Prophylactic and / or therapeutic agent for kidney disease containing a tricyclic compound

Abstract

To provide a preventive and / or therapeutic agent for kidney diseases. 【Solution】Provided is a preventive and / or therapeutic agent for kidney diseases containing a compound represented by formula (I) or a salt thereof. TIFF2026071419000089.tif5653 In the formula, R 1 is, for example, COOH; X 1 , X 2 and X 3 are each independently N, CH, etc.; Y represents O or S, and the ring containing Y is a 7- or 8-membered ring; Z represents CHR 10 or O, and R 10 is H, halogen, OH group, etc.; other substituents each represent a specific group.

Description

[Technical Field]

[0001] This disclosure relates to the following general formula (I) [ka] This invention relates to a preventive and / or therapeutic agent for kidney disease containing a compound represented by (wherein all symbols have the same meaning as described below) or a salt thereof (hereinafter sometimes abbreviated as the "inventive compound"). [Background technology]

[0002] Prostaglandins are known as metabolites in the arachidonic acid cascade, and their effects are known to include cytoprotection, uterine contraction, pain induction, promotion of gastrointestinal peristalsis, stimulant effects, suppression of gastric acid secretion, hypotensive effects, and diuretic effects. Furthermore, it is known that there are subtypes of PGE (prostaglandin E) receptors, each with a different role. There are currently four known subtypes, broadly classified as EP1, EP2, EP3, and EP4 (Non-Patent Literature 1). Incidentally, Non-Patent Documents 2 and 3 concerning tricyclic compounds are known. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Journal of Biological Chemistry, Vol. 282, No. 16, pp. 11613-11617 [Non-Patent Document 2] Phytochemistry, Vol. 16, No. 4, pp. 494-495 [Non-Patent Document 3] Journal of Organic Chemistry, Vol. 64, No. 17, pp. 6380-6386.

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of the present invention is to provide a preventive and / or therapeutic agent for kidney diseases containing a compound having EP3 agonist activity.

Means for Solving the Problems

[0005] As a result of intensive studies to solve the above problems, the present inventors have found that the following compounds have strong EP3 agonist activity and can be a preventive and / or therapeutic agent for kidney diseases.

[0006] The present invention is, for example, the following aspects. [1] General formula (I)

Chemical formula

Chemical formula

[10] The agent described in [9], wherein the chronic kidney disease is diabetic nephropathy, nephrosclerosis, IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative glomerulonephritis, lupus nephritis, minimal change nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, Alport syndrome, or polycystic kidney disease.

[11] The agent described in any one of items [1] to [8], wherein the kidney disease is acute kidney injury.

[12] The agent described in

[11] , wherein the acute kidney injury is acute kidney injury associated with organ surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis, contrast-induced nephropathy, or drug-induced kidney injury. A method for preventing and / or treating kidney disease, characterized by administering an effective amount of a compound or salt thereof described in any one of items

[13] [1] to [8] to a mammal (preferably a patient in need thereof).

[14] A compound or salt thereof described in any one of items [1] to [8], for use in the prevention and / or treatment of kidney disease.

[15] Use of any compound or salt thereof described in any one of [1] to [8] for the manufacture of agents for the prevention and / or treatment of kidney disease.

[16] A pharmaceutical composition comprising any one of the compounds or salts thereof described in [1] to [8] for use in the prevention and / or treatment of kidney disease.

[17] An EP3 agonist comprising any one of the compounds described in [1] to [8] or a salt thereof, for use in the prevention and / or treatment of renal disease.

[18] A pharmaceutical composition comprising any one of the compounds or salts thereof described in [1] to [8] for the manufacture of an agent for the prevention and / or treatment of kidney disease.

[19] An EP3 agonist comprising any one of the compounds described in [1] to [8] or a salt thereof, for the manufacture of an agent for the prevention and / or treatment of renal disease. [Effects of the Invention]

[0007] The compound of the present invention has potent EP3 agonist activity and is therefore useful as a preventive and / or therapeutic agent for kidney disease. [Modes for carrying out the invention]

[0008] The present invention will be described in detail below. In the present invention, C1-6 alkyl groups include linear or branched C1-6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, and their isomers. In the present invention, halogens include fluorine, chlorine, bromine, and iodine. In the present invention, C1-4 alkyl groups include linear or branched C1-4 alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and their isomers. In this invention, C1-2 alkyl means methyl or ethyl. In the present invention, examples of C3-4 saturated carbon rings include cyclopropane and cyclobutane.

[0009] In the present invention, C1-4 haloalkyl refers to a group in which any hydrogen atom of a linear or branched C1-4 alkyl group is substituted with one or more halogen atoms. Examples include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, and their isomers.

[0010] In the present invention, C2-4 alkenyls include linear or branched C2-4 alkenyls, such as ethenyl, propenyl, butenyl, and their isomers. In the present invention, a C2-4 haloalkenyl refers to a group in which any hydrogen atom of a linear or branched C2-4 alkenyl group is substituted with one or more halogen atoms. Examples include 1-fluoroethenyl, 2-fluoroethenyl, 2-chloroethenyl, trifluoroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl, and their isomers.

[0011] In the present invention, C2-4 alkynyl refers to linear or branched C2-4 alkynyl groups, such as ethynyl, propynyl, butynyl, and their isomers. In the present invention, C2-4 haloalkynyl refers to a group in which any hydrogen atom of a linear or branched C2-4 alkynyl group is substituted with one or more halogen atoms. Examples include 1-fluoroethynyl, 2-fluoroethynyl, 2-chloroethynyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl, and their isomers.

[0012] In the present invention, examples of C3-6 saturated carbon rings include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0013] In the present invention, a 3-6 member saturated heterocycle refers to a saturated heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, for example, aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, thiirane, thiethane, tetrahydrothiophene, tetrahydrothiopyran, tetrahydrooxazole (oxazo Examples include lysine, tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathian, dioxolane, dioxane, dithiolane, and dithiane.

[0014] In the present invention, C3-7 alkyl includes linear or branched C3-7 alkyl groups, such as propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methyl Examples include rupentyl, 4-methylpentyl, 2,3-dimethylbutyl, 1-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1-ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl, 1,1,3-trimethylbutyl, 1,1-diethylpropyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 3-ethylpentyl, and their isomers.

[0015] In the present invention, C3-7 alkenyls include linear or branched C3-7 alkenyls, such as propenyl, butenyl, pentenyl, hexenyl, heptenyl, isopropenyl, isobutenyl, 1-methylbutenyl, 1-ethylpropenyl, 1,1-dimethylpropenyl, 1,2-dimethylpropenyl, 2-methylbutenyl, 3-methylbutenyl, 1-methylpentenyl, 1-ethylbutenyl, 2-ethylbutenyl, 1-ethyl-1-methylpropenyl, 1-ethyl-2-methylpropenyl, 1,1-dimethylbutenyl, 1,2-dimethylbutenyl, 1,3-dimethylbutenyl, 2-methylpentenyl, 3-methylpentenyl, and 4-methylpentenyl. Examples include nyl, 2,3-dimethylbutenyl, 1-methylhexenyl, 1-ethylpentenyl, 2-ethylpentenyl, 1-propylbutenyl, 2-methyl-3-hexenyl, 1,2-dimethylpentenyl, 1,3-dimethylpentenyl, 1,4-dimethylpentenyl, 1-ethyl-1-methylbutenyl, 1-methyl-2-ethylbutenyl, 1-ethyl-2-methylbutenyl, 1-ethyl-3-methylbutenyl, 1,1-dimethylpentenyl, 1,1,3-trimethylbutenyl, 1,1-diethylpropenyl, 2-methylhexenyl, 3-methylhexenyl, 4-methylhexenyl, 5-methylhexenyl, 3-ethylpentenyl, and their isomers.

[0016] In the present invention, C3-7 alkynyl includes linear or branched C3-7 alkynyl compounds, such as propynyl, butynyl, pentynyl, hexynyl, heptynyl, 1-methylbutynyl, 1-ethylpropynyl, 1,1-dimethylpropynyl, 2-methylbutynyl, 3-methylbutynyl, 1-methylpentynyl, 1-ethylbutynyl, 2-ethylbutynyl, 1-ethyl-1-methylpropynyl, 1,1-dimethylbutynyl, 1,2-dimethylbutynyl, 2-methylpentynyl, 3-methylpentynyl, 4-methylpentynyl, and 1-methyl Examples include methylhexynyl, 1-ethylpentynyl, 2-ethylpentynyl, 1-propylbutynyl, 2-methyl-3-hexynyl, 1,2-dimethylpentynyl, 1,3-dimethylpentynyl, 1,4-dimethylpentynyl, 1-ethyl-1-methylbutynyl, 1-methyl-2-ethylbutynyl, 1-ethyl-2-methylbutynyl, 1,1-dimethylpentynyl, 1,1-diethylpropynyl, 2-methylhexynyl, 3-methylhexynyl, 4-methylhexynyl, 5-methylhexynyl, 3-ethylpentynyl, and their isomers.

[0017] In the present invention, C2-6 alkoxy refers to linear or branched C2-6 alkoxy groups, and examples include ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, and isohexyloxy. In the present invention, C1-4 alkoxy refers to linear or branched C1-4 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, and their isomers. In the present invention, C1-4 haloalkoxy refers to a group in which any hydrogen atom of a linear or branched C1-4 alkoxy group is substituted with one or more halogen atoms. Examples include trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy, and 1-chlorobutoxy.

[0018] In the present invention, examples of C3-6 carbon rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

[0019] In the present invention, a 3- to 6-membered heterocycle refers to a heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom. Examples include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiadiazine, thiadiazine, and aziridine. Azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, oxiran, oxetane, dihydrofuran, tetrahydrofuran, Examples include dihydropyran, tetrahydropyran, thiran, thiethane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxazine, dihydrothiadiazole (thiadiazolidine), dihydrothiadin, tetrahydrothiazole (thiadiazolidine), dihydrothiadin, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadin, morpholine, thiomorpholine, oxatian, dioxolane, dioxane, dithiolane, and dithiane.

[0020] In the present invention, examples of C5-10 carbon rings include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, spiro[4.4]nonane, and spiro[4.5]decane.

[0021] In the present invention, a 5-10 membered heterocycle refers to a 5-10 membered heterocycle containing heteroatoms selected from oxygen, nitrogen, and sulfur atoms, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiadi N, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indidine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinoridine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, clomen, benzoflazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidin, triazoli Triazolidine, tetrazoline, tetrazolidine, pyrazolidine, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydro Ropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),Dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiadin, tetrahydrothiadin, dihydrothiadi Adin, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxatian, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydro Ndazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrosinnoline, tetrahydrosinnoline, perhydrosinnoline, benzox Satian, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithian, dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane,Examples include thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, and oxazaspiro[4.5]decane.

[0022] In the present invention, examples of C5-6 carbon rings include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene. In the present invention, the 5-6 membered heterocycle is, for example, isoxazole, isothiazole, imidazole, imidazolidine, imidazoline, oxadiazine, oxadiazole, oxazine, oxazole, oxatian, dioxane, dioxolane, dithian, dithiolan, dihydroisoxazole, dihydroisothiazole, dihydrooxadiazine, dihydrooxadiazole, dihydrooxazine, dihydrooxazole, dihydrothiadiazine, dihydrothiadiazole, dihydrothiazole, dihydrothiopyran, dihydrothiophene, dihydropyrazine, dihydropyran, dihydropyridine, dihydropyridazine, dihydropyrimidine, dihydrofurazan, dihydrofuran, thiadiazine, thiadiazole, thiadin, thiazoline, thiophene, thiomorpholine, tetrazole, tetrazolidine, tetrazoline, tetrahydroisoxazole (isoxazoli Examples include tetrahydroisothiazole (isothiazolidine), tetrahydrooxadiazine, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxazole (oxazolidine), tetrahydrothiadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiadin, tetrahydrothiazole (thiazolidine), tetrahydrothiopyran, tetrahydrothiophene, tetrahydropyrazine, tetrahydropyran, tetrahydropyridine, tetrahydropyridazine, tetrahydropyrimidine, tetrahydrofurazan, tetrahydrofuran, triazole, triazolidine, triazoline, perhydropyridazine, perhydropyrimidine, piperazine, piperidine, pyrazine, pyrazole, pyrazolidine, pyrazolin, pyran, pyridine, pyridazine, pyrimidine, pyrrole, pyrrolidine, pyrroline, furazan, furan, and morpholine.

[0023] In the present invention, the following substructures in each general formula [ka] teeth, [ka] This represents, The substructure includes, for example, [ka] It includes.

[0024] In the present invention, R 1 COOH is preferred. In the present invention, R 11 C1-C2 alkyl groups are preferred. In the present invention, R 12 C1-6 alkyl groups are preferred, C1-2 alkyl groups are more preferred, and methyl groups are even more preferred. In the present invention, X 1 For example, CH or CR 21 This is preferable, CR 21 This is preferable. In the present invention, X 2 For example, CH or CR 21 CH is preferred, and CH is more preferred. In the present invention, X 3 For example, CH or CR 21 CH is preferred, and CH is more preferred. In the present invention, R 21 The preferred elements are (1) halogens, (2) C1-4 alkyls, or (3) vinyls, with halogens or methyls being more preferred.

[0025] In the present invention, the following substructures in general formula (I) [ka] As for, [ka] This is preferable, [ka] More preferable, [ka] is more preferable,

Chemical formula

[0026] In the present invention, R 6 is preferably C1-4 alkyl, and more preferably methyl. In the present invention, p is preferably 0. In the present invention, Y is preferably an oxygen atom. In the present invention, R 2 is preferably a hydrogen atom. In the present invention, R 3 is preferably a hydrogen atom. In the present invention, Z is preferably CHR 10 is preferred. In the present invention, R 10 is preferably a hydroxyl group. In the present invention, L is preferably -CHR L1 - or -CR L2 R L3 - is preferred, and -CR L2 R L3 - is more preferred.

[0027] In the present invention, L is

Chemical formula

Chemical formula

[0028] In the present invention, R L1 is preferably (1) halogen, (2) C1-4 alkyl, or (3) C1-4 haloalkyl, more preferably C1-4 alkyl, and still more preferably methyl or ethyl. In the present invention, R L2Examples thereof include (1) halogen, (2) C1-C4 alkyl, (3) C1-C4 haloalkyl, or (4) a hydroxyl group, with C1-C4 alkyl or a hydroxyl group being more preferred. In the present invention, R L3 Examples thereof include (1) halogen, (2) C1-C4 alkyl, (3) C1-C4 haloalkyl, or (4) a hydroxyl group, with halogen or a hydroxyl group being more preferred. Also, in the present invention, R L2 and R L3 When they form a ring together with the carbon atom to which they are attached, the ring is preferably a C3-C6 saturated carbon ring, more preferably a C3-C4 saturated carbon ring, and even more preferably cyclobutane.

[0029] In the present invention, R 4 Examples thereof include (1) C3-C7 alkyl optionally substituted with 1-5 R 41 , (2) C3-C7 alkenyl optionally substituted with 1-5 R 42 , or (3) Cyc 1 . Examples of R 4 include (1) C3-C5 alkyl optionally substituted with 1-3 R 41 , (2) C3-C5 alkenyl optionally substituted with 1-3 R 42 , or (3) Cyc 1 , which are more preferred. In the present invention, R 41 and R 42 are each independently preferably a hydrogen atom or halogen.

[0030] In the present invention, Cyc 1 is preferably (1) a C5-C6 carbon ring optionally substituted with 1-5 R 51 , or (2) a 5-6 membered heterocyclic ring optionally substituted with 1-5 R 52 , more preferably (1) phenyl optionally substituted with 1-5 R 51 , (2) thiophene optionally substituted with 1-3 R 52 , or (3) pyridine optionally substituted with 1-4 R 52 , and 1-5 R51 Phenyls that may be substituted with halogens are even more preferred, and phenyls that may be substituted with 1 to 3 halogens are particularly preferred.

[0031] In the present invention, Cyc 1 As for, [ka] (In the formula, r represents an integer from 0 to 5, and the other symbols have the same meaning as above.) is also preferable. [ka] (In the formula, R 71 (1) represents a halogen or (2) a C1-4 alkyl, R 72 (1) represents a halogen or (2) a C1-4 alkyl, and s represents an integer of 0 or 1. This is preferable.

[0032] In the present invention, R 71 Halogens are preferred as such. In the present invention, R 72 Halogens are preferred as such. In this invention, r is preferably an integer between 0 and 2. In the present invention, R 51 The preferred elements are (1) halogens, (2) C1-4 alkyls, or (3) C1-4 haloalkyls, with halogens being more preferred. In the present invention, R 52 The preferred elements are (1) halogens, (2) C1-4 alkyls, or (3) C1-4 haloalkyls, with halogens being more preferred.

[0033] In the present invention, one embodiment of the compound represented by general formula (I) is general formula (I-1) [ka] (In the formula, all symbols have the same meaning as above.) The compound is represented by the formula, and one embodiment of the compound represented by general formula (I-1) is general formula (I-2) [ka] (In the formula, all symbols have the same meaning as above.) The compound is represented by the formula, and one embodiment of the compound represented by general formula (I-2) is general formula (I-3) [ka] (In the formula, L 10 ha-CHR L1 - or -CR L2 R L3 - represents R 4a This is 1 to 3 R 41 C3-7 alkyl, which may be substituted with 1-3 R 42 C3-7 alkenyls, or Cyclones, which may be substituted with 1 It represents the compound indicated by ), and the other symbols have the same meaning as above.

[0034] Another embodiment of the compound represented by general formula (I) is general formula (I-4). [ka] (In the formula, all symbols have the same meaning as above.) The compound is represented by the formula, and one embodiment of the compound represented by general formula (I-4) is general formula (I-5) [ka] This is the compound represented by (all symbols in the formula have the same meaning as above). Another embodiment of the compound represented by general formula (I) is general formula (I-6). [ka] (In the formula, all symbols have the same meaning as above.) The compound is represented by the formula, and one embodiment of the compound represented by general formula (I-6) is general formula (I-7) [ka] This is the compound represented by (all symbols in the formula have the same meaning as above).

[0035] In the present invention, one embodiment of a compound represented by general formula (I) or a salt thereof is: (1)(1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (2)(1R,2R,3aS,10aR)-5-fluoro-1-[(1E)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (3)(1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (4)(1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,5-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (5)(1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-4-(2,6-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (6)(1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (7)(1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-ethyl-3-hydroxy-7-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (8)(1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (9)(1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (10)(1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4ξ)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (11)(1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (12)(1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (13)(1R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (14)(1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-6-methoxy-4-methylene-1-hexen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (15)(1R,3aS,10aR)-5-chloro-1-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (16)(1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (17)(1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-pentenyl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (18)(1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (19)(1R,2R,3aS,10aR)-2-Chloro-5-fluoro-1-{ (1E,3ξ)-3-[3-(2-fluorophenyl)-3-oxetan-1-yl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (20)(1R,2R,3aS,10aR)-2-Chloro-5-fluoro-1-{ (1E,3ξ)-3-hydroxy-3-[(2ξ)-2-phenyl-2-oxetan-1-yl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (21)(1R,3aR,10aR)-1-{ (1E,3ξ,4S)-3-hydroxy-4-methyl-1-octen-1-yl}-5-methyl-1,3,3a,9,10,10a-hexahydrofuro[3,4-b][1]benzoxepin-6-carboxylic acid, (22)(1R,3aR,10aR)-1-{ (1E,3ξ)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen-1-yl}-5-methyl-1,3,3a,9,10,10a-hexahydrofuro[3,4-b][1]benzoxepin-6-carboxylic acid, (23)(1R,2R,3aS,10aR)-5-Fluoro-2-hydroxy-1-{ (1E,3ξ)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or (24)(1R,2R,3aS,10aR)-2-Hydroxy-1-{ (1E,3R)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or a salt thereof.

[0036] [Isomers] In the present invention, [Chemistry] represents being bonded to the far side of the paper plane (i.e., α configuration). [Chemistry] represents being bonded to the near side of the paper plane (i.e., β configuration). In the present invention, for those bonded to an asymmetric atom, [Chemistry] represents being in the α configuration, β configuration, or a mixture of any ratio thereof, unless otherwise specified. In the present invention, for those bonded to an asymmetric atom, [Chemistry] represents being in either the α configuration or the β configuration. Also, the description of ξ in the chemical name indicates that the stereoconfiguration of the substituent bonded to the asymmetric atom is either the α configuration or the β configuration (IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019 - ) created by S. J. Chalk. ISBN 0 - 9678550 - 9 - 8. https: / / doi.org / 10.1351 / goldbook.).

[0037] For example, the chemical names of Example 7 - 3 and Example 7 - 4 (1R,2R,3aS,10aR)-2 - hydroxy - 1 - [(1E,3ξ,4ξ)-3 - hydroxy - 4 - (trifluoromethyl)-1 - octen - 1 - yl]-2,3,3a,9,10,10a - hexahydro - 1H - benzo[b]cyclopenta[f]oxepin - 6 - carboxylic acid are respectively (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3R,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3R,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid. For example, in one embodiment, when Example 7-3 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, then Example 7-4 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid. In another embodiment, when Example 7-3 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, then Example 7-4 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid.

[0038] As will be obvious to those skilled in the art, other compounds of the present invention in which the stereochemistry of a substituent bonded to a chiral atom is represented by ξ can be interpreted similarly. In the present invention, isomers are encompassed in all forms. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene, and alkenylidene include both linear and branched forms. Furthermore, isomers at double bonds, rings, and fused rings (E, Z, cis, trans isomers), isomers due to the presence of chiral carbons, etc. (R, S isomers, α, β configurations, enantiomers, diastereomers), optically active isomers with optical activity (D, L, d, l isomers), polar isomers separated by chromatography (highly polar, low polar), equilibrium compounds, rotational isomers, mixtures of these in any proportion, racemic mixtures, and tautomers are all included in the present invention. Furthermore, the optically active compound in this invention may not be 100% pure, but may also contain less than 50% of other optical isomers. In the present invention, all references to the compounds of the present invention include compounds represented by general formula (I), etc., salts thereof, solvates (e.g., hydrates) thereof, N-oxides thereof, or cocrystals thereof, or solvates (e.g., hydrates) or cocrystals thereof of salts of compounds represented by general formula (I), etc.

[0039] Compounds represented by general formula (I), etc., are converted to corresponding salts by known methods. Water-soluble salts are preferred. Furthermore, pharmaceutically acceptable salts are preferred. Such salts include alkali metal salts (lithium, potassium, sodium, etc.), alkaline earth metal salts (calcium, magnesium, etc.), salts of other metals (silver, zinc, etc.), ammonium salts (tetramethylammonium salt), and pharmaceutically acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, N Examples include salts of benzyl-2-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc., acid adduct salts (inorganic salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, napadisylate, glucuronate, gluconate, etc.)).

[0040] Compounds represented by general formula (I), etc., or salts thereof may exist in an unsolvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvates are preferably low in toxicity and water-soluble, and more preferably hydrates. Compounds represented by general formula (I), etc., or salts thereof can be converted to solvates by known methods. The N-oxide form of a compound represented by general formula (I), etc., refers to a compound in which the nitrogen atom of the compound represented by general formula (I), etc., has been oxidized. Furthermore, the N-oxide form of a compound represented by general formula (I), etc., may also be an alkali (earth) metal salt, ammonium salt, organic amine salt, or acid adduct salt.

[0041] Compounds represented by general formula (I), etc., or salts thereof may exist in the form of cocrystals formed with a suitable cocrystal-forming agent. The cocrystals are preferably pharmaceutically acceptable and formed with a pharmaceutically acceptable cocrystal-forming agent. A cocrystal is typically defined as a crystal formed by two or more different intermolecular interactions. Furthermore, a cocrystal may be a complex of a neutral molecule and a salt. Cocrystals can be prepared by known methods, such as by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable cocrystal-forming agents include organic acids (malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, isonicotinic acid, etc.), organic amines (imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzylphenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, 4-(2-hydroxyethyl)morpholine, N-methyl-D-glucamine, glycine, histidine, proline, etc.), and other organic compounds (caffeine, saccharin, etc.).

[0042] A prodrug of a compound represented by general formula (I), etc., is a compound that is converted in the body by reactions with enzymes, gastric acid, etc., to the compound represented by general formula (I), etc. For example, if the compound represented by general formula (I), etc. has an amino group, the prodrug is a compound in which the amino group has been acylated, alkylated, or phosphorylated (for example, a compound in which the amino group of the compound represented by general formula (I), etc., has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); if the compound represented by general formula (I), etc., has a hydroxyl group, the prodrug is a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, a compound in which the hydroxyl group of the compound represented by general formula (I), etc., has been acetylated, Examples include compounds that have been palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated; and, in the case of compounds represented by general formula (I), etc., which have a carboxyl group, compounds in which the carboxyl group has been esterified or amidated (for example, compounds in which the carboxyl group of compounds represented by general formula (I), etc., has been ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolenn-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidated). These compounds can be produced by methods known to the public. Furthermore, the prodrug of the compound represented by general formula (I), etc., may be a solvate. Furthermore, the prodrug of the compound represented by general formula (I), etc., may transform into the compound represented by general formula (I), etc., under physiological conditions as described on pages 163-198 of "Molecular Design," Volume 7 of "Pharmaceutical Development," published by Hirokawa Shoten in 1990. In addition, the compound represented by general formula (I), etc., may be an isotope (for example, 2 H, 3 H, 11 C, 13 C,14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I, 125 etc.) etc. may be labeled with.

[0043] [Method for Producing the Compound of the Present Invention] The compound of the present invention can be produced by appropriately improving and combining known methods, for example, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or the methods shown in the examples. Among the compounds represented by the general formula (I), the general formula (I-A) [Chemical Formula] (wherein all symbols have the same meaning as described above) can be produced by the following reaction process formula 1. [Chemical Formula] (wherein T represents a protecting group for a hydroxyl group, R 101 each independently represents C1-6 alkyl, and other symbols have the same meaning as described above.)

[0044] In reaction step formula 1, reaction 1 is known and is carried out by reacting a compound represented by general formula (A1) and a compound represented by general formula (A2) in an organic solvent (e.g., tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), dioxane, acetonitrile, ethanol, dichloromethane, etc.), or in water, or a mixture thereof, in the presence of a base (e.g., sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium tert-butoxide, potassium carbonate, tertiary amine + lithium chloride, etc.) at a temperature of -20 to 70°C. In reaction step 1, reaction 2 is known and is carried out by reacting the compound represented by general formula (A3) obtained in reaction 1 in an organic solvent (e.g., THF, DME, toluene, dichloromethane, diethyl ether, dioxane, etc.) in the presence or absence of cerium chloride with a reducing agent (e.g., sodium borohydride, zinc borohydride, etc.) at a temperature of -20 to 50°C. Furthermore, when selectively producing only one stereoisomer, the reaction is carried out at a temperature of -100 to 50°C using an asymmetric reducing agent (e.g., chlorodiisopinocamphenylborane, etc.) or a combination of an asymmetric auxiliary and a reducing agent (e.g., (R)-2-methyl-CBS-oxazaborolidine and boron hydride tetrahydrofuran complex or boranedimethyl sulfide complex, (S)-(-)-binaphthol and aluminum lithium hydride, etc.). In reaction step formula 1, the deprotection reaction of the protecting group is well known and can be carried out by the following methods. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrolysis, (4) deprotection reaction of silyl groups, (5) deprotection reaction using a metal, and (6) deprotection reaction using a metal complex.

[0045] To explain these methods in detail, (1) Deprotection reactions by alkaline hydrolysis are carried out at 0 to 40°C in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane, etc.) using alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (e.g., barium hydroxide, calcium hydroxide, etc.), or carbonates (e.g., sodium carbonate, potassium carbonate, etc.), or aqueous solutions thereof, or mixtures thereof. (2) The deprotection reaction under acidic conditions is carried out at 0 to 100°C in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.), an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), with or without 2,2,2-trifluoroethanol. (3) The deprotection reaction by hydrolysis is carried out at 0 to 200°C in a solvent (e.g., ether-based solvents (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based solvents (e.g., methanol, ethanol, etc.), benzene-based solvents (e.g., benzene, toluene, etc.), ketone-based solvents (e.g., acetone, methyl ethyl ketone, etc.), nitrile-based solvents (e.g., acetonitrile, etc.), amide-based solvents (e.g., N,N-dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of these solvents, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, Raney nickel, etc.), under normal pressure or under a pressurized hydrogen atmosphere, or in the presence of ammonium formate. (4) The deprotection reaction of the silyl group is carried out at 0 to 40°C using tetrabutylammonium fluoride in an organic solvent that is miscible with water (e.g., tetrahydrofuran, acetonitrile, etc.). Alternatively, it may be carried out at -10 to 100°C in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.). (5) Deprotection reactions using metals are carried out at 0 to 40°C in the presence of zinc powder, in an acidic solvent (e.g., acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of these solutions with an organic solvent such as tetrahydrofuran), if necessary, while applying sonication. (6) Deprotection reactions using metal complexes are carried out at 0 to 40°C in an organic solvent (e.g., dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixture thereof, in the presence of a trap reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetrakistriphenylphosphine palladium(O), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.). In addition to the methods described above, deprotection reactions can also be carried out by other methods, such as those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014.

[0046] Examples of hydroxyl group protecting groups (including T) include methyl group, trityl group, methoxymethyl (MOM) group, 1-ethoxyethyl (EE) group, methoxyethoxymethyl (MEM) group, 2-tetrahydropyranyl (THP) group, trimethylsilyl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, p-phenylbenzoyl group, benzyl (Bn) group, p-methoxybenzyl group, allyloxycarbonyl (Alloc) group, and 2,2,2-trichloroethoxycarbonyl (Troc) group. Examples of protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, trifluoroacetyl group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, and 2-(trimethylsilyl)ethoxymethyl (SEM) group. As the protecting group for the hydroxyl group, a 2-tetrahydropyranyl (THP) group or a tert-butyldimethylsilyl (TBDMS) group is preferred. The protecting group for the hydroxyl group is not particularly limited as long as it is a group that can be easily and selectively removed, in addition to those mentioned above. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014 can be used.

[0047] Of the general formulas (I), general formula (IB) [ka] The compound represented by (wherein all symbols have the same meaning as above) can be produced by subjecting the compound represented by general formula (IA) to a hydrolysis reaction. This hydrolysis reaction (deprotection reaction of the carboxyl group) is well known, and examples include the alkaline hydrolysis described above. If necessary, this reaction may be followed by a known method to convert the salt of interest or its solvate (e.g., hydrate).

