Tricyclic compound

Abstract

The present invention provides compounds having EP3 agonist activity. A compound represented by general formula (I) (in the formula, all symbols are as described in the description) or a salt thereof has a potent EP3 agonist activity, and thus is useful as an EP3 agonist.

Description

Technical Field

[0001] The present invention relates to a compound represented by the following general formula (I) or a salt thereof (hereinafter, sometimes simply referred to as the compound of the present invention).

[0002] [Chemical Formula 1]

[0003]

[0004] In the formula, all symbols have the same meanings as below. Background Art

[0005] Prostaglandin (PG) is known as the metabolite in the arachidonic acid cascade, and its known effect has cytoprotective effect, uterine contraction, analgesia, promotes the peristaltic movement of the digestive tract, arousal effect, gastric acid secretion inhibitory effect, hypotensive effect or diuresis etc.In addition, there is the different hypotype of effect separately in known PGE (prostaglandin E) receptor.Current known hypotype is roughly divided into 4 kinds, is respectively referred to as EP1, EP2, EP3 and EP4 (non-patent literature 1).

[0006] However, Non-Patent Documents 2 and 3 are known regarding tricyclic compounds.

[0007] Prior art literature

[0008] Non-patent literature

[0009] Non-patent document 1: Journal of Biological Chemistry, Vol. 282, No. 16, pp. 11613-11617

[0010] Non-patent document 2: Phytochemistry, Vol. 16, No. 4, pp. 494-195

[0011] Non-patent document 3: Journal of Organic Chemistry, Vol. 64, No. 17, pp. 6380-6386 Summary of the Invention

[0012] Technical problem solved by the invention

[0013] The problem underlying the present invention is to provide compounds which have EP3 agonist activity.

[0014] Technical means to solve the problem

[0015] The present inventors conducted intensive studies to solve the above problems and found that the compounds shown below have potent EP3 agonist activity.

[0016] The present invention has the following aspects, for example.

[0017] [1] A compound represented by the general formula (I) or a salt thereof,

[0018] [Chemical Formula 2]

[0019]

[0020] Where,

[0021] R 1 Indicates COOH, COOR 11 、CONHSO2R 12 or tetrazolyl,

[0022] R 11 represents a C1~6 alkyl group,

[0023] R 12 represents a C1-6 alkyl group or a phenyl group, the phenyl group being optionally substituted with 1 to 5 (1) halogen or (2) C1-4 alkyl groups,

[0024] X 1 、X 2 and X 3 Each independently represents N, CH or CR 21 ,

[0025] Multiple R 21 Each independently represents (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) -(CH2) t -(C3~4 saturated carbocyclic ring) or (5) vinyl optionally substituted with 1~3 halogens,

[0026] t represents an integer of 0 or 1,

[0027] [Chemical Formula 3]

[0028]

[0029] The structure shown in Chemical Formula 3 represents the structure shown in Chemical Formula 4,

[0030] [Chemical Formula 4]

[0031]

[0032] R 6 represents (1) halogen, (2) C1~4 alkyl, (3) C1~4 haloalkyl, or (4) -(CH2) q -(C3~4 saturated carbocyclic ring),

[0033] q represents an integer of 0 or 1,

[0034] p represents an integer from 0 to 3,

[0035] Multiple R 6 Optionally, together with the carbon atoms to which they are bonded, they form a C3-4 saturated carbocyclic ring optionally substituted with 1 to 6 halogens,

[0036] Y represents an oxygen atom or a sulfur atom,

[0037] R 2 and R 3 Each independently represents (1) a hydrogen atom, (2) a halogen, (3) a C1-4 alkyl group, or (4) a C1-4 haloalkyl group,

[0038] R 2 and R 3 Optionally, together with the carbon atom to which it is bonded, it forms a C3-4 saturated carbocyclic ring optionally substituted with 1 to 6 halogens,

[0039] Z stands for CHR 10 or oxygen atoms,

[0040] R 10 represents a hydrogen atom, a halogen, a hydroxyl group or a methoxy group,

[0041] L represents -CH2-, -CHR L1 -、-CR L2 R L3 - or -C(=CH2)-,

[0042] 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,

[0043] R L2 and R L3 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) hydroxyl, or

[0044] R L2 and R L3 Optionally, together with the carbon atom to which it is bonded, it forms (1) a C3-6 saturated carbocyclic ring optionally substituted with 1 to 10 halogens, or (2) a 3-6 membered saturated heterocyclic ring optionally substituted with 1 to 8 halogens,

[0045] R 4 Indicates (1) optionally substituted with 1 to 5 R 41 C3~7 alkyl, (2) optionally substituted with 1~5 R 42C3~7 alkenyl, (3) optionally substituted with 1~5 R 43 C3~7 alkynyl, (4) optionally substituted with 1~5 R 44 C2~6 alkoxy, (5)Cyc 1 or (6)-O-Cyc 1 ,

[0046] R 4 Indicates optional substitution with 1 to 5 R 41 When the C3~7 alkyl group is a C3~7 alkyl group, one carbon atom in the C3~7 alkyl group is optionally substituted by an oxygen atom,

[0047] R 41 、R 42 、R 43 and R 44 Each independently represents (1) halogen, (2) C3-6 carbocycle or (3) 3-6 membered heterocycle, wherein the C3-6 carbocycle and 3-6 membered heterocycle are optionally substituted with 1 to 10 (1) halogen or (2) C1-2 alkyl groups,

[0048] Cyc 1 Indicates (1) optionally substituted with 1 to 5 R 51 C5~10 carbon ring or (2) optionally substituted with 1~5 R 52 5-10 membered heterocyclic ring,

[0049] R 51 and R 52 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, (8) C1-4 alkoxy, (9) C1-4 haloalkoxy, (10) hydroxy, (11) C3-6 saturated carbocyclic ring or (12) 3-6 membered saturated heterocyclic ring,

[0050] R L1 and R 51 optionally together with the carbon atoms to which it is bonded, form (1) a C3-6 saturated carbocyclic ring or (2) a 3-6 membered saturated heterocyclic ring,

[0051] R 5 represents a hydrogen atom or a hydroxyl group,

[0052] Multiple R 6 、R 41 、R 42 、R 43 、R 44 、R 51 and R 52 can be the same as or different from each other,

[0053] [Chemical Formula 5]

[0054]

[0055] The structure shown in Chemical Formula 5 represents a single bond or a double bond, wherein adjacent structures shown in Chemical Formula 6 do not both represent double bonds.

[0056] [Chemical Formula 6]

[0057]

[0058] [Chemical Formula 7]

[0059]

[0060] The structure shown in Chemical Formula 7 indicates that the bond is formed on the opposite side of the paper (i.e., α configuration).

[0061] [Chemical Formula 8]

[0062]

[0063] The structure shown in Chemical Formula 8 indicates that the bond is formed near the front side of the paper (i.e., β configuration).

[0064] In the formula, the structure shown in Chemical Formula 9 bonded to an asymmetric atom represents an α configuration, a β configuration, or a mixture thereof in any ratio unless otherwise specified.

[0065] [Chemical Formula 9]

[0066] .

[0067] [2] The compound or salt thereof according to [1], wherein

[0068] X 1 、X 2 and X 3 Each independently is CH or CR 21 .

[0069] [3] The compound or salt thereof according to [1] or [2], wherein

[0070] Y is an oxygen atom.

[0071] [4] The compound or salt thereof according to any one of [1] to [3], wherein

[0072] R 4 is optionally substituted with 1 to 3 R 41 C3~7 alkyl, optionally substituted with 1~3 R 42 C3~7 alkenyl, or Cyc 1 .

[0073] [5] The compound or salt thereof according to any one of [1] to [4], wherein

[0074] Z is CHR 10 , R 10 It is a hydroxyl group.

[0075] [6] The compound or salt thereof according to any one of [1] to [5], wherein

[0076] R 1 is COOH.

[0077] [7] The compound or salt thereof according to [1], wherein

[0078] The general formula (I) is represented by the general formula (I-3),

[0079] [Chemical Formula 10]

[0080]

[0081] Where, L 10 Indicates -CHR L1 -or-CR L2 R L3 -, R 4a Indicates optional substitution with 1 to 3 R 41 C3~7 alkyl, optionally substituted with 1~3 R 42 C3~7 alkenyl, or Cyc 1 , other symbols have the same meanings as above.

[0082] [8] The compound or salt thereof according to [1], wherein

[0083] The compound represented by general formula (I) or a salt thereof is the following compound or a salt thereof:

[0084] (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,

[0085] (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,

[0086] (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,

[0087] (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,

[0088] (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,

[0089] (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,

[0090] (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,

[0091] (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,

[0092] (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,

[0093] (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,

[0094] (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,

[0095] (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,

[0096] (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,

[0097] (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,

[0098] (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,

[0099] (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,

[0100] (17)(1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-pentenyl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid,

[0101] (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,

[0102] (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,

[0103] (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,

[0104] (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,

[0105] (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,

[0106] (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

[0107] (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.

[0108] [9] A pharmaceutical composition comprising the compound or a salt thereof according to any one of [1] to [8].

[0109]

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

[0110]

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

[10] , which is used for preventing and / or treating diseases such as myocardial infarction, dysuria, and glaucoma.

[0111]

[12] A preventive and / or therapeutic agent for kidney disease, comprising the compound or a salt thereof according to any one of [1] to [8].

[0112]

[13] The reagent according to

[12] , wherein

[0113] Kidney disease is chronic kidney disease.

[0114]

[14] The reagent according to

[13] , wherein

[0115] Chronic kidney disease included diabetic nephropathy, nephrosclerosis, IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative nephritis, lupus nephritis, minimal change disease nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, Alport syndrome, or polycystic kidney disease.

[0116]

[15] The reagent according to

[12] , wherein

[0117] Kidney disease is acute kidney injury.

[0118]

[16] The reagent according to

[15] , wherein

[0119] Acute kidney injury includes acute kidney injury associated with organ surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis, contrast-induced nephropathy, or drug-induced kidney injury.

[0120]

[17] A method for preventing and / or treating kidney disease, comprising:

[0121] An effective amount of the compound or salt thereof according to any one of [1] to [8] is administered to a mammal (preferably a patient in need thereof).

[0122]

[18] The compound or salt thereof according to any one of [1] to [8], which is used for the prevention and / or treatment of kidney disease.

[0123]

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

[0124]

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

[10] , which is used for the prevention and / or treatment of renal disease.

[0125]

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

[10] , which is used for manufacturing a preventive and / or therapeutic agent for renal disease.

[0126]

[22] A method for producing the compound or a salt thereof according to any one of [1] to [8], comprising the following steps:

[0127] Step of subjecting the compound represented by general formula (I') to a hydrolysis reaction and / or a deprotection reaction

[0128] [Chemical Formula 11]

[0129]

[0130] Where,

[0131] T 10 is a hydrogen atom or R 11 , T 20 is a protecting group for a hydrogen atom or a hydroxyl group, T 10 and T 20 Unless they are hydrogen atoms, other symbols have the same meanings as defined in the general formula (I).

[0132]

[23] The method according to

[22] , which is used to produce a compound of the general formula (I) (R 1 =COOH, Z=CHR 10 , R 10 =hydroxy) or a salt thereof, wherein

[0133] The method comprises the following steps:

[0134] (A) Formula (I')(T 10 =R 11 , T 20 = hydrogen) is subjected to a hydrolysis reaction of a compound represented by

[0135] Effects of the Invention

[0136] The compounds of the present invention have potent EP3 agonist activity and can therefore be used to prevent and / or treat renal diseases and other diseases associated with EP3 receptors. DETAILED DESCRIPTION

[0137] Hereinafter, the present invention will be described in detail.

[0138] In the present invention, the C1-6 alkyl group includes a linear or branched C1-6 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, and isomers thereof.

[0139] In the present invention, halogen includes fluorine, chlorine, bromine and iodine.

[0140] In the present invention, the C1-4 alkyl group includes a linear or branched C1-4 alkyl group, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, and isomers thereof.

[0141] In the present invention, C1~2 alkyl refers to methyl or ethyl.

[0142] In the present invention, examples of the C3-4 saturated carbocycle include cyclopropane and cyclobutane.

[0143] In the present invention, the C1-4 haloalkyl group refers to a group in which any hydrogen atom of a linear or branched C1-4 alkyl group is substituted by 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.

[0144] In the present invention, the C2-4 alkenyl group includes a linear or branched C2-4 alkenyl group, and examples thereof include ethenyl, propenyl, butenyl, and isomers thereof.

[0145] In the present invention, the C2~4 haloalkenyl group refers to a group in which any hydrogen atom of a linear or branched C2~4 alkenyl group is substituted by one or more halogen atoms, and examples thereof include 1-fluorovinyl, 2-fluorovinyl, 2-chlorovinyl, trifluorovinyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl, and isomers thereof.

[0146] In the present invention, the C2-4 alkynyl group includes a linear or branched C2-4 alkynyl group, and examples thereof include ethynyl, propynyl, butynyl, and isomers thereof.

[0147] In the present invention, the C2-4 haloalkynyl group refers to a group in which any hydrogen atom of a linear or branched C2-4 alkynyl group is substituted with one or more halogen atoms, and examples thereof include 1-fluoroethynyl, 2-fluoroethynyl, 2-chloroethynyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl, and isomers thereof.

[0148] In the present invention, examples of the C3-6 saturated carbocycle include cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[0149] 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, dithiane

[0150] In the present invention, the C3~7 alkyl group includes a linear or branched C3~7 alkyl group, and examples thereof include propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 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.

[0151] In the present invention, the C3~5 alkyl group includes a linear or branched C3~5 alkyl group, 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.

[0152] In the present invention, the C3-7 alkenyl group includes a linear or branched C3-7 alkenyl group, and examples thereof include propenyl, butenyl, pentenyl, hexenyl, heptenyl, isopropenyl, isobutenyl, 1-methylbutenyl, 1-ethylpropenyl, 1,1-dimethylpropenyl, 1,2-dimethylpropenyl, 2-methylbutenyl, 3-methylbutenyl, 1-methylpentenyl, 1-ethylbutenyl, 2-ethylbutenyl, 1-ethyl-1-methylpropenyl, 1-ethyl-2-methylpropenyl, 1,1-dimethylbutenyl, 1,2-dimethylbutenyl, 1,3-dimethylbutenyl, 2-methylpentenyl, 3-methylpentenyl, and 4-methylpentenyl. , 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.

[0153] In the present invention, the C3~5 alkenyl group includes a linear or branched C3~5 alkenyl group, 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.

[0154] In the present invention, the C3~7 alkynyl linear or branched C3~7 alkynyl includes, for example, 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 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.

[0155] In the present invention, the C2-6 alkoxy group includes a linear or branched C2-6 alkoxy group, and examples thereof include ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, and isohexyloxy.

[0156] In the present invention, the C1-4 alkoxy group includes a linear or branched C1-4 alkoxy group, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and isomers thereof.

[0157] In the present invention, the C1-4 haloalkoxy group refers to a group in which any hydrogen atom of a linear or branched C1-4 alkoxy group is substituted by 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.

[0158] In the present invention, examples of the C3-6 carbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

[0159] In the present invention, the 3- to 6-membered heterocyclic ring refers to a 3- to 6-membered heterocyclic ring 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, aziridine, azetidine, pyrroline, tetrahydropyrrole, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, oxirane, oxazine, Cyclobutane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thioethane, 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, thioxane, dioxolane, dioxane, dithiolane and dithiane.

[0160] In the present invention, examples of the C5-10 carbon 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.

[0161] In the present invention, the 5- to 10-membered heterocyclic ring refers to a 5- to 10-membered heterocyclic ring 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, oxydiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiazine, indazole, Quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, tetrahydropyrrole, imidazoline, imidazolidine, triazoline, 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, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene , dihydrothiopyran, tetrahydrothiopyran, dihydrothiapine (thiepine), tetrahydrothiapine (thiepine), perhydrothiapine (thiepine), dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxydiazepine, tetrahydrooxydiazepine, perhydrooxydiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydro Hydrothiadiazine, Tetrahydrothiadiazine, Dihydrothiazepine, Tetrahydrothiazepine, Perhydrothiazepine, Dihydrothiadiazepine, Tetrahydrothiadiazepine, Perhydrothiadiazepine, Morpholine, Thiomorpholine, Thioxane, Indoline, Isoindoline, Dihydrobenzofuran, Perhydrobenzofuran, Dihydroisobenzofuran, Perhydroisobenzofuran, Dihydrobenzothiophene, Perhydrobenzothiophene, Dihydroisobenzo thiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,Tetrahydrocinnoline, perhydrocinnoline, benzothioxane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane, azaspiro[4.4]nonane, oxaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxaspiro[4.5]decane.

[0162] In the present invention, examples of the C5-6 carbon ring include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

[0163] In the present invention, examples of the 5- to 6-membered heterocycle include isoxazole, isothiazole, imidazole, imidazolidine, imidazoline, oxadiazine, oxadiazole, oxazine, oxazole, thioxane, dioxane, dioxolane, dithiane, dithiolane, dihydroisoxazole, dihydroisothiazole, dihydrooxadiazine, dihydrooxadiazole, dihydrooxazine, dihydrooxazole, dihydrothiadiazine, dihydrothiadiazole, dihydrothiazine, dihydrothiazine, dihydrothiazine, dihydrothiazine, dihydrothiazine, dihydrothiapyran, 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, tetrahydrothiazolidine (thiazolidine), tetrahydrothiapyran, tetrahydrothiophene, tetrahydropyrazine, tetrahydropyran, tetrahydropyridine, tetrahydropyridazine, tetrahydropyrimidine, tetrahydrofurazan, tetrahydrofuran, triazole, triazolidine, triazoline, perhydropyridazine, perhydropyrimidine, piperazine, piperidine, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyran, pyridine, pyridazine, pyrimidine, pyrrole, tetrahydropyrrole, pyrroline, furazan, furan, morpholine.

[0164] In the present invention, the following partial structure in each general formula, that is, the structure shown in Chemical Formula 12, represents the structure shown in Chemical Formula 13,

[0165] [Chemical Formula 12]

[0166]

[0167] [Chemical Formula 13]

[0168]

[0169] This partial structure includes, for example, the structure represented by Chemical Formula 14.

[0170] [Chemical Formula 14]

[0171]

[0172] In the present invention, as R 1 , preferably COOH.

[0173] In the present invention, as R 11 , preferably a C1~2 alkyl group.

[0174] In the present invention, as R 12 , preferably a C1~6 alkyl group, more preferably a C1~2 alkyl group, and further preferably a methyl group.

[0175] In the present invention, as X 1 , preferably CH or CR 21 , more preferably CR 21 .

[0176] In the present invention, as X 2 , preferably CH or CR 21 , more preferably CH.

[0177] In the present invention, as X 3 , preferably CH or CR 21 , more preferably CH.

[0178] In the present invention, as R 21 , preferably (1) halogen, (2) C1~4 alkyl or (3) vinyl, more preferably halogen or methyl.

[0179] In the present invention, the following partial structure in general formula (I), namely the structure shown in Chemical Formula 15, is preferably the structure shown in Chemical Formula 16, more preferably the structure shown in Chemical Formula 17, further preferably the structure shown in Chemical Formula 18, and particularly preferably the structure shown in Chemical Formula 19.

[0180] [Chemical Formula 15]

[0181]

[0182] [Chemical Formula 16]

[0183]

[0184] [Chemical Formula 17]

[0185]

[0186] [Chemical Formula 18]

[0187] ,or

[0188] [Chemical Formula 19]

[0189] ,or .

[0190] In the present invention, as R 6 , preferably a C1~4 alkyl group, more preferably a methyl group.

[0191] In the present invention, p is preferably 0.

[0192] In the present invention, Y is preferably an oxygen atom.

[0193] In the present invention, as R 2 , preferably a hydrogen atom.

[0194] In the present invention, as R 3 , preferably a hydrogen atom.

[0195] In the present invention, Z is preferably CHR 10 .

[0196] In the present invention, as R 10 , preferably a hydroxyl group.

[0197] In the present invention, L is preferably -CHR L1 -or-CR L2 R L3 -, more preferably -CR L2 R L3 -.

