acetic acid [Compound 125] The compound obtained in Example 88 (1) (0.46 g, 0.75 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.38 mL, 0.76 mmol as NaOH) was added at room temperature. Compound 125 (0.40 g, 89%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0234] Example 89 (1) Preparation of 4-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl butyrate 4-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl butyrate hydrochloride (0.60 g, 1.4 mmol), the compound obtained in Example 1 (28-5) (0.37 g, 1.4 mmol), sodium triacetoxyborohydride (0.45 g, 2.2 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (30 mL) and the title compound (0.50 g, 56%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 4-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyric acid [Compound 4] The compound obtained in Example 89(1) (0.50 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and Compound 4 (0.30 g, 61%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0235] Example 90 (1) Preparation of 4-{10-[1-({3-[(E)-2-(5-chloro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl butyrate 0.43 g, 1.4 mmol, compound obtained in Example 1 (12) (0.6 g, 1.4 mmol), sodium triacetoxyborohydride (0.46 g, 2.2 mmol), and TEA (0.3 mL, 1.8 mmol) were added to DCM (30 mL) and the title compound (0.57 g, 60%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 4-{10-[1-({3-[(E)-2-(5-chloro-1,3-benzothiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyric acid [Compound 5] The compound obtained in Example 90 (1) (0.57 g, 0.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and Compound 5 (0.47 g, 84%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0236] Example 91 (1) Preparation of 4-{10-[1-({3-[(4-cyclopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl butyrate 4-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl butyrate hydrochloride (0.24 g, 0.6 mmol), the compound obtained in Example 1 (29-5) (0.15 g, 0.6 mmol), sodium triacetoxyborohydride (0.18 g, 0.9 mmol), and TEA (0.1 mL, 0.6 mmol) were added to DCM (10 mL), and the title compound (0.16 g, 44%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 4-{10-[1-({3-[(4-cyclopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyric acid [Compound 6] The compound obtained in Example 91 (1) (0.16 g, 0.3 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature, and Compound 6 (0.15 g, 96%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0237] Example 92 (1) Preparation of 4-{10-[1-({3-[(E)-2-(4-cyclobutylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl butyrate. 4-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl butyrate hydrochloride (0.50 g, 1.2 mmol), the compound obtained in Example 1 (10) (0.32 g, 1.2 mmol), sodium triacetoxyborohydride (0.38 g, 1.8 mmol), and TEA (0.3 mL, 1.7 mmol) were mixed in DCM (30 mL) to obtain the title compound (0.77 g, quant.) as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 4-{10-[1-({3-[(E)-2-(4-cyclobutylthiazole-2-yl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyric acid [Compound 32] The compound obtained in Example 92 (1) (0.77 g, 1.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.6 mL, as NaOH) was added at room temperature. Compound 32 (0.32 g, 45%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0238] Example 93 (1) Preparation of 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}methyl butyrate 4-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]methyl butyrate hydrochloride (0.50 g, 1.2 mmol), the compound obtained in Example 1(1) (0.42 g, 1.4 mmol), sodium triacetoxyborohydride (0.42 g, 1.9 mmol), and TEA (0.2 mL, 1.2 mmol) were added to DCM (50 mL), and the title compound (0.77 g, 96%) was obtained as an oil in the same manner as the synthesis in Example 3(1). (2) Preparation of 3-{10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-yl}butyric acid [Compound 81] The compound obtained in Example 93 (1) (0.77 g, 1.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature, and Compound 81 (0.5 g, 64%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0239] Example 94 (1) Preparation of 10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-carboxylate methyl 4-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-8-yl]formate methyl hydrochloride (0.50 g, 1.4 mmol), 2 (0.44 g, 1.5 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 1.8 mmol) were added to DCM (50 mL), and the title compound (0.48 g, 54%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 10-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-8-carboxylic acid [Compound 46] The compound obtained in Example 94 (1) (0.48 g, 0.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.2 mL, as 1.2 mmol of NaOH) was added at room temperature, and Compound 46 (0.4 g, 90%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0240] Example 95 (1) Preparation of methyl 2-(3-hydroxyphenyl)acetate A solution of 2-(3-hydroxyphenyl)acetic acid (25.0 g, 164 mmol) in methanol (400 mL) was mixed with concentrated sulfuric acid (3.0 mL) and heated under reflux for 24 hours. After removing the solvent under reduced pressure, ethyl acetate and water were added to the residue, and saturated sodium bicarbonate aqueous solution was added to adjust the pH of the aqueous layer to approximately 8. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (27.46 g, quant.) as an oily substance.

[0241] (2) Preparation of 3-{[3-(2-methoxy-2-oxo-ethyl)phenoxy]methyl}thiophene-2-carboxylate methyl 3-(bromomethyl)thiophene-2-carboxylate methyl 3-methyl-2-thiophenecarboxylate (28.11 g, 180 mmol), NBS (35.6 g, 200 mmol), and AIBN (0.2 g) according to the previously prepared method. A mixture of 3-(bromomethyl)thiophene-2-carboxylate methyl 3-(bromomethyl)thiophene-2-carboxylate and the compound obtained in Example 95 (1) (27.25 g, 164 mmol), potassium carbonate (45.61 g, 330 mmol), and DMF (250 mL) was stirred at room temperature for 24 hours. The reaction mixture was added to water (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the compound was purified by silica gel column chromatography (n-hexane:ethyl acetate = 4:1) to obtain the title compound (34.71 g, 66%) as an oil.

[0242] (3) Preparation of 3-{[3-(carboxymethyl)phenoxy]methyl}thiophene-2-carboxylic acid: To a methanol solution (1000 mL) of the compound obtained in Example 95 (2) (34.71 g, 108 mmol), 2 mol / L aqueous sodium hydroxide solution (125 mL, 250 mmol as NaOH) was added, and the mixture was heated under reflux for 24 hours. After cooling, the solvent was removed under reduced pressure, and the resulting residue was dissolved in water (500 mL), and 2 mol / L hydrochloric acid (300 mL) was added. The precipitated crystals were filtered, washed with water, and dried on phosphorus pentoxide under reduced pressure at 50°C to obtain the title compound (28.84 g, 91%) as crystals. Mp. 179-180°C.

[0243] (4) Preparation of methyl 2-(10-oxo-4H-thieno[3,2-c][1]benzooxepin-7-yl)acetate The compound obtained in Example 95 (3) (28.65 g, 98 mmol) and TFAA (31 mL, 220 mmol) were stirred in DCE (300 mL) at 60°C for 24 hours. After the reaction solution was allowed to cool, methanol (100 mL) was added and the mixture was heated under reflux for a further 24 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate (300 mL) and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The oily residue was crystallized from a 4:1 mixed solvent of n-hexane and ethyl acetate, and the crude product obtained was purified by silica gel column chromatography (toluene:ethyl acetate = 49:1) to obtain the title compound (16.00 g, 57%) as crystals. Mp. 106-108℃.MS (EI) m / z: 288 [M]+.