[0048] The compound represented by general formula (A1) in reaction step formula 1 can be produced by the following reaction step formula 2. [ka] (In the formula, T 1 R represents a protecting group for hydroxyl groups. 102R represents a hydrogen atom, phenyl, or substituted phenyl (e.g., 4-fluorophenyl), 103 is a halogen atom or COOR 11 This represents the above, and the other symbols have the same meaning as above. T 1 The protecting group of the hydroxyl group represented by is the same as the protecting group T described above.

[0049] In reaction step 2, the compound represented by general formula (A7) can be produced by subjecting the compound represented by general formula (A6) to a protective reaction. For example, this is carried out at a temperature of -100 to 50°C using a silane compound (e.g., trimethylsilane chloride (TESCl), tert-butyldimethylsilane chloride (TBSCl), tert-butyldiphenylsilane chloride (TBDPSCl), etc.) in an organic solvent (e.g., DMF) with a base (e.g., imidazole). In reaction step 2, the compound represented by general formula (A8) can be produced by subjecting the compound represented by general formula (A7) to a reduction reaction. For example, this is carried out at -78 to 80°C in an organic solvent (e.g., toluene, ethanol, tetrahydrofuran, hexane, etc.) using a reducing agent (e.g., diisobutylaluminum hydride (DIBAL), lithium aluminum hydride, etc.).

[0050] In reaction step 2, reaction 3 is known and is carried out, for example, in an organic solvent (e.g., anhydrous toluene, dimethoxyethane, tetrahydrofuran, etc.) in the presence of a base (e.g., lithium hexamethyldisilazane (LHMDS), lithium diisopropylamide (LDA), butyllithium, potassium tert-butoxide, sodium hydride, etc.) using Wittig's reagent (e.g., methyltriphenylphosphonium bromide, etc.) at a temperature of -78 to 50°C. In reaction step 2, reaction 4 is known and is carried out at a temperature of 20 to 100°C in an organic solvent (e.g., anhydrous toluene, benzene, 1,4-dioxane, dimethoxyethane, methanol, etc.) using a ruthenium catalyst (e.g., carbonylchlorohydride tris(triphenylphosphine)ruthenium(II), metathesis catalyst, etc.) or a cobalt catalyst (e.g., Jacobsen catalyst, etc.). In reaction step formula 2, the Mitsunobu reactions of reactions 5 and 7 are known and are carried out, for example, in an organic solvent (e.g., dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene) in the presence of (1) an azo compound (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine (ADDP), 1,1'-azobis(N,N-dimethylformamide)) and a phosphine compound (e.g., triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine), or (2) an ylide compound (cyanomethylenetributylphosphoran, cyanomethylenetrimethylphosphoran), at 0 to 100°C. In reaction step formula 2, reaction 6 is known and is carried out at a temperature of 0 to 100°C using, for example, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.), or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.).

[0051] In reaction step 2, reaction 8 is known and is carried out at a temperature of 20 to 80°C using a metathesis catalyst (e.g., 2,6-diisopropylphenylimidoneophyllidenemorbidenium(VI)bis(tert-butoxide), 2,6-diisopropylphenylimidoneophyllidenemorbidenium(VI)bis(hexafluorotert-butoxide), etc.) in an organic solvent (e.g., toluene, dichloromethane, dichloroethane, etc.). In reaction step 2, reaction 9 is known and is carried out at a temperature of 50-100°C under a carbon monoxide stream in the presence of an organic solvent (e.g., toluene, THF, DMF, etc.), a nucleophile (e.g., an alcohol, etc.), and a palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium (Pd(P(t-Bu)3)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), etc.). In reaction step formula 2, reaction 10 is known and can be carried out by (1) using a metal catalyst (e.g., palladium-carbon, platinum oxide, rhodium-alumina, Raney nickel, Wilkinson complex, ruthenium catalyst, iridium catalyst, etc.) in an organic solvent (e.g., methanol, ethanol, ethyl acetate, dichloromethane, dichloroethane, etc.) using hydrogen gas, etc., at atmospheric pressure or high pressure at 0°C to 80°C, or (2) This is carried out by reacting with a reducing agent (e.g., sodium borohydride) in an organic solvent (e.g., methanol, ethanol, etc.) at -40 to 80°C, with or without the presence of an additive such as cerium chloride.

[0052] In reaction step formula 2, the compound represented by general formula (A18) can be produced by subjecting the compound represented by general formula (A17) to the deprotection reaction described above. In reaction step formula 2, the compound represented by general formula (A1) can be produced by subjecting the compound represented by general formula (A18) to an oxidation reaction. Examples of oxidation reactions include: (1) A method using DMSO oxidation (e.g., Swern oxidation), (2) Method using Dess-Martin Reagent, (3) Method using TEMPO(2,2,6,6-tetramethylpiperidine 1-oxyl) reagent These are some examples.

[0053] To specifically describe the method using DMSO oxidation as an example, the alcohol compound is reacted in an organic solvent (e.g., chloroform, dichloromethane, ethyl acetate, etc.) in the presence of an activator (e.g., oxalyl chloride, acetic anhydride, pyridine-sulfur trioxide complex, etc.) and an oxidizing agent (e.g., dimethyl sulfoxide (DMSO), etc.), and then further reacted with a tertiary amine (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, diazabicyclo[5.4.0]undecé-7-ene, etc.) at -78 to 40°C. In each reaction described herein, the compound having a chiral center may be a compound obtained by optical resolution using a conventional method (for example, a method using an optical resolution column) to isolate the desired optical isomer. In reaction step formula 2, reactions 4 and / or 9 can be omitted as appropriate depending on the compound to be obtained and the intermediates used.

[0054] Among the compounds represented by general formula (I), general formula (IC) [ka] The compound represented by (wherein all symbols have the same meaning as above) can be prepared by the following reaction step formula 3. [ka] (All symbols in the formula have the same meaning as above.) In reaction step 3, reaction 11 is known and is carried out, for example, by reacting a compound represented by general formula (A1) and a compound represented by general formula (A19) in an organic solvent (e.g., tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), toluene, etc.) in the presence of a base (e.g., potassium hexamethyldisilazide, lithium diisopropylamide, butyllithium, etc.) at a temperature of -100 to -20°C. In reaction step 3, the deprotection reaction of the protecting group is well known and can be carried out by the method of the deprotection reaction described above.

[0055] Of the general formulas (I), general formula (ID) [ka] The compound represented by (wherein all symbols have the same meaning as above) can be produced by subjecting the compound represented by general formula (IC) to a hydrolysis reaction. This hydrolysis reaction (deprotection reaction of the carboxyl group) is well known, and examples include the alkaline hydrolysis described above. If necessary, this reaction may be followed by a known method to convert the product to the desired salt.

[0056] In each reaction described herein, the compounds used as starting materials, such as those represented by general formulas (A2), (A6), (A10-1), (A13), and (A19), are either known or can be readily produced by known methods. In each of the reactions described herein, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath, or microwaves, as will be obvious to those skilled in the art. In each reaction described herein, a solid-phase supported reagent supported on a polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate. In each reaction described herein, the reaction product can be purified by conventional purification methods, such as distillation under atmospheric or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resin, scavenger resin or column chromatography, or washing and recrystallization. Purification may be performed after each reaction or after several reactions have been completed.

[0057] [toxicity] The toxicity of the preventive and / or therapeutic agent for kidney disease containing the compound of the present invention is sufficiently low, and it can be safely used as a pharmaceutical product.

[0058] [Application to pharmaceuticals] The compound of the present invention can be used as an EP3 agonist having EP3 agonistic activity. Because the compound of the present invention has EP3 agonist activity, it is considered useful for the treatment and / or prevention of diseases such as kidney disease (e.g., chronic kidney disease or acute kidney injury), myocardial infarction, urinary disorders, and glaucoma. The compounds of the present invention are useful, for example, in the treatment and / or prevention of kidney diseases. Certain embodiments of kidney diseases include chronic kidney disease and acute kidney injury. In a preferred embodiment, chronic kidney disease includes, for example, chronic kidney disease based on lifestyle-related diseases, chronic glomerulonephritis, nephrotic syndrome, and hereditary kidney disease. Among these, chronic kidney disease based on lifestyle-related diseases includes diabetic nephropathy and nephrosclerosis. Chronic glomerulonephritis includes IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative glomerulonephritis, and lupus nephritis. Nephrotic syndrome includes minimal change nephrotic syndrome, focal segmental glomerulosclerosis, and membranous nephropathy. Hereditary kidney disease includes Alport syndrome and polycystic kidney disease.

[0059] Other embodiments of chronic kidney disease include, for example, chronic signs of renal failure and / or renal insufficiency, renal hypoperfusion, hypertensive nephrosclerosis, immunological kidney injury, and pyelonephritis. Other embodiments of chronic kidney disease include, for example, dehydration via forced diuresis after partial nephrectomy, uncontrolled hypertension with malignant hypertension, urinary tract obstruction, infections and amyloidosis and systemic diseases involving the glomeruli, such as rheumatoid immunological systemic disorders, such as chronic renal failure in lupus erythematosus, as well as renal artery stenosis, renal artery thrombosis, renal venous thrombosis, analgesic nephropathy and renal tubular acidosis, radiocontrast-induced and drug-induced chronic interstitial kidney disease, and chronic renal failure due to metabolic syndrome and dyslipidemia. In a preferred embodiment, chronic kidney disease includes pathological symptoms and diseases resulting from chronic kidney disease. Examples of pathological symptoms and diseases resulting from chronic kidney disease include obstructive urinary tract disorders, tubulointerstitial disorders, glomerular and tubular proteinuria, renal edema, hematuria, abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, such as glutamyl synthetase, altered urinary molar osmolality or urine volume, elevated microalbuminuria, overt albuminuria, glomerular and arteriole lesions, tubular dilation, and hyperphosphatemia. In a preferred embodiment, acute kidney injury includes, for example, acute kidney injury with ischemia-reperfusion injury and drug-induced (antibiotics, anticancer drugs, etc.) kidney injury. Among these, acute kidney injury with ischemia-reperfusion injury includes acute kidney injury associated with organ surgery such as cardiac surgery, liver surgery, and lung surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis, and contrast-induced nephropathy. Other embodiments of acute kidney injury include, for example, partial nephrectomy, dehydration via forced diuresis, uncontrolled hypertension with malignant hypertension, urinary tract obstruction, and infections and amyloidosis and systemic diseases involving the glomeruli, such as rheumatoid immunological systemic diseases, such as those in lupus erythematosus, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, as well as contrast agent-induced and drug-induced acute interstitial kidney injury.

[0060] The compound of the present invention is 1) Complementing and / or enhancing the preventive and / or therapeutic effects of the compound, 2) Improvement of the kinetics and absorption of the compound, reduction of dosage, and / or 3) Reducing the side effects of the compound For this reason, it may be administered as a combination drug in combination with other medications. The compound of the present invention and other drugs may be administered in the form of a combination preparation containing both components in a single formulation, or in the form of separate formulations. When administered in separate formulations, this includes simultaneous administration and administration with a time difference. Furthermore, in the case of administration with a time difference, the compound of the present invention may be administered first and the other drug afterward, or the other drug may be administered first and the compound of the present invention afterward. The respective administration methods may be the same or different. The diseases for which the above-mentioned combination agents provide therapeutic and / or preventive effects are not particularly limited, and any disease that complements and / or enhances the therapeutic and / or preventive effects of the compound of the present invention is acceptable. Furthermore, the concomitant agents used in combination with the compounds of the present invention include not only those discovered to date but also those that may be discovered in the future.

[0061] In the present invention, a pharmaceutical composition comprises the compound of the present invention and any pharmaceutically acceptable carrier. For use in the prevention and / or treatment of the above-mentioned diseases, the pharmaceutical composition containing the compound of the present invention is usually formulated with the active ingredient, the compound of the present invention, together with a pharmaceutically acceptable carrier such as various additives or solvents, and then administered systemically or topically, orally or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient that is generally used in the formulation of pharmaceuticals. A pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Furthermore, a pharmaceutically acceptable carrier can also be used for purposes such as enhancing the usefulness of the active ingredient and formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances such as those listed in the "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association), published by Yakuji Nippo Co., Ltd. in 2000, can be appropriately selected according to the purpose.

[0062] To use the compound of the present invention or a combination of the compound of the present invention and other agents for the above purposes, it is usually administered systemically or locally, or orally or parenterally. The dosage varies depending on age, weight, symptoms, therapeutic effect, method of administration, processing time, etc., but is usually administered orally once to several times a day in the range of 1 ng to 1000 mg per adult, or parenterally once to several times a day in the range of 0.1 ng to 10 mg per adult, or continuously administered intravenously for a range of 1 to 24 hours per day. Of course, as mentioned above, the dosage will vary depending on various conditions, so in some cases a smaller amount than the above dosage may be sufficient, and in other cases it may be necessary to administer more than the range.

[0063] Oral preparations include, for example, oral liquid preparations (e.g., elixirs, syrups, pharmacokinetically acceptable liquid preparations, suspensions, emulsions), oral solid preparations (e.g., tablets (including sublingual tablets and orally disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and lozenges). Parenteral preparations include, for example, liquid preparations (e.g., injections (intravitreal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), eye drops (e.g., aqueous eye drops (aqueous eye drops, aqueous suspension eye drops, viscous eye drops, solubilized eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspension eye drops, etc.)), topical preparations (e.g., ointments (eye ointments, etc.)), ear drops, etc.). These preparations may also be controlled-release agents such as immediate-release and sustained-release preparations. These preparations can be manufactured by known methods, such as those described in the Japanese Pharmacopoeia. Oral preparations are manufactured, for example, by dissolving, suspending, or emulsifying the active ingredient in a commonly used diluent (e.g., purified water, ethanol, or a mixture thereof). Furthermore, these preparations may contain wetting agents, suspending agents, emulsifiers, sweeteners, flavoring agents, fragrances, preservatives, buffering agents, etc. For oral solid preparations, for example, the active ingredient is mixed with excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), disintegrants (e.g., calcium cellulose glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, solubilizers (glutamic acid, aspartic acid, etc.), etc., and formulated according to conventional methods. Furthermore, if necessary, the preparation may be coated with a coating agent (e.g., sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or coated with two or more layers.

[0064] Topical preparations for parenteral use are manufactured by known methods or commonly used formulations. For example, ointments are manufactured by grinding or melting the active ingredient in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (e.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate ester, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., For example, a single or mixed collection of two or more substances selected from the following are used: dimethylpolysiloxane, hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (e.g., mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and anti-rash agents. Furthermore, it may also contain humectants, preservatives, stabilizers, antioxidants, fragrances, etc. Parenteral injectable preparations include solutions, suspensions, emulsions, and solid injectable preparations that are dissolved or suspended in a solvent before use. Injectable preparations are used, for example, by dissolving, suspending, or emulsifying the active ingredient in a solvent. Solvents include, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, these injectable preparations may contain stabilizers, solubilizers (e.g., glutamic acid, aspartic acid, polysorbate 80®, etc.), suspending agents, emulsifiers, analgesics, buffers, preservatives, antioxidants, isotonic agents, pH adjusters, excipients, etc. These are sterilized in the final step or manufactured using aseptic techniques. Alternatively, sterile solid preparations, such as lyophilized products, can be manufactured and sterilized before use or dissolved in sterile distilled water for injection or other solvents. [Examples]

[0065] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. The solvents indicated in parentheses in the chromatography separation section and the TLC section represent the elution or developing solvent used, and the percentages are expressed as volume ratios. The conditions used for LC / MS analysis in the following examples are as follows: Column: YMC Triart C18, 2.0 mm × 30 mm, 1.9 μm; Flow rate: 1.0 mL / min; Temperature: 30°C; Mobile phase A: 0.1% TFA (trifluoroacetic acid) aqueous solution; Mobile phase B: 0.1% TFA acetonitrile solution; Gradient (ratio of mobile phase A to mobile phase B indicated): 0-0.10 min (95:5), 0.10-1.20 min (95:5 to 5:95), 1.20-1.50 min (5:95). The information in parentheses next to "NMR" indicates the solvent used for the measurement. The compound names used herein are generally named using ACD / Name®, a computer program from Advanced Chemistry Development, which names compounds according to IUPAC rules, or by following IUPAC nomenclature.

[0066] Reference Example 1: (1R,2R,3S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl formate (1S,2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-prop-1-enyl-4-tetrahydropyran-2-yloxy-2-cyclopentanol (CAS No.: 1262874-63-4, 7.2g) was dissolved in tetrahydrofuran (THF) (5.8mL), to which triphenylphosphine (10g) and formic acid (1.5mL) were added and cooled to -30°C. Diethyl azodicarboxylate (18mL) was added to the reaction solution and stirred under ice cooling for 3 hours. The mixture was washed with saturated sodium bicarbonate aqueous solution, water, and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 → 90:10) to obtain the title compound (7.7g) with the following physical properties. TLC: Rf 0.85 (Hexane:ethyl acetate = 2:1).

[0067] Reference Example 2: (1R,2R,3S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol To a solution of the compound (7.7 g) prepared in Reference Example 1 in ethanol (50 mL), potassium carbonate (2.67 g) was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, filtered, and then washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure, diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 → 85:15) to obtain the title compound (6.0 g) with the following physical properties. TLC: Rf 0.60 (Hexane:ethyl acetate = 2:1).

[0068] Reference Example 3: 3-bromo-2-fluoro-6-vinylphenol To a solution of methyltriphenylphosphonium bromide (2.45 g) in THF (12 mL), potassium t-butoxide (666 mg) was added at 0°C and the mixture was stirred at room temperature for 1 hour. After cooling to 0°C, a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (CAS number: 1427373-29-2, 1.0 g) in THF (15 mL) was added and the mixture was stirred at 0°C for 1 hour. A 1N hydrochloric acid aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 85:15) to obtain the title compound (1.1 g) with the following physical properties. TLC: Rf 0.44 (Hexane:ethyl acetate = 6:4); 1 H-NMR (CDCl3): δ 7.10, 7.03, 6.91, 5.82, 5.47, 5.38.

[0069] Reference Example 4: {[(1S,2R,3S,5R)-3-(3-bromo-2-fluoro-6-vinylphenoxy)-2-(1-propen-1-yl)-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]methoxy}(dimethyl)(2-methyl-2-propanyl)silane Triphenylphosphine (1.7g) was added to a THF (17mL) solution of the compound prepared in Reference Example 2 (1.7g) and the compound prepared in Reference Example 3 (1.0g), and the mixture was cooled under ice. Diethyl azodicarboxylate (2.9mL) was added to the reaction solution and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 90:10) to obtain the title compound (2.39g) with the following physical properties. TLC: Rf 0.79 (Hexane:ethyl acetate = 9:1); 1H-NMR(CDCl3):δ 7.12-7.24, 5.62-5.74, 5.46-5.61, 5.27, 4.68-4.78, 4.56, 4.27-4.36, 4.16, 3.83-3.93, 3.69-3.79, 3.54-3.68, 3.38-3.51, 2.57-2.63, 2.45-2.52, 2.09-2.33, 1.91-2.04, 1.76-1.89, 1.41-1.74, 1.23-1.33, 0.84-0.94, 0.01-0.07.

[0070] Reference Example 5: {[(1S,2R,3aS,10aR)-6-bromo-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,10a-tetrahydro-1H-benzo[b]cyclopenta[f]oxepin-1-yl]methoxy}(dimethyl)(2-methyl-2-propanyl)silane A solution of the compound (2.39 g) prepared in Reference Example 4 in toluene (83.7 mL) was stirred at 100°C for 30 minutes under a nitrogen stream. After cooling to 80°C, tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene][3-phenyl-1H-indene-1-ylidene]ruthenium(II) dichloride (397 mg) was added, and the reaction solution was stirred at 80°C for 100 minutes. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 90:10) to obtain the title compound (2.21 g) with the following physical properties. TLC: Rf 0.64 (Hexane:ethyl acetate = 9:1); 1 H-NMR(CDCl3):δ 7.14, 6.81, 6.30, 6.02, 4.70, 4.21-4.28, 3.96-4.08, 3.81-3.91, 3.48-3.57, 2.72, 2.51-2.66, 2.31-2.47, 2.15-2.28, 1.80-1.90, 1.46-1.78, 1.22-1.35, 0.86-0.93, 0.03-0.11.

[0071] Reference Example 6: Ethyl (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,10a-tetrahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate Diisopropylamine (1.69 mL) was added to a solution of the compound (2.06 g) prepared in Reference Example 5 in ethanol (12.4 mL) / dimethylformamide (DMF) (6.18 mL). Under a nitrogen stream, [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (319 mg) was added, and the mixture was stirred at 90°C for 19 hours under a carbon monoxide stream. The reaction solution was cooled to room temperature, poured into a cooled saturated ammonium chloride aqueous solution, and extracted with an ethyl acetate / n-hexane mixed solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 → 75:25) to obtain the title compound (1.65 g) with the following physical properties. TLC: Rf 0.43 (Hexane:ethyl acetate = 9:1); 1 H-NMR(CDCl3):δ 7.53, 6.95, 6.36, 6.12, 4.68-4.72, 4.35-4.41, 4.19-4.28, 3.96-4.08, 3.82-3.91, 3.47-3.57, 2.76, 2.66, 2.56, 2.32-2.48, 2.15-2.32, 1.47-1.90, 1.39, 1.22-1.33, 0.86-0.93, 0.05-0.11.

[0072] Reference Example 7: Ethyl (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound prepared in Reference Example 6 (1.65 g) in ethanol (25.1 mL), 10% palladium-carbon (165 mg) was added and the mixture was stirred at room temperature under a hydrogen stream for 3 hours. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was not further purified and was subjected to the next reaction. TLC: Rf 0.87 (Hexane:ethyl acetate = 4:6); 1 H-NMR(CDCl3):δ 7.45, 6.86, 4.70, 4.32-4.41, 4.15-4.22, 3.85-4.00, 3.67-3.81, 3.47-3.56, 3.01-3.12, 2.78, 2.53, 2.25-2.43, 1.97-2.23, 1.81-1.93, 1.47-1.81, 1.38, 1.23-1.29, 0.87-0.93, 0.04-0.09.

[0073] Reference Example 8: Ethyl (1S,2R,3aS,10aR)-5-fluoro-1-(hydroxymethyl)-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a THF solution (11.6 mL) of the crude product prepared in Reference Example 7, a 1 M THF solution (4.8 mL) of tetrabutylammonium fluoride was added at room temperature and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 40:60 → 0:100) to obtain the title compound (1.20 g) with the following physical properties. TLC: Rf 0.36 (Hexane:ethyl acetate = 4:6); 1H-NMR(CDCl3):δ 7.45, 6.85, 4.77-4.80, 4.60-4.64, 4.37, 4.07-4.17, 3.83-4.00, 3.62-3.73, 3.46-3.61, 3.01-3.12, 2.92, 2.81, 2.48-2.62, 2.24-2.42, 2.10-2.24, 1.98-2.10, 1.70-1.95, 1.49-1.70, 1.38.

[0074] Reference Example 9: Ethyl (1R,2R,3aS,10aR)-5-fluoro-1-formyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound (500 mg) prepared in Reference Example 8 in dichloromethane (5 mL), dimethyl sulfoxide (DMSO) (1 mL) and triethylamine (854 μL) were added, and the reaction solution was cooled to 0°C. Sulfur trioxide-pyridine complex (584 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to obtain the title compound (446 mg) with the following physical properties. TLC: Rf 0.40 (Hexane:ethyl acetate = 2:1); 1 H-NMR(CDCl3):δ 9.84, 7.48, 6.87, 4.67, 4.32-4.48, 3.78-3.94, 3.43-3.55, 3.06-3.33, 2.72-2.82, 2.51-2.64, 2.28-2.40, 2.16-2.22, 2.00-2.08, 1.68-1.94, 1.47-1.66, 1.38.

[0075] Reference Example 10: Methyl (2S)-2-(2,4-difluorophenyl)propanoate To a methanol (100 mL) solution of (2S)-2-(2,4-difluorophenyl)propanoic acid (CAS No.: 1630485-27-6, 6.50 g), an n-hexane solution of 2 M trimethylsilyldiazomethane (82.3 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 83:17) to obtain the title compound (6.08 g) with the following physical properties. TLC: Rf 0.50 (Hexane:ethyl acetate = 5:1); 1 H-NMR (CDCl3): δ 7.24-7.29, 6.78-6.86, 3.98, 3.69, 1.49.

[0076] Reference Example 11: Dimethyl [(3S)-3-(2,4-difluorophenyl)-2-oxobutyl]phosphonate To a 50 mL solution of dimethyl methylphosphonate (7.85 g) in THF, 38.9 mL of a 1.55 M n-hexane solution of n-butyllithium was added dropwise at -60°C, and the mixture was stirred at -78°C for 1 hour. To the reaction mixture, a 50 mL solution of the compound prepared in Reference Example 10 (6.05 g) in THF was added dropwise at -78°C, and the mixture was stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 → 0:100) to obtain the title compound (4.74 g) with the following physical properties. TLC: Rf 0.41 (ethyl acetate); 1 H-NMR (CDCl3): δ 7.13-7.17, 6.83-6.89, 4.25, 3.74-3.80, 3.10-3.19, 2.90-2.99, 1.41.

[0077] Reference Example 12: (4S)-4-benzyl-3-[(2R)-2-(2,4-difluorophenyl)propanoyl]-1,3-oxazolidine-2-one To a solution of 2-(2,4-difluorophenyl)propanoic acid (CAS No.: 1250572-63-4, 1 g) in dichloromethane (17.7 mL), (4S)-4-benzyloxazolidine-2-one (CAS No.: 180917-48-0, 1.43 g) was added. Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.54 g), 4-dimethylaminopyridine (131 mg), and triethylamine (1.5 mL) were added at 0°C, and the mixture was stirred overnight at room temperature. A 1N hydrochloric acid aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 → 65:35) to obtain the title compound (1.13 g, highly polar) with the following physical properties. 1 H-NMR (CDCl3): δ 7.22-7.35, 7.16, 6.79-6.93, 5.20, 4.73, 4.21, 4.12, 3.32, 2.63, 1.51.

[0078] Reference Example 13: (2R)-2-(2,4-difluorophenyl)propanoic acid To a solution of the compound (1.13 g) prepared in Reference Example 12 in THF (15 mL), 30% hydrogen peroxide aqueous solution (2.8 mL) and lithium hydroxide aqueous solution (157 mg) (10 mL) were added at 0°C and the mixture was stirred at room temperature for 3 hours. After adding saturated sodium thiosulfate aqueous solution to the reaction mixture, 1N hydrochloric acid aqueous solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20 → 60:40) to obtain the title compound (861 mg) with the following physical properties. 1 H-NMR (CDCl3): δ 7.23-7.34, 6.76-6.92, 4.02, 1.51.

[0079] Reference Example 14: Dimethyl [(3R)-3-(2,4-difluorophenyl)-2-oxobutyl]phosphonate By using the compound prepared in Reference Example 13 (610 mg) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid and subjecting it to the same procedure as in Reference Example 10 → Reference Example 11, the title compound (614 mg) having the following physical properties was obtained. 1 H-NMR (CDCl3): δ 1.40, 2.94, 3.15, 3.72-3.83, 4.25, 6.80-6.93, 7.11-7.21.

[0080] Reference Example 15: Ethyl (1R,2R,3aS,10aR)-1-[(1E,4S)-4-(2,4-difluorophenyl)-3-oxo-1-penten-1-yl]-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound prepared in Reference Example 9 (80 mg) in THF (1 mL), the compound prepared in Reference Example 11 (115 mg), lithium chloride (18 mg), and triethylamine (60 μL) were added and the mixture was stirred overnight at room temperature. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 → 75:25) to obtain the title compound (117 mg) with the following physical properties. 1 H-NMR(CDCl3):δ 7.46, 7.14, 6.76-6.88, 6.18-6.31, 4.65, 4.20-4.43, 4.04-4.10, 3.80-3.95, 3.48-3.58, 3.37-3.47, 3.28-3.35, 2.82-3.05, 2.53-2.74, 2.16, 1.99-2.06, 1.86-1.94, 1.63-1.83, 1.35-1.53.

[0081] Reference Example 16: Ethyl (1R,2R,3aS,10aR)-1-[(1E,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a methanol (2 mL) solution of the compound (117 mg) prepared in Reference Example 15, p-toluenesulfonic acid monohydrate (8 mg) was added at 0°C and the mixture was stirred at room temperature for 1 hour. Triethylamine (14 μL) was added to the reaction mixture and stirred at room temperature for 5 minutes. Then, cerium chloride (151 mg) and sodium tetrahydroboro (19 mg) were added at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, 1N hydrochloric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ISCO Gold High Performance Silica, hexane:ethyl acetate = 60:40 → 55:45) to obtain a mixture containing two diastereomers. TLC: Rf 0.45, 0.40 (Hexane:ethyl acetate = 2:3); 1 H-NMR(CDCl3):δ 7.45-7.51, 7.18-7.31, 6.76-6.89, 5.58-5.69, 5.39-5.56, 4.25-4.40, 3.91, 3.74-3.80, 3.15-3.24, 3.03, 2.63-2.75, 2.42-2.61, 2.00-2.12, 1.71-2.00, 1.61, 1.33-1.40.

[0082] Example 1: (1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] The diastereomer mixture prepared in Reference Example 16 was dissolved in dimethoxyethane (0.5 mL) / methanol (1 mL), and 2N sodium hydroxide aqueous solution (0.5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 15 hours. After concentrating the reaction mixture under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated into two diastereomers using an SFC column (CHIRALPAK ID, CO2:methanol = 82:18), and the highly polar product (17.5 mg) was obtained. The stereochemistry was determined by single-crystal X-ray diffraction. HPLC retention time (min): 0.93; MS(ESI, Pos.):445(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.45, 7.34-7.41, 6.84-6.97, 5.63, 5.49, 4.35, 4.23, 3.87, 3.19, 3.05, 2.80, 2.54-2.67, 1.73-1.96, 1.26.

[0083] Reference Example 17: Ethyl (1R,2R,3aS,10aR)-1-[(1E,4R)-4-(2,4-difluorophenyl)-3-oxo-1-penten-1-yl]-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound prepared in Reference Example 9 (80 mg) in THF (1 mL), the compound prepared in Reference Example 14 (115 mg), lithium chloride (18 mg), and triethylamine (60 μL) were added and the mixture was stirred overnight at room temperature. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 → 75:25) to obtain the title compound (103 mg) with the following physical properties. 1 H-NMR(CDCl3):δ 7.46, 7.15, 6.73-6.89, 6.18-6.31, 4.64-4.66, 4.23-4.41, 4.05-4.11, 3.81-3.94, 3.57, 3.40-3.47, 3.33, 2.90-3.02, 2.81-2.90, 2.54-2.71, 2.13-2.21, 2.05, 1.62-1.98, 1.22-1.61.