[0198] In the present invention, L is preferably a structure represented by Chemical Formula 20, and more preferably a structure represented by Chemical Formula 21.

[0199] [Chemical Formula 20]

[0200]

[0201] [Chemical Formula 21]

[0202]

[0203] In the present invention, as R L1 , preferably (1) halogen, (2) C1~4 alkyl or (3) C1~4 haloalkyl, more preferably C1~4 alkyl, further preferably methyl or ethyl.

[0204] In the present invention, as R L2, preferably (1) halogen, (2) C1~4 alkyl, (3) C1~4 haloalkyl or (4) hydroxy, more preferably C1~4 alkyl or hydroxy.

[0205] In the present invention, as R L3 , preferably (1) halogen, (2) C1~4 alkyl, (3) C1~4 haloalkyl or (4) hydroxy, more preferably halogen or hydroxy.

[0206] Furthermore, in the present invention, in R L2 and R L3 When forming a ring together with the carbon atoms to which it is bonded, the ring is preferably a C3-6 saturated carbocycle, more preferably a C3-4 saturated carbocycle, and even more preferably cyclobutane.

[0207] In the present invention, as R 4 , preferably (1) optionally substituted with 1 to 5 R 41 C3~7 alkyl, (2) optionally substituted with 1~5 R 42 C3~7 alkenyl or (3)Cyc 1 As R 4 , preferably (1) optionally substituted with 1 to 3 R 41 C3~7 alkyl, (2) optionally substituted with 1~3 R 42 C3~7 alkenyl or (3)Cyc 1 As R 4 , more preferably (1) optionally substituted with 1 to 3 R 41 C3~5 alkyl, (2) optionally substituted with 1~3 R 42 C3~5 alkenyl or (3)Cyc 1 .

[0208] In the present invention, R 41 and R 42 Each independently preferably is halogen.

[0209] In the present invention, as Cyc 1 , preferably (1) optionally substituted with 1 to 5 R 51 C5~6 carbon ring or (2) optionally substituted with 1~5 R 52 5- to 6-membered heterocyclic ring, more preferably (1) optionally substituted with 1 to 5 R 51 Phenyl, (2) optionally substituted with 1 to 3 R 52 Thiophene or (3) optionally substituted with 1 to 4 R 52 Pyridine, more preferably optionally substituted with 1 to 5 R 51 The phenyl group is particularly preferably a phenyl group optionally substituted with 1 to 3 halogens.

[0210] In the present invention, as Cyc 1 , preferably the structure shown in Chemical Formula 22, more preferably the structure shown in Chemical Formula 23.

[0211] [Chemical Formula 22]

[0212]

[0213] (In the formula, r represents an integer from 0 to 5, and other symbols have the same meanings as above.)

[0214] [Chemical Formula 23]

[0215]

[0216] (Where R 71 represents (1) halogen or (2) C1~4 alkyl, R 72 represents (1) halogen or (2) C1-4 alkyl, and s represents an integer of 0 or 1.

[0217] In the present invention, as R 71 , preferably halogen.

[0218] In the present invention, as R 72 , preferably halogen.

[0219] In the present invention, r is preferably an integer of 0 to 2.

[0220] In the present invention, as R 51 , preferably (1) halogen, (2) C1~4 alkyl or (3) C1~4 haloalkyl, more preferably halogen.

[0221] In the present invention, as R 52 , preferably (1) halogen, (2) C1~4 alkyl or (3) C1~4 haloalkyl, more preferably halogen.

[0222] In the present invention, one embodiment of the compound represented by the general formula (I) is a compound represented by the general formula (I-1),

[0223] [Chemical Formula 24]

[0224]

[0225] (In the formula, all symbols have the same meanings as above.)

[0226] One embodiment of the compound represented by general formula (I-1) is a compound represented by general formula (I-2),

[0227] [Chemical Formula 25]

[0228]

[0229] (In the formula, all symbols have the same meanings as above.)

[0230] One embodiment of the compound represented by general formula (I-2) is a compound represented by general formula (I-3),

[0231] [Chemical Formula 26]

[0232]

[0233] (Where, L 10 Indicates -CHR L1 -or-CR L2 R L3 -, R 4a Indicates optional substitution with 1 to 3 R 41 C3~7 alkyl, optionally substituted with 1~3 R 42 C3~7 alkenyl, or Cyc 1 , other symbols have the same meanings as above.)

[0234] Another embodiment of the compound represented by general formula (I) is a compound represented by general formula (I-4).

[0235] [Chemical Formula 27]

[0236]

[0237] (In the formula, all symbols have the same meanings as above.)

[0238] One embodiment of the compound represented by general formula (I-4) is a compound represented by general formula (I-5),

[0239] [Chemical Formula 28]

[0240]

[0241] (In the formula, all symbols have the same meanings as above.)

[0242] Another embodiment of the compound represented by general formula (I) is a compound represented by general formula (I-6).

[0243] [Chemical Formula 29]

[0244]

[0245] (In the formula, all symbols have the same meanings as above.)

[0246] One embodiment of the compound represented by general formula (I-6) is a compound represented by general formula (I-7),

[0247] [Chemical formula 30]

[0248]

[0249] (In the formula, all symbols have the same meanings as above.)

[0250] In the present invention, one embodiment of the compound represented by general formula (I) or a salt thereof is the following compound or a salt thereof:

[0251] (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,

[0252] (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,

[0253] (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,

[0254] (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,

[0255] (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,

[0256] (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,

[0257] (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,

[0258] (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,

[0259] (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,

[0260] (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,

[0261] (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,

[0262] (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,

[0263] (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,

[0264] (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,

[0265] (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,

[0266] (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,

[0267] (17)(1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-pentenyl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid,

[0268] (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,

[0269] (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,

[0270] (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,

[0271] (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,

[0272] (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,

[0273] (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

[0274] (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.

[0275] [Isomers]

[0276] In the present invention,

[0277] [Chemical Formula 31]

[0278]

[0279] The structure shown in Chemical Formula 31 indicates that the bond is formed on the opposite side of the paper (i.e., α configuration).

[0280] [Chemical Formula 32]

[0281]

[0282] The structure shown in Chemical Formula 32 indicates bonding to the front side of the paper (ie, β configuration).

[0283] In the present invention, the structure represented by Chemical Formula 33 that is bonded to an asymmetric atom represents an α configuration, a β configuration, or a mixture thereof in any ratio, unless otherwise specified.

[0284] [Chemical Formula 33]

[0285]

[0286] In the present invention, the structure represented by Chemical Formula 34 bonded to an asymmetric atom represents either an α configuration or a β configuration.

[0287] [Chemical Formula 34]

[0288]

[0289] In addition, the notation of ξ in a chemical name indicates that the stereoconfiguration of the substituent bonded to the asymmetric atom is either α-configuration or β-configuration (IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "GoldBook"). 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.).

[0290] For example, in the chemical names of Example 7-3 and Example 7-4:

[0291] (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 each represents:

[0292] (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

[0293] (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, or

[0294] (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,

[0295] (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,

[0296] (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

[0297] (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.

[0298] 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 embodiment, when Example 7-3 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, 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.

[0299] It is apparent to those skilled in the art that other compounds of the present invention in which the stereoconfiguration of a substituent bonded to an asymmetric atom is represented by ξ can be interpreted in the same manner.

[0300] In the present invention, isomers include all of these. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene, and alkenylidene also include straight-chain and branched groups. In addition, double bond, ring, and fused ring isomers (E, Z, cis, and trans isomers), isomers formed by the presence of asymmetric carbons (R, S, α, β configurations, enantiomers, and diastereomers), optically active forms with optical activity (D, L, d, and l forms), polar forms separated by chromatography (high polarity forms, low polarity forms), equilibrium compounds, rotational isomers, mixtures of any proportion thereof, racemic mixtures, and tautomers are all included in the present invention.

[0301] Furthermore, the optically active compound in the present invention is not limited to a 100% pure compound but may contain less than 50% of other optical isomers.

[0302] In the present invention, references to the compounds of the present invention include compounds represented by general formula (I), etc., their salts, solvates (e.g., hydrates), N-oxides, or cocrystals thereof, or solvates (e.g., hydrates) of salts of compounds represented by general formula (I), etc., or their cocrystals.

[0303] The compound represented by the general formula (I) etc. is converted into a suitable salt by a known method. The salt is preferably a water-soluble salt. In addition, the salt is preferably a pharmaceutically acceptable salt. 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), pharmaceutically acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenylethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-2-phenylethylamine, dimethylaminoethanol, 2-(diethylamino)ethanol, salts of 1-(2-hydroxyethyl)tetrahydropyrrole, 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, naphthalene disulfonate, glucuronate, gluconate, etc.), etc.), etc.

[0304] The compound represented by the general formula (I) or its salt may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. As a solvate, it is preferably low-toxic and water-soluble, and more preferably a hydrate. The compound represented by the general formula (I) or its salt may be converted into a solvate by a known method.

[0305] N-oxides of compounds represented by general formula (I) and the like are compounds obtained by oxidizing the nitrogen atom of the compounds represented by general formula (I) and the like. Furthermore, N-oxides of compounds represented by general formula (I) and the like may be further in the form of alkaline (earth) metal salts, ammonium salts, organic amine salts, or acid addition salts.

[0306] The compound represented by the general formula (I) or its salt can exist in the form of a cocrystal formed with an appropriate cocrystal former. As a cocrystal, preferably a pharmaceutically acceptable cocrystal formed with a pharmaceutically acceptable cocrystal former. Cocrystals are typically defined as crystals formed by interactions between two or more different molecules. In addition, cocrystals can be complexes of neutral molecules and salts. Cocrystals can be prepared by known methods, for example, by melt crystallization, recrystallization from a solvent, or physical pulverization with the components. Suitable co-crystal formers include organic acids (malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, isonicotinic acid, etc.), organic amines (imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-phenethylamine, dimethylaminoethanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)tetrahydropyrrole, 4-(2-hydroxyethyl)morpholine, N-methyl-D-glucamine, glycine, histidine, proline, etc.), and other organic compounds (caffeine, saccharin, etc.).

[0307] Prodrugs of compounds represented by general formula (I) and the like refer to compounds that are converted into compounds represented by general formula (I) and the like by reactions based on enzymes, gastric acid, and the like in vivo. Examples of prodrugs of compounds represented by general formula (I) and the like include, for example, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of the compound represented by general formula (I) and the like is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidinomethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); and compounds in which the hydroxy group is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the amino group of the compound represented by general formula (I) and the like is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidinomethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated). If the compound represented by the general formula (I) has a carboxyl group, examples include compounds in which the carboxyl group is esterified or amidated (for example, compounds in which the carboxyl group of the compound represented by the general formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterified, cyclohexyloxycarbonyloxyethyl esterified, or methylamidated). These compounds themselves can be produced by known methods. In addition, the prodrug of the compound represented by the general formula (I) may be a solvate. Furthermore, prodrugs of compounds represented by general formula (I) and the like can be converted into compounds represented by general formula (I) and the like under physiological conditions as described in "Development of Pharmaceuticals" Vol. 7, "Molecular Design" pp. 163-198, published by Hirokawa Bookstore in 1990. Furthermore, compounds represented by general formula (I) and the like can be converted into compounds represented by isotopes (e.g. 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 35 S. 18 F. 36 Cl, 123 I. 125 I, etc.) and other marks.

[0308] [Method for producing the compound of the present invention]

[0309] The compounds of the present invention can be produced by appropriately modifying or 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.

[0310] Among the compounds represented by the general formula (I), the compound represented by the general formula (IA) can be produced by the following reaction process formula 1.

[0311] [Chemical Formula 35]

[0312]

[0313] (In the formula, all symbols have the same meanings as above.)

[0314] [Chemical Formula 36]

[0315]

[0316] (wherein, T represents a protective group for hydroxyl, R 101 Each independently represents a C1-6 alkyl group, and other symbols have the same meanings as above.

[0317] In the reaction process formula 1, reaction 1 is well known and is carried out, for example, by reacting a compound represented by the general formula (A1) and a compound represented by the general formula (A2) in an organic solvent (e.g., tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), dioxane, acetonitrile, ethanol, dichloromethane, etc.), or in water, or in a mixture thereof, in the presence of a base (e.g., sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium tert-butoxide, potassium carbonate, tertiary amine + lithium chloride, etc.) at a temperature of -20°C to 70°C.

[0318] In the reaction process formula 1, reaction 2 is well known and is carried out by reacting the compound represented by general formula (A3) obtained in reaction 1 in an organic solvent (e.g., THF, DME, toluene, dichloromethane, diethyl ether, dioxane, etc.) in the presence or absence of cerium chloride using a reducing agent (e.g., sodium borohydride, zinc borohydride, etc.) at a temperature of -20 to 50°C. Furthermore, when selectively producing only one stereoisomer, an asymmetric reducing agent (e.g., diisopinocampheylchloroborane, etc.) or a combination of an asymmetric auxiliary and a reducing agent (e.g., (R)-2-methyl-CBS-oxazaborolidine and a borohydride / tetrahydrofuran complex or a borane dimethyl sulfide complex, (S)-(-)-binaphthol and lithium aluminum hydride, etc.) is used at a temperature of -100 to 50°C.

[0319] In the reaction process formula 1, the deprotection reaction of the protecting group is well known and can be carried out by the following methods. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenolysis, (4) deprotection reaction of silyl group, (5) deprotection reaction using metal, (6) deprotection reaction using metal complex, etc.

[0320] The following will describe these methods in detail.

[0321] (1) Deprotection reaction by alkaline hydrolysis, 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.

[0322] (2) Deprotection reaction under acidic conditions, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropanol, tetrahydrofuran, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) or 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 0-100°C.

[0323] (3) Deprotection reaction by hydrogenolysis, for example, is carried out in a solvent (e.g., ethers (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g., benzene, toluene, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (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 normal pressure or pressurized hydrogen atmosphere or in the presence of ammonium formate, at 0 to 200°C.

[0324] (4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile, etc.) at 0 to 40°C. Alternatively, it can be carried out, for example, in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic 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.

[0325] (5) 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 a solution thereof and an organic solvent such as tetrahydrofuran) in the presence of powdered zinc, with ultrasonication applied if necessary, at 0 to 40°C.

[0326] (6) Deprotection reaction using a metal complex, for example, in an organic solvent (e.g., dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof, in the presence of a capture reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, tetrahydropyrrole, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetrakistriphenylphosphine palladium (0), dichlorobis(triphenylphosphine)palladium (II), palladium (II) acetate, tris(triphenylphosphine)rhodium (I) chloride, etc.), at 0-40°C.

[0327] In addition to the above, the deprotection reaction can be carried out by, for example, the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014.

[0328] Examples of the protecting group for the hydroxyl group (including T as described in reaction formula 1) include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyran (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, p-phenylbenzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc).

[0329] Examples of the amino protecting group include benzyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenylmethyloxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), and 2-(trimethylsilyl)ethoxymethyl (SEM).

[0330] As the protective group for the hydroxyl group, a 2-tetrahydropyranyl (THP) group or a tert-butyldimethylsilyl (TBDMS) group is preferred.

[0331] As the protecting group of hydroxyl, in addition to the above, there is no particular limitation as long as it is a group that can be easily and selectively removed. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014 can be used.

[0332] Among the compounds represented by the general formula (I), the compound represented by the general formula (IB) can be produced by subjecting the compound represented by the general formula (IA) to a hydrolysis reaction.

[0333] [Chemical Formula 37]

[0334]

[0335] (In the formula, all symbols have the same meanings as above.)

[0336] This hydrolysis reaction (deprotection reaction of the carboxyl group) is well known, and examples thereof include the above-mentioned alkaline hydrolysis.

[0337] Furthermore, if necessary, this reaction may be followed by an operation of converting the reaction into a target salt or a solvate thereof (for example, a hydrate) by a known method.

[0338] The compound represented by the general formula (A1) in the reaction process formula 1 can be produced by the following reaction process formula 2.

[0339] [Chemical Formula 38]

[0340]

[0341] (Where, T 1 represents a protecting group for a hydroxyl group, R 102 represents a hydrogen atom, a phenyl group or a substituted phenyl group (such as 4-fluorophenyl group), R 103 Represents a halogen atom or COOR 11 , other symbols have the same meanings as above. 1 The protective group of the hydroxyl group represented by is the same as that of the protective group T described above.

[0342] In reaction process formula 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, the reaction is carried out in an organic solvent (e.g., DMF) using a base (e.g., imidazole) and a silane compound (e.g., trimethylsilyl chloride (TESCl), tert-butyldimethylsilyl chloride (TBSCl), tert-butyldiphenylsilyl chloride (TBDPSCl), etc.) at a temperature of -100 to 50°C.

[0343] In reaction process formula 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 can be 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 -78 to 80°C.

[0344] In the reaction process formula 2, reaction 3 is well known and can be carried out, for example, in an organic solvent (e.g., anhydrous toluene, dimethoxyethane, tetrahydrofuran, etc.) in the presence of a base (e.g., lithium hexamethyldisilazide (LHMDS), lithium diisopropylamide (LDA), butyl lithium, potassium tert-butoxide, sodium hydride, etc.) using a Wittig reagent (e.g., methyltriphenylphosphonium bromide, etc.) at a temperature of -78 to 50°C.

[0345] In the reaction process formula 2, reaction 4 is well known and can be 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., carbonyl chloride hydrochloride tris(triphenylphosphine)ruthenium (II), a metathesis catalyst, etc.) or a cobalt catalyst (e.g., a Jacobson catalyst, etc.) at a temperature of 20 to 100°C.

[0346] In the reaction process formula 2, the Mitsunobu reaction of reaction 5 and reaction 7 is well known and can be carried out, for example, in an organic solvent (e.g., dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene) in the presence of (1) an azo compound (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine (ADDP), 1,1'-azobis(N,N-dimethylformamide)) and a phosphine compound (e.g., triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine) or (2) a ylide compound (cyanomethylenetributylphosphine, cyanomethylenetrimethylphosphine) at 0°C to 100°C.

[0347] In the reaction process formula 2, reaction 6 is well known and can be carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) using an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of 0 to 100°C.

[0348] In reaction process formula 2, reaction 8 is well known and can be carried out, for example, in an organic solvent (e.g., toluene, dichloromethane, dichloroethane, etc.) using a metathesis catalyst (e.g., 2,6-diisopropylphenylimide neophylidenemorbidenium(VI) bis(tert-butoxide) or 2,6-diisopropylphenylimide neophylidenemorbidenium(VI) bis(hexafluoro-tert-butanol)) at a temperature of 20 to 80°C.

[0349] In the reaction process formula 2, reaction 9 is well known, for example, in an organic solvent (such as toluene, THF, DMF, etc.), in the presence of a nucleophile (such as an alcohol, etc.) and a palladium catalyst (such as bis(tri-tert-butylphosphine)palladium (Pd(P(t-Bu)3)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2)), etc.), under a carbon monoxide gas flow at a temperature of 50°C to 100°C.

[0350] In the reaction process formula 2, reaction 10 is well known, and (1) a metal catalyst (e.g., palladium carbon, platinum oxide, rhodium-alumina, Raney nickel, Wilkinson complex, ruthenium catalyst, iridium catalyst, etc.) is used in an organic solvent (e.g., methanol, ethanol, ethyl acetate, dichloromethane, dichloroethane, etc.) and, for example, hydrogen is used to carry out the reaction at 0 to 80° C. and atmospheric pressure or high pressure, or (2) a reducing agent (e.g., sodium borohydride, etc.) is used in an organic solvent (e.g., methanol, ethanol, etc.) and in the presence or absence of cerium chloride as an additive at −40 to 80° C.

[0351] In Reaction Process Formula 2, the compound represented by General Formula (A18) can be produced by subjecting the compound represented by General Formula (A17) to the above-described deprotection reaction.

[0352] In the reaction process formula 2, the compound represented by the general formula (A1) can be produced by subjecting the compound represented by the general formula (A18) to an oxidation reaction. As an example of the oxidation reaction, the following method can be mentioned:

[0353] (1) Methods using DMSO oxidation (e.g., Swern oxidation);

[0354] (2) Method using Dess-Martin Reagent;

[0355] (3) Methods using TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) reagent, etc.