[0244] (5) Preparation of 2-[10-hydroxy-10-(1-methyl-4-piperidyl)-4H-thieno[3,2-c][1]benzooxepin-7-yl]methyl acetate Grignard reagent obtained by heating magnesium (2.67 g, 110 mmol), 4-chloro-1-methylpiperidine (14.5 mL, 110 mmol), and 1,2-dibromoethane (0.2 mL) in THF (160 mL) to 110°C on an oil bath was cooled in an ice-salt bath, and a solution of the compound obtained in Example 95 (4) (16.0 g, 55 mmol) in THF (150 mL) was added dropwise over 1 hour. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride (300 mL) was added and stirred at room temperature for 1 hour. Extraction with ethyl acetate, washing with water and saturated saline solution, and then drying over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to obtain the title compound (10.34 g, 49%) as an oily substance. MS (EI) m / z: 388 [M+H]+.

[0245] (6) To a solution of the compound obtained in Production Example 95 (5) (10.3 g, 26 mmol) of 2-[10-(1-methyl-4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-7-yl]methyl acetate (200 mL), TFA (43 mL, 560 mmol) was added dropwise over 30 minutes under ice cooling, and the mixture was gradually returned to room temperature and stirred for 20 hours. The reaction mixture was cooled on ice, and an aqueous solution of potassium carbonate (83 g, 600 mmol) (400 mL) was added dropwise over 1 hour. After separating the organic layer, the aqueous layer was extracted with DCM (100 mL x 2). The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain the title compound (6.6 g, 69%) as an oil. MS (EI) m / z: 369 [M]+.

[0246] (7) To a solution of the compound obtained in Production Example 95(6) of 4-[7-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-c][1]benzooxepin-10-ylidene]piperidine-1-carboxylic acid 2,2,2-trichloroethyl (6.60 g, 17.8 mmol) in toluene (50 mL), potassium carbonate (0.3 g, 2 mmol) was added, and Troc-Cl (3 mL, 22 mmol) was added dropwise over 15 minutes at room temperature. After heating under reflux for 24 hours, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with saturated ammonium chloride aqueous solution (100 mL), water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (8.19 g, 87%) as an oil. MS (EI) m / z: 529 [M]+.

[0247] (8) Preparation of methyl 2-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-7-yl]acetate The compound obtained in Example 95(7) (8.19 g, 15 mmol) was stirred with zinc powder (6.86 g, 105 mmol) in acetic acid (100 mL) at room temperature for 72 hours. Insoluble matter was filtered off, the mixture was washed with methanol, and the solvent was removed under reduced pressure. Water (100 mL) was added to the residue, and potassium carbonate (10 g) was gradually added. Ethyl acetate (100 mL) was added and stirred for 1 hour, after which insoluble matter was filtered off with Celite. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (NH-DM1020, chloroform), and the title compound (4.00 g, 75%) was crystallized from petroleum ether. Mp. 149-151℃.

[0248] Example 96 (1) Preparation of (E)-3-(3-benzyloxyphenyl)-2-acrylate ethyl To a mixture of sodium hydride (60%, liquid paraffin, 4.8 g, 120 mmol) and THF (100 mL), a solution of triethyl phosphonoacetate (24 mL, 120 mmol) in THF (50 mL) was added dropwise over 30 minutes under ice cooling, and the mixture was stirred at room temperature for 2 hours. After cooling the reaction mixture again under ice, a solution of 3-benzyloxybenzaldehyde (21.2 g, 100 mmol) in THF (150 mL) was added dropwise over 1 hour. After stirring for a further 2 hours under ice cooling and 20 hours at room temperature, water (100 mL) was added to the reaction solution. After removing the organic solvent under reduced pressure, the residue was extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water, saturated ammonium chloride aqueous solution, and saturated brine, and then dried over anhydrous sodium sulfate. The title compound (27.27 g, 97%) was obtained as an oil by purification using silica gel column chromatography (n-hexane:ethyl acetate = 19:1).

[0249] (2) Preparation of ethyl 3-(3-hydroxyphenyl)propionate The compound obtained in Example 96 (1) (97 mmol, 27.27 g) was dissolved in ethanol (300 mL), 10% Pd-C (3.0 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 20 hours. After filtering off the catalyst, the solvent was removed by distillation under reduced pressure to obtain the title compound (18.8 g, 100%) as an oil.

[0250] (3) Preparation of 3-{[3-(3-ethoxy-3-oxopropyl)phenoxy]methyl}thiophene-2-carboxylate methyl 3-(bromomethyl)thiophene-2-carboxylate methyl 3-methyl-2-thiophenecarboxylate (17.18 g, 110 mmol), NBS (19.58 g, 110 mmol), and AIBN (0.1 g) according to the previously established method. The crude product obtained by processing 3-(bromomethyl)thiophene-2-carboxylate methyl 3-(bromomethyl)thiophene-2-carboxylate with the compound obtained in Example 96(2) (18.8 g, 97 mmol), potassium carbonate (27.64 g, 200 mmol), and DMF (200 mL) in the same manner as the synthesis in Example 95(2) was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (32.11 g, 95%) as an oil. MS (EI) m / z: 348 [M]+.

[0251] (4) Preparation of 3-{[3-(2-carboxyethyl)phenoxy]methyl}thiophene-2-carboxylic acid: The compound obtained in Example 96(3) (32.11 g, 92 mmol), 2 mol / L aqueous sodium hydroxide solution (125 mL, 250 mmol as NaOH), and methanol (1000 mL) were treated in the same manner as in the synthesis of Example 95(3) to obtain the title compound (25.27 g, 90%) as crystals. Mp. 159-160℃.

[0252] (5) Preparation of methyl 3-(10-oxo-4H-thieno[3,2-c][1]benzooxepin-7-yl)propionate: The compound obtained in Example 96(4) (25.12 g, 82 mmol) and TFAA (25 mL, 180 mmol) were stirred in DCE (300 mL) at 60°C for 24 hours. After the reaction solution cooled, methanol (100 mL) was added and the mixture was heated under reflux for a further 24 hours. The crude product obtained by processing in the same manner as in the synthesis of Example 95(4) was purified by silica gel column chromatography (toluene:ethyl acetate = 49:1) to obtain the title compound (19.05 g, 77%) as crystals. Mp. 78-80°C. MS (EI) m / z: 302 [M+H]+.

[0253] (6) Preparation of methyl 3-[10-hydroxy-10-(1-methyl-4-piperidyl)-4H-thieno[3,2-c][1]benzooxepin-7-yl]propionate: In the same manner as in the synthesis of Example 95(5), the Grignard reagent obtained from magnesium (3.06 g, 126 mmol), 4-chloro-1-methylpiperidine (17 mL, 126 mmol), and 1,2-dibromoethane (0.2 mL) in THF (170 mL) was cooled in an ice-salt bath, and a solution of the compound obtained in Example 96(5) (19.05 g, 63 mmol) in THF (150 mL) was added dropwise over 1 hour. After stirring at the same temperature for 1 hour, the product was treated in the same manner as in the synthesis of Example 95(5) to obtain the title compound (20.14 q g, 80%) as an oil. MS (EI) m / z: 402 [M+H]+.