[0084] Reference Example 18: Ethyl (1R,2R,3aS,10aR)-1-[(1E,3ξ,4R)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a methanol (2 mL) solution of the compound (103 mg) prepared in Reference Example 17, p-toluenesulfonic acid monohydrate (7 mg) was added at 0°C and the mixture was stirred at room temperature for 1 hour. Triethylamine (13 μL) was added to the reaction mixture and stirred at room temperature for 5 minutes. Then, cerium chloride (133 mg) and sodium tetrahydroboro (17 mg) were added at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and after adding 1N hydrochloric acid aqueous solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ISCO Gold High Performance Silica, hexane:ethyl acetate = 60:40 → 55:45) to separate it into two diastereomers, and the highly polar product (20.6 mg) was obtained. 1 H-NMR(CDCl3):δ 7.48, 7.16-7.23, 6.74-6.88, 5.58, 5.37, 4.37, 4.21-4.30, 3.82-3.92, 3.16, 2.95, 2.39-2.63, 1.95-2.13, 1.80, 1.42-1.76, 1.33-1.41.

[0085] Example 2: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4R)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid To a DME (0.5 mL) / methanol (1 mL) solution of the compound (high polar form: 20.6 mg) prepared in Reference Example 18, 2N sodium hydroxide aqueous solution (0.5 mL) was added and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction mixture under reduced pressure, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. By concentrating the filtrate under reduced pressure, the title compound (14.6 mg) with the following physical properties was obtained. HPLC retention time (min): 0.88; MS(ESI, Pos.):445(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.39-7.46, 7.29-7.38, 6.88-6.96, 5.51, 5.29, 4.24-4.29, 4.12-4.19, 3.75-3.83, 3.10, 2.89, 2.54-2.65, 2.44, 1.88, 1.64, 1.23-1.46.

[0086] Reference Example 19(1): (4S)-4-benzyl-3-[(2S)-2-(2-fluorophenyl)propanoyl]-1,3-oxazolidine-2-one Reference Example 19(2): (4S)-4-benzyl-3-[(2R)-2-(2-fluorophenyl)propanoyl]-1,3-oxazolidine-2-one To a solution of 2-(2-fluorophenyl)propanoic acid (CAS number: 73041-90-4, 2.5 g) in dichloromethane (49 mL), (4S)-4-benzyloxazolidine-2-one (3.95 g) was added. At 0°C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.27 g), 4-dimethylaminopyridine (363 mg), and triethylamine (4.14 mL) were added, and the mixture was stirred overnight at room temperature. 1N hydrochloric acid aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 → 65:35) to obtain the title compound (low polarity: 1.76 g, high polarity: 2.93 g) with the following physical properties. Low polarity: 1 H-NMR (CDCl3): δ 7.20-7.37, 7.12, 7.04, 5.26, 4.63-4.70, 4.12-4.18, 3.35, 2.81, 1.57. Highly polar: 1 H-NMR (CDCl3): δ 7.23-7.34, 7.05-7.18, 5.25, 4.74, 4.09-4.22, 3.34, 2.63, 1.53.

[0087] Reference Example 20: Dimethyl[(3S)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate By using the compound prepared in Reference Example 19(1) (low polarity: 1.76 g) instead of the compound prepared in Reference Example 12, and subjecting it to the same objective procedure as in Reference Example 13 → Reference Example 10 → Reference Example 11, the title compound (941 mg) with the following physical properties was obtained. 1 H-NMR (CDCl3): δ 7.24-7.30, 7.06-7.21, 4.28, 3.77, 3.11-3.22, 2.87-2.97, 1.39-1.44.

[0088] Reference Example 21: Dimethyl[(3R)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate By using the compound prepared in Reference Example 19(2) (high polarity: 2.93 g) instead of the compound prepared in Reference Example 12, and subjecting it to the same objective procedures as in Example 13 → Example 10 → Example 11, the title compound (970 mg) having the following physical properties was obtained. 1 H-NMR (CDCl3): δ 7.24-7.31, 7.06-7.21, 4.24-4.32, 3.77, 3.12-3.22, 2.87-2.98, 1.41.

[0089] Reference Example 22: Ethyl (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,4S)-4-(2-fluorophenyl)-3-oxo-1-penten-1-yl]-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound prepared in Reference Example 9 (80 mg) in THF (1 mL), the compound prepared in Reference Example 20 (108 mg), lithium chloride (18 mg), and triethylamine (60 μL) were added and the mixture was stirred overnight at room temperature. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 → 75:25) to obtain the title compound (105 mg) with the following physical properties. TLC: Rf 0.65 (Hexane:ethyl acetate = 2:1); 1 H-NMR(CDCl3):δ 7.45, 7.02-7.29, 6.75-6.86, 6.18-6.32, 4.65, 4.24-4.41, 4.04-4.10, 3.91, 3.79-3.86, 3.48-3.56, 3.37-3.44, 3.27-3.32, 2.79-3.03, 2.50-2.74, 2.15, 1.98-2.11, 1.88, 1.72-1.84, 1.22-1.72.

[0090] Reference Example 23: Ethyl (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3R,4S)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a methanol (2 mL) solution of the compound (105 mg) prepared in Reference Example 22, p-toluenesulfonic acid monohydrate (7 mg) was added at 0°C and the mixture was stirred at room temperature for 1 hour. Triethylamine (13 μL) was added to the reaction mixture and stirred at room temperature for 5 minutes. Then, cerium chloride (140 mg) and sodium tetrahydroboro (18 mg) were added at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ISCO Gold High Performance Silica, hexane:ethyl acetate = 60:40 → 55:45) to separate two diastereomers, and the highly polar product (18.6 mg) was obtained. 1 H-NMR(CDCl3):δ 7.48, 7.00-7.35, 6.87, 5.68, 5.50, 4.29-4.40, 3.85-3.93, 3.25, 3.06, 2.62-2.75, 2.49, 1.99-2.11, 1.72-1.98, 1.56-1.61, 1.38, 1.31.

[0091] Example 3: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] To a solution of the compound (high polar form: 18.6 mg) prepared in Reference Example 23 in dimethoxyethane (0.5 mL) / methanol (1 mL), 0.5 mL of 2 N sodium hydroxide aqueous solution was added, and the reaction mixture was stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. By concentrating the filtrate under reduced pressure, the title compound (13.1 mg) with the following physical properties was obtained. The stereochemistry was determined by single-crystal X-ray diffraction. HPLC retention time (min): 0.91; MS(ESI, Pos.):427(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.44, 7.35, 7.16-7.23, 7.11, 7.01, 7.01, 6.93, 5.63, 5.46, 4.33, 4.26, 3.85, 3.19-3.27, 3.04, 2.78, 2.53-2.65, 1.81-1.94, 1.69-1.79, 1.26.

[0092] Reference Example 24: Ethyl (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,4R)-4-(2-fluorophenyl)-3-oxo-1-penten-1-yl]-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound prepared in Reference Example 9 (80 mg) in THF (1 mL), the compound prepared in Reference Example 21 (108 mg), lithium chloride (18 mg), and triethylamine (60 μL) were added and the mixture was stirred overnight at room temperature. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 → 75:25) to obtain the title compound (114 mg) with the following physical properties. TLC: Rf 0.65 (Hexane:ethyl acetate = 2:1); 1 H-NMR(CDCl3):δ 7.45, 7.04-7.28, 6.71-6.85, 6.17-6.32, 4.63-4.66, 4.28-4.40, 4.04-4.10, 3.80-3.92, 3.49-3.59, 3.38-3.46, 3.27, 2.79-3.00, 2.52-2.70, 2.15, 1.99-2.05, 1.33-1.92.

[0093] Reference Example 25: Ethyl (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3ξ,4R)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a methanol (2 mL) solution of the compound (117 mg) prepared in Reference Example 24, p-toluenesulfonic acid monohydrate (8 mg) was added at 0°C and the mixture was stirred at room temperature for 1 hour. Triethylamine (14 μL) was added to the reaction mixture and stirred at room temperature for 5 minutes. Then, cerium chloride (151 mg) and sodium tetrahydroboro (19 mg) were added at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and after adding 1N hydrochloric acid aqueous solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ISCO Gold High Performance Silica, hexane:ethyl acetate = 60:40 → 55:45) to separate it into two diastereomers, and the highly polar product (19 mg) was obtained. 1 H-NMR(CDCl3):δ 7.47, 7.16-7.25, 7.06-7.13, 6.98-7.04, 6.85, 5.59, 5.37, 4.33-4.40, 4.37, 4.23-4.31, 3.81-3.89, 3.20, 2.93, 2.50-2.60, 2.43, 1.97-2.06, 1.75, 1.62-1.70, 1.34-1.54.

[0094] Example 4: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3ξ,4R)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid To a solution of the compound (high polar form: 19 mg) prepared in Reference Example 25 in dimethoxyethane (0.5 mL) / methanol (1 mL), 2N sodium hydroxide aqueous solution (0.5 mL) was added, and the reaction mixture was stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. By concentrating the filtrate under reduced pressure, the title compound (14.1 mg) with the following physical properties was obtained. HPLC retention time (min): 0.86; MS(ESI, Pos.):427(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.35-7.41, 7.26, 7.16-7.23, 7.07-7.13, 6.99-7.05, 6.87, 5.48, 5.23, 4.13-4.23, 3.71-3.78, 3.47, 3.24, 3.08, 2.77-2.86, 2.47-2.58, 2.35-2.43, 1.83, 1.55, 1.38, 1.10-1.34.

[0095] Reference Example 26: Dimethyl {2-[1-(2-fluorophenyl)cyclobutyl]-2-oxoethyl}phosphonate By using 1-(2-fluorophenyl)cyclobutanecarboxylic acid (CAS number: 151157-48-1, 10.4g) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid and subjecting it to the same procedure as in Reference Example 10 → Reference Example 11, the title compound (12.64g) having the following physical properties was obtained. 1H-NMR(CDCl3):δ 7.25-7.34, 7.17-7.22, 7.01-7.08, 3.69-3.77, 2.99, 2.93, 2.79-2.82, 2.86, 2.41-2.50, 2.03, 1.83-1.94.

[0096] Reference Example 27: Dimethyl [2-oxo-2-(1-phenylcyclopropyl)ethyl]phosphonate By using 1-phenylcyclopropanecarboxylic acid (CAS number: 6120-95-2, 3.0 g) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid and subjecting it to the same procedure as in Reference Example 10 → Reference Example 11, the title compound (2.6 g) having the following physical properties was obtained. 1 H-NMR (CDCl3): δ 7.30-7.42, 3.71-3.75, 3.05, 3.00, 1.71, 1.26-1.30.

[0097] Reference Example 28: Ethyl (2,6-difluorophenyl)(difluoro)acetate To a 24 mL solution of 1,3-difluoro-2-iodobenzene (CAS No.: 13697-89-7, 4.7 g) in DMSO (2), 2.5 mL of bromodifluoroethyl acetate (CAS No.: 667-27-6, 2.5 mL) and activated copper (3.2 g) were added and the mixture was stirred at 65°C for 20 hours. Tert-butyl methyl ether (MTBE) was added to the reaction mixture to separate the DMSO layer, and then saturated ammonium chloride aqueous solution was added and extracted with MTBE. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 → 93:7) to obtain the title compound (3.31 g) with the following physical properties. TLC: Rf 0.36 (Hexane:ethyl acetate = 9:1); 1 H-NMR (CDCl3): δ 7.42-7.50, 6.95-7.02, 4.39, 1.35.

[0098] Reference Example 29: Dimethyl [3-(2,6-difluorophenyl)-3,3-difluoro-2-oxopropyl]phosphonate By using the compound prepared in Reference Example 28 (3.31 g) instead of the compound prepared in Reference Example 10, and subjecting it to the same procedure as in Reference Example 11, the title compound (4.02 g) having the following physical properties was obtained. TLC: Rf 0.55 (ethyl acetate); 1 H-NMR (CDCl3): δ 7.41-7.52, 6.98, 3.78-3.86, 3.43-3.54.

[0099] Example 5: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 14, and subjecting it to the same objective procedure as in Reference Example 17 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. HPLC retention time (min): 0.93; MS(ESI, Pos.):453(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.95-13.20, 7.33-7.43, 7.16-7.24, 7.09, 5.25-5.43, 4.94, 4.72, 4.27, 4.13-4.20, 3.62-3.72, 2.70-2.98, 2.54-2.62, 2.34-2.44, 2.20-2.31, 1.99, 1.41-1.81.

[0100] Examples 5-1 to 5-21: By using the corresponding phosphonate instead of the compound prepared in Reference Example 14 and following the same procedure as in Reference Example 17 → Reference Example 18 → Example 2, the following example compounds were obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by diastereomer separation. The corresponding phosphonate was either a known compound or prepared from a known compound by following the same procedure as in Reference Example 10 → Reference Example 11.

[0101] Example 5-1: (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.88; MS(ESI, Pos.):421(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.37-7.47, 7.28, 7.18-7.22, 6.96, 5.56, 5.40, 4.32, 3.81-3.92, 3.05, 2.77, 2.51-2.65, 1.78-1.95, 1.61-1.77, 0.89-1.02, 0.71-0.83.

[0102] Example 5-2: (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.94; MS(ESI, Pos.):435(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.43, 7.25-7.30, 7.07-7.15, 6.95, 5.60, 5.32, 4.30, 4.11-4.15, 3.78-3.86, 3.03, 2.69-2.82, 2.50-2.64, 2.48, 1.91, 1.69-1.82, 1.63, 1.05-1.15, 0.73-0.80, 0.65.

[0103] Example 5-3: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-chlorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):469,471(M+H-H2O,M+H+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.37-7.44, 7.15-7.32, 6.90-6.95, 5.24-5.92, 4.56, 4.29, 3.83, 2.85-3.10, 2.48-2.74, 1.99-2.13, 1.91, 1.79, 1.24-1.39.

[0104] Example 5-4: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-4-(4-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.88; MS(ESI, Pos.):427(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.42, 7.28, 6.99-7.05, 6.94, 5.64, 5.46-5.52, 4.37, 4.17, 3.85-3.91, 3.05, 2.76-2.91, 2.56-2.68, 1.85-1.97, 1.79, 1.27.

[0105] Example 5-5: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3ξ,4ξ)-4-(4-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.87; MS(ESI, Pos.):427(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.26-7.49, 7.20-7.25, 7.02, 6.81-6.94, 5.45, 5.26, 4.25, 4.06-4.12, 3.79, 2.73-2.93, 2.59, 2.43, 1.81-1.92, 1.56-1.70, 1.37.

[0106] Examples 5-6: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3ξ,4ξ)-4-(4-fluoro-2-methylphenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.94; MS(ESI, Pos.):423(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.41-7.48, 7.24-7.33, 6.86-6.97, 5.69, 5.42-5.59, 4.38, 4.20, 3.85-3.92, 2.97-3.20, 2.82, 2.49-2.73, 2.38, 1.85-2.04, 1.69-1.85, 1.29-1.37, 1.22.

[0107] Examples 5-7: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2-chloro-4-fluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.96; MS(ESI, Pos.):461,463(M-H2O,M+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.39-7.50, 7.20, 7.07, 6.94, 5.65, 5.49, 4.29-4.38, 3.80-3.92, 3.35-3.52, 3.00-3.10, 2.75-2.88, 2.54-2.69, 1.81-1.97, 1.70-1.81, 1.29-1.35, 1.26.

[0108] Examples 5-8: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2-chloro-4-fluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.93; MS(ESI, Pos.):461,463(M-H2O,M+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.37-7.44, 7.24, 7.06, 6.91, 5.57, 5.27, 4.25, 4.15, 3.79, 3.35-3.45, 2.89, 2.53-2.64, 2.46, 1.88, 1.63, 1.37, 1.24-1.33.

[0109] Examples 5-9: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(2-fluoro-6-methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.95; MS(ESI, Pos.):453(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.88-13.30, 7.33-7.41, 7.12, 6.95, 5.45-5.58, 5.20-5.33, 5.06-5.18, 4.80, 4.71, 4.21-4.37, 4.09, 3.78-3.95, 3.42, 2.84-2.96, 2.69-2.83, 2.57-2.65, 2.33-2.46, 2.16-2.30, 1.33-1.77, 0.93-1.31, 0.39-0.70.

[0110] Examples 5-10: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(5-fluoro-2-methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.96; MS(ESI, Pos.):453(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.97-13.22, 7.35-7.42, 7.13, 6.90-7.01, 5.41, 5.13-5.26, 4.81, 4.74, 4.30, 3.94-4.02, 3.64, 2.86-2.98, 2.70-2.83, 2.52-2.60, 2.44, 2.35-2.39, 1.48-1.74, 1.00-1.09, 0.95, 0.64, 0.53.

[0111] Example 5-11: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(3-fluoro-2-methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.95; 1 H-NMR(CD3OD):δ 7.42, 7.04-7.21, 6.88-7.02, 5.59, 5.34, 4.31, 3.99-4.22, 3.77-3.95, 2.90-3.10, 2.76, 2.46-2.68, 2.39, 1.91, 1.69-1.84, 1.64, 1.04-1.17, 0.72-0.86, 0.66.

[0112] Example 5-12: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(4-fluoro-2-methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.94; MS(ESI, Pos.):453(M+H-H2O)+,435(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.38-7.50, 7.03-7.27, 6.88-7.03, 5.50-5.74, 5.42, 4.33, 3.94-4.23, 3.83, 3.05, 2.71-2.90, 2.48-2.70, 2.29-2.45, 1.80-1.97, 1.58-1.80, 1.10, 0.63-0.81.

[0113] Example 5-13: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,3-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.93; MS(ESI, Pos.):445(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.91-13.24, 7.37, 7.10-7.26, 6.98, 5.38-5.54, 4.85, 4.77-4.83, 4.35, 4.06-4.12, 3.71, 3.04-3.14, 2.93, 2.82, 2.53-2.63, 2.34-2.46, 1.59-1.84, 1.13-1.28.

[0114] Example 5-14: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,3-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):445(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.81-13.30, 7.36, 7.14, 6.95, 5.34, 5.16, 5.00, 4.74, 4.25, 4.01, 3.61, 3.04, 2.72-2.83, 2.53-2.65, 2.43, 2.15-2.31, 1.44-1.72, 1.13-1.35.

[0115] Example 5-15: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,5-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.92; MS(ESI, Pos.):445(M-OH)+.; 1 H-NMR(DMSO-d6):δ 13.07, 7.37, 7.18, 7.15, 7.02-7.08, 6.98, 5.35-5.51, 4.86, 4.79, 4.35, 4.09, 3.70, 3.06, 2.89-3.00, 2.74-2.86, 2.52-2.56, 2.33-2.45, 1.59-1.82, 1.12-1.25.

[0116] Example 5-16: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,5-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.89; MS(ESI, Pos.):445(M-OH)+.; 1 H-NMR(DMSO-d6):δ 13.06, 7.36, 7.17, 7.02-7.09, 6.96, 5.37, 5.15-5.23, 4.97, 4.74, 4.26, 3.98-4.07, 3.62, 2.98, 2.77, 2.61, 2.52-2.56, 2.38-2.46, 2.13-2.31, 1.62-1.72, 1.54, 1.14-1.34.

[0117] Example 5-17: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,6-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):445(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.45, 7.23-7.31, 6.90-6.97, 5.47, 5.30, 4.36, 4.20-4.25, 3.73-3.81, 3.25, 2.80, 2.47-2.60, 2.38, 1.86, 1.50-1.59, 1.46, 0.97-1.23.

[0118] Example 5-18: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,6-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.94; MS(ESI, Pos.):445(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.47, 7.20-7.28, 6.89-6.98, 5.71-5.77, 5.60-5.67, 4.34-4.43, 3.94, 3.24-3.31, 3.07-3.16, 2.87, 2.63-2.72, 1.93-2.03, 1.82-1.91, 1.30.

[0119] Example 5-19: (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-[(1E,3ξ,4ξ)-3-hydroxy-4-(2,4,6-trifluorophenyl)-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.95; MS(ESI, Pos.):463(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.47, 6.97, 6.81, 5.60-5.80, 4.40, 4.32, 4.12, 3.93, 3.07-3.31, 2.87, 2.51-2.78, 1.78-2.05, 1.20-1.37.

[0120] Example 5-20: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1―(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.116; MS(ESI, Pos.):471(M+H-H2O)+,453(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.42-7.46, 7.10-7.16, 6.94, 6.86, 6.78-6.85, 5.48-5.55, 5.39-5.48, 4.28-4.34, 3.80-3.86, 2.98-3.05, 2.70-2.79, 2.44-2.64, 2.32-2.43, 2.05-2.13, 1.73-1.93, 1.66.

[0121] Example 5-21: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.102; MS(ESI, Pos.):435(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.43-7.47, 7.12-7.18, 6.94-7.02, 5.39-5.46, 5.31-5.38, 4.29-4.33, 4.24, 3.80-3.86, 2.99-3.07, 2.74-2.82, 2.47-2.64, 2.24-2.42, 2.00-2.08, 1.76-1.92, 1.66-1.75.

[0122] Reference Example 30: Ethyl (1R,2R,3aS,10aR)-1-[(1E)-4-(2,6-difluorophenyl)-4,4-difluoro-3-oxo-1-buten-1-yl]-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[bcyclopenta[f]oxepin-6-carboxylate To a solution of the compound (309 mg) prepared in Reference Example 29 in THF (0.5 mL), sodium hydride (17.5 mg, 60% oil suspension) was added and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, a solution of the compound (100 mg) prepared in Reference Example 9 in THF (0.5 mL) and a solution of zinc chloride in 2-methyltetrahydrofuran (0.37 mL) were added and the mixture was stirred overnight at 50°C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 → 80:20) to obtain the title compound (114 mg) with the following physical properties. TLC: Rf 0.43 (Hexane:ethyl acetate = 7:3); 1 H-NMR(CDCl3):δ 7.42-7.50, 7.22, 7.17, 6.98, 6.74-6.88, 4.69-4.72, 4.57, 4.37, 4.01-4.20, 3.85-3.92, 3.71, 3.39-3.51, 3.01-3.19, 2.60-2.82, 2.24, 1.91-2.12, 1.77-1.87, 1.56-1.77, 1.45-1.53, 1.38.

[0123] Example 6: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-(2,6-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 30 instead of the compound prepared in Reference Example 17, and subjecting it to the same procedure as in Reference Example 18 → Example 2, the title compound exhibiting the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. HPLC retention time (min): 0.83; MS(ESI, Pos.):467(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.95-13.20, 7.54-7.66, 7.35-7.41, 7.20, 6.99, 6.01, 5.56-5.61, 4.86, 4.36-4.50, 4.31, 3.71, 2.84-2.98, 2.69-2.80, 2.53-2.63, 2.35-2.47, 1.73, 1.39-1.62.

[0124] Examples 6-1 to 6-17: The following example compounds were obtained by using the corresponding phosphonate instead of the compound prepared in Reference Example 29 and following the same procedure as in Reference Example 30 → Reference Example 18 → Example 2. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by diastereomer separation. The corresponding phosphonate was either a known compound or prepared from a known compound by following the same procedure as in Reference Example 28 → Reference Example 29.

[0125] Example 6-1: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.86; MS(ESI, Pos.):431(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.40-7.55, 6.79-7.03, 5.57-5.65, 4.41-4.56, 4.19-4.40, 3.84-3.91, 3.01, 2.74, 2.55-2.66, 1.89-1.96, 1.81, 1.63.

[0126] Example 6-2: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.87; MS(ESI, Pos.):449(M-OH)+.; 1H-NMR(DMSO-d6):δ 12.88-13.32, 7.50-7.57, 7.28-7.40, 6.98, 5.84, 5.54, 5.45, 4.85, 4.37-4.51, 4.32, 3.70, 2.71-3.02, 2.54-2.63, 2.35-2.47, 1.74.

[0127] Example 6-3: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-(4-methylphenyl)-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):445(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.85-13.34, 7.35, 7.26, 6.99, 5.76, 5.50-5.58, 5.43, 4.83, 4.36-4.46, 4.32, 3.66-3.76, 2.84-2.97, 2.70-2.81, 2.53-2.63, 2.35-2.45, 2.34, 1.44-1.80.

[0128] Example 6-4: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-(4-chlorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.92; MS(ESI, Pos.):465(M-OH)+.; 1H-NMR(DMSO-d6):δ 13.07, 7.46-7.57, 7.37, 6.99, 5.87, 5.51-5.60, 5.43, 4.85, 4.44, 4.33, 3.70, 2.90, 2.79, 2.53-2.64, 2.45, 1.65-1.81, 1.46-1.65.

[0129] Example 6-5: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-(2,4-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.86; MS(ESI, Pos.):467(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.57-7.64, 7.42, 7.07-7.14, 6.93, 5.63-5.74, 4.61, 4.31-4.35, 3.85-3.92, 2.96-3.04, 2.73, 2.56-2.67, 1.78-1.96, 1.69, 1.57.

[0130] Example 6-6: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-(2-chlorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.86; MS(ESI, Pos.):465(M-OH)+.; 1H-NMR(DMSO-d6):δ 13.06, 7.44-7.62, 7.37, 6.98, 5.85, 5.46-5.62, 4.86, 4.77, 4.30, 3.66-3.75, 2.82-2.92, 2.68-2.74, 2.52-2.62, 2.45-2.46, 2.34-2.42, 1.63-1.75, 1.32-1.53.

[0131] Examples 6-7: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-(2-methylphenyl)-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.87; MS(ESI, Pos.):445(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.42-7.49, 7.31-7.38, 7.27, 6.95, 5.68, 5.53-5.61, 4.53-4.62, 4.28-4.35, 3.87, 3.00, 2.67-2.78, 2.54-2.66, 2.48-2.53, 1.92, 1.73-1.85, 1.51-1.71.

[0132] Examples 6-8: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(4-fluoro-2-methylphenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):463(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.36, 6.83-6.93, 5.46-5.60, 4.43, 4.20-4.25, 3.76, 3.23-3.27, 2.91, 2.60-2.73, 2.43-2.55, 2.40, 1.43-1.85.

[0133] Examples 6-9: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-(2,5-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.84; MS(ESI, Pos.):467(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.35, 7.11-7.22, 6.83, 5.49-5.64, 4.76, 4.52, 4.19-4.25, 3.77, 2.90, 2.45-2.67, 1.81, 1.65-1.75, 1.51-1.62, 1.40-1.51.

[0134] Examples 6-10: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(2-fluoro-6-methylphenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.87; MS(ESI, Pos.):463(M-OH)+.; 1 H-NMR(DMSO-d6):δ 13.06, 7.35-7.42, 7.08-7.15, 6.99, 5.87, 5.50-5.65, 4.85, 4.45, 4.30, 3.71, 2.88, 2.68-2.80, 2.52-2.56, 2.36-2.47, 1.72, 1.49.

[0135] Example 6-11: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(2-fluoro-3-methylphenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.89; MS(ESI, Pos.):463(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.88-13.22, 7.28-7.46, 7.16-7.22, 6.98, 5.85, 5.51-5.56, 4.85, 4.43-4.59, 4.31, 3.71, 2.82-2.92, 2.69-2.78, 2.52-2.60, 2.45, 2.26, 1.69, 1.37-1.60, 1.23.

[0136] Example 6-12: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-(2-chloro-6-fluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.88; MS(ESI, Pos.):483(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.90-13.25, 7.55, 7.33-7.45, 6.99, 5.97, 5.52-5.66, 4.86, 4.49-4.65, 4.30, 3.71, 2.84-2.96, 2.67-2.77, 2.54-2.65, 2.35-2.46, 1.66-1.76, 1.36-1.57, 1.23.

[0137] Example 6-13: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(5-fluoro-2-methylphenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):463(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.12-7.28, 7.04-7.11, 6.93-7.02, 6.72-6.81, 5.46-5.60, 4.40-4.53, 4.14-4.25, 3.67-3.84, 3.24-3.30, 2.81-2.96, 2.66, 2.50, 2.36, 1.74-1.86, 1.34-1.74.

[0138] Example 6-14: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(2-fluoro-5-methylphenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):463(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.45, 7.30-7.38, 7.08, 6.94, 5.55-5.71, 4.59-4.68, 4.29-4.34, 3.87, 2.97, 2.53-2.75, 2.38, 1.92, 1.72-1.81, 1.56-1.67, 1.37-1.51.

[0139] Example 6-15: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(3-fluoro-2-methylphenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.91; MS(ESI, Pos.):463(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.42-7.49, 7.26-7.35, 7.12-7.22, 6.95, 5.65, 4.52-4.61, 4.30-4.36, 3.88, 3.02, 2.75, 2.55-2.67, 2.41, 1.78-1.96, 1.55-1.75.

[0140] Example 6-16: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-(5-chloro-2-fluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.92; MS(ESI, Pos.):483(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.90-13.24, 7.63-7.69, 7.48-7.53, 7.39, 6.95-7.00, 5.98, 5.55, 4.86, 4.42-4.58, 4.28-4.38, 3.67, 2.85-2.96, 2.71-2.82, 2.54-2.63, 2.35-2.46, 1.66-1.78, 1.36-1.64.

[0141] Example 6-17: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(2-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.86; MS(ESI, Pos.):449(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.51-7.60, 7.41, 7.30, 7.17-7.25, 6.92, 5.57-5.73, 4.66, 4.30, 3.84-3.91, 2.93-3.01, 2.54-2.73, 1.92, 1.77, 1.60, 1.29-1.52.

[0142] Reference Example 31: 5-bromo-2-vinylphenol By using 4-bromo-2-hydroxybenzaldehyde (CAS number: 22532-62-3) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde and subjecting it to the same procedure as in Reference Example 3, the title compound having the following physical properties was obtained. 1 H-NMR (CDCl3): δ 7.24, 7.05, 6.98-7.00, 6.80-6.92, 5.77, 5.71, 5.40, 5.09.