[0356] As an example, a method using DMSO oxidation will be specifically described. For example, an alcohol compound is reacted in an organic solvent (such as chloroform, dichloromethane, ethyl acetate, etc.) in the presence of an activating agent (such as oxalyl chloride, acetic anhydride, pyridine-sulfur trioxide complex, etc.) and an oxidizing agent (such as dimethyl sulfoxide (DMSO)), and further reacted with a tertiary amine (such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, diazabicyclo[5.4.0]undec-7-ene, etc.) at -78 to 40°C.

[0357] In each reaction in the present specification, a compound having a chiral center can be optically resolved by a conventional method (eg, a method using an optical resolution column) to produce a compound in which the desired optical isomer is separated.

[0358] In the reaction process formula 2, reaction 4 and / or reaction 9 may be omitted as appropriate depending on the desired compound or the intermediate to be used.

[0359] Among the compounds represented by the general formula (I), the compound represented by the general formula (IC) can be produced by the following reaction process formula 3.

[0360] [Chemical Formula 39]

[0361]

[0362] (In the formula, all symbols have the same meanings as above.)

[0363] [Chemical Formula 40]

[0364]

[0365] (In the formula, all symbols have the same meanings as above.)

[0366] In the reaction process formula 3, reaction 11 is well known. For example, a compound represented by the general formula (A1) and a compound represented by the general formula (A19) are reacted in an organic solvent (such as tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), toluene, etc.) in the presence of a base (such as potassium hexamethyldisilazide, lithium diisopropylamide, butyl lithium, etc.) at a temperature of -100 to -20°C.

[0367] In the reaction process formula 3, the deprotection reaction of the protecting group is well known and can be carried out by the above-mentioned deprotection reaction method.

[0368] Among the compounds represented by the general formula (I), the compound represented by the general formula (ID) can be produced by subjecting the compound represented by the general formula (IC) to a hydrolysis reaction.

[0369] [Chemical Formula 41]

[0370]

[0371] (In the formula, all symbols have the same meanings as above.)

[0372] This hydrolysis reaction (deprotection reaction of the carboxyl group) is well known, and examples thereof include the above-mentioned alkaline hydrolysis.

[0373] Furthermore, if necessary, this reaction may be followed by an operation of converting the reaction into a target salt by a known method.

[0374] In each reaction in this specification, 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 well known or can be easily produced by known methods.

[0375] In each reaction in the present specification, the reaction to be heated can be carried out using a water bath, an oil bath, a sand bath or a microwave known to those skilled in the art.

[0376] In each reaction in the present specification, a solid-phase supported reagent supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) can be appropriately used.

[0377] In each reaction described herein, the reaction products can be purified by conventional purification methods, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resins, scavenger resins, column chromatography, washing, recrystallization, and the like. Purification may be performed after each reaction or after several reactions have been completed.

[0378] Specific embodiments of the method for producing the compound of the present invention include the following embodiments.

[0379] A method for producing a compound represented by general formula (I) or a salt thereof, comprising the following steps:

[0380] A step of subjecting the compound represented by the general formula (I') to a hydrolysis reaction and / or a deprotection reaction.

[0381] [Chemical Formula 42]

[0382]

[0383] Where,

[0384] T 10 is a hydrogen atom or R 11 , T 20 is a protecting group for a hydrogen atom or a hydroxyl group, T 10 and T 20 Except for hydrogen atoms, other symbols have the same meanings as defined in the general formula (I).

[0385] For T 20 The protecting group of the hydroxyl group represented by is the same as that described for the protecting group T above.

[0386] T 10 R 11 The hydrolysis reaction in the case of (deprotection reaction of the carboxyl group) is well known, and examples thereof include alkaline hydrolysis.

[0387] T 20In the case of a protecting group for a hydroxyl group, its deprotection reaction can be carried out by a known 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, (6) deprotection reaction using a metal complex, etc. The details are as described above.

[0388] Furthermore, if necessary, these reactions may be followed by an operation of converting the reaction into a target salt by a known method.

[0389] In the production method, the hydrolysis reaction may be to make (A) of the general formula (I')(T 10 =R 11 、T 20 = hydrogen atom) is subjected to a hydrolysis reaction, in which case the compound of the general formula (I) (R 1 =COOH、Z=CHR 10 、R 10 =hydroxy) or a salt thereof.

[0390] [toxicity]

[0391] The compounds of the present invention have sufficiently low toxicity that they can be used safely as pharmaceutical products.

[0392] [Application in pharmaceutical products]

[0393] The compound of the present invention can be used as an EP3 agonist having EP3 agonist activity.

[0394] Since the compounds of the present invention have EP3 agonist activity, they are considered to be useful for the treatment and / or prevention of diseases such as renal disease (eg, chronic kidney disease or acute kidney injury), myocardial infarction, dysuria, and glaucoma.

[0395] The compounds of the present invention are useful, for example, for the treatment and / or prevention of renal diseases. Some forms of renal diseases include chronic kidney disease and acute kidney injury.

[0396] In a preferred embodiment, chronic kidney disease includes, for example, chronic kidney disease based on lifestyle-related diseases, chronic glomerulonephritis, nephrotic syndrome, and hereditary kidney disease. Among them, chronic kidney disease based on lifestyle-related diseases includes diabetic nephropathy and nephrosclerosis. Chronic glomerulonephritis includes IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative nephritis, and lupus nephritis. Nephrotic syndrome includes minimal change nephrotic syndrome, focal segmental glomerulosclerosis, and membranous nephropathy. Hereditary kidney disease includes Alport syndrome and polycystic kidney disease. Polycystic kidney disease includes, for example, autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease.

[0397] Another embodiment of chronic kidney disease includes, for example, chronic signs of renal insufficiency and / or renal failure, renal hypoperfusion, hypertensive nephrosclerosis, immune renal injury, and pyelonephritis.

[0398] As another embodiment of chronic kidney disease, for example, dehydration due to forced diuresis after partial nephrectomy, uncontrolled blood pressure increase associated with malignant hypertension, urinary tract obstruction, and infections and amyloidosis associated with glomerular involvement and systemic diseases, such as rheumatoid immune system diseases, for example, chronic renal failure in lupus erythematosus, as well as renal artery stenosis, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, X-ray contrast agent-induced and drug-induced chronic interstitial renal damage, metabolic syndrome and chronic renal failure caused by dyslipidemia.

[0399] 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, abnormal decrease in creatinine and / or water excretion, abnormal increase in blood concentrations 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, increase in microalbuminuria, overt albuminuria, lesions in glomeruli and arterioles, renal tubular dilatation, and hyperphosphatemia.

[0400] In a preferred embodiment, acute kidney injury includes, for example, acute kidney injury associated with ischemia-reperfusion injury and drug-induced kidney injury (such as antibiotics and anticancer agents). Examples of acute kidney injury associated with ischemia-reperfusion injury include acute kidney injury associated with organ surgery such as cardiac surgery, liver surgery, and lung surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis, and contrast-induced nephropathy.

[0401] As another embodiment of acute kidney injury, for example, dehydration due to forced diuresis after partial nephrectomy, uncontrolled blood pressure increase associated with malignant hypertension, urinary tract obstruction, and infections and amyloidosis associated with glomerular involvement and systemic diseases such as rheumatoid immune system diseases, such as diseases in lupus erythematosus, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, as well as X-ray contrast agent-induced and drug-induced acute interstitial renal injury can be cited.

[0402] Preferred examples of renal diseases to be treated and / or prevented using the compounds of the present invention include diabetic nephropathy, IgA nephropathy, Alport syndrome, and autosomal dominant polycystic kidney disease.

[0403] The compounds of the present invention can be combined with other pharmaceutical agents and administered as a combination agent for the following purposes 1) to 3): 1) supplementing and / or enhancing the preventive and / or therapeutic effects of the compound; 2) improving the kinetics and absorption of the compound and reducing the dosage; and / or 3) alleviating the side effects of the compound.

[0404] The combination of the compound of the present invention and other drugs can be administered in the form of a compounding agent with two ingredients in a single preparation, or can be administered in the form of a separate preparation. If the separate preparations are administered, simultaneous administration and administration with a time difference are included. In addition, with respect to administration with a time difference, the compound of the present invention can be administered first, followed by the other drug, or the other drug can be administered first, followed by the compound of the present invention. Each method of administration can be the same or different.

[0405] The diseases for which the combination agent exerts therapeutic and / or preventive effects are not particularly limited, as long as they complement and / or enhance the therapeutic and / or preventive effects of the compound of the present invention.

[0406] Furthermore, agents to be used in combination with the compound of the present invention include not only those discovered so far but also those to be discovered in the future.

[0407] The pharmaceutical composition of the present invention comprises a compound of the present invention and an optional pharmaceutically acceptable carrier. For the purpose of preventing and / or treating the disease, the pharmaceutical composition comprising the compound of the present invention is usually formulated with a compound of the present invention as an active ingredient together with a pharmaceutically acceptable carrier such as various additives or solvents, and is administered to the whole body or locally in an oral or non-oral form. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient used in the preparation of a general drug. A pharmaceutically acceptable carrier is preferably a carrier that does not exhibit a pharmacological effect, is harmless, and does not inhibit the therapeutic effect of the active ingredient in the dosage of the preparation. In addition, a pharmaceutically acceptable carrier can be used for the purpose of improving the usefulness of the active ingredient and the preparation, facilitating preparation, stabilizing quality, or improving usability. Specifically, a substance described in the 2000 edition of the Yakuji Nippo Press "Pharmaceutical Additives Dictionary" (edited by the Japan Pharmaceutical Additives Association) can be selected according to an appropriate purpose.

[0408] In order to use the compound of the present invention or the combination of the compound of the present invention and other agents for the purpose, it is usually administered orally or parenterally or topically. The dosage varies according to age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., and is usually administered orally once a day to multiple times per adult per person, each time, within the range of 1 ng to 1000 mg, or once a day to multiple times per adult per person, each time, within the range of 0.1 ng to 10 mg, or continuously administered intravenously within the range of 1 hour to 24 hours per day. Of course, as described above, the dosage varies due to various conditions, so there is a situation where an amount less than the dosage is sufficient, or there is a situation where the dosage needs to be exceeded.

[0409] Examples of oral preparations include liquid preparations for internal use (e.g., elixirs, syrups, pharmaceutically acceptable aqueous solutions, suspensions, and emulsions), solid preparations for internal use (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). Examples of parenteral preparations include liquid preparations (e.g., injections (intravitreal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drips), eye drops (e.g., aqueous eye drops (aqueous eye drops, aqueous suspension eye drops, viscous eye drops, soluble eye drops, and the like), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspension eye drops, and the like)), external preparations (e.g., ointments (eye ointments, and the like)), and ear drops. These preparations may also be rapid-release preparations, sustained-release preparations, and other release-controlled preparations. These preparations can be produced by known methods, for example, methods described in the Japanese Pharmacopoeia.

[0410] Liquid preparations for oral administration 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). In addition, the liquid preparation may also contain a wetting agent, a suspending agent, an emulsifier, a sweetener, a flavoring agent, an aromatic, a preservative, a buffer, and the like.

[0411] As a solid dosage form for oral administration, for example, the active ingredient is mixed with an excipient (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (e.g., hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesium aluminum metasilicate, etc.), a disintegrant (e.g., cellulose calcium glycolate, etc.), a lubricant (e.g., magnesium stearate, etc.), a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, etc.), etc., and formulated according to a conventional method. In addition, the formulation may be coated with a coating agent (e.g., white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.) as needed, or may be coated with two or more layers.

[0412] External preparations for parenteral administration are manufactured using known methods or commonly used formulations. For example, ointments are manufactured by grinding or melting the active ingredient in a base. The ointment base is selected from known or commonly used substances. For example, the following substances may be used alone or in combination: higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate, myristate, palmitate, stearate, oleate, etc.), waxes (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (e.g., cetyl alcohol, stearyl alcohol, cetearyl alcohol, etc.), silicone oils (e.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic paraffin, white paraffin, purified lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, etc.), vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine, etc.), animal oils (e.g., mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption promoters, anti-inflammatory agents. Furthermore, moisturizers, preservatives, stabilizers, antioxidants, fragrances, etc. may also be included.

[0413] Injections as non-oral preparations include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent for use. Injections, for example, dissolve, suspend, or emulsify the active ingredient in a solvent for use. As solvents, for example, alcohols such as distilled water for injection, physiological saline, vegetable oils, propylene glycol, polyethylene glycol, ethanol, and combinations thereof can be used. In addition, the injection may also include stabilizers, solubilizers (such as glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, painkillers, buffers, preservatives, antioxidants, isotonic agents, pH regulators, excipients, etc. They are manufactured by sterilization or aseptic operation in the final process. In addition, sterile solid preparations, such as freeze-dried products, can also be manufactured and dissolved in sterilized or sterile distilled water for injection or other solvents before use.

[0414] Example

[0415] Hereinafter, the present invention will be described in detail with reference to the embodiments, but the present invention is not limited thereto.

[0416] The solvents in parentheses shown at the separation points based on chromatography and TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

[0417] The following are the conditions used for LC / MS analysis in the following examples: Column: YMC Triart C18, 2.0 mm × 30 mm, 1.9 μm; Flow rate: 1.0 mL / min; Temperature: 30°C; Mobile phase A: 0.1% TFA (trifluoroacetic acid) in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient (mobile phase A:mobile phase B ratio is shown): 0-0.10 min (95:5), 0.10-1.20 min (95:5-5:95), 1.20 min-1.50 min (5:95).

[0418] The parentheses in NMR indicate the solvent used in the measurement.

[0419] The compound names used in this specification are generally named using a naming program based on IUPAC rules, ACD / Name (registered trademark) of Advanced Chemistry Development, Inc., or based on IUPAC nomenclature.

[0420] Reference Example 1: (1R,2R,3S,4R)-3-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-oxy)cyclopentyl formate

[0421] To a solution of (1S,2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-prop-1-enyl-4-tetrahydropyran-2-oxy-2-cyclopentanol (CAS No.: 1262874-63-4, 7.2 g) in tetrahydrofuran (hereinafter referred to as THF) (5.8 mL) were added triphenylphosphine (10 g) and formic acid (1.5 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 sodium bicarbonate aqueous solution, water, and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 → 90:10) to obtain the title compound (7.7 g) having the following physical properties.

[0422] TLC: Rf 0.85 (hexane:ethyl acetate=2:1).

[0423] Reference Example 2: (1R,2R,3S,4R)-3-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-oxy)cyclopentanol

[0424] To an ethanol (50 mL) solution of the compound (7.7 g) manufactured in Reference Example 1 was added potassium carbonate (2.67 g) and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, filtered, and washed with ethyl acetate. The filtrate obtained was concentrated under reduced pressure, diluted with ethyl acetate, added with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 85: 15) to obtain the title compound (6.0 g) having the following physical property values.

[0425] TLC: Rf 0.60 (hexane:ethyl acetate=2:1).

[0426] Reference Example 3: 3-Bromo-2-fluoro-6-vinylphenol

[0427] To a solution of methyltriphenylphosphonium bromide (2.45 g) in THF (12 mL) was added potassium tert-butoxide (666 mg) at 0°C, followed by stirring 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 No. 1427373-29-2, 1.0 g) in THF (15 mL) was added, followed by stirring at 0°C for 1 hour. A 1N aqueous hydrochloric acid 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, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 85:15) to obtain the title compound (1.1 g) having the following physical properties.

[0428] TLC: Rf 0.44 (hexane:ethyl acetate=6:4);

[0429] 1 H-NMR(CDCl3): δ 7.10, 7.03, 6.91, 5.82, 5.47, 5.38.

[0430] Reference Example 4: {[(1S,2R,3S,5R)-3-(3-bromo-2-fluoro-6-vinylphenoxy)-2-(1-propen-1-yl)-5-(tetrahydro-2H-pyran-2-oxy)cyclopentyl]methoxy}(dimethyl)(2-methyl-2-propyl)silane

[0431] To a THF (17 mL) solution of the compound (1.7 g) prepared in Reference Example 2 and the compound (1.0 g) prepared in Reference Example 3 was added triphenylphosphine (1.7 g), followed by ice cooling. Diethyl azodicarboxylate (2.9 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 90:10) to obtain the title compound (2.39 g) having the following physical property values.

[0432] TLC: Rf 0.79 (hexane:ethyl acetate=9:1);

[0433] 1 H-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.

[0434] Reference Example 5: {[(1S,2R,3aS,10aR)-6-bromo-5-fluoro-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,10a-tetrahydro-1H-benzo[b]cyclopenta[f]oxepin-1-yl]methoxy}(dimethyl)(2-methyl-2-propyl)silane

[0435] A toluene (83.7 mL) solution of the compound prepared in Reference Example 4 (2.39 g) was stirred at 100°C for 30 minutes under a nitrogen stream. After cooling to 80°C, tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl) imidazole-2-ylidene] [3-phenyl-1H-indene-1-ylidene] dichlororuthenium (II) (397 mg) was added, and the reaction solution was stirred at 80°C for 100 minutes. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 90:10) to obtain the title compound (2.21 g) having the following physical property values.

[0436] TLC: Rf 0.64 (hexane:ethyl acetate=9:1);

[0437] 1H-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.

[0438] Reference Example 6: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-5-fluoro-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,10a-tetrahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0439] To a solution of the compound (2.06 g) prepared in Reference Example 5 in ethanol (12.4 mL) / dimethylformamide (hereinafter referred to as DMF) (6.18 mL) was added diisopropylamine (1.69 mL). Under a nitrogen stream, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (319 mg) was added, and the mixture was stirred at 90°C for 19 hours under a stream of carbon monoxide. The reaction solution was cooled to room temperature, poured into a cooled saturated aqueous ammonium chloride solution, and then extracted with an ethyl acetate / n-hexane mixed solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5→75:25) to obtain the title compound (1.65 g) having the following physical property values.

[0440] TLC: Rf 0.43 (hexane:ethyl acetate=9:1);

[0441] 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.

[0442] Reference Example 7: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-5-fluoro-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0443] To a solution of the compound (1.65 g) prepared 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 for 3 hours under a stream of hydrogen. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was used in the next reaction without subsequent purification.

[0444] TLC: Rf 0.87 (hexane:ethyl acetate=4:6);

[0445] 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.

[0446] Reference Example 8: (1S,2R,3aS,10aR)-5-fluoro-1-(hydroxymethyl)-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0447] In the THF (11.6 mL) solution of the crude product manufactured in Reference Example 7, a 1M THF solution (4.8 mL) of tetrabutylammonium fluoride was added at room temperature and stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 60 → 0: 100) to obtain the title compound (1.20 g) having the following physical property values.

[0448] TLC: Rf 0.36 (hexane:ethyl acetate=4:6);

[0449] 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.

[0450] Reference Example 9: (1R,2R,3aS,10aR)-5-fluoro-1-formyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0451] To a dichloromethane (5mL) solution of the compound (500mg) manufactured in Reference Example 8, dimethyl sulfoxide (hereinafter referred to as DMSO) (1mL) and triethylamine (854μL) were added, and the reaction solution was cooled to 0°C. Sulfur trioxide-pyridine complex (584mg) was added to the reaction solution and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (446mg) having the following physical property values.

[0452] TLC: Rf 0.40 (hexane:ethyl acetate=2:1);

[0453] 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.

[0454] Reference Example 10: Methyl (2S)-2-(2,4-difluorophenyl)propionate

[0455] To a solution of (2S)-2-(2,4-difluorophenyl)propanoic acid (CAS No. 1630485-27-6, 6.50 g) in methanol (100 mL) was added dropwise a 2M solution of trimethylsilyldiazomethane in n-hexane (82.3 mL) 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, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 83:17) to obtain the title compound (6.08 g) having the following physical property values.

[0456] TLC: Rf 0.50 (hexane:ethyl acetate=5:1);

[0457] 1 H-NMR(CDCl3): δ 7.24-7.29, 6.78-6.86, 3.98, 3.69, 1.49.