[0254] (7) Preparation of methyl 3-[10-(1-methyl-4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-7-yl]propionate. The compound obtained in Example 96(6) (20.14 g, 50 mmol), TFA (38 mL, 500 mmol), and DCM (320 mL) were reacted and processed in the same manner as in the synthesis of Example 95(6). The crude product obtained was purified by silica gel column chromatography (chloroform:methanol = 49:1) to obtain the title compound (6.29 g, 33%) as an oil.

[0255] (8) The compound obtained in Production Example 96(7) of 4-[7-(3-methoxy-3-oxopropyl)-4H-thieno[3,2-c][1]benzooxepin-10-ylidene]piperidine-1-carboxylic acid 2,2,2-trichloroethyl (7.41 g, 19 mmol), Troc-Cl (3.1 mL, 23 mmol), and potassium carbonate (0.3 g, 2 mmol) were treated in toluene (100 mL) in the same manner as in the synthesis of Example 95(7). The resulting crude product was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (8.77 g, 85%) as an oil. MS (EI) m / z: 543 [M]+.

[0256] (9) The compound obtained in Production Example 95(8) of methyl 3-[10-(4-piperidylidene)-4H-thieno[3,2-c][1]benzooxepin-7-yl]propionate (8.77 g, 16 mmol) was stirred with zinc powder (10.46 g, 160 mmol) in acetic acid (100 mL) at room temperature for 72 hours. Insoluble matter was filtered off, the mixture was washed with methanol, and the solvent was removed under reduced pressure. Water (100 mL) was added to the residue, and potassium carbonate (15 g) was gradually added. Ethyl acetate (100 mL) was added and stirred for 1 hour, after which insoluble matter was filtered off with Celite. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (NH-DM1020, chloroform) and crystallized from petroleum ether to obtain the title compound (3.95 g, 67%). Max. 110–112°C.

[0257] Example 97 (1) Preparation of 2-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}methyl acetate 0.64 g, 1.8 mmol of the compound obtained in Example 95 (8), 0.50 g, 1.9 mmol of the compound obtained in Example 1 (28-5), sodium triacetoxyborohydride (0.57 g, 2.7 mmol), and TEA (0.3 mL, 1.8 mmol) were added to DCM (30 mL), and the title compound (0.72 g, 67%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}acetic acid [Compound 28] The compound obtained in Example 97 (1) (0.72 g, 1.2 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.6 mL, as 1.2 mmol of NaOH) was added at room temperature. Compound 28 (0.58 g, 55%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0258] Example 98 (1) Preparation of 2-{10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}methyl acetate 0.50 g, 1.4 mmol of the compound obtained in Example 95 (8), 0.68 g, 1.5 mmol of 3-[(E)-2-(7-chloro-2-quinolyl)vinyl]benzaldehyde, 0.45 g, 2.1 mmol of sodium triacetoxyborohydride, and 0.3 mL, 1.7 mmol of TEA were added to DCM (30 mL), and the title compound (0.89 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}acetic acid [Compound 29] The compound obtained in Example 98 (1) (0.89 g, 1.4 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.7 mL, as NaOH) was added at room temperature. Compound 29 (0.39 g, 45%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0259] Example 99 (1) Preparation of methyl 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}propionate 0.50 g, 1.4 mmol of the compound obtained in Example 96 (9), 3-[(E)-2-(7-chloro-2-quinolyl)vinyl]benzaldehyde (0.38 g, 1.4 mmol), sodium triacetoxyborohydride (0.43 g, 2.0 mmol), and TEA (0.3 mL, 1.8 mmol) were added to DCM (30 mL), and the title compound (0.60 g, 72%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(4-isopropylthiazole-2-yl)methoxy]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}propionic acid [Compound 30] The compound obtained in Example 99 (1) (0.60 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as NaOH) was added at room temperature. Compound 30 (0.30 g, 51%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0260] Example 100 (1) Preparation of methyl 3-{10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}propionate 0.50 g, 1.4 mmol of the compound obtained in Example 96 (9), 3-[(E)-2-(7-chloro-2-quinolyl)vinyl]benzaldehyde (0.65 g, 1.4 mmol), sodium triacetoxyburohydride (0.43 g, 2.0 mmol), and TEA (0.3 mL, 1.8 mmol) were added to DCM (30 mL), and the title compound (0.91 g, quant.) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 3-{10-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-4H-thieno[3,2-c][1]benzooxepin-7-yl}propionic acid [Compound 31] The compound obtained in Example 100 (1) (0.91 g, 1.4 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.7 mL, as NaOH) was added at room temperature. Compound 31 (0.40 g, 47%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0261] Example 101 (1) Preparation of 4-[2-(2-methoxy-2-oxo-ethyl)-6H-benzo[c][1]benzooxepin-11-ylidene]piperidine-1-carboxylic acid t-butyl Under an argon atmosphere, zinc powder (7.6 g, 116 mmol) was added to anhydrous THF (50 mL), and titanium tetrachloride (10.9 g, 58 mmol) was added dropwise over 1 hour under ice-salt cooling. After heating under reflux for 2 hours, it was allowed to cool, and a solution of 2-(11-oxo-6H-benzo[c][1]benzooxepin-2-yl)methyl acetate (4.00 g, 14 mmol) and 1-Boc-4-piperidone (2.80 g, 14 mmol) in anhydrous THF (50 mL) was added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to 100 mL of ice-cooled aqueous solution of potassium carbonate (32 g, 231 mmol), followed by ethyl acetate (100 mL). The mixture was stirred under ice for 2 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (100 mL) and TEA (6.0 mL, 41 mmol) was added. After adding a solution of (Boc)2O (4.0 g, 18.5 mmol) in DCM (30 mL) under ice, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate = 19:1) to obtain the title compound (3.60 g, 56%) as an oil. (2) Preparation of 2-[11-(4-piperidylidene)-6H-benzo[c][1]benzooxepin-2-yl]methyl acetate hydrochloride Compound obtained in Example 101 (1) (3.60 g, 7.95 mmol) was added dropwise to a solution of ethyl acetate (50 mL) with 4 mol / L hydrogen chloride-ethyl acetate solution (30.0 mL, 120 mmol as HCl) over 30 minutes under ice cooling. After stirring at room temperature for 4 hours, the solvent was removed under reduced pressure. The resulting oily residue was solidified from ether to obtain the title compound (2.2 g, 72%) as a hygroscopic solid.

[0262] Example 102 Preparation of 2-[11-(4-piperidylidene)-6H-benzo[c][1]benzooxepin-2-yl]ethyl acetate In a 500 mL three-necked flask fitted with a Liebig condenser, zinc powder (17.3 g, 264 mmol) was added to anhydrous THF (100 mL), and titanium tetrachloride (25 mL, 132 mmol) was added dropwise over 30 minutes under ice-salt cooling. After heating under reflux for 2 hours, the mixture was allowed to cool, and a solution of 2-(11-oxo-6H-benzo[c][1]benzooxepin-2-yl)ethyl acetate (9.50 g, 32 mmol) and 1-Boc-4-piperidone (6.40 g, 32 mmol) in anhydrous THF (50 mL) was added dropwise over 30 minutes under ice bath. After heating under reflux for 20 hours, the reaction solution was added to an ice-cooled aqueous solution of potassium carbonate (100 g, 720 mmol) (200 mL), followed by ethyl acetate (160 mL). The mixture was stirred under ice for 2 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The layers were then passed through a short column of NH silica (NH-DM1020) and anhydrous sodium sulfate and dried. The solvent was removed under reduced pressure to obtain the title compound (11.7 g, quant.) as an oily substance. 1H-NMR (500 MHz, DMSO) δ 7.46 (d, J = 7.3 Hz, 1H), 7.33 (d, J = 0.9 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 6.97 (d, J = 10.5 Hz, 1H), 6.97 (d, J = 6.3 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 5.59 (d, J = 12.1 Hz, 1H), 4.85 (d, J = 12.1 Hz, 1H), 4.07-4.00 (m, 2H), 3.56-3.47 (m, 2H), 2.90-2.87 (m, 1H), 2.79-2.77 (m, 1H), 2.69-2.64 (m, 1H), 2.53-2.39 (m, 4H), 2.23-2.10 (m, 2H), 1.18-1.14 (m, 3H).

