Tricyclic compounds

Abstract

Invention details;

Description

tricyclic compound

[0001] The present disclosure provides a compound of the following general formula (I): (wherein all symbols have the same meanings as defined below) or a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention).

[0002] Prostaglandins are known as metabolic products in the arachidonic acid cascade, and their actions are known to have cytoprotective effects, uterine contraction, analgesic effects, promotion of gastrointestinal peristalsis, stimulating effects, gastric acid secretion suppression, hypotensive effects, diuretic effects, etc. It has also been found that there are subtypes of PGE (prostaglandin E) receptors, each with a different role. Currently known subtypes are roughly divided into four, called EP1, EP2, EP3, and EP4 (Non-Patent Document 1). Meanwhile, Non-Patent Document 2 and Non-Patent Document 3, which relate to tricyclic compounds, are known.

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

[0004] An object of the present invention is to provide a compound having EP3 agonist activity.

[0005] As a result of extensive investigations to solve the above problems, the present inventors have found that the following compounds have potent EP3 agonist activity.

[0006] The present invention has the following aspects, for example: [1] General formula (I) [In the formula, R 1 COOH, COOR 11 , CONHSO2R 12 or tetrazolyl, R 11 represents C1-6 alkyl, R 12represents C1-6 alkyl or phenyl, and the phenyl may be substituted with 1 to 5 (1) halogen or (2) C1-4 alkyl; X 1 , X 2 and X 3 are each independently N, CH, or CR 21 represents a plurality of R 21 are each independently (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4) —(CH2) t -(C3-4 saturated carbocyclic ring), or (5) vinyl optionally substituted with 1 to 3 halogens, t represents an integer of 0 or 1, teeth, represents R 6 is (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4) —(CH2) q -(C3-4 saturated carbocyclic ring), q represents an integer of 0 or 1, p represents an integer of 0 to 3, and a plurality of R 6 may be taken together with the carbon atom to which they are attached to form a C3-4 saturated carbocyclic 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 independently represents (1) a hydrogen atom, (2) a halogen atom, (3) a C1-4 alkyl group, or (4) a C1-4 haloalkyl group; R 2 and R 3 may be taken together with the carbon atom to which it is attached to form a C3-4 saturated carbocyclic ring optionally substituted with 1 to 6 halogens, and Z is CHR 10 or an oxygen atom, R 10 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a methoxy group; L represents -CH2-, -CHR L1 -, -CR L2 R L3 - or -C(=CH2)-, R L1 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 RL3 each 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, or (8) a hydroxyl group, or R L2 and R L3 may be taken together with the carbon atom to which it is attached to form (1) a C3-6 saturated carbocyclic ring optionally substituted with 1 to 10 halogens, or (2) a 3- to 6-membered saturated heterocyclic ring optionally substituted with 1 to 8 halogens, 4 (1) 1 to 5 R 41 (2) 1 to 5 R 42 (3) C3-7 alkenyl optionally substituted with 1 to 5 R 43 (4) a C3-7 alkynyl optionally substituted with 1 to 5 R 44 (5) C2-6 alkoxy optionally substituted with Cyc 1 or (6) —O-Cyc 1 represents R 4 1 to 5 R 41 When R represents a C3-7 alkyl optionally substituted by R, one carbon atom in the C3-7 alkyl may be replaced by an oxygen atom; 41 , R 42 , R 43 , and R 44 each independently represents (1) a halogen, (2) a C3-6 carbocyclic ring, or (3) a 3- to 6-membered heterocyclic ring, and the C3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are optionally substituted with 1 to 10 (1) halogens or (2) C1-2 alkyls; Cyc 1 (1) 1 to 5 R 51 or (2) a C5-10 carbocyclic ring optionally substituted with 1 to 5 R 52 represents a 5- to 10-membered heterocycle optionally substituted by R 51 and R 52each 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, (11) C3-6 saturated carbocycle, or (12) 3- to 6-membered saturated heterocycle; R L1 and R 51 may form, together with the carbon atom to which it is attached, (1) a C3-6 saturated carbocyclic ring, or (2) a 3- to 6-membered saturated heterocyclic ring, 5 represents a hydrogen atom or a hydroxyl group, and a plurality of R 6 , R 41 , R 42 , R 43 , R 44 , R 51 , and R 52 may be the same or different, represents a single bond or a double bond, provided that adjacent does not have a double bond at the same time, indicates bonding to the other side of the paper (i.e., α-configuration), represents bonding to the front side of the paper (i.e., β configuration), and in the formula, represents bonding to an asymmetric atom, Unless otherwise specified, X represents an α-configuration, a β-configuration, or a mixture thereof in any ratio.] or a salt thereof. 1 , X 2 and X 3 are each independently CH or CR 21 [3] The compound or salt thereof according to [1], wherein Y is an oxygen atom. [4] R 4 But 1 to 3 R 41 C3-7 alkyl optionally substituted with 1 to 3 R 42 C3-7 alkenyl optionally substituted with Cyc 1 [5] The compound or salt thereof according to any one of [1] to [3], wherein Z is CHR 10 and R 10[6] The compound or salt thereof according to any one of [1] to [4], wherein R is a hydroxyl group. 1 [7] The compound or salt thereof according to any one of [1] to [5], wherein the general formula (I) is the general formula (I-3) [In the formula, L 10 Ha-CHR L1 -or-CR L2 R L3 represents -, and R 4a is 1 to 3 R 41 C3-7 alkyl optionally substituted with 1 to 3 R 42 C3-7 alkenyl optionally substituted with Cyc 1and other symbols have the same meanings as above.], The compound or salt thereof according to [1], [8] The compound represented by the 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-penten-yl]-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-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,The compound or salt thereof according to [1], which is 10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or a salt thereof. [9] A pharmaceutical composition comprising the compound or salt thereof according to any one of [1] to [8].

[10] An EP3 agonist comprising the compound or salt thereof according to any one of [1] to [8].

[11] The pharmaceutical composition according to [9] or the EP3 agonist according to

[10] , for use in the prevention and / or treatment of myocardial infarction, dysuria, and glaucoma.

[12] An agent for the prevention and / or treatment of kidney disease, comprising the compound or salt thereof according to any one of [1] to [8].

[13] The agent according to

[12] , wherein the kidney disease is chronic kidney disease.

[14] The agent according to

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

[15] The agent according to

[12] , wherein the renal disease is acute kidney injury.

[16] The agent according to

[15] , 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 nephropathy, or drug-induced nephropathy.

[17] A method for preventing and / or treating kidney disease, comprising administering an effective amount of the compound according to any one of [1] to [8] or a salt thereof to a mammal (preferably a patient in need thereof).

[18] The compound according to any one of [1] to [8] or a salt thereof for use in the prevention and / or treatment of renal disease.

[19] Use of the compound according to any one of [1] to [8] or a salt thereof for producing a prophylactic and / or therapeutic agent for renal disease.

[20] The pharmaceutical composition according to [9] or the EP3 agonist according to

[10] for use in the prevention and / or treatment of renal disease.

[21] The pharmaceutical composition according to [9] or the EP3 agonist according to

[10] for producing a prophylactic and / or therapeutic agent for renal disease.

[22] A method for producing the compound according to any one of [1] to [8] or a salt thereof, comprising the steps of: [In the formula, T 10 is a hydrogen atom or R 11 and T 20is a protecting group for a hydrogen atom or a hydroxyl group, and T 10 and T 20 is not a hydrogen atom, and the other symbols have the same meanings as defined in general formula (I).]

[23] The above production method, comprising the steps of: (A) subjecting a compound represented by general formula (I') (T 10 =R 11 , T 20 = hydrogen) to a hydrolysis reaction, 1 =COOH, Z=CHR 10 , R 10 = hydroxyl group) or a salt thereof.

[0007] The compound of the present invention has a strong EP3 agonist activity and is therefore useful for the prevention and / or treatment of renal diseases and other diseases that occur in relation to the EP3 receptor.

[0008] The present invention will be described in detail below. In the present invention, C1-6 alkyl includes linear or branched C1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, and isomers thereof. In the present invention, halogen includes fluorine, chlorine, bromine, and iodine. In the present invention, C1-4 alkyl includes linear or branched C1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isomers thereof. In the present invention, C1-2 alkyl means methyl or ethyl. In the present invention, C3-4 saturated carbocyclic ring includes, for example, cyclopropane and cyclobutane.

[0009] In the present invention, C1-4 haloalkyl refers to a linear or branched C1-4 alkyl group in which any hydrogen atom has been substituted with one or more halogen atoms, and examples thereof 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 isomers thereof.

[0010] In the present invention, C2-4 alkenyl includes straight-chain or branched-chain C2-4 alkenyl, such as ethenyl, propenyl, butenyl, and isomers thereof. In the present invention, C2-4 haloalkenyl refers to a straight-chain or branched-chain C2-4 alkenyl group in which any hydrogen atom has been substituted with one or more halogen atoms, and examples thereof include 1-fluoroethenyl, 2-fluoroethenyl, 2-chloroethenyl, trifluoroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl, and isomers thereof.

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

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

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

[0014] In the present invention, C3-7 alkyl includes linear or branched C3-7 alkyl, for example, 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 ...2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 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-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, Examples of alkyl ethers include butyl pentyl, 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 isomers thereof.

[0015] In the present invention, C3-5 alkyl includes linear or branched C3-5 alkyl, and examples thereof include propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and isomers thereof.

[0016] In the present invention, C3-7 alkenyl includes linear or branched C3-7 alkenyl, 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, 4-methylpentenyl, and the like. methylpentenyl, 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 isomers thereof.

[0017] In the present invention, C3-5 alkenyl includes straight-chain or branched-chain C3-5 alkenyl, and examples thereof include propenyl, butenyl, pentenyl, isopropenyl, isobutenyl, 1-methylbutenyl, 1-ethylpropenyl, 1,1-dimethylpropenyl, 1,2-dimethylpropenyl, 2-methylbutenyl, 3-methylbutenyl, and isomers thereof.

[0018] In the present invention, C3-7 alkynyl includes linear or branched C3-7 alkynyl, 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, 1-methyl hexynyl, 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 isomers thereof.

[0019] In the present invention, C2-6 alkoxy includes linear or branched C2-6 alkoxy groups, such as ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, and isohexyloxy. In the present invention, C1-4 alkoxy includes linear or branched C1-4 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, and isomers thereof. In the present invention, C1-4 haloalkoxy refers to a group in which any hydrogen atom of a straight-chain or branched-chain C1-4 alkoxy group has been substituted with one or more halogen atoms, and examples thereof 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.

[0020] In the present invention, examples of C3-6 carbocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

[0021] In the present invention, the term "3- to 6-membered heterocycle" refers to a 3- to 6-membered heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, 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, oxirane, oxetane, dihydrofuran, tetrahydrofuran, Dihydropyran, tetrahydropyran, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, and dithiane.

[0022] In the present invention, examples of a C5-10 carbocyclic ring include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, spiro[4.4]nonane, and spiro[4.5]decane.

[0023] In the present invention, the 5- to 10-membered heterocycle refers to a 5- to 10-membered heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and examples thereof include 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, thiadiazole, thiadiazole. thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazolidine triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydro thiazole, dihydrothiazole (thiazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),Dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiazine, tetrahydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroisobenzo Indazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxazole Sathian, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxaindane, 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.

[0024] In the present invention, examples of C5-6 carbocyclic rings include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene. In the present invention, examples of the 5- to 6-membered heterocycle include isoxazole, isothiazole, imidazole, imidazolidine, imidazoline, oxadiazine, oxadiazole, oxazine, oxazole, oxathiane, dioxane, dioxolane, dithiane, dithiolane, dihydroisoxazole, dihydroisothiazole, dihydrooxadiazine, dihydrooxadiazole, dihydrooxazine, dihydrooxazole, dihydrothiadiazine, dihydrothiazole, dihydrothiazine, dihydrothiazole, dihydrothiopyran, dihydrothiophene, dihydropyrazine, dihydropyran, dihydropyridine, dihydropyridazine, dihydropyrimidine, dihydrofurazan, dihydrofuran, thiadiazine, thiadiazole, thiazine, thiazole, thiopyran, thiophene, thiomorpholine, tetrazole, tetrazolidine, tetrazoline, tetrahydroisoxazole (isoxazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrooxadiazine, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxazole (oxazolidine), tetrahydrothiadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiazole (thiazolidine), tetrahydrothiopyran, tetrahydrothiophene, tetrahydropyrazine, tetrahydropyran, tetrahydropyridine, tetrahydropyridazine, tetrahydropyrimidine, tetrahydrofurazan, tetrahydrofuran, triazole, triazolidine, triazoline, perhydropyridazine, perhydropyrimidine, piperazine, piperidine, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyran, pyridine, pyridazine, pyrimidine, pyrrole, pyrrolidine, pyrroline, furazan, furan, and morpholine.

[0025] In the present invention, the following partial structures in each general formula are teeth, The partial structure may include, for example, Includes:

[0026] In the present invention, R 1 In the present invention, R is preferably COOH. 11 In the present invention, R is preferably C1-2 alkyl. 12 As for X, C1-6 alkyl is preferable, C1-2 alkyl is more preferable, and methyl is even more preferable. 1 As the hydroxyl group, CH or CR 21 is preferred, and CR 21 In the present invention, X 2 As the hydroxyl group, CH or CR 21 In the present invention, X is preferably 3 As the hydroxyl group, CH or CR 21 is preferred, and CH is more preferred. 21 is preferably (1) halogen, (2) C1-4 alkyl, or (3) vinyl, more preferably halogen or methyl.

[0027] In the present invention, the following partial structure in general formula (I) As for is preferred, is more preferred, is more preferred, is particularly preferred.

[0028] In the present invention, R 6 is preferably a C1-4 alkyl, 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 In the present invention, R is preferably a hydrogen atom. 3 In the present invention, Z is preferably a hydrogen atom. 10 In the present invention, R 10In the present invention, L is preferably a hydroxyl group. L1 -or-CR L2 R L3 - is preferred, and -CR L2 R L3 - is more preferable.

[0029] In the present invention, L is Also preferred are is more preferred.