[0458] Reference Example 11: Dimethyl [(3S)-3-(2,4-difluorophenyl)-2-oxobutyl]phosphonate

[0459] To a solution of dimethyl methylphosphonate (7.85 g) in THF (50 mL), a 1.55 M n-hexane solution (38.9 mL) of n-butyllithium was added dropwise at -60 ° C and stirred at -78 ° C for 1 hour. To the reaction mixture, a THF (50 mL) solution of the compound (6.05 g) prepared in Reference Example 10 was added dropwise at -78 ° C and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50→0:100) to obtain the title compound (4.74 g) having the following physical property values.

[0460] TLC: Rf 0.41 (ethyl acetate);

[0461] 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.

[0462] Reference Example 12: (4S)-4-Benzyl-3-[(2R)-2-(2,4-difluorophenyl)propionyl]-1,3-oxazolidin-2-one

[0463] To a solution of 2-(2,4-difluorophenyl)propanoic acid (CAS No. 1250572-63-4, 1 g) in dichloromethane (17.7 mL) was added (4S)-4-benzyloxazolidin-2-one (CAS No. 180917-48-0, 1.43 g). Furthermore, 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 hydrochloric acid 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, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 → 65:35) to obtain the title compound (1.13 g, highly polar) having the following physical property values.

[0464] 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.

[0465] Reference Example 13: (2R)-2-(2,4-difluorophenyl)propionic acid

[0466] In a THF (15 mL) solution of the compound (1.13 g) manufactured in Reference Example 12, 30% aqueous hydrogen peroxide solution (2.8 mL) and an aqueous solution (10 mL) of lithium hydroxide (157 mg) were added at 0 ° C and stirred at room temperature for 3 hours. After adding a saturated aqueous sodium thiosulfate solution to the reaction mixture, a 1N aqueous hydrochloric acid solution was added and 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 obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 60: 40) to obtain the title compound (861 mg) having the following physical property values.

[0467] 1 H-NMR (CDCl3): δ 7.23-7.34, 6.76-6.92, 4.02, 1.51.

[0468] Reference Example 14: Dimethyl [(3R)-3-(2,4-difluorophenyl)-2-oxobutyl]phosphonate

[0469] The same procedures as in Reference Example 10 → Reference Example 11 were carried out using the compound prepared in Reference Example 13 (610 mg) instead of (2S)-2-(2,4-difluorophenyl)propionic acid to give the title compound (614 mg) having the following physical property values.

[0470] 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.

[0471] Reference Example 15: (1R,2R,3aS,10aR)-1-[(1E,4S)-4-(2,4-difluorophenyl)-3-oxo-1-penten-1-yl]-5-fluoro-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0472] To a THF (1 mL) solution of the compound (80 mg) manufactured in Reference Example 9, the compound (115 mg), lithium chloride (18 mg) and triethylamine (60 μL) manufactured in Reference Example 11 were added and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 75: 25) to obtain the title compound (117 mg) having the following physical property values.

[0473] 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.

[0474] Reference Example 16: (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-carboxylic acid ethyl ester

[0475] To a methanol (2 mL) solution of the compound (117 mg) manufactured in Reference Example 15, 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 after stirring at room temperature for 5 minutes, 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 hydrochloric acid aqueous solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane: ethyl acetate = 60: 40 → 55: 45) to obtain a mixture containing two diastereomers.

[0476] TLC: Rf 0.45, 0.40 (hexane:ethyl acetate=2:3);

[0477] 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.

[0478] 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

[0479] [Chemical Formula 43]

[0480]

[0481] The diastereoisomer mixture manufactured in Reference Example 16 was dissolved in dimethoxyethane (0.5mL) / methanol (1mL), 2N sodium hydroxide aqueous solution (0.5mL) was added at room temperature, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added and 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 obtained residue was separated using SFC columns (CHIRALPAK ID, CO2: methanol = 82: 18) to separate the two diastereoisomers, thereby obtaining a highly polar body (17.5mg). It should be noted that the stereo configuration was determined by single crystal X-ray.

[0482] HPLC retention time (min): 0.93;

[0483] MS(ESI, Pos.):445(M+H-H2O)+.;

[0484] 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.

[0485] Reference Example 17: (1R,2R,3aS,10aR)-1-[(1E,4R)-4-(2,4-difluorophenyl)-3-oxo-1-penten-1-yl]-5-fluoro-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0486] To a THF (1 mL) solution of the compound (80 mg) manufactured in Reference Example 9, the compound (115 mg), lithium chloride (18 mg) and triethylamine (60 μL) manufactured in Reference Example 14 were added and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 75: 25) to obtain the title compound (103 mg) having the following physical property values.

[0487] 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.

[0488] Reference Example 18: (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 ethyl ester

[0489] To a methanol (2 mL) solution of the compound (103 mg) prepared in Reference Example 17, p-toluenesulfonic acid monohydrate (7 mg) was added at 0 ° C and stirred at room temperature for 1 hour. Triethylamine (13 μL) was added to the reaction mixture, and after stirring at room temperature for 5 minutes, 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 solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane: ethyl acetate = 60:40→55:45), thereby separating into two diastereomers and obtaining a highly polar body (20.6 mg).

[0490] 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.

[0491] 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

[0492] To a solution of the compound (high polarity: 20.6 mg) prepared in Reference Example 18 in DME (0.5 mL) / methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL) and stirred at room temperature for 15 hours. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added and extracted 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 obtain the title compound (14.6 mg) having the following physical property values.

[0493] HPLC retention time (min): 0.88;

[0494] MS(ESI, Pos.):445(M+H-H2O)+.;

[0495] 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.

[0496] Reference Example 19(1): (4S)-4-Benzyl-3-[(2S)-2-(2-fluorophenyl)propionyl]-1,3-oxazolidin-2-one

[0497] Reference Example 19(2): (4S)-4-Benzyl-3-[(2R)-2-(2-fluorophenyl)propionyl]-1,3-oxazolidin-2-one

[0498] (4S)-4-benzyloxazolidin-2-one (3.95 g) was added to a solution of 2-(2-fluorophenyl)propionic acid (CAS No. 73041-90-4, 2.5 g) in dichloromethane (49 mL). 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 stirred overnight at room temperature. 1N aqueous hydrochloric acid was added to the reaction mixture, and extraction was performed with dichloromethane and ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 → 65:35) to obtain the title compounds (low-polarity form: 1.76 g, high-polarity form: 2.93 g) with the following physical property values.

[0499] Low polarity body: 1H-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.

[0500] 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.

[0501] Reference Example 20: Dimethyl [(3S)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate

[0502] The compound prepared in Reference Example 19(1) (low polar form: 1.76 g) was used instead of the compound prepared in Reference Example 12, and the same operations as Reference Example 13 → Reference Example 10 → Reference Example 11 were performed to obtain the title compound (941 mg) having the following physical property values.

[0503] 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.

[0504] Reference Example 21: Dimethyl [(3R)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate

[0505] The compound prepared in Reference Example 19(2) (high polarity form: 2.93 g) was used instead of the compound prepared in Reference Example 12, and the same operations as in Example 13 → Example 10 → Example 11 were carried out to obtain the title compound (970 mg) having the following physical property values.

[0506] 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.

[0507] Reference Example 22: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,4S)-4-(2-fluorophenyl)-3-oxo-1-penten-1-yl]-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0508] To a THF (1 mL) solution of the compound (80 mg) manufactured in Reference Example 9, the compound (108 mg), lithium chloride (18 mg), and triethylamine (60 μL) manufactured in Reference Example 20 were added and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 75: 25) to obtain the title compound (105 mg) having the following physical property values.

[0509] TLC: Rf 0.65 (hexane:ethyl acetate=2:1);

[0510] 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.

[0511] Reference Example 23: (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-carboxylic acid ethyl ester

[0512] To a methanol (2 mL) solution of the compound (105 mg) prepared in Reference Example 22, p-toluenesulfonic acid monohydrate (7 mg) was added at 0°C and stirred at room temperature for 1 hour. Triethylamine (13 μL) was added to the reaction mixture, and after stirring at room temperature for 5 minutes, 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 solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane: ethyl acetate = 60:40→55:45) to separate the two diastereomers and obtain a highly polar body (18.6 mg).

[0513] 1H-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.

[0514] 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

[0515] [Chemical Formula 44]

[0516]

[0517] In dimethoxyethane (0.5 mL) / methanol (1 mL) solution of the compound (high polarity body: 18.6 mg) manufactured in Reference Example 23, 2N sodium hydroxide aqueous solution (0.5 mL) was added, and the reaction mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added and extracted 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 obtain the title compound (13.1 mg) having the following physical property values. It should be noted that the stereo configuration was determined by single crystal X-ray.

[0518] HPLC retention time (min): 0.91;

[0519] MS(ESI, Pos.):427(M+H-H2O)+.;

[0520] 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.

[0521] Reference Example 24: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,4R)-4-(2-fluorophenyl)-3-oxo-1-penten-1-yl]-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0522] To a THF (1 mL) solution of the compound (80 mg) manufactured in Reference Example 9, the compound (108 mg), lithium chloride (18 mg) and triethylamine (60 μL) manufactured in Reference Example 21 were added and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 75: 25) to obtain the title compound (114 mg) having the following physical property values.

[0523] TLC: Rf 0.65 (hexane:ethyl acetate=2:1);

[0524] 1 H-NMR(CDCl3): δ 7.45, 7.04-7.28, 6.71-6.85, 6.17-6.32, 4.63-4.66,4.28-4.40, 4.04-4.10, 3.80-3.92, 3.49-3.59, 3.38-3.46, 3.27, 2.79-3.00, 2.52-2.70, 2.15, 1.99-2.05, 1.33-1.92.

[0525] Reference Example 25: (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 ethyl ester

[0526] To a methanol (2 mL) solution of the compound (117 mg) prepared in Reference Example 24, p-toluenesulfonic acid monohydrate (8 mg) was added at 0 ° C and stirred at room temperature for 1 hour. Triethylamine (14 μL) was added to the reaction mixture, and after stirring at room temperature for 5 minutes, 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 solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane: ethyl acetate = 60: 40 → 55: 45), thereby separating into two diastereomers and obtaining a highly polar body (19 mg).

[0527] 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.

[0528] 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

[0529] In the dimethoxyethane (0.5mL) / methanol (1mL) solution of the compound (high polarity: 19mg) manufactured in Reference Example 25, 2N sodium hydroxide aqueous solution (0.5mL) was added, and the reaction mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added and extracted 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 obtain the title compound (14.1mg) having the following physical property values.

[0530] HPLC retention time (min): 0.86;

[0531] MS(ESI, Pos.):427(M+H-H2O)+.;

[0532] 1H-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.

[0533] Reference Example 26: Dimethyl {2-[1-(2-fluorophenyl)cyclobutyl]-2-oxoethyl}phosphonate

[0534] By using 1-(2-fluorophenyl)cyclobutanecarboxylic acid (CAS No.: 151157-48-1, 10.4 g) instead of (2S)-2-(2,4-difluorophenyl)propionic acid, the same procedures as in Reference Example 10 → Reference Example 11 were carried out to obtain the title compound (12.64 g) having the following physical property values.

[0535] 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.

[0536] Reference Example 27: Dimethyl [2-oxo-2-(1-phenylcyclopropyl)ethyl]phosphonate

[0537] The same procedures as in Reference Example 10 → Reference Example 11 were carried out using 1-phenylcyclopropanecarboxylic acid (CAS No. 6120-95-2, 3.0 g) instead of (2S)-2-(2,4-difluorophenyl)propionic acid to give the title compound (2.6 g) having the following physical properties.

[0538] 1 H-NMR (CDCl3): δ 7.30-7.42, 3.71-3.75, 3.05, 3.00, 1.71, 1.26-1.30.

[0539] Reference Example 28: Ethyl (2,6-difluorophenyl)(difluoro)acetate

[0540] To a solution of 1,3-difluoro-2-iodobenzene (CAS No. 13697-89-7, 4.7 g) in DMSO (24 mL) was added ethyl bromodifluoroacetate (CAS No. 667-27-6, 2.5 mL) and activated copper (3.2 g), and the mixture was stirred at 65°C for 20 hours. Tert-butyl methyl ether (hereinafter referred to as MTBE) was added to the reaction mixture to separate the DMSO layer. Saturated aqueous ammonium chloride was then added and extracted with MTBE. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 → 93:7) to obtain the title compound (3.31 g) having the following physical properties.

[0541] TLC: Rf 0.36 (hexane:ethyl acetate=9:1);

[0542] 1 H-NMR (CDCl3): δ 7.42-7.50, 6.95-7.02, 4.39, 1.35.

[0543] Reference Example 29: Dimethyl [3-(2,6-difluorophenyl)-3,3-difluoro-2-oxopropyl]phosphonate

[0544] The same operation as in Reference Example 11 was carried out using the compound prepared in Reference Example 28 (3.31 g) instead of the compound prepared in Reference Example 10 to give the title compound (4.02 g) having the following physical property values.

[0545] TLC: Rf 0.55 (ethyl acetate);

[0546] 1 H-NMR (CDCl3): δ 7.41-7.52, 6.98, 3.78-3.86, 3.43-3.54.

[0547] 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

[0548] The title compound having the following physical property values ​​was obtained by performing the same procedures as in Reference Example 17 → Reference Example 18 → Example 2 using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 14. Note that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by a diastereoisomer separation procedure.

[0549] HPLC retention time (min): 0.93;

[0550] MS (ESI, Pos.): 453 (M-OH) + .;

[0551] 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.

[0552] Examples 5-1 to 5-21:

[0553] The following example compounds were obtained by performing the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, using the corresponding phosphonate instead of the compound prepared in Reference Example 14. The intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by diastereoisomer separation. The corresponding phosphonate is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11.

[0554] 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

[0555] HPLC retention time (min): 0.88;

[0556] MS(ESI, Pos.):421(M+H-H2O)+.;

[0557] 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.

[0558] 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

[0559] HPLC retention time (min): 0.94;

[0560] MS(ESI, Pos.):435(M+H-H2O)+.;

[0561] 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.

[0562] 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

[0563] HPLC retention time (min): 0.99;

[0564] MS(ESI, Pos.):469,471(M+H-H2O,M+H+2-H2O)+.;

[0565] 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.

[0566] 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

[0567] HPLC retention time (min): 0.88;

[0568] MS(ESI, Pos.):427(M+H-H2O)+.;

[0569] 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.

[0570] 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

[0571] HPLC retention time (min): 0.87;

[0572] MS(ESI, Pos.):427(M+H-H2O)+.;

[0573] 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.

[0574] 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

[0575] HPLC retention time (min): 0.94;

[0576] MS(ESI, Pos.):423(M+H-2H2O)+.;

[0577] 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.

[0578] 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

[0579] HPLC retention time (min): 0.96;

[0580] MS(ESI, Pos.):461,463(M-H2O,M+2-H2O)+.;

[0581] 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.

[0582] 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

[0583] HPLC retention time (min): 0.93;

[0584] MS(ESI, Pos.):461,463(M-H2O,M+2-H2O)+.;

[0585] 1H-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.

[0586] 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

[0587] HPLC retention time (min): 0.95;

[0588] MS (ESI, Pos.): 453 (M-OH) + .;

[0589] 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.

[0590] 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

[0591] HPLC retention time (min): 0.96;

[0592] MS (ESI, Pos.): 453 (M-OH) + .;

[0593] 1H-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.

[0594] 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

[0595] HPLC retention time (min): 0.95;

[0596] 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.

[0597] 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

[0598] HPLC retention time (min): 0.94;

[0599] MS(ESI, Pos.):453(M+H-H2O)+,435(M+H-2H2O)+.;

[0600] 1H-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.

[0601] 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

[0602] HPLC retention time (min): 0.93;

[0603] MS (ESI, Pos.): 445 (M-OH) + .;

[0604] 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.

[0605] 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

[0606] HPLC retention time (min): 0.9;

[0607] MS (ESI, Pos.): 445 (M-OH) + .;

[0608] 1H-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.

[0609] 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

[0610] HPLC retention time (min): 0.92;

[0611] MS (ESI, Pos.): 445 (M-OH) + .;

[0612] 1 H-NMR(DMSO-d6): δ 13.07, 7.37, 7.18, 7.15, 7.02-7.08, 6.98, 5.35-5.51,4.86, 4.79, 4.35, 4.09, 3.70, 3.06, 2.89-3.00, 2.74-2.86, 2.52-2.56, 2.33-2.45, 1.59-1.82, 1.12-1.25.

[0613] 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

[0614] HPLC retention time (min): 0.89;

[0615] MS (ESI, Pos.): 445 (M-OH) + .;

[0616] 1H-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.

[0617] 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

[0618] HPLC retention time (min): 0.9;

[0619] MS(ESI, Pos.):445(M+H-H2O)+.;

[0620] 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.

[0621] 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

[0622] HPLC retention time (min): 0.94;

[0623] MS(ESI, Pos.):445(M+H-H2O)+.;

[0624] 1H-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.

[0625] 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

[0626] HPLC retention time (min): 0.95;

[0627] MS(ESI, Pos.):463(M+H-H2O)+.;

[0628] 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.

[0629] 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

[0630] HPLC retention time (min): 1.116;

[0631] MS(ESI, Pos.):471(M+H-H2O)+,453(M+H-2H2O)+.;

[0632] 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.

[0633] 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

[0634] HPLC retention time (min): 1.102;

[0635] MS(ESI, Pos.):435(M+H-2H2O)+.;

[0636] 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.

[0637] Reference Example 30: (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-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0638] To a solution of the compound (309 mg) prepared in Reference Example 29 in THF (0.5 mL), sodium hydride (17.5 mg, 60% oil suspension) was added and stirred at room temperature for 2 hours. A solution of the compound (100 mg) prepared in Reference Example 9 in THF (0.5 mL) was added to the reaction mixture, and a solution of zinc chloride in 2-methyltetrahydrofuran (0.37 mL) was added and stirred at 50 ° C overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained 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 property values.

[0639] TLC: Rf 0.43 (hexane:ethyl acetate=7:3);

[0640] 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.

[0641] 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

[0642] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Reference Example 18 → Example 2 using the compound prepared in Reference Example 30 instead of the compound prepared in Reference Example 17. Note that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by a diastereoisomer separation procedure.

[0643] HPLC retention time (min): 0.83;

[0644] MS (ESI, Pos.): 467 (M-OH) + .;

[0645] 1H-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.

[0646] Examples 6-1 to 6-17:

[0647] The following example compounds were obtained by performing the same procedures as in Reference Example 30 → Reference Example 18 → Example 2, using the corresponding phosphonate instead of the compound prepared in Reference Example 29. The intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by diastereoisomer separation. The corresponding phosphonate is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 28 → Reference Example 29.

[0648] 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

[0649] HPLC retention time (min): 0.86;

[0650] MS(ESI, Pos.):431(M+H-H2O)+.;

[0651] 1 H-NMR(CD3OD): δ 7.40-7.55, 6.79-7.03, 5.57-5.65, 4.41-4.56, 4.19-4.40,3.84-3.91, 3.01, 2.74, 2.55-2.66, 1.89-1.96, 1.81, 1.63.

[0652] 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

[0653] HPLC retention time (min): 0.87;

[0654] MS (ESI, Pos.): 449 (M-OH) + .;

[0655] 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.

[0656] 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

[0657] HPLC retention time (min): 0.9;

[0658] MS (ESI, Pos.): 445 (M-OH) + .;

[0659] 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.

[0660] 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

[0661] HPLC retention time (min): 0.92;

[0662] MS (ESI, Pos.): 465 (M-OH) + .;

[0663] 1H-NMR(DMSO-d6): δ 13.07, 7.46-7.57, 7.37, 6.99, 5.87, 5.51-5.60, 5.43, 4.85, 4.44, 4.33, 3.70, 2.90, 2.79, 2.53-2.64, 2.45, 1.65-1.81, 1.46-1.65.

[0664] 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

[0665] HPLC retention time (min): 0.86;

[0666] MS(ESI, Pos.):467(M+H-H2O)+.;

[0667] 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.

