Griseofluvin compounds

Abstract

The present invention addresses the problem of providing a compound having an anti-inflammatory activity or a pharmacologically acceptable salt thereof. The solution according to the present invention is a compound represented by general formula (1) or a pharmacologically acceptable salt thereof. [In the formula, symbols are defined as follows: R1: a C1-C6 alkyl group or the like; R2: a C1-C6 alkyl group; A: an oxygen atom or the like; and R3: a C1-C6 alkyl group or the like.]

Description

Griseofulvin compound The present invention relates to a compound having a specific chemical structure having an anti-inflammatory effect or a pharmacologically acceptable salt thereof. In 1939, griseofulvin was first isolated as an antibiotic from Penicillium griseofulvum, a kind of blue mold of the family Trichocomaceae, by AE Oxford et al. (Non-Patent Document 1). It is mainly administered orally, but it is a poorly soluble and easily absorbable drug, and its oral absorption kinetics are complex. It is used as an antifungal drug against dermatophytes such as Microsporum, Trichophyton, and Epidermophyton (Non-Patent Documents 2 and 3). Griseofulvin binds to tubulin intracellularly. As a result, the cell cycle stops at the G2 / M phase, causing mitotic abnormalities and suppressing the growth of various cells such as fungi, plants, and mammals. Compared with mammalian cells, growth inhibition in fungal cells is induced at very low concentrations, which is thought to be because the binding affinity for fungal tubulin is higher than that for mammalian tubulin. It also has the effect of suppressing the dynamic instability of microtubules and stabilizing microtubule movement by binding to microtubule-associated proteins (MAPs) (Non-Patent Document 4). Griseofulvin has a growth inhibitory effect and apoptosis-inducing activity against human cancer cells, and also shows antitumor activity against tumors transplanted into thymus-deficient nude mice when combined with nocodazole. Therefore, its effect as an anticancer agent is also expected (Non-Patent Document 5). On the other hand, it has long been known to have an anti-inflammatory effect apart from its antifungal effect. For example, it has been found to show an anti-inflammatory effect against formalin edema and cotton pellet granuloma, which are rat inflammation models (Non-Patent Document 6). In actual clinical practice, it has also been reported to be effective against lichen planus (Non-Patent Document 7), plasma cell cheilitis (Non-Patent Document 8), and pigmented purpuric dermatosis (Non-Patent Document 9), which are non-fungal inflammatory skin diseases. In addition, it has been reported that it also exhibits efficacy against livedoid vasculitis (Non-Patent Document 9), shoulder-hand syndrome which is a form of polyarthritis, scapulo-humeral peryarthritis, etc. (Non-Patent Documents 6 and 10). It has been found to act on the microtubules of white blood cells and to have an antagonistic effect against histamine, serotonin, prostaglandin, etc., which are chemical mediators of inflammation in vitro (Non-Patent Document 6), but the detailed mechanism of action of glisofulvin in its anti-inflammatory effect is not clear. Glisofulvin, which has various physiological activities in this way, has undergone conversion of various substituents, and derivatives have been synthesized to date (Non-Patent Document 11). Oxford AE, Raistrick H, Simonart P. Studies in the biochemistry of micro-organisms: Griseofulvin, C(17)H(17)O(6)Cl, a metabolic product of Penicillium griseo-fulvum Dierckx. Biochem J. 1939 Feb;33(2):240-8Gentles JC. Experimental ringworm in guinea pigs: oral treatment with griseofulvin. Nature. 1958 Aug 16;182(4633):476-7.Williams DI, Marten RH, Sarkany I. Oral treatment of ringworm with griseofulvin. Lancet. 1958 Dec 6;2(7058):1212-3.Wehland J, Herzog W, Weber K. Interaction of griseofulvin with microtubules, microtubule protein and tubulin. J Mol Biol. 1977 Apr 15;111(3):329-42Ho YS, Duh JS, Jeng JH, Wang YJ, Liang YC, Lin CH, Tseng CJ, Yu CF, Chen RJ,Lin JK. Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2 / M cell cycle arrest in human colorectal cancer cells. Int J Cancer. 2001 Feb 1;91(3):393-401Sorrentino L, Capasso F, Di Rosa M. Anti-inflammatory properties of griseofulvin. Agents Actions.1977 Mar;7(1):157-62Sehgal VN, Bikhchandani R, Koranne RV, Nayar M, Saxena HM. Histopathological evaluation of griseofulvin therapy in lichen planus. A double-blind controlled study. Dermatologica. 1980;161(1):22-7Tamaki K, Osada A, Tsukamoto K, Ohtake N, Furue M. Treatment of plasma cell cheilitis with griseofulvin. J Am Acad Dermatol. 1994 May;30(5 Pt 1):789-90.Tamaki K, Yasaka N, Osada A, Shibagaki N, Furue M. Successful treatment of pigmented purpuric dermatosis with griseofulvin. Br J Dermatol. 1995Jan;132(1):159-60Cohen A, Goldman J, Daniels R, Kanenson W. Treatment of shoulder-hand syndrome with griseofulvin. J Am Med Assoc. 1960 Jun 4;173:542-3Petersen AB, Ronnest MH, Larsen, TO, Clausen MH. The Chemistry of Griseofulvin. Chem. Rev. 2014 Dec;114:12088-12107. The present invention provides a compound having a specific chemical structure with an anti-inflammatory action, which is useful as an active ingredient for the prevention and treatment of inflammatory diseases, its pharmaceutically acceptable salts, etc., or a novel production method and intermediate thereof. The compound of the present invention and its pharmaceutically acceptable salts are considered to be useful as novel pharmaceuticals because they have characteristics different from those of existing anti-inflammatory agents in various aspects. The inventors of the present invention have conducted intensive research for the purpose of developing a compound useful as an active ingredient for the prevention and treatment of inflammatory diseases, its pharmacologically acceptable salts, etc., and as a result, have found the compound of the present invention, its pharmacologically acceptable salts, etc. That is, the present invention is as described below. [1] A compound of general formula (1) or a pharmacologically acceptable salt thereof. [The symbols in the formula are defined as follows. R 1 : a C1-C6 alkyl group or a hydroxy C1-C6 alkyl group R 2 : a C1-C6 alkyl group A: a 5-membered aromatic heterocycle having a bond and containing 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom; or an oxygen atom R 3 : when A is a 5-membered aromatic heterocycle having a bond and containing 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom: a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, or a C1-C6 alkoxy C1-C6 alkyl group; when A is an oxygen atom: a hydroxy C1-C6 alkyl group or a C1-C6 alkoxy C1-C6 alkyl group [2] R 1 is a methyl group, an ethyl group, or a hydroxyethyl group, the compound or a pharmacologically acceptable salt thereof according to [1]. [3] R 2 is a methyl group, the compound or a pharmacologically acceptable salt thereof according to [1] or [2]. [4] A is a 5-membered aromatic heterocycle having a bond and containing 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and R 3 is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group, the compound or a pharmacologically acceptable salt thereof according to any one of [1]-[3]. [5] The compound according to any one of [1]-[4] or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered aromatic heterocycle having any one of the linking groups selected from the following group. [* represents a linking group.] [6] The compound according to any one of [1]-[3] or a pharmaceutically acceptable salt thereof, wherein A is an oxygen atom. [7] The compound of general formula (1) or a pharmaceutically acceptable salt thereof. [The symbols in the formula are defined as follows. R 1 : methyl group, ethyl group or hydroxyethyl group R 2 : methyl group A: a 5-membered aromatic heterocycle having any one of the linking groups selected from the following group [* represents a linking group.] R 3 : methyl group, ethyl group or hydroxy C1-C3 alkyl group] [8] Any compound selected from the following group or a pharmaceutically acceptable salt thereof. (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-Chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione [9] A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[0010] The pharmaceutical composition according to [9], which is for the prevention and / or treatment of inflammatory diseases.

[0011] The inflammatory disease is any one selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic fatty liver disease, cirrhosis, peripheral neuritis, ankylosing spondylitis, eczema (acute / subacute / chronic), contact dermatitis, solar (ultraviolet) dermatitis, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, psoriatic arthritis, psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, bedsore, wound, burn, conjunctivitis, keratitis, scleritis, acute / chronic otitis media, perennial allergic rhinitis, pollinosis, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behcet's disease, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis and chronic heart failure, the pharmaceutical composition according to

[0010] .