[0030] 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 even more preferably methyl or ethyl. L2 is preferably (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4) hydroxyl group, more preferably C1-4 alkyl or hydroxyl group. L3 is preferably (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4) hydroxyl group, more preferably halogen or hydroxyl group. L2 and R L3 When the ring is formed together with the carbon atom to which it is bonded, the ring is preferably a C3-6 saturated carbocyclic ring, more preferably a C3-4 saturated carbocyclic ring, and even more preferably cyclobutane.

[0031] In the present invention, R 4 (1) 1 to 5 R 41 (2) 1 to 5 R 42 (3) C3-7 alkenyl optionally substituted with Cyc 1 is preferred. 4 (1) 1 to 3 R 41 (2) 1 to 3 R 42 (3) C3-7 alkenyl optionally substituted with Cyc 1 is preferred. 4 (1) 1 to 3 R 41(2) 1 to 3 R 42 (3) C3-5 alkenyl optionally substituted with Cyc 1 In the present invention, R 41 and R 42 are each independently preferably halogen.

[0032] In the present invention, Cyc 1 (1) 1 to 5 R 51 or (2) a C5-6 carbocyclic ring optionally substituted with 1 to 5 R 52 (1) a 5- or 6-membered heterocycle optionally substituted with 1 to 5 R 51 (2) phenyl optionally substituted with 1 to 3 R 52 or (3) a thiophene optionally substituted with 1 to 4 R 52 Pyridine optionally substituted with 1 to 5 R 51 Phenyl optionally substituted with 1 to 3 halogens is more preferred, and phenyl optionally substituted with 1 to 3 halogens is particularly preferred.

[0033] In the present invention, Cyc 1 As for (wherein r represents an integer of 0 to 5, and the other symbols have the same meanings as above) is also preferred, (In the formula, R 71 represents (1) halogen or (2) C1-4 alkyl, and R 72 represents (1) halogen or (2) C1-4 alkyl, and s represents an integer of 0 or 1.) is more preferred.

[0034] In the present invention, R 71 In the present invention, R 72 In the present invention, r is preferably an integer of 0 to 2. 51 is preferably (1) halogen, (2) C1-4 alkyl, or (3) C1-4 haloalkyl, and more preferably halogen. 52is preferably (1) halogen, (2) C1-4 alkyl, or (3) C1-4 haloalkyl, more preferably halogen.

[0035] In the present invention, an embodiment of the compound represented by general formula (I) is a compound represented by general formula (I-1): (wherein all symbols have the same meaning as defined above), and an embodiment of the compound represented by general formula (I-1) is a compound represented by general formula (I-2) (wherein all symbols have the same meaning as defined above), and an embodiment of the compound represented by general formula (I-2) is a compound represented by general formula (I-3) (In the formula, L 10 Ha-CHR L1 -or-CR L2 R L3 represents -, and R 4a is 1 to 3 R 41 C3-7 alkyl optionally substituted with 1 to 3 R 42 C3-7 alkenyl optionally substituted with Cyc 1 and the other symbols have the same meanings as above.

[0036] Another embodiment of the compound represented by general formula (I) is a compound represented by general formula (I-4): (wherein all symbols have the same meaning as defined above), and an embodiment of the compound represented by general formula (I-4) is a compound represented by general formula (I-5) (wherein all symbols have the same meaning as above). Another embodiment of the compound represented by general formula (I) is a compound represented by general formula (I-6): (wherein all symbols have the same meaning as defined above), and an embodiment of the compound represented by general formula (I-6) is a compound represented by general formula (I-7) (wherein all symbols have the same meanings as defined above).

[0037] In the present invention, certain embodiments of the compound represented by general formula (I) or a salt thereof include: (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-penten-yl]-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-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.

[0038] [Isomers] In the present invention, indicates bonding to the other side of the paper (i.e., α-configuration), indicates that the group is bonded to the front side of the paper (i.e., the β-configuration). Unless otherwise specified, represents an α-configuration, a β-configuration, or a mixture thereof in any ratio. indicates either the α-configuration or the β-configuration. The notation ξ in a chemical name indicates that the configuration of the substituent attached 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 AD McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by SJ Chalk. ISBN 0-9678550-9-8. https: / / doi.org / 10.1351 / goldbook.).

[0039] For example, the chemical names of Examples 7-3 and 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 (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, 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 aspect, 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, 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.

[0040] As will be apparent to those skilled in the art, other compounds of the present invention in which the configuration of a substituent bonded to an asymmetric atom is represented by ξ can be similarly interpreted. In the present invention, all isomers are encompassed. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene, and alkenylidene include straight-chain and branched-chain isomers. Furthermore, isomers (E, Z, cis, trans) in double bonds, rings, and fused rings, isomers due to the presence of asymmetric carbons, etc. (R, S, α, β configurations, enantiomers, diastereomers), optically active isomers with optical rotation (D, L, d, l), polar isomers (high polarity, low polarity) obtained by chromatographic separation, equilibrium compounds, rotational isomers, mixtures of these in any proportion, racemic mixtures, and tautomers are all encompassed by the present invention. Furthermore, the optically active compounds of the present invention may not only be 100% pure, but may also contain less than 50% of other optical isomers. In the present invention, all references to the compound of the present invention include the compound represented by general formula (I) etc., a salt thereof, a solvate (e.g., hydrate) thereof, an N-oxide thereof, or a co-crystal thereof, or a solvate (e.g., hydrate) of a salt of the compound represented by general formula (I) etc., or a co-crystal thereof.

[0041] The compounds represented by general formula (I) and the like can be converted into corresponding salts by known methods. The salts are preferably water-soluble. Furthermore, the salts are preferably pharmaceutically acceptable salts. Examples of such salts include salts of alkali metals (lithium, potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), salts of other metals (silver, zinc, etc.), ammonium salts (tetramethylammonium salts), salts of 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 -benzyl-2-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc.), acid addition salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, napadisilate, glucuronate, gluconate, etc.) and the like).

[0042] The compound represented by general formula (I) or a salt thereof may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvate is preferably low-toxic and water-soluble, and more preferably a hydrate. The compound represented by general formula (I) or a salt thereof can be converted into a solvate by a known method. The N-oxide of the compound represented by general formula (I) or a salt thereof refers to a compound in which the nitrogen atom of the compound represented by general formula (I) or a salt thereof is oxidized. The N-oxide of the compound represented by general formula (I) or a salt thereof may further be the above-mentioned alkali (earth) metal salt, ammonium salt, organic amine salt, or acid addition salt.

[0043] The compound represented by general formula (I) or a salt thereof may exist in the form of a co-crystal formed with a suitable co-crystal former. The co-crystal is preferably a pharmaceutically acceptable co-crystal formed with a pharmaceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different types of intermolecular interactions. A co-crystal may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include organic acids (such as malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, and isonicotinic acid), organic amines (such as imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, 4-(2-hydroxyethyl)morpholine, N-methyl-D-glucamine, glycine, histidine, and proline), and other organic compounds (such as caffeine and saccharin).

[0044] A prodrug of a compound represented by the general formula (I) or the like refers to a compound that is converted into a compound represented by the general formula (I) or the like in vivo by a reaction catalyzed by an enzyme, gastric acid, or the like. Examples of prodrugs of a compound represented by the general formula (I) or the like include, when the compound represented by the general formula (I) or the like has an amino group, compounds in which the amino group has been acylated, alkylated, or phosphorylated (for example, compounds in which the amino group of a compound represented by the general formula (I) or the like has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when the compound represented by the general formula (I) or the like has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group of a compound represented by the general formula (I) or the like has been acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); when the compound represented by general formula (I) etc. has a carboxy group, compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group of the compound represented by general formula (I) etc. is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidized compounds, etc.). These compounds can be produced by methods known per se. In addition, the prodrug of the compound represented by general formula (I) etc. may be a solvate. Furthermore, the prodrug of the compound represented by the general formula (I) etc. may be one that is converted into the compound represented by the general formula (I) etc. under physiological conditions as described in "Drug Development", Vol. 7, "Molecular Design", pp. 163-198, Hirokawa Publishing, 1990. Furthermore, the compound represented by the general formula (I) etc. may contain an isotope (e.g., 2 H. 3 H. 11 C. 13C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 35 S. 18 F. 36 Cl, 123 I, 125 It may be labeled with, for example, I.

[0045] [Method for Producing the Compound of the Present Invention] The compound of the present invention can be produced by appropriately modifying 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 general formula (I), the compounds represented by general formula (IA) (wherein all symbols have the same meanings as defined above) can be prepared according to the following reaction scheme 1. (wherein T represents a protecting group for a hydroxyl group, R 101 each independently represents C1-6 alkyl, and the other symbols have the same meanings as above.

[0046] In reaction scheme 1, reaction 1 is known, and can be carried out, for example, by reacting a compound represented by general formula (A1) with 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, a tertiary amine plus lithium chloride, etc.) at a temperature of −20 to 70° C. In Reaction Scheme 1, Reaction 2 is known and can be 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.) with a reducing agent (e.g., sodium borohydride, zinc borohydride, etc.) in the presence or absence of cerium chloride at −20 to 50° C. In addition, when selectively producing only one stereoisomer, Reaction 2 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 ((R)-2-methyl-CBS-oxazaborolidine and boron hydride-tetrahydrofuran complex or borane dimethyl sulfide complex, (S)-(−)-binaphthol and lithium aluminum hydride, etc.). In Reaction Scheme 1, the deprotection reaction of the protecting group is known and can be carried out by the following method. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenolysis, (4) deprotection reaction of a silyl group, (5) deprotection reaction using a metal, and (6) deprotection reaction using a metal complex.

[0047] These methods are specifically described below. (1) Deprotection by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane, etc.) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.), or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an aqueous solution thereof, or a mixture thereof, at 0 to 40° C. (2) Deprotection under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.) in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0 to 100° C. (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., an ether (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), an alcohol (e.g., methanol, ethanol, etc.), a benzene (e.g., benzene, toluene, etc.), a ketone (e.g., acetone, methyl ethyl ketone, etc.), a nitrile (e.g., acetonitrile, etc.), an amide (e.g., N,N-dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) under a hydrogen atmosphere at normal or elevated pressure or in the presence of ammonium formate, at 0 to 200°C. (4) The deprotection reaction of a silyl group is carried out, for example, in a water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40°C. Alternatively, the reaction may be carried out in, for example, an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.) at −10 to 100° C.(5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution having a pH of 4.2 to 7.2, or a mixture of such a solution with an organic solvent such as tetrahydrofuran) in the presence of zinc powder at 0 to 40°C, if necessary, under ultrasonic irradiation. (6) The deprotection reaction using a metal complex is carried out, for example, in an organic solvent (e.g., dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, or the like), water, or a mixed solvent thereof, in the presence of a trapping reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, or the like), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, or the like) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, or the like), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, or the like), using a metal complex (e.g., tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, or the like), at 0 to 40°C. In addition to the above, the deprotection reaction can also be carried out by, for example, the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014.

[0048] Examples of hydroxyl-protecting groups (including T in Reaction Scheme 1) include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, a 2-tetrahydropyranyl (THP) group, a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a t-butyldimethylsilyl (TBDMS) group, a t-butyldiphenylsilyl (TBDPS) group, an acetyl (Ac) group, a pivaloyl group, a benzoyl group, a p-phenylbenzoyl group, a benzyl (Bn) group, a p-methoxybenzyl group, an allyloxycarbonyl (Alloc) group, and a 2,2,2-trichloroethoxycarbonyl (Troc) group. Examples of protecting groups for amino groups include benzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), and 2-(trimethylsilyl)ethoxymethyl (SEM). Protective groups for hydroxy groups are preferably 2-tetrahydropyranyl (THP) or tert-butyldimethylsilyl (TBDMS). In addition to the above, other protecting groups for hydroxy groups may also be used, as long as they can be easily and selectively removed. For example, those described in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014, may be used.

[0049] Among the compounds represented by general formula (I), those represented by general formula (IB) (wherein all symbols have the same meaning as defined above) can be produced by subjecting a compound represented by general formula (IA) to hydrolysis. This hydrolysis (deprotection reaction of a carboxyl group) is known, and examples thereof include the alkaline hydrolysis described above. If necessary, this reaction may be followed by a known procedure to convert the compound into the desired salt or a solvate thereof (e.g., a hydrate).

[0050] The compound represented by general formula (A1) in Reaction Scheme 1 can be produced according to the following Reaction Scheme 2. (In the formula, T 1 represents a protecting group for a hydroxyl group, R 102 represents a hydrogen atom, phenyl or substituted phenyl (e.g., 4-fluorophenyl, etc.), R 103 is a halogen atom or COOR 11 The other symbols have the same meanings as above. 1 The protecting group for the hydroxyl group represented by is the same as that described above for the protecting group T.)

[0051] In Reaction Scheme 2, the compound represented by general formula (A7) can be produced by subjecting the compound represented by general formula (A6) to a protection reaction. For example, this is carried out in an organic solvent (e.g., DMF, etc.) using a base (e.g., imidazole, etc.) and a silane compound (e.g., trimethylsilane chloride (TESCl), tert-butyldimethylsilane chloride (TBSCl), tert-butyldiphenylsilane chloride (TBDPSCl)), etc.) at a temperature of −100 to 50° C. In Reaction Scheme 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 in an organic solvent (e.g., toluene, ethanol, tetrahydrofuran, hexane, etc.) using a reducing agent (e.g., diisobutylaluminum hydride (DIBAL), lithium aluminum hydride, etc.) at a temperature of −78 to 80° C.

[0052] In Reaction Scheme 2, Reaction 3 is known and is carried out, for example, in an organic solvent (e.g., anhydrous toluene, dimethoxyethane, tetrahydrofuran, etc.) using a Wittig reagent (e.g., methyltriphenylphosphonium bromide, etc.) in the presence of a base (e.g., lithium hexamethyldisilazane (LHMDS), lithium diisopropylamide (LDA), butyllithium, potassium tert-butoxide, sodium hydride, etc.) at a temperature of −78 to 50° C. In Reaction Scheme 2, Reaction 4 is known and is carried out, for example, in an organic solvent (e.g., anhydrous toluene, benzene, 1,4-dioxane, dimethoxyethane, methanol, etc.) using a ruthenium catalyst (e.g., carbonylchlorohydridotris(triphenylphosphine)ruthenium(II), metathesis catalyst, etc.) or a cobalt catalyst (e.g., Jacobsen catalyst, etc.) at a temperature of 20 to 100° C. In Reaction Scheme 2, the Mitsunobu reactions of Reactions 5 and 7 are known and can be carried out, for example, in an organic solvent (e.g., dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene) at 0 to 100°C 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 (cyanomethylenetributylphosphorane, cyanomethylenetrimethylphosphorane). In Reaction Scheme 2, Reaction 6 is known and can be carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide), or a carbonate (e.g., sodium carbonate, potassium carbonate), or an aqueous solution thereof, or a mixture thereof, at a temperature of 0 to 100°C.