[0668] 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

[0669] HPLC retention time (min): 0.86;

[0670] MS (ESI, Pos.): 465 (M-OH) + .;

[0671] 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.

[0672] 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

[0673] HPLC retention time (min): 0.87;

[0674] MS(ESI, Pos.):445(M+H-H2O)+.;

[0675] 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.

[0676] 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

[0677] HPLC retention time (min): 0.9;

[0678] MS(ESI, Pos.):463(M+H-H2O)+.;

[0679] 1H-NMR(CD3OD): δ 7.36, 6.83-6.93, 5.46-5.60, 4.43, 4.20-4.25, 3.76, 3.23-3.27, 2.91, 2.60-2.73, 2.43-2.55, 2.40, 1.43-1.85.

[0680] 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

[0681] HPLC retention time (min): 0.84;

[0682] MS(ESI, Pos.):467(M+H-H2O)+.;

[0683] 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.

[0684] 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

[0685] HPLC retention time (min): 0.87;

[0686] MS (ESI, Pos.): 463 (M-OH) + .;

[0687] 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.

[0688] 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

[0689] HPLC retention time (min): 0.89;

[0690] MS (ESI, Pos.): 463 (M-OH) + .;

[0691] 1 H-NMR(DMSO-d6): δ 12.88-13.22, 7.28-7.46, 7.16-7.22, 6.98, 5.85, 5.51-5.56, 4.85, 4.43-4.59, 4.31, 3.71, 2.82-2.92, 2.69-2.78, 2.52-2.60, 2.45,2.26, 1.69, 1.37-1.60, 1.23.

[0692] 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

[0693] HPLC retention time (min): 0.88;

[0694] MS (ESI, Pos.): 483 (M-OH) + .;

[0695] 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.

[0696] 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

[0697] HPLC retention time (min): 0.9;

[0698] MS(ESI, Pos.):463(M+H-H2O)+.;

[0699] 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.

[0700] 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

[0701] HPLC retention time (min): 0.9;

[0702] MS(ESI, Pos.):463(M+H-H2O)+.;

[0703] 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.

[0704] 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

[0705] HPLC retention time (min): 0.91;

[0706] MS(ESI, Pos.):463(M+H-H2O)+.;

[0707] 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.

[0708] 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

[0709] HPLC retention time (min): 0.92;

[0710] MS (ESI, Pos.): 483 (M-OH) + .;

[0711] 1 H-NMR(DMSO-d6): δ 12.90-13.24, 7.63-7.69, 7.48-7.53, 7.39, 6.95-7.00,5.98, 5.55, 4.86, 4.42-4.58, 4.28-4.38, 3.67, 2.85-2.96, 2.71-2.82, 2.54-2.63, 2.35-2.46, 1.66-1.78, 1.36-1.64.

[0712] 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

[0713] HPLC retention time (min): 0.86;

[0714] MS(ESI, Pos.):449(M+H-H2O)+.;

[0715] 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.

[0716] Reference Example 31: 5-Bromo-2-vinylphenol

[0717] By carrying out the same procedures as in Reference Example 3 using 4-bromo-2-hydroxybenzaldehyde (CAS No. 22532-62-3) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde, the title compound having the following physical property values ​​was obtained.

[0718] 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.

[0719] Reference Example 32: (1R,2R,3aS,10aR)-1-formyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0720] Using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3, the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 were performed to obtain the title compound having the following physical property values.

[0721] TLC: Rf 0.50 (hexane:ethyl acetate=2:1);

[0722] 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.

[0723] 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

[0724] By following 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 title compound having the following physical property values ​​was obtained. The stereoconfiguration was determined by single crystal X-ray spectroscopy.

[0725] HPLC retention time (min): 0.91;

[0726] MS(ESI, Pos.):403(M+H-H2O)+,385(M+H-2H2O)+.;

[0727] 1 H-NMR(CD3OD): δ 7.58, 7.48, 7.34-7.40, 7.22-7.29, 7.15-7.21, 5.53,5.38, 4.30-4.35, 3.88, 3.77-3.85, 3.00, 2.80, 2.59, 2.42-2.51, 1.65-1.87,0.87-1.00, 0.68-0.82.

[0728] Examples 7-1 to 7-50:

[0729] The following example compounds were obtained by performing 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 corresponding phosphonate ester instead of the compound prepared in Reference Example 14. The intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by a diastereoisomer separation procedure. The corresponding phosphonate ester is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0730] 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

[0731] MS(ESI, Pos.):357(M+H-H2O)+.;

[0732] 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.

[0733] 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

[0734] HPLC retention time (min): 0.97;

[0735] MS(ESI, Pos.):425(M+H-H2O)+,407(M+H-2H2O)+.;

[0736] 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.

[0737] 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

[0738] HPLC retention time (min): 0.99;

[0739] MS(ESI, Pos.):425(M+H-H2O)+,407(M+H-2H2O)+.;

[0740] 1H-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.

[0741] 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

[0742] HPLC retention time (min): 0.99;

[0743] MS(ESI, Pos.):425(M+H-H2O)+,407(M+H-2H2O)+.;

[0744] 1 H-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.

[0745] 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

[0746] HPLC retention time (min): 0.86;

[0747] MS(ESI, Pos.):413(M+H-H2O)+.;

[0748] 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.

[0749] 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

[0750] HPLC retention time (min): 0.97;

[0751] MS(ESI, Pos.):417(M+H-H2O)+.;

[0752] 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.

[0753] 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

[0754] HPLC retention time (min): 0.92;

[0755] MS(ESI, Pos.):373(M+H-2H2O)+.;

[0756] 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.

[0757] Examples 7-8: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3ξ,4S)-3-hydroxy-4-phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0758] HPLC retention time (min): 0.92;

[0759] MS(ESI, Pos.):373(M+H-2H2O)+.;

[0760] 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.

[0761] 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

[0762] HPLC retention time (min): 0.99;

[0763] MS(ESI, Pos.):383(M+H-H2O)+.;

[0764] 1 H-NMR(CD3OD): δ 7.59, 7.51, 7.19, 5.50-5.67, 4.41, 3.86-3.94, 3.03,2.89, 2.52-2.69, 1.83-1.98, 1.52, 1.24-1.43, 0.89-0.96, 0.50-0.58, 0.26-0.34.

[0765] Examples 7-10: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S)-3-hydroxy-4-(3-thienyl)-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0766] HPLC retention time (min): 0.84;

[0767] MS(ESI, Pos.):383(M+H-H2O)+.;

[0768] 1H-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.

[0769] 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

[0770] HPLC retention time (min): 0.94;

[0771] MS (ESI, Pos.): 421 (M+H-H2O);

[0772] 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.

[0773] 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

[0774] HPLC retention time (min): 0.94;

[0775] MS (ESI, Pos.): 421 (M+H-H2O);

[0776] 1H-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.

[0777] 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

[0778] [Chemical Formula 45]

[0779]

[0780] HPLC retention time (min): 0.97;

[0781] MS(ESI, Pos.):435(M+H-H2O)+,417(M+H-2H2O)+.;

[0782] 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.

[0783] 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

[0784] HPLC retention time (min): 0.97;

[0785] MS(ESI, Pos.):435(M+H-H2O)+.;

[0786] 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.

[0787] 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

[0788] HPLC retention time (min): 0.96;

[0789] MS(ESI, Pos.):371(M+H-H2O)+,353(M+H-2H2O)+.;

[0790] 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.

[0791] 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

[0792] HPLC retention time (min): 0.96;

[0793] MS(ESI, Pos.):371(M+H-H2O)+,353(M+H-2H2O)+.;

[0794] 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.

[0795] 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

[0796] HPLC retention time (min): 1.1;

[0797] MS(ESI, Pos.):417(M+H-2H2O)+.;

[0798] 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.

[0799] 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

[0800] HPLC retention time (min): 0.88;

[0801] MS(ESI, Pos.):391(M+H-2H2O)+.;

[0802] 1H-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.

[0803] 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

[0804] HPLC retention time (min): 0.89;

[0805] MS(ESI, Pos.):409(M+H-H2O)+.,391(M+H-2H2O)+.;

[0806] 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.

[0807] 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

[0808] HPLC retention time (min): 0.913;

[0809] MS(ESI, Pos,):437(M+H-H2O)+.;

[0810] 1H-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.

[0811] 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

[0812] HPLC retention time (min): 0.915;

[0813] MS(ESI, Pos.):455(M+H-H2O)+;

[0814] 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.

[0815] 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

[0816] HPLC retention time (min): 0.885;

[0817] MS(ESI, Pos.):439(M+H-H2O)+;

[0818] 1H-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.

[0819] 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

[0820] HPLC retention time (min): 0.99;

[0821] MS(ESI, Pos.):405(M+H-2H2O)+.;

[0822] 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.

[0823] 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

[0824] HPLC retention time (min): 0.97;

[0825] MS (ESI, Pos.): 437 (M-OH) + .;

[0826] 1H-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.

[0827] 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

[0828] HPLC retention time (min): 1.02;

[0829] MS (ESI, Pos.): 451 (M-OH) + .;

[0830] 1 H-NMR(DMSO-d6): δ 12.62-13.01, 7.48, 7.11-7.34, 5.17-5.60, 4.80-5.00,4.71, 4.24-4.38, 3.55-3.72, 2.69-2.95, 2.57-2.63, 2.52-2.55, 2.39-2.46, 1.88-1.97, 1.67.

[0831] 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

[0832] HPLC retention time (min): 0.94;

[0833] MS (ESI, Pos.): 435 (M-OH) + .;

[0834] 1H-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.

[0835] 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

[0836] HPLC retention time (min): 0.9;

[0837] MS (ESI, Pos.): 439 (M-OH) + .;

[0838] 1 H-NMR(DMSO-d6): δ 12.68-13.15, 7.50, 7.27-7.39, 7.21, 6.96-7.04, 5.45-5.53, 5.20, 4.89, 4.69, 4.27, 3.93-3.99, 3.51-3.76, 2.69-2.93, 2.52-2.55,2.44, 2.26, 1.62, 1.48, 1.00-1.11, 0.67, 0.49-0.58.

[0839] 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

[0840] HPLC retention time (min): 0.98;

[0841] MS (ESI, Pos.): 471 (M-OH) + .;

[0842] 1H-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.

[0843] 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

[0844] HPLC retention time (min): 1;

[0845] MS (ESI, Pos.): 487 (M-OH) + .;

[0846] 1 H-NMR(DMSO-d6): δ 12.68-12.97, 7.49, 7.32-7.41, 7.26, 7.19, 5.31-5.35,4.94, 4.71, 4.27-4.34, 3.82, 3.58-3.71, 2.71-2.96, 2.55, 2.36-2.46, 2.19-2.31, 1.50-1.75, 0.62-0.99.

[0847] 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

[0848] [Chemical Formula 46]

[0849]

[0850] HPLC retention time (min): 1.12;

[0851] MS(ESI, Pos.):435(M+H-2H2O)+.;

[0852] 1H-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.

[0853] 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

[0854] HPLC retention time (min): 0.96;

[0855] MS(ESI, Pos.):417(M+H-H2O)+.;

[0856] 1 H-NMR(CD3OD): δ 7.59, 7.49, 7.27, 7.07-7.20, 5.59, 5.32, 4.32, 4.12,3.76-3.84, 3.35-3.43, 2.96-3.04, 2.80, 2.56-2.65, 2.48, 2.00, 1.69-1.88,1.64, 1.32-1.36, 1.04-1.14, 0.74-0.79, 0.65.

[0857] 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

[0858] HPLC retention time (min): 0.93;

[0859] MS(ESI, Pos.):439(M+H-H2O)+.;

[0860] 1H-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.

[0861] 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

[0862] HPLC retention time (min): 0.99;

[0863] MS(ESI, Pos.):453(M+H-H2O)+.;

[0864] 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.

[0865] 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

[0866] HPLC retention time (min): 1.03;

[0867] MS(ESI, Pos.):469,471(M-H2O,M+2-H2O)+.;

[0868] 1H-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.

[0869] 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

[0870] HPLC retention time (min): 0.99;

[0871] MS(ESI, Pos.):453(M+H-H2O)+.;

[0872] 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.

[0873] 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

[0874] HPLC retention time (min): 0.95;

[0875] MS(ESI, Pos.):417(M+H-H2O)+.;

[0876] 1H-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.

[0877] 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

[0878] HPLC retention time (min): 0.98;

[0879] MS(ESI, Pos.):453(M+H-H2O)+,435(M+H-2H2O)+.;

[0880] 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.

[0881] 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

[0882] HPLC retention time (min): 0.96;

[0883] MS(ESI, Pos.):435(M+H-H2O)+.417(M-2H2O)+.;

[0884] 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.

[0885] 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

[0886] HPLC retention time (min): 0.96;

[0887] MS(ESI, Pos.):455,457(M+H-H2O)+.437,439(M+H-2H2O)+.;

[0888] 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.

[0889] 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

[0890] HPLC retention time (min): 0.95;

[0891] MS(ESI, Pos.):435(M+H-H2O)+.417(M+H-2H2O)+.;

[0892] 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.

[0893] 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

[0894] HPLC retention time (min): 1;

[0895] MS(ESI, Pos.):413(M+H-2H2O)+.;

[0896] 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.

[0897] 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

[0898] HPLC retention time (min): 0.89;

[0899] MS(ESI, Pos.):415(M+H-2H2O)+.;

[0900] 1H-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.

[0901] 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

[0902] HPLC retention time (min): 1.02;

[0903] MS (ESI, Pos.): 451 (M-OH) + .;

[0904] 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.

[0905] 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

[0906] HPLC retention time (min): 0.99;

[0907] MS(ESI, Pos.):413(M+H-2H2O)+.;

[0908] 1H-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.

[0909] 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

[0910] HPLC retention time (min): 0.93;

[0911] MS(ESI, Pos.):407(M+H-H2O)+.;

[0912] 1 H-NMR(CD3OD): δ 7.57, 7.49, 7.13-7.18, 5.66-5.78, 4.80-4.83, 4.36-4.41, 4.16-4.24, 3.87-3.95, 3.26, 2.99-3.06, 2.79-2.89, 2.55-2.69, 1.79-2.02,1.52-1.64, 1.35-1.47, 0.91-0.95, 0.93.

[0913] 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

[0914] HPLC retention time (min): 0.89;

[0915] MS(ESI, Pos.):369(M+H-H2O)+,351(M+H-2H2O)+.;

[0916] 1H-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.

[0917] 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

[0918] HPLC retention time (min): 0.91;

[0919] MS(ESI, Pos.):369(M+H-H2O)+,351(M+H-2H2O)+.;

[0920] 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.

[0921] 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

[0922] HPLC retention time (min): 0.86;

[0923] MS(ESI, Pos.):395(M+H-H2O)+,377(M+H-2H2O)+.;

[0924] 1H-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.

[0925] 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

[0926] HPLC retention time (min): 0.77;

[0927] MS (ESI, Pos.): 399 (M + Na) + .;

[0928] 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.

[0929] 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

[0930] HPLC retention time (min): 1;

[0931] MS (ESI, Pos.): 385 (M-OH) + .;

[0932] 1 H-NMR(DMSO-d6): δ 12.58-13.08, 7.48, 7.34, 7.18, 5.38-5.52, 4.75,4.46, 4.34, 3.92, 3.71, 2.76-3.00, 2.54-2.62, 2.35-2.47, 1.66-1.82, 1.06-1.54, 0.80-0.90.

[0933] Reference Example 33: 3-Bromo-2-chloro-6-vinylphenol

[0934] By carrying out the same procedures as in Reference Example 3 using 4-bromo-3-chloro-2-hydroxybenzaldehyde (CAS No. 1427438-98-9) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde, the title compound having the following physical property values ​​was obtained.

[0935] 1 H-NMR(CDCl3): δ 7.23-7.28, 7.15-7.19, 6.89-6.97, 5.86, 5.80, 5.37.

[0936] Reference Example 34: (1R,2R,3aS,10aR)-5-chloro-1-formyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[0937] Using the compound prepared in Reference Example 33 instead of the compound prepared in Reference Example 3, the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 were performed to obtain the title compound having the following physical property values.

[0938] 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.

[0939] 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

[0940] [Chemical Formula 47]

[0941]

[0942] The compound prepared in Reference Example 34 was used in place of the compound prepared in Reference Example 9, and the same procedures as in Reference Example 30 → Reference Example 18 → Example 2 were followed to give the title compound having the following physical properties. The configuration was determined by crystal X-ray.

[0943] HPLC retention time (min): 1.045;

[0944] MS (ESI, Pos.): 523 (M + Na) + .;

[0945] 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.

[0946] Examples 8-1 to 8-8:

[0947] The following example compounds were obtained by performing the same procedures as in Reference Example 30 → Reference Example 18 → Example 2, using the compound prepared in Reference Example 34 instead of the compound prepared in Reference Example 9, and the corresponding phosphonate ester instead of the compound prepared in Reference Example 29. The intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by a diastereoisomer separation procedure. The corresponding phosphonate ester is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[0948] 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

[0949] HPLC retention time (min): 0.85;

[0950] MS(ESI, Pos.):447,449(M-H2O,M+2-H2O)+.;

[0951] 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.

[0952] 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

[0953] HPLC retention time (min): 0.88;

[0954] MS(ESI, Pos.):437,439(M-H2O,M+2-H2O)+.;

[0955] 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.

[0956] 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

[0957] HPLC retention time (min): 1.117;

[0958] MS(ESI, Pos.):451(M+H-2H2O)+.;

[0959] 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.

[0960] 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

[0961] HPLC retention time (min): 0.89;

[0962] MS(ESI, Pos.):443,445(M-H2O,M+2-H2O)+.;

[0963] 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.

[0964] 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

[0965] HPLC retention time (min): 0.92;

[0966] MS(ESI, Pos.):443,445(M-H2O,M+2-H2O)+.;

[0967] 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.

[0968] 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

[0969] HPLC retention time (min): 1.081;

[0970] MS(ESI, Pos.):425,427(M-2H2O,M+2-2H2O)+.;

[0971] 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.

[0972] 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

[0973] HPLC retention time (min): 1.125;

[0974] MS(ESI, Pos.):469(M+H-2H2O)+.;

[0975] 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.

[0976] 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

[0977] HPLC retention time (min): 1.115;

[0978] MS(ESI, Pos.):469(M+H-H2O)+.;

[0979] 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.

[0980] Reference Example 35: Methyl 3-hydroxy-2-methyl-4-vinylbenzoate

[0981] To a solution of methyltriphenylphosphonium bromide (51.5 g) in THF (93.4 mL) was added potassium tert-butoxide (14.0 g) at 0°C, and the mixture was stirred at 0°C for 1 hour. A solution of methyl 4-formyl-3-hydroxy-2-methyl-benzoate (CAS No. 1427361-42-9, 9.34 g) in THF (46.7 mL) was added, and the mixture was stirred at 0°C for 3 hours. Saturated aqueous ammonium chloride and 1N aqueous hydrochloric acid were added to the reaction mixture at 0°C, and the mixture was extracted with a mixed solvent of ethyl acetate and 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 column chromatography (hexane:ethyl acetate = 97:3 → 90:10 → 80:20 → 70:30) to obtain the title compound (9.22 g) having the following physical properties.

[0982] 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.

[0983] Reference Example 36: Methyl 3-{[(1S,2R,3S,4R)-3-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-oxy)cyclopentyl]oxy}-2-methyl-4-vinylbenzoate

[0984] To a THF (70 mL) solution of the compound (7.0 g) manufactured in Reference Example 35 and the compound (13.5 g) manufactured in Reference Example 2, triphenylphosphine (12.4 g) was added and cooled under ice-cooling. A 2.2 M toluene solution of diethyl azodicarboxylate (22 mL) was added to the reaction solution and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and MTBE: normal hexane (2: 1, 150 mL) was added to the obtained residue and stirred for 1 hour. After filtering the precipitate, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 → 85: 15) to obtain the title compound (14.3 g) having the following physical property values.

[0985] 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.