[0143] Reference Example 32: Ethyl (1R,2R,3aS,10aR)-1-formyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, and subjecting it to the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, the title compound having the following physical properties was obtained. TLC: Rf 0.50 (Hexane:ethyl acetate = 2:1); 1 H-NMR(CDCl3):δ 9.82-9.86, 7.60-7.65, 7.13, 4.64-4.69, 4.32-4.49, 3.79-3.95, 3.44-3.55, 3.23-3.30, 3.14-3.21, 3.02-3.11, 2.77-2.88, 2.52-2.66, 2.18-2.41, 1.98-2.15, 1.70-1.97, 1.59-1.70, 1.48-1.57, 1.39.

[0144] Example 7: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3R)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 32 instead of the compound prepared in Reference Example 9, and the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 14, and by subjecting the compound to the same objective as in Reference Example 17 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. The stereochemistry was determined by single-crystal X-ray diffraction. HPLC retention time (min): 0.91; MS(ESI, Pos.):403(M+H-H2O)+,385(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.58, 7.48, 7.34-7.40, 7.22-7.29, 7.15-7.21, 5.53, 5.38, 4.30-4.35, 3.88, 3.77-3.85, 3.00, 2.80, 2.59, 2.42-2.51, 1.65-1.87, 0.87-1.00, 0.68-0.82.

[0145] Examples 7-1 to 7-50: The following example compounds were obtained by using the compound prepared in Reference Example 32 instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 14, and following the same procedure as in Reference Example 17 → Reference Example 18 → Example 2. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by a diastereomer separation procedure. The corresponding phosphonate was either a known compound or prepared from a known compound by following the same procedure as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0146] Example 7-1: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S)-3-hydroxy-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):357(M+H-H2O)+.; 1 H-NMR(DMSO-d6):δ 12.80, 7.47, 7.33, 7.18, 5.31-5.53, 4.77, 4.55, 4.35, 3.81-3.94, 3.63-3.76, 2.76-2.98, 2.40-2.58, 2.24-2.38, 1.63-1.85, 1.16-1.49.

[0147] Example 7-2: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.97; MS(ESI, Pos.):425(M+H-H2O)+,407(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.47, 7.39, 7.06, 5.51-5.63, 4.40-4.45, 4.28, 3.66-3.82, 2.84-2.96, 2.68-2.83, 2.40-2.62, 2.00-2.27, 1.70-1.93, 1.12-1.61, 0.84.

[0148] Example 7-3: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):425(M+H-H2O)+,407(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.60, 7.51, 7.19, 5.60-5.75, 4.38-4.46, 3.91, 3.05, 2.86, 2.56-2.70, 2.21-2.32, 1.82-1.97, 1.59-1.74, 1.29-1.53, 0.92-0.98.

[0149] Example 7-4: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):425(M+H-H2O)+,407(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.59, 7.51, 7.19, 5.60-5.75, 4.38-4.43, 3.90, 3.04, 2.87, 2.55-2.70, 2.29-2.38, 1.82-1.97, 1.68-1.77, 1.53-1.62, 1.28-1.49, 0.90-0.98.

[0150] Example 7-5: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.86; MS(ESI, Pos.):413(M+H-H2O)+.; 1 H-NMR (CD3OD): δ 7.60, 7.43-7.55, 7.19, 5.57-5.62, 4.94, 4.42-4.57, 4.34, 3.82-3.89, 2.89-3.05, 2.71-2.87, 2.62, 1.85.

[0151] Example 7-6: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclobutyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.97; MS(ESI, Pos.):417(M+H-H2O)+.; 1 H-NMR(CDCl3):δ 7.62-7.68, 7.27-7.35, 7.12-7.25, 5.57, 5.39, 4.32-4.38, 3.73-3.82, 2.99-3.08, 2.79, 2.26-2.61, 2.02-2.11, 1.74-2.00.

[0152] Example 7-7: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4R)-3-hydroxy-4-phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.92; MS(ESI, Pos.):373(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.46, 7.35, 7.15-7.20, 7.02-7.11, 5.33, 5.13, 4.12-4.16, 3.98-4.03, 3.62-3.68, 2.62-2.75, 2.41-2.54, 2.20-2.28, 1.69, 1.42-1.51, 1.23-1.32.

[0153] Examples 7-8: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4S)-3-hydroxy-4-phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.92; MS(ESI, Pos.):373(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.47, 7.38, 7.12-7.20, 7.01-7.11, 5.52, 5.35, 4.25, 4.08, 3.74, 2.86-2.95, 2.68-2.78, 2.37-2.56, 1.62-1.80, 1.07-1.24.

[0154] Examples 7-9: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-3-(1-butylcyclopropyl)-3-hydroxy-1-propen-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):383(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.59, 7.51, 7.19, 5.50-5.67, 4.41, 3.86-3.94, 3.03, 2.89, 2.52-2.69, 1.83-1.98, 1.52, 1.24-1.43, 0.89-0.96, 0.50-0.58, 0.26-0.34.

[0155] Examples 7-10: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S)-3-hydroxy-4-(3-thienyl)-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.84; MS(ESI, Pos.):383(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.59, 7.49, 7.32, 7.18, 7.10, 7.02, 5.63, 5.42, 4.30-4.36, 3.80-3.87, 2.92-3.02, 2.74-2.87, 2.62, 2.49, 1.86, 1.74, 1.58-1.67.

[0156] Example 7-11: (1R,2R,3aS,10aR)-1-{(1E,3ξ,4ξ)-3-[1-(2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.94; MS(ESI, Pos.):421(M+H-H2O); 1H-NMR(DMSO-d6):δ 12.78, 7.48, 7.18-7.34, 7.03-7.11, 5.40, 5.19, 4.80, 4.68, 4.22-4.31, 3.96, 3.56-3.66, 2.80-2.92, 2.67-2.79, 2.49, 2.19-2.28, 1.41-1.69, 0.88-1.03, 0.61-0.70, 0.50-0.58.

[0157] Example 7-12: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(3-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.94; MS(ESI, Pos.):421(M+H-H2O); 1 H-NMR(DMSO-d6):δ 12.78, 7.48, 7.32, 7.24-7.31, 7.16-7.21, 7.11-7.15, 7.06-7.11, 6.98, 5.23-5.40, 4.87, 4.69, 4.26-4.32, 3.84, 3.59-3.68, 3.16, 2.81-2.92, 2.70-2.81, 2.41-2.49, 2.21-2.31, 1.51-1.72, 0.80-0.99, 0.58-0.80.

[0158] Example 7-13: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 0.97; MS(ESI, Pos.):435(M+H-H2O)+,417(M+H-2H2O)+.; 1 H-NMR(DMSO-d6):δ 12.78, 7.49, 7.33, 7.21, 7.03-7.10, 5.33, 5.14, 4.83, 4.68, 4.27-4.33, 4.09, 3.60-3.69, 3.16, 2.75-2.93, 2.49, 2.20-2.33, 2.09-2.19, 1.87-2.00, 1.57-1.77.

[0159] Example 7-14: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(3-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.97; MS(ESI, Pos.):435(M+H-H2O)+.; 1 H-NMR(DMSO-d6):δ 12.79, 7.48, 7.26-7.34, 7.20, 6.95, 6.88-6.92, 6.80-6.86, 5.34, 5.15, 4.90, 4.68, 4.27-4.32, 4.06-4.12, 3.61-3.69, 3.16, 2.74-2.92, 2.49, 2.11-2.35, 1.89-2.00, 1.58-1.77.

[0160] Example 7-15: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4R)-3-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.96; MS(ESI, Pos.):371(M+H-H2O)+,353(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.57, 7.48, 7.16, 5.62, 5.49, 4.38, 3.83-3.92, 3.03, 2.84, 2.49-2.68, 1.79-1.96, 1.45-1.61, 1.21-1.41, 1.02-1.16, 0.86-0.96.

[0161] Example 7-16: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4S)-3-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.96; MS(ESI, Pos.):371(M+H-H2O)+,353(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.57, 7.49, 7.17, 5.62, 5.46-5.54, 4.38, 3.84-3.91, 3.03, 2.85, 2.47-2.71, 1.76-2.00, 1.46-1.66, 1.21-1.46, 1.05-1.17, 0.86-0.96.

[0162] Example 7-17: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.1; MS(ESI, Pos.):417(M+H-2H2O)+.; 1H-NMR(DMSO-d6):δ 12.80, 7.49, 7.33, 7.17-7.23, 7.01-7.12, 5.76, 5.28-5.39, 4.92, 4.68, 4.27-4.32, 4.16, 3.60-3.68, 2.83-2.92, 2.71-2.80, 2.52-2.55, 2.39-2.48, 1.91-2.08, 1.50-1.78.

[0163] Example 7-18: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-thienyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.88; MS(ESI, Pos.):391(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.59, 7.50, 7.29, 7.16-7.20, 7.12, 5.57-5.63, 5.46-5.51, 4.36, 3.94, 3.85, 2.96-3.04, 2.83, 2.62, 2.49, 1.77-1.89, 1.73, 0.76-1.00.

[0164] Example 7-19: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(4-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.89; MS(ESI, Pos.):409(M+H-H2O)+.,391(M+H-2H2O)+.; 1H-NMR(DMSO-d6):δ 12.80, 7.48, 7.32, 7.16-7.24, 7.04-7.10, 5.26-5.33, 5.14-5.21, 4.80, 4.70, 4.24-4.29, 3.94-4.00, 3.57-3.65, 2.64-2.82, 2.41-2.49, 2.18, 1.51-1.67, 1.34-1.44, 1.23.

[0165] Example 7-20: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-chlorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.913; MS(ESI, Pos.):437(M+H-H2O); 1 H-NMR(CD3OD):δ 7.58, 7.48, 7.31-7.42, 7.15-7.25, 5.58, 5.31, 4.38, 4.30, 3.75-3.82, 2.97, 2.76, 2.58, 2.41-2.51, 1.61-1.86, 1.51-1.61, 1.29, 1.07-1.21, 0.67-0.83.

[0166] Example 7-21: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-chloro-6-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.915; MS(ESI, Pos.):455(M+H-H2O); 1H-NMR(CD3OD):δ 7.58, 7.48, 7.16-7.27, 6.99-7.05, 5.65-5.75, 5.38, 5.25, 4.24-4.35, 3.70-3.84, 2.91-3.04, 2.67-2.84, 2.42-2.63, 1.76-1.88, 1.56-1.76, 1.43-1.52, 1.15-1.33, 0.81-0.92, 0.77, 0.62-0.73.

[0167] Example 7-22: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,4-difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.885; MS(ESI, Pos.):439(M+H-H2O); 1 H-NMR(CD3OD):δ 7.58, 7.48, 7.38, 7.18, 6.82-6.91, 5.56, 5.38, 4.33, 3.96, 3.80, 2.94-3.04, 2.75-2.85, 2.59, 2.42-2.53, 1.61-1.89, 1.27-1.35, 0.95-1.07, 0.95-0.97, 0.65-0.81.

[0168] Example 7-23: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-thienyl)cyclobutyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):405(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.60, 7.49, 7.32, 7.19, 7.09, 7.02, 5.36-5.47, 4.32-4.36, 4.23, 3.83, 2.99, 2.81, 2.39-2.65, 2.17-2.32, 1.61-1.99.

[0169] Example 7-24: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(3-chlorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.97; MS(ESI, Pos.):437(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.63-13.00, 7.50, 7.19-7.35, 5.32, 4.92, 4.72, 4.31, 3.79-3.84, 3.66, 3.38-3.43, 3.24-3.31, 2.52-2.58, 2.52-2.61, 2.44-2.47, 1.66, 0.90, 0.68.

[0170] Example 7-25: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-chlorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.02; MS(ESI, Pos.):451(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.62-13.01, 7.48, 7.11-7.34, 5.17-5.60, 4.80-5.00, 4.71, 4.24-4.38, 3.55-3.72, 2.69-2.95, 2.57-2.63, 2.52-2.55, 2.39-2.46, 1.88-1.97, 1.67.

[0171] Example 7-26: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluoro-6-methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.94; MS(ESI, Pos.):435(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.48-13.10, 7.49, 7.33, 7.21, 7.08-7.16, 6.86-6.98, 5.49, 5.05-5.33, 4.78, 4.68, 4.25, 4.05-4.12, 3.86-3.92, 2.69-2.92, 2.53-2.63, 2.39-2.46, 2.16-2.31, 1.66, 1.08, 0.38-0.70.

[0172] Example 7-27: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,6-difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):439(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.68-13.15, 7.50, 7.27-7.39, 7.21, 6.96-7.04, 5.45-5.53, 5.20, 4.89, 4.69, 4.27, 3.93-3.99, 3.51-3.76, 2.69-2.93, 2.52-2.55, 2.44, 2.26, 1.62, 1.48, 1.00-1.11, 0.67, 0.49-0.58.

[0173] Example 7-28: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-{1-[3-(trifluoromethyl)phenyl]cyclopropyl}-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.98; MS(ESI, Pos.):471(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.71-12.98, 7.61, 7.50, 7.33, 7.16-7.23, 5.32, 4.97, 4.71, 4.28-4.36, 3.77-3.85, 3.60-3.68, 2.71-2.90, 2.57-2.62, 2.52-2.56, 2.34-2.46, 1.49-1.74, 0.62-1.01.

[0174] Example 7-29: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-{1-[3-(trifluoromethoxy)phenyl]cyclopropyl}-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1; MS(ESI, Pos.):487(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.68-12.97, 7.49, 7.32-7.41, 7.26, 7.19, 5.31-5.35, 4.94, 4.71, 4.27-4.34, 3.82, 3.58-3.71, 2.71-2.96, 2.55, 2.36-2.46, 2.19-2.31, 1.50-1.75, 0.62-0.99.

[0175] Example 7-30: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,5-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.12; MS(ESI, Pos.):435(M+H-2H2O)+.; 1 H-NMR(DMSO-d6):δ 12.70-12.92, 7.48, 7.33, 7.19, 7.00-7.15, 6.79-6.89, 5.32-5.37, 5.01, 4.70, 4.27-4.33, 4.12-4.20, 3.58-3.71, 2.72-2.93, 2.52-2.56, 2.45, 2.18-2.32, 1.99, 1.68.

[0176] Example 7-31: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.96; MS(ESI, Pos.):417(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.59, 7.49, 7.27, 7.07-7.20, 5.59, 5.32, 4.32, 4.12, 3.76-3.84, 3.35-3.43, 2.96-3.04, 2.80, 2.56-2.65, 2.48, 2.00, 1.69-1.88, 1.64, 1.32-1.36, 1.04-1.14, 0.74-0.79, 0.65.

[0177] Example 7-32: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,5-difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.93; MS(ESI, Pos.):439(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.59, 7.50, 6.97-7.19, 5.58, 5.39, 4.33, 4.05, 3.79-3.86, 3.36-3.43, 3.01, 2.75-2.87, 2.47-2.65, 1.73-1.89, 1.60-1.72, 1.24-1.38, 1.03-1.10, 0.72-0.86.

[0178] Example 7-33: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):453(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.57, 7.49, 7.13-7.17, 6.84, 6.90, 5.37-5.61, 4.34, 4.33, 3.83, 2.94-3.06, 2.70-2.84, 2.60, 2.49, 2.41, 2.05-2.19, 1.55-1.91.

[0179] Example 7-34: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-chloro-6-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.03; MS(ESI, Pos.):469,471(M-H2O,M+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.47, 7.38, 7.03-7.11, 6.84-6.91, 5.76-5.89, 5.67, 5.33-5.46, 5.20, 4.29-4.40, 4.15-4.25, 3.62-3.78, 2.78-2.94, 2.42-2.69, 2.31-2.39, 1.85-2.06, 1.55-1.79, 1.48, 1.27-1.43, 1.21-1.27.

[0180] Example 7-35: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,6-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):453(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.60, 7.50, 7.17-7.26, 6.87, 5.68, 5.48, 4.31-4.40, 3.83, 3.00, 2.79, 2.48-2.67, 2.10-2.22, 1.74-1.91, 1.62-1.72.

[0181] Example 7-36: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.95; MS(ESI, Pos.):417(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.48, 7.38, 7.01-7.12, 6.90, 5.42, 5.27, 4.23, 3.68-3.79, 2.90, 2.70, 2.49, 2.36, 2.21, 1.53-1.77, 0.74-0.89, 0.56-0.70.

[0182] Example 7-37: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,3-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.98; MS(ESI, Pos.):453(M+H-H2O)+.,435(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.47, 7.38, 7.05, 6.92-7.01, 6.77-6.88, 5.32-5.49, 4.12-4.40, 3.72, 2.87, 2.59-2.77, 2.49, 2.19-2.43, 1.94-2.17, 1.60-1.83, 1.54.

[0183] Example 7-38: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluoro-3-methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.96; MS(ESI, Pos.):435(M+H-H2O)+.417(M-2H2O)+.; 1 H-NMR(CD3OD):δ 7.58, 7.48, 7.13-7.21, 7.04-7.12, 6.93-6.99, 5.57, 5.35, 4.31, 4.04, 3.75-3.84, 3.33-3.37, 2.98, 2.78, 2.53-2.62, 2.41-2.51, 2.17-2.29, 1.71-1.90, 1.56-1.71, 1.27-1.35, 0.96-1.06, 0.59-0.82.

[0184] Example 7-39: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(5-chloro-2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.96; MS(ESI, Pos.):455,457(M+H-H2O)+.437,439(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.58, 7.46-7.50, 7.33-7.40, 7.14-7.26, 6.99-7.07, 5.55, 5.36, 4.32, 4.03, 3.75-3.85, 3.00, 2.81, 2.40-2.66, 1.70-1.91, 1.55-1.70, 1.27-1.45, 0.98-1.11, 0.65-0.85.

[0185] Example 7-40: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluoro-5-methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.95; MS(ESI, Pos.):435(M+H-H2O)+.417(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.58, 7.48, 7.13-7.20, 6.99-7.05, 6.84-6.91, 5.56, 5.34, 4.32, 4.03, 3.76-3.83, 2.97, 2.79, 2.58, 2.40-2.51, 1.70-1.90, 1.55-1.67, 1.27-1.37, 0.96-1.06, 0.61-0.83.

[0186] Example 7-41: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-methylphenyl)cyclobutyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1; MS(ESI, Pos.):413(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.57, 7.47, 7.12-7.19, 6.91-6.99, 5.30-5.45, 4.32, 4.22, 3.81, 2.94-3.03, 2.75-2.85, 2.22-2.62, 1.96-2.08, 1.65-1.87.

[0187] Example 7-42: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-methoxyphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.89; MS(ESI, Pos.):415(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.58, 7.48, 7.13-7.21, 6.95, 6.76, 5.53, 5.38, 4.28-4.35, 3.87-3.92, 3.74-3.85, 2.98, 2.79, 2.54-2.64, 2.41-2.51, 1.62-1.89, 0.86-1.00, 0.64-0.86.

[0188] Example 7-43: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(3-chlorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.02; MS(ESI, Pos.):451(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.81, 7.49, 7.34, 7.27-7.32, 7.18-7.24, 7.07, 7.03, 5.36, 5.14, 4.94, 4.70, 4.31, 4.12, 3.67, 2.86, 2.54-2.63, 2.40-2.46, 2.10-2.31, 1.91-2.03, 1.58-1.79.

[0189] Example 7-44: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(2-methylphenyl)cyclobutyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):413(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.58, 7.48, 7.17, 6.95-7.11, 5.47-5.61, 5.26-5.47, 4.26-4.43, 3.76-3.85, 2.97, 2.70-2.86, 2.39-2.64, 2.26-2.34, 2.00, 1.58-1.86.

[0190] Example 7-45: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-7-methyl-1-octen-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.93; MS(ESI, Pos.):407(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.57, 7.49, 7.13-7.18, 5.66-5.78, 4.80-4.83, 4.36-4.41, 4.16-4.24, 3.87-3.95, 3.26, 2.99-3.06, 2.79-2.89, 2.55-2.69, 1.79-2.02, 1.52-1.64, 1.35-1.47, 0.91-0.95, 0.93.

[0191] Example 7-46: (1R,2R,3aS,10aR)-1-[(1E,3S)-6-cyclopropyl-3-hydroxy-1-hexen-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.89; MS(ESI, Pos.):369(M+H-H2O)+,351(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.55, 7.47, 7.14, 5.55-5.71, 5.32-5.55, 4.28-4.43, 3.96-4.10, 3.86, 3.01, 2.84, 2.62, 2.44-2.56, 1.78-2.00, 1.38-1.64, 1.14-1.31, 0.60-0.74, 0.30-0.51, -0.06-0.08.

[0192] Example 7-47: (1R,2R,3aS,10aR)-1-[(1E,3S)-5-cyclobutyl-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.91; MS(ESI, Pos.):369(M+H-H2O)+,351(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.56, 7.48, 7.15, 5.56-5.63, 5.45-5.53, 4.37, 4.00, 3.86, 3.02, 2.84, 2.47-2.67, 2.29, 2.01-2.10, 1.76-1.98, 1.56-1.66, 1.33-1.52.

[0193] Example 7-48: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S)-6,7,7-trifluoro-3-hydroxy-1,6-heptadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.86; MS(ESI, Pos.):395(M+H-H2O)+,377(M+H-2H2O)+.; 1 H-NMR (CD3OD): δ 7.55, 7.48, 7.13, 5.53-5.68, 4.38, 4.10, 3.87, 2.99, 2.80-2.89, 2.59-2.68, 2.54, 2.37-2.49, 1.73-1.95.

[0194] Example 7-49: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3R)-3-hydroxy-4-propoxy-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.77; MS(ESI, Pos.):399(M+Na)+.; 1 H-NMR(CD3OD):δ 7.57, 7.48, 7.15, 5.59-5.69, 4.36-4.40, 4.23-4.28, 3.85-3.91, 3.39-3.51, 2.98-3.05, 2.80-2.88, 2.63, 2.53, 1.80-1.95, 1.61, 0.90-0.98.

[0195] Example 7-50: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1; MS(ESI, Pos.):385(M-OH)+.; 1 H-NMR(DMSO-d6):δ 12.58-13.08, 7.48, 7.34, 7.18, 5.38-5.52, 4.75, 4.46, 4.34, 3.92, 3.71, 2.76-3.00, 2.54-2.62, 2.35-2.47, 1.66-1.82, 1.06-1.54, 0.80-0.90.

[0196] Reference Example 33: 3-Bromo-2-chloro-6-vinylphenol By using 4-bromo-3-chloro-2-hydroxybenzaldehyde (CAS number: 1427438-98-9) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde and subjecting it to the same procedure as in Reference Example 3, the title compound having the following physical properties was obtained. 1 H-NMR (CDCl3): δ 7.23-7.28, 7.15-7.19, 6.89-6.97, 5.86, 5.80, 5.37.

[0197] Reference Example 34: Ethyl (1R,2R,3aS,10aR)-5-chloro-1-formyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 33 instead of the compound prepared in Reference Example 3, and subjecting it to the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, the title compound having the following physical properties was obtained. 1 H-NMR(CDCl3):δ 9.85, 7.41, 7.02, 4.69, 4.47, 4.38, 4.22-4.27, 3.79-3.86, 3.42-3.54, 3.32-3.42, 3.09-3.24, 2.63-2.72, 2.51-2.60, 2.22-2.37, 1.97-2.05, 1.70-1.88, 1.55-1.67, 1.39, 1.22-1.33.

[0198] Example 8: (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-4-(2,6-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] By using the compound prepared in Reference Example 34 instead of the compound prepared in Reference Example 9, and subjecting it to the same procedure as in Reference Example 30 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. The stereochemistry was determined by crystalline X-ray diffraction. HPLC retention time (min): 1.045; MS(ESI, Pos.): 523(M+Na)+.; 1 H-NMR(CD3OD):δ 7.50-7.58, 7.37, 7.05-7.14, 5.79, 5.65, 4.52-4.61, 4.20, 3.92, 3.07, 2.57-2.77, 1.98-2.04, 1.80, 1.50-1.70.

[0199] Examples 8-1 to 8-8: The following example compounds were obtained by using the compound prepared in Reference Example 34 instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 29, and following the same procedure as in Reference Example 30 → Reference Example 18 → Example 2. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. The corresponding phosphonate was either a known compound or prepared from a known compound by following the same procedure as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0200] Example 8-1: (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.85; MS(ESI, Pos.):447,449(M-H2O,M+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.51-7.56, 7.48, 7.39, 7.13, 5.58-5.65, 4.46-4.54, 4.21, 3.90, 3.06, 2.57-2.73, 1.96-2.06, 1.65-1.85, 1.53-1.63.

[0201] Example 8-2: (1R,2R,3aS,10aR)-5-chloro-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.88; MS(ESI, Pos.):437,439(M-H2O,M+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.37-7.42, 7.24-7.32, 7.18-7.22, 7.12, 5.56, 5.36-5.44, 4.21, 3.83-3.92, 3.04-3.16, 2.56-2.71, 1.96-2.04, 1.80, 1.64, 0.89-1.03, 0.78-0.84, 0.71-0.76.

[0202] Example 8-3: (1R,2R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.117; MS(ESI, Pos.):451(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.30, 7.08-7.24, 7.00, 5.54, 5.39-5.46, 4.36, 4.18, 3.83-3.90, 3.02, 2.31-2.68, 2.10, 1.96-2.05, 1.75, 1.58.

[0203] Example 8-4: (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ,4ξ)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.89; MS(ESI, Pos.):443,445(M-H2O,M+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.36, 7.30, 7.18-7.26, 7.02-7.15, 5.52, 5.26, 4.19, 4.08-4.15, 3.81, 3.05-3.16, 2.81-2.93, 2.41-2.59, 1.94, 1.57, 1.41, 1.15-1.26.

[0204] Example 8-5: (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ,4ξ)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.92; MS(ESI, Pos.):443,445(M-H2O,M+2-H2O)+.; 1 H-NMR(CD3OD):δ 7.33-7.44, 7.19-7.26, 7.09-7.18, 6.99-7.08, 5.63-5.72, 5.45-5.56, 4.19-4.33, 3.91, 3.22-3.31, 2.98-3.19, 2.52-2.76, 1.97-2.07, 1.78-1.92, 1.56-1.78, 1.24-1.37.

[0205] Example 8-6: (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ,4ξ)-4-(4-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.081; MS(ESI, Pos.):425,427(M-2H2O,M+2-2H2O)+.; 1 H-NMR(CD3OD):δ 7.37, 7.29, 7.12, 6.99-7.06, 5.65, 5.49, 4.22-4.27, 4.14-4.21, 3.91, 3.07-3.13, 2.87, 2.58-2.76, 1.96-2.09, 1.81-1.93, 1.73, 1.24-1.30.

[0206] Example 8-7: (1R,2R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1―(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.125; MS(ESI, Pos.):469(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.39, 7.09-7.17, 6.86-6.92, 6.79-6.86, 5.49-5.56, 5.40-5.47, 4.32, 4.19, 3.83-3.90, 3.02-3.09, 2.51-2.68, 2.33-2.50, 2.05-2.13, 1.94-2.01, 1.71-1.89, 1.56-1.65.

[0207] Example 8-8: (1R,2R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.115; MS(ESI, Pos.):469(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.40, 7.11-7.18, 7.00, 5.40-5.47, 5.32-5.39, 4.24, 4.17-4.21, 3.82-3.90, 3.00-3.11, 2.50-2.72, 2.24-2.43, 2.01, 1.94-2.00, 1.73-1.89, 1.60-1.71.

[0208] Reference Example 35: 3-Hydroxy-2-methyl-4-vinyl methyl benzoate To a solution of methyltriphenylphosphonium bromide (51.5 g) in THF (93.4 mL), potassium tert-butoxide (14.0 g) was added at 0°C and the mixture was stirred at 0°C for 1 hour. A solution of 4-formyl-3-hydroxy-2-methylbenzoate methyl benzoate (CAS number: 1427361-42-9, 9.34 g) in THF (46.7 mL) was added and the mixture was stirred at 0°C for 3 hours. Saturated ammonium chloride aqueous solution and 1N hydrochloric acid aqueous solution were added to the reaction mixture at 0°C and extracted with ethyl acetate / n-hexane mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 → 90:10 → 80:20 → 70:30) to obtain the title compound (9.22 g) with the following physical properties. 1 H-NMR (CDCl3): δ 7.10-7.16, 7.00-7.07, 6.79-6.88, 5.69, 5.42, 5.17, 2.35.

[0209] Reference Example 36: 3-{[(1S,2R,3S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}-2-methyl-4-vinyl methyl benzoate To a THF (70 mL) solution of the compound prepared in Reference Example 35 (7.0 g) and the compound prepared in Reference Example 2 (13.5 g), triphenylphosphine (12.4 g) was added and the mixture was cooled under ice. To the reaction solution, a toluene solution of 2.2 M diethylazodicarboxylate (22 mL) was added and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and MTBE:n-hexane (2:1, 150 mL) was added to the resulting residue and stirred for 1 hour. After filtering the precipitate, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0 → 85:15) to obtain the title compound (14.3 g) with the following physical properties. 1H-NMR(CDCl3):δ 7.58, 7.36-7.41, 7.12-7.23, 5.69-5.86, 5.54-5.64, 5.27-5.34, 4.67-4.70, 4.59, 4.26-4.41, 3.79-3.93, 3.57-3.75, 3.39-3.52, 2.99-3.09, 2.57-2.66, 2.47-2.54, 2.24-2.41, 1.46-1.94, 0.84-0.94, 0.02-0.05.

[0210] Reference Example 37: Methyl (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,10a-tetrahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate A toluene (200 mL) solution of the compound (14.3 g) prepared in Reference Example 36 was stirred at 60°C for 20 minutes under a nitrogen stream and degassed. Heating was stopped, and tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene][3-phenyl-1H-indene-1-ylidene]ruthenium(II) dichloride (1.21 g) was added, and the mixture was stirred overnight at 85°C under a nitrogen stream. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 97:3 → 93:7) to obtain the title compound (13.2 g) with the following physical properties. 1 H-NMR(CDCl3):δ 7.52, 7.04, 6.33-6.38, 6.02-6.10, 4.67-4.76, 4.22-4.29, 4.06-4.15, 3.84-4.02, 3.47-3.57, 2.68-2.74, 2.40-2.64, 2.21-2.34, 2.12-2.21, 1.69-1.90, 1.47-1.67, 0.85-0.92, 0.04-0.10.

[0211] Reference Example 38: Methyl (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound (13.2 g) prepared in Reference Example 37 in ethyl acetate (132 mL), 10% palladium-carbon (1.32 g) was added and the mixture was stirred at room temperature under a hydrogen stream for 3 hours. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. No further purification was performed, and the mixture was subjected to the next reaction.