[0263] Example 103 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (30 mL), the compound obtained in Example 101 (2) (0.48 g, 1.3 mmol), the compound obtained in Example 1 (2) (0.39 g, 1.3 mmol), sodium triacetoxyborohydride (0.40 g, 1.9 mmol), and TEA (0.22 mL, 1.3 mmol) were added, and the title compound (0.59 g, 73%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 101] The compound obtained in Example 103 (1) (0.59 g, 0.95 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.48 mL, as 0.96 mmol of NaOH) was added at room temperature. Compound 101 (0.57 g, 99%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0264] Example 104 (1) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (30 mL), the compound obtained in Example 101 (2) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (13) (0.43 g, 1.3 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.22 mL, 1.3 mmol) were added, and the title compound (0.32 g, 38%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 103] The compound obtained in Example 104 (1) (0.32 g, 0.49 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.25 mL, as 0.5 mmol of NaOH) at room temperature was added, and compound 103 (0.24 g, 76%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0265] Example 105 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,6,7-trichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (30 mL), add (0.50 g, 1.3 mmol) obtained in Example 101 (2), 3-[(E)-2-(5,6,7-trichloro-2-quinolyl)vinyl]benzaldehyde (0.40 g, 1.3 mmol), sodium triacetoxyburohydride (0.41 g, 1.9 mmol), and TEA (0.22 mL, 1.3 mmol), and proceed in the same manner as in the synthesis of Example 3 (1) to obtain the title compound (0.70 g, 84%) as an oil. (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,6,7-trichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 105] The compound obtained in Example 105 (1) (0.70 g, 1.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.55 mL, as NaOH) was added at room temperature. Compound 105 (0.33 g, 48%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0266] Example 106 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-6-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), add (0.60 g, 1.6 mmol) obtained in Example 101 (2), the compound obtained in Example 1 (14) (0.51 g, 1.6 mmol), sodium triacetoxyborohydride (0.50 g, 2.3 mmol), and TEA (0.27 mL, 1.6 mmol), and the title compound (0.30 g, 30%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-6-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 110] The compound obtained in Example 106 (1) (0.30 g, 0.47 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.24 mL, as 0.48 mmol of NaOH) was added at room temperature. Compound 110 (0.20 g, 68%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0267] Example 107 (1) Preparation of 2-{11-[1-({3-[(E)-2-(8-fluoro-7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 101 (2) (0.60 g, 1.6 mmol), the compound obtained in Example 1 (16) (0.51 g, 1.6 mmol), sodium triacetoxyborohydride (0.50 g, 2.3 mmol), and TEA (0.27 mL, 1.6 mmol) were added, and the title compound (0.64 g, 64%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(8-fluoro-7-chloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 111] The compound obtained in Example 107 (1) (0.64 g, 1.0 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) at room temperature was added, and compound 111 (0.48 g, 76%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0268] Example 108 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), add the compound obtained in Example 101 (2) (0.50 g, 1.3 mmol), the compound obtained in Example 1 (17) (0.43 g, 1.3 mmol), sodium triacetoxyborohydride (0.41 g, 1.9 mmol), and TEA (0.27 mL, 1.6 mmol), and the title compound (0.34 g, 40%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)-4-piperidylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 121] The compound obtained in Example 108 (1) (0.34 g, 0.51 mmol) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.26 mL, as 0.52 mmol of NaOH) was added at room temperature. Compound 121 (0.33 g, quant.) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0269] Example 109 (1) Preparation of 3-[2-(2-methoxy-2-oxo-ethyl)-6H-benzo[c][1]benzooxepin-11-ylidene]-azetidine-1-carboxylic acid t-butyl Under an argon atmosphere, zinc powder (7.6 g, 116 mmol) was added to anhydrous THF (120 mL), and titanium tetrachloride (11 g, 58 mmol) was added dropwise over 1 hour under ice-salt cooling. After heating under reflux for 2 hours, it was allowed to cool, and a solution of methyl 2-(11-oxo-6H-benzo[c][1]benzooxepin-2-yl)acetate (4.00 g, 14 mmol) and 1-Boc-3-azetidinone (2.4 g, 14 mmol) in anhydrous THF (50 mL) was added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to 100 mL of ice-cooled aqueous solution of potassium carbonate (32 g, 232 mmol), followed by ethyl acetate (100 mL). The mixture was stirred under ice for 2 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (100 mL) and TEA (4.9 mL, 35 mmol) was added. After adding a solution of (Boc)2O (4.00 g, 18 mmol) in DCM (30 mL) under ice, the mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to obtain the title compound (4.4 g, 73%) as an oil. MS (ESI) m / z: 422 [M+H]+. (2) Preparation of 2-[11-(azetidine-3-ylidene)-6H-benzo[c][1]benzooxepin-2-yl]methyl acetate hydrochloride. To a solution of the compound obtained in Example 109 (1) (4.4 g, 10 mmol) in DCM (100 mL), 4 mol / L hydrogen chloride / dioxane solution (25 mL, 100 mmol as HCl) was added dropwise over 30 minutes under ice cooling. After stirring at room temperature for 4 hours, the solvent was removed under reduced pressure to obtain the title compound (3.0 g, 81%) as a hygroscopic solid. MS (ESI) m / z: 322 [M+H]+.

[0270] Example 110 (1) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 109 (2) (0.49 g, 1.4 mmol), the compound obtained in Example 1 (1) (0.40 g, 1.4 mmol), sodium triacetoxyborohydride (0.43 g, 2.0 mmol), and TEA (0.3 mL, 1.8 mmol) were added, and the title compound (0.48 g, 59%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). MS (ESI) m / z: 601 [M+H]+. (2) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 102] The compound obtained in Example 110 (1) (0.48 g, 0.8 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.4 mL, as 0.8 mmol of NaOH) was added at room temperature, and compound 102 (0.44 g, 94%) was obtained as a monohydrate crystal in the same manner as the synthesis in Example 3 (2). (3) In addition, fumarate, malonate, tartrate, besylate, sodium salt, and choline salt of compound 102 were prepared from compound 102 and various organic acids or metals, etc., according to conventional methods. The sodium salt was obtained as a dihydrate.