[0053] In Reaction Scheme 2, Reaction 8 is known and is carried out, for example, in an organic solvent (e.g., toluene, dichloromethane, dichloroethane, etc.) using a metathesis catalyst (e.g., 2,6-diisopropylphenylimideneophyllidenemorbidenium(VI) bis(tert-butoxide), 2,6-diisopropylphenylimideneophyllidenemorbidenium(VI) bis(hexafluorotert-butoxide), etc.) at a temperature of 20 to 80°C. In Reaction Scheme 2, Reaction 9 is known and can be carried out, for example, in an organic solvent (e.g., toluene, THF, DMF, etc.) in the presence of a nucleophile (e.g., alcohol, etc.) and a palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium (Pd(P(t-Bu)), tetrakis(triphenylphosphine)palladium (Pd(PPh), bis(triphenylphosphine)palladium dichloride (PdCl(PPh))), etc.) under a carbon monoxide stream at a temperature of 50 to 100°C. In Reaction Scheme 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, for example, hydrogen gas at 0°C to 80°C under atmospheric or elevated pressure, or (2) using a reducing agent (e.g., sodium borohydride, etc.) in an organic solvent (e.g., methanol, ethanol, etc.) in the presence or absence of an additive such as cerium chloride at -40 to 80°C.

[0054] In Reaction Scheme 2, the compound represented by general formula (A18) can be produced by subjecting the compound represented by general formula (A17) to the above-mentioned deprotection reaction. In Reaction Scheme 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) a method using Dess-Martin reagent, and (3) a method using TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) reagent.

[0055] As an example, a method using DMSO oxidation will be specifically described. For example, an 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 oxidant (e.g., dimethyl sulfoxide (DMSO)), followed by further reaction with a tertiary amine (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, diazabicyclo[5.4.0]undec-7-ene, etc.) at −78 to 40° C. In each reaction in this specification, a compound having a chiral center may be subjected to optical resolution by a conventional method (e.g., a method using an optical resolution column) to separate the desired optical isomer. In Reaction Scheme 2, Reactions 4 and / or 9 may be omitted as appropriate depending on the compound to be obtained and the intermediates used.

[0056] Among the compounds represented by general formula (I), those represented by general formula (IC) (wherein all symbols have the same meanings as defined above) can be prepared according to the following reaction scheme 3. (In the formula, all symbols have the same meaning as defined above.) In Reaction Scheme 3, Reaction 11 is known, and can be carried out, for example, by reacting a compound represented by general formula (A1) with 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 Scheme 3, the deprotection reaction of the protecting group is known, and can be carried out by the above-mentioned deprotection reaction method.

[0057] Among the compounds represented by general formula (I), those represented by general formula (ID) (wherein all symbols have the same meaning as defined above) can be produced by subjecting a compound represented by general formula (IC) to hydrolysis. This hydrolysis (deprotection reaction of a carboxyl group) is known, and examples thereof include the alkaline hydrolysis described above. If necessary, this reaction may be followed by a known method to convert the compound into a desired salt.

[0058] In each reaction herein, the compounds used as starting materials, such as compounds represented by general formula (A2), general formula (A6), general formula (A10-1), general formula (A13), and general formula (A19), are known or can be easily produced by known methods. In each reaction herein, reactions involving heating can be carried out using a water bath, oil bath, sand bath, or microwave, as will be apparent to those skilled in the art. In each reaction herein, a solid-phase-supported reagent supported on a polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may also be used, as appropriate. In each reaction herein, the reaction product can be purified by conventional purification means, 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 carried out for each reaction, or after completion of several reactions.

[0059] Specific embodiments of the method for producing the compound of the present invention include the following: A method for producing a compound represented by general formula (I) or a salt thereof, comprising the following steps: [In the formula, T 10 is a hydrogen atom or R 11 and T 20 is a protecting group for a hydrogen atom or a hydroxyl group, and T 10 and T 20 is not a hydrogen atom, and the other symbols have the same meanings as defined in general formula (I). 20 The protecting group for the hydroxyl group represented by is the same as that described above for the protecting group T. 10 is R 11 The hydrolysis reaction (deprotection reaction of the carboxyl group) in this case is known, and examples thereof include alkaline hydrolysis. 20When is a protecting group for a hydroxyl group, the deprotection reaction can be carried out by a known method. Examples include (1) a deprotection reaction by alkaline hydrolysis, (2) a deprotection reaction under acidic conditions, (3) a deprotection reaction by hydrogenolysis, (4) a deprotection reaction of a silyl group, (5) a deprotection reaction using a metal, and (6) a deprotection reaction using a metal complex. Details are described above. Furthermore, if necessary, these reactions may be followed by a conversion operation to the desired salt by a known method. In the above production method, the hydrolysis reaction is carried out by: (A) a compound of general formula (I') (T 10 =R 11 , T 20 = hydrogen atom) to a hydrolysis reaction, in which case the compound of general formula (I) (R 1 =COOH, Z=CHR 10 , R 10 = hydroxyl group) or a salt thereof can be produced.

[0060] [Toxicity] The toxicity of the compound of the present invention is sufficiently low, and it can be used safely as a pharmaceutical.

[0061] [Application to Pharmaceuticals] The compound of the present invention can be used as an EP3 agonist having EP3 agonist activity. Because the compound of the present invention has EP3 agonist activity, it is considered to be useful for the treatment and / or prevention of diseases such as renal diseases (e.g., chronic kidney disease or acute kidney injury), myocardial infarction, dysuria, and glaucoma. The compound of the present invention is useful, for example, for the treatment and / or prevention of renal diseases. Some embodiments of renal diseases include chronic kidney disease and acute kidney injury. In a preferred embodiment, chronic kidney diseases include, for example, chronic kidney disease due to lifestyle-related diseases, chronic glomerulonephritis, nephrotic syndrome, and hereditary kidney diseases. Among these, chronic kidney diseases due to lifestyle-related diseases include diabetic nephropathy and nephrosclerosis. Examples of chronic glomerulonephritis include IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative nephritis, and lupus nephritis. Examples of nephrotic syndrome include minimal change nephrotic syndrome, focal segmental glomerulosclerosis, and membranous nephropathy. Examples of hereditary kidney diseases include Alport syndrome and polycystic kidney disease, including autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease.

[0062] Other embodiments of chronic kidney disease include, for example, chronic signs of renal failure and / or renal insufficiency, renal hypoperfusion, hypertensive nephrosclerosis, immunological nephropathy, and pyelonephritis. Other embodiments of chronic kidney disease include, for example, dehydration due to forced diuresis after partial nephrectomy, uncontrolled elevated blood pressure associated with malignant hypertension, urinary tract obstruction and chronic renal insufficiency due to infection and amyloidosis and systemic diseases, such as rheumatoid immunological systemic disorders, chronic renal insufficiency in lupus erythematosus, and chronic renal insufficiency due to renal artery stenosis, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, radiographic contrast-induced and drug-induced chronic interstitial nephropathy, metabolic syndrome, and dyslipidemia. In a preferred embodiment, chronic kidney disease includes pathological symptoms and diseases caused by chronic kidney disease. Examples of pathological symptoms and diseases caused by chronic kidney disease include obstructive uropathy, tubulointerstitial damage, glomerular and tubular proteinuria, renal edema, hematuria, abnormally reduced creatinine and / or water excretion, abnormally elevated blood levels of urea, nitrogen, potassium and / or creatinine, changes in the activity of renal enzymes such as glutamyl synthetase, changes in urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, lesions of glomeruli and arterioles, renal tubular dilation, and hyperphosphatemia. In a preferred embodiment, examples of acute kidney injury include acute kidney injury accompanied by ischemia-reperfusion injury and drug-induced (antibacterial, anticancer drug, etc.) kidney injury. Among these, acute kidney injury associated 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 nephropathy. Other embodiments of acute kidney injury include partial nephrectomy, dehydration due to forced diuresis, uncontrolled elevated blood pressure associated with malignant hypertension, urinary tract obstruction and infections and amyloidosis and systemic diseases involving glomerular involvement, such as rheumatoid immunological systemic diseases, for example, those in lupus erythematosus, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, and radiographic contrast-induced and drug-induced acute interstitial kidney injury.The renal diseases to be treated and / or prevented using the compound of the present invention preferably include diabetic nephropathy, IgA nephropathy, Alport syndrome, and autosomal dominant polycystic kidney disease.

[0063] The compound of the present invention may be administered in combination with other drugs as a concomitant agent for the following purposes: 1) complementing and / or enhancing the preventive and / or therapeutic effects of the compound; 2) improving the kinetics and absorption of the compound, reducing the dosage, and / or 3) reducing the side effects of the compound. A concomitant agent containing the compound of the present invention and another drug may be administered in the form of a combined drug formulation containing both components in a single formulation, or in the form of separate formulations. Administration in these separate formulations includes simultaneous administration and staggered administration. Staggered administration may involve administering the compound of the present invention first and the other drug later, or may involve administering the other drug first and the compound of the present invention later. The administration methods for each drug may be the same or different. The diseases for which the concomitant agent provides therapeutic and / or preventive effects are not particularly limited, and may be any disease for which the therapeutic and / or preventive effects of the compound of the present invention can be complemented and / or enhanced. Furthermore, concomitant agents to be combined with the compound of the present invention include not only those discovered to date but also those to be discovered in the future.

[0064] In the present invention, the 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 typically formulated with a pharmaceutically acceptable carrier, such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, the term "pharmaceutically acceptable carrier" refers to a substance other than the active ingredient that is generally used in pharmaceutical formulations. Pharmaceutically acceptable carriers are preferably those that do not exhibit pharmacological activity at the dosage of the formulation, are harmless, and do not interfere with the therapeutic effect of the active ingredient. Pharmaceutically acceptable carriers 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 described in "Dictionary of Pharmaceutical Additives," published by Yakuji Nipposha in 2000 (edited by the Japan Pharmaceutical Additives Association) can be appropriately selected depending on the purpose.

[0065] When the compound of the present invention or a combination of the compound of the present invention and another drug is used for the above-mentioned purposes, it is usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered in the range of 1 ng to 1000 mg per dose per adult once to several times a day, or parenterally administered in the range of 0.1 ng to 10 mg per dose per adult once to several times a day, or continuously administered intravenously for 1 to 24 hours a day. Of course, as mentioned above, the dosage varies depending on various conditions, so that a smaller amount than the above-mentioned dosage may be sufficient, or an amount exceeding the above range may be necessary.

[0066] Oral preparations include, for example, liquid preparations for oral administration (e.g., elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for oral administration (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 (ophthalmic ointments, etc.)), ear drops, etc. These preparations may be controlled-release preparations such as immediate-release preparations and sustained-release preparations. These preparations can be prepared by known methods, such as those described in the Japanese Pharmacopoeia. Oral liquid preparations are prepared, for example, by dissolving, suspending, or emulsifying the active ingredient in a commonly used diluent (e.g., purified water, ethanol, or a mixture thereof). These liquid preparations may further contain wetting agents, suspending agents, emulsifiers, sweeteners, flavoring agents, fragrances, preservatives, buffers, etc. Oral solid preparations are prepared, for example, by mixing the active ingredient 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 then formulated according to conventional methods. If necessary, the substrate may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, etc.), or may be coated with two or more layers.

[0067] External preparations as parenteral agents are prepared by known methods or commonly used formulations. For example, ointments are prepared by triturating or dissolving the active ingredient in a base. The ointment base is selected from known or commonly used bases. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate esters, myristate esters, palmitate esters, stearate esters, oleate esters, etc.), waxes (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate esters, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified 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 may be used alone or in combination of two or more. The formulation may further contain humectants, preservatives, stabilizers, antioxidants, flavoring agents, etc. Parenteral injections include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent before use. Injections are used, for example, by dissolving, suspending, or emulsifying the active ingredient in a solvent. Examples of solvents that can be used include distilled water for injection, physiological saline, vegetable oils, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, the injection may contain stabilizers, solubilizers (e.g., glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, soothing agents, buffers, preservatives, antioxidants, isotonicity agents, pH adjusters, excipients, etc. These are sterilized in the final process or produced by aseptic procedures. Alternatively, sterile solid formulations, such as lyophilized products, can be produced and then dissolved in sterilized or sterile distilled water for injection or other solvents before use.

[0068] The present invention will be described in detail below with reference to examples, but is not limited thereto. The solvents in parentheses shown in chromatographic separations and TLC indicate the elution or development solvents used, and the ratios are by volume. The conditions used for LC / MS analysis in the following examples are as follows: Column: YMC Triart C18, 2.0 mm x 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:mobile phase B is listed): 0-0.10 min (95:5), 0.10-1.20 min (95:5 to 5:95), 1.20 min-1.50 min (5:95). The solvents used for the measurements are listed in parentheses in the NMR sections. The compound names used in this specification are generally determined using ACD / Name (registered trademark) from Advanced Chemistry Development, Inc., a computer program that determines names according to IUPAC rules, or are determined according to IUPAC nomenclature.

[0069] 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 Triphenylphosphine (10 g) and formic acid (1.5 mL) were added to a solution of (1S,2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-prop-1-enyl-4-tetrahydropyran-2-yloxy-2-cyclopentanol (CAS number: 1262874-63-4, 7.2 g) in tetrahydrofuran (hereinafter, THF) (5.8 mL), and the mixture was cooled to -30°C. Diethyl azodicarboxylate (18 mL) was added to the reaction solution, and the mixture was stirred under ice-cooling for 3 hours. The mixture was washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→90:10) to give the title compound (7.7 g) having the following physical properties: TLC: Rf 0.85 (hexane:ethyl acetate=2:1).