[0212] Reference Example 39: Methyl (1S,2R,3aS,10aR)-1-(hydroxymethyl)-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a THF solution (13.2 mL) of the crude product prepared in Reference Example 38, a 1 mol / L THF solution (52.4 mL) of tetrabutylammonium fluoride was added at room temperature and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction by TLC, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 50:50 → 0:100, ethyl acetate:methanol = 85:15) to obtain the title compound (9.08 g) with the following physical properties. 1 H-NMR(CDCl3):δ 7.46, 6.94, 4.76-4.80, 4.61-4.67, 4.09-4.20, 3.85-4.01, 3.61-3.72, 3.48-3.59, 3.04-3.14, 2.95-3.00, 2.63-2.73, 2.38-2.55, 2.11-2.21, 1.96-2.06, 1.72-1.89, 1.49-1.67.

[0213] Reference Example 40: Methyl (1R,2R,3aS,10aR)-1-formyl-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound (2.0 g) prepared in Reference Example 39 in dichloromethane (20 mL), DMSO (10 mL) and triethylamine (3.57 mL) were added and the mixture was cooled to 0°C. Sulfur trioxide-pyridine complex (2.45 g) was added to the reaction mixture and stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution and 1N hydrochloric acid aqueous solution were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10 → 70:30 → 55:45) to obtain the title compound (2.0 g) with the following physical properties. 1 H-NMR(CDCl3):δ 9.82-9.86, 7.49, 6.96, 4.64-4.69, 4.44-4.53, 4.14-4.18, 3.80-3.94, 3.43-3.55, 3.34-3.40, 3.25-3.31, 3.09-3.19, 2.51-2.68, 2.46, 2.25-2.35, 2.12-2.18, 1.96-2.04, 1.69-1.88, 1.49-1.67.

[0214] Example 9: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 40 instead of the compound prepared in Reference Example 9, and the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 14, and subjecting the compound to the same objective as in Reference Example 17 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation operation. HPLC retention time (min): 0.9; MS(ESI, Pos.):417(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.35, 7.28, 7.06-7.19, 6.90, 5.44, 5.28, 3.96-4.01, 3.72-3.80, 2.95, 2.43-2.58, 2.29-2.33, 1.80, 1.60-1.75, 1.46-1.56, 0.77-0.91, 0.59-0.72.

[0215] Examples 9-1 to 9-23: The following example compounds were obtained by using the compound prepared in Reference Example 40 instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 29, and by subjecting them to the same objective procedure as in Reference Example 30 → Reference Example 18 → Example 2. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. The corresponding phosphonate was either a known compound or prepared from a known compound by subjecting it to the same objective procedure as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0216] Example 9-1: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.86; MS(ESI, Pos.):427(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.53-7.55, 7.45-7.50, 7.38-7.44, 6.99, 5.58-5.62, 4.46-4.53, 4.08-4.15, 3.90, 3.02, 2.66-2.74, 2.54-2.63, 2.42, 1.93, 1.66-1.79, 1.50-1.60.

[0217] Example 9-2: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.97; MS(ESI, Pos.):449(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.41, 7.10-7.24, 6.97-7.03, 5.52-5.59, 5.39-5.47, 4.36, 4.07-4.11, 3.84-3.90, 2.99-3.07, 2.48-2.67, 2.38-2.47, 2.07-2.16, 1.82-1.95, 1.68-1.78, 1.56.

[0218] Example 9-3: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.9; MS(ESI, Pos.):407(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.38, 6.98, 5.69-5.81, 4.15-4.26, 3.95-4.01, 3.08, 2.78, 2.60-2.68, 2.43, 1.85-2.02, 1.73, 1.34-1.56, 1.31.

[0219] Example 9-4: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1―(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.139; MS(ESI, Pos.): 507(M+Na)+.; 1 H-NMR(CD3OD):δ 7.46, 7.10-7.17, 7.00, 6.86-6.92, 6.79-6.86, 5.49-5.55, 5.40-5.48, 4.32, 4.07-4.11, 3.83-3.89, 2.99-3.07, 2.51-2.68, 2.33-2.49, 2.03-2.15, 1.71-1.94, 1.58.

[0220] Example 9-5: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.166; MS(ESI, Pos.):489(M+Na)+.; 1H-NMR(CD3OD):δ 7.47, 7.15, 6.97-7.04, 5.40-5.48, 5.31-5.38, 4.25, 4.05-4.13, 3.82-3.90, 3.00-3.09, 2.47-2.67, 2.25-2.43, 1.97-2.13, 1.74-1.93, 1.58-1.69.

[0221] Example 9-6: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1―(2,6-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.134; MS(ESI, Pos.): 507(M+Na)+.; 1 H-NMR(CD3OD):δ 7.46, 7.16-7.24, 7.00, 6.82-6.88, 5.63-5.71, 5.43-5.50, 4.37, 4.05-4.09, 3.83-3.89, 3.00-3.08, 2.47-2.71, 2.42, 2.08-2.20, 1.71-1.94, 1.52-1.61.

[0222] Example 9-7: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclobutyl)-1-propen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.117; MS(ESI, Pos.):471(M+Na)+.; 1H-NMR(CD3OD):δ 7.44-7.47, 7.25-7.30, 7.13-7.18, 6.99-7.02, 5.32-5.45, 4.25, 4.05-4.10, 3.82-3.89, 3.03, 2.51-2.66, 2.30-2.44, 2.01-2.09, 1.72-1.93, 1.60.

[0223] Example 9-8: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-(3-thienyl)-1-penten-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.083; MS(ESI, Pos.):465(M+Na)+.; 1 H-NMR(CD3OD):δ 7.45, 7.29-7.32, 7.12-7.16, 7.07-7.10, 6.98, 5.45-5.52, 5.30-5.38, 4.05-4.12, 3.80-3.87, 2.94-3.03, 2.51-2.62, 2.41, 1.86-1.92, 1.63-1.73, 1.48-1.59, 1.26-1.35.

[0224] Example 9-9: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-thienyl)cyclobutyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.099; MS(ESI, Pos.):477(M+Na)+.; 1H-NMR(CD3OD):δ 7.46, 7.29-7.32, 7.06-7.08, 6.98-7.02, 5.34-5.45, 4.20-4.23, 4.06-4.10, 3.83-3.89, 2.97-3.05, 2.46-2.64, 2.35-2.44, 2.15-2.30, 1.83-1.99, 1.69-1.78, 1.53-1.62.

[0225] Examples 9-10: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-thienyl)cyclopropyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.064; MS(ESI, Pos.):463(M+Na)+.; 1 H-NMR(CD3OD):δ 7.44-7.47, 7.25-7.29, 7.15-7.17, 7.09-7.12, 6.97-7.00, 5.56-5.63, 5.41-5.49, 4.09, 3.83-3.93, 2.98-3.06, 2.52-2.70, 2.41, 1.87-1.95, 1.72-1.84, 1.60, 0.93-0.98, 0.84-0.92, 0.73-0.83.

[0226] Examples 9-11: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.151; MS(ESI, Pos.):439(M+Na)+.; 1H-NMR(CD3OD):δ 7.44, 6.98, 5.62-5.68, 5.46-5.53, 4.12-4.16, 4.03-4.08, 3.89-3.95, 3.04-3.13, 2.57-2.76, 2.42, 1.81-1.97, 1.66-1.77, 1.52-1.63, 1.40-1.50, 1.20-1.39, 0.88-0.97.

[0227] Examples 9-12: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-3-(1-butylcyclobutyl)-3-hydroxy-1-propen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.185; MS(ESI, Pos.):451(M+Na)+.; 1 H-NMR(CD3OD):δ 7.43-7.47, 6.96-7.00, 5.66-5.73, 5.50-5.57, 4.12-4.16, 3.90-3.98, 3.05-3.12, 2.57-2.78, 2.43, 2.05-2.15, 1.78-1.98, 1.58-1.75, 1.37-1.49, 1.28-1.37, 0.90-0.97, -0.03--0.01.

[0228] Example 9-13: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-4,4-dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.168; MS(ESI, Pos.):439(M+Na)+.; 1H-NMR(CD3OD):δ 7.45, 6.98, 5.68-5.75, 5.46-5.52, 4.15, 3.89-3.95, 3.78, 3.05-3.13, 2.58-2.75, 2.43, 1.83-1.99, 1.72, 1.21-1.38, 0.85-0.95.

[0229] Example 9-14: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4R)-4-ethyl-3-hydroxy-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.169; MS(ESI, Pos.):381(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.44, 6.98, 5.62, 5.51, 4.13-4.16, 4.00-4.04, 3.88-3.96, 3.04-3.13, 2.67-2.76, 2.57-2.66, 2.42, 1.81-1.98, 1.67-1.77, 1.14-1.55, 0.92.

[0230] Example 9-15: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-3-(1-butylcyclopropyl)-3-hydroxy-1-propen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.118; MS(ESI, Pos.):437(M+Na)+.; 1H-NMR(CD3OD):δ 7.46, 6.98, 5.60-5.68, 5.47-5.55, 4.12-4.17, 3.87-3.95, 3.04-3.14, 2.56-2.76, 2.43, 1.82-1.98, 1.67-1.77, 1.45-1.64, 1.25-1.42, 0.87-0.94, 0.48-0.57, 0.23-0.33.

[0231] Example 9-16: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-methylbutyl)cyclopropyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.155; MS(ESI, Pos.):451(M+Na)+.; 1 H-NMR(CD3OD):δ 7.45, 6.98, 5.59-5.66, 5.48-5.55, 4.14, 3.88-3.96, 3.05-3.13, 2.56-2.77, 2.43, 1.81-1.99, 1.74, 1.22-1.50, 0.84-0.93, 0.49-0.57, 0.23-0.32.

[0232] Example 9-17: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.135; MS(ESI, Pos.):479(M+Na)+.; 1H-NMR(CD3OD):δ 7.43, 6.97, 5.68-5.75, 5.57-5.65, 4.41-4.45, 4.13, 3.90-3.97, 3.03-3.12, 2.75, 2.57-2.65, 2.42, 2.18-2.31, 1.83-1.98, 1.57-1.75, 1.45, 1.28-1.41, 0.94.

[0233] Example 9-18: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenoxy-1-penten-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.085; MS(ESI, Pos.):475(M+Na)+.; 1 H-NMR(CD3OD):δ 7.46, 7.24-7.30, 7.02-7.10, 6.98, 5.83-5.90, 5.61-5.69, 4.07-4.17, 3.92-3.99, 3.06-3.14, 2.71-2.81, 2.58-2.69, 2.43, 1.85-2.00, 1.67-1.78, 1.21-1.30.

[0234] Example 9-19: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.104; MS(ESI, Pos.):487(M+Na)+.; 1H-NMR(CD3OD):δ 7.45, 7.21-7.27, 6.99, 6.95, 6.88, 5.84-5.90, 5.59-5.66, 4.49, 4.14, 3.90-3.96, 3.13, 2.77, 2.57-2.67, 2.30-2.45, 1.81-1.99, 1.64-1.78.

[0235] Example 9-20: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-fluoro-3-hydroxy-4-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.07; MS(ESI, Pos.):443(M+Na)+,383(M+H-H2O-HF)+.; 1 H-NMR(CD3OD):δ 7.41, 6.97, 5.69-5.76, 5.59-5.66, 4.15, 4.01-4.07, 3.90-3.97, 3.04-3.12, 2.69-2.79, 2.57-2.67, 2.41, 1.68-1.97, 1.46-1.64, 1.26-1.44, 0.94.

[0236] Example 9-21: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-fluoro-3-hydroxy-4-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.067; MS(ESI, Pos.):443(M+Na)+,383(M+H-H2O-HF)+.; 1H-NMR(CD3OD):δ 7.41, 6.97, 5.61-5.71, 4.13-4.17, 4.05-4.11, 3.90-3.97, 3.04-3.12, 2.58-2.77, 2.41, 1.84-1.97, 1.57-1.76, 1.25-1.45, 0.91-0.97.

[0237] Example 9-22: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(5-methyl-3-thienyl)cyclobutyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.128; MS(ESI, Pos.):491(M+Na)+.; 1 H-NMR(CD3OD):δ 7.46, 6.99, 6.76-6.80, 6.66, 5.35-5.45, 4.04-4.22, 3.82-3.90, 2.96-3.07, 2.52-2.67, 2.42, 2.08-2.28, 1.82-1.95, 1.74, 1.52-1.66.

[0238] Example 9-23: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-5-ethoxy-3-hydroxy-4,4-dimethyl-1-penten-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.094; MS(ESI, Pos.):441(M+Na)+.; 1H-NMR(CD3OD):δ 7.46, 6.99, 5.69-5.76, 5.47-5.55, 4.13-4.18, 3.89-3.99, 3.42-3.53, 3.32-3.36, 3.28-3.34, 3.23, 3.05-3.14, 2.57-2.76, 2.43, 1.82-1.99, 1.69-1.79, 1.18, 0.87-0.95.

[0239] Example 10: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-ethyl-3-hydroxy-7-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] By using the compound prepared in Reference Example 40 instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 14, and subjecting the compound to the same objective as in Reference Example 17 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was the highly polar product separated in the diastereomer separation operation. Furthermore, the diastereomer obtained in the operation of Example 2 was separated using an SFC column (CHIRALPAK IG, CO2:2-propanol=72:28) to obtain the highly polar product. The corresponding phosphonate was prepared by using methyl 2-ethyl-5-methylhexanoate (CAS number: 1896760-61-4) instead of the compound prepared in Reference Example 10, and subjecting the compound to the same objective as in Reference Example 11. HPLC retention time (min): 1.196; MS(ESI, Pos.):453(M+Na)+.; 1H-NMR(CD3OD):δ 7.44, 6.98, 5.62-5.68, 5.46-5.53, 4.12-4.16, 4.03-4.08, 3.89-3.95, 3.04-3.12, 2.57-2.76, 2.42, 1.81-1.97, 1.67-1.76, 1.40-1.61, 1.18-1.37, 0.88-0.94.

[0240] Reference Example 41: 6,7,7-trifluoro-3-hydroxy-3-methyl-6-heptenoate ethyl To a solution of lithium hexamethyldisilazide (1 mol / L toluene solution, 670 mL) in THF (270 mL), ethyl acetate (65.5 mL) was added dropwise at -78 °C and the mixture was stirred at -78 °C for 15 minutes. To the reaction mixture, a solution of 5,6,6-trifluoro-5-hexen-2-one (CAS number: 155630-33-4, 670 mmol) in THF (40 mL) was added and the mixture was stirred at -78 °C for 30 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture and extracted with MTBE. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (130 g) with the following physical properties. 1 H-NMR (CDCl3): δ 4.14-4.25, 3.68, 2.32-2.57, 1.65-1.85, 1.26-1.34, -0.06-0.20.

[0241] Reference example 42: 6,7,7-trifluoro-3-hydroxy-3-methyl-6-heptenoic acid To a solution of the compound (130 g) prepared in Reference Example 41 in ethanol (270 mL), 162 mL of 5 N sodium hydroxide aqueous solution was added and the mixture was stirred at room temperature for 1 hour. MTBE was added to the reaction mixture, and the separated aqueous layer was acidified with 5 N hydrochloric acid aqueous solution and extracted with MTBE. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (106 g) with the following physical properties. 1H-NMR (CDCl3): δ 6.33, 3.24, 2.34-2.64, 1.70-1.93, 1.32.

[0242] Reference Example 43: (1R,2S)-2-hydroxy-1,2-diphenylethanaminonium (3S)-6,7,7-trifluoro-3-hydroxy-6-octenate To a solution of the compound (106 g) prepared in Reference Example 42 in 2-butanol (1.06 L), (1S, 2R)-diphenylethanolamine (106 g) was added at 80°C and the mixture was stirred at room temperature for 4 hours. The precipitate was filtered and washed with n-heptane. By performing the washing procedure two more times, the title compound (56.94 g) with the following physical properties was obtained. 1 H-NMR(CDCl3):δ 7.18-7.31, 7.05-7.17, 5.04, 4.28, 3.49-3.85, 2.20-2.39, 1.42-1.72, 1.11-1.22, 0.93, 0.00-0.01.

[0243] Reference example 44: (3S)-6,7,7-trifluoro-3-methyl-6-heptene-1,3-diol The compound (56.4 g) prepared in Reference Example 43 was extracted with aqueous hydrochloric acid and ethyl acetate to obtain a carboxylic acid compound (24.0 g). The carboxylic acid compound was dissolved in THF (340 mL), and triethylamine (15.8 mL) and isobutyl chloroformate (14.7 mL) were added at -10°C and the mixture was stirred for 30 minutes. The precipitate was filtered, and sodium borohydride (6.4 g) and water (10 mL) were added to the filtrate at -10°C and the mixture was stirred at 0°C for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (17.5 g) having the following physical properties. 1 H-NMR (CDCl3): δ 3.86-4.08, 2.65-2.82, 2.30-2.52, 1.64-1.86, 1.27.

[0244] Reference Example 45: (3S)-6,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazole-5-yl)thio]-6-hepten-3-ol To a toluene (71 mL) solution of the compound (17.5 g) prepared in Reference Example 44, 5N sodium hydroxide aqueous solution (71 mL) and tetrabutylammonium bromide (2.9 g) were added. Furthermore, p-toluenesulfonyl chloride (18.6 g) was added at 0°C and the mixture was stirred at 0°C for 1 hour. 1-phenyl-1H-tetrazole-5-thiol (20.5 g) was added to the mixture and the mixture was stirred at 60°C for 5 hours. The reaction solution was poured into ice water and extracted with toluene. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 7:1 → 4:1) to obtain the title compound (24.8 g) with the following physical properties. 1 H-NMR (CDCl3): δ 7.47-7.60, 3.37-3.56, 2.36-2.51, 2.29, 2.02-2.10, 1.72-1.81, 1.29.

[0245] Reference Example 46: (3S)-6,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazole-5-yl)sulfonyl]-6-hepten-3-ol A mixture of sodium tungstate dihydrate (114 mg), benzenephosphonic acid (55 mg), and methyltri-n-octylammonium chloride (140 mg) was mixed with a 30% aqueous solution of hydrogen peroxide and stirred at room temperature for 15 minutes. A toluene (70 mL) solution of the compound prepared in Reference Example 45 (24.8 g) was added to the mixture and stirred at 50°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (26.7 g) exhibiting the following physical properties. 1H-NMR (CDCl3): δ 7.55-7.73, 3.81-3.99, 2.32-2.51, 2.04-2.23, 1.71-1.85, 1.30.

[0246] Reference example 47: 1-Phenyl-5-({(3S)-6,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]-6-hepten-1-yl}sulfonyl)-1H-tetrazol To a solution of the compound (5 g) prepared in Reference Example 46 in DMF (30 mL), imidazole (2.6 g) and trimethylchlorosilane (2.4 mL) were added at room temperature and the mixture was stirred. The reaction mixture was diluted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was washed with n-hexane to obtain the title compound (5.1 g) having the following physical properties. 1 H-NMR (CDCl3): δ 7.57-7.73, 3.73-3.88, 2.24-2.44, 1.96-2.19, 1.66-1.82, 1.35, 0.14-0.17.

[0247] Reference Example 48: Methyl (1R,2R,3aS,10aR)-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-1-{(1E,4S)-7,8,8-trifluoro-4-methyl-4-[(trimethylsilyl)oxy]-1,7-octadien-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound (4.29 g) prepared in Reference Example 47 in dimethoxyethane (19.2 mL), a 1 mol / L solution of potassium hexamethyldisilazide in THF (9.27 mL) was added dropwise at -78 °C and the mixture was stirred for 20 minutes. To the reaction mixture, a solution of the compound (2.4 g) prepared in Reference Example 40 in dimethoxyethane (16.8 mL) was added dropwise at -78 °C over 40 minutes and the mixture was then stirred for 2 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 90:10 → 80:20 → 70:30) to obtain a crude product (2.11 g) containing the title compound. This was not purified and was subjected to the next reaction.

[0248] Reference Example 49: Methyl (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a methanol (21 mL) solution of the crude product (2.11 g) prepared in Reference Example 48, p-toluenesulfonic acid monohydrate (128 mg) was added at room temperature and the mixture was stirred for 2 hours at room temperature. Triethylamine (0.47 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 70:30 → 30:70 → 0:100) to obtain the title compound (1.49 g) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 7.50, 6.97, 5.63-5.71, 5.39-5.46, 4.16, 3.97-4.04, 3.87, 3.07-3.15, 2.74-2.81, 2.56-2.63, 2.36-2.47, 2.27, 2.17-2.22, 2.07-2.13, 1.68-1.95, 1.44, 1.23.

[0249] Example 11: (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] To a solution of the compound (1.49 g) prepared in Reference Example 49 in THF (5 mL) / methanol (10 mL), 6.36 mL of 2 N sodium hydroxide aqueous solution was added at room temperature, and the mixture was stirred overnight at 40 °C. The reaction mixture was concentrated under reduced pressure, and 2 N hydrochloric acid aqueous solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was crystallized with ethyl acetate (14.5 mL) / n-hexane (5.8 mL) to obtain the title compound (1.16 g) exhibiting the following physical properties. HPLC retention time (min): 1.083; MS(ESI, Pos.):477(M+Na)+,437(M+H-H2O)+,419(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.44, 6.98, 5.64-5.72, 5.36-5.43, 4.13, 3.87-3.93, 3.04-3.12, 2.56-2.74, 2.35-2.49, 2.27, 1.90-1.97, 1.80-1.87, 1.66-1.77, 1.20.

[0250] Reference example 50: 7,7,7-Ethyl trifluoro-3-hydroxy-3-methylheptanoate Magnesium (1.53 g) was added to diethyl ether (52 mL), and the mixture was activated with dibromoethane (0.45 mL) at room temperature. Bromotrifluorobutane (10 g) was then added dropwise, and the mixture was stirred at 50°C to prepare the organometallic reagent. In a separate container, a solution of N-methoxy-N-methylacetamide (5.56 mL) in diethyl ether (45 mL) was cooled to -15°C. The prepared organometallic reagent was added dropwise to this solution and stirred for 90 minutes. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with diethyl ether. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, and filtered to obtain the ketone body as a diethyl ether solution. To a solution of lithium hexamethyldisilazide (1 mol / L THF solution, 62.8 mL) in THF (52 mL), ethyl acetate (6.14 mL) was added dropwise at -78°C and the mixture was stirred for 25 minutes at -78°C. A solution of the ketone body in diethyl ether was then added dropwise over 20 minutes and the mixture was stirred for 50 minutes at -78°C. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 90:10 → 65:35) to obtain the title compound (16.7 g) with the following physical properties. 1 H-NMR(CDCl3): δ 4.16-4.23, 3.61, 2.42-2.54, 2.02-2.17, 1.53-1.74, 1.29, 1.25.

[0251] Reference Example 51: 7,7,7-trifluoro-3-hydroxy-3-methylheptanoic acid To a solution of the compound (16.7 g) prepared in Reference Example 50 in ethanol (130 mL), 2N sodium hydroxide aqueous solution (52 mL) was added and the mixture was stirred at room temperature for 1 hour. 2N hydrochloric acid aqueous solution was added to the reaction mixture to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (8.49 g) with the following physical properties. 1H-NMR (CDCl3): δ 2.48-2.64, 2.02-2.21, 1.56-1.76, 1.31.

[0252] Reference Example 52: (1R)-1-phenylethanolaminium (3S)-7,7,7-trifluoro-3-hydroxy-3-methylheptanoate To a solution of the compound (8.49 g) prepared in Reference Example 51 in ethyl acetate (50 mL), (R)-1-phenylethylamine (5 mL) was added and concentrated to obtain crude crystals. To the obtained crude crystals, ethyl methyl ketone (65 mL) and n-heptane (130 mL) were added at 70 °C and the mixture was cooled to room temperature. The precipitate was filtered and washed with n-heptane. By performing the washing operation two more times, the title compound (2.64 g) with the following physical properties was obtained. 1 H-NMR (CDCl3): δ 7.26-7.39, 6.64-7.09, 4.12-4.23, 1.84-2.12, 1.27-1.62, 1.00-1.10.

[0253] Reference Example 53: (3S)-7,7,7-trifluoro-3-methyl-1,3-heptanediol The compound (2.64 g) prepared in Reference Example 52 was extracted with aqueous hydrochloric acid and ethyl acetate, and concentrated under reduced pressure. The obtained carboxylic acid was dissolved in THF (40 mL). The solution was cooled to 0°C, lithium aluminum hydride (0.3 g) was added, and the mixture was stirred at 60°C. The solution was cooled to 0°C, water was added, and the mixture was stirred. After removing the precipitate by filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (1.74 g) having the following physical properties. 1 H-NMR (CDCl3): δ 3.82-4.01, 2.41-2.61, 2.01-2.35, 1.76-1.89, 1.50-1.74.

[0254] Reference Example 54: (3S)-7,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazole-5-yl)thio]-3-heptanol To a toluene (20 mL) solution of the compound (1.74 g) prepared in Reference Example 53, 6.5 mL of 5N sodium hydroxide aqueous solution and tetrabutylammonium bromide (254 mg) were added. To the mixture, p-toluenesulfonyl chloride (1.65 g) was added at 0°C and the mixture was stirred at 0°C for 1 hour and 45 minutes. Further, 1-phenyl-1H-tetrazole-5-thiol (1.69 g) was added and the mixture was stirred overnight at 60°C. The reaction mixture was extracted with MTBE. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 80:20 → 60:40 → 55:45) to obtain the title compound (2.65 g) with the following physical properties. 1 H-NMR (CDCl3): δ 7.54-7.73, 3.85-3.94, 2.02-2.21, 1.53-1.73, 1.42-1.54, 1.28.

[0255] Reference Example 55: (3S)-7,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazole-5-yl)sulfonyl]-3-heptanol To a solution of the compound (2.65 g) prepared in Reference Example 54 in dichloromethane (35 mL), methachloroperbenzoic acid (4.5 g) was added at 0°C and stirred overnight. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 80:20 → 75:25) to obtain the title compound (2.76 g) with the following physical properties. 1 H-NMR (CDCl3): δ 7.54-7.73, 3.85-3.94, 2.02-2.21, 1.53-1.73, 1.42-1.54, 1.28.

[0256] Reference Example 56: 1-Phenyl-5-({(3S)-7,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]heptyl}sulfonyl)-1H-tetrazol A solution of the compound (2.76 g) prepared in Reference Example 55 in DMF (25 mL) was cooled to 0°C, and imidazole (1.44 g) and trimethylchlorosilane (1.34 mL) were added and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture and extracted with ethyl acetate / n-hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 95:5 → 85:15) to obtain the title compound (2.88 g) with the following physical properties. 1 H-NMR(CDCl3): δ 7.66-7.72, 7.56-7.64, 3.74-3.87, 3.49, 1.95-2.17, 1.50-1.69, 1.32, 0.13-0.15.

[0257] Reference Example 57: Methyl (1R,2R,3aS,10aR)-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-1-{(1E,4S)-8,8,8-trifluoro-4-methyl-4-[(trimethylsilyl)oxy]-1-octen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound (3.95 g) prepared in Reference Example 56 in dimethoxyethane (17.6 mL), a 1 M solution of potassium hexamethyldisilazide in THF (8.49 mL) was added dropwise at -78°C and the mixture was stirred for 20 minutes. To the reaction mixture, a solution of the compound (2.2 g) prepared in Reference Example 40 in dimethoxyethane (15.4 mL) was added dropwise over 40 minutes at -78°C and the mixture was stirred for 30 minutes. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture and extracted with ethyl acetate / n-hexane. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 97:3 → 90:10 → 80:20) to obtain a crude product (3.53 g) containing the title compound. No further purification was performed, and the product was subjected to the next reaction.

[0258] Reference Example 58: Methyl (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-8,8-trifluoro-4-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a methanol (35.3 mL) solution of the crude product (3.53 g) prepared in Reference Example 57, p-toluenesulfonic acid monohydrate (149 mg) was added at room temperature and the mixture was stirred for 3 hours. Triethylamine (0.55 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 50:50 → 30:70 → 0:100) to obtain the title compound (1.80 g) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 7.50, 6.97, 5.62-5.71, 5.38-5.45, 4.16, 3.96-4.03, 3.87, 3.07-3.15, 2.73-2.80, 2.56-2.63, 2.39-2.47, 2.21-2.28, 2.03-2.17, 1.80-1.95, 1.58-1.78, 1.50-1.59, 1.47, 1.21.

[0259] Example 12: (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] To a THF (6 mL)-methanol (12 mL) solution of the compound (1.80 g) prepared in Reference Example 58, 2N sodium hydroxide aqueous solution (6 mL) was added at room temperature and the mixture was stirred overnight at 40°C. The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid aqueous solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product (1.8 g) was washed with ethyl acetate / n-hexane to obtain the title compound (1.51 g) exhibiting the following physical properties. HPLC retention time (min): 1.088; MS(ESI, Pos.):479(M+Na)+,421(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.44, 6.98, 5.63-5.72, 5.33-5.41, 4.13, 3.86-3.94, 3.04-3.14, 2.54-2.74, 2.42, 2.25, 2.07-2.21, 1.86-1.98, 1.82, 1.61-1.75, 1.49-1.60, 1.18.

[0260] Examples 12-1 to 12-4: The following example compounds were obtained by using the corresponding tetrazolylsulfonyl compound instead of the compound prepared in Reference Example 56, and subjecting it to the same objective procedures as in Reference Example 57 → Reference Example 58 → Example 12. The corresponding tetrazolylsulfonyl compound was either a known compound or prepared from a known compound by subjecting it to the same objective procedures as in Reference Example 50 → Reference Example 51 → Reference Example 52 → Reference Example 53 → Reference Example 54 → Reference Example 55 → Reference Example 56.

[0261] Example 12-1: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4S)-4-hydroxy-4-methyl-1,7-octadien-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.048; MS(ESI, Pos.):423(M+Na)+.; 1 H-NMR(CD3OD):δ 7.46, 6.98, 5.80-5.90, 5.64-5.73, 5.32-5.42, 4.99-5.06, 4.90-4.96, 4.10-4.15, 3.86-3.94, 3.04-3.12, 2.55-2.74, 2.43, 2.25, 2.08-2.20, 1.89-2.01, 1.79-1.87, 1.66-1.76, 1.51-1.61, 1.18.