[0271] Example 111 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 109 (2) (0.71 g, 2.0 mmol), the compound obtained in Example 1 (2) (0.65 g, 2.1 mmol), sodium triacetoxyborohydride (0.63 g, 3.0 mmol), and TEA (5.0 mL, 30.0 mmol) were added, and the title compound (0.69 g, 56%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 108] The compound obtained in Example 111(1) (0.69 g, 1.1 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.6 mL, as NaOH) was added at room temperature. Compound 108 (0.61 g, 91%) was obtained as crystals in the same manner as the synthesis in Example 3(2).

[0272] Example 112 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-6-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate 0.71 g, 2.0 mmol of the compound obtained in Example 109 (2), 0.65 g, 2.1 mmol of the compound obtained in Example 1 (14), 0.63 g, 3.0 mmol of sodium triacetoxyborohydride, and 5.0 mL, 30.0 mmol of TEA were added to DCM (50 mL), and the title compound (0.30 g, 24%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-6-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 109] The compound obtained in Example 112 (1) (0.30 g, 0.48 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.24 mL, 0.48 mmol as NaOH) was added at room temperature. Compound 109 (0.20 g, 69%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0273] Example 113 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 109 (2) (0.53 g, 1.5 mmol), the compound obtained in Example 1 (3) (0.46 g, 1.5 mmol), sodium triacetoxyborohydride (0.47 g, 2.2 mmol), and TEA (0.3 mL, 2.2 mmol) were added, and the title compound (0.46 g, 51%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,6,7-trifluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 120] The compound obtained in Example 113 (1) (0.46 g, 0.77 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.39 mL, 0.78 mmol as NaOH) was added at room temperature. Compound 120 (0.37 g, 82%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0274] Example 114 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 109 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (17) (0.46 g, 1.4 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 2.2 mmol) were added, and the title compound (0.55 g, 63%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 122] The compound obtained in Example 114 (1) (0.55 g, 0.88 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.44 mL, 0.88 mmol as NaOH) was added at room temperature. Compound 122 (0.45 g, 83%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0275] Example 115 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 109 (2) (0.50 g, 1.4 mmol), the compound obtained in Example 1 (18) (0.41 g, 1.4 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 2.2 mmol) were added, and the title compound (0.55 g, 66%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 127] The compound obtained in Example 115 (1) (0.55 g, 0.92 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.46 mL, 0.92 mmol as NaOH) was added at room temperature. Compound 127 (0.42 g, 78%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0276] Example 116 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 109 (2) (0.50 g, 1.4 mmol), 3-[(E)-2-(7-chloro-2-quinolyl)vinyl]benzaldehyde (0.41 g, 1.4 mmol), sodium triacetoxyburohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 2.2 mmol) were added, and the title compound (0.75 g, 89%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 135] The compound obtained in Example 116 (1) (0.75 g, 1.25 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.63 mL, 1.26 mmol as NaOH) was added at room temperature. Compound 135 (0.62 g, 85%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0277] Example 117 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 109 (2) (0.50 g, 1.4 mmol), 3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]benzaldehyde (0.39 g, 1.4 mmol), sodium triacetoxyborohydride (0.45 g, 2.1 mmol), and TEA (0.3 mL, 2.2 mmol) were added, and the title compound (0.56 g, 69%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 136] The compound obtained in Example 117 (1) (0.56 g, 0.97 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.49 mL, 0.98 mmol as NaOH) was added at room temperature. Compound 136 (0.53 g, 97%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0278] Example 118 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,6-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To 250 mL of THF and 50 mL of methanol, the compound obtained in Example 109 (2) (12.86 g, 40.0 mmol), the compound obtained in Example 1 (19) (10.33 g, 35.0 mmol), and sodium triacetoxyborohydride (10.60 g, 50.0 mmol, added in 5 portions of 2.12 g) were added and stirred for 2 days. The reaction solution was added to 250 mL of ice-cold aqueous solution of potassium carbonate (13.8 g, 100 mmol), and then ethyl acetate (100 mL) was added. The aqueous layer was further extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene:ethyl acetate = 7:3) to obtain the title compound (4.67 g, 22%) as an oil. (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,6-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetate hydrochloride [Compound 149] The compound obtained in Example 118 (1) (4.5 g, 7.5 mmol) was added to a mixed solvent of THF (60 mL) and water (60 mL), and a 2 mol / L aqueous sodium hydroxide solution (7.5 mL, as NaOH) was added at room temperature, and the mixture was stirred for 3 days. The solvent was removed under reduced pressure, and 1 mol / L hydrochloric acid was added to the resulting residue to adjust the pH to 2.0. The precipitated crystals were then filtered off. After thorough washing with water, the mixture was dried under reduced pressure on phosphorus pentoxide at 50°C to obtain compound 149 (4.49 g, 96%) as crystals.

[0279] Example 119 (1) Preparation of 2-{11-[1-({4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To DCM (50 mL) and TEA (5 mL), the compound obtained in Example 109 (2) (0.62 g, 1.7 mmol), 4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]benzaldehyde (0.80 g, 2.6 mmol), and sodium triacetoxyborohydride (0.55 g, 2.6 mmol) were added and stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue and extracted with DCM (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.10 g, 10%) as an oil. (2) Preparation of 2-{11-[1-({4-[(7-chloro-6-fluoro-2-quinolyl)methoxy]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 113] The compound obtained in Example 119 (1) (0.10 g, 0.20 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.10 mL, as NaOH) was added at room temperature, and compound 113 (0.10 g, quant.) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0280] Example 120 Preparation of 2-[11-(azetidine-3-ylidene)-6H-benzo[c][1]benzooxepin-2-yl]methyl acetate In a 1 L three-necked flask fitted with a Liebig condenser, zinc powder (51.39 g, 786 mmol) was added to anhydrous THF (300 mL), and titanium tetrachloride (75 mL, 395 mmol) was added dropwise over 30 minutes under ice-salt cooling. After heating under reflux for 3 hours, the mixture was allowed to cool, and a solution of 2-(11-oxo-6H-benzo[c][1]benzooxepin-2-yl)methyl acetate (28.2 g, 100 mmol) and 1-Boc-3-azetidinone (17.1 g, 100 mmol) in THF (150 mL) was added dropwise over 30 minutes under ice bath. After heating under reflux for 20 hours, the reaction solution was added to a 3 L beaker with 500 mL of ice-cooled potassium carbonate (250 g, 1810 mmol) aqueous solution, followed by 200 mL of ethyl acetate. The mixture was stirred under ice for 3 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The mixture was then passed through a short column of NH silica (NH-DM1020) and anhydrous sodium sulfate and dried. The solvent was removed under reduced pressure to obtain the title compound (32.1 g, quant.) as an oily substance. MS (ESI) m / z: 322 [M+H]+.