[0070] 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 produced in Reference Example 1 (7.7 g) in ethanol (50 mL) was added potassium carbonate (2.67 g), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was then filtered and washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure, diluted with ethyl acetate, and water was added, 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 purified by silica gel column chromatography (hexane:ethyl acetate=95:5→85:15) to give the title compound (6.0 g) having the following physical properties. TLC: Rf 0.60 (hexane:ethyl acetate=2:1).

[0071] 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. The mixture was cooled to 0°C, and a solution of 4-bromo-3-fluoro-2-hydroxy-benzaldehyde (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. To the reaction mixture, 1N aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. 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 give the title compound (1.1 g) having 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.

[0072] 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. To a solution of the compound (1.7 g) produced in Reference Example 2 and the compound (1.0 g) produced in Reference Example 3 in THF (17 mL) was added triphenylphosphine (1.7 g) and the mixture was cooled on ice. Diethyl azodicarboxylate (2.9 mL) was added to the reaction solution and 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 give the title compound (2.39 g) having 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.

[0073] 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 prepared in Reference Example 4 (2.39 g) 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)imidazol-2-ylidene][3-phenyl-1H-inden-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 give the title compound (2.21 g) having 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.

[0074] 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

[0043] Diisopropylamine (1.69 mL) was added to a solution of the compound produced in Reference Example 5 (2.06 g) in ethanol (12.4 mL) and dimethylformamide (hereinafter, 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 and poured into a cooled saturated aqueous ammonium chloride solution, followed by extraction 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 give the title compound (1.65 g) having 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.

[0075] 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 (1.65 g) produced in Reference Example 6 in ethanol (25.1 mL) was added 10% palladium on carbon (165 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was subjected to the next reaction without further purification. 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.

[0076] 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 solution of the crude product prepared in Reference Example 7 in THF (11.6 mL) was added a 1 M THF solution (4.8 mL) of tetrabutylammonium fluoride at room temperature, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then 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 give the title compound (1.20 g) having 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.

[0077] 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 Dimethyl sulfoxide (hereinafter, DMSO) (1 mL) and triethylamine (854 μL) were added to a solution of the compound produced in Reference Example 8 (500 mg) in dichloromethane (5 mL), 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. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (446 mg) having 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.

[0078] Reference Example 10: Methyl (2S)-2-(2,4-difluorophenyl)propanoate To a solution of (2S)-2-(2,4-difluorophenyl)propanoic acid (CAS number: 1630485-27-6, 6.50 g) in methanol (100 mL) was added dropwise a 2 M n-hexane solution (82.3 mL) of trimethylsilyldiazomethane at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 30 minutes. Acetic acid was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→83:17) to give the title compound (6.08 g) having 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.

[0079] Reference Example 11: Dimethyl [(3S)-3-(2,4-difluorophenyl)-2-oxobutyl]phosphonate To a solution of dimethyl methylphosphonate (7.85 g) in THF (50 mL), a 1.55 M n-butyllithium solution (38.9 mL) was added dropwise at −60° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction mixture, a solution of the compound prepared in Reference Example 10 (6.05 g) in THF (50 mL) was added dropwise at −78° C., and the mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution 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, and then filtered. 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 give the title compound (4.74 g) having 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.

[0080] Reference Example 12: (4S)-4-benzyl-3-[(2R)-2-(2,4-difluorophenyl)propanoyl]-1,3-oxazolidin-2-one To a solution of 2-(2,4-difluorophenyl)propanoic acid (CAS number: 1250572-63-4, 1 g) in dichloromethane (17.7 mL) was added (4S)-4-benzyloxazolidin-2-one (CAS number: 180917-48-0, 1.43 g). 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 aqueous solution of hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. 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 give the title compound (1.13 g, highly polar) having 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.

[0081] Reference Example 13: (2R)-2-(2,4-difluorophenyl)propanoic acid To a solution of the compound prepared in Reference Example 12 (1.13 g) in THF (15 mL), 30% aqueous hydrogen peroxide (2.8 mL) and an aqueous solution (10 mL) of lithium hydroxide (157 mg) were added at 0°C, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, followed by the addition of 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered. 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 give the title compound (861 mg) having the following physical properties: 1 H-NMR (CDCl3): δ 7.23-7.34, 6.76-6.92, 4.02, 1.51.

[0082] Reference Example 14: Dimethyl [(3R)-3-(2,4-difluorophenyl)-2-oxobutyl]phosphonate The title compound (614 mg) having the following physical properties was obtained by the same procedure as in Reference Example 10 → Reference Example 11, except that the compound (610 mg) prepared in Reference Example 13 was used instead of (2S)-2-(2,4-difluorophenyl)propanoic acid. 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.

[0083] 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 produced in Reference Example 9 (80 mg) in THF (1 mL), the compound produced in Reference Example 11 (115 mg), lithium chloride (18 mg), and triethylamine (60 μL) were added, and the mixture was stirred at room temperature overnight. 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, and then filtered. 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 give the title compound (117 mg) having 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.

[0084] 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 solution of the compound prepared in Reference Example 15 (117 mg) in methanol (2 mL), p-toluenesulfonic acid monohydrate (8 mg) was added at 0°C and 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 tetrahydroborate (19 mg) were added at 0°C and stirred at room temperature for 1 hour. The reaction mixture was concentrated, 1N aqueous hydrochloric acid 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 give 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.

[0085] 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 The diastereomeric mixture prepared in Reference Example 16 was dissolved in dimethoxyethane (0.5 mL) / methanol (1 mL), and 2N aqueous sodium hydroxide solution (0.5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of 1N hydrochloric acid and extraction 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 more polar form (17.5 mg) was obtained. The configuration was identified by single crystal X-ray analysis. HPLC retention time (min): 0.93; MS (ESI, Pos.): 445 (M+H-HO)+. 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.

[0086] 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 produced in Reference Example 9 (80 mg) in THF (1 mL) were added the compound produced in Reference Example 14 (115 mg), lithium chloride (18 mg), and triethylamine (60 μL), and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution 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, and then filtered. 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 give the title compound (103 mg) having the following physical properties: 1H-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.

[0087] 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 solution of the compound prepared in Reference Example 17 (103 mg) in methanol (2 mL), p-toluenesulfonic acid monohydrate (7 mg) was added at 0°C and 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 tetrahydroborate (17 mg) were added at 0°C and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 1N aqueous hydrochloric acid 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 the two diastereomers, yielding the more polar form (20.6 mg). 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.

[0088] 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 solution of the compound prepared in Reference Example 18 (high polarity: 20.6 mg) in DME (0.5 mL) / methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (14.6 mg) having the following physical properties: 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.

[0089] Reference Example 19 (1): (4S)-4-benzyl-3-[(2S)-2-(2-fluorophenyl)propanoyl]-1,3-oxazolidin-2-one Reference Example 19 (2): (4S)-4-benzyl-3-[(2R)-2-(2-fluorophenyl)propanoyl]-1,3-oxazolidin-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-benzyloxazolidin-2-one (3.95 g) was added. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.27 g), 4-dimethylaminopyridine (363 mg), and triethylamine (4.14 mL) were added at 0 ° C., and the mixture was stirred overnight at room temperature. A 1N aqueous solution of hydrochloric acid 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 give the title compounds (less polar: 1.76 g, more polar: 2.93 g) having the following physical properties. Less polar: 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 body: 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.

[0090] Reference Example 20: Dimethyl [(3S)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate

[0123] Instead of the compound prepared in Reference Example 12, the compound prepared in Reference Example 19(1) (less polar: 1.76 g) was used and subjected to the same procedures as in Reference Example 13 → Reference Example 10 → Reference Example 11 to obtain the title compound (941 mg) having the following physical properties. 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.

[0091] Reference Example 21: Dimethyl [(3R)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate

[0123] Instead of the compound prepared in Reference Example 12, the compound prepared in Reference Example 19(2) (highly polar: 2.93 g) was used and subjected to the same procedures as in Example 13 → Example 10 → Example 11 to obtain the title compound (970 mg) having the following physical properties. 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.

[0092] 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 produced in Reference Example 9 (80 mg) in THF (1 mL), the compound produced in Reference Example 20 (108 mg), lithium chloride (18 mg), and triethylamine (60 μL) were added, and the mixture was stirred at room temperature overnight. 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, and then filtered. 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 give the title compound (105 mg) having 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.

[0093] 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 solution of the compound prepared in Reference Example 22 (105 mg) in methanol (2 mL), p-toluenesulfonic acid monohydrate (7 mg) was added at 0°C and 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 tetrahydroborate (18 mg) were added at 0°C and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 1N aqueous hydrochloric acid 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 the two diastereomers, yielding 18.6 mg of the more polar form. 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.

[0094] 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 To a solution of the compound prepared in Reference Example 23 (highly polar: 18.6 mg) in dimethoxyethane (0.5 mL) / methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, followed by the addition of 1N hydrochloric acid and extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (13.1 mg) having the following physical properties. The configuration was identified by single crystal X-ray. HPLC retention time (min): 0.91; MS (ESI, Pos.): 427 (M+H-HO)+.; 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.

[0095] 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 produced in Reference Example 9 (80 mg) in THF (1 mL), the compound produced in Reference Example 21 (108 mg), lithium chloride (18 mg), and triethylamine (60 μL) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution 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, and then filtered. 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 give the title compound (114 mg) having the following physical properties: TLC: Rf 0.65 (hexane:ethyl acetate=2:1); 1H-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.

[0096] 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 solution of the compound prepared in Reference Example 24 (117 mg) in methanol (2 mL), p-toluenesulfonic acid monohydrate (8 mg) was added at 0°C and 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 tetrahydroborate (19 mg) were added at 0°C and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 1N aqueous hydrochloric acid 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 residue was purified by silica gel column chromatography (ISCO Gold High Performance Silica, hexane:ethyl acetate=60:40→55:45) to separate the two diastereomers, yielding the more polar form (19 mg). 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.

[0097] 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 prepared in Reference Example 25 (high polarity: 19 mg) in dimethoxyethane (0.5 mL) / methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, followed by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (14.1 mg) having the following physical properties: 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.

[0098] Reference Example 26: Dimethyl {2-[1-(2-fluorophenyl)cyclobutyl]-2-oxoethyl}phosphonate By performing the same operations as in Reference Example 10 → Reference Example 11, except that 1-(2-fluorophenyl)cyclobutanecarboxylic acid (CAS number: 151157-48-1, 10.4 g) was used instead of (2S)-2-(2,4-difluorophenyl)propanoic acid, the title compound (12.64 g) having the following physical properties was obtained. 1 H-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.

[0099] Reference Example 27: Dimethyl [2-oxo-2-(1-phenylcyclopropyl)ethyl]phosphonate

[0123] By performing the same procedures as in Reference Example 10 → Reference Example 11 except that 1-phenylcyclopropanecarboxylic acid (CAS number: 6120-95-2, 3.0 g) was used instead of (2S)-2-(2,4-difluorophenyl)propanoic acid, 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.

[0100] Reference Example 28: Ethyl (2,6-difluorophenyl) (difluoro)acetate To a solution of 1,3-difluoro-2-iodobenzene (CAS number: 13697-89-7, 4.7 g) in DMSO (24 mL), ethyl bromodifluoroacetate (CAS number: 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. To the reaction mixture, tert-butyl methyl ether (MTBE) was added, and the DMSO layer was separated. After that, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with MTBE. The organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. 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 give the title compound (3.31 g) having 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.

[0101] Reference Example 29: Dimethyl [3-(2,6-difluorophenyl)-3,3-difluoro-2-oxopropyl]phosphonate The title compound (4.02 g) having the following physical properties was obtained by the same procedure as in Reference Example 11, except that the compound (3.31 g) prepared in Reference Example 28 was used instead of the compound prepared in Reference Example 10. 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.

[0102] 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 Using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 14, the title compound was obtained by the same procedures 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 compound separated by the diastereomeric 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.

[0103] Examples 5-1 to 5-21: The following example compounds were obtained by using the corresponding phosphonates instead of the compound prepared in Reference Example 14 and subjecting them to the same procedures 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 compound separated by a diastereomer separation procedure. The corresponding phosphonates are known compounds or were prepared from known compounds by subjecting them to the same procedures as in Reference Example 10 → Reference Example 11.

[0104] 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-HO)+;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.

[0105] 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-HO)+; 1 H-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.

[0106] 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+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.

[0107] 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-HO)+; 1 H-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.

[0108] 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-HO)+; 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.

[0109] Example 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)+; 1H-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.

[0110] Example 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-HO, M+2-HO)+; 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.

[0111] Example 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-HO, M+2-HO)+; 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.

[0112] Example 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.

[0113] Example 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.

[0114] 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.

[0115] 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-HO) +, 435 (M + H-2HO) +. 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.

[0116] 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.

[0117] 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.

[0118] 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)+; 1H-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.

[0119] 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.

[0120] 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-HO)+; 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.

[0121] 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-HO)+; 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.

[0122] 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-HO)+; 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.

[0123] 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-HO) +, 453 (M + H-2HO) +. 1H-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.

[0124] 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-2HO)+; 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.

[0125] 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 prepared in Reference Example 29 (309 mg) in THF (0.5 mL), sodium hydride (17.5 mg, 60% oil suspension) was added and stirred at room temperature for 2 hours. To the reaction mixture, a solution of the compound prepared in Reference Example 9 (100 mg) in THF (0.5 mL) and a solution of zinc chloride in 2-methyltetrahydrofuran (0.37 mL) were added, and the mixture was stirred at 50 ° C. overnight. 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 = 95:5 → 80:20) to give the title compound (114 mg) having 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.

[0126] 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

[0079] The title compound exhibiting the following physical properties was obtained by using the compound prepared in Reference Example 30 instead of the compound prepared in Reference Example 17 and carrying out the same procedures as in Reference Example 18 → Example 2. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar compound separated by the diastereomeric 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.

[0127] Examples 6-1 to 6-17: The following example compounds were obtained by using the corresponding phosphonates instead of the compound prepared in Reference Example 29 and subjecting them to the same procedures 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 compound separated by a diastereomer separation procedure. The corresponding phosphonates are known compounds or were prepared from known compounds by subjecting them to the same procedures as in Reference Example 28 → Reference Example 29.