[0012] The inflammatory disease is any one selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic fatty liver disease, ankylosing spondylitis, contact dermatitis, solar (ultraviolet) dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, psoriatic arthritis, psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, alopecia areata, pemphigus group, erythroderma, acne vulgaris, bedsore, wound, burn, sinusitis, laryngitis, esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis and Behcet's disease, the pharmaceutical composition according to

[0010] .

[0013] The inflammatory disease is any one selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, ankylosing spondylitis, atopic dermatitis, psoriasis vulgaris, psoriatic arthritis, psoriatic erythroderma, pustular psoriasis, lichen planus, bedsore, wound, intractable stomatitis, glossitis and Behcet's disease, the pharmaceutical composition according to

[0010] .

[0014] A compound according to any one of [1]-[8] or a pharmaceutically acceptable salt thereof for treating an inflammatory disease.

[0015] A method of administering an effective amount of a pharmaceutical composition according to [9] for preventing and / or treating an inflammatory disease.

[0016] A TNF-α inhibitor containing, as an active ingredient, a compound according to any one of [1]-[8] or a pharmaceutically acceptable salt thereof. The compounds of the present invention, pharmaceutically acceptable salts thereof, etc. are useful as active ingredients for preventing and / or treating inflammatory diseases. Specific examples of inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic fatty liver disease, cirrhosis, peripheral neuritis, ankylosing spondylitis, eczema (acute / subacute / chronic), contact dermatitis, solar (ultraviolet) dermatitis, radiation dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata, pemphigus group, erythroderma, acne vulgaris, decubitus ulcer, wound, burn, conjunctivitis, keratitis, scleritis, acute / chronic otitis media, perennial allergic rhinitis, pollinosis, sinusitis, laryngitis, esophagitis, intractable stomatitis and glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behçet's disease, multiple sclerosis, type I diabetes, type II diabetes, atherosclerosis, pancreatitis, chronic heart failure, etc. Preferably, rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, non-alcoholic fatty liver disease, ankylosing spondylitis, contact dermatitis, solar (ultraviolet) dermatitis, atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, lichen planus, erythema, rosacea, alopecia areata, pemphigus group, erythroderma, acne vulgaris, decubitus ulcer, wound, burn, sinusitis, laryngitis, esophagitis, intractable stomatitis and glossitis, acute / chronic sialadenitis, angular cheilitis, cheilitis, Behçet's disease, etc. More preferably, examples include rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis, alcoholic hepatitis, non-alcoholic steatohepatitis, ankylosing spondylitis, atopic dermatitis, psoriasis vulgaris, psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, lichen planus, decubitus ulcer, wound, intractable stomatitis, glossitis, Behcet's disease and the like. In addition, since the present invention provides a novel and efficient production method and an intermediate therefor for producing the compound of the present invention and the like, it has advantageous properties for production as a medicine. The present invention will be described in detail below. (Explanation of substituents, terms, etc.) The present invention is a compound of general formula (1) or a pharmaceutically acceptable salt thereof. [The symbols in the formula are defined as follows. R 1 : a C1-C6 alkyl group or a hydroxy C1-C6 alkyl group R 2 : a C1-C6 alkyl group A: a 5-membered aromatic heterocycle having a bond and containing 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; or an oxygen atom R 3 : when A is a 5-membered aromatic heterocycle having a bond and containing 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom: a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group or a C1-C6 alkoxy C1-C6 alkyl group; when A is an oxygen atom: a hydroxy C1-C6 alkyl group or a C1-C6 alkoxy C1-C6 alkyl group] R 1 The C1-C6 alkyl group in R means a linear or branched alkyl group having 1-6 carbon atoms, preferably a methyl group or an ethyl group. R 1 The hydroxy C1-C6 alkyl group in R means a group in which a hydroxy group is substituted on a linear or branched alkyl group having 1-6 carbon atoms, preferably a hydroxyethyl group. R 2The C1-C6 alkyl group in refers to a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group. R 3 The C1-C6 alkyl group in refers to a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group or an ethyl group. R 3 The hydroxy C1-C6 alkyl group in refers to a group in which a hydroxy group is substituted for a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a hydroxy C1-C3 alkyl group, and specifically, a hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxy-1-methyl-ethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, etc. R 3 The C1-C6 alkoxy C1-C6 alkyl group in refers to a group in which a C1-C6 alkoxy group is substituted for a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methoxy C1-C3 alkyl group, and specifically, a methoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 1-methoxypropyl group, 2-methoxypropyl group, etc. The 5-membered aromatic heterocycle in A refers to a 5-membered aromatic heterocycle containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom and having two bonds. Specifically, for example, the following 5-membered aromatic heterocycles can be mentioned. Pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, isoxazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole, thiophene, thiazole, isothiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole Furthermore, preferably, the following 5-membered rings are shown. [* indicates a bond.] The 5-membered aromatic heterocycle forms the following compounds as the compound of general formula (1) by its bond. [wherein, R 1 , R 2 and R 3 have the same meanings as described above.] The "pharmaceutically acceptable salt" refers to a salt that can be used as a medicine. In the case of a compound having an acidic group or a basic group, it can be converted into a basic salt or an acidic salt by reacting with a base or an acid, so it refers to such a salt. As the "basic salt" of the compound that is pharmaceutically acceptable, preferably, alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt, etc. Organic base salts or amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, and aspartate salt, and preferably, alkali metal salts. As the "acidic salt" of the compound that is pharmaceutically acceptable, preferably, hydrohalic acid salts such as hydrofluoride salt, hydrochloride salt, hydrobromide salt, and hydroiodide salt, inorganic acid salts such as nitrate salt, perchlorate salt, sulfate salt, and phosphate salt; lower alkanesulfonic acid salts such as methanesulfonate salt, trifluoromethanesulfonate salt, and ethanesulfonate salt, arylsulfonic acid salts such as benzenesulfonate salt and p-toluenesulfonate salt, organic acid salts such as acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, oxalate salt, and maleate salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, and aspartate salt, and most preferably, hydrohalic acid salts (especially, hydrochloride salt). The compound of the present invention or its pharmaceutically acceptable salt may absorb moisture, adsorb water, or become a hydrate when left in the air or recrystallized, and the present invention also includes such various hydrates, solvates, and crystalline polymorphs of the compound. The compounds of the present invention, their pharmaceutically acceptable salts or their solvates may have various isomers such as geometric isomers (e.g., cis isomers, trans isomers), tautomers, or optical isomers (e.g., d-form, l-form) depending on the types and combinations of substituents. However, the compounds include all of these isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio when not particularly limited. Mixtures of these isomers can be separated by known separation means. The compounds of the present invention also include labeled compounds, i.e., compounds in which one or more atoms of the compound are substituted with isotopes (e.g., 2H, 3H, 13C, 14C, 35S, etc.). In addition, the present invention also includes so-called prodrugs. A prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. of a compound by hydrolysis or under physiological conditions. Examples of such groups that form prodrugs are those described in Prog. Med., Vol. 5, pages 2157 - 2161, 1985, etc. More specifically, as the prodrug, when an amino group is present in the compound, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5 - methyl - 2 - oxo - 1,3 - dioxolen - 4 - yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert - butylated, etc.) can be mentioned. When a hydroxyl group is present in the compound, compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.) can be mentioned. Also, when When a carboxy group is present, examples of the compound in which the carboxy group is esterified or amidated include a compound in which the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated or methylamidated. (Production method) The production method will be described below. However, the production method of the salt of the compound or the crystal of its hydrate is not limited to the following method at all. [Method A] Method A is a method for producing the compound (A-III) of the present invention. [In the formula, R 1 , R 2 and R 3 represent the same meanings as described above. X represents a leaving group such as a halogen group. ] (Step A1) Demethylation step This is a step of obtaining the compound (A-II) from the compound (A-I) using a metal halide in the presence of a base and a crown ether. Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like. Examples of the crown ether include 18-crown-6 and the like. Examples of the metal halide include potassium iodide and the like. Examples of the solvent include N,N-dimethylformamide or the like, or no solvent can be mentioned. The reaction temperature is usually about 60 to 120°C, and the reaction time is usually about 1 to 24 hours. (Step A2) Alkylation step (When using an alkyl halide) This is a step of obtaining the compound (A-III) from the compound (A-II) using the corresponding alkylating reagent in the presence of a base. Examples of the alkylating reagent include alkyl halides such as alkyl iodide and alkyl bromide, or sulfonic acid esters such as alkyl tosylate and alkyl mesylate. Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, and the like. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, N,N-dimethylformamide, and the like, or a mixture thereof. The reaction temperature is usually about 0 to 100 °C, and the reaction time is usually about 0.5 to 24 hours. (When using the Mitsunobu reaction) This is a step of obtaining compound (A-III) from compound (A-II) using the corresponding alcohol in the presence of phosphine and an azodicarboxylic acid ester or diazodicarboxamide. Examples of the phosphine include triphenylphosphine, tri-n-butylphosphine, and the like. Examples of the azodicarboxylic acid ester or diazodicarboxamide include diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1'-(azodicarbonyl)dipyridine, and the like. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, toluene, and the like, or a mixture thereof. The reaction temperature is usually about 0 to 100 °C, and the reaction time is usually about 0.5 to 24 hours. [Method B] Method B is a method for producing compound (B-III) (a compound corresponding to compound (A-I) used in Method A). When R 1 is a methyl group, compound (B-III) can be produced without performing these steps. [wherein, R 1 , R 2 and X have the same meanings as described above. ] (Step B1) Demethylation step This is a step of obtaining compound (B-II) from compound (B-I) using a metal halide. Examples of the metal halide include magnesium iodide and the like. Examples of the solvent include toluene, tetrahydrofuran, 1,4-dioxane and the like, or a mixture thereof. The reaction temperature is usually about 60 to 120 °C, and the reaction time is usually about 0.5 to 24 hours. (Step B2) Step of alkylating phenol This is a step of obtaining compound (B-III) from compound (B-II). It can be carried out in the same manner as (Step A2). [Method C] Method C is a method for producing the compound (C-III) of the present invention from the compound (C-I) (a compound corresponding to the compound (A-II) used in Method A). [In the formula, R 1 , R 2 , R 3 and A represent the same meanings as described above. Tf represents a trifluoromethanesulfonyl group, B * represents a borono group (-B(OH)2) or a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group. ]] (Step C1) Step of trifluoromethanesulfonylation This is a step of obtaining compound (C-II) from compound (C-I) using a trifluoromethanesulfonylating reagent in the presence of a base. Examples of the trifluoromethanesulfonylating reagent include trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid chloride, or N-phenylbis(trifluoromethanesulfonimide) and the like. Examples of the base include triethylamine, diisopropylethylamine and the like. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane and the like, or a mixture thereof. The reaction temperature is usually about -20 °C to room temperature, and the reaction time is usually about 0.5 to 24 hours. (Step C2) Step of performing a coupling reaction using a transition metal catalyst Step of obtaining compound (C-III) from compound (C-II) in the presence of a base using a palladium catalyst and R 3 -A-B * is a step of obtaining compound (C-III). Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, palladium acetylacetonate, bis(triphenylphosphine)palladium dichloride, and the like. Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, or sodium phosphate, and the like. Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, toluene, etc., or a mixture thereof. The reaction temperature is usually about 60 to 120°C, and the reaction time is usually about 0.5 to 12 hours. [Method D] Method D is a method for producing the compound (D-IV) of the present invention from compound (D-I) (a compound corresponding to compound (C-II) used in Method C). [In the formula, R 1 , R 2 , R 3 and Tf have the same meanings as described above. R 4 represents a phenyl group which may have a substituent.] (Step D1) Step of coupling with a formate ester Step of obtaining compound (D-II) from compound (D-I) in the presence of a base and a palladium catalyst (phosphine ligand) using a formate ester. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide. Examples of the formate ester include phenyl formate or (2,4,6-trichlorophenyl) formate. Examples of the palladium catalyst include palladium acetate, palladium acetylacetonate, palladium trifluoroacetate, palladium dichloride, tris(dibenzylideneacetone)dipalladium, or bis(triphenylphosphine)palladium dichloride. Examples of the phosphine ligand used simultaneously with the palladium catalyst include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2,2'-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), bis(diphenylphosphino)methane (DPPM), triphenylphosphine, or 1,2-bis(diphenylphosphino)ethane (DPPE). Examples of the solvent include N,N-dimethylformamide, toluene, tetrahydrofuran, acetonitrile, or a mixture thereof. The reaction temperature is usually about room temperature to 120°C, and the reaction time is usually about 1 to 8 hours. (Step D2) Step of performing amidation with acylhydrazine This is a step of obtaining compound (D-III) from compound (D-II) using the corresponding acylhydrazine in the presence of a base. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide. As additives, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), etc. may be advantageous for the smooth progress of the reaction. Examples of the solvent include N,N-dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, etc., or a mixture thereof. The reaction temperature is usually about 0 to 60 °C, and the reaction time is usually about 1 to 12 hours. (D3 step) Step of forming a ring This is a step of obtaining compound (D-IV) from compound (D-III) using a dehydrating agent. Examples of the dehydrating agent include (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt, phosphoryl chloride, polyphosphoric acid, sulfuric acid, triphenylphosphine / iodine, tosic acid, tosyl chloride, etc. Examples of the solvent include toluene, acetonitrile, dichloromethane, etc., or a mixed solvent thereof, or no solvent. The reaction temperature is usually about 0 to 100 °C, and the reaction time is usually about 0.5 to 24 hours. [E method] The E method is a method for producing the compound (E-III) of the present invention from the compound (E-I) (a compound corresponding to the compound (D-II) used in the D method). [wherein, R 1 , R 2 , R 3 and R 4 have the same meanings as described above. ] (E1 step) Step of performing amidoxime and acylation This is a step of obtaining compound (E-II) from compound (E-I) using the corresponding amidoxime in the presence of a base. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide, etc. As additives, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), etc. may be advantageous for the smooth progress of the reaction. Examples of the solvent include N,N-dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, etc., or a mixture thereof. The reaction temperature is usually about room temperature to 80°C, and the reaction time is usually about 1 to 12 hours. (Step E2) Step of forming a ring This is a step of obtaining compound (E-III) by stirring compound (E-II) in a solvent at room temperature or under heating. Examples of the solvent include toluene, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, etc., or a mixture thereof. The reaction temperature is usually about room temperature to 100°C, and the reaction time is usually about 0.5 to 24 hours. [Method F] Method F is a method for producing compound (F-V) of the present invention from compound (F-I) (a compound corresponding to compound (C-II) used in Method C). [In the formula, R 1 , R 2 , R 3 , and Tf have the same meanings as described above. ] (Step F1) Step of performing cyanation using a transition metal catalyst This is a step of obtaining compound (F-II) from compound (F-I) in the presence of zinc cyanide and a palladium catalyst, in the presence or absence of phosphine. Examples of the palladium catalyst include tris(dibenzylideneacetone)dipalladium, bis[tri(tert-butyl)phosphine]palladium, tetrakis(triphenylphosphine)palladium, bis(trifluoroacetoxy)palladium, etc. Examples of the phosphine include triphenylphosphine, tri(tert-butyl)phosphine, tri-o-tolylphosphine, diphenylphosphinofluorene, diphenylphosphinobutane, etc. Examples of the solvent include N-methyl-2-pyrrolidone or N,N-dimethylformamide, etc., or a mixture thereof. The reaction temperature is usually about 80 to 120 °C, and the reaction time is usually about 1 to 8 hours. (Step F2) Step of adding hydroxylamine It is a step of obtaining compound (F-III) from compound (F-II) using hydroxylamine. Examples of the solvent include methanol, ethanol, dimethyl sulfoxide, water, etc., or a mixed solvent thereof. The reaction temperature is usually about room temperature to 100 °C, and the reaction time is usually about 0.5 to 24 hours. (Step F3) Step of acylating oxime It is a step of obtaining compound (F-IV) from compound (F-III) using the corresponding carboxylic acid in the presence of a condensing agent and a base. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine (DMT-MM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC, or EDCI), etc. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, etc. As additives, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), etc. may be advantageous for the smooth progress of the reaction. Examples of the solvent include ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dichloromethane, toluene, etc., or a mixed solvent thereof. The reaction temperature is usually about room temperature to 60 °C, and the reaction time is usually about 0.5 to 24 hours. (Step F4) Step of forming a ring It is a step of obtaining compound (F-V) by stirring compound (F-IV) in a solvent at room temperature or under heating. Examples of the solvent include toluene, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, or a mixture thereof. The reaction temperature is generally about 60 to 120 °C, and the reaction time is generally about 0.5 to 24 hours. [G method] The G method is a method for producing the compound (G-III) of the present invention from the compound (G-I). [wherein, R 1 , R 2 , R 3 , A and X have the same meanings as described above. ] (G1 step) Demethylation step This is a step of obtaining the compound (G-II) from the compound (G-I). It can be carried out in the same manner as in the (B1 step). (G2 step) Alkylation step This is a step of obtaining the compound (G-III) from the compound (G-II). It can be carried out in the same manner as in the (A2 step). [H method] The H method is a method for producing the compound (H-I) of the present invention from the compound (H-II). By deprotecting the protecting group contained in R 1’ or R 3’ to convert it to R 1 or R 3 . [wherein, R 1 , R 2 , R 3 and A have the same meanings as described above. R 1’ and R 3’ represent protected R 1 and R 3 , for example, when R 1 is a hydroxy C1-C6 alkyl group, it represents a hydroxy C1-C6 alkyl group protected with a protecting group such as a tetrahydropyranyl group or a t-butyldimethylsilyl group. ] (H1 step) Deprotection step (In the case of a tetrahydropyranyl (THP) group) This is a step of obtaining compound (H-II) from a compound (H-I) containing a hydroxy group protected with a tetrahydropyranyl group using an acid. Examples of the acid include hydrochloric acid, sulfuric acid, hydrochloric acid - methanol, hydrochloric acid - 1,4 - dioxane, hydrochloric acid - ethyl acetate, acetic acid, p - toluenesulfonic acid, or pyridinium p - toluenesulfonate, etc. Examples of the solvent include methanol, ethanol, tetrahydrofuran, water, or a mixture thereof, etc. The reaction temperature is usually about 0 to 80 °C, and the reaction time is usually about 0.5 to 24 hours. (In the case of a silyl group) In this step, the silyl group refers to a silyl group generally used as a protecting group in synthesis, such as a trimethylsilyl group, a t - butyldimethylsilyl group, etc. This is a step of obtaining compound (H-II) from a compound (H-I) containing a hydroxy group protected with a silyl group using a desilylation reagent. Examples of the desilylation reagent include an acid or tetrabutylammonium fluoride (TBAF), hydrogen fluoride, or hydrogen fluoride pyridine, etc. Examples of the acid include hydrochloric acid, sulfuric acid, hydrochloric acid - methanol, hydrochloric acid - 1,4 - dioxane, hydrochloric acid - ethyl acetate, acetic acid, p - toluenesulfonic acid, or trifluoroacetic acid, etc., and it is also possible to react in a catalytic amount. Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,2 - dimethoxyethane, 1,4 - dioxane, acetonitrile, water, etc., or a mixture thereof. The reaction temperature is usually about 0 to 60 °C, and the reaction time is usually about 0.5 to 24 hours. The compound produced by the above method can be isolated and purified by known methods, such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization, etc. In addition, when the compound or the intermediate of the production has an asymmetric carbon, optical isomers exist. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt splitting) by recrystallizing with an appropriate salt and column chromatography. As a reference for methods of resolving optical isomers from a racemate, "Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc." by J. Jacques et al. can be cited. (Dosage form) Administration can be in any form, including oral administration by tablets, pills, capsules, granules, powders, solutions, etc., or parenteral administration by injections such as intramuscular, intravenous, and subcutaneous injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc. As solid compositions for oral administration, tablets, powders, granules, etc. are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and / or magnesium aluminometasilicate. The composition may contain inert additives such as lubricants like magnesium stearate, disintegrants like sodium carboxymethyl starch, stabilizers, and solubilizing aids according to conventional methods. Tablets or pills may be coated with a sugar coating or a film of a gastric-soluble or enteric-soluble substance if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and generally contain an inert diluent such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain solubilizers, wetting agents, auxiliary agents such as suspending agents, sweeteners, flavoring agents, fragrances, and preservatives. Injections for parenteral administration It contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80, etc. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing aids. These are sterilized, for example, by filtration through a bacteria-retaining filter, incorporation of a bactericide, or irradiation. Also, these can be used by manufacturing a sterile solid composition and dissolving or suspending it in sterile water or a sterile injection solvent before use. As for external preparations, It includes ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, etc. It contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, etc. For example, as the ointment or lotion base, polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. can be mentioned. Transmucosal agents such as inhalants and nasal preparations can be in solid, liquid or semi-solid forms and can be manufactured according to conventionally known methods. For example, known excipients, and further, pH adjusters, preservatives, surfactants, lubricants, stabilizing agents, thickening agents, etc. may be appropriately added. Administration can be carried out using a device suitable for inhalation or insufflation. For example, using a known device such as a metered-dose inhaler or a nebulizer, the compound can be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers, etc. can be for single or multiple administrations, and dry powder or powder-containing capsules can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluorocarbon, hydrofluorocarbon or carbon dioxide. (Dosage) In the case of oral administration, the daily dosage is preferably about 0.001 - 100 mg / kg, more preferably 0.1 - 30 mg / kg, and still more preferably 0.1 - 10 mg / kg per body weight, and this can be administered once or divided into two or more times. In the case of intravenous administration, the daily dosage is preferably about 0.0001 - 10 mg / kg per body weight, and it is administered once a day or divided into multiple times. Also, as a transmucosal agent, about 0.001 - 100 mg / kg per body weight is administered once a day or divided into multiple times. The dosage is appropriately determined according to individual cases considering symptoms, age, gender, etc. (Combined use) In the present invention, it can be used in combination with various therapeutic or prophylactic agents for diseases considered to exhibit its effectiveness. Such combined use may be administered simultaneously, or separately continuously, or at desired time intervals. The simultaneous administration preparation may be a formulated agent or separately formulated. (Formulation Example 1) Powder A powder is obtained by mixing 5 g of the salt of the present invention or its hydrate, 895 g of lactose, and 100 g of corn starch in a blender. (Formulation Example 2) Granules After mixing 5 g of the salt of the present invention or its hydrate, 865 g of lactose, and 100 g of low-substituted hydroxypropyl cellulose, 300 g of a 10% aqueous solution of hydroxypropyl cellulose is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules. (Formulation Example 3) Tablets Tablets are obtained by mixing 5 g of the salt of the present invention or its hydrate, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate in a blender and then tableting with a tableting machine. The pharmacological activity of the compound of the present invention or its pharmaceutically acceptable salt was confirmed by the following tests. (Test Example) Measurement of TNF-α inhibition rate The test substance suspended in 0.5% (w / v) methyl cellulose was orally administered to mice at 100 mg / kg. One hour later, 0.4 mg / kg of lipopolysaccharide (LPS, Sigma - Aldrich, L2630 (trade name)) was intraperitoneally administered to induce inflammation. One hour after the administration of LPS, blood was collected from the large vein under isoflurane anesthesia and collected into a tube containing a serum separator. After standing at room temperature for 20 - 30 minutes, it was centrifuged at 12,000 rpm for 5 minutes at 4 degrees, and the serum was collected. Then, using Mouse TNF - α ELISA Kit (Invitrogen, KMC3011C (trade name)) or Mouse TNF - α Immunoassay kit (PerkinElmer, AL505 (trade name)), the amount of TNFα in the serum was measured according to the protocol of this kit. The serum was diluted 10 - fold with the diluent attached to the kit before use. The TNF - α inhibition rate (%) of the test substance was calculated from the following formula. TNF - α inhibition rate (%) = [(TNF - α amount in the control group) - (TNF - α amount in the test substance - administered group)] × 100 / (TNF - α amount in the control group) Hereinafter, the present invention will be described in more detail with reference to examples and test examples, but the scope of the present invention is not limited thereto. In the following examples, nuclear magnetic resonance (hereinafter, 