[0281] Example 121 (1) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate To THF (18 mL) and MeOH (3 mL), the compound obtained in Example 120 (1.00 g, 3.1 mmol), the compound obtained in Example 1 (13) (0.82 g, 2.5 mmol), and sodium triacetoxyborohydride (0.79 g, 3.7 mmol) were added and stirred at room temperature for 48 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.12 g, 6%) as an oil. MS (ESI) m / z: 634 [M+H]+. (2) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-dichloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 153] The compound obtained in Example 121 (1) (0.12 g, 0.19 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.1 mL, as 0.2 mmol of NaOH) was added at room temperature, and Compound 153 (0.10 g, 87%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0282] Example 122 (1) Preparation of 2-{11-[1-({3-[(E)-2-(8-fluoro-7-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate THF (18 mL) and MeOH (3 mL) were mixed with the compound obtained in Example 120 (1.00 g, 3.1 mmol), the compound obtained in Example 1 (16) (0.78 g, 2.5 mmol), and sodium triacetoxyborohydride (0.79 g, 3.7 mmol), and the title compound (0.08 g, 4%) was obtained as an oil in the same manner as the synthesis in Example 121 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(8-fluoro-7-chloro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid [Compound 154] The compound obtained in Example 122 (1) (0.08 g, 0.12 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.06 mL, as 0.12 mmol of NaOH) was added at room temperature. Compound 154 (0.06 g, 80%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0283] Example 123 (1) Preparation of 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-9-yl)acetic acid-d2 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-9-yl)acetic acid (16.7 g, 62.1 mmol), potassium carbonate (872 mg, 6.21 mmol), 4-dimethylaminopyridine (DMAP) (776 mg, 6.21 mmol), and pivalic anhydride (2.3 mL, 12.4 mmol) were stirred in DMSO (25 mL) and deuterated acetone (46 mL) at 60°C for 2 days under an argon atmosphere. Deuterium water (28 mL) was added to the reaction mixture and stirred at room temperature for 2.5 hours. 1 mol / L hydrochloric acid (50 mL) was added and extracted with DCM. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM:methanol = 99:1) to obtain an oily substance (11.0 g). Potassium carbonate (640 mg, 4.56 mmol), DMAP (570 mg, 4.56 mmol), and pivalic anhydride (1.7 mL, 9.12 mmol) were added to the oily substance, and the mixture was stirred at 60°C for 2 days under an argon atmosphere. The above post-treatment and column chromatography purification were repeated to obtain an oily substance (6.5 g, 39%, 99.9 atm%D (1H-NMR)).

[0284] (2) Preparation of 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-9-yl)methyl-d2 A mixture of the compound obtained in Example 123 (1) (6.5 g, 24.1 mmol) and methanol (1000 mL) was mixed with concentrated sulfuric acid (0.3 mL) and heated under reflux at 100°C for 3 hours. After cooling, the solvent was removed under reduced pressure and water (100 mL) was added to the residue to precipitate the solid, which was then filtered off. After thorough washing with water, the mixture was dried under reduced pressure on phosphorus pentoxide at 50°C to obtain a hygroscopic solid (6.0 g, 88%).

[0285] (3) Preparation of 2-[11-(azetidine-3-ylidene)-6,11-dihydrodibenzo[b,e]oxepin-9-yl]methyl acetate-d2 In a 500 mL three-necked flask fitted with a Liebig condenser, zinc powder (17.3 g, 264 mmol) was added to anhydrous THF (100 mL), and titanium tetrachloride (25 mL, 132 mmol) was added dropwise over 30 minutes under ice-salt cooling. After heating under reflux for 2 hours, the mixture was allowed to cool, and under an ice bath, a solution of the compound obtained in Example 123(2) (6.0 g, 21 mmol) and 1-Boc-4-piperidone (3.63 g, 21 mmol) in anhydrous THF (50 mL) was added dropwise over 30 minutes. After heating under reflux for 20 hours, the reaction solution was added to an ice-cooled aqueous solution of potassium carbonate (100 g, 720 mmol) (200 mL), and then ethyl acetate (160 mL) was added. The mixture was stirred under ice cooling for 2 hours, and the precipitated gel was filtered off using Celite and thoroughly washed with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The mixture was then passed through a short column of NH silica (NH-DM1020) and anhydrous sodium sulfate and dried. The solvent was removed under reduced pressure to obtain the title compound (4.8 g, 69%) as an oil.

[0286] Example 124 (1) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate-d2 Add the compound obtained in Example 123(3) (1.00 g, 3.1 mmol) and the compound obtained in Example 1(1) (0.73 g, 2.5 mmol) to THF (18 mL) and methanol (3 mL), and stir at room temperature for 1 hour. Add sodium triacetoxyborohydride (0.79 g, 3.7 mmol) and stir at room temperature for 3 days. Distill off the solvent under reduced pressure, add water (30 mL) to the residue, and extract with DCM (30 mL x 3). Wash the organic layer with water and saturated brine, and then dry over anhydrous sodium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (PSQ-100B, chloroform:methanol = 19:1) to obtain the title compound (0.34 g, 18%) as an oil. (2) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid-d2 [Compound 150] The compound obtained in Example 124 (1) (0.34 g, 0.56 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.28 mL, 0.56 mmol as NaOH) was added at room temperature. Compound 150 (0.29 g, 88%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0287] Example 125 (1) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate-d2 Add the compound obtained in Example 123 (3) (1.00 g, 3.1 mmol) and the compound obtained in Example 1 (2) (0.73 g, 2.5 mmol) to THF (18 mL) and methanol (3 mL), and stir at room temperature for 1 hour. Add sodium triacetoxyborohydride (0.79 g, 3.7 mmol) and stir at room temperature for 1 day. The title compound (0.45 g, 24%) was obtained as an oil in the same manner as in the synthesis of Example 124 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(7-chloro-6-fluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid-d2 [Compound 151] The compound obtained in Example 125 (1) (0.45 g, 0.74 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.37 mL, 0.74 mmol as NaOH) was added at room temperature. Compound 151 (0.30 g, 67%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0288] Example 126 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}methyl acetate-d2 Add the compound obtained in Example 123 (3) (1.00 g, 3.1 mmol) and the compound obtained in Example 1 (18) (0.73 g, 2.5 mmol) to THF (18 mL) and methanol (3 mL), and stir at room temperature for 1 hour. Add sodium triacetoxyborohydride (0.79 g, 3.7 mmol) and stir at room temperature for 1 day. The title compound (0.24 g, 13%) was obtained as an oil in the same manner as in the synthesis of Example 124. (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-2-yl}acetic acid-d2 [Compound 152] The compound obtained in Example 126 (1) (0.24 g, 0.40 mmol) was added to a mixed solvent of methanol (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.20 mL, as 0.40 mmol of NaOH) was added at room temperature. Compound 152 (0.16 g, 68%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0289] Example 127 (1) Preparation of methyl 5-bromo-2-(phenoxymethyl)benzoate In DMF (250 mL), 5-bromo-2-methylbenzoic acid (50 g, 233 mmol), potassium bicarbonate (50 g, 500 mmol), and methyl iodide (31 mL, 500 mmol) were stirred at room temperature for 20 hours. The reaction mixture was added to water (500 mL) and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in DCE (400 mL), NBS (44.5 g, 250 mmol) and AIBN (0.2 g) were added, and the mixture was heated under reflux for 4 hours. After cooling, the reaction solution was washed twice with 1 mol / L aqueous potassium carbonate solution and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was mixed with phenol (22.6 g, 240 mmol) and potassium carbonate (69 g, 500 mmol) in DMF (300 mL) at room temperature for 20 hours. The reaction mixture was added to water (500 mL), the precipitated crystals were filtered off, and the mixture was dried under reduced pressure at 50°C for 24 hours to obtain 11 (69.07 g, 92%). (Mp. 60-62°C)

[0290] (2) Preparation of 5-bromo-2-(phenoxymethyl)benzoic acid. A mixture of the compound obtained in Example 127 (1) (73.87 g, 230 mmol) and methanol (1000 mL) was mixed with an aqueous solution of sodium hydroxide (16 g, 400 mmol) (100 mL) and heated under reflux for 20 hours. After cooling, the solvent was removed under reduced pressure, and water (500 mL) and 6 mol / L hydrochloric acid (80 mL) were added to the resulting residue. The precipitated crystals were filtered off. After thorough washing with water, the mixture was dried under reduced pressure on phosphorus pentoxide at 50°C to obtain the title compound (79.71 g, 87%). Mp. 144-146°C.