[0128] 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-HO)+; 1H-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.

[0129] 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)+; 1 H-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.

[0130] 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.

[0131] 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)+; 1 H-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.

[0132] 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-HO)+; 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.

[0133] 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.

[0134] Example 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-HO)+; 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.

[0135] Example 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-HO)+; 1 H-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.

[0136] Example 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-HO)+; 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.

[0137] Example 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.

[0138] 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)+; 1H-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.

[0139] 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.

[0140] 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-HO)+; 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.

[0141] 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-HO)+; 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.

[0142] 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-HO)+; 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.

[0143] 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)+; 1H-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.

[0144] 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-HO)+; 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.

[0145] Reference Example 31: 5-Bromo-2-vinylphenol

[0123] Using 4-bromo-2-hydroxybenzaldehyde (CAS number: 22532-62-3) instead of 4-bromo-3-fluoro-2-hydroxy-benzaldehyde, the title compound having the following physical properties was obtained by the same procedure as in Reference Example 3. 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.

[0146] 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

[0073] Using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, the title compound was obtained by the same procedures as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 to obtain the title compound having the following physical properties. 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.

[0147] 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. The title compound was obtained by the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, 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. The configuration was identified by single crystal X-ray analysis. HPLC retention time (min): 0.91; MS (ESI, Pos.): 403 (M+H-HO)+, 385 (M+H-2HO)+. 1H-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.

[0148] 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 by carrying out the same procedures 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 compound separated by a diastereomer separation procedure. The corresponding phosphonates are known compounds or were prepared from known compounds by carrying out the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0149] 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-HO)+; 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.

[0150] 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-HO) +, 407 (M + H-2HO) +. 1 H-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.

[0151] 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-HO) +, 407 (M + H-2HO) +. 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.

[0152] 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-HO) +, 407 (M + H-2HO) +. 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.

[0153] 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-HO)+; 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.

[0154] 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-HO)+; 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.

[0155] 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.

[0156] Example 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.

[0157] Example 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-HO)+; 1H-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.

[0158] Example 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-HO)+; 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.

[0159] 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-HO); 1 H-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.

[0160] 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-HO); 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.

[0161] 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 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.

[0162] 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-HO)+; 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.

[0163] 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-HO) +, 353 (M + H-2HO) +. 1 H-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.

[0164] 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-HO) +, 353 (M + H-2HO) +. 1H-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.

[0165] 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-2HO)+. 1 H-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.

[0166] 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.

[0167] 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-HO) + , 391 (M + H-2HO) + ; 1 H-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.

[0168] 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-HO); 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.

[0169] 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-HO); 1 H-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.

[0170] 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-HO); 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.

[0171] 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)+; 1 H-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.

[0172] 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.

[0173] 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)+; 1H-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.

[0174] 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.

[0175] 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)+; 1H-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.

[0176] 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.

[0177] 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)+; 1H-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.

[0178] 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 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.

[0179] 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-HO)+; 1H-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.

[0180] 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-HO)+; 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.

[0181] 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-HO)+; 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.

[0182] 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-HO, M+2-HO)+; 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.

[0183] 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-HO)+; 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.

[0184] 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-HO)+; 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.

[0185] 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-HO) + , 435 (M + H-2HO) + ; 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.

[0186] 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-HO)+, 417 (M-2HO)+; 1H-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.

[0187] 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-HO) + 437,439 (M + H-2HO) + ; 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.

[0188] 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-HO) + 417 (M + H-2HO) + ; 1H-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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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-HO)+; 1H-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.

[0194] 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-HO) +, 351 (M + H-2HO) +. 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.

[0195] 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-HO) +, 351 (M + H-2HO) +. 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.

[0196] 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-HO) +, 377 (M + H-2HO) +. 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.

[0197] 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.

[0198] 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)+; 1H-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.

[0199] Reference Example 33: 3-Bromo-2-chloro-6-vinylphenol

[0123] Using 4-bromo-3-chloro-2-hydroxybenzaldehyde (CAS number: 1427438-98-9) instead of 4-bromo-3-fluoro-2-hydroxy-benzaldehyde, the title compound having the following physical properties was obtained by the same procedure as in Reference Example 3. 1 H-NMR (CDCl3): δ 7.23-7.28, 7.15-7.19, 6.89-6.97, 5.86, 5.80, 5.37.

[0200] 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

[0123] Using the compound prepared in Reference Example 33 instead of the compound prepared in Reference Example 3, and subjecting to the same procedures 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.

[0201] 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 The title compound having the following physical properties was obtained by subjecting the compound prepared in Reference Example 34, instead of the compound prepared in Reference Example 9, to the same procedures as in Reference Example 30, Reference Example 18, and Example 2. The configuration was identified by crystal X-ray analysis. 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.

[0202] 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 by carrying out the same procedures 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 compound separated by a diastereomer separation procedure. The corresponding phosphonate is either a known compound or was prepared from a known compound by carrying out the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0203] 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-HO, M+2-HO)+; 1H-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.

[0204] 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-HO, M+2-HO)+; 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.

[0205] 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-2HO)+; 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.

[0206] 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-HO, M+2-HO)+; 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.

[0207] 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-HO, M+2-HO)+; 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.

[0208] 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.

[0209] 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-2HO)+; 1 H-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.

[0210] 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-HO)+; 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.

[0211] Reference Example 35: Methyl 3-hydroxy-2-methyl-4-vinylbenzoate 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 methyl 4-formyl-3-hydroxy-2-methylbenzoate (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. A saturated aqueous ammonium chloride solution and a 1N aqueous hydrochloric acid solution were added to the reaction mixture at 0°C, and the mixture was extracted with an ethyl acetate / n-hexane mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. 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 give the title compound (9.22 g) having 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.

[0212] Reference Example 36: Methyl 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-vinylbenzoate. Triphenylphosphine (12.4 g) was added to a solution of the compound produced in Reference Example 35 (7.0 g) and the compound produced in Reference Example 2 (13.5 g) in THF (70 mL), and the mixture was cooled on ice. A 2.2 M solution of diethyl azodicarboxylate in toluene (22 mL) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and MTBE:n-hexane (2:1, 150 mL) was added to the resulting residue, followed by stirring for 1 hour. The precipitate was 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→85:15) to give the title compound (14.3 g) having the following physical properties: 1 H-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.

[0213] 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 solution of the compound prepared in Reference Example 36 (14.3 g) in toluene (200 mL) was stirred at 60° C. for 20 minutes under a nitrogen stream to degas the mixture. Heating was stopped, and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride (1.21 g) was added, followed by stirring at 85° C. overnight under a nitrogen stream. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=97:3→93:7) to give the title compound (13.2 g) having 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.

[0214] 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

[0123] 10% palladium on carbon (1.32 g) was added to a solution of the compound prepared in Reference Example 37 (13.2 g) in ethyl acetate (132 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate and then filtered, and the filtrate was concentrated under reduced pressure. This product was subjected to the next reaction without further purification.

[0215] 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 solution of the crude product prepared in Reference Example 38 in THF (13.2 mL) was added a 1 mol / L THF solution (52.4 mL) of tetrabutylammonium fluoride at room temperature, and the mixture was stirred at room temperature overnight. 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, and then filtered. The filtrate was concentrated under reduced pressure. The obtained 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) having 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.

[0216] 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 prepared in Reference Example 39 (2.0 g) 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 the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and a 1N aqueous hydrochloric acid solution 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 sodium sulfate, and then filtered. 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 give the title compound (2.0 g) having 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.

[0217] 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. 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, the same procedures as in Reference Example 17 → Reference Example 18 → Example 2 were carried out to obtain the title compound having the following physical properties. The intermediate corresponding to the compound prepared in Reference Example 18 was the highly polar product separated by the diastereomeric separation procedure. HPLC retention time (min): 0.9; MS (ESI, Pos.): 417 (M+H−HO)+. ; 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.

[0218] 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 carrying out the same procedures 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 compound separated by a diastereomer separation procedure. The corresponding phosphonates are known compounds or were prepared from known compounds by carrying out the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0219] 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-HO)+; 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.

[0220] 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-HO)+; 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.

[0221] 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-HO)+; 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.

[0222] 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.

[0223] 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 HPLC retention time (min): 1.166; MS (ESI, Pos.): 489 (M+Na)+. ; 1 H-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.

[0224] 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.

[0225] 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)+. 1 H-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.

[0226] 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)+. 1H-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.

[0227] 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)+. 1 H-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.

[0228] Example 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)+. 1H-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.

[0229] Example 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)+. 1 H-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.

[0230] Example 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)+. 1H-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.

[0231] 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)+. 1 H-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.

[0232] 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.

[0233] 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)+. 1 H-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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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)+. 1 H-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.

[0238] 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-HO-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.

[0239] 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-HO-HF)+. 1 H-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.

[0240] 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)+. 1H-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.

[0241] 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)+. 1 H-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.

[0242] 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 The title compound having the following physical properties was obtained by the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, 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. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar product separated by the diastereomer separation procedure. Furthermore, the diastereomers obtained by the procedure in Example 2 were separated using an SFC column (CHIRALPAK IG, CO:2-propanol = 72:28) to obtain a highly polar product. The corresponding phosphonate was prepared by the same procedures as in Reference Example 11, using methyl 2-ethyl-5-methylhexanoate (CAS No.: 1896760-61-4) instead of the compound prepared in Reference Example 10. HPLC retention time (min): 1.196; MS (ESI, Pos.): 453 (M+Na)+. ; 1 H-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.

[0243] Reference Example 41: Ethyl 6,7,7-trifluoro-3-hydroxy-3-methyl-6-heptenoate 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. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with MTBE. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (130 g) having the following physical properties: 1H-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.

[0244] Reference Example 42: 6,7,7-trifluoro-3-hydroxy-3-methyl-6-heptenoic acid To a solution of the compound produced in Reference Example 41 (130 g) in ethanol (270 mL), 5N aqueous sodium hydroxide solution (162 mL) was added and stirred at room temperature for 1 hour. MTBE was added to the reaction solution, and the separated aqueous layer was acidified with 5N aqueous hydrochloric acid solution and extracted with MTBE. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (106 g) having the following physical properties: 1 H-NMR (CDCl3): δ 6.33, 3.24, 2.34-2.64, 1.70-1.93, 1.32.

[0245] Reference Example 43: (1R,2S)-2-Hydroxy-1,2-diphenylethanaminium (3S)-6,7,7-trifluoro-3-hydroxy-6-octenoate To a solution of the compound (106 g) produced 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. The washing operation was repeated two more times to obtain the title compound (56.94 g) having the following physical properties: 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.

[0246] Reference Example 44: (3S)-6,7,7-trifluoro-3-methyl-6-heptene-1,3-diol The compound (56.4 g) produced in Reference Example 43 was extracted with aqueous hydrochloric acid and ethyl acetate to give a carboxylic acid form (24.0 g). The carboxylic acid form was dissolved in THF (340 mL), and triethylamine (15.8 mL) and isobutyl chloroformate (14.7 mL) were added at -10°C and stirred for 30 minutes. Sodium borohydride (6.4 g) and water (10 mL) were added to the filtrate obtained by filtration of the precipitate at -10°C and stirred at 0°C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 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.

[0247] Reference Example 45: (3S)-6,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-6-hepten-3-ol To a solution of the compound produced in Reference Example 44 (17.5 g) in toluene (71 mL), 5N aqueous sodium hydroxide 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, and then filtered. 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 give the title compound (24.8 g) having 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.

[0248] Reference Example 46: (3S)-6,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-6-hepten-3-ol. A 30% aqueous solution of hydrogen peroxide was added to a mixture of sodium tungstate dihydrate (114 mg), benzenephosphonic acid (55 mg), and methyltri-n-octylammonium chloride (140 mg), and the mixture was stirred at room temperature for 15 minutes. A solution of the compound prepared in Reference Example 45 (24.8 g) in toluene (70 mL) was added to the mixture, and the mixture was stirred at 50°C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (26.7 g) showing the following physical properties: 1 H-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.

[0249] Reference Example 47: 1-phenyl-5-({(3S)-6,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]-6-hepten-1-yl}sulfonyl)-1H-tetrazole To a solution of the compound (5 g) produced in Reference Example 46 in DMF (30 mL) were added imidazole (2.6 g) and trimethylchlorosilane (2.4 mL) at room temperature, followed by stirring. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was washed with n-hexane to give 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.

[0250] 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 prepared in Reference Example 47 (4.29 g) in dimethoxyethane (19.2 mL) was added dropwise a 1 mol / L solution of potassium hexamethyldisilazide in THF (9.27 mL) at −78° C., and the mixture was stirred for 20 minutes. To the reaction mixture, a solution of the compound prepared in Reference Example 40 (2.4 g) in dimethoxyethane (16.8 mL) was added dropwise at -78°C over 40 minutes, followed by stirring for 2 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, 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 purified by silica gel chromatography (n-hexane:ethyl acetate = 90:10 → 80:20 → 70:30) to give a crude product (2.11 g) containing the title compound. This was not purified here, but was subjected to the next reaction.

[0251] 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 solution of the crude product (2.11 g) prepared in Reference Example 48 in methanol (21 mL), p-toluenesulfonic acid monohydrate (128 mg) was added at room temperature and stirred at room temperature for 2 hours. Triethylamine (0.47 mL) was added to the reaction solution, which was then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 70:30 → 30:70 → 0:100) to give the title compound (1.49 g) showing the following physical properties. 1H-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.

[0252] 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 To a solution of the compound prepared in Reference Example 49 (1.49 g) in THF (5 mL) / methanol (10 mL) was added 2N aqueous sodium hydroxide solution (6.36 mL) at room temperature, and the mixture was stirred at 40°C overnight. The reaction mixture was concentrated under reduced pressure, and 2N aqueous hydrochloric acid 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 from ethyl acetate (14.5 mL) / n-hexane (5.8 mL) to give 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-HO)+, 419 (M+H-2HO)+. 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.