[0262] Example 12-2: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4S)-4-hydroxy-4-methyl-1-nonen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.14; MS(ESI, Pos.):439(M+Na)+.; 1 H-NMR(CD3OD):δ 7.46, 6.98, 5.64-5.73, 5.31-5.39, 4.10-4.16, 3.86-3.94, 3.04-3.13, 2.54-2.74, 2.43, 2.23, 1.89-1.99, 1.78-1.86, 1.67-1.76, 1.26-1.50, 1.16, 0.92.

[0263] Example 12-3: (1R,2R,3aS,10aR)-1-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-pentenyl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.171; MS(ESI, Pos.):451(M+Na)+.; 1H-NMR(CD3OD):δ 7.44, 6.98, 5.65-5.73, 5.30-5.39, 4.13, 3.87-3.93, 3.04-3.13, 2.56-2.75, 2.42, 2.26, 1.78-2.00, 1.49-1.76, 1.29, 1.13-1.21.

[0264] Example 12-4: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4S)-4-hydroxy-4,7-dimethyl-1,7-octadien-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.113; MS(ESI, Pos.):437(M+Na)+.; 1 H-NMR(CD3OD):δ 7.45, 6.97, 5.65-5.73, 5.34-5.41, 4.69, 4.13, 3.87-3.93, 3.04-3.14, 2.56-2.73, 2.42, 2.21-2.30, 2.06-2.12, 1.90-1.98, 1.79-1.87, 1.74, 1.58-1.65, 1.19.

[0265] Example 13: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4ξ)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] Using the corresponding racemic compound instead of the compound prepared in Reference Example 56, the same procedure as in Reference Example 57 → Reference Example 58 → Example 12 was performed, and the two diastereomers were separated using an SFC column (CHIRALPAK IG, CO2:methanol = 69:31) to obtain the title compound (low polarity) exhibiting the following physical properties. The corresponding racemic compound was prepared from a known compound by performing the same procedure as in Reference Example 50 → Reference Example 51 → Reference Example 52 → Reference Example 53 → Reference Example 54 → Reference Example 55 → Reference Example 56. HPLC retention time (min): 1.123; MS(ESI, Pos.):439(M+Na)+,381(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.43, 6.97, 5.72, 5.31-5.39, 4.10-4.15, 3.86-3.94, 3.04-3.12, 2.56-2.74, 2.42, 2.17-2.28, 1.90-1.99, 1.78-1.87, 1.67-1.76, 1.46-1.55, 1.23-1.30, 1.15, 0.90-0.94.

[0266] Example 13-1: (1R,2R,3aS,10aR)-1-[(1E,4ξ)-6-cyclobutyl-4-hydroxy-4-methyl-1-hexen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid Using the corresponding racemic compound instead of the compound prepared in Reference Example 56, the same procedure as in Reference Example 57 → Reference Example 58 → Example 12 was performed, and the two diastereomers were separated using an SFC column (CHIRALPAK IG, CO2:2-propanol=70:30) to obtain the title compound (low polarity) exhibiting the following physical properties. The corresponding racemic compound was prepared from a known compound by performing the same procedure as in Reference Example 50 → Reference Example 51 → Reference Example 52 → Reference Example 53 → Reference Example 54 → Reference Example 55 → Reference Example 56. HPLC retention time (min): 1.149; MS(ESI, Pos.):451(M+Na)+.; 1 H-NMR(CD3OD):δ 7.45, 6.98, 5.64-5.72, 5.32-5.39, 4.13, 3.87-3.93, 3.05-3.14, 2.56-2.73, 2.42, 2.17-2.28, 2.01-2.10, 1.78-1.98, 1.73, 1.57-1.68, 1.29-1.49, 1.15.

[0267] Reference example 59: 5-bromo-4-fluoro-2-vinylphenol By using 4-bromo-5-fluoro-2-hydroxybenzaldehyde (CAS number: 1427405-76-2) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde and subjecting it to the same procedure as in Reference Example 3, the title compound having the following physical properties was obtained. 1 H-NMR (CDCl3): δ 7.15, 7.00, 6.79-6.88, 5.71-5.77, 5.41, 5.20-5.28.

[0268] Reference Example 60: Ethyl (1R,2R,3aS,10aR)-7-fluoro-1-formyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 59 instead of the compound prepared in Reference Example 3, and subjecting it to the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, the title compound having the following physical properties was obtained. 1H-NMR(CDCl3):δ 9.81-9.85, 7.48-7.51, 6.84, 4.63-4.67, 4.28-4.48, 3.87-3.93, 3.78-3.85, 3.43-3.54, 3.22-3.29, 3.13-3.19, 2.99-3.08, 2.69-2.78, 2.50-2.63, 2.26-2.37, 2.17-2.23, 1.98-2.11, 1.68-1.93, 1.50-1.67, 1.38.

[0269] Example 14: (1R,2R,3aS,10aR)-7-fluoro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 60 instead of the compound prepared in Reference Example 9, and the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 14, and by subjecting the compound to the same objective as in Reference Example 17 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. Note that the intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation operation. HPLC retention time (min): 0.97; MS(ESI, Pos.):453(M-OH)+.; 1 H-NMR(DMSO-d6):δ 13.04-13.20, 7.17-7.28, 7.01-7.14, 5.32, 4.93, 4.69, 4.22-4.27, 4.16, 3.59-3.72, 2.80-2.93, 2.68-2.77, 2.21-2.32, 1.46-1.81.

[0270] Reference example 61: 5-bromo-3-fluoro-2-vinylphenol By using 4-bromo-2-fluoro-6-hydroxybenzaldehyde (CAS number: 1427438-90-1) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde and subjecting it to the same procedure as in Reference Example 3, the title compound having the following physical properties was obtained. 1 H-NMR (CDCl3): δ 6.79-6.90, 6.69, 5.79-5.97, 5.60-5.67.

[0271] Reference Example 62: Ethyl (1R,2R,3aS,10aR)-8-fluoro-1-formyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 61 instead of the compound prepared in Reference Example 3, and subjecting it to the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, the title compound having the following physical properties was obtained. 1 H-NMR(CDCl3):δ 9.83, 7.35-7.45, 4.65, 4.41-4.54, 4.29-4.42, 4.12, 3.77-3.98, 3.39-3.66, 3.01-3.19, 2.71-2.82, 2.61, 2.28-2.47, 2.16-2.28, 1.93-2.13, 1.67-1.89, 1.48-1.66, 1.38.

[0272] Example 15: (1R,2R,3aS,10aR)-8-fluoro-2-hydroxy-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 62 instead of the compound prepared in Reference Example 9, and the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 14, and subjecting the compound to the same objective as in Reference Example 17 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation operation. HPLC retention time (min):; MS(ESI, Pos.):403(M+H-2H2O)+,421(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.36-7.42, 7.31-7.36, 7.25-7.30, 7.16-7.22, 5.54, 5.40, 4.46, 3.92, 3.79, 3.04, 2.68-2.81, 2.63, 2.27-2.50, 1.70-1.95, 0.87-1.11, 0.70-0.87.

[0273] Reference Example 63: Ethyl 6-hydroxy-5-vinyl-2-pyridinecarboxylate To a solution of ethyl 5-bromo-6-hydroxy-2-pyridine carboxylate (CAS number: 1214346-74-3, 482 mg) in DMSO (2.4 mL), toluene (7.2 mL), tributylvinyltin (931 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (160 mg) were added and the mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 → 100:0) to obtain the title compound (170 mg) with the following physical properties. TLC: Rf 0.52 (Hexane:ethyl acetate = 3:7); 1 H-NMR (DMSO-d6): δ 11.50-12.12, 7.73, 7.02, 6.77, 6.24, 5.42, 4.30, 1.27-1.34.

[0274] Reference Example 64: Ethyl (6aR,7R,8R,9aS)-7-formyl-8-(tetrahydro-2H-pyran-2-yloxy)-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[6,7]oxepin[2,3-b]pyridine-2-carboxylate By using the compound prepared in Reference Example 63 instead of the compound prepared in Reference Example 3, and subjecting it to the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, the title compound having the following physical properties was obtained. 1 H-NMR(CDCl3):δ 9.86, 7.77, 7.56, 4.62-4.70, 4.37-4.49, 3.76-3.83, 3.44-3.50, 3.15-3.24, 2.94, 2.59, 2.31-2.40, 1.93-2.07, 1.77-1.86, 1.66-1.77, 1.55-1.65, 1.48-1.53, 1.41.

[0275] Reference Example 65: Ethyl (6aR,7R,8R,9aS)-7-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-8-hydroxy-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[6,7]oxepin[2,3-b]pyridine-2-carboxylate Using the compound prepared in Reference Example 64 (45 mg) instead of the compound prepared in Reference Example 9, and using the compound prepared in Reference Example 26 (49 mg) instead of the compound prepared in Reference Example 14, the same procedure as in Reference Example 17 was followed to obtain the enone compound (21 mg). The enone compound (21 mg) was cooled to -15°C in a THF (0.2 mL) solution. (S)-2-methyl-CBS-oxazaborolidine (0.037 mL, 1 mol / L toluene solution) and N,N-diethylaniline borane (0.013 mL) were added, and the mixture was stirred overnight at -15°C. The completion of the reaction was confirmed by TLC, and the reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 → 100:0) to obtain the reduced product. The reduced product was cooled to 0°C in a methanol (0.2 mL) solution, p-toluenesulfonic acid monohydrate (1.8 mg) was added, and the mixture was stirred at room temperature for 2 hours. Triethylamine (0.022 mL) was added to the reaction solution, and the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 → 100:0) to obtain the title compound (7 mg) with the following physical properties. 1 H-NMR(CD3OD):δ 7.62-7.67, 6.96-7.11, 6.83-6.90, 5.47-5.58, 5.25-5.46, 4.50, 4.24-4.32, 3.71, 3.42-3.61, 3.23-3.31, 2.83, 2.45-2.59, 2.23-2.45, 1.99, 1.80-1.94, 1.53-1.79, 1.29.

[0276] Example 16: (6aR,7R,8R,9aS)-7-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-8-hydroxy-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[6,7]oxepin[2,3-b]pyridine-2-carboxylic acid By using the compound prepared in Reference Example 65 instead of the compound prepared in Reference Example 18, and subjecting it to the same procedure as in Example 2, the title compound having the following physical properties was obtained. HPLC retention time (min): 0.996; MS(ESI, Pos.):454(M+H)+.; 1 H-NMR(CD3OD):δ 7.61-7.73, 7.10, 6.92-7.01, 5.39-5.67, 4.52-4.63, 4.39-4.43, 3.74-3.85, 3.36, 3.26, 2.89, 2.31-2.70, 2.03-2.14, 1.59-1.99, 0.90.

[0277] Reference Example 66: Ethyl (2R,3R,3aR,11aS)-3-formyl-2-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylate By using (1R,2R,3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol (CAS number: 1262874-94-1) instead of the compound prepared in Reference Example 2, and using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, and subjecting the compound to the same objective as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, the title compound having the following physical properties was obtained. 1 H-NMR(CDCl3):δ 9.74, 9.70, 7.66-7.72, 7.16, 4.64-4.68, 4.31-4.43, 3.77-3.97, 3.43-3.56, 3.21, 2.94-3.08, 2.59-2.90, 2.30, 1.47-2.24, 1.40-1.47.

[0278] Example 17: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid By using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 9, and dimethyl-2-oxoheptylphosphonate (CAS number: 36969-89-8) instead of the compound prepared in Reference Example 14, and subjecting the compound to the same objective as in Reference Example 17 → Reference Example 18 → Example 2, the title compound having the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. TLC: Rf 0.37 (CH2Cl2 / methanol, 9 / 1); MS(ESI, Pos.):777(2M+H)+.; 1 H-NMR(CDCl3):δ 7.67-7.72, 7.17, 5.61-5.70, 5.49, 4.56-4.64, 4.05-4.16, 3.83-3.93, 2.85-3.03, 2.55-2.68, 2.45, 1.91-2.14, 1.42-1.87, 1.20-1.52, 0.83-0.95, -0.15-0.01.

[0279] Examples 17-1 to 17-31: The following example compounds were obtained by using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 14, and following the same procedure as in Reference Example 17 → Reference Example 18 → Example 2. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. The corresponding phosphonate was either a known compound or prepared from a known compound by following the same procedure as in Reference Example 10 → Reference Example 11.

[0280] Example 17-1: (2R,3R,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-7-methyl-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Neg.):401(MH)-.; 1H-NMR(CDCl3):δ 7.66-7.73, 7.16, 5.62, 5.50, 4.59, 4.10, 3.87, 2.93, 2.59, 2.37-2.51, 1.91-2.16, 1.68-1.89, 1.40-1.68, 1.33, 1.04-1.27, 0.86.

[0281] Example 17-2: (2R,3R,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-1-nonen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Neg.):401(MH)-.; 1 H-NMR(CD3OD):δ 7.57, 7.59, 7.16, 5.40-5.60, 4.38-4.71, 3.99, 3.78, 2.95, 2.51-2.82, 2.33, 1.82-2.10, 1.58-1.81, 1.51, 1.29, 0.75-0.95.

[0282] Example 17-3: (2R,3R,11aS)-3-[(1E,3S)-6-cyclopropyl-3-hydroxy-1-hexen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Neg.):399(MH)-.; 1 H-NMR(CD3OD):δ 7.59, 7.57, 7.16, 5.39-5.63, 4.51-4.67, 4.00, 3.78, 2.94, 2.66, 2.19-2.47, 1.82-2.12, 1.69-1.79, 1.38-1.66, 0.97-1.33, 0.58-0.73, 0.22-0.50, -0.11-0.15.

[0283] Example 17-4: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4ξ)-3-hydroxy-7-methyl-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 1.01; MS(ESI, Pos.):453(M+H-H2O)+,435(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.59-7.62, 7.17, 5.58-5.70, 4.58-4.63, 4.42, 3.82, 2.95, 2.69, 2.36-2.43, 2.22, 1.91-2.04, 1.47-1.86, 1.25-1.42, 0.88-0.95.

[0284] Example 17-5: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4R)-3-hydroxy-4-methyl-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):385(M+H-H2O)+,367(M+H-2H2O)+.; 1 H-NMR(CDCl3):δ 7.61-7.78, 7.16, 5.57-5.76, 5.32-5.56, 4.59, 3.78-4.03, 2.77-3.13, 2.52-2.75, 2.47, 1.88-2.26, 1.58-1.87, 1.34-1.56, 1.17-1.33, 1.08, 0.76-0.99.

[0285] Example 17-6: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-5-(2-methylcyclopropyl)-1-penten-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):365(M+H-2H2O)+.; 1 H-NMR(CDCl3):δ 7.64-7.74, 6.98-7.26, 5.58-5.77, 5.49, 4.59, 4.16, 3.74-3.94, 2.78-3.07, 2.60, 2.26-2.50, 1.90-2.25, 1.52-1.88, 1.15-1.51, 1.01, 0.63, -0.17-0.00, -0.34.

[0286] Example 17-7: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-4-methyl-1-octen-6-in-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):381(M+H-H2O)+.,363(M+H-2H2O)+.; 1 H-NMR(CDCl3):δ 7.66-7.75, 7.16, 5.46-5.72, 4.59, 4.17, 3.95-4.08, 3.88, 2.77-3.10, 2.60, 2.47, 2.17-2.34, 1.90-2.15, 1.75-1.89, 1.56-1.74, 1.49, 1.38, 1.25, 0.97, 0.76-0.91.

[0287] Example 17-8: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4S)-3-hydroxy-4-methyl-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):385(M+H-H2O)+,367(M+H-2H2O)+.; 1H-NMR(DMSO-d6):δ 12.67-13.00, 7.44-7.50, 7.19, 5.36, 4.73, 4.55, 4.49, 3.71, 3.52-3.67, 2.87-3.01, 2.73-2.85, 2.14, 1.90, 1.61-1.77, 1.49, 1.40, 1.14-1.31, 0.89-1.07, 0.74-0.86.

[0288] Example 17-9: (2R,3R,3aR,11aS)-3-[(1E,3ξ)-4,4-difluoro-3-hydroxy-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):407(M+H-H2O)+.; 1 H-NMR(DMSO-d6):δ 12.61-12.98, 7.41-7.54, 7.19, 5.62, 5.37-5.54, 4.80, 4.50-4.64, 4.01-4.18, 3.55-3.74, 2.88-3.06, 2.68-2.88, 2.04-2.29, 1.61-1.94, 1.41-1.62, 1.33, 0.82-0.88.

[0289] Example 17-10: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-4-methylene-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):383(M+H-H2O)+,.365(M+H-2H2O)+.; 1H-NMR(DMSO-d6):δ 12.73-12.95, 7.39-7.59, 7.20, 5.27-5.54, 5.00, 4.90, 4.66-4.82, 4.58, 4.35, 3.58-3.71, 2.94, 2.81, 2.51, 2.07-2.33, 1.83-2.05, 1.64-1.83, 1.57, 1.45, 1.17-1.42, 0.85.

[0290] Example 17-11: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-4-fluoro-3-hydroxy-4-methyl-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.95; MS(ESI, Pos.):383(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.55-7.65, 7.17, 5.55-5.73, 4.60, 4.02, 3.83, 2.83-3.08, 2.56-2.83, 2.42, 1.86-2.07, 1.79, 1.43-1.63, 1.30-1.44, 1.26-1.28, 0.81-1.06.

[0291] Example 17-12: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-4-fluoro-3-hydroxy-4-methyl-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.95; MS(ESI, Pos.):383(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.58-7.68, 7.17, 5.57-5.72, 4.51-4.66, 3.96-4.15, 3.83, 2.84-3.06, 2.55-2.84, 2.32-2.49, 1.87-2.10, 1.81, 1.53-1.75, 1.24-1.49, 0.85-1.02.

[0292] Example 17-13: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-4-vinyl-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):379(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.57-7.62, 7.17, 5.52-5.69, 5.40-5.51, 4.96-5.11, 4.56-4.61, 3.93, 3.79, 2.90-2.99, 2.62-2.72, 2.30-2.42, 1.86-2.14, 1.42-1.83, 1.40, 1.13-1.37, 0.83-0.94.

[0293] Example 17-14: (2R,3R,3aR,11aS)-3-[(1E,3ξ)-4-fluoro-3-hydroxy-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(FAB, Neg.):405(MH)-.; 1 H-NMR(CD3OD):δ 7.60-7.68, 7.19, 5.57-5.77, 4.51-4.71, 4.33-4.50, 4.20-4.33, 3.96-4.18, 3.83, 2.97, 2.70, 2.33-2.54, 1.89-2.07, 1.78-1.87, 1.46-1.72, 1.31-1.44, 0.93.

[0294] Example 17-15: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 1.17; MS(ESI, Pos.):381(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.56-7.60, 7.16, 5.54-5.62, 5.42-5.49, 4.55-4.61, 4.02, 3.79, 2.94, 2.62-2.71, 2.31-2.40, 1.86-2.02, 1.73-1.82, 1.12-1.72, 0.84-0.93.

[0295] Example 17-16: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4R)-4-ethyl-3-hydroxy-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):399(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.57-7.60, 7.16, 5.54-5.62, 5.41-5.50, 4.55-4.61, 3.94-3.99, 3.79, 2.94, 2.62-2.71, 2.31-2.39, 1.86-2.05, 1.09-1.81, 0.83-0.93.

[0296] Example 17-17: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 1.01; MS(ESI, Pos.):439(M+H-H2O)+,421(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.60-7.63, 7.19, 5.58-5.71, 4.59-4.64, 4.42, 3.83, 3.35-3.43, 3.28, 2.97, 2.65-2.74, 2.40, 2.17-2.31, 1.91-2.05, 1.77-1.87, 1.29-1.76, 0.93.

[0297] Examples 17-18: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):439(M+H-H2O),421(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.47-7.52, 7.07, 5.45-5.58, 4.46-4.53, 4.24, 3.70, 2.85, 2.58, 2.10-2.32, 1.79-1.92, 1.65-1.75, 1.51-1.66, 1.28-1.51. 1.18-1.28, 0.81.

[0298] Examples 17-19: (2R,3R,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-7-methyl-1,7-octadien-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Neg.):399(MH)-.; 1 H-NMR(CD3OD):δ 7.54-7.61, 7.15, 5.41-5.62, 4.51-4.73, 4.02, 3.78, 2.94, 2.54-2.78, 2.33, 1.82-2.14, 1.63-1.78, 1.38-1.63, 1.28.

[0299] Examples 17-20: (2R,3R,11aS)-2-hydroxy-3-[(1E,3S,6Z)-3-hydroxy-1,6-octadien-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Neg.):385(MH)-.; 1 H-NMR(CD3OD):δ 7.56-7.60, 7.16, 5.31-5.62, 4.49-4.68, 4.01, 3.78, 2.94, 2.57-2.75, 2.24-2.41, 2.08, 1.96, 1.42-1.79, 1.28.

[0300] Example 17-21: (2R,3R,3aR,11aS)-3-[(1E,3ξ)-3-(1-butylcyclopropyl)-3-hydroxy-1-propen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):379(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.56-7.70, 7.15, 5.46-5.65, 4.60, 3.86-4.12, 3.81, 2.95, 2.62-2.77, 2.29-2.46, 1.89-2.16, 1.64-1.88, 1.48, 1.16-1.42, 0.83-1.09, 0.42-0.70, 0.17-0.39.

[0301] Example 17-22: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid MS(ESI, Pos.):399(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.56-7.62, 7.30-7.37, 7.12-7.24, 5.43-5.51, 5.30-5.38, 4.51-4.56, 3.88, 3.69-3.79, 2.88-2.96, 2.57-2.66, 2.21-2.31, 1.85-1.98, 1.27-1.70, 0.83-0.97, 0.65-0.79.

[0302] Example 17-23: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclobutyl)-1-propen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 1; MS(ESI, Pos.):431(M+H); 1 H-NMR(CDCl3):δ 7.63-7.67, 7.29, 7.24-7.30, 7.07-7.19, 5.51, 5.25-5.32, 4.48-4.55, 4.30, 3.62, 2.82-2.95, 2.43-2.55, 2.19-2.43, 1.77-2.06, 1.35-1.77.

[0303] Example 17-24: (2R,3R,3aR,11aS)-3-{(1E,3ξ)-3-[1-(2,5-difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.91; MS(ESI, Pos.):453(M+H-H2O)+.,435(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.56-7.61, 7.03-7.17, 6.89-6.99, 5.59, 5.41, 4.50-4.57, 3.89, 3.72, 2.91, 2.57-2.66, 2.22-2.31, 1.85-1.96, 1.55-1.71, 1.49, 1.38, 0.90-1.04, 0.74-0.79.

[0304] Example 17-25: (2R,3R,3aR,11aS)-3-{(1E,3ξ)-3-[1-(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 1; MS(ESI, Pos.):467(M+H-H2O)+.,449(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.55-7.61, 7.16, 7.10, 6.75-6.86, 5.35-5.49, 4.52-4.58, 4.28, 3.71, 2.84-2.99, 2.43-2.65, 2.19-2.40, 2.00, 1.78-1.95, 1.42-1.69, 1.27-1.38.

[0305] Example 17-26: (2R,3R,3aR,11aS)-3-{(1E,3ξ)-3-[1-(2,5-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.99; MS(ESI, Pos.):467(M+H-H2O)+.,449(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.56-7.62, 7.16, 6.91-6.97, 6.80-6.90, 5.43-5.51, 5.33-5.40, 4.50-4.56, 4.29, 3.71, 2.90, 2.44-2.66, 2.19-2.40, 1.98-2.09, 1.79-1.95, 1.43-1.67, 1.28-1.36.

[0306] Example 17-27: (2R,3R,3aR,11aS)-3-{(1E,3ξ)-3-[1-(2,6-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.79; MS(ESI, Pos.):467(M+H-H2O)+,449(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.56-7.62, 7.10-7.19, 6.78, 5.59, 5.40, 4.49-4.55, 4.32, 3.71, 2.85-2.96, 2.44-2.64, 2.04-2.29, 1.77-2.01, 1.52-1.69, 1.42-1.52, 1.31-1.42.

[0307] Examples 17-28: (2R,3R,3aR,11aS)-2-hydroxy-3-{(1E,3ξ)-3-hydroxy-3-[1-(3-methylphenyl)cyclopropyl]-1-propen-1-yl}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.77; MS(ESI, Pos.):431(M+H-H2O)+,413(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.56-7.61, 7.07-7.18, 6.97, 5.47, 5.34, 4.51-4.56, 3.86, 3.72, 3.33-3.37, 3.23-3.29, 2.92, 2.57-2.66, 2.17-2.36, 1.81-2.04, 1.47-1.72, 1.33-1.42, 0.82-0.97, 0.71-0.78, 0.63-0.69.

[0308] Example 17-29: (2R,3R,3aR,11aS)-3-{(1E,3ξ)-3-[1-(3-chlorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.77; MS(ESI, Pos.):452(M+H-H2O)+,434(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.56-7.62, 7.35, 7.14-7.28, 5.34-5.49, 4.51-4.56, 3.86, 3.73, 2.86-2.96, 2.62, 2.23-2.31, 1.85-2.02, 1.49-1.71, 1.32-1.44, 0.85-1.00, 0.68-0.81.

[0309] Example 17-30: (2R,3R,3aR,11aS)-3-{(1E,3ξ)-3-[1-(3-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.78; MS(ESI, Pos.):449(M+H-H2O)+,431(M+H-2H2O)+.; 1H-NMR(CD3OD):δ 7.60, 7.57, 7.20-7.28, 7.16, 6.93, 6.82-6.88, 5.35-5.43, 5.25-5.32, 4.50-4.55, 4.20, 3.72, 2.91, 2.47-2.66, 2.18-2.43, 1.77-2.07, 1.46-1.72, 1.27-1.40.

[0310] Example 17-31: (2R,3R,3aR,11aS)-3-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid HPLC retention time (min): 0.98; MS(ESI, Pos.):450(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.62, 7.59, 7.11-7.21, 6.98, 5.28-5.45, 4.54-4.61, 4.22, 3.74, 2.89-3.00, 2.60-2.68, 2.49-2.57, 2.22-2.42, 1.79-2.08, 1.50-1.74, 1.34-1.45.

[0311] Example 18: (2R,3R,3aR,11aS)-10-fluoro-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid By using the corresponding aldehyde instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 14, and following the same objective procedures as in Reference Example 17 → Reference Example 18 → Example 2, the title compound exhibiting the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 31, and following the same objective procedures as in Reference Example 66. The corresponding phosphonate was prepared by using 1-phenoxycyclobutanecarboxylic acid (CAS number: 2287791-08-4) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid, and following the same objective procedures as in Reference Example 10 → Reference Example 11. HPLC retention time (min): 1.107; MS(ESI, Pos.): 505(M+Na)+.; 1 H-NMR(CD3OD):δ 7.51-7.56, 7.22, 6.90-6.98, 6.83-6.88, 5.79-5.86, 5.55-5.62, 4.41-4.48, 3.76-3.84, 2.97-3.07, 2.76-2.86, 2.60-2.70, 2.23-2.51, 2.05-2.17, 1.92-2.03, 1.60-1.82, 1.45-1.57.

[0312] Example 19: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen-1-yl]-10-methyl-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid By using the corresponding aldehyde instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 14, and following the same objective procedures as in Reference Example 17 → Reference Example 18 → Example 2, the title compound exhibiting the following physical properties was obtained. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 35 instead of the compound prepared in Reference Example 31, and following the same objective procedures as in Reference Example 66. The corresponding phosphonate was prepared by using 1-phenoxycyclobutanecarboxylic acid instead of (2S)-2-(2,4-difluorophenyl)propanoic acid, and following the same objective procedures as in Reference Example 10 → Reference Example 11. HPLC retention time (min): 1.134; MS(ESI, Pos.):501(M+Na)+.; 1 H-NMR(CD3OD):δ 7.53, 7.22, 7.00, 6.93, 6.83-6.88, 5.80-5.86, 5.56-5.63, 4.45, 4.22-4.27, 3.78-3.85, 3.01-3.09, 2.61-2.75, 2.48-2.58, 2.46, 2.24-2.42, 2.03-2.10, 1.93-2.02, 1.60-1.77, 1.53, 1.43.

[0313] Example 20: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid By using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 40, and subjecting it to the same objective procedure as in Reference Example 48 → Reference Example 49 → Example 11, the title compound exhibiting the following physical properties was obtained. HPLC retention time (min): 0.94; MS(ESI, Pos.):437(M+H-H2O)+,419(M+H-2H2O)+.; 1 H-NMR(CD3OD):δ 7.58-7.64, 7.19, 5.60-5.69, 5.35-5.43, 4.58-4.64, 3.76-3.83, 2.97, 2.62-2.73, 2.32-2.47, 2.20-2.31, 1.88-2.06, 1.65-1.82, 1.47-1.62, 1.20.

[0314] Example 21: (2R,3R,3aR,11aS)-10-fluoro-2-hydroxy-3-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid By using the corresponding aldehyde instead of the compound prepared in Reference Example 66 and following the same procedure as in Reference Example 48 → Reference Example 49 → Example 11, the title compound exhibiting the following physical properties was obtained. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 31 and following the same procedure as in Reference Example 66. HPLC retention time (min): 1.079; MS(ESI, Pos.):495(M+Na)+.; 1 H-NMR(CD3OD):δ 7.50-7.55, 6.96, 5.61-5.69, 5.33-5.42, 4.41-4.46, 3.73-3.82, 2.96-3.06, 2.74-2.86, 2.60-2.69, 2.33-2.47, 2.17-2.30, 2.02-2.14, 1.88-2.02, 1.60-1.82, 1.44-1.57, 1.25-1.40, 1.17.

[0315] Example 22: (2R,3R,3aR,5Z,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-1-octen-1-yl]-1,2,3,3a,4,11a-hexahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid By using (1R,2R,3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol (CAS number: 1262874-94-1) instead of the compound prepared in Reference Example 2, and using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, the aldehyde was obtained by following the same objectives as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 8 → Reference Example 9. By using the aldehyde of the compound prepared in Reference Example 9 instead of the compound prepared in Reference Example 9, and using dimethyl-2-oxoheptylphosphonate (CAS number: 36969-89-8) instead of the compound prepared in Reference Example 14, the title compound having the following physical properties was obtained by following the same objectives as in Reference Example 17 → Reference Example 18 → Example 2. The intermediate corresponding to the compound produced in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. MS(ESI, Pos.):351(M+H-2H2O)+; 1 H-NMR(CDCl3):δ 7.71, 7.65, 7.16, 6.46, 5.85, 5.47-5.75, 4.68, 4.12, 4.02, 2.27-2.64, 1.91-2.15, 1.45-1.68, 1.18-1.42, 0.75-1.07.