[0291] (3) Preparation of 9-bromodibenzo[b,e]oxepin-11(6H)-one. To a solution of the compound obtained in Example 127(2) (31.0 g, 101 mmol) in DCM (250 mL), TFAA (17 mL, 120 mmol) was added dropwise over 30 minutes at room temperature. After stirring for 4 hours at room temperature, BF3 ether complex (1 mL) was added and the mixture was stirred for a further 20 hours. Water (300 mL) was added to the reaction mixture under ice cooling, and then potassium carbonate (50 g) was added in small increments. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distillation of the solvent was crystallized from ether and petroleum ether to obtain the title compound (30.27 g, quant.). Mp. 91-93℃.

[0292] (4) Preparation of 2-(11-oxo-6,11-dihydrobenzo[b,e]oxepin-9-yl)t-butyl acetate Under an argon atmosphere, dicyclohexylamine (25 mL, 125 mmol) was added to anhydrous toluene (300 mL), and after cooling to 0°C, a hexane solution of 1.6 mol / L n-butyllithium (80 mL, 125 mmol) was added dropwise over 30 minutes. Then, a toluene solution of t-butyl acetate (15 mL, 110 mmol) in toluene (40 mL) was added dropwise at 0°C over 30 minutes. After stirring at room temperature for 30 minutes, Pd(dba)2 (dba: dibenzylideneacetone, 3.0 g, 5 mmol) and a 10 w / v% hexane solution of P(t-Bu)3 (2.0 mL, 5 mmol) were added. Next, a toluene (150 mL) solution of the compound obtained in Example 127(3) (29.0 g, 100 mmol) was added and stirred at room temperature for 20 hours. The reaction mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate = 9:1) to obtain the title compound (12.86 g, 40%) as an oil.

[0293] (5) Preparation of 2-(11-oxo-6,11-dihydrobenzo[b,e]oxepin-9-yl)acetic acid. To a solution of the compound obtained in Example 127 (4) (15.27 g, 47 mmol) in DCM (200 mL), TFA (36 mL, 470 mmol) was added dropwise over 30 minutes under ice cooling. After stirring at room temperature for 48 hours, the solvent was removed under reduced pressure. To the resulting residue, toluene (100 mL) was added and removed again under reduced pressure. The precipitated crystals were filtered from ether / petroleum ether to obtain the title compound (8.38 g, 70%). Mp. 125-127℃.

[0294] (6) Preparation of methyl 2-(11-oxo-6,11-dihydrobenzo[b,e]oxepin-9-yl)acetate A mixture of methanol (400 mL), the compound obtained in Example 127(5) (23.0 g, 86 mmol), and concentrated sulfuric acid (0.5 mL) was heated under reflux for 20 hours. The solvent was removed under reduced pressure, and the resulting residue was dissolved in ethyl acetate (150 mL) and washed with water and saturated brine. It was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (26.10 g, 87%) as an oily substance.

[0295] (7) Preparation of 2-{11-(azetidine-3-ylidene)-6,11-dihydrodibenzo[b,e]oxepin-9-yl}methyl acetate hydrochloride Zinc (34.6 g, 524 mmol) was added to anhydrous THF (300 mL), and titanium tetrachloride (50 g, 262 mmol) was added dropwise over 30 minutes under ice-salt cooling. After heating the reaction mixture under reflux for 2 hours, a mixed solution of the compound obtained in Example 127(6) (19.5 g, 69 mmol) and t-butyl-3-oxoazetidine-1-carboxylate (11.8 g, 69 mmol) in THF (150 mL) was added dropwise over 30 minutes under ice cooling. The mixture was heated under reflux again for 20 hours. After cooling, the reaction mixture was added to ice-cooled potassium carbonate (166 g) aqueous solution (500 mL) and stirred for 3 hours. The resulting gel was filtered off using Celite, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in DCM (250 mL). A 4 ml / L solution of dioxane hydrogen chloride (100 mL, HCl 400 mmol) was added dropwise under ice cooling. After stirring at room temperature for 20 hours, the solvent was removed by distillation under reduced pressure, and the resulting residue was solidified from ether to obtain the title compound (19.61 g, 79%) as a hygroscopic solid.

[0296] Example 128 (1) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 127 (7) (0.48 g, 1.4 mmol), the compound obtained in Example 1 (1) (0.40 g, 1.4 mmol), sodium triacetoxyborohydride (0.43 g, 2.0 mmol), and TEA (0.4 mL, 2.4 mmol) were added, and the title compound (0.26 g, 31%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(6,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [Compound 143] The compound obtained in Example 128 (1) (0.26 g, 0.4 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.25 mL, as 0.5 mmol of NaOH) was added at room temperature. After stirring at room temperature for 24 hours, Compound 143 (0.18 g, 77%) was obtained as crystals in the same manner as the synthesis in Example 3 (2).

[0297] Example 129 (1) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}methyl acetate To DCM (50 mL), the compound obtained in Example 127 (7) (0.48 g, 1.4 mmol), the compound obtained in Example 1 (18) (0.40 g, 1.4 mmol), sodium triacetoxyborohydride (0.43 g, 2.0 mmol), and TEA (0.4 mL, 2.4 mmol) were added, and the title compound (0.47 g, 56%) was obtained as an oil in the same manner as the synthesis in Example 3 (1). (2) Preparation of 2-{11-[1-({3-[(E)-2-(5,7-difluoro-2-quinolyl)vinyl]phenyl}methyl)azetidine-3-ylidene]-6H-benzo[c][1]benzooxepin-9-yl}acetic acid [Compound 144] The compound obtained in Example 129 (1) (0.47 g, 0.8 mmol) was added to a mixed solvent of THF (20 mL) and water (20 mL), and a 2 mol / L aqueous sodium hydroxide solution (0.5 mL, as 1.0 mmol of NaOH) was added at room temperature. After stirring at room temperature for 24 hours, Compound 144 (0.35 g, 75%) was obtained as a trihydrate crystal in the same manner as the synthesis in Example 3 (2).