[0253] Reference Example 50: Diethyl ether (52 mL) was added to ethyl magnesium 7,7,7-trifluoro-3-hydroxy-3-methylheptanoate (1.53 g), and dibromoethane (0.45 mL) was added at room temperature to activate the mixture. Bromotrifluorobutane (10 g) was then added dropwise, and the mixture was stirred at 50°C to prepare an 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 the mixture was stirred for 90 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered to obtain the ketone (6,6,6-trifluorohexan-2-one) as a diethyl ether solution. Ethyl acetate (6.14 mL) was added dropwise to a solution of lithium hexamethyldisilazide (1 mol / L THF solution, 62.8 mL) in THF (52 mL) at −78°C, and the mixture was stirred at −78°C for 25 minutes. A diethyl ether solution of the ketone was added dropwise thereto over 20 minutes, and the mixture was stirred at −78°C for 50 minutes. A saturated aqueous ammonium chloride 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, and then filtered. 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 give the title compound (16.7 g) having 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.

[0254] Reference Example 51: 7,7,7-trifluoro-3-hydroxy-3-methylheptanoic acid To a solution of the compound produced in Reference Example 50 (16.7 g) in ethanol (130 mL) was added 2N aqueous sodium hydroxide solution (52 mL) and stirred at room temperature for 1 hour. The reaction solution was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (8.49 g) having the following physical properties:1 H-NMR (CDCl3): δ 2.48-2.64, 2.02-2.21, 1.56-1.76, 1.31.

[0255] Reference Example 52: (1R)-1-Phenylethanolaminium (3S)-7,7,7-trifluoro-3-hydroxy-3-methylheptanoate To a solution of the compound produced in Reference Example 51 (8.49 g) in ethyl acetate (50 mL), (R)-1-phenylethylamine (5 mL) was added and the mixture was 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 temperature was lowered to room temperature. The precipitate was filtered and washed with n-heptane. The washing operation was performed two more times to obtain the title compound (2.64 g) having the following physical properties: 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.

[0256] Reference Example 53: (3S)-7,7,7-trifluoro-3-methyl-1,3-heptanediol Aqueous hydrochloric acid and ethyl acetate were added to the compound produced in Reference Example 52 (2.64 g), followed by extraction and concentration under reduced pressure. The resulting 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. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 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.

[0257] Reference Example 54: (3S)-7,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-3-heptanol To a solution of the compound produced in Reference Example 53 (1.74 g) in toluene (20 mL), 5N aqueous sodium hydroxide solution (6.5 mL) and tetrabutylammonium bromide (254 mg) were added. p-Toluenesulfonyl chloride (1.65 g) was added to the mixture at 0°C, and the mixture was stirred at 0°C for 1 hour and 45 minutes. 1-Phenyl-1H-tetrazole-5-thiol (1.69 g) was further added, and the mixture was stirred at 60°C overnight. The reaction solution was extracted with MTBE. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. 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 give the title compound (2.65 g) having 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.

[0258] Reference Example 55: (3S)-7,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-3-heptanol. To a solution of the compound produced in Reference Example 54 (2.65 g) in dichloromethane (35 mL) was added metachloroperbenzoic acid (4.5 g) at 0°C and stirred overnight. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. 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 give the title compound (2.76 g) having 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.

[0259] Reference Example 56: 1-phenyl-5-({(3S)-7,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]heptyl}sulfonyl)-1H-tetrazole A solution of the compound prepared in Reference Example 55 (2.76 g) in DMF (25 mL) was cooled to 0°C, and imidazole (1.44 g) and trimethylchlorosilane (1.34 mL) were added, followed by stirring at room temperature for 3.5 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate / n-hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then 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 give the title compound (2.88 g) having 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.

[0260] 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 prepared in Reference Example 56 (3.95 g) in dimethoxyethane (17.6 mL) was added dropwise a 1 M solution of potassium hexamethyldisilazide in THF (8.49 mL) at −78° C., and the mixture was stirred for 20 minutes. To the reaction mixture, a solution of the compound prepared in Reference Example 40 (2.2 g) in dimethoxyethane (15.4 mL) was added dropwise at −78° C. over 40 minutes, and the mixture was stirred for 30 minutes. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate / n-hexane. 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 = 97:3 → 90:10 → 80:20) to give a crude product (3.53 g) containing the title compound. This was subjected to the next reaction without further purification.

[0261] Reference Example 58: Methyl (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-carboxylate. To a solution of the crude product (3.53 g) prepared in Reference Example 57 in methanol (35.3 mL), p-toluenesulfonic acid monohydrate (149 mg) was added at room temperature and stirred for 3 hours. Triethylamine (0.55 mL) was added to the reaction solution, 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 give the title compound (1.80 g) showing 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.

[0262] 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 To a solution of the compound prepared in Reference Example 58 (1.80 g) in THF (6 mL)-methanol (12 mL) was added 2N aqueous sodium hydroxide solution (6 mL) at room temperature, and the mixture was stirred at 40°C overnight. The reaction mixture was concentrated under reduced pressure, and 2N aqueous hydrochloric acid 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 give the title compound (1.51 g) showing the following physical properties. HPLC retention time (min): 1.088; MS (ESI, Pos.): 479 (M+Na)+, 421 (M+H-2HO)+. 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.

[0263] Examples 12-1 to 12-4: The following example compounds were obtained by using the corresponding tetrazolylsulfonyl compounds instead of the compound prepared in Reference Example 56 and subjecting them to the same procedures as in Reference Example 57 → Reference Example 58 → Example 12. The corresponding tetrazolylsulfonyl compounds are known compounds, or were prepared from known compounds by subjecting them to the same procedures as in Reference Example 50 → Reference Example 51 → Reference Example 52 → Reference Example 53 → Reference Example 54 → Reference Example 55 → Reference Example 56.

[0264] 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)+. 1H-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.

[0265] 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.

[0266] Example 12-3: (1R,2R,3aS,10aR)-1-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-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): 1.171; MS (ESI, Pos.): 451 (M+Na)+. 1 H-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.

[0267] 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.

[0268] 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 The corresponding racemic compound was used instead of the compound prepared in Reference Example 56, and the same procedures as in Reference Example 57, Reference Example 58, and Example 12 were carried out. The two diastereomers were separated on an SFC column (CHIRALPAK IG, CO:methanol=69:31) to obtain the title compound (less polar) exhibiting the following physical properties. The corresponding racemic compound was prepared from a known compound by the same procedures as in Reference Example 50, Reference Example 51, Reference Example 52, Reference Example 53, Reference Example 54, Reference Example 55, and Reference Example 56. HPLC retention time (min): 1.123; MS (ESI, Pos.): 439 (M+Na)+, 381 (M+H-2HO)+. 1H-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.

[0269] 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 Instead of the compound produced in Reference Example 56, the corresponding racemic compound was subjected to the same procedures as in Reference Example 57 → Reference Example 58 → Example 12 to obtain the intended product, and the two diastereomers were separated using an SFC column (CHIRALPAK IG, CO:2-propanol=70:30) to obtain the title compound (less polar) showing the following physical property values. The corresponding racemic compound was prepared from a known compound by subjecting it to 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.

[0270] Reference Example 59: 5-Bromo-4-fluoro-2-vinylphenol Using 4-bromo-5-fluoro-2-hydroxybenzaldehyde (CAS number: 1427405-76-2) instead of 4-bromo-3-fluoro-2-hydroxy-benzaldehyde, and subjected to the same procedure as in Reference Example 3 to obtain the title compound having the following physical properties. 1H-NMR (CDCl3): δ 7.15, 7.00, 6.79-6.88, 5.71-5.77, 5.41, 5.20-5.28.

[0271] 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

[0123] Using the compound prepared in Reference Example 59 instead of the compound prepared in Reference Example 3, and subjecting to the same procedures 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 9.81-9.85, 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.

[0272] 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

[0123] The title compound having the following physical properties was obtained by using the compound produced in Reference Example 60 instead of the compound produced in Reference Example 9, and the compound produced in Reference Example 26 instead of the compound produced in Reference Example 14, and by carrying out the same procedures 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 compound separated by the diastereomeric separation procedure. HPLC retention time (min): 0.97; MS (ESI, Pos.): 453 (M-OH)+. ; 1H-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.

[0273] Reference Example 61: 5-Bromo-3-fluoro-2-vinylphenol Using 4-bromo-2-fluoro-6-hydroxybenzaldehyde (CAS number: 1427438-90-1) instead of 4-bromo-3-fluoro-2-hydroxy-benzaldehyde, the title compound having the following physical properties was obtained by the same procedure as in Reference Example 3. 1 H-NMR (CDCl3): δ 6.79-6.90, 6.69, 5.79-5.97, 5.60-5.67.

[0274] 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 Using the compound prepared in Reference Example 61 instead of the compound prepared in Reference Example 3, and subjecting to the same procedures 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.

[0275] 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

[0123] The title compound having the following physical properties was obtained by using the compound produced in Reference Example 62 instead of the compound produced in Reference Example 9, and the compound produced in Reference Example 27 instead of the compound produced in Reference Example 14, and by carrying out the same procedures 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 compound separated by the diastereomeric separation procedure. 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.

[0276] Reference Example 63: Ethyl 6-hydroxy-5-vinyl-2-pyridinecarboxylate. To a solution of ethyl 5-bromo-6-hydroxy-2-pyridinecarboxylate (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 give the title compound (170 mg) having the following physical properties. TLC: Rf 0.52 (hexane:ethyl acetate = 3:7); 1H-NMR (DMSO-d6): δ 11.50-12.12, 7.73, 7.02, 6.77, 6.24, 5.42, 4.30, 1.27-1.34.

[0277] 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

[0123] Using the compound prepared in Reference Example 63 instead of the compound prepared in Reference Example 3, and subjecting to the same procedures 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.

[0278] 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

[0079] Using the compound prepared in Reference Example 64 (45 mg) instead of the compound prepared in Reference Example 9, and 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 used to give the enone form (21 mg). A solution of the enone form (21 mg) in THF (0.2 mL) was cooled to -15°C. To this was added (S)-2-methyl-CBS-oxazaborolidine (0.037 mL, 1 mol / L toluene solution) and N,N-diethylaniline borane (0.013 mL), followed by stirring overnight at -15°C. 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. A solution of the reduced product in methanol (0.2 mL) was cooled to 0°C, and p-toluenesulfonic acid monohydrate (1.8 mg) was added, followed by stirring 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) having 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.

[0279] 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 Using the compound prepared in Reference Example 65 instead of the compound prepared in Reference Example 18, and subjecting to the same procedures 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.

[0280] 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]oxocine-9-carboxylate

[0123] 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 procedure was repeated as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 to obtain the title compound having the following physical properties. 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.

[0281] 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]oxocine-9-carboxylic acid

[0123] The title compound having the following physical properties was obtained by the same procedures as in Reference Example 17, Reference Example 18, and Example 2, using the compound produced in Reference Example 66 instead of the compound produced in Reference Example 9 and dimethyl-2-oxoheptylphosphonate (CAS number: 36969-89-8) instead of the compound produced in Reference Example 14. Note that the intermediate corresponding to the compound produced in Reference Example 18 was a highly polar compound separated by the diastereomeric 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.

[0282] 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 by carrying out the same procedures 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 compound separated by a diastereomer separation procedure. The corresponding phosphonate is either a known compound or was prepared from a known compound by carrying out the same procedures as in Reference Example 10 → Reference Example 11.

[0283] 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]oxocine-9-carboxylic acid MS (ESI, Neg.): 401 (M-H) -. 1 H-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.

[0284] 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]oxocine-9-carboxylic acid MS (ESI, Neg.): 401 (M-H) -. 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.

[0285] 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]oxocine-9-carboxylic acid MS (ESI, Neg.): 399 (M-H)-. 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.

[0286] 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]oxocine-9-carboxylic acid HPLC retention time (min): 1.01; MS (ESI, Pos.): 453 (M + H-H2O)+, 435 (M + H-H2O)+; 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.

[0287] 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 385 (M + H-HO) +, 367 (M + H-2HO) +.; 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.

[0288] 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 365 (M+H-2HO)+.; 1H-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.

[0289] Example 17-7: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ)-3-hydroxy-4-methyl-1-octen-6-yn-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid MS (ESI, Pos.): 381 (M + H-HO) + , 363 (M + H-2HO) + ; 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.

[0290] 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 385 (M + H-HO) +, 367 (M + H-2HO) +.; 1 H-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.

[0291] 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 407 (M+H-HO)+; 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.

[0292] 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 383 (M + H-HO) +, 365 (M + H-2HO) +; 1 H-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.

[0293] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.95; MS (ESI, Pos.): 383 (M+H-2H2O)+; 1H-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.

[0294] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.95; MS (ESI, Pos.): 383 (M+H-2H2O)+; 1 H-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.

[0295] 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]oxocine-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.

[0296] 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]oxocine-9-carboxylic acid MS (FAB, Neg.): 405 (M-H)-. 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.

[0297] 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]oxocine-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.

[0298] 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 399 (M+H-HO)+; 1H-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.

[0299] 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]oxocine-9-carboxylic acid HPLC retention time (min): 1.01; MS (ESI, Pos.): 439 (M + H-H2O)+, 421 (M + H-H2O)+; 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.

[0300] Example 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 439 (M + H-H2O), 421 (M + H-H2O) +.; 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.

[0301] 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]oxocine-9-carboxylic acid MS (ESI, Neg.): 399 (M-H)-. 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.

[0302] 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]oxocine-9-carboxylic acid MS (ESI, Neg.): 385 (M-H)-. 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.

[0303] 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]oxocine-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.

[0304] 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]oxocine-9-carboxylic acid MS (ESI, Pos.): 399 (M+H-2H2O)+; 1 H-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.

[0305] 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]oxocine-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.

[0306] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.91; MS (ESI, Pos.): 453 (M + H-HO) + , 435 (M + H-2HO) + ; 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.

[0307] 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]oxocine-9-carboxylic acid HPLC retention time (min): 1; MS (ESI, Pos.): 467 (M + H-HO) + , 449 (M + H-2HO) + ; 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.

[0308] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.99; MS (ESI, Pos.): 467 (M + H-HO) + , 449 (M + H-2HO) + ; 1 H-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.

[0309] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.79; MS (ESI, Pos.): 467 (M + H-HO) +, 449 (M + H-2HO) +. 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.

[0310] Example 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.77; MS (ESI, Pos.): 431 (M + H-HO) +, 413 (M + H-2HO) +. 1 H-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.

[0311] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.77; MS (ESI, Pos.): 452 (M + H-HO) +, 434 (M + H-2HO) +. 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.