[0986] Reference Example 37: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-5-methyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,10a-tetrahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid methyl ester

[0987] A toluene (200 mL) solution of the compound (14.3 g) prepared in Reference Example 36 was stirred at 60° C. for 20 minutes under a nitrogen stream and degassed. Heating was stopped, and tricyclohexylphosphine [1,3-bis (2,4,6-trimethylphenyl) imidazole-2-ylidene] [3-phenyl-1H-indene-1-ylidene] dichlororuthenium (II) (1.21 g) was added, and stirred overnight at 85° C. under a nitrogen stream. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 97:3 → 93:7) to obtain the title compound (13.2 g) having the following physical property values.

[0988] 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.

[0989] Reference Example 38: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-5-methyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid methyl ester

[0990] To a solution of the compound (13.2 g) prepared in Reference Example 37 in ethyl acetate (132 mL) was added 10% palladium on carbon (1.32 g), and the mixture was stirred at room temperature for 3 hours under a hydrogen stream. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The subsequent reaction was carried out without subsequent purification.

[0991] Reference Example 39: (1S,2R,3aS,10aR)-1-(hydroxymethyl)-5-methyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid methyl ester

[0992] In the THF (13.2 mL) solution of the crude product manufactured in Reference Example 38, a 1 mol / L THF solution (52.4 mL) of tetrabutylammonium fluoride was added at room temperature and stirred overnight at room temperature. After confirming that the reaction was completed by TLC, the reaction solution was injected into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The 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 property values.

[0993] 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.

[0994] Reference Example 40: (1R,2R,3aS,10aR)-1-formyl-5-methyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid methyl ester

[0995] To a dichloromethane (20 mL) solution of the compound (2.0 g) prepared in Reference Example 39, DMSO (10 mL) and triethylamine (3.57 mL) were added and cooled to 0 ° C. Sulfur trioxide-pyridine complex (2.45 g) was added to the reaction mixture and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 70: 30 → 55: 45) to obtain the title compound (2.0 g) having the following physical property values.

[0996] 1H-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.

[0997] 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

[0998] The title compound having the following physical property values ​​was obtained by performing 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 compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 14. It should be noted that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by a diastereoisomer separation procedure.

[0999] HPLC retention time (min): 0.9;

[1000] MS(ESI, Pos.):417(M+H-H2O)+.;

[1001] 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.

[1002] Examples 9-1 to 9-23:

[1003] The following example compounds were obtained by performing the same procedures as in Reference Example 30 → 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 ester instead of the compound prepared in Reference Example 29. It should be noted that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by a diastereoisomer separation procedure. The corresponding phosphonate ester is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[1004] 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

[1005] HPLC retention time (min): 0.86;

[1006] MS(ESI, Pos.):427(M+H-H2O)+.;

[1007] 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.

[1008] 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

[1009] HPLC retention time (min): 0.97;

[1010] MS(ESI, Pos.):449(M+H-H2O)+.;

[1011] 1H-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.

[1012] 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

[1013] HPLC retention time (min): 0.9;

[1014] MS(ESI, Pos.):407(M+H-H2O)+.;

[1015] 1 H-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.

[1016] 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

[1017] HPLC retention time (min): 1.139;

[1018] MS (ESI, Pos.): 507 (M + Na) + .;

[1019] 1H-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.

[1020] 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

[1021] [Chemical Formula 48]

[1022]

[1023] HPLC retention time (min): 1.166;

[1024] MS (ESI, Pos.): 489 (M + Na) + .;

[1025] 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.

[1026] 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

[1027] HPLC retention time (min): 1.134;

[1028] MS (ESI, Pos.): 507 (M + Na) + .;

[1029] 1H-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.

[1030] 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

[1031] HPLC retention time (min): 1.117;

[1032] MS (ESI, Pos.): 471 (M + Na) + .;

[1033] 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.

[1034] 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

[1035] HPLC retention time (min): 1.083;

[1036] MS (ESI, Pos.): 465 (M + Na) + .;

[1037] 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.

[1038] 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

[1039] HPLC retention time (min): 1.099;

[1040] MS (ESI, Pos.): 477 (M + Na) + .;

[1041] 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.

[1042] Examples 9-10: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3-thienyl)cyclopropyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[1043] HPLC retention time (min): 1.064;

[1044] MS (ESI, Pos.): 463 (M + Na) + .;

[1045] 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.

[1046] Examples 9-11: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[1047] HPLC retention time (min): 1.151;

[1048] MS (ESI, Pos.): 439 (M + Na) + .;

[1049] 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.

[1050] Examples 9-12: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-3-(1-butylcyclobutyl)-3-hydroxy-1-propen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[1051] HPLC retention time (min): 1.185;

[1052] MS (ESI, Pos.): 451 (M + Na) + .;

[1053] 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.

[1054] Examples 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

[1055] HPLC retention time (min): 1.168;

[1056] MS (ESI, Pos.): 439 (M + Na) + .;

[1057] 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.

[1058] Examples 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

[1059] HPLC retention time (min): 1.169;

[1060] MS(ESI, Pos.):381(M+H-2H2O)+.;

[1061] 1H-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.

[1062] 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

[1063] HPLC retention time (min): 1.118;

[1064] MS (ESI, Pos.): 437 (M + Na) + .;

[1065] 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.

[1066] 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

[1067] HPLC retention time (min): 1.155;

[1068] MS (ESI, Pos.): 451 (M + Na) + .;

[1069] 1H-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.

[1070] 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

[1071] HPLC retention time (min): 1.135;

[1072] MS (ESI, Pos.): 479 (M + Na) + .;

[1073] 1 H-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.

[1074] 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

[1075] HPLC retention time (min): 1.085;

[1076] MS (ESI, Pos.): 475 (M + Na) + .;

[1077] 1H-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.

[1078] 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

[1079] HPLC retention time (min): 1.104;

[1080] MS (ESI, Pos.): 487 (M + Na) + .;

[1081] 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.

[1082] Examples 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

[1083] HPLC retention time (min): 1.07;

[1084] MS(ESI, Pos.):443(M+Na)+,383(M+H-H2O-HF)+.;

[1085] 1H-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.

[1086] 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

[1087] HPLC retention time (min): 1.067;

[1088] MS(ESI, Pos.):443(M+Na)+,383(M+H-H2O-HF)+.;

[1089] 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.

[1090] 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

[1091] HPLC retention time (min): 1.128;

[1092] MS (ESI, Pos.): 491 (M + Na) + .;

[1093] 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.

[1094] 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

[1095] HPLC retention time (min): 1.094;

[1096] MS (ESI, Pos.): 441 (M + Na) + .;

[1097] 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.

[1098] 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

[1099] [Chemical Formula 49]

[1100]

[1101] The compound prepared in Reference Example 40 was used instead of the compound prepared in Reference Example 9, and the corresponding phosphonate was used instead of the compound prepared in Reference Example 14. The title compound having the following physical property values ​​was obtained by performing the same operation as Reference Example 17 → Reference Example 18 → Example 2. It should be noted that the intermediate equivalent to the compound prepared in Reference Example 18 used a highly polar form separated by a diastereoisomer separation operation. In addition, the diastereoisomers obtained by the operation of Example 2 were separated using an SFC column (CHIRALPAK IG, CO2: 2-propanol = 72: 28) to obtain a highly polar form. It should be noted that the corresponding phosphonate was prepared by performing the same operation as Reference Example 11 using methyl 2-ethyl-5-methylhexanoate (CAS No.: 1896760-61-4) instead of the compound prepared in Reference Example 10.

[1102] HPLC retention time (min): 1.196;

[1103] MS (ESI, Pos.): 453 (M + Na) + .;

[1104] 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.

[1105] Reference Example 41: Ethyl 6,7,7-trifluoro-3-hydroxy-3-methyl-6-heptenoate

[1106] To a solution of lithium hexamethyldisilazide (1 mol / L toluene solution, 670 mL) in THF (270 mL) was added dropwise ethyl acetate (65.5 mL) at -78°C, and the mixture was stirred at -78°C for 15 minutes. A solution of 5,6,6-trifluoro-5-hexen-2-one (CAS No.: 155630-33-4, 670 mmol) in THF (40 mL) was added to the reaction mixture, and the mixture was stirred at -78°C for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, followed by water and extraction with MTBE. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the title compound (130 g) having the following physical properties.

[1107] 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.

[1108] Reference Example 42: 6,7,7-Trifluoro-3-hydroxy-3-methyl-6-heptenoic acid

[1109] In the ethanol (270mL) solution of the compound (130g) manufactured in Reference Example 41, 5N sodium hydroxide aqueous solution (162mL) was added and stirred at room temperature for 1 hour. MTBE was added to the reaction solution, and the separated water layer was made acidic with 5N hydrochloric acid aqueous solution and extracted with MTBE. The organic layer was washed with saturated aqueous common salt water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (106g) with the following physical property values.

[1110] 1 H-NMR (CDCl3): δ 6.33, 3.24, 2.34-2.64, 1.70-1.93, 1.32.

[1111] Reference Example 43: (1R,2S)-2-Hydroxy-1,2-diphenylethylammonium (3S)-6,7,7-trifluoro-3-hydroxy-6-octenoate

[1112] To a solution of the compound (106 g) prepared in Reference Example 42 in 2-butanol (1.06 L) was added (1S,2R)-diphenylethanolamine (106 g) at 80°C, and the mixture was stirred at room temperature for 4 hours. The precipitate was filtered and washed with n-heptane. This washing procedure was repeated two more times to obtain the title compound (56.94 g) having the following physical property values.

[1113] 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.

[1114] Reference Example 44: (3S)-6,7,7-trifluoro-3-methyl-6-heptene-1,3-diol

[1115] To the compound (56.4 g) prepared in Reference Example 43, aqueous hydrochloric acid solution and ethyl acetate were added and extracted to obtain a carboxylic acid body (24.0 g). The carboxylic acid body was dissolved in THF (340 mL), 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 filtering the precipitate at -10°C, and stirred at 0°C for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (17.5 g) having the following physical property values.

[1116] 1 H-NMR (CDCl3): δ 3.86-4.08, 2.65-2.82, 2.30-2.52, 1.64-1.86, 1.27.

[1117] Reference Example 45: (3S)-6,7,7-Trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-6-hepten-3-ol

[1118] To a toluene (71 mL) solution of the compound (17.5 g) manufactured in Reference Example 44, 5N aqueous sodium hydroxide solution (71 mL) and tetrabutylammonium bromide (2.9 g) were added. In addition, p-toluenesulfonyl chloride (18.6 g) was added at 0°C and stirred at 0°C for 1 hour. 1-phenyl-1H-tetrazole-5-thiol (20.5 g) was added to the mixture and stirred at 60°C for 5 hours. The reaction solution was poured into ice water and extracted with toluene. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 7: 1 → 4: 1) to obtain the title compound (24.8 g) having the following physical property values.

[1119] 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.

[1120] Reference Example 46: (3S)-6,7,7-Trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-6-hepten-3-ol

[1121] To a mixture of sodium tungstate dihydrate (114 mg), phenylphosphonic acid (55 mg) and methyltri-n-octylammonium chloride (140 mg) was added an aqueous solution of hydrogen peroxide (30%) and stirred at room temperature for 15 minutes. A toluene (70 mL) solution of the compound (24.8 g) manufactured in Reference Example 45 was added to the mixture and stirred at 50 ° C for 2 hours. The reaction solution was injected into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (26.7 g) showing the following physical property values.

[1122] 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.

[1123] Reference Example 47: 1-phenyl-5-({(3S)-6,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]-6-hepten-1-yl}sulfonyl)-1H-tetrazolyl

[1124] To a DMF (30 mL) solution of the compound (5 g) prepared in Reference Example 46, imidazole (2.6 g) and trimethylsilyl chloride (2.4 mL) were added and stirred at room temperature. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was washed with n-hexane to obtain the title compound (5.1 g) having the following physical property values.

[1125] 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.

[1126] Reference Example 48: (1R,2R,3aS,10aR)-5-methyl-2-(tetrahydro-2H-pyran-2-oxy)-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-carboxylic acid methyl ester

[1127] To a solution of the compound (4.29 g) in dimethoxyethane (19.2 mL) prepared in Reference Example 47, a 1 mol / L THF (9.27 mL) solution of potassium hexamethyldisilazide was added dropwise at -78 ° C. and stirred for 20 minutes. A solution of the compound (2.4 g) in dimethoxyethane (16.8 mL) prepared in Reference Example 40 was added dropwise at -78 ° C. for 40 minutes, followed by stirring for 2 hours. Saturated aqueous sodium bicarbonate 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 sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 90: 10 → 80: 20 → 70: 30) to obtain a crude product (2.11 g) containing the title compound. No purification was performed here, and the following reaction was carried out.

[1128] Reference Example 49: (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 methyl ester

[1129] 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 and 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) exhibiting the following physical property values.

[1130] 1 H-NMR(CDCl3): δ 7.50, 6.97, 5.63-5.71, 5.39-5.46, 4.16, 3.97-4.04,3.87, 3.07-3.15, 2.74-2.81, 2.56-2.63, 2.36-2.47, 2.27, 2.17-2.22, 2.07-2.13,1.68-1.95, 1.44, 1.23.

[1131] 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

[1132] [Chemical Formula 50]

[1133]

[1134] To a solution of the compound (1.49 g) prepared in Reference Example 49 in THF (5 mL) / methanol (10 mL), 2N aqueous sodium hydroxide solution (6.36 mL) was added at room temperature and stirred overnight at 40 ° C. The reaction solution was concentrated under reduced pressure, 2N aqueous hydrochloric acid solution was added under ice-cold conditions and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized with ethyl acetate (14.5 mL) / n-hexane (5.8 mL) to give the title compound (1.16 g) showing the following physical property values.

[1135] HPLC retention time (min): 1.083;

[1136] MS(ESI, Pos.):477(M+Na)+,437(M+H-H2O)+,419(M+H-2H2O)+.;

[1137] 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.

[1138] Reference Example 50: Ethyl 7,7,7-trifluoro-3-hydroxy-3-methylheptanoate

[1139] Diethyl ether (52 mL) was added to magnesium (1.53 g), and dibromoethane (0.45 mL) was added at room temperature for activation. Bromotrifluorobutane (10 g) was further added dropwise and stirred at 50°C to prepare an organometallic reagent. In another container, a diethyl ether (45 mL) solution of N-methoxy-N-methylacetamide (5.56 mL) was cooled to -15°C. The prepared organometallic reagent was added dropwise to the solution and stirred for 90 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered to obtain a ketone body (6,6,6-trifluorohexane-2-one) in the form of a diethyl ether solution.

[1140] To a solution of lithium hexamethyldisilazide (1 mol / L THF solution, 62.8 mL) in THF (52 mL) was added dropwise ethyl acetate (6.14 mL) at -78°C and stirred at -78°C for 25 minutes. A solution of the ketone in diethyl ether was added dropwise over 20 minutes and stirred at -78°C for 50 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by water and extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 90:10 → 65:35) to obtain the title compound (16.7 g) having the following physical property values.

[1141] 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.

[1142] Reference Example 51: 7,7,7-Trifluoro-3-hydroxy-3-methylheptanoic acid

[1143] In the ethanol (130mL) solution of the compound (16.7g) manufactured in Reference Example 50, 2N sodium hydroxide aqueous solution (52mL) was added and stirred at room temperature for 1 hour. 2N hydrochloric acid aqueous solution was added to the reaction solution to make it acidic and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (8.49g) with the following physical property values.

[1144] 1 H-NMR (CDCl3): δ 2.48-2.64, 2.02-2.21, 1.56-1.76, 1.31.

[1145] Reference Example 52: (1R)-1-phenylethanolammonium (3S)-7,7,7-trifluoro-3-hydroxy-3-methylheptanoate

[1146] To a solution of the compound (8.49 g) prepared in Reference Example 51 in ethyl acetate (50 mL) was added (R)-1-phenylethylamine (5 mL) and concentrated to give crude crystals. Ethyl methyl ketone (65 mL) and n-heptane (130 mL) were added to the obtained crude crystals at 70°C and cooled to room temperature. The precipitate was filtered and washed with n-heptane. The washing operation was further repeated twice to give the title compound (2.64 g) having the following physical property values.

[1147] 1H-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.

[1148] Reference Example 53: (3S)-7,7,7-Trifluoro-3-methyl-1,3-heptanediol

[1149] The compound (2.64 g) manufactured in Reference Example 52 was added with aqueous hydrochloric acid solution and ethyl acetate and concentrated under reduced pressure. The obtained carboxylic acid was dissolved in THF (40 mL). The solution was cooled to 0°C, lithium aluminum hydride (0.3 g) was added, and stirred at 60°C. The solution was cooled to 0°C, water was added and stirred. After removing the precipitate by filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (1.74 g) having the following physical property values.

[1150] 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.

[1151] Reference Example 54: (3S)-7,7,7-Trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-3-heptanol

[1152] To a toluene (20 mL) solution of the compound (1.74 g) manufactured in Reference Example 53, 5N aqueous sodium hydroxide solution (6.5 mL) and tetrabutylammonium bromide (254 mg) were added. To the mixture, p-toluenesulfonyl chloride (1.65 g) was added at 0 ° C and stirred at 0 ° C for 1 hour and 45 minutes. 1-phenyl-1H-tetrazole-5-thiol (1.69 g) was further added and 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, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 80: 20 → 60: 40 → 55: 45) to obtain the title compound (2.65 g) having the following physical property values.

[1153] 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.

[1154] Reference Example 55: (3S)-7,7,7-Trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-3-heptanol

[1155] In a dichloromethane (35 mL) solution of the compound (2.65 g) manufactured in Reference Example 54, m-chloroperbenzoic acid (4.5 g) was added at 0 ° C and stirred overnight. The reaction solution was injected into a saturated aqueous sodium bicarbonate 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 obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 80: 20 → 75: 25) to obtain the title compound (2.76 g) having the following physical property values.

[1156] 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.

[1157] Reference Example 56: 1-phenyl-5-({(3S)-7,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]heptyl}sulfonyl)-1H-tetrazolyl

[1158] A DMF (25 mL) solution of the compound (2.76 g) manufactured in Reference Example 55 was cooled to 0 ° C, imidazole (1.44 g) and trimethylsilyl chloride (1.34 mL) were added and stirred at room temperature for 3.5 hours. Water was added to the reaction solution and extracted with ethyl acetate / n-hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 95: 5 → 85: 15) to obtain the title compound (2.88 g) having the following physical property values.

[1159] 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.

[1160] Reference Example 57: (1R,2R,3aS,10aR)-5-methyl-2-(tetrahydro-2H-pyran-2-oxy)-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-carboxylic acid methyl ester

[1161] In the dimethoxyethane (17.6 mL) solution of the compound (3.95 g) manufactured in Reference Example 56, a 1M THF (8.49 mL) solution of potassium hexamethyldisilazide was added dropwise at -78 ° C. and stirred for 20 minutes. In the reaction mixture, a dimethoxyethane (15.4 mL) solution of the compound (2.2 g) manufactured in Reference Example 40 was added dropwise at -78 ° C. for 40 minutes and stirred for 30 minutes. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture and extracted with ethyl acetate / n-hexane. The organic layer was washed with saturated brine, anhydrous sodium sulfate was added and dried, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 97: 3 → 90: 10 → 80: 20) to obtain a crude product (3.53 g) containing the title compound. The next reaction was carried out without further purification.

[1162] Reference Example 58: (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 methyl ester

[1163] 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 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) exhibiting the following physical property values.

[1164] 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.

[1165] 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

[1166] [Chemical Formula 51]

[1167]

[1168] To a solution of the compound (1.80 g) prepared in Reference Example 58 in THF (6 mL)-methanol (12 mL), 2N aqueous sodium hydroxide solution (6 mL) was added at room temperature and stirred overnight at 40 ° C. The reaction solution was concentrated under reduced pressure, 2N aqueous hydrochloric acid solution was added under ice-cold conditions 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 obtained crude product (1.8 g) was washed with ethyl acetate / n-hexane to give the title compound (1.51 g) showing the following physical property values.

[1169] HPLC retention time (min): 1.088;

[1170] MS(ESI, Pos.):479(M+Na)+,421(M+H-2H2O)+.;

[1171] 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.