1 1H NMR) spectra were described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern was indicated as singlet by s, doublet by d, triplet by t, quartet by q, multiplet by m, and broad by br. (Example 1) (2S,5'R)-7 - chloro - 6-(2 - hydroxyethoxy)-3',4 - dimethoxy - 5'-methyl - spiro[benzofuran - 2,4'-cyclohex - 2 - en]-1',3 - dione (1a) (2S,5'R)-7-chloro-6-hydroxy-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-hydroxy-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (+)-Glycerofulvin (CAS number: 126-07-8, product code: G0384 (Tokyo Chemical Industry)) (50 g), potassium iodide (23.5 g), 18-crown-6-ether (41.2 g) were dissolved in pyridine (500 mL), stirred at 120 °C for 9 hours, and left to stand overnight at room temperature. The reaction mixture was concentrated, 4% aqueous sodium bicarbonate was added, and the mixture was washed twice with ethyl acetate. The aqueous layer was neutralized with 1 mol / l hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography [elution solvent: dichloromethane / ethanol = 99 / 1 (V / V)] to obtain 19.4 g of a crude product. Ethyl acetate was added to solidify the product, which was then collected by filtration to obtain 15.2 g (yield: 32%) of the title compound as a white solid. (1b) (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-hydroxy-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (0.1 g) of Example 1 (1a) was dissolved in N,N-dimethylformamide (3 mL), 2-bromoethanol (0.0738 g) and potassium carbonate (0.102 g) were added, and the mixture was stirred at 100 °C for 6 hours. The reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: ethyl acetate] to obtain 38 mg (yield: 34%) of the title compound as a pale yellow solid. (Example 2) (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-hydroxy-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (30 mg) of Example 1 (1a) was dissolved in N,N-dimethylformamide (1 mL), 2-bromoethyl methyl ether (136 mg) and potassium carbonate (135 mg) were added, and the mixture was stirred at 80 °C for 6 hours. The reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: ethyl acetate] to obtain 20 mg (yield: 57%) of the title compound as a white solid. (Example 3) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (3a) [(2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate [(2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate Dissolve (2S,5'R)-7-chloro-6-hydroxy-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (20 g) of Example 1(1a) in dichloromethane (300 mL), add N-phenylbis(trifluoromethanesulfonimide) (25.3 g) and triethylamine (20.6 mL), and leave the mixture at room temperature overnight. Dilute the reaction solution with dichloromethane, wash the organic layer with water and saturated brine, and dry it over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 8 / 2 - 3 / 7 (V / V)] to obtain 23.5 g (yield: 85%) of the title compound as a white solid. (3b) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve [(2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate (76 mg) of Example 3 (3a) in N,N-dimethylformamide (1.6 mL), add 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0403 g), potassium carbonate (0.0669 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.0131 g) at room temperature, and stir at 80 °C for 3 hours. After returning the reaction temperature to room temperature, dilute the reaction mixture with ethyl acetate, filter off the insoluble matter. Pour the filtrate into water and extract with ethyl acetate. Wash the organic layer with water and saturated brine, and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure, and purify the residue obtained by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 27 mg (yield: 42%) of the title compound as a white solid. (Example 4) (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve [(2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate (0.5 g) of Example 3 (3a) in toluene (10 mL), add 1-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.283 g), chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) (0.167 g), and saturated aqueous sodium hydrogen carbonate (5 mL), and stir at 90 °C for 2 hours. Pour the reaction mixture into water, and extract the reaction mixture with ethyl acetate. Wash the organic layer with water and saturated brine, and dry over anhydrous sodium sulfate. Distill off the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 266 mg (yield: 60%) of the title compound as a white solid. (Example 5) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (5a) (2,4,6-trichlorophenyl) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (2,4,6-trichlorophenyl) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate [(2S,5'R)-7-Chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate (20 g) of Example 3 (3a) was dissolved in toluene (200 mL), and palladium(II) acetate (0.477 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.46 g), and N,N-diisopropylethylamine (14.8 mL) were added, and the mixture was heated to 80 °C. Trichlorophenyl formate (12.5 g) was added in three portions at 30-minute intervals. After stirring at 80 °C for 30 minutes, the reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 7 / 3 - 3 / 7 (V / V)] to obtain 19.5 g (yield: 84%) of the title compound as a white solid. (5b) (2S,5'R)-N'-Acetyl-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2S,5'R)-N'-acetyl-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2,4,6-Trichlorophenyl) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (35 g) of Example 5 (5a) was dissolved in dichloromethane (400 mL), and 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (8.72 g), acetohydrazide (purity: 90%, 7.12 g), 4-dimethylaminopyridine (0.783 g), and triethylamine (26.8 mL) were added, and the mixture was left at room temperature overnight. The reaction solution 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 [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 23.4 g of the title compound (yield: 86%) as a white solid. (5c) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-N'-acetyl-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (0.25 g) of Example 5(5b) was dissolved in toluene (5 mL) and anhydrous 1,4-dioxane (5 mL), and (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (0.169 g) was added, and the mixture was stirred at 60 °C for 1 hour. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 49 mg of the title compound (yield: 20%) as a white solid. (Example 6) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (6a) [(Z)-1-Aminoethylideneamino] (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate [(Z)-1-aminoethylideneamino] (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate Example 5 (5a) (2,4,6-trichlorophenyl) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (3 g) was dissolved in dichloromethane (50 mL), N'-hydroxyethanimidamide (0.488 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.748 g), 4-dimethylaminopyridine (0.0671 g), and triethylamine (2.28 mL) were added, and the mixture was allowed to stand overnight at room temperature. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 80 / 20-0 / 100 (V / V)] to obtain 2.32 g (yield: quantitative) of the title compound as a white solid. (6b) (2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione [(Z)-1-Aminoethylideneamino](2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.95 g) of Example 6 (6a) was dissolved in toluene (20 mL) and stirred at 110 ° C for 6 hours. The residue obtained by concentrating the reaction solution was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 8 / 2 - 3 / 7 (V / V)], and triturated with n-hexane and ethyl acetate to obtain 756 mg (yield: 83%) of the title compound as a white solid. (Example 7) (2S,5'R)-7-Chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (7a) (2S,5'R)-7-Chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbonitrile (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbonitrile [(2S,5'R)-7-Chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate (1 g) of Example 3 (3a) was dissolved in N,N-dimethylformamide (10 mL), tetrakis(triphenylphosphine)palladium(0) (0.245 g) and zinc cyanide (0.499 g) were added, and the mixture was stirred at 90 ° C for 5 hours. The reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 8 / 2 - 3 / 7 (V / V)] to obtain 540 mg (yield: 73%) of the title compound as a pale yellow solid. (7b) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbonitrile (0.54 g) of Example 7(7a) was dissolved in ethanol (10 mL), 50% hydroxylamine solution (0.19 mL) was added, and the mixture was stirred at 90 °C for 6 hours. The reaction solution was concentrated and azeotroped twice with toluene. The residue was dissolved in dichloromethane (20 mL), acetic acid (0.0891 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.299 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.0424 g), and triethylamine (0.652 mL) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with dichloromethane, 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 roughly purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)]. The obtained crude product was suspended in toluene (5 mL) and stirred at 100 °C for 7 hours. Water was added to the reaction mixture, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 7 / 3 - 2 / 8 (V / V)], and 34 mg of the title compound (yield: 5.4%, 3 steps) was obtained as a white solid. Example 8 (2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (8a) (2S,5'R)-7-chloro-N'-(2-hydroxy-2-methyl-propanoyl)-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2S,5'R)-7-chloro-N'-(2-hydroxy-2-methyl-propanoyl)-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2,4,6-Trichlorophenyl) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.5 g) of Example 5 (5a) was dissolved in dichloromethane (10 mL), and 2-hydroxy-2-methylpropanohydrazide (0.162 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.125 g), 4-dimethylaminopyridine (0.0224 g), and triethylamine (0.639 mL) were added, and the mixture was left at room temperature overnight. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)], and 415 mg of the title compound (yield: 97%) was obtained as a white solid. (8b) (2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-N'-(2-hydroxy-2-methyl-propanoyl)-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (0.415 g) of Example 8(8a) was dissolved in dichloromethane (5 mL), triethylamine (0.62 mL) and p-toluenesulfonyl chloride (0.254 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 141 mg (yield: 35%) of the title compound as a white solid. (Example 9) (2S,5'R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (9a) (2S)-2-tetrahydropyran-2-yloxypropanehydrazide (2S)-2-tetrahydropyran-2-yloxypropanehydrazide Methyl (2S)-2-tetrahydropyran-2-yloxypropanoate (CAS Registry Number: 153829-63-1, J. Org. Chem. 1991, 56, 1088-1093.) (2.2 g) was dissolved in ethanol (8 mL), hydrazine monohydrate (1.8 g) was added, and the mixture was left overnight at room temperature. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 1.6 g (yield: 73%) of the title compound as a white solid. (9b) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-N'-[(2S)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-N'-[(2S)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2,4,6-Trichlorophenyl) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.5 g) of Example 5(5a) was dissolved in dichloromethane (10 mL), and (2S)-2-tetrahydropyran-2-yloxypropanohydrazide (0.258 g) of Example 9(9a), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.125 g), 4-dimethylaminopyridine (0.0112 g), and N,N-diisopropylethylamine (0.478 mL) were added, and the mixture was left overnight at room temperature. The reaction mixture was poured into water, neutralized with 1 mol / l hydrochloric acid, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 490 mg of the title compound (yield: quantitative) as a white solid. (9c) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve (0.49 g) of (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-N'-[(2S)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide of Example 9(9b) in dichloromethane (5 mL), add triethylamine (0.637 mL) and p-toluenesulfonyl chloride (0.209 g), and stir at room temperature for 3 hours. The reaction mixture was poured into water, neutralized with 1 mol / l hydrochloric acid, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 452 mg of the title compound (yield: 95%) as a white solid. (9d) (2S,5'R)-7-Chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Example 9 (9c) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (0.452 g) was dissolved in ethanol (4 mL), and water (1 mL) and p-toluenesulfonic acid monohydrate (0.0828 g) were added and stirred at 50°C for 1 hour. The reaction mixture was poured into water, 1 mol / l hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 1-1 / 19 (V / V)] to obtain 119 mg (yield: 31%) of the title compound as a white solid. Example 10 (2S,5'R)-7-Chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (10a) (2R)-2-Tetrahydropyran-2-yloxypropanehydrazide (2R)-2-tetrahydropyran-2-yloxypropanehydrazide Methyl (2R)-2-tetrahydropyran-2-yloxypropanoate (CAS Registry Number: 124508-74-3, Tetrahedron, 2012, 68, 2068-2073.) (1.6 g) was dissolved in ethanol (8 mL), hydrazine monohydrate (1.2 mL) was added, and the mixture was stirred at 90 °C for 4 hours. After standing at room temperature overnight, the mixture was stirred at 90 °C for 10 hours. After standing at room temperature overnight again, the mixture was stirred at 90 °C for 10 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 1 - 1 / 9 (V / V)] to obtain 1 g (yield: 62%) of the title compound as a white solid. (10b) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-N'-[(2R)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-N'-[(2R)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2,4,6-Trichlorophenyl) (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.5 g) of Example 5 (5a) was dissolved in dichloromethane (10 mL), and (2R)-2-tetrahydropyran-2-yloxypropanohydrazide (0.19 g) of Example 10 (10a), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.124 g), 4-dimethylaminopyridine (0.0112 g), and N,N-diisopropylethylamine (0.478 mL) were added, and the mixture was left standing at room temperature overnight. The reaction mixture was poured into water and neutralized with 1 mol / l hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 460 mg (yield: 94%) of the title compound as a white solid. (10c) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-[(1R)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-[(1R)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-N'-[(2R)-2-tetrahydropyran-2-yloxypropanoyl]spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (0.46 g) from Example 10(10b) in dichloromethane (5 mL), add triethylamine (0.598 mL) and p-toluenesulfonyl chloride (0.196 g), and stir at room temperature for 2 hours. The reaction mixture was poured into water and neutralized with 1 mol / l hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 315 mg (yield: 71%) of the title compound as a white solid. (10d) (2S,5'R)-7-Chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Example 10 (10c) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-[(1R)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (0.315 g) was dissolved in ethanol (4 mL), water (1 mL) and p-toluenesulfonic acid monohydrate (0.0577 g) were added, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was poured into water, 1 mol / l hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10-1 / 19 (V / V)] to obtain 112 mg (yield: 42%) of the title compound as a white solid. Example 11 (2S,5'R)-7-Chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (11a) (2S,5'R)-7-Chloro-4-hydroxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-hydroxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Magnesium, in shavings (0.41 g), was added to diethyl ether (60 mL), and iodine (3.9 g) was added in three portions at 20-minute intervals. After stirring at room temperature for 1 hour, (2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (6.3 g) of Example 8 (8b) and toluene (150 mL) were added, and the mixture was stirred at 90 °C for 7 hours. Water was added to the reaction mixture, and after neutralization with 1 mol / l hydrochloric acid, the mixture was made weakly alkaline with saturated aqueous sodium hydrogen carbonate, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / l hydrochloric acid 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 2.7 g (yield: 44%) of the title compound as a white solid. (11b) (2S,5'R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-hydroxy-6-[5-(1-hydroxy-1-methylethyl)-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (0.3 g) of Example 11(11a) was dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (0.191 g) and iodoethane (0.0827 mL) were added, and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into water and neutralized with 1 mol / l hydrochloric acid, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 6 / 4 - 1 / 9 (V / V)] to obtain 42 mg (yield: 13%) of the title compound as a white solid. (Example 12) (2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]-3'-methoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Magnesium, in shavings (0.073 g), was added to diethyl ether (20 mL), and a small amount of iodine (0.70 g) was added. The mixture was stirred at room temperature for 10 minutes. Further, iodine (0.70 g) was added in three portions at 20-minute intervals. After stirring at room temperature for 30 minutes, toluene (50 mL) and (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[5-[(1S)-1-tetrahydropyran-2-yloxyethyl]-1,3,4-oxadiazol-2-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (1.3 g) of Example 9 (9c) were added, and the mixture was stirred at 80 °C for 8 hours. Water was added to the reaction mixture, and the mixture was neutralized with 1 mol / l hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.36 g) and iodoethane (0.485 mL) were added, and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was poured into water and neutralized with 1 mol / l hydrochloric acid. The reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 7 / 3 - 2 / 8 (V / V)], and the obtained solid was triturated with n-hexane and ethyl acetate to obtain 122 mg (yield: 13%) of the title compound as a white solid. (Example 13) (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (13a) 2-tetrahydropyran-2-yloxypropanenitrile 2-tetrahydropyran-2-yloxypropanenitrile Dissolve 2-hydroxypropanenitrile (5.0 g) in dichloromethane (150 mL), add 3,4-dihydro-2H-pyran (7.7 g) and p-toluenesulfonic acid monohydrate (1.3 g), and stir at room temperature for 14 hours. After adding triethylamine to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 97 / 3 - 7 / 3 (V / V)] to obtain 5.7 g (yield: 52%) and 2.5 g (yield: 23%) of the title compound as two kinds of diastereomers, respectively, as pale yellow solids. (13b) N'-Hydroxy-2-tetrahydropyran-2-yloxy-propanamidine N'-hydroxy-2-tetrahydropyran-2-yloxy-propanamidine Dissolve one of the diastereomers of 2-tetrahydropyran-2-yloxypropanenitrile (5.6 g) obtained in Example 13 (13a) in ethanol (36 mL), add 50% hydroxylamine solution (4.3 mL), heat to 80 °C and stir for 5 hours. After returning to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 10 / 1 - 1 / 0 (V / V)] to obtain 5.0 g (yield: 74%) of the title compound as a pale yellow solid. (13c) [(Z)-(1-Amino-2-tetrahydropyran-2-yloxy-propylidene)amino] (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate [(Z)-(1-amino-2-tetrahydropyran-2-yloxy-propylidene)amino] (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-6-[(2,4,6-trichlorophenyl)carboxylate]spiro[benzofuran-2,6'-cyclohexene] (0.5 g) of Example 5(5a) was dissolved in dichloromethane (10 mL), and N'-hydroxy-2-tetrahydropyran-2-yloxy-propanamidine (0.207 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.125 g), 4-dimethylaminopyridine (0.0112 g), and N,N-diisopropylethylamine (0.478 mL) of Example 13(13b) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and neutralized with 1 mol / l hydrochloric acid, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 410 mg (yield: 83%) of the title compound as a white solid. (13d) (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[3-(1-tetrahydropyran-2-yloxyethyl)-1,2,4-oxadiazol-5-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[3-(1-tetrahydropyran-2-yloxyethyl)-1,2,4-oxadiazol-5-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione of Example 13(13c) [(Z)-(1-Amino-2-tetrahydropyran-2-yloxy-propylidene)amino] (2S,5'R)-7-chloro-1',4-dimethoxy-5'-methyl-3,3'-dioxo-spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.41 g) was dissolved in toluene (5 mL) and stirred at 110 °C for 7 hours. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 1 / 9 (V / V)] to obtain 375 mg (yield: 95%) of the title compound as a white solid. (13e) (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-[3-(1-tetrahydropyran-2-yloxyethyl)-1,2,4-oxadiazol-5-yl]spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (0.375 g) of Example 13(13d) was dissolved in ethanol (4 mL), p-toluenesulfonic acid monohydrate (0.0687 g) and water (1 mL) were added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 195 mg (yield: 62%) of the title compound as a white solid. (Example 14) (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (14a) (2S,5'R)-7-chloro-4-hydroxy-3',6-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-hydroxy-3',6-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Magnesium, turnings (1.03 g) was added to diethyl ether (50 mL), and iodine (8.63 g) was added little by little over 1 hour. After stirring at room temperature for 30 minutes, toluene (100 mL) and (+)-glyceofulvin (10 g) were added, and the mixture was stirred at 80 °C for 3 hours. Water was added to the reaction mixture, and the mixture was neutralized with 1 mol / l hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 7.8 g (yield: 81%) of the title compound as a white solid. (14b) (2S,5'R)-7-chloro-3',6-dimethoxy-5'-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3',6-dimethoxy-5'-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve (2S,5'R)-7-chloro-4-hydroxy-3',6-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (5.1 g) of Example 14(14a) in N,N-dimethylformamide (60 mL), add 2-(2-bromoethoxy)tetrahydro-2H-pyran (3.8 g) and potassium carbonate (6.2 g), and stir at 80 °C for 7 hours. Pour the reaction mixture into water, and extract the reaction mixture with ethyl acetate. Wash the organic layer with water and saturated brine, and dry over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 8 / 2 - 3 / 7 (V / V)] to obtain 6.9 g (yield: 98%) of the title compound as a white solid. (14c) (2S,5'R)-7-chloro-6-hydroxy-3'-methoxy-5'-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-6-hydroxy-3'-methoxy-5'-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve (2S,5'R)-7-chloro-3',6-dimethoxy-5'-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (6.9 g) of Example 14(14b) in pyridine (70 mL), add 18-crown-6-ether (4.3 g) and potassium iodide (2.5 g), and stir at 120 °C for 8 hours. The reaction solution was concentrated, the reaction mixture was poured into water, and 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 3.8 g of the title compound (yield: 57%) as a white solid. (14d) [(2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate [(2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate Dissolve 3.8 g of (2S,5'R)-7-chloro-6-hydroxy-3'-methoxy-5'-methyl-4-(2-tetrahydropyran-2-yloxyethoxy)spirobenzofuran-2,4'-cyclohex-2-en]-1',3-dione from Example 14(14c) in dichloromethane (40 mL), add triethylamine (2.9 mL) and N-phenylbis(trifluoromethanesulfonimide) (3.6 g), and leave at room temperature overnight. The reaction solution was diluted with dichloromethane, 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 [elution solvent: n-hexane / ethyl acetate = 8 / 2 - 4 / 6 (V / V)] to obtain 3.2 g of the title compound (yield: 65%) as a white solid. (14e) (2,4,6-Trichlorophenyl) (2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (2,4,6-trichlorophenyl) (2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate [(2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-yl] trifluoromethanesulfonate (1 g) of Example 14(14d) was dissolved in toluene (200 mL), and palladium(II) acetate (0.0192 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0989 g), and N,N-diisopropylethylamine (0.596 mL) were added, and the mixture was heated to 80°C. 2,4,6-Trichlorophenyl formate (0.501 g) was added in three portions at 10-minute intervals. After stirring at 80°C for 30 minutes, the reaction mixture was returned to room temperature, poured into water, and 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 [elution solvent: n-hexane / ethyl acetate = 8 / 2 - 4 / 6 (V / V)] to obtain 850 mg (yield: 75%) of the title compound as a white solid. (14f) (2S,5'R)-N'-acetyl-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2S,5'R)-N'-acetyl-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (2,4,6-Trichlorophenyl) (2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.4 g) of Example 14(14e) was dissolved in dichloromethane (20 mL), and acetohydrazide (purity: 90%, 0.0673 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.0824 g), 4-dimethylaminopyridine (0.0148 g), and triethylamine (0.254 mL) were added, and the mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into water, neutralized with 1 mol / l hydrochloric acid, and the reaction mixture was 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 [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 280 mg (yield: 86%) of the title compound as a white solid. (14g) (2S,5'R)-7-chloro-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-N'-acetyl-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carbohydrazide (0.28 g) of Example 14(14f) was dissolved in dichloromethane (5 mL), and p-toluenesulfonyl chloride (0.149 g) and triethylamine (0.364 mL) were added, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into water and 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 [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 202 mg (yield: 75%) of the title compound as a white solid. (14h) (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (0.202 g) of Example 14(14g) was dissolved in ethanol (2 mL), and p-toluenesulfonic acid monohydrate (0.037 g) and water (5 mL) were added, followed by stirring at 50 °C for 2 hours. The reaction mixture was poured into water and 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 [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 39 mg (yield: 23%) of the title compound as a white solid. (Example 15) (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (15a) [(Z)-1-aminoethylideneamino] (2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate [(Z)-1-aminoethylideneamino] (2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (2,4,6-Trichlorophenyl) (2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.45 g) of Example 14 (14e) was dissolved in dichloromethane (10 mL), and N'-hydroxyethanimidamide (0.0758 g), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.0928 g), 4-dimethylaminopyridine (0.00833 g), and triethylamine (0.285 mL) were added, and the mixture was left at room temperature overnight. The reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 345 mg of the title compound (yield: 94%) as a white solid. (15b) (2S,5'R)-7-chloro-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione [(Z)-1-aminoethylideneamino] (2S,5'R)-7-chloro-1'-methoxy-5'-methyl-3,3'-dioxo-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,6'-cyclohexene]-6-carboxylate (0.345 g) of Example 15(15a) was suspended in toluene (5 mL) and stirred at 100 °C for 5 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 1 / 1 - 0 / 1 (V / V)] to obtain 283 mg of the title compound (yield: 85%) as a white solid. (15c) (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(2-tetrahydropyran-2-yloxyethoxy)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (0.283 g) of Example 15(15b) was dissolved in ethanol (2 mL), p-toluenesulfonic acid monohydrate (0.0518 g) and water (5 mL) were added, and the mixture was stirred at 50 °C for 3 hours. The reaction mixture was poured into water, and the reaction mixture was 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 [elution solvent: methanol / ethyl acetate = 0 / 10 - 1 / 9 (V / V)] to obtain 128 mg (yield: 54%) of the title compound as a white solid. (Example 16) (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (16a) (2S,5'R)-7-chloro-4-hydroxy-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-hydroxy-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2.3 g) of Example 7(7b) in a mixed solvent of toluene (20 mL) and ether (40 mL), add magnesium iodide (1.52 g), and stir at 80 °C for 5 hours. Water was added to the reaction mixture, and after neutralization with 4N hydrochloric acid, the reaction mixture was 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 [elution solvent: petroleum ether / ethyl acetate = 1 / 1 (V / V)] to obtain 1.7 g (yield: 64%) of the title compound as a yellow solid. (16b) (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Dissolve palladium chloride (0.45 mg) in water (2 mL), add tetrabutylammonium bromide (10.3 mg) and potassium carbonate (4.42 mg). After stirring at 60 °C for 15 minutes, add (2S,5'R)-7-chloro-4-hydroxy-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione (50 mg) of Example 16(16a) and oxirane (28.1 mg), and stir at 60 °C for 12 hours. The reaction mixture was poured into water, and the reaction mixture was extracted with dichloromethane. 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 thin-layer chromatography [developing solvent: ethyl acetate] to obtain 16 mg of the title compound (yield: 29%) as a yellow solid. The structural formulas of the compounds described in the examples and their physicochemical data are summarized below.