[0312] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.78; MS (ESI, Pos.): 449 (M + H-HO) +, 431 (M + H-2HO) +. 1 H-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.

[0313] 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]oxocine-9-carboxylic acid HPLC retention time (min): 0.98; MS (ESI, Pos.): 450 (M+H-HO)+; 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.

[0314] 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]oxocine-9-carboxylic acid

[0079] The title compound exhibiting the following physical properties was obtained by using the corresponding aldehyde compound instead of the compound prepared in Reference Example 9, the corresponding phosphonate instead of the compound prepared in Reference Example 14, and the same procedures 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 compound separated by the diastereomeric separation procedure. The corresponding aldehyde compound was prepared by using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 31 and the same procedures as in Reference Example 66. The corresponding phosphonate was prepared by the same procedure as in Reference Example 10 → Reference Example 11, using 1-phenoxycyclobutanecarboxylic acid (CAS No.: 2287791-08-4) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid. HPLC retention time (min): 1.107; MS (ESI, Pos.): 505 (M+Na)+. 1H-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.

[0315] 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]oxocine-9-carboxylic acid

[0079] The title compound exhibiting the following physical properties was obtained by using the corresponding aldehyde compound instead of the compound prepared in Reference Example 9, the corresponding phosphonate instead of the compound prepared in Reference Example 14, and the same procedures as in Reference Example 17, Reference Example 18, and Example 2. The intermediate corresponding to the compound prepared in Reference Example 18 was a highly polar compound separated by the diastereomeric separation procedure. The corresponding aldehyde compound was prepared by using the compound prepared in Reference Example 35 instead of the compound prepared in Reference Example 31 and the same procedures as in Reference Example 66. The corresponding phosphonate was prepared by the same procedure as in Reference Example 10 → Reference Example 11, using 1-phenoxycyclobutanecarboxylic acid instead of (2S)-2-(2,4-difluorophenyl)propanoic acid. 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.

[0316] 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]oxocine-9-carboxylic acid Using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 40, the same procedures as in Reference Example 48 → Reference Example 49 → Example 11 were carried out to obtain the title compound showing the following physical properties. HPLC retention time (min): 0.94; MS (ESI, Pos.): 437 (M+H-H2O)+, 419 (M+H-H2O)+. 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.

[0317] 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]oxocine-9-carboxylic acid. The title compound exhibiting the following physical properties was obtained by using the corresponding aldehyde compound instead of the compound prepared in Reference Example 66 and subjecting it to the same procedures as in Reference Example 48, Reference Example 49, and Example 11. The corresponding aldehyde compound was prepared by using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 31 and subjecting it to the same procedures as in Reference Example 66. HPLC retention time (min): 1.079; MS (ESI, Pos.): 495 (M+Na)+. 1H-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.

[0318] 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]oxocine-9-carboxylic acid

[0123] 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 reaction was subjected to the same procedures as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 8 → Reference Example 9 to obtain the desired aldehyde form. The title compound having the following physical properties was obtained by carrying out the same procedures as in Reference Example 17, Reference Example 18, and Example 2, using the aldehyde compound instead of the compound produced in Reference Example 9 and dimethyl-2-oxoheptylphosphonate (CAS number: 36969-89-8) instead of the compound produced in Reference Example 14. The intermediate corresponding to the compound produced in Reference Example 18 was a highly polar compound separated by the diastereomeric separation procedure. MS (ESI, Pos.): 351 (M+H-2HO)+; 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.

[0319] 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]oxocine-9-carboxylate To a solution of the compound produced in Example 17-17 (125 mg) in methanol (1 mL), a 2 M n-hexane solution (0.5 mL) of trimethylsilyldiazomethane was added dropwise with stirring at room temperature until the reaction solution turned yellow. After adding acetic acid to the reaction mixture, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (126 mg).

[0320] 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]oxocine-9-carboxylate. To a dichloromethane (2 mL) solution of the compound prepared in Reference Example 67, triethylamine (0.22 mL) and N,N-dimethyl-4-aminopyridine (13 mg) were added at room temperature, and the mixture was cooled on 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 yield the title compound (204 mg).

[0321] 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]oxocine-9-carboxylate To a solution of the compound prepared in Reference Example 68 in dichloromethane (1.5 mL) was added 2,6-dimethylpyridine (0.1 mL) at room temperature, and the mixture was cooled on ice. tert-Butyldimethylsilyl trifluoromethanesulfonate (0.1 mL) 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 yield the title compound (174 mg).

[0322] 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]oxocine-9-carboxylic acid To a solution of the compound prepared in Reference Example 69 in dimethoxyethane (1.5 mL)-methanol (1.5 mL), 2N aqueous sodium hydroxide solution (0.5 mL) was added at room temperature, and the mixture was stirred at 35°C for 15 hours. The reaction mixture was concentrated under reduced pressure, and then 1N hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (154 mg) having the following physical properties: 1H-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.

[0323] 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]oxocine-9-carboxamide To a solution of the compound prepared in Reference Example 70 (40 mg) in DMF (1 mL) were added methanesulfonamide (9.4 mg), N,N-dimethyl-4-aminopyridine (12 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, THF (1 mL) and a 1M THF solution of 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 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 (ethyl acetate:methanol = 5:1) to give the title compound (2.5 mg) having the following physical properties. HPLC retention time (min): 0.99; MS (ESI, Pos.): 516 (M+H-HO)+.; 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.

[0324] 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]oxocine-9-carboxamide To a solution of the compound prepared in Reference Example 70 (114 mg) in DMF (1.1 mL) were added ammonium chloride (15 mg), 7-aza-1-hydroxybenzotriazole (38 mg), diisopropylethylamine (0.1 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg) at room temperature, and the mixture was stirred at room temperature for 15 hours. 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 yield the title compound (105 mg).

[0325] 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]oxocine-9-carbonitrile The compound prepared in Reference Example 71 was dissolved in THF (2 mL), and pyridine (0.03 mL) was added at room temperature. The reaction solution was cooled under ice-cooling, and trifluoroacetic anhydride (0.03 mL) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (99.7 mg) having the following physical properties: 1H-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.

[0326] 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]oxocin-2-ol. To a solution of the compound prepared in Reference Example 72 (99.7 mg) in toluene (2 mL), 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 give the tetrazole compound (98 mg). To a solution of the obtained tetrazole compound in THF (1 mL), 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 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 (ethyl acetate:methanol = 3:1) to give the title compound (35.2 mg) having the following physical properties. HPLC retention time (min): 0.99; MS (ESI, Pos.): 463 (M+H-HO)+.; 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.

[0327] 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 Using the compound prepared in Example 17 instead of the compound prepared in Example 17-17, the title compound was obtained by the same procedures as in Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Reference Example 71 → Reference Example 72 → Example 24. TLC: Rf 0.26 (CHCl / methanol, 5 / 1) MS (APCI, Pos.): 381 (M-HO)+. 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.

[0328] 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 dichloromethane solution (50 mL) of the compound (8.3 g) produced 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 solution was poured into a 1N aqueous hydrochloric acid solution / ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting crude product was dissolved in methanol (50 mL), and p-toluenesulfonic acid monohydrate (378 mg) was added at room temperature, followed by stirring 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 give the title compound (10.7 g) showing the following physical properties:1 H-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.

[0329] 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 solution of the compound prepared in Reference Example 73 (15.6 g) in acetonitrile (78 mL), 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 at room temperature for 3 hours. The reaction solution was poured into a 1N aqueous hydrochloric acid solution / ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. 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 give the title compound (20.2 g) showing 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.

[0330] 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 prepared in Reference Example 74 (20.2 g) in dimethoxyethane (150 mL)-DMF (10 mL) were added water (15 mL), sodium iodide (16.6 g), and zinc (14.4 g) at room temperature, and the mixture was stirred at 80°C overnight. Further, sodium iodide (4 g) and zinc (3.5 g) were 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, and then filtered. 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 give the title compound (13.1 g) showing 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.

[0331] 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

[0123] Using the compound produced in Reference Example 75 instead of the compound produced in Reference Example 7, and performing the same procedures as in Reference Example 8 → Reference Example 9 to obtain the title compound showing the following physical properties. 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.

[0332] 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

[0123] The enone form (97 mg) was obtained by the same procedure as in Reference Example 17, except that the compound prepared in Reference Example 76 (70 mg) was used instead of the compound prepared in Reference Example 9, and the compound prepared in Reference Example 26 (136 mg) was used instead of the compound prepared in Reference Example 14. A solution of the enone form (97 mg) in THF (1 mL) was cooled to -15°C. To this was added (S)-2-methyl-CBS-oxazaborolidine (1 mol / L toluene solution, 0.204 mL) and N,N-diethylaniline borane (0.073 mL), followed by stirring at -15°C for 8 hours. Methanol and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then 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 a reduced form. The reduced form was dissolved in methanol (1 mL) and dimethoxyethane (0.5 mL), and 2N aqueous sodium hydroxide solution (0.5 mL) was added, followed by stirring overnight. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated, acidified with aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified on an SFC column (CHIRALPAK IG, CO:methanol=65:35) to give the title compound (19 mg) having the following physical properties: HPLC retention time (min): 1.09; MS (ESI, Pos.): 437 (M+H-HO)+; 1 H-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.

[0333] Examples 25-1 to 25-15: The title compounds exhibiting the following physical properties were obtained by using the corresponding phosphonates instead of the compound prepared in Reference Example 26 and carrying out the same procedures as in Example 25. Note that, for 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 phosphonates are known compounds, or were prepared from known compounds by carrying out the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0334] 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-HO)+; 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.

[0335] 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)+; 1H-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.

[0336] 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-HO)+; 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.

[0337] 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.

[0338] 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-HO)+; 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.

[0339] 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.

[0340] 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 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.

[0341] 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-HO)+; 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.

[0342] 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-HO)+; 1H-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.

[0343] 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-HO) +. 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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)+. 1H-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.

[0348] 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.

[0349] Examples 26-1 to 26-23: The title compounds exhibiting the following physical properties were obtained by subjecting the compounds to the same procedures as in Example 25, except that the corresponding aldehyde compound was used in place of the compound prepared in Reference Example 76 and the corresponding phosphonate was used in place of the compound prepared in Reference Example 26. For Examples 26-1, 26-3, and 26-6, 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 compound was prepared by subjecting the compounds to the same procedures 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, using the corresponding phenol compound in place of the compound prepared in Reference Example 3. The corresponding phosphonates are known compounds, or were prepared from known compounds by subjecting them to the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0350] 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 (M-H)-. 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.

[0351] 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-HO)+; 1 H-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.

[0352] 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-HO)+.; 1H-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.

[0353] 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-HO)+.; 1 H-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.

[0354] 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-HO)+.; 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.

[0355] 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-HO)+; 1 H-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.

[0356] 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-HO)+; 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.

[0357] 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-HO)+; 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.

[0358] 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 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.

[0359] 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) + ; 1 H-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.

[0360] 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-HO)+.; 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.

[0361] 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-HO)+; 1 H-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.

[0362] 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-HO)+; 1H-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.

[0363] 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-HO)+. 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.

[0364] 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-HO)+; 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.

[0365] 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-HO)+; 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.

[0366] 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 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.

[0367] 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-HO)+; 1H-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.

[0368] 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 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.

[0369] 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 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.

[0370] 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 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.

[0371] 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.

[0372] Example 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-HO)+.; 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.

[0373] 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 Using the compound prepared in Example 26-13 instead of the compound prepared in Example 17-17, the same procedures as in Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23 were carried out to obtain the title compound showing the following physical properties. 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.

[0374] 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 To a solution of the compound prepared in Reference Example 73 (4.87 g) in THF (39 mL) was added triphenylphosphine (4.54 g) 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, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0 → 80:20) to give a formate (4.53 g). Potassium carbonate (2.12 g) was added to a solution of the formate (4.53 g) in ethanol (31.7 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with MTBE and then filtered. The filtrate was poured into a saturated aqueous ammonium chloride solution / 1N aqueous hydrochloric acid 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 give the title compound (4.08 g) showing 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.

[0375] 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 produced in Reference Example 77 (6.0 g) in MTBE (27 mL) was cooled to −78° C., and bis(2-methoxyethyl)aminosulfur trifluoride (9.8 mL) was added dropwise thereto, followed by stirring at −78° C. After confirming the disappearance of the starting materials by TLC, the temperature was raised to −20° C., and the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered. 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 give the title compound (2.59 g) showing 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.

[0376] 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

[0123] Using the compound produced in Reference Example 78 instead of the compound produced in Reference Example 7, and performing the same procedure as in Reference Example 8 for the intended purpose, the title compound showing the following physical properties was obtained. 1H-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.

[0377] 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 prepared in Reference Example 79 (600 mg) in dichloromethane (6 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-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 give the title compound (550 mg) showing 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.

[0378] Example 28: (1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-penten-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid The title compound was obtained by the same procedure as in Reference Example 24, except that the compound prepared in Reference Example 80 (300 mg) was used instead of the compound prepared in Reference Example 76, and dimethyl-3-methyl-2-oxo-3-phenylbutylphosphonate (CAS No.: 87929-30-4, 375 mg) was used instead of the compound prepared in Reference Example 26. The title compound showed the following physical properties: HPLC retention time (min): 1.157; MS (ESI, Pos.): 405 (M+H-HO-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.

[0379] Examples 28-1 to 28-3: The title compounds having the following physical properties were obtained 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 carrying out the same procedures as in Example 25. The corresponding phosphonates are known compounds, or were prepared from known compounds by carrying out the same procedures as in Reference Example 10 → Reference Example 11.

[0380] 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)+. 1H-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.

[0381] 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 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.

[0382] 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-HO)+. 1H-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.

[0383] Examples 29-1 to 29-4: The title compounds showing the following physical properties were obtained by using the corresponding aldehyde compound instead of the compound prepared in Reference Example 76, and the corresponding phosphonate compound instead of the compound prepared in Reference Example 26, and by carrying out the same procedures as in Example 25. The corresponding aldehyde compound was prepared by using the compound prepared in Reference Example 39 instead of the compound prepared in Reference Example 8, and by carrying out the same procedures as in Reference Example 73 → Reference Example 77 → Reference Example 78 → Reference Example 79 → Reference Example 80. The corresponding phosphonates are known compounds, or were prepared from known compounds by carrying out the same procedures as in Reference Example 10 → Reference Example 11.