[1172] Examples 12-1 to 12-4:

[1173] The following example compounds were obtained by performing the same procedures as in Reference Example 57 → Reference Example 58 → Example 12 using the corresponding tetrazolylsulfonyl compound instead of the compound prepared in Reference Example 56. The corresponding tetrazolylsulfonyl compound is a known compound or can be prepared from a known compound by performing 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.

[1174] 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

[1175] HPLC retention time (min): 1.048;

[1176] MS (ESI, Pos.): 423 (M + Na) + .;

[1177] 1 H-NMR(CD3OD): δ 7.46, 6.98, 5.80-5.90, 5.64-5.73, 5.32-5.42, 4.99-5.06, 4.90-4.96, 4.10-4.15, 3.86-3.94, 3.04-3.12, 2.55-2.74, 2.43, 2.25,2.08-2.20, 1.89-2.01, 1.79-1.87, 1.66-1.76, 1.51-1.61, 1.18.

[1178] 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

[1179] HPLC retention time (min): 1.14;

[1180] MS (ESI, Pos.): 439 (M + Na) + .;

[1181] 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.

[1182] Example 12-3: (1R,2R,3aS,10aR)-1-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-pentenyl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[1183] HPLC retention time (min): 1.171;

[1184] MS (ESI, Pos.): 451 (M + Na) + .;

[1185] 1H-NMR(CD3OD): δ 7.44, 6.98, 5.65-5.73, 5.30-5.39, 4.13, 3.87-3.93, 3.04-3.13, 2.56-2.75, 2.42, 2.26, 1.78-2.00, 1.49-1.76, 1.29, 1.13-1.21.

[1186] 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

[1187] HPLC retention time (min): 1.113;

[1188] MS (ESI, Pos.): 437 (M + Na) + .;

[1189] 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.

[1190] 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

[1191] [Chemical Formula 52]

[1192]

[1193] Using the corresponding racemic compound instead of the compound prepared in Reference Example 56, the same procedures as in Reference Example 57 → Reference Example 58 → Example 12 were carried out, and the two diastereomers were separated using an SFC column (CHIRALPAK IG, CO2:methanol = 69:31) to obtain the title compound (low-polarity form) exhibiting the following physical property values. It should be noted that the corresponding racemic compound was prepared from a known compound by carrying out 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.

[1194] HPLC retention time (min): 1.123;

[1195] MS(ESI, Pos.):439(M+Na)+,381(M+H-2H2O)+.;

[1196] 1 H-NMR(CD3OD): δ 7.43, 6.97, 5.72, 5.31-5.39, 4.10-4.15, 3.86-3.94,3.04-3.12, 2.56-2.74, 2.42, 2.17-2.28, 1.90-1.99, 1.78-1.87, 1.67-1.76, 1.46-1.55, 1.23-1.30, 1.15, 0.90-0.94.

[1197] 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

[1198] Using the corresponding racemic compound instead of the compound prepared in Reference Example 56, the same procedures as in Reference Example 57 → Reference Example 58 → Example 12 were carried out, and the two diastereomers were separated using an SFC column (CHIRALPAK IG, CO2:2-propanol = 70:30) to obtain the title compound (low-polarity form) exhibiting the following physical property values. It should be noted that the corresponding racemic compound was prepared from a known compound by carrying out 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.

[1199] HPLC retention time (min): 1.149;

[1200] MS (ESI, Pos.): 451 (M + Na) + .;

[1201] 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.

[1202] Reference Example 59: 5-Bromo-4-fluoro-2-vinylphenol

[1203] By carrying out the same procedures as in Reference Example 3 using 4-bromo-5-fluoro-2-hydroxybenzaldehyde (CAS No. 1427405-76-2) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde, the title compound having the following physical property values ​​was obtained.

[1204] 1 H-NMR(CDCl3): δ 7.15, 7.00, 6.79-6.88, 5.71-5.77, 5.41, 5.20-5.28.

[1205] Reference Example 60: (1R,2R,3aS,10aR)-7-fluoro-1-formyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[1206] Using the compound prepared in Reference Example 59 instead of the compound prepared in Reference Example 3, the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 were performed to obtain the title compound having the following physical property values.

[1207] 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.

[1208] 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

[1209] The title compound having the following physical property values ​​was obtained by performing the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, using the compound prepared in Reference Example 60 instead of the compound prepared in Reference Example 9, and using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 14. It should be noted that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar product isolated by a diastereoisomer separation procedure.

[1210] HPLC retention time (min): 0.97;

[1211] MS (ESI, Pos.): 453 (M-OH) + .;

[1212] 1 H-NMR(DMSO-d6): δ 13.04-13.20, 7.17-7.28, 7.01-7.14, 5.32, 4.93, 4.69, 4.22-4.27, 4.16, 3.59-3.72, 2.80-2.93, 2.68-2.77, 2.21-2.32, 1.46-1.81.

[1213] Reference Example 61: 5-Bromo-3-fluoro-2-vinylphenol

[1214] By carrying out the same procedures as in Reference Example 3 using 4-bromo-2-fluoro-6-hydroxybenzaldehyde (CAS No. 1427438-90-1) instead of 4-bromo-3-fluoro-2-hydroxybenzaldehyde, the title compound having the following physical property values ​​was obtained.

[1215] 1 H-NMR (CDCl3): δ 6.79-6.90, 6.69, 5.79-5.97, 5.60-5.67.

[1216] Reference Example 62: Ethyl (1R,2R,3aS,10aR)-8-fluoro-1-formyl-2-(tetrahydro-2H-pyran-2-oxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate

[1217] Using the compound prepared in Reference Example 61 instead of the compound prepared in Reference Example 3, the same operations as Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 were performed to obtain the title compound having the following physical property values.

[1218] 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.

[1219] 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

[1220] The title compound having the following physical property values ​​was obtained by performing the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, using the compound prepared in Reference Example 62 instead of the compound prepared in Reference Example 9 and the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 14. It should be noted that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar product isolated by a diastereoisomer separation procedure.

[1221] HPLC retention time (min):

[1222] MS(ESI, Pos.):403(M+H-2H2O)+,421(M+H-H2O)+.;

[1223] 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.

[1224] Reference Example 63: Ethyl 6-hydroxy-5-vinyl-2-pyridinecarboxylate

[1225] To a solution of ethyl 5-bromo-6-hydroxy-2-pyridinecarboxylate (CAS No. 1214346-74-3, 482 mg) in DMSO (2.4 mL) were added toluene (7.2 mL), tributyl vinyl tin (931 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (160 mg), and the mixture was stirred at 100°C for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 → 100:0) to obtain the title compound (170 mg) having the following physical properties.

[1226] TLC: Rf 0.52 (hexane:ethyl acetate=3:7);

[1227] 1 H-NMR(DMSO-d6): δ 11.50-12.12, 7.73, 7.02, 6.77, 6.24, 5.42, 4.30,1.27-1.34.

[1228] Reference Example 64: (6aR,7R,8R,9aS)-7-Formyl-8-(tetrahydro-2H-pyran-2-oxy)-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[6,7]oxepin[2,3-b]pyridine-2-carboxylic acid ethyl ester

[1229] Using the compound prepared in Reference Example 63 instead of the compound prepared in Reference Example 3, the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 were performed to obtain the title compound having the following physical property values.

[1230] 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.

[1231] Reference Example 65: (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 ethyl ester

[1232] The compound prepared in Reference Example 9 was replaced with the compound prepared in Reference Example 64 (45 mg), and the compound prepared in Reference Example 26 (49 mg) was replaced with the compound prepared in Reference Example 14. The same operation as in Reference Example 17 was performed to obtain an enone compound (21 mg). A solution of the enone compound (21 mg) in THF (0.2 mL) was cooled to -15°C. (S)-2-methyl-CBS-oxazole borane (0.037 mL, 1 mol / L toluene solution) and N,N-diethylaniline borane (0.013 mL) were added thereto, and the mixture was stirred overnight at -15°C. The reaction was confirmed to be complete by TLC, and the reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 → 100:0) to obtain a reduced form. A solution of the reduced form in methanol (0.2 mL) was cooled to 0°C, p-toluenesulfonic acid monohydrate (1.8 mg) was added, and the mixture was stirred at room temperature for 2 hours. After adding triethylamine (0.022 mL) to the reaction solution, 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 property values.

[1233] 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.

[1234] 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

[1235] By performing the same operations as in Example 2 using the compound prepared in Reference Example 65 instead of the compound prepared in Reference Example 18, the title compound having the following physical property values ​​was obtained.

[1236] HPLC retention time (min): 0.996;

[1237] MS (ESI, Pos.): 454 (M+H) +.;

[1238] 1H-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.

[1239] Reference Example 66: Ethyl (2R,3R,3aR,11aS)-3-formyl-2-(tetrahydro-2H-pyran-2-oxy)-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxoctane-9-carboxylate

[1240] Instead of the compound prepared in Reference Example 2, (1R,2R,3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-oxy)cyclopentanol (CAS No.: 1262874-94-1) was used, and instead of the compound prepared in Reference Example 3, the compound prepared in Reference Example 31 was used. By carrying out the same operations as 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 property values ​​was obtained.

[1241] 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.

[1242] 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]oxoctane-9-carboxylic acid

[1243] The title compound having the following physical property values ​​was obtained by following the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 9 and dimethyl 2-oxoheptylphosphonate (CAS No.: 36969-89-8) instead of the compound prepared in Reference Example 14. Note that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by diastereoisomer separation.

[1244] TLC: Rf 0.37 (CH2Cl2 / methanol, 9 / 1);

[1245] MS (ESI, Pos.): 777 (2M+H)+.;

[1246] 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.

[1247] Examples 17-1 to 17-31:

[1248] The following example compounds were obtained by performing the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 9 and the corresponding phosphonate ester instead of the compound prepared in Reference Example 14. The intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form isolated by a diastereoisomer separation procedure. The corresponding phosphonate ester is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11.

[1249] 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]oxoctane-9-carboxylic acid

[1250] MS (ESI, Neg.): 401 (MH)-.;

[1251] 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.

[1252] 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]oxoctane-9-carboxylic acid

[1253] MS (ESI, Neg.): 401 (MH)-.;

[1254] 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.

[1255] 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]oxoctane-9-carboxylic acid

[1256] MS (ESI, Neg.): 399 (MH)-.;

[1257] 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.

[1258] 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]oxoctane-9-carboxylic acid

[1259] HPLC retention time (min): 1.01;

[1260] MS(ESI, Pos.):453(M+H-H2O)+,435(M+H-2H2O)+.;

[1261] 1H-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.

[1262] 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]oxoctane-9-carboxylic acid

[1263] MS(ESI, Pos.):385(M+H-H2O)+,367(M+H-2H2O)+.;

[1264] 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.

[1265] 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]oxoctane-9-carboxylic acid

[1266] MS(ESI, Pos.):365(M+H-2H2O)+.;

[1267] 1 H-NMR(CDCl3): δ 7.64-7.74, 6.98-7.26, 5.58-5.77, 5.49, 4.59, 4.16,3.74-3.94, 2.78-3.07, 2.60, 2.26-2.50, 1.90-2.25, 1.52-1.88, 1.15-1.51, 1.01,0.63, -0.17-0.00, -0.34.

[1268] 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]oxoctane-9-carboxylic acid

[1269] MS(ESI, Pos.):381(M+H-H2O)+,.363(M+H-2H2O)+.;

[1270] 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.

[1271] 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]oxoctane-9-carboxylic acid

[1272] MS(ESI, Pos.):385(M+H-H2O)+,367(M+H-2H2O)+.;

[1273] 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.

[1274] 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]oxoctane-9-carboxylic acid

[1275] MS(ESI, Pos.):407(M+H-H2O)+.;

[1276] 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.

[1277] 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]oxoctane-9-carboxylic acid

[1278] MS(ESI, Pos.):383(M+H-H2O)+,.365(M+H-2H2O)+.;

[1279] 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.

[1280] 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]oxoctane-9-carboxylic acid

[1281] HPLC retention time (min): 0.95;

[1282] MS(ESI, Pos.):383(M+H-2H2O)+.;

[1283] 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.

[1284] 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]oxoctane-9-carboxylic acid

[1285] HPLC retention time (min): 0.95;

[1286] MS(ESI, Pos.):383(M+H-2H2O)+.;

[1287] 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.

[1288] 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]oxoctane-9-carboxylic acid

[1289] MS(ESI, Pos.):379(M+H-2H2O)+.;

[1290] 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.

[1291] 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]oxoctane-9-carboxylic acid

[1292] MS (FAB, Neg.): 405 (MH)-.;

[1293] 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.

[1294] 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]oxoctane-9-carboxylic acid

[1295] HPLC retention time (min): 1.17;

[1296] MS(ESI, Pos.):381(M+H-2H2O)+.;

[1297] 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.

[1298] 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]oxoctane-9-carboxylic acid

[1299] MS(ESI, Pos.):399(M+H-H2O)+.;

[1300] 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.

[1301] 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]oxoctane-9-carboxylic acid

[1302] HPLC retention time (min): 1.01;

[1303] MS(ESI, Pos.):439(M+H-H2O)+,421(M+H-2H2O)+.;

[1304] 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.

[1305] Examples 17-18: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3ξ,4ξ)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxoctane-9-carboxylic acid

[1306] MS(ESI, Pos.):439(M+H-H2O),421(M+H-2H2O)+.;

[1307] 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.

[1308] 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]oxoctane-9-carboxylic acid

[1309] MS (ESI, Neg.): 399 (MH)-.;

[1310] 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.

[1311] 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]oxoctane-9-carboxylic acid

[1312] MS (ESI, Neg.): 385 (MH)-.;

[1313] 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.

[1314] Examples 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]oxoctane-9-carboxylic acid

[1315] MS(ESI, Pos.):379(M+H-2H2O)+.;

[1316] 1H-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.

[1317] Examples 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]oxoctane-9-carboxylic acid

[1318] MS(ESI, Pos.):399(M+H-2H2O)+.;

[1319] 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.

[1320] Examples 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]oxoctane-9-carboxylic acid

[1321] HPLC retention time (min): 1;

[1322] MS (ESI, Pos.): 431 (M+H);

[1323] 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.

[1324] Examples 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]oxoctane-9-carboxylic acid

[1325] HPLC retention time (min): 0.91;

[1326] MS(ESI, Pos.):453(M+H-H2O)+,435(M+H-2H2O)+.;

[1327] 1 H-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.

[1328] Examples 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]oxoctane-9-carboxylic acid

[1329] HPLC retention time (min): 1;

[1330] MS(ESI, Pos.):467(M+H-H2O)+,.449(M+H-2H2O)+.;

[1331] 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.

[1332] Examples 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]oxoctane-9-carboxylic acid

[1333] HPLC retention time (min): 0.99;

[1334] MS(ESI, Pos.):467(M+H-H2O)+,.449(M+H-2H2O)+.;

[1335] 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.

[1336] Examples 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]oxoctane-9-carboxylic acid

[1337] HPLC retention time (min): 0.79;

[1338] MS(ESI, Pos.):467(M+H-H2O)+,449(M+H-2H2O)+.;

[1339] 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.

[1340] Examples 17-28: (2R,3R,3aR,11aS)-2-hydroxy-3-{(1E,3ξ)-3-hydroxy-3-[1-(3-methylphenyl)cyclopropyl]-1-propen-1-yl}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxoctane-9-carboxylic acid

[1341] HPLC retention time (min): 0.77;

[1342] MS(ESI, Pos.):431(M+H-H2O)+,413(M+H-2H2O)+.;

[1343] 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.

[1344] Examples 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]oxoctane-9-carboxylic acid

[1345] HPLC retention time (min): 0.77;

[1346] MS(ESI, Pos.):452(M+H-H2O)+,434(M+H-2H2O)+.;

[1347] 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.

[1348] 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]oxoctane-9-carboxylic acid

[1349] HPLC retention time (min): 0.78;

[1350] MS(ESI, Pos.):449(M+H-H2O)+,431(M+H-2H2O)+.;

[1351] 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.

[1352] 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]oxoctane-9-carboxylic acid

[1353] HPLC retention time (min): 0.98;

[1354] MS(ESI, Pos.):450(M+H-H2O)+.;

[1355] 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.

[1356] 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]oxoctane-9-carboxylic acid

[1357] The title compound exhibiting the following physical property values ​​was obtained by performing the same operations as in Reference Example 17 → Reference Example 18 → Example 2 using the corresponding aldehyde instead of the compound prepared in Reference Example 9 and the corresponding phosphonate instead of the compound prepared in Reference Example 14. It should be noted that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form separated by a diastereoisomer separation operation. The corresponding aldehyde was prepared by performing the same operations as in Reference Example 66 using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 3. The corresponding phosphonate was prepared by performing the same operations as in Reference Example 10 → Reference Example 11 using 1-phenoxycyclobutanecarboxylic acid (CAS No.: 2287791-08-4) instead of (2S)-2-(2,4-difluorophenyl)propionic acid.

[1358] HPLC retention time (min): 1.107;

[1359] MS (ESI, Pos.): 505 (M + Na) + .;

[1360] 1 H-NMR(CD3OD): δ 7.51-7.56, 7.22, 6.90-6.98, 6.83-6.88, 5.79-5.86,5.55-5.62, 4.41-4.48, 3.76-3.84, 2.97-3.07, 2.76-2.86, 2.60-2.70, 2.23-2.51,2.05-2.17, 1.92-2.03, 1.60-1.82, 1.45-1.57.

[1361] 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]oxoctane-9-carboxylic acid

[1362] The title compound exhibiting the following physical property values ​​was obtained by using the corresponding aldehyde instead of the compound prepared in Reference Example 9 and the corresponding phosphonate instead of the compound prepared in Reference Example 14, and performing the same operations as in Reference Example 17 → Reference Example 18 → Example 2. It should be noted that the intermediate corresponding to the compound prepared in Reference Example 18 used a highly polar form separated by a diastereoisomer separation operation. The corresponding aldehyde was prepared by using the compound prepared in Reference Example 35 instead of the compound prepared in Reference Example 31 and performing the same operations as in Reference Example 66. The corresponding phosphonate was prepared by using 1-phenoxycyclobutanecarboxylic acid instead of (2S)-2-(2,4-difluorophenyl)propionic acid and performing the same operations as in Reference Example 10 → Reference Example 11.

[1363] HPLC retention time (min): 1.134;

[1364] MS (ESI, Pos.): 501 (M + Na) + .;

[1365] 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.

[1366] 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]oxoctane-9-carboxylic acid

[1367] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Reference Example 48 → Reference Example 49 → Example 11 using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 40.

[1368] HPLC retention time (min): 0.94;

[1369] MS(ESI, Pos.):437(M+H-H2O)+,419(M+H-2H2O)+.;

[1370] 1H-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.

[1371] 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]oxoctane-9-carboxylic acid

[1372] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Reference Example 48 → Reference Example 49 → Example 11, using the corresponding aldehyde instead of the compound prepared in Reference Example 66. The corresponding aldehyde was prepared by performing the same procedures as in Reference Example 66, using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 31.

[1373] HPLC retention time (min): 1.079;

[1374] MS (ESI, Pos.): 495 (M + Na) + .;

[1375] 1 H-NMR(CD3OD): δ 7.50-7.55, 6.96, 5.61-5.69, 5.33-5.42, 4.41-4.46, 3.73-3.82, 2.96-3.06, 2.74-2.86, 2.60-2.69, 2.33-2.47, 2.17-2.30, 2.02-2.14,1.88-2.02, 1.60-1.82, 1.44-1.57, 1.25-1.40, 1.17.

[1376] 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]oxoctane-9-carboxylic acid

[1377] By following the same procedures as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 8 → Reference Example 9, using (1R,2R,3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-oxy)cyclopentanol (CAS No. 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, an aldehyde was obtained. By following the same procedures as in Reference Example 17 → Reference Example 18 → Example 2, using this aldehyde instead of the compound prepared in Reference Example 9 and using dimethyl 2-oxoheptylphosphonate (CAS No. 36969-89-8) instead of the compound prepared in Reference Example 14, the title compound having the following physical property values ​​was obtained. In addition, the intermediate corresponding to the compound produced in Reference Example 18 used a highly polar product separated by a diastereoisomer separation operation.