Claims

------29 / 03 / 2560------(OCR) Page 1 of 6 Claims 1. Compounds of the general formula (1) or its pharmacologically acceptable salts:[Formula1] where the symbols in the formula are defined below:R1:C1-C6 alkyl group or hydroxylC1-C6 alkyl group,R2:C1-C6 alkyl group,A:Aromatic heterocyclic 5-members with bonds and containing 1-4 atoms chosen from groups containing nitrogen atoms, oxygen atoms and sulfur atoms, or oxygen atoms,andR3:ifA is an aromatic heterocyclic 5-member with bonds and containing 1-4 atoms chosen from groups containing nitrogen atoms, oxygen atoms and sulfur atoms,thenR3 is aC1-C6 alkyl group, hydroxylC1-C6 alkyl group or C1-C6 alkoxyC1-C6 alkyl group;and ifA is an oxygen atom,thenR3 is a hydroxylC1-C6 alkyl group or C1-C6 alkoxyC1-C6 alkyl group2. Pharmaceutically acceptable compounds or their salts under claim1, where R1 is a methyl, ethyl or hydroxyethyl group3. Pharmaceutically acceptable compounds or their salts under claim1 or 2,4. A pharmaceutically acceptable compound or its salt under any of the claims 1 to 3, where A is an aromatic heterocyclic 5-member with -bonds and has 1-4 faces 2 of 6 faces selected from groups consisting of nitrogen atoms, oxygen atoms and sulfur atoms; and R3 is a methyl group, ethyl group, hydroxyl C1-C3 alkyl group or methoxy C1-C3 alkyl group.

5. A pharmaceutically acceptable compound or its salt under any of the claims 1 to 4, where A is an aromatic heterocyclic r-member with bonds selected from the following groups: [Formula 2] chemical formula where * represents bonds.

6. A pharmaceutically acceptable compound or its salt under any of the claims 1 to 3, where A is an oxygen atom.

7. Compounds of general formula (1) or their salts that are pharmaceutically acceptable: [Formula 3] Chemical formulas where the symbols in the formula are defined below: R1: methyl group, ethyl group or hydroxyl group, R2: methyl group, A: aromatic heterocyclic 5-member with a bond chosen from the subsequent group: Page 3 of 6 pages [Formula 4] Chemical formulas where * represents a bond, and R3: methyl group,Ethyl or hydroxyl C1-C3 alkyl groups 8. Pharmaceutically acceptable compounds or salts selected from the following groups: (2S,5'R)-7-chloro-6-(2-hydroxyethoxy)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R-7-chloro-3',4-dimethoxy-6-(2-methoxyethoxy)-5'-methyl-spiro[benzofuran- 2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(1-methylpyrazole-3-il)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-6-(1-ethylpyrazole-3-il)-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione, (2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazoll-2-il)spiro[benzofuran-2,4'-cyclohex-2-ine]-1',3-dione,(2S,5'R)-7-chloro-3',4-dimethoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazoll (2S,5'R)-7-chloro-3',4-chymethoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-il)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiasol-2-yl]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione, page 4 of number 6 (2S,5'R)-7-chloro-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiasol- 2-il]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-6-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-il]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione, (2S,5'R)-7-chloro-4-ethoxy-6-[5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-il]-3'-methoxy-4'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-4-ethoxy-6-[5-[(1S)-1-hydroxyethyl]-1,3,4-oxadiazol-2-il]-3'-methoxy-5'-methyl-spiro [benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-6-[3-(1-hydroxyethyl)-1,2,4-oxadiazol-5-il]-3',4-dimethoxy-5'-methyl-spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,3,4-oxadiazole-2-il)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,(2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(3-methyl-1,2,4-oxadiazole-5-il)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione,and (2S,5'R)-7-chloro-4-(2-hydroxyethoxy)-3'-methoxy-5'-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)spiro[benzofuran-2,4'-cyclohex-2-ene]-1',3-dione9. A pharmaceutical composition containing any of the pharmaceutically acceptable compounds or their salts under any of the claims 1 through 8, as the active ingredient.

10. A pharmaceutical composition under claim 9, for the prevention and / or treatment of inflammatory diseases.

11. Pharmaceutical components according to claim10, where the inflammatory disease is selected from a group comprising rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, bronchial asthmatic disease, interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, acute nephritis, chronic nephritis, severe nephritis, autoimmune nephritis, primary biliary cirrhosis,Cholecystitis (page 5 of 6), Primary hepatitis, Alcoholic hepatitis, Non-alcoholic hepatitis, Cirrhosis, Peripheral neuropathy, Ankylosing spondylitis, Dermatitis (acute, subacute, chronic), Contact dermatitis, Photodermatitis (ultraviolet radiation), Radiation dermatitis, Atopic dermatitis, Seborrheic dermatitis, Plaqueous psoriasis, Psoriatic arthritis, Generalized erythematous psoriasis, Pustular psoriasis, Lichen planus, Skin characteristics Eczema, rosacea, urticaria, alopecia areata, pemphigus, generalized erythema, acne, pressure sores, wounds, burns, conjunctivitis, keratitis, ocular inflammation, acute / chronic otitis media, year-round allergic rhinitis, hay fever, sinusitis, laryngitis, esophagitis, treatment-resistant stomatitis, glossitis, severe / chronic salivary gland inflammation, cheilitis, rimelitis, Behcet's disease, multiple sclerosis, diabetes mellitus type I, diabetes mellitus type II, atherosclerosis.Pancreatitis and chronic heart failure12. Pharmaceutical components according to claim10, where the inflammatory disease is selected from a group comprising rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerotic cholangitis, alcoholic hepatitis, fatty liver disease with hepatitis, ankylosing spondylitis, contact dermatitis, photodermatitis (UV), atopic dermatitis, Sebaceous dermatitis, psoriatic arthritis, psoriatic erythematous eczema, pustular psoriasis, lichen planus, erythematous dermatitis, rosacea, alopecia areata, pemphigus, psoriatic erythematous eczema, acne, pressure sores, wounds, burns, sinusitis, laryngitis, esophagitis, treatment-resistant stomatitis, glossitis, severe / chronic salivary gland inflammation, cheilitis, rimal stomatitis, and Behcet's disease.

13. Pharmaceutical components according to claim10, where the inflammatory disease is selected from a group comprising rheumatoid arthritis,Systemic lupus erythematosus, autoimmune hepatitis, alcoholic hepatitis, fatty liver disease with hepatitis, ankylosing spondylitis, atopic dermatitis, psoriatic arthritis, psoriatic erythematosus (six out of six faces) of the body, pustular psoriasis, lichen planus, pressure ulcers, wounds, refractory stomatitis, glossitis, and Behcet's disease.

14. Pharmaceutically acceptable compounds or their salts under any of the claims 1 to 8, for the treatment of inflammatory diseases.

15. Method for the effective dosage of the pharmaceutical components under claim 9, for the prevention and / or treatment of inflammatory diseases.

16. TNF inhibitors - chemical formulations containing a compound or its salts that are pharmaceutically acceptable under any of Claims 1 to 8, with the active ingredient being the compound------------Revised 02 / 10 / 2018, page 1 of 5 pages, Claims 1. A compound of the general formulation (1) or its salts that are pharmaceutically acceptable; (chemical formulation structure) (1) where the symbols in the formulation are defined below: R1: alkyl C1-C6 group or hydroxyl C1-C6 alkyl group, R2: alkyl C1-C6 group,A: An aromatic heterocycle 5-member containing 1-4 atoms chosen from a group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, or just oxygen atoms; and R3: If A is an aromatic heterocycle 5-member containing 1-4 atoms chosen from a group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, then R3 is a C1-C6 alkyl group, a hydroxyl C1-C6 alkyl group, or a C1-C6 alkoxyC1-C6 alkyl group; and if A is an oxygen atom, then R3 is a hydroxyl C1-C6 alkyl group or a C1-C6 alkoxyC1-C6 alkyl group;