[0316] Reference Example 67: Methyl (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylate To a methanol (1 mL) solution of the compound prepared in Example 17-17 (125 mg), 0.5 mL of n-hexane solution of 2 M trimethylsilyldiazomethane was added dropwise while stirring at room temperature until the reaction solution turned yellow. Acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the title compound (126 mg).

[0317] Reference Example 68: Methyl (2R,3R,3aR,11aS)-2-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylate To a 2 mL solution of the compound prepared in Reference Example 67 in dichloromethane, triethylamine (0.22 mL) and N,N-dimethyl-4-aminopyridine (13 mg) were added at room temperature and cooled under ice. Further, tert-butyldiphenylchlorosilane (0.21 mL) was added and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1) to obtain the title compound (204 mg).

[0318] Reference Example 69: Methyl (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylate To a 1.5 mL solution of the compound prepared in Reference Example 68 in dichloromethane, 0.1 mL of 2,6-dimethylpyridine was added at room temperature and cooled under ice. 0.1 mL of tert-butyldimethylsilyl trifluoromethanesulfonate was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1) to obtain the title compound (174 mg).

[0319] Reference Example 70: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid To a dimethoxyethane (1.5 mL)-methanol (1.5 mL) solution of the compound prepared in Reference Example 69, 0.5 mL of 2 N sodium hydroxide aqueous solution was added at room temperature, and the mixture was stirred at 35°C for 15 hours. After concentrating the reaction mixture under reduced pressure, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. By concentrating the filtrate under reduced pressure, the title compound (154 mg) with the following physical properties was obtained. 1 H-NMR(CDCl3):δ 7.63-7.71, 7.35-7.46, 7.14, 5.32-5.40, 4.34-4.40, 3.83-3.97, 2.92, 2.78-2.86, 2.52, 2.17-2.26, 1.95-2.08, 1.80-1.94, 1.38-1.68, 1.26, 1.13-1.21, 1.07, 0.77-0.85, -0.04--0.01.

[0320] Example 23: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-N-(methylsulfonyl)-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxamide To a solution of the compound (40 mg) prepared in Reference Example 70 in DMF (1 mL), methanesulfonamide (9.4 mg), N,N-dimethyl-4-aminopyridine (12 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg) were added at room temperature and the mixture was stirred for 1 hour at room temperature. To the reaction solution, THF (1 mL) and a THF solution of 1 M tetra-n-butylammonium fluoride (0.25 mL) were added at room temperature and the reaction mixture was stirred at 45°C for 15 hours. Saturated ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol = 5:1) to obtain the title compound (2.5 mg) with the following physical properties. HPLC retention time (min): 0.99; MS(ESI, Pos.):516(M+H-H2O)+.; 1 H-NMR(CDCl3):δ 7.61-7.67, 7.08, 5.60-5.70, 4.55, 4.40-4.43, 3.81, 3.12, 2.80-3.03, 2.65, 2.34-2.48, 2.15-2.30, 1.90-2.07, 1.27-1.81, 0.93.

[0321] Reference Example 71: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxamide To a solution of the compound (114 mg) prepared in Reference Example 70 in DMF (1.1 mL), ammonium chloride (15 mg), 7-aza-1-hydroxybenzotriazole (38 mg), diisopropylethylamine (0.1 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg) were added at room temperature and the mixture was stirred for 15 hours at room temperature. The reaction mixture was diluted with ethyl acetate, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the title compound (105 mg).

[0322] Reference Example 72: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carbonitrile The compound prepared in Reference Example 71 was dissolved in THF (2 mL) solution, and pyridine (0.03 mL) was added at room temperature. The reaction solution was cooled under ice, anhydrous trifluoroacetic acid (0.03 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (99.7 mg) with the following physical properties. 1 H-NMR(CDCl3):δ 7.64-7.72, 7.34-7.47, 7.18-7.25, 7.10-7.15, 5.36-5.41, 4.33-4.44, 3.89, 2.87, 2.48-2.54, 2.14-2.33, 1.77, 1.44-1.60, 1.13-1.35, 1.07, 0.80-0.89, -0.04-0.03.

[0323] Example 24: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-9-(1H-tetrazol-5-yl)-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-2-ol To a toluene (2 mL) solution of the compound (99.7 mg) prepared in Reference Example 72, dibutyltin oxide (38 mg) and azidotrimethylsilane (58 mg) were added at room temperature, and the mixture was stirred at 95°C for 15 hours. The reaction mixture was diluted with ethyl acetate, and the solution was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1) to obtain the tetrazole compound (98 mg). To a THF (1 mL) solution of the obtained tetrazole compound, 1 M tetra-n-butylammonium fluoride in THF (0.17 mL) was added, and the mixture was stirred at 35°C for 15 hours. 1N hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol = 3:1) to obtain the title compound (35.2 mg) with the following physical properties. HPLC retention time (min): 0.99; MS(ESI, Pos.):463(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.64, 7.60, 7.31, 5.56-5.75, 4.74, 4.43, 3.84, 3.02-3.13, 2.87-3.00, 2.68-2.76, 2.39, 2.16-2.31, 1.79-2.03, 1.52-1.75, 1.30-1.50, 0.93.

[0324] Example 24-1: (1R,2R,3aS,10aR)-1-[(1E,3S)-3-hydroxy-1-octen-1-yl]-6-(1H-tetrazol-5-yl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-2-ol By using the compound prepared in Example 17 instead of the compound prepared in Example 17-17, and subjecting it to the same objective operations as in Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Reference Example 71 → Reference Example 72 → Example 24, the title compound having the following physical properties was obtained. TLC: Rf 0.26 (CH2Cl2 / methanol, 5 / 1) MS(APCI, Pos.):381(M-H2O)+.; 1 H-NMR(CD3OD):δ 7.51-7.61, 7.21, 5.45-5.66, 4.39-4.47, 4.04, 3.87, 2.96-3.08, 2.79-2.92, 2.48-2.76, 1.80-1.97, 1.31-1.64, 0.88-0.98.

[0325] Reference Example 73: Ethyl (1S,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a 50 mL dichloromethane solution of the compound (8.3 g) prepared in Reference Example 8, triethylamine (9.1 mL), tert-butyldiphenylchlorosilane (8.9 mL), and dimethylaminopyridine (0.31 g) were added at room temperature, and the mixture was stirred at 35 °C for 3 hours. The reaction mixture was poured into a 1 N hydrochloric acid aqueous solution / ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was dissolved in methanol (50 mL), p-toluenesulfonic acid monohydrate (378 mg) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Triethylamine (3.0 mL) was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10 → 30:70) to obtain the title compound (10.7 g) exhibiting the following physical properties. 1H-NMR(CDCl3):δ 7.63-7.70, 7.37-7.52, 6.85, 4.34-4.41, 4.19-4.26, 3.88-3.93, 3.65-3.71, 2.97-3.05, 2.63-2.71, 2.55, 2.20-2.33, 2.12-2.20, 2.00-2.07, 1.84-1.92, 1.71-1.79, 1.38, 1.06.

[0326] Reference Example 74: Ethyl (1S,2R,3aS,10aR)-5-fluoro-2-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a 78 mL acetonitrile solution of the compound (15.6 g) prepared in Reference Example 73, triethylamine (12.8 mL), trimethylamine hydrochloride (344 mg), and p-toluenesulfonyl chloride (6.34 g) were added at room temperature, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into a 1N hydrochloric acid aqueous solution / ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10 → 70:30) to obtain the title compound (20.2 g) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 7.81, 7.56-7.66, 7.35-7.49, 7.29, 6.82, 5.05-5.11, 4.33-4.40, 4.25, 3.80-3.87, 3.55-3.61, 2.86-2.94, 2.53-2.61, 2.40-2.48, 2.25-2.34, 2.16-2.23, 2.03-2.13, 1.66-1.76, 1.48-1.53, 1.38, 1.03.

[0327] Reference Example 75: Ethyl (1S,3aS,10aR)-5-fluoro-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound (20.2 g) prepared in Reference Example 74 in dimethoxyethane (150 mL) - DMF (10 mL), water (15 mL), sodium iodide (16.6 g), and zinc (14.4 g) were added at room temperature, and the mixture was stirred overnight at 80°C. Further addition of sodium iodide (4 g) and zinc (3.5 g) was added, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 → 5:1) to obtain the title compound (13.1 g) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 7.64-7.69, 7.36-7.46, 6.84, 4.34-4.41, 3.63-3.74, 2.94-3.02, 2.68-2.76, 2.23-2.33, 1.89-2.12, 1.79-1.87, 1.56-1.62, 1.48-1.54, 1.38, 1.06.

[0328] Reference Example 76: Ethyl (1S,3aS,10aR)-5-fluoro-1-formyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 75 instead of the compound prepared in Reference Example 7, and subjecting it to the same procedure as in Reference Example 8 → Reference Example 9, the title compound exhibiting the following physical properties was obtained. 1 H-NMR(CDCl3):δ 9.73, 7.45-7.51, 6.88, 4.43, 4.34-4.41, 2.98-3.12, 2.74-2.85, 2.42-2.50, 2.26-2.38, 2.13-2.23, 1.92-2.07, 1.38.

[0329] Example 25: (1R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid Using the compound prepared in Reference Example 76 (70 mg) instead of the compound prepared in Reference Example 9, and using the compound prepared in Reference Example 26 (136 mg) instead of the compound prepared in Reference Example 14, the same procedure as in Reference Example 17 was followed to obtain the enone compound (97 mg). The enone compound (97 mg) was cooled to -15°C in a THF (1 mL) solution. (S)-2-methyl-CBS-oxazaborolidine (1 mol / L toluene solution, 0.204 mL) and N,N-diethylaniline borane (0.073 mL) were added, and the mixture was stirred at -15°C for 8 hours. Methanol and water were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ISCO Gold High Performance Silica, n-hexane:ethyl acetate) to obtain the reduced product. The reduced product was dissolved in methanol (1 mL) and dimethoxyethane (0.5 mL), and 2N sodium hydroxide aqueous solution (0.5 mL) was added. The mixture was stirred overnight. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated, acidified with hydrochloric acid aqueous solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using an SFC column (CHIRALPAK IG, CO2:methanol = 65:35) to obtain the title compound (19 mg) with the following physical properties. HPLC retention time (min): 1.09; MS(ESI, Pos.):437(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.28-7.33, 6.97-7.12, 6.81-6.90, 5.26-5.39, 4.77, 4.20-4.26, 2.86-2.93, 2.35-2.64, 2.30, 1.80-2.07, 1.68-1.79, 1.51-1.68, 1.24-1.35.

[0330] Examples 25-1 to 25-15: By using the corresponding phosphonate instead of the compound prepared in Reference Example 26 and subjecting it to the same procedure as in Example 25, the title compound exhibiting the following physical properties was obtained. Note that in Example 25-6, the reduction reaction was carried out using (R)-2-methyl-CBS-oxazaborolidine instead of (S)-2-methyl-CBS-oxazaborolidine used in Example 25. The corresponding phosphonate was either a known compound or prepared from a known compound by subjecting it to the same procedure as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0331] Example 25-1: (1R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.05; MS(ESI, Pos.):423(M+H-H2O)+.; 1 H-NMR(DMSO-d6):δ 12.96-13.32, 7.28-7.47, 7.11-7.20, 7.07, 5.44-5.53, 5.22-5.31, 4.92, 4.41, 3.96-4.01, 3.49-3.49, 2.93-3.04, 2.59-2.63, 2.10-2.21, 1.92-2.04, 1.80-1.92, 1.54-1.71, 1.27-1.41, 0.96-1.08, 0.73, 0.62.

[0332] Example 25-2: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 0.97; MS(ESI, Pos.):433(M+H)+.; 1 H-NMR(DMSO-d6):δ 13.12, 7.49-7.57, 7.42-7.48, 7.07, 5.87, 5.46-5.66, 4.40-4.54, 2.89-3.09, 2.74-2.87, 2.58-2.73, 2.13-2.23, 1.97-2.07, 1.70-1.93, 1.66, 1.33-1.45.

[0333] Example 25-3: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.01; MS(ESI, Pos.):451(M+H)+.,433(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.40-7.46, 7.29-7.34, 7.08, 6.83, 5.46-5.54, 5.35-5.43, 4.77, 4.25-4.38, 2.87-2.95, 2.53-2.70, 2.02-2.12, 1.82-2.00, 1.55-1.74, 1.23-1.38.

[0334] Example 25-4: (1R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.218; MS(ESI, Pos.):429(M-OH)+.; 1 H-NMR(DMSO-d6):δ 13.07, 7.33-7.42, 7.07-7.14, 7.00, 5.42-5.49, 5.33-5.41, 4.84, 4.41, 4.02-4.12, 3.17, 2.90-3.09, 2.73-2.83, 2.52-2.61, 2.07-2.18, 1.90-2.02, 1.77-1.89, 1.72, 1.28-1.40, 1.16.

[0335] Example 25-5: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.17; MS(ESI, Pos.):405(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.41-7.46, 7.32-7.38, 7.22-7.28, 7.14-7.20, 6.95, 5.42-5.48, 5.32-5.40, 4.35, 3.83, 2.98-3.07, 2.69-2.80, 2.58-2.68, 2.09-2.19, 1.90-2.06, 1.68-1.87, 1.34-1.45, 0.93-0.99, 0.84-0.91, 0.75-0.81, 0.68-0.74.

[0336] Example 25-6: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ,4S)-3-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.273; MS(ESI, Pos.):373(M-OH)+.; 1 H-NMR(DMSO-d6):δ 7.30-7.37, 6.97, 5.35-5.50, 4.56, 4.41, 3.73, 2.93-3.02, 2.74-2.82, 2.59, 2.10-2.19, 1.95-2.03, 1.70-1.89, 1.37-1.47, 1.15-1.35, 0.94-1.06, 0.87, 0.79.

[0337] Example 25-7: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.212; MS(ESI, Pos.):447(M+Na)+.; 1 H-NMR(CD3OD):δ 7.41-7.46, 7.36-7.41, 7.28, 7.12-7.19, 6.92, 5.25-5.39, 4.28-4.35, 4.15, 2.87-2.98, 2.62-2.72, 2.48-2.59, 2.08-2.17, 1.88-2.04, 1.48-1.68, 1.33.

[0338] Example 25-8: (1R,3aS,10aR)-1-[(1E,3ξ)-3-(1-butylcyclopropyl)-3-hydroxy-1-propen-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.27; MS(ESI, Pos.):385(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.41-7.47, 6.94, 5.47-5.59, 4.41, 3.82-3.88, 3.00-3.11, 2.65-2.85, 2.16-2.25, 2.05-2.14, 1.80-2.03, 1.43-1.62, 1.24-1.40, 0.85-0.96, 0.41-0.56, 0.20-0.34.

[0339] Example 25-9: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.089; MS(ESI, Pos.):421(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.44-7.50, 7.36, 7.24-7.29, 7.08, 6.97, 5.49-5.57, 5.31-5.41, 4.97-5.03, 4.92, 4.50, 4.38, 2.98-3.07, 2.73-2.82, 2.60-2.70, 2.13-2.22, 1.93-2.09, 1.68-1.82, 1.38-1.49.

[0340] Example 25-10: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-(3-thienyl)-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.18; MS(ESI, Pos.):453(M+Na)+,413(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.39-7.45, 7.28-7.32, 7.11-7.14, 7.06-7.08, 6.92, 5.29-5.41, 4.31-4.36, 4.07, 2.92-3.01, 2.63-2.77, 2.52-2.63, 2.09-2.19, 1.89-2.06, 1.58-1.74, 1.26-1.45.

[0341] Example 25-11: (1R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.23; MS(ESI, Pos.):477(M+Na)+.; 1 H-NMR(CD3OD):δ 7.43-7.48, 7.14, 6.94-7.02, 5.38-5.47, 5.21-5.30, 4.36, 4.22, 2.97-3.07, 2.71-2.82, 2.56-2.68, 2.47-2.56, 2.24-2.40, 1.91-2.19, 1.71-1.88, 1.35-1.46.

[0342] Example 25-12: (1R,3aS,10aR)-1-[(1E,3ξ)-3-(1-benzylcyclobutyl)-3-hydroxy-1-propen-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.276; MS(ESI, Pos.):473(M+Na)+.; 1 H-NMR(CD3OD):δ 7.33-7.38, 7.08-7.20, 6.85, 5.58-5.65, 5.40-5.47, 4.78, 4.32, 3.86, 2.94-3.02, 2.79, 2.61-2.75, 2.57, 1.72-2.17, 1.53-1.66, 1.34-1.46.

[0343] Example 25-13: (1R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[3-(2-fluorophenyl)-3-oxetanyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.095; MS(ESI, Pos.):479(M+Na)+.; 1 H-NMR(CD3OD):δ 7.42, 7.26-7.33, 7.14-7.21, 7.02-7.10, 6.93, 5.44-5.54, 4.89-5.01, 4.49, 4.32-4.37, 2.94-3.04, 2.58-2.78, 1.91-2.18, 1.61-1.78, 1.35-1.47.

[0344] Example 25-14: (1R,3aS,10aR)-1-[(1E,3ξ)-5-ethoxy-3-hydroxy-4,4-dimethyl-1-penten-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.173; MS(ESI, Pos.):429(M+Na)+.; 1 H-NMR(CD3OD):δ 7.41-7.48, 6.94, 5.59-5.66, 5.47-5.55, 4.39-4.45, 3.94, 3.41-3.52, 3.19-3.23, 3.02-3.11, 2.65-2.86, 2.06-2.25, 1.81-2.03, 1.43-1.55, 1.18, 0.89.

[0345] Example 25-15: (1R,3aS,10aR)-5-fluoro-1-{(1E,3ξ)-3-[3-(4-fluorophenyl)-3-oxetanyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.071; MS(ESI, Pos.):479(M+Na)+.; 1 H-NMR(CD3OD):δ 7.42-7.48, 7.07, 6.95, 5.49-5.56, 5.30-5.38, 4.90-4.98, 4.49, 4.37, 2.96-3.05, 2.71-2.83, 2.63, 2.11-2.21, 1.92-2.08, 1.68-1.81, 1.35-1.47.

[0346] Examples 26-1 to 26-23 By using the corresponding aldehyde instead of the compound prepared in Reference Example 76, and the corresponding phosphonate instead of the compound prepared in Reference Example 26, and performing the same objective procedure as in Example 25, the title compound exhibiting the following physical properties was obtained. Note that in Examples 26-1, 26-3, and 26-6, the reduction was carried out using (R)-2-methyl-CBS-oxazaborolidine instead of (S)-2-methyl-CBS-oxazaborolidine used in the reaction corresponding to Example 25. The corresponding aldehyde was prepared by using the corresponding phenol instead of the compound prepared in Reference Example 3, and performing the same objective procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 73 → Reference Example 74 → Reference Example 75 → Reference Example 76. The corresponding phosphonate was either a known compound or prepared from a known compound by performing the same objective procedure as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0347] Example 26-1: (1R,3aS,10aR)-1-[(1E,3S)-3-hydroxy-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(FAB, Neg.):357(MH)-.; 1 H-NMR(CDCl3):δ 7.60-7.67, 7.15, 5.48-5.58, 4.42-4.46, 4.06-4.12, 2.97-3.06, 2.77-2.85, 2.60-2.70, 2.04-2.21, 1.22-2.01, 0.78-0.96.

[0348] Example 26-2: (1R,3aS,10aR)-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclobutyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):401(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.45-7.51, 7.36, 7.14-7.20, 7.02-7.10, 5.24-5.36, 5.12-5.22, 4.78, 4.25-4.29, 4.13, 2.85-2.93, 2.65-2.76, 2.38-2.51, 2.16-2.33, 1.86-2.10, 1.58-1.83, 1.15-1.36.

[0349] Example 26-3: (1R,3aS,10aR)-1-[(1E,3ξ)-3-hydroxy-4-phenoxy-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):377(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.57-7.61, 7.49, 7.26-7.31, 7.18, 6.92-6.98, 5.66-5.78, 4.43-4.48, 3.91-4.00, 3.27-3.31, 2.98-3.06, 2.78-2.88, 2.65-2.76, 2.07-2.29, 1.81-2.00, 1.47-1.58.

[0350] Example 26-4: (1R,3aS,10aR)-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):387(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.57-7.63, 7.48, 7.38, 7.25-7.30, 7.17-7.23, 5.36-5.49, 4.37-4.42, 3.85, 2.97-3.05, 2.77-2.85, 2.55-2.65, 2.13-2.23, 1.98-2.07, 1.69-1.95, 1.30-1.46, 0.95-1.00, 0.87-0.93, 0.77-0.83, 0.70-0.76.

[0351] Example 26-5: (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):405(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.45-7.50, 7.36, 7.26, 7.08, 6.85-6.91, 5.25-5.36, 4.78, 4.27-4.31, 3.68, 2.86-2.94, 2.66-2.75, 2.43-2.53, 2.01-2.11, 1.86-1.95, 1.59-1.83, 1.22-1.33, 0.82-0.89, 0.74-0.81, 0.59-0.69.

[0352] Example 26-6: (1R,3aS,10aR)-1-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.13; MS(ESI, Pos.):409(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.57-7.62, 7.50, 7.19, 5.59-5.69, 4.41-4.48, 2.99-3.08, 2.77-2.91, 2.71, 2.17-2.30, 2.06-2.15, 1.81-2.00, 1.27-1.72, 0.89-0.99.

[0353] Example 26-7: (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.262; MS(ESI, Pos.):419(M+H-H2O)+; 1 H-NMR(CD3OD):δ 7.56-7.59, 7.46, 7.11-7.20, 6.96-7.02, 5.39-5.47, 5.22-5.29, 4.36-4.40, 4.22, 2.95-3.03, 2.73-2.86, 2.48-2.61, 2.24-2.40, 1.96-2.20, 1.70-1.93, 1.33-1.44.

[0354] Example 26-8: (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.07; MS(ESI, Pos.):405(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.58-7.61, 7.48, 7.35-7.40, 7.22-7.26, 7.20, 7.08-7.12, 7.02, 5.48-5.56, 5.32-5.41, 4.36-4.40, 3.99, 2.95-3.05, 2.81, 2.59, 2.15, 1.97-2.06, 1.86-1.96, 1.65-1.80, 1.30-1.43, 0.99-1.07, 0.76-0.83, 0.72.

[0355] Example 26-9: (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.14; MS(ESI, Pos.):419(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.58-7.61, 7.48, 7.09-7.23, 6.95-7.02, 5.38-5.50, 4.37, 4.34, 2.94-3.03, 2.80, 2.35-2.64, 1.97-2.22, 1.65-1.94, 1.35-1.48.

[0356] Example 26-10: (1R,3aS,10aR)-1-{(1E)-3-[1―(2,6-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):437(M+H)+.; 1H-NMR(CDCl3):δ 7.64-7.67, 7.62, 7.11-7.19, 6.81, 5.50-5.60, 4.50-4.54, 4.35-4.42, 2.97-3.06, 2.72-2.83, 2.51-2.71, 2.33-2.45, 1.99-2.17, 1.69-1.97, 1.30-1.41, -0.05--0.01.

[0357] Example 26-11: (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1―(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):437(M+H-H2O)+.; 1 H-NMR(CDCl3):δ 7.64-7.67, 7.62, 7.16, 6.98-7.05, 6.80-6.85, 6.70-6.76, 5.43-5.54, 4.40, 2.94-3.05, 2.73-2.83, 2.59-2.70, 2.46-2.56, 2.28-2.46, 2.00-2.18, 1.68-1.97, 1.31-1.42.

[0358] Example 26-12: (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1―(2,4-difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos.):423(M+H-H2O)+.; 1H-NMR(CDCl3):δ 7.64-7.67, 7.62, 7.23-7.31, 7.16, 6.73-6.83, 5.46-5.53, 5.37-5.44, 4.38-4.42, 3.82, 2.95-3.05, 2.75-2.83, 2.62, 2.09-2.18, 1.99-2.07, 1.64-1.97, 1.29-1.39, 0.90-1.03, 0.77-0.87.

[0359] Example 26-13: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.06; MS(ESI, Pos.):397(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.40-7.58, 7.11-7.19, 5.42-5.61, 4.32-4.47, 2.84-3.00, 2.70-2.80, 2.59, 2.10-2.19, 1.82-2.08, 1.53-1.77, 1.26-1.47.

[0360] Example 26-14: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.04; MS(ESI, Pos.):377(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.47, 7.37, 7.06, 5.60-5.68, 5.47-5.54, 4.76, 4.33, 4.02-4.11, 2.88-2.97, 2.68-2.77, 2.54-2.66, 2.06-2.16, 1.95-2.05, 1.68-1.90, 1.23-1.45, 0.85.

[0361] Example 26-15: (1R,3aS,10aR)-1-[(1E,3ξ)-3-hydroxy-4-methylene-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.06; MS(ESI, Pos.):353(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.56-7.61, 7.49, 7.18, 5.50-5.64, 5.11, 4.85-4.89, 4.50, 4.43-4.47, 2.99-3.08, 2.78-2.89, 2.63-2.73, 2.18-2.27, 2.05-2.15, 1.82-1.99, 1.31-1.55, 0.96.

[0362] Example 26-16: (1R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.2; MS(ESI, Pos.):439(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.31-7.42, 7.19-7.26, 7.05-7.13, 6.96-7.03, 5.46-5.55, 5.29-5.38, 4.21, 3.97, 2.97-3.10, 2.58-2.79, 1.97-2.17, 1.56-1.81, 1.32-1.47, 0.94-1.09, 0.65-0.83.

[0363] Example 26-17: (1R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.25; MS(ESI, Pos.):453(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.36, 7.07-7.21, 6.97, 5.35-5.49, 4.32, 4.21, 2.99-3.07, 2.67-2.77, 2.36-2.64, 1.97-2.16, 1.80-1.88, 1.57-1.78, 1.36-1.47.

[0364] Example 26-18: (1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-4-methylene-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.255; MS(ESI, Pos.):387(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.30, 7.01, 5.40-5.52, 5.00, 4.72-4.85, 4.39, 4.19, 2.96-3.04, 2.66-2.77, 2.53-2.62, 1.89-2.12, 1.64-1.86, 1.20-1.48, 0.81-0.87.

[0365] Example 26-19: (1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-6-methoxy-4-methylene-1-hexen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.069; MS(ESI, Pos.):389(M-OH)+; 1 H-NMR(CD3OD):δ 7.36, 7.09, 5.57-5.64, 5.49-5.56, 5.15, 4.92, 4.52, 4.29, 3.54, 3.06-3.14, 2.75-2.87, 2.63-2.72, 2.25-2.41, 2.02-2.22, 1.74-1.97, 1.47-1.58.

[0366] Example 26-20: (1R,3aS,10aR)-5-chloro-1-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.301; MS(ESI, Pos.):443(M+Na)+,403(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.30, 7.01, 5.36-5.50, 4.78, 4.19, 3.92-3.97, 2.97-3.06, 2.67-2.78, 2.54-2.63, 1.91-2.12, 1.80-1.89, 1.64-1.75, 1.06-1.51, 0.77-0.88.

[0367] Example 26-21: (1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.085; MS(ESI, Pos.):477(M+Na)+.; 1 H-NMR(CD3OD):δ 7.32-7.40, 7.22-7.27, 7.04-7.13, 5.47-5.54, 5.30-5.36, 4.89-5.01, 4.81-4.84, 4.48, 4.23, 3.02, 2.59-2.77, 1.98-2.16, 1.61-1.78, 1.37-1.49.

[0368] Example 26-22: (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.278; MS(ESI, Pos.):473(M+Na)+.; 1 H-NMR(CD3OD):δ 7.38, 7.05, 6.87-6.94, 5.30-5.38, 5.12-5.20, 4.78, 4.14, 4.01-4.06, 2.90-2.98, 2.59-2.69, 2.36-2.53, 2.16-2.33, 1.83-2.08, 1.68-1.80, 1.53-1.64, 1.28-1.39.

[0369] Examples 26-23: (1R,3aS,10aR)-8-fluoro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid MS(ESI, Pos,):437(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.31-7.35, 7.31, 7.18-7.24, 7.08-7.17, 6.99, 5.38-5.50, 4.51, 4.34, 2.94-3.03, 2.67-2.81, 2.36-2.60, 2.15-2.26, 1.95-2.13, 1.80-1.92, 1.70-1.78, 1.30-1.43.

[0370] Example 27: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-N-(methylsulfonyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxamide By using the compound prepared in Example 26-13 instead of the compound prepared in Example 17-17, and subjecting it to the same objective procedures as in Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23, the title compound exhibiting the following physical properties was obtained. HPLC retention time (min): 0.99; MS(ESI, Pos.):492(M+H)+.; 1 H-NMR(CD3OD):δ 7.40-7.53, 7.17-7.25, 5.54-5.61, 5.43-5.50, 4.38-4.52, 2.91-3.01, 2.73-2.84, 2.57-2.65, 2.11-2.22, 1.97-2.07, 1.84-1.95, 1.60-1.79, 1.28-1.47.

[0371] Reference Example 77: Ethyl (1S,2S,3aS,10aR)-5-fluoro-2-hydroxy-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate Triphenylphosphine (4.54 g) was added to a solution of the compound (4.87 g) prepared in Reference Example 73 in THF (39 mL) at room temperature. The mixture was cooled to 0°C, and formic acid (0.98 mL) and diethyl azodicarboxylate (2.2 mol / L toluene solution, 7.9 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0 → 80:20) to obtain the formic acid ester (4.53 g). To a solution of formate ester (4.53 g) in ethanol (31.7 mL), potassium carbonate (2.12 g) was added at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with MTBE and filtered. The filtrate was poured into saturated ammonium chloride aqueous solution / 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 88:12 → 75:25) to obtain the title compound (4.08 g) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 7.64-7.71, 7.39-7.50, 7.31-7.36, 6.81, 4.67-4.72, 4.53-4.58, 4.33-4.39, 4.02-4.08, 3.81-3.87, 2.99, 2.82-2.90, 2.70-2.78, 2.27-2.42, 2.12-2.22, 1.56, 1.37, 1.08.

[0372] Reference Example 78: Ethyl (1S,2R,3aS,10aR)-2,5-difluoro-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate A solution of the compound (6.0 g) prepared in Reference Example 77 in MTBE (27 mL) was cooled to -78°C, bis(2-methoxyethyl)aminosulfate trifluoride (9.8 mL) was added dropwise, and the mixture was stirred at -78°C. After confirming the disappearance of the starting material by TLC, the temperature was raised to -20°C, and the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 93:7 → 86:14) to obtain the title compound (2.59 g) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 7.61-7.68, 7.37-7.50, 6.86, 5.25-5.31, 5.11-5.17, 4.32-4.40, 3.95-3.99, 3.67-3.73, 2.98-3.06, 2.58-2.67, 2.44, 2.21-2.37, 2.12-2.19, 1.85, 1.67-1.76, 1.38, 1.06.