[0298] Example 130 (1) Preparation of 2-{(4-bromophenoxy)methyl}benzoic acid Methyl o-toluate (45 g, 300 mmol), NBS (58.7 g, 330 mmol), and AIBN (0.2 g) were heated under reflux in DCE (400 mL) for 5 hours. After cooling, the reaction solution was washed twice with 1 mol / L aqueous potassium carbonate solution, and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was stirred with 4-bromophenol (53.6 g, 310 mmol) and potassium carbonate (82.9 g, 600 mmol) in DMF (400 mL) at room temperature for 20 hours. Water (500 mL) was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methanol (1000 mL), and an aqueous solution of sodium hydroxide (16 g, 400 mmol) (100 mL) was added and the mixture was heated under reflux for 20 hours. After cooling, the solvent was distilled off under reduced pressure, and water (500 mL) and 6 mol / L hydrochloric acid (100 mL) were added to the remaining residue. The precipitated crystals were filtered off. After thorough washing with water, the mixture was dried under reduced pressure on phosphorus pentoxide at 50°C to obtain the title compound (79.71 g, 87%). Mp. 110-113°C.

[0299] (2) Preparation of 2-bromodibenzo[b,e]oxepin-11(6H)-one. To a solution of the compound obtained in Example 130 (1) (50.6 g, 165 mmol) in DCM (300 mL), TFAA (28 mL, 200 mmol) was added dropwise over 30 minutes at room temperature. After stirring for 4 hours at room temperature, BF3 ether complex (3 mL) was added, and the mixture was stirred for a further 20 hours. Water (300 mL) was added to the reaction mixture under ice cooling, and then potassium carbonate (50 g) was added in small amounts. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distillation of the solvent was crystallized from ether and petroleum ether to obtain the title compound (45.27 g, 95%). Mp. 120-122℃.

[0300] (3) t-Butyl 3-{2-bromodibenzo[b,e]oxepin-11(6H)-ylidene}azetidine-1-carboxylic acid Production of t-butyl Zinc (34.6 g, 524 mmol) was added to anhydrous THF (300 mL), and titanium tetrachloride (50 g, 262 mmol) was added dropwise over 30 minutes under ice-salt cooling. After heating the reaction mixture under reflux for 2 hours, a mixed solution of the compound obtained in Example 130 (2) (17.9 g, 62 mmol) and t-butyl-3-oxoazetidine-1-carboxylate (10.6 g, 62 mmol) in THF (150 mL) was added dropwise over 30 minutes under ice cooling. The mixture was heated under reflux again for 20 hours. After cooling, the reaction mixture was added to ice-cooled potassium carbonate (166 g) aqueous solution (500 mL) and stirred for 3 hours. The resulting gel was filtered off using Celite, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DCM (200 mL), and TEA (11 mL, 70 mmol) was added at room temperature. Then, a solution of (Boc)2O (15.3 g, 70 mmol) in DCM (50 mL) was added dropwise over 30 minutes. After stirring at room temperature for 20 hours, the reaction mixture was washed with water and saturated brine. The residue was dried over anhydrous sodium sulfate and distilled off under reduced pressure. The residue was crystallized from petroleum ether to obtain the title compound (18.53 g, 70%). Maximum temperature: 150-151°C.

[0301] (4) 3-[2-{(2-methoxy-2-oxoethyl)thio}dibenzo[b,e]oxepin-11(6H)-ylidene]azetidine-1-carboxylic acid A mixture of the compound obtained in Example 130 (3) (27.4 g, 64 mmol), methyl mercaptoacetate (6 mL, 66 mmol), ethyl diisopropylamine (22 mL, 128 mmol), xanthophos (0.75 g, 1.3 mmol), and Pd2(dba3) (0.6 g, 0.65 mmol) was heated under an argon atmosphere for 48 hours under reflux. After cooling, saturated ammonium chloride water was added and the precipitated insoluble material was filtered off. The organic layer of the filtrate was separated and washed with water and saturated brine. The organic l...

Claims

A cyclic amine derivative represented by the following general formula (I), or a pharmaceutically acceptable salt or hydrate thereof. [In the formula, R 1 is hydrogen or -R 6 -CO-R 7 Represents R 6 R represents a single bond, a deuterated alkyl, -S-alkyl-, -S-methylcycloalkylmethyl-, or -O-alkyl-, 7 represents an amino, hydroxy, or alkoxy which may be substituted with a hydroxyalkyl group; R 2 represents hydrogen, halogen, carboxy, carboxymethylsulfanyl, or carboxyalkyl; Ring W represents piperidyl, azaspiroheptyl, or azetidyl; R 3 represents pyridyl, phenyl which may be substituted with one or two halogens, or thienyl which may be substituted with an alkyl group; R 4 represents -O-CH2-, -CH2-O-CH2-, or -CH=CH-; R 5 represents a substituent selected from the following (a) to (e); (a) Quinolyls which may be substituted with halogens 1 to 4 (b) Benzothiazolyl which may be substituted with one or two halogens, (c) (1) Phenyl which may be substituted with a halogen, (2) Thiazolyl which may be substituted with a substituent selected from alkyl or (3) cycloalkyl, (d) Kinoxalil, (e) Tetrahydroquinolyl, A represents carbon or oxygen; X and Y either represent -CH- and -S-, or either represent -CH- and -CH=CH-; and n represents an integer between 1 and 3; However, R 1 If R represents hydrogen, 2 represents carboxy, carboxymethylsulfanyl, or carboxyalkyl; R 1 ga-R 6 -CO-R 7 When representing R, 2 [This represents hydrogen or halogen.] A cyclic amine derivative according to claim 1, wherein ring W is azetidyl, or a pharmaceutically acceptable salt or hydrate thereof. R 3 A cyclic amine derivative according to claim 1 or 2, or a pharmaceutically acceptable salt or hydrate thereof, wherein is a phenyl which may be substituted with one or two halogens. R 4 A cyclic amine derivative according to any one of claims 1 to 3, wherein -CH=CH-, or a pharmaceutically acceptable salt or hydrate thereof. R 5 A cyclic amine derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or hydrate thereof, wherein is a quinolyl which may be substituted with 1 to 4 halogens. A is oxygen, a cyclic amine derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or hydrate thereof. A cyclic amine derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or hydrate thereof, wherein one of X and Y is -CH- and the other is -CH=CH-. A cyclic amine derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or hydrate thereof, wherein n is 1. R 1 ga-R 6 -CO-R 7 A cyclic amine derivative according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or hydrate thereof. R 6 It is an alkyl which may be deuterated, and R 7 A cyclic amine derivative according to claim 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein the hydroxyl group may be substituted with an alkyl group. R 2 A cyclic amine derivative according to claim 9 or 10, or a pharmaceutically acceptable salt or hydrate thereof, wherein the derivative is hydrogen. R 2 A cyclic amine derivative according to any one of claims 1 to 8, wherein is a carboxyalkyl group, or a pharmaceutically acceptable salt or hydrate thereof. A pharmaceutical product comprising a cyclic amine derivative according to any one of claims 1 to 12, and at least one pharmaceutically acceptable salt and hydrate thereof. The pharmaceutical agent according to claim 13, which is a preventive and / or therapeutic agent for allergic diseases. The pharmaceutical product according to claim 14, wherein the allergic disease is a disease involving histamine and leukotrienes. The pharmaceutical product according to claim 14 or 15, wherein the allergic disease is bronchial asthma, allergic rhinitis, urticaria, allergic dermatitis, atopic dermatitis, or hay fever.

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