[0384] 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.

[0385] 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-HO-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.

[0386] 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.

[0387] 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.

[0388] 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 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, the procedure was repeated as in Example 25 → Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23 to obtain the title compound showing the following physical properties. 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 it to the same procedures 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 it to the same procedures 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.

[0389] 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]oxocine-9-carboxylic acid 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, the procedure was repeated as in Example 25 → Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23 to obtain the title compound showing the following physical properties. 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 by subjecting the compound to the same procedures 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 No.: 37828-19-6) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid, and by subjecting the compound to the same procedures 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.

[0390] 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) and cooled to 0°C. Triethylamine (3.71 mL), trimethylamine hydrochloride (145 mg), and p-toluenesulfonyl chloride (2.32 g) were added, and the mixture was stirred at room temperature overnight and then at 50°C for 1 hour. 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, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0→75:25) to give the title compound (a mixture with the starting material), which was used in the next reaction without further purification.

[0391] 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 produced in Reference Example 81 was dissolved in toluene (32.7 mL), tetrabutylammonium chloride (3.17 g) was added, and the mixture was stirred at 60°C overnight. After confirming the completion of the reaction by TLC, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. 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 give the title compound (2.68 g) showing 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.

[0392] 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

[0123] Instead of the compound prepared in Reference Example 7, the compound prepared in Reference Example 82 (2.68 g) was used, and the intended procedure was carried out in the same manner as in Reference Example 8 to give the title compound (1.10 g) showing the following physical properties. 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.

[0393] 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

[0123] Instead of the compound prepared in Reference Example 79, the compound prepared in Reference Example 83 (1.10 g) was used, and the mixture was subjected to the same procedure as in Reference Example 80 to obtain the title compound (0.80 g) showing the following physical properties. 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.

[0394] 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 The title compound showing the following physical properties was obtained by subjecting the compound to the same procedure as in Reference Example 24, 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. The corresponding phosphonate was prepared by subjecting the compound to the same procedure as in Reference Example 10 → Reference Example 11, using 3-phenyl-3-oxetanecarboxylic acid (CAS number: 114012-42-9) instead of (2S)-2-(2,4-difluorophenyl)propanoic acid. HPLC retention time (min): 1.089; MS (ESI, Pos.): 513 (M+Na)+, 473 (M+H-HO)+. 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.

[0395] Examples 32-1 to 32-8: The title compounds showing the following physical properties were obtained by subjecting the target operations to the same procedures as in Reference Example 24, 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. The corresponding phosphonates are known compounds, or were prepared from known compounds by subjecting them to the same procedures as in Reference Example 10 → Reference Example 11.

[0396] 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.

[0397] 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-HO)+. 1 H-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.

[0398] 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-HO) +. 1H-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.

[0399] 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-HO) +, 421 (M + H-HO-HCl) +. 1 H-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.

[0400] 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)+. 1H-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.

[0401] 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 HPLC retention time (min): 1.097; MS (ESI, Pos.): 455 (M+H-H2O)+. ; 1 H-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.

[0402] 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)+. 1H-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.

[0403] 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-HO)+. 1 H-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.

[0404] 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

[0123] The title compound showing the following physical properties was obtained by the same procedure as in Example 25, except that the corresponding aldehyde compound was used instead of the compound prepared in Reference Example 9, and the compound prepared in Reference Example 27 was used instead of the compound prepared in Reference Example 26. The corresponding aldehyde was prepared by subjecting the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3 to 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.

[0405] 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 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, the title compound showing the following physical properties was obtained by the same procedure as in Example 25. The corresponding aldehyde was prepared using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, and by 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 following the procedure described in Reference Example 28 → Reference Example 29, using iodobenzene instead of 1,3-difluoro-2-iodobenzene. 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.

[0406] 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 Using the compound prepared in Reference Example 84 instead of the compound prepared in Reference Example 40, the same procedures as in Reference Example 48 → Reference Example 49 → Example 11 were carried out to obtain the title compound showing the following physical properties. HPLC retention time (min): 1.194; MS (ESI, Pos.): 459 (M+H−HO)+.; 1H-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.

[0407] 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 treating the target compound in the same manner as in Reference Example 73, except for using the compound prepared in Reference Example 39 instead of the compound prepared in Reference Example 8.

[0408] 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 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) and THF (4 mL) were added to the compound prepared in Reference Example 85 (2.01 g) to dissolve the solution, and the mixture was cooled to −50° C. A solution of sodium tert-butoxide (1.06 g) in THF (1 mL) was added to the solution over 10 minutes, and then iodomethane (0.345 mL) was added and the mixture was stirred at −10° C. for 2 hours. To the reaction mixture was added ice-cooled 1N aqueous hydrochloric acid solution, followed by extraction 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 give the title compound (1.50 g) showing the following physical properties: 1H-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.

[0409] 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

[0123] Using the compound produced in Reference Example 86 instead of the compound produced in Reference Example 7, and performing the same procedures as in Reference Example 8 → Reference Example 9 to obtain the title compound showing the following physical properties. 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.

[0410] 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

[0123] The title compound showing the following physical properties was obtained by using the compound produced in Reference Example 87 instead of the compound produced in Reference Example 76 and the corresponding phosphonate instead of the compound produced in Reference Example 26, and by carrying out the same procedure as in Example 25. The corresponding phosphonate was prepared by using methyl 1-(4-fluorophenyl)cyclobutanecarboxylate (CAS No.: 1090553-79-9) instead of the compound produced in Reference Example 10, and by carrying out the same procedure as in Reference Example 11. HPLC retention time (min): 1.206; MS (ESI, Pos.): 503 (M+Na)+. ; 1H-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.

[0411] Example 37: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen-1-yl]-2-methoxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0123] The title compound showing the following physical properties was obtained by the same procedure as in Example 25, using the compound produced in Reference Example 87 instead of the compound ...

Claims

DEPCT691. Compounds represented by the general formula (I) or their salts: (chemical formula)(I) where R1 means COOH, COOR11, CONHSO2R12 or tetrazolyl, R11 means C1-6 alkyl, R12 means C1-6 alkyl or phenyl, which phenyl may be chosen to be replaced by 1 to 5 (1) halogen atoms or (2) C1-4 alkyl groups, X1, X2 and X3 each independently mean N, CH or CR21, R21 multiple groups which each independently mean (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) -(CH2)t-(saturated carbocycle type C3-4), or (5) vinyl which may be chosen to be replaced by 1 to 3 halogen atoms, t- R6 represents (1) a halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4) -(CH2)q-(saturated C3-4 carbocycle), q represents an integer 0 or 1, p represents an integer 0 to 3, multiple R6 groups may form a saturated C3-4 carbocycle which may be selectively replaced by 1 to 6 halogen atoms along with the carbon atom to which each R6 group is attached, Y represents an oxygen atom or a sulfur atom, each R2 and R3 independently represents (1) a hydrogen atom, (2) a halogen, (3) C1-4 alkyl, or (4) C1-4 haloalkyl,R2 and R3 may form a saturated C3-4 carbocycle which may be selectively replaced by 1 to 6 halogen atoms along with the carbon atom to which R2 and R3 are attached; Z means CHR10 or oxygen atom; R10 means hydrogen atom, halogen, hydroxyl group, or methoxy group; L means -CH2-, -CHRL1, -CRL2RL3- or -C(=CH2)-; RL1 means (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; RL2 and RL3 each independently mean (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 haloalkinyl or(8) hydroxyl group, or RL2 and RL3 may constitute (1) a saturated C3-6 carbocycle which may be selectively replaced by 1 to 10 halogen atoms or (2) a saturated 3-6 member heterocycle which may be selectively replaced by 1 to 8 halogen atoms, together with carbon atoms to which RL2 and RL3 are attached, R4 means (1) C3-7 alkyl which may be selectively replaced by 1 to 5R41,(2)C3-7 alkynyl which may be selectively replaced by 1 to 5R42,(3)C3-7 alkynyl which may be selectively replaced by 1 to 5R43,(4)C2-6 alkoxy, which may be selectively replaced by 1 to 5R44 or (5)Cyc1,R41,R42,R43 and R44 each independently mean (1) halogen, (2)C3-6 carbocycle or (3) 3-6 member heterocycle, in which C3-6 carbocycle and 3-6 member heterocycle may be selectively replaced by 1 to 10 (1) halogen atoms or (2) C1-2 alkyl groups,Cyc1 means (1)C5-10 carbocycle, which may be selectively replaced by 1 to 5R51 or (2) 5-10 member heterocycle, which may be selectively replaced by 1 to 5R52,R51 and R52 each independently mean (1) halogen, (2)C1-4 alkyl, (3)C1-4 halogen Alkyl,(4)C2-4alkenyl,(5)C2-4haloalkenyl,(6)C2-4alkinyl,(7)C2-4haloalkinyl,(8)C1-4alkoxy,(9)C1-4haloalkoxy,(10)hydroxy group,(11)saturated C3-6 carbocycle or(12)saturated 3-6 member heterocycle,RL1 and R51 may form (1)saturated C3-6 carbocycle or (2)saturated 3-6 member heterocycle, together with the carbon atom to which RL1 and R51 are attached,R5 means hydrogen atom or hydroxyl group, where R6,R41,R42,R43,R44,R51 and R52 many may be the same or different,(symbol) means single or double bond,Provided that (symbols) adjacent to each other are not double bonds at the same time, (symbols) represent bonds located beneath the paper surface (i.e., alpha configuration), (symbols) represent bonds located in front of the paper surface (i.e., beta configuration), where (symbols) attached to an asymmetric atom represent alpha configuration, beta configuration, or a mixture of alpha configuration and beta configuration in any ratio, unless otherwise indicated.

2. Compounds or their salts according to claim 1, Where X1, X2, and X3 are each independently CH or CR213. Compounds or salts according to claim 1 or 2, where Y is an oxygen atom.

4. Compounds or salts according to any one of claims 1 through 3, where R4 is a C3-7 alkyl which may be selectively replaced by 1 through 3R41 or Cyc15. Compounds or salts according to any one of claims 1 through 4, where Z is CHR10, and R10 is a hydroxyl group.

6. Compounds or salts according to any one of claims 1 through 5,where R1 is COOH7. Compounds or their salts according to claim 1, where the general formula (I) is expressed by general formula (I-3) (chemical formula) (I-3), where L10 means -CHRL1 or -CRL2,RL3-,R4a means C3-7 alkyl which may be selectively replaced by 1 to 3R41, C3-7 alkenyl which may be selectively replaced by 1 to 3R42, or Cyc1, and other symbols represent all the same meanings as in claim 18. Compounds or their salts according to claim 1, where the compounds expressed by general formula (I) or their salts are (1)(1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)- [b]cyclopenta[f]oxypene-6-carboxylic acid,(2)(1R,2R,3aS,10aR)-5-fluoro-1-[(1E)-4-(2-fluorophenyl)-3-hydroxy-1-pentane-1-il]-2-hydroxy-2,3,3a,9,10,10a-hexahydro- 1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(3)(1R,2R,3aS,10aR)-1-{(1E,3C)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propane-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(4)(1R,2R,3aS,10aR)-1-{(1E,3C)-3-[1-(2,5-difluorophenyl)cyclobutyl]-3-hydroxy-1-propane-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(5)(1R,2R,3aS,10aR)-5-chloro-1-[(1E,3C)-4-(2,6-difluorophenyl)-4,4-difl [b]cyclopenta[f]oxypene-6-carboxylic acid,(6)(1R,2R,3aS,10aR)-1-{(1E,3C)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propane-1-il}-2-hydroxy-5-methyl-2,3,3a,9, 10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(7)(1R,2R,3aS,10aR)-1-[(1E,3C,4C)-4-ethyl-3-hydroxy-7-methyl-1-octane-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid Sid,(8)(1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadienne-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(9)(1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octane-1-il]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(10)(1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4C)-4-hydroxy-4,7-dimethyl-1-octane-1-il]-5-methyl-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(11)(1R,3aS,10aR)-5-fluoro-1-[(1E,3C)-3-hydroxy-4-methyl-4-phenyl-1-pentane-1-il]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(12)(1R,3aS,10aR)-1-{(1E,3C)-3- [1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propane-1-il}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(13)(1R,3aS,10aR)-5-chloro-1-{(1E,3C)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propane-1-il}-2,3,3a,9, 10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(14)(1R,3aS,10aR)-5-chloro-1-[(1E,3C)-3-hydroxy-6-methoxy-4-methylene-1-hexane-1-il]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(15)(1R,3aS,10aR)-5-chloro-1-[(1E,3C,4S)-4-ethyl-3-hydroxy-1-octane-1-il]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(16)(1R,3aS,10aR)-5-chloro-1-[(1E,3C)-3-hydroxy-3-(3-phenyl-3-oxytanyl)-1-propane-1-il]-2,3,3a,9,1 0,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(17)(1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3C)-3-hydroxy-4-methyl-4-phenyl-1-pentane-il]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(18)(1 R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3C)-3-hydroxy-3-(3-phenyl-3-oxytanyl)-1-propane-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(19)(1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3C)-3-[3-(2-fluorophenyl )-3-oxytanil]-3-hydroxy-1-propane-1-il}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(20)(1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3C)-3-hydroxy-3-[(2C)-2-phenyl-2-oxytanil]-1-propane-1-il}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid,(21)(1R,3aR,10aR)-1-[(1E,3C,4S)-3-hydroxy-4-methyl-1-octane-1-yl]-5-methyl-1,3,3a,9,10,10a-hexahydrofuro[3,4-b][1]benzoxipene-6-carboxylic acid,(22)(1R,3aR,10aR)-1-[(1E, 3C)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propane-1-yl]-5-methyl-1,3,3a,9,10,10a-hexahydrofuro[3,4-b][1]benzoxypine-6-carboxylic acid,(23)(1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-{(1E,3C)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propane -1-il}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid, or (24)(1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3R)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propane-1-il]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxypene-6-carboxylic acid, or its salts.

9. Pharmaceutical compositions which are combined with any of the compounds or their salts according to any of Claims 1 to 8.10.EP3 agonists which are combined with any of the compounds or their salts according to any of Claims 1 to 8;,