[0373] Reference Example 79: Ethyl (1S,2R,3aS,10aR)-2,5-difluoro-1-(hydroxymethyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 78 instead of the compound prepared in Reference Example 7, and subjecting it to the same procedure as in Reference Example 8, the title compound exhibiting the following physical properties was obtained. 1 H-NMR(CDCl3):δ 7.47-7.51, 6.88, 5.14-5.20, 5.00-5.06, 4.34-4.40, 3.94-4.01, 3.72-3.78, 3.07-3.16, 2.72-2.79, 2.48-2.66, 2.26-2.48, 2.01-2.12, 1.94, 1.44, 1.35-1.41.

[0374] Reference Example 80: Ethyl (1S,2R,3aS,10aR)-2,5-difluoro-1-formyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To a solution of the compound (600 mg) prepared in Reference Example 79 in dichloromethane (6 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (Dess Martin reagent, 1.17 g) was added at 0°C and the mixture was stirred at room temperature. After confirming the completion of the reaction by TLC, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 75:25 → 60:40) to obtain the title compound (550 mg) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 9.98, 7.46-7.54, 6.90, 5.44-5.51, 5.31-5.37, 4.34-4.41, 3.49-3.55, 3.41-3.49, 3.09-3.20, 2.72-2.83, 2.42-2.57, 2.27-2.27, 2.23-2.39, 2.07-2.17, 1.92-2.03, 1.38.

[0375] Example 28: (1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-pentenyl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] By using the compound prepared in Reference Example 80 (300 mg) instead of the compound prepared in Reference Example 76, and dimethyl-3-methyl-2-oxo-3-phenylbutylphosphonate (CAS number: 87929-30-4, 375 mg) instead of the compound prepared in Reference Example 26, and subjecting the compound to the same procedure as in Reference Example 24, the title compound exhibiting the following physical properties was obtained. HPLC retention time (min): 1.157; MS(ESI, Pos.):405(M+H-H2O-HF)+.; 1 H-NMR(CD3OD):δ 7.44-7.49, 7.36-7.42, 7.29, 7.13-7.18, 6.95, 5.44-5.51, 5.31-5.38, 4.78-4.83, 4.64-4.71, 4.19-4.24, 2.92-3.00, 2.75-2.89, 2.44-2.66, 2.05-2.17, 1.68-1.76, 1.48-1.62, 1.35.

[0376] Examples 28-1 to 28-3: By using the compound prepared in Reference Example 80 instead of the compound prepared in Reference Example 76, and the corresponding phosphonate instead of the compound prepared in Reference Example 26, and by subjecting the compound to the same procedure as in Example 25, the title compound exhibiting the following physical properties was obtained. The corresponding phosphonate was either a known compound or prepared from a known compound by subjecting it to the same procedure as in Reference Example 10 → Reference Example 11.

[0377] Example 28-1: (1R,2R,3aS,10aR)-2,5-difluoro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.01; MS(ESI, Pos.):441(M-OH)+.; 1 H-NMR(DMSO-d6):δ 13.10, 7.42, 7.22-7.35, 7.04-7.14, 5.52-5.59, 5.25-5.34, 4.97, 4.73, 4.27, 3.95-4.00, 2.94, 2.69-2.88, 1.92-2.06, 1.71-1.81, 1.53, 0.91-1.04, 0.66-0.73, 0.53-0.61.

[0378] Example 28-2: (1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.035; MS(ESI, Pos.):439(M+H-H2O)+,419(M+H-H2O-HF)+.; 1 H-NMR(CD3OD):δ 7.36-7.41, 7.25, 7.13-7.18, 6.97, 6.88, 5.34-5.51, 4.75-4.92, 4.59-4.65, 4.42, 4.16, 2.89-2.98, 2.73-2.88, 2.57-2.65, 2.38-2.50, 1.97-2.11, 1.69-1.79, 1.53-1.68.

[0379] Example 28-3: (1R,2R,3aS,10aR)-2,5-difluoro-1-{(1E,3ξ)-3-hydroxy-3-[(2ξ)-2-phenyl-2-oxetanyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.053; MS(ESI, Pos.):479(M+Na)+,439(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.24-7.49, 6.91-6.98, 5.40-5.57, 4.58-4.83, 4.43-4.52, 4.13-4.28, 3.24-3.28, 3.12-3.20, 2.96-3.09, 2.81-2.95, 2.63-2.81, 2.43-2.61, 2.06-2.21, 1.75-1.87, 1.57-1.75.

[0380] Examples 29-1 to 29-4: The title compound exhibiting the following physical properties was obtained by using the corresponding aldehyde instead of the compound prepared in Reference Example 76, and the corresponding phosphonate instead of the compound prepared in Reference Example 26, and by performing the same procedure as in Example 25. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 39 instead of the compound prepared in Reference Example 8, and by performing the same procedure as in Reference Example 73 → Reference Example 77 → Reference Example 78 → Reference Example 79 → Reference Example 80. The corresponding phosphonate was either a known compound or was prepared from a known compound by performing the same procedure as in Reference Example 10 → Reference Example 11.

[0381] Example 29-1: (1R,2R,3aS,10aR)-2-fluoro-1-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclobutyl)-1-propen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.224; MS(ESI, Pos.):473(M+Na)+.; 1 H-NMR(CD3OD):δ 7.38-7.42, 7.15-7.21, 7.03-7.09, 6.89-6.96, 5.28-5.41, 4.81-4.90, 4.78, 4.60-4.60, 4.56-4.68, 4.17-4.22, 3.94, 2.81-3.00, 2.20-2.49, 1.91-2.11, 1.63-1.79, 1.52.

[0382] Example 29-2: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-3-(1-butylcyclobutyl)-3-hydroxy-1-propen-1-yl]-2-fluoro-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.281; MS(ESI, Pos.):453(M+Na)+,393(M+H-H2O-HF)+.; 1 H-NMR(CD3OD):δ 7.39, 6.92, 5.61-5.68, 5.48-5.56, 4.71-4.91, 4.00, 3.88, 2.94-3.08, 2.40-2.53, 2.35, 1.95-2.16, 1.48-1.88, 1.16-1.37, 0.79-0.89.

[0383] Example 29-3: (1R,2R,3aS,10aR)-2-fluoro-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.217; MS(ESI, Pos.):491(M+Na)+.; 1 H-NMR(CD3OD):δ 7.47-7.51, 7.15, 6.97-7.05, 5.38-5.51, 4.70-4.92, 4.28, 4.05, 2.92-3.10, 2.44-2.60, 2.28-2.43, 2.01-2.21, 1.74-1.89, 1.64.

[0384] Example 29-4: (1R,2R,3aS,10aR)-2-fluoro-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-thienyl)cyclobutyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.193; MS(ESI, Pos.):479(M+Na)+.; 1H-NMR(CD3OD):δ 7.48, 7.29-7.33, 7.05-7.07, 6.98-7.03, 5.38-5.50, 4.71-4.92, 4.24, 4.03, 2.90-3.07, 2.37-2.56, 2.08-2.30, 1.84-1.99, 1.69-1.83, 1.60.

[0385] Example 30: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2-fluoro-N-(methylsulfonyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxamide The title compound exhibiting the following physical properties was obtained by using the corresponding aldehyde instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 26, and by subjecting the compound to the same objective as in Example 25 → Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, and by subjecting the compound to the same objective as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 73 → Reference Example 77 → Reference Example 78 → Reference Example 79 → Reference Example 80. The corresponding phosphonate was prepared by using iodobenzene instead of 1,3-difluoro-2-iodobenzene and by subjecting the compound to the same objective as in Reference Example 28 → Reference Example 29. HPLC retention time (min): 0.96; MS(ESI, Pos.):510(M+H)+.; 1 H-NMR(DMSO-d6):δ 12.02, 7.55, 7.45-7.52, 7.25-7.31, 5.88-5.98, 5.53-5.70, 4.73-4.98, 4.40-4.55, 4.26-4.33, 2.57-3.03, 1.74-2.08, 1.59, 1.24.

[0386] Example 31: (2R,3R,3aR,11aS)-2-fluoro-3-[(1E,3ξ)-3-hydroxy-3-(1-phenylcyclobutyl)-1-propen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxosin-9-carboxylic acid By using the corresponding aldehyde instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 26, and subjecting the compound to the same objective as in Example 25 → Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23, the title compound exhibiting the following physical properties was obtained. The corresponding aldehyde was prepared by using (1R,2R,3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol instead of the compound prepared in Reference Example 2, and the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, and subjecting the compound to the same objective as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 73 → Reference Example 77 → Reference Example 78 → Reference Example 79 → Reference Example 80. The corresponding phosphonate was prepared by using 1-phenylcyclobutanecarboxylic acid (CAS number: 37828-19-6) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid and subjecting it to the same procedure as in Reference Example 10 → Reference Example 11. MS(ESI, Pos.):433(M+H-H2O)+,413(M+H-H2O-HF)+.; 1 H-NMR(CD3OD):δ 7.65-7.69, 7.62, 7.18-7.29, 7.10-7.15, 5.31-5.43, 4.59-4.80, 4.49-4.54, 4.23, 2.94-3.02, 2.82-2.91, 2.48-2.70, 2.24-2.44, 2.10-2.23, 1.96-2.08, 1.77-1.88, 1.52-1.74, 1.24-1.48.

[0387] Reference Example 81: Ethyl (1S,2S,3aS,10aR)-5-fluoro-2-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate The compound prepared in Reference Example 77 (4.28 g) was dissolved in acetonitrile (34.2 mL), cooled to 0°C, and triethylamine (3.71 mL), trimethylamine hydrochloride (145 mg), and p-toluenesulfonyl chloride (2.32 g) were added. The mixture was stirred overnight at room temperature, and then stirred again at 50°C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0 → 75:25) to obtain the title compound (mixture with the starting materials). No further purification was performed, and the mixture was subjected to the next reaction.

[0388] Reference Example 82: Ethyl (1S,2R,3aS,10aR)-2-chloro-5-fluoro-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate The mixture prepared in Reference Example 81 was dissolved in toluene (32.7 mL), tetrabutylammonium chloride (3.17 g) was added, and the mixture was stirred overnight at 60°C. After confirming the completion of the reaction by TLC, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0 → 83:17 → 70:30) to obtain the title compound (2.68 g) exhibiting the following physical properties. 1H-NMR(CDCl3):δ 7.63-7.69, 7.37-7.48, 6.84, 4.34-4.43, 4.21-4.30, 3.98-4.04, 3.71-3.77, 2.92-3.00, 2.70-2.88, 2.25-2.42, 2.13-2.24, 1.85-1.94, 1.67-1.75, 1.38, 1.07.

[0389] Reference Example 83: Ethyl (1S,2R,3aS,10aR)-2-chloro-5-fluoro-1-(hydroxymethyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 82 (2.68 g) instead of the compound prepared in Reference Example 7, and subjecting it to the same procedure as in Reference Example 8, the title compound (1.10 g) exhibiting the following physical properties was obtained. 1 H-NMR(CDCl3):δ 7.44-7.49, 6.86, 4.34-4.44, 4.06-4.14, 3.96-4.02, 3.79-3.85, 3.01-3.10, 2.79-2.89, 2.32-2.41, 1.93-2.17, 1.43, 1.38.

[0390] Reference Example 84: Ethyl (1S,2R,3aS,10aR)-2-chloro-5-fluoro-1-formyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 83 (1.10 g) instead of the compound prepared in Reference Example 79, and subjecting it to the same procedure as in Reference Example 80, the title compound (0.80 g) exhibiting the following physical properties was obtained. 1 H-NMR(CDCl3):δ 9.90, 7.48-7.53, 6.88, 4.34-4.45, 3.35-3.41, 3.08-3.15, 2.79-2.90, 2.34-2.49, 2.09-2.18, 1.93-2.02, 1.39.

[0391] Example 32: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-[3-(2-fluorophenyl)-3-oxetanyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] By using the compound prepared in Reference Example 84 (170 mg) instead of the compound prepared in Reference Example 76, and the corresponding phosphonate (226 mg) instead of the compound prepared in Reference Example 26, and performing the same procedure as in Reference Example 24, the title compound exhibiting the following physical properties was obtained. The corresponding phosphonate was prepared by using 3-phenyl-3-oxetanecarboxylic acid (CAS number: 114012-42-9) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid, and performing the same procedure as in Reference Example 10 → Reference Example 11. HPLC retention time (min): 1.089; MS(ESI, Pos.):513(M+Na)+,473(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.44-7.48, 7.27-7.33, 7.15-7.20, 7.05-7.11, 6.94, 5.58-5.65, 5.48-5.55, 4.80-4.82, 4.80-5.01, 4.53, 4.34-4.38, 3.84-3.92, 2.84-3.03, 2.68-2.81, 2.15-2.22, 1.84-1.93, 1.63-1.81.

[0392] Examples 32-1 to 32-8: By using the compound (170 mg) prepared in Reference Example 84 instead of the compound prepared in Reference Example 76, and the corresponding phosphonate (226 mg) instead of the compound prepared in Reference Example 26, and subjecting the mixture to the same procedure as in Reference Example 24, the title compound exhibiting the following physical properties was obtained. The corresponding phosphonate was either a known compound or prepared from a known compound by subjecting it to the same procedure as in Reference Example 10 → Reference Example 11.

[0393] Example 32-1: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.06; MS(ESI, Pos.):495(M+Na)+.; 1 H-NMR(CD3OD):δ 7.42-7.47, 7.31-7.37, 7.23-7.28, 7.09, 6.94, 5.44-5.54, 4.92-5.01, 4.49-4.52, 4.34-4.38, 3.84-3.92, 2.85-3.03, 2.67-2.82, 2.14-2.22, 1.84-1.93, 1.64-1.82.

[0394] Example 32-2: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-[(1E,3ξ)-3-hydroxy-6-methoxy-4-methylene-1-hexen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.102; MS(ESI, Pos.):407(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.43-7.49, 6.94, 5.66-5.73, 5.54-5.62, 5.17, 4.94, 4.58, 4.41-4.45, 3.91-3.99, 3.55, 3.01-3.09, 2.77-2.98, 2.28-2.42, 2.17-2.26, 1.83-2.04.

[0395] Example 32-3: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-(3-thienyl)-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.181; MS(ESI, Pos.):487(M+Na)+,447(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.42-7.48, 7.29-7.33, 7.13-7.15, 7.07-7.10, 6.93, 5.50-5.57, 5.28-5.36, 4.33-4.38, 4.15, 3.82-3.90, 2.84-3.01, 2.62-2.79, 2.13-2.21, 1.59-1.85, 1.33.

[0396] Example 32-4: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.163; MS(ESI, Pos.):457(M+H-H2O)+,421(M+H-H2O-HCl)+.; 1H-NMR(CD3OD):δ 7.43-7.49, 7.34-7.40, 7.20-7.26, 7.06-7.10, 6.97-7.03, 6.93-6.97, 5.63-5.71, 5.29-5.36, 4.32-4.37, 4.05, 3.81-3.89, 2.95-3.06, 2.83-2.92, 2.68-2.81, 2.13-2.22, 1.73-1.88, 1.59-1.71, 1.00-1.07, 0.67-0.83.

[0397] Example 32-5: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-[3-(4-fluorophenyl)-3-oxetanyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.078; MS(ESI, Pos.):513(M+Na)+.; 1 H-NMR(CD3OD):δ 7.43-7.49, 7.04-7.13, 6.95, 5.46-5.56, 4.90-4.99, 4.51-4.55, 4.36-4.40, 3.84-3.92, 2.86-3.04, 2.69-2.84, 2.15-2.22, 1.68-1.94.

[0398] Example 32-6: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-hydroxy-3-[(2ξ)-2-phenyl-2-oxetanyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid [ka] HPLC retention time (min): 1.097; MS(ESI, Pos.):455(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.41-7.51, 7.31-7.38, 7.23-7.29, 6.94, 5.42-5.51, 4.58-4.64, 4.42-4.49, 4.33-4.38, 4.22-4.25, 3.84-3.91, 3.12-3.20, 2.85-3.01, 2.65-2.79, 2.14-2.21, 1.62-1.90.

[0399] Example 32-7: (1R,2R,3aS,10aR)-2-chloro-1-[(1E,3ξ)-3-(2,3-dihydro-1-benzofuran-3-yl)-3-hydroxy-1-propen-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.102; MS(ESI, Pos.):481(M+Na)+.; 1 H-NMR(CD3OD):δ 7.43-7.50, 7.28-7.39, 7.11, 6.96, 6.93, 6.78-6.85, 6.69-6.74, 5.62-5.71, 5.50-5.58, 5.33-5.41, 4.46-4.61, 4.30-4.41, 4.20, 3.82-3.97, 3.66-3.72, 3.55, 2.62-3.03, 2.13-2.26, 1.88-1.99, 1.70-1.86, 1.56.

[0400] Example 32-8: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-[(2ξ)-2-(4-fluorophenyl)-2-oxetanyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid HPLC retention time (min): 1.114; MS(ESI, Pos.):473(M+H-H2O)+.; 1H-NMR(CD3OD):δ 7.40-7.45, 7.32-7.37, 7.05-7.11, 6.93, 5.43-5.53, 4.57-4.63, 4.43-4.49, 4.34-4.38, 4.24-4.26, 3.84-3.91, 3.11-3.20, 2.86-3.02, 2.66-2.80, 2.15-2.22, 1.63-1.92.

[0401] Example 33: (1R,2R,3aS,10aR)-2-chloro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the corresponding aldehyde instead of the compound prepared in Reference Example 9, and the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 26, and by subjecting the same procedure as in Example 25, the title compound exhibiting the following physical properties was obtained. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, and by subjecting the same procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 73 → Reference Example 77 → Reference Example 81 → Reference Example 82 → Reference Example 83 → Reference Example 84. HPLC retention time (min): 1.05; MS(ESI, Pos.):439(M-OH)+; 1 H-NMR(DMSO-d6):δ 12.85, 7.50-7.54, 7.38, 7.29-7.35, 7.21-7.29, 7.05-7.12, 5.53-5.60, 5.19-5.27, 4.97, 4.36, 3.90-4.01, 2.72-2.93, 1.97-2.04, 1.73-1.81, 1.47-1.62, 0.93-1.03, 0.64-0.71, 0.54-0.60.

[0402] Example 34: (1R,2R,3aS,10aR)-2-chloro-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid The title compound exhibiting the following physical properties was obtained by using the corresponding aldehyde instead of the compound prepared in Reference Example 9, and the corresponding phosphonate instead of the compound prepared in Reference Example 26, and performing the same procedure as in Example 25. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, and performing the same procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 73 → Reference Example 77 → Reference Example 81 → Reference Example 82 → Reference Example 83 → Reference Example 84. The corresponding phosphonate was prepared by using iodobenzene instead of 1,3-difluoro-2-iodobenzene and performing the same procedure as in Reference Example 28 → Reference Example 29. HPLC retention time (min): 0.97; MS(ESI, Pos.):431(M-OH)+.; 1 H-NMR(DMSO-d6):δ 7.50-7.59, 7.44, 7.29, 5.99, 5.58-5.69, 4.50-4.60, 4.42-4.48, 4.04-4.13, 2.90-3.02, 2.69-2.88, 2.59-2.64, 2.04-2.12, 1.87-1.96, 1.58-1.74.

[0403] Example 35: (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 84 instead of the compound prepared in Reference Example 40, and subjecting it to the same objective procedure as in Reference Example 48 → Reference Example 49 → Example 11, the title compound exhibiting the following physical properties was obtained. HPLC retention time (min): 1.194; MS(ESI, Pos.):459(M+H-H2O)+.; 1 H-NMR(CD3OD):δ 7.40-7.46, 6.92, 5.69-5.79, 5.30-5.39, 4.42, 3.88, 3.85-3.94, 3.01-3.09, 2.71-2.98, 2.34-2.50, 2.28, 2.16-2.24, 1.79-2.01, 1.71, 1.21.

[0404] Reference Example 85: Methyl (1S,2R,3aS,10aR)-2-hydroxy-5-methyl-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate The title compound was obtained by using the compound prepared in Reference Example 39 instead of the compound prepared in Reference Example 8, and subjecting it to the same procedure as in Reference Example 73.

[0405] Reference Example 86: Methyl (1S,2R,3aS,10aR)-2-methoxy-5-methyl-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-Hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate To the compound (2.01 g) prepared in Reference Example 85, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) and THF (4 mL) were added and dissolved, and the solution was cooled to -50°C. To this solution, a solution of sodium tert-butoxide (1.06 g) in THF (1 mL) was added over 10 minutes, and then iodomethane (0.345 mL) was added and the mixture was stirred at -10°C for 2 hours. Ice-cooled 1N hydrochloric acid aqueous solution was added to the reaction mixture and extracted with n-hexane:ethyl acetate (3:1). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1) to obtain the title compound (1.50 g) exhibiting the following physical properties. 1 H-NMR(CDCl3):δ 7.64-7.73, 7.47, 7.33-7.45, 6.94, 4.06-4.18, 3.85-3.94, 3.74-3.80, 3.36, 3.03, 2.42-2.55, 2.33, 2.19-2.27, 2.12, 1.82-1.93, 1.62-1.72, 1.04-1.08.

[0406] Reference Example 87: Methyl (1R,2R,3aS,10aR)-1-formyl-2-methoxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate By using the compound prepared in Reference Example 86 instead of the compound prepared in Reference Example 7, and subjecting it to the same procedure as in Reference Example 8 → Reference Example 9, the title compound exhibiting the following physical properties was obtained. 1 H-NMR(CDCl3):δ 9.94, 7.51, 6.97, 4.09-4.18, 3.87, 3.40, 3.28-3.36, 3.13-3.22, 2.56-2.65, 2.47, 2.31-2.43, 2.20-2.27, 1.94-2.06, 1.78-1.88.

[0407] Example 36: (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-methoxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid By using the compound prepared in Reference Example 87 instead of the compound prepared in Reference Example 76, and the corresponding phosphonate instead of the compound prepared in Reference Example 26, and subjecting the mixture to the same procedure as in Example 25, the title compound exhibiting the following physical properties was obtained. The corresponding phosphonate was prepared by using methyl 1-(4-fluorophenyl)cyclobutane carboxylate (CAS number: 1090553-79-9) instead of the compound prepared in Reference Example 10, and subjecting the mixture to the same procedure as in Reference Example 11. HPLC retention time (min): 1.206; MS(ESI, Pos.): 503(M+Na)+.; 1 H-NMR(CD3OD):δ 7.45-7.49, 7.13-7.18, 6.97-7.04, 5.48-5.55, 5.32-5.39, 4.26, 4.04-4.07, 3.60-3.67, 3.01-3.08, 2.73-2.82, 2.43-2.59, 2.42, 2.26-2.40, 1.93-2.10, 1.75-1.88, 1.62.

[0408] Example 37: (1R,2R,3aS,10aR)-1-[...

Claims

1. General formula (I) 【Chemistry 1】 [In the formula, R 1 COOH, COOR 11 CONHSO 2 R 12 Or it represents tetrazolyl, R 11 This represents C1-6 alkyl, R 12 represents a C1-6 alkyl or phenyl, and the phenyl may be substituted with 1 to 5 (1) halogens or (2) C1-4 alkyls. X 1 , X 2 and X 3 each independently represents N, CH or CR 21 and represents Multiple R 21 These are, independently, (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, and (4) -(CH 2 ) t - Represents a vinyl which may be substituted with one to three halogens, (5) a C3-4 saturated carbon ring, t represents an integer of 0 or 1, 【Chemistry 2】 teeth, 【Transformation 3】 This represents, R 6 (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4)-(CH 2 ) q - represents a saturated carbon ring (C3-4), q represents an integer of 0 or 1, p represents an integer between 0 and 3. Multiple R 6 These may, together with the carbon atoms to which they are bonded, form a C3-4 saturated carbon ring which may be substituted with 1 to 6 halogens. Y represents an oxygen atom or a sulfur atom. R 2 and R 3 Each of these independently represents (1) a hydrogen atom, (2) a halogen, (3) a C1-4 alkyl group, or (4) a C1-4 haloalkyl group. R 2 and R 3 Together with the bonded carbon atom, it may form a C3-4 saturated carbon ring which may be substituted with 1 to 6 halogens. Z is CHR 10 , or represents an oxygen atom, R 10 This represents a hydrogen atom, halogen, hydroxyl group, or methoxy group. L is -CH 2 -----CHR L1 -, -CR L2 R L3 -, or -C (=CH 2 ) represents, R L1 This represents (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) C2-4 alkenyl, (5) C2-4 haloalkenyl, (6) C2-4 alkynyl, or (7) C2-4 haloalkynyl. R L2 and R L3 Each of these independently represents (1) a halogen, (2) a C1-4 alkyl, (3) a C1-4 haloalkyl, (4) a C2-4 alkenyl, (5) a C2-4 haloalkenyl, (6) a C2-4 alkynyl, (7) a C2-4 haloalkynyl, or (8) a hydroxyl group. R L2 and R L3 Together with the bonded carbon atom, it may form (1) a C3-6 saturated carbon ring which may be substituted with 1 to 10 halogens, or (2) a 3-6 member saturated heteroring which may be substituted with 1 to 8 halogens. R 4 (1) 1 to 5 R 41 (2) C3-7 alkyl groups which may be substituted with (2) 1-5 R 42 (3) C3-7 alkenyls which may be substituted with (4) 1-5 R 43 C3-7 alkynyl which may be substituted, (4) 1-5 R 44 A C2-6 alkoxy which may be substituted with (5) Cycl 1 This represents, R 41 , R 42 , R 43 , and R 44 Each of these independently represents (1) a halogen, (2) a C3-6 carbon ring, or (3) a 3-6 membered heteroring, and the C3-6 carbon ring and the 3-6 membered heteroring may be substituted with 1 to 10 (1) halogens or (2) C1-2 alkyl groups. Cycle 1 (1) 1 to 5 R 51 (2) A C5-10 carbon ring which may be substituted with, or 1-5 R 52 Represents a 5- to 10-membered heteroring which may be substituted with R 51 and R 52 Each of these independently represents (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) C2-4 alkenyl, (5) C2-4 haloalkenyl, (6) C2-4 alkynyl, (7) C2-4 haloalkynyl, (8) C1-4 alkoxy, (9) C1-4 haloalkoxy, (10) hydroxyl group, (11) C3-6 saturated carbon ring, or (12) 3-6 membered saturated heterocycle. R L1 and R 51 Together with the bonded carbon atom, it may form (1) a C3-6 saturated carbon ring, or (2) a 3-6 member saturated heteroring. R 5 This represents a hydrogen atom or a hydroxyl group. Multiple R 6 , R 41 , R 42 , R 43 , R 44 , R 51 , and R 52 They can be the same or different. 【Chemistry 4】 The symbol represents a single bond or a double bond, but only adjacent bonds. 【Transformation 5】 They do not form double bonds at the same time. 【Transformation 6】 This indicates that it is connected to the other side of the paper (i.e., in an α configuration). 【Transformation 7】 This indicates that the elements are joined on the front side of the page (i.e., in a β configuration). In the formula, bonded to the chiral atom, 【Transformation 8】 Unless otherwise specified, this indicates an α configuration, a β configuration, or a mixture of any ratio thereof. A preventive and / or therapeutic agent for kidney disease containing the compound indicated by or a salt thereof.

2. X 1 , X 2 and X 3 However, each independently, CH or CR 21 The agent according to claim 1.

3. The agent according to claim 1 or 2, wherein Y is an oxygen atom.

4. R 4 However, 1 to 3 R 41 C3-7 alkyl, which may be substituted with, 1-3 R 42 C3-7 alkenyls, or Cyclones, which may be substituted with 1 The agent according to any one of claims 1 to 3.

5. Z is CHR 10 And R 10 The agent according to any one of claims 1 to 4, wherein is a hydroxyl group.

6. R 1 The agent according to any one of claims 1 to 5, wherein is COOH.

7. General formula (I) is general formula (I-3) 【Chemistry 9】 [In the formula, L 10 Ha-CHR L1 - or -CR L2 R L3 - represents R 4a This is 1 to 3 R 41 C3-7 alkyl, which may be substituted with, 1-3 R 42 C3-7 alkenyls, or Cyclones, which may be substituted with 1 The agent according to claim 1, represented by ], where the other symbols have the same meaning as in claim 1.

8. A compound represented by general formula (I) or a salt thereof, (1) (1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (2) (1R,2R,3aS,10aR)-5-fluoro-1-[(1E)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (3) (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (4) (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,5-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (5) (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-4-(2,6-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (6) (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (7) (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-ethyl-3-hydroxy-7-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (8) (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (9) (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (10) (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4ξ)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (11) (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (12) (1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (13) (1R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (14) (1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-6-methoxy-4-methylene-1-hexen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (15) (1R,3aS,10aR)-5-chloro-1-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (16) (1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (17) (1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-pentenyl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (18) (1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (19) (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-[3-(2-fluorophenyl)-3-oxetanyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (20) (1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-hydroxy-3-[(2ξ)-2-phenyl-2-oxetanyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (21) (1R,3aR,10aR)-1-[(1E,3ξ,4S)-3-hydroxy-4-methyl-1-octen-1-yl]-5-methyl-1,3,3a,9,10,10a-hexahydrofl[3,4-b][1]benzooxepin-6-carboxylic acid, (22) (1R,3aR,10aR)-1-[(1E,3ξ)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen-1-yl]-5-methyl-1,3,3a,9,10,10a-hexahydrofl[3,4-b][1]benzooxepin-6-carboxylic acid, (23) (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or (24) (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3R)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, The agent according to claim 1, or a salt thereof.

9. The agent according to any one of claims 1 to 8, wherein the kidney disease is chronic kidney disease.

10. The agent according to claim 9, wherein the chronic kidney disease is diabetic nephropathy, nephrosclerosis, IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative glomerulonephritis, lupus nephritis, minimal change nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, Alport syndrome, or polycystic kidney disease.

11. The agent according to any one of claims 1 to 8, wherein the kidney disease is acute kidney injury.

12. The agent according to claim 11, wherein the acute kidney injury is acute kidney injury associated with organ surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis, contrast-induced nephropathy, or drug-induced kidney injury.

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