[1378] MS(ESI, Pos.):351(M+H-2H2O)+;

[1379] 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.

[1380] Reference Example 67: (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]oxoctane-9-carboxylic acid methyl ester

[1381] To a solution of the compound prepared in Example 17-17 (125 mg) in methanol (1 mL) was added dropwise a 2M solution of trimethylsilyldiazomethane in n-hexane (0.5 mL) while stirring at room temperature until the reaction solution turned yellow. 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 (n-hexane:ethyl acetate = 1:1) to obtain the title compound (126 mg).

[1382] Reference Example 68: (2R,3R,3aR,11aS)-2-{[dimethyl(2-methyl-2-propyl)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]oxoctane-9-carboxylic acid methyl ester

[1383] In the dichloromethane (2mL) solution of the compound manufactured in Reference Example 67, triethylamine (0.22mL) and N, N-dimethyl-4-aminopyridine (13mg) were added at room temperature and cooled under ice-cold. In addition, tert-butyldiphenylchlorosilane (0.21mL) was added and stirred at room temperature for 2 days. Ethyl acetate was added to the reaction mixture and diluted, saturated ammonium chloride was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the title compound (204mg).

[1384] Reference Example 69: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxoctane-9-carboxylic acid methyl ester

[1385] 2,6-lutidine (0.1 mL) was added to a dichloromethane (1.5 mL) solution of the compound manufactured in Reference Example 68 at room temperature and cooled under ice-cold. Tert-butyldimethylsilyl trifluoromethanesulfonate (0.1 mL) was added and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture and diluted, saturated ammonium chloride was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give the title compound (174 mg).

[1386] Reference Example 70: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxoctane-9-carboxylic acid

[1387] In a dimethoxyethane (1.5 mL) -methanol (1.5 mL) solution of the compound manufactured in Reference Example 69, 2N aqueous sodium hydroxide solution (0.5 mL) was added at room temperature and stirred at 35 ° C for 15 hours. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added and extracted 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 obtain the title compound (154 mg) having the following physical property values.

[1388] 1 H-NMR(CDCl3): δ 7.63-7.71, 7.35-7.46, 7.14, 5.32-5.40, 4.34-4.40,3.83-3.97, 2.92, 2.78-2.86, 2.52, 2.17-2.26, 1.95-2.08, 1.80-1.94, 1.38-1.68,1.26, 1.13-1.21, 1.07, 0.77-0.85, -0.04--0.01.

[1389] 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]oxoctane-9-carboxamide

[1390] To a solution of the compound (40 mg) prepared in Reference Example 70 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. THF (1 mL) and a 1M tetra-n-butylammonium fluoride THF solution (0.25 mL) were added to the reaction solution at room temperature, and the reaction mixture was stirred at 45 ° C for 15 hours. Saturated ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 5: 1) to obtain the title compound (2.5 mg) having the following physical property values.

[1391] HPLC retention time (min): 0.99;

[1392] MS(ESI, Pos.):516(M+H-H2O)+.;

[1393] 1H-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.

[1394] Reference Example 71: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxoctane-9-carboxamide

[1395] At room temperature, ammonium chloride (15 mg), 7-aza-1-hydroxybenzotriazole (38 mg), diisopropylethylamine (0.1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg) were added to a DMF (1.1 mL) solution of the compound (114 mg) manufactured in Reference Example 70 and stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction mixture and diluted, saturated ammonium chloride solution was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give the title compound (105 mg).

[1396] Reference Example 72: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxoctane-9-carbonitrile

[1397] The compound manufactured in Reference Example 71 was dissolved in THF (2 mL) solution, and pyridine (0.03 mL) was added at room temperature. The reaction solution was cooled on ice, anhydrous trifluoroacetic acid (0.03 mL) was added, and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture and diluted, saturated ammonium chloride solution was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (99.7 mg) with the following physical property values.

[1398] 1 H-NMR(CDCl3): δ 7.64-7.72, 7.34-7.47, 7.18-7.25, 7.10-7.15, 5.36-5.41,4.33-4.44, 3.89, 2.87, 2.48-2.54, 2.14-2.33, 1.77, 1.44-1.60, 1.13-1.35,1.07, 0.80-0.89, -0.04-0.03.

[1399] 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]oxoctan-2-ol

[1400] To a toluene (2 mL) solution of the compound (99.7 mg) prepared in Reference Example 72, dibutyltin oxide (38 mg) and trimethylsilyl azide (58 mg) were added at room temperature and stirred at 95 ° C for 15 hours. Ethyl acetate was added to the reaction mixture and diluted, and the solution was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain a tetrazolium compound (98 mg). 1M tetra-n-butylammonium fluoride in THF (0.17 mL) was added to the obtained tetrazolium compound in THF (1 mL) and stirred at 35 ° C for 15 hours. 1N hydrochloric acid was added to the reaction mixture and 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 obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 3: 1) to obtain the title compound (35.2 mg) having the following physical property values.

[1401] HPLC retention time (min): 0.99;

[1402] MS(ESI, Pos.):463(M+H-H2O)+.;

[1403] 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.

[1404] 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

[1405] Using the compound prepared in Example 17 instead of the compound prepared in Example 17-17, the title compound having the following physical property values ​​was obtained by performing the same operations as Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Reference Example 71 → Reference Example 72 → Example 24.

[1406] TLC: Rf 0.26 (CH2Cl2 / methanol, 5 / 1)

[1407] MS(APCI, Pos.):381(M-H2O)+.;

[1408] 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.

[1409] Reference Example 73: (1S,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-({[(2-methyl-2-propyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[1410] To a dichloromethane solution (50 mL) of the compound (8.3 g) prepared in Reference Example 8, triethylamine (9.1 mL), tert-butyldiphenylsilyl chloride (8.9 mL) and dimethylaminopyridine (0.31 g) were added at room temperature and stirred at 35 ° C for 3 hours. The reaction solution was injected 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, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in methanol (50 mL), p-toluenesulfonic acid monohydrate (378 mg) was added at room temperature, and stirred at room temperature for 1 hour. Triethylamine (3.0 mL) was added to the reaction solution, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 30: 70) to obtain the title compound (10.7 g) exhibiting the following physical property values.

[1411] 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.

[1412] Reference Example 74: (1S,2R,3aS,10aR)-5-fluoro-2-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(2-methyl-2-propyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[1413] In an acetonitrile solution (78 mL) of the compound (15.6 g) manufactured in Reference Example 73, triethylamine (12.8 mL), trimethylamine hydrochloride (344 mg), p-toluenesulfonyl chloride (6.34 g) were added at room temperature and stirred for 3 hours at room temperature. The reaction solution was injected 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, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 70: 30) to obtain the title compound (20.2 g) showing the following physical property values.

[1414] 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.

[1415] Reference Example 75: (1S,3aS,10aR)-5-fluoro-1-({[(2-methyl-2-propyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[1416] In a dimethoxyethane (150 mL) -DMF (10 mL) solution of the compound (20.2 g) manufactured in Reference Example 74, water (15 mL), sodium iodide (16.6 g) and zinc (14.4 g) were added at room temperature and stirred at 80 ° C overnight. Sodium iodide (4 g) and zinc (3.5 g) were further added and stirred at 80 ° C for 5 hours. The reaction mixture was cooled to room temperature, added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 5: 1) to obtain the title compound (13.1 g) showing the following physical property values.

[1417] 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.

[1418] Reference Example 76: (1S,3aS,10aR)-5-fluoro-1-formyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[1419] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Reference Examples 8 → 9 using the compound prepared in Reference Example 75 instead of the compound prepared in Reference Example 7.

[1420] 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.

[1421] 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

[1422] The compound (70 mg) manufactured in Reference Example 76 was used instead of the compound manufactured in Reference Example 9, and the compound (136 mg) manufactured in Reference Example 26 was used instead of the compound manufactured in Reference Example 14. By performing the same operation as in Reference Example 17, an enone body (97 mg) was obtained. A THF (1 mL) solution of the enone body (97 mg) was cooled to -15 ° C. (S)-2-methyl-CBS-oxazole borane (1 mol / L toluene solution, 0.204 mL) and N, N-diethylaniline borane (0.073 mL) were added thereto and stirred at -15 ° C for 8 hours. Methanol and water were added to the reaction solution and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, it was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Gold High Performance Silica, n-hexane: ethyl acetate manufactured by ISCO) to obtain a reduced body. The reduced form was dissolved in methanol (1 mL) and dimethoxyethane (0.5 mL), 2N sodium hydroxide aqueous solution (0.5 mL) was added and stirred overnight. After the reaction was confirmed by TLC, the reaction solution was concentrated, acidified with aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified with an SFC column (CHIRALPAK IG, CO2: methanol = 65: 35) to obtain the title compound (19 mg) with the following physical property values.

[1423] HPLC retention time (min): 1.09;

[1424] MS(ESI, Pos.):437(M+H-H2O)+.;

[1425] 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.

[1426] Examples 25-1 to 25-15:

[1427] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Example 25, using the corresponding phosphonate instead of the compound prepared in Reference Example 26. Note that, in Example 25-6, the reduction reaction was performed using (R)-2-methyl-CBS-oxazaborolidine instead of the (S)-2-methyl-CBS-oxazaborolidine used in Example 25. The corresponding phosphonate is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[1428] 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

[1429] HPLC retention time (min): 1.05;

[1430] MS(ESI, Pos.):423(M+H-H2O)+.;

[1431] 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.

[1432] 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

[1433] HPLC retention time (min): 0.97;

[1434] MS (ESI, Pos.): 433 (M+H) +.;

[1435] 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.

[1436] 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

[1437] HPLC retention time (min): 1.01;

[1438] MS(ESI, Pos.):451(M+H)+.,433(M+H-H2O)+.;

[1439] 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.

[1440] 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

[1441] HPLC retention time (min): 1.218;

[1442] MS (ESI, Pos.): 429 (M-OH) + .;

[1443] 1H-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.

[1444] 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

[1445] HPLC retention time (min): 1.17;

[1446] MS(ESI, Pos.):405(M+H-H2O)+.;

[1447] 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.

[1448] 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

[1449] HPLC retention time (min): 1.273;

[1450] MS (ESI, Pos.): 373 (M-OH) + .;

[1451] 1H-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.

[1452] 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

[1453] [Chemical Formula 53]

[1454]

[1455] HPLC retention time (min): 1.212;

[1456] MS (ESI, Pos.): 447 (M + Na) + .;

[1457] 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.

[1458] 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

[1459] HPLC retention time (min): 1.27;

[1460] MS(ESI, Pos.):385(M+H-H2O)+.;

[1461] 1H-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.

[1462] 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

[1463] HPLC retention time (min): 1.089;

[1464] MS(ESI, Pos.):421(M+H-H2O)+.;

[1465] 1 H-NMR(CD3OD): δ 7.44-7.50, 7.36, 7.24-7.29, 7.08, 6.97, 5.49-5.57,5.31-5.41, 4.97-5.03, 4.92, 4.50, 4.38, 2.98-3.07, 2.73-2.82, 2.60-2.70,2.13-2.22, 1.93-2.09, 1.68-1.82, 1.38-1.49.

[1466] 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

[1467] HPLC retention time (min): 1.18;

[1468] MS(ESI, Pos.):453(M+Na)+,413(M+H-H2O)+.;

[1469] 1H-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.

[1470] 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

[1471] HPLC retention time (min): 1.23;

[1472] MS (ESI, Pos.): 477 (M + Na) + .;

[1473] 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.

[1474] 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

[1475] HPLC retention time (min): 1.276;

[1476] MS (ESI, Pos.): 473 (M + Na) + .;

[1477] 1H-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.

[1478] 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

[1479] HPLC retention time (min): 1.095;

[1480] MS (ESI, Pos.): 479 (M + Na) + .;

[1481] 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.

[1482] 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

[1483] HPLC retention time (min): 1.173;

[1484] MS (ESI, Pos.): 429 (M + Na) + .;

[1485] 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.

[1486] 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

[1487] HPLC retention time (min): 1.071;

[1488] MS (ESI, Pos.): 479 (M + Na) + .;

[1489] 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.

[1490] Examples 26-1 to 26-23

[1491] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Example 25, using the corresponding aldehyde instead of the compound prepared in Reference Example 76, and the corresponding phosphonate instead of the compound prepared in Reference Example 26. Note that, for Examples 26-1, 26-3, and 26-6, (R)-2-methyl-CBS-oxazaborolidine was used instead of (S)-2-methyl-CBS-oxazaborolidine in the reaction corresponding to Example 25, and reduction was performed. The corresponding aldehyde was prepared by performing 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 instead of the compound prepared in Reference Example 3. The corresponding phosphonate is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11 or Reference Example 28 → Reference Example 29.

[1492] 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

[1493] MS (FAB, Neg.): 357 (MH)-.;

[1494] 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.

[1495] 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

[1496] MS(ESI, Pos.):401(M+H-H2O)+.;

[1497] 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.

[1498] 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

[1499] MS(ESI, Pos.):377(M+H-H2O)+.;

[1500] 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.

[1501] 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

[1502] MS(ESI, Pos.):387(M+H-H2O)+.;

[1503] 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.

[1504] 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

[1505] MS(ESI, Pos.):405(M+H-H2O)+.;

[1506] 1H-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.

[1507] 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

[1508] HPLC retention time (min): 1.13;

[1509] MS(ESI, Pos.):409(M+H-H2O)+.;

[1510] 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.

[1511] 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

[1512] HPLC retention time (min): 1.262;

[1513] MS(ESI, Pos.):419(M+H-H2O)+;

[1514] 1H-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.

[1515] 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

[1516] HPLC retention time (min): 1.07;

[1517] MS(ESI, Pos.):405(M+H-H2O)+.;

[1518] 1 H-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.

[1519] 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

[1520] [Chemical Formula 54]

[1521]

[1522] HPLC retention time (min): 1.14;

[1523] MS(ESI, Pos.):419(M+H-H2O)+.;

[1524] 1H-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.

[1525] 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

[1526] MS (ESI, Pos.): 437 (M+H) +.;

[1527] 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.

[1528] 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

[1529] MS(ESI, Pos.):437(M+H-H2O)+.;

[1530] 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.

[1531] 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

[1532] MS(ESI, Pos.):423(M+H-H2O)+.;

[1533] 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.

[1534] 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

[1535] HPLC retention time (min): 1.06;

[1536] MS(ESI, Pos.):397(M+H-H2O)+.;

[1537] 1 H-NMR(CD3OD): δ 7.40-7.58, 7.11-7.19, 5.42-5.61, 4.32-4.47, 2.84-3.00,2.70-2.80, 2.59, 2.10-2.19, 1.82-2.08, 1.53-1.77, 1.26-1.47.

[1538] 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

[1539] HPLC retention time (min): 1.04;

[1540] MS(ESI, Pos.):377(M+H-H2O)+.;

[1541] 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.

[1542] 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

[1543] HPLC retention time (min): 1.06;

[1544] MS(ESI, Pos.):353(M+H-H2O)+.;

[1545] 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.

[1546] 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

[1547] HPLC retention time (min): 1.2;

[1548] MS(ESI, Pos.):439(M+H-H2O)+.;

[1549] 1H-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.

[1550] 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

[1551] [Chemical Formula 55]

[1552]

[1553] HPLC retention time (min): 1.25;

[1554] MS(ESI, Pos.):453(M+H-H2O)+.;

[1555] 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.

[1556] 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

[1557] HPLC retention time (min): 1.255;

[1558] MS(ESI, Pos.):387(M+H-H2O)+.;

[1559] 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.

[1560] 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

[1561] [Chemical Formula 56]

[1562]

[1563] HPLC retention time (min): 1.069;

[1564] MS (ESI, Pos.): 389 (M-OH) +;

[1565] 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.

[1566] 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

[1567] [Chemical Formula 57]

[1568]

[1569] HPLC retention time (min): 1.301;

[1570] MS(ESI, Pos.):443(M+Na)+,403(M+H-H2O)+.;

[1571] 1H-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.

[1572] 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

[1573] [Chemical Formula 58]

[1574]

[1575] HPLC retention time (min): 1.085;

[1576] MS (ESI, Pos.): 477 (M + Na) + .;

[1577] 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.

[1578] 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

[1579] HPLC retention time (min): 1.278;

[1580] MS (ESI, Pos.): 473 (M + Na) + .;

[1581] 1H-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.

[1582] 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

[1583] MS(ESI, Pos,):437(M+H-H2O)+.;

[1584] 1 H-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.

[1585] 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

[1586] Using the compound prepared in Example 26-13 instead of the compound prepared in Example 17-17, the same operations as Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23 were performed to obtain the title compound showing the following physical property values.

[1587] HPLC retention time (min): 0.99;

[1588] MS (ESI, Pos.): 492 (M+H) +.;

[1589] 1H-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.

[1590] Reference Example 77: (1S,2S,3aS,10aR)-5-fluoro-2-hydroxy-1-({[(2-methyl-2-propyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid ethyl ester

[1591] To a solution of the compound (4.87 g) prepared in Reference Example 73 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 and stirred 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 obtain a formate (4.53 g).

[1592] To a solution of formate (4.53 g) in ethanol (31.7 mL) was added potassium carbonate (2.12 g) at room temperature and stirred at room temperature for 1 hour. The reaction mixture was diluted with MTBE and filtered. The filtrate was injected 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 obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 88:12 → 75:25) to obtain the title compound (4.08 g) exhibiting the following physical property values.

[1593] 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.

[1594] Reference Example 78: Ethyl (1S,2R,3aS,10aR)-2,5-difluoro-1-({[(2-methyl-2-propyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate

[1595] A solution of MTBE (27 mL) of the compound (6.0 g) manufactured in Reference Example 77 was cooled to -78 ° C, bis (2-methoxyethyl) aminosulfur trifluoride (9.8 mL) was added dropwise, and the mixture was stirred at -78 ° C. After confirming the disappearance of the raw material by TLC, the temperature was raised to -20 ° C, the reaction solution was injected into a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained 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 property values.

[1596] 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.

[1597] 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

[1598] The title compound exhibiting the following physical property values ​​was obtained by performing the same operation as in Reference Example 8 using the compound prepared in Reference Example 78 instead of the compound prepared in Reference Example 7.

[1599] 1 H-NMR (CDCl3): δ 7.47-7.51, 6.88, 5.14-5.20, 5.00-5.06, 4.34-4.40, 3.94-4.01, 3.72-3.78, 3.07-3.16, 2.72-2.79, 2.48-2.66, 2.26-2.48, 2.01-2.12,1.94, 1.44, 1.35-1.41.

[1600] 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

[1601] To a solution of the compound (600 mg) prepared in Reference Example 79 in dichloromethane (6 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3-(1H)-one (Dess-Martin reagent, 1.17 g) at 0°C and stirred at room temperature. After confirming the completion of the reaction by TLC, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 75:25 → 60:40) to obtain the title compound (550 mg) exhibiting the following physical property values.

[1602] 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.

[1603] 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

[1604] [Chemical Formula 59]

[1605]

[1606] The compound prepared in Reference Example 76 was replaced with the compound prepared in Reference Example 80 (300 mg), 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. By performing the same operations as in Reference Example 24, the title compound exhibiting the following physical property values ​​was obtained.

[1607] HPLC retention time (min): 1.157;

[1608] MS(ESI, Pos.):405(M+H-H2O-HF)+.;

[1609] 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.

[1610] Examples 28-1 to 28-3:

[1611] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Example 25, using the compound prepared in Reference Example 80 instead of the compound prepared in Reference Example 76, and using the corresponding phosphonate ester instead of the compound prepared in Reference Example 26. The corresponding phosphonate ester is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11.

[1612] 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

[1613] HPLC retention time (min): 1.01;

[1614] MS (ESI, Pos.): 441 (M-OH) + .;

[1615] 1 H-NMR(DMSO-d6): δ 13.10, 7.42, 7.22-7.35, 7.04-7.14, 5.52-5.59, 5.25-5.34, 4.97, 4.73, 4.27, 3.95-4.00, 2.94, 2.69-2.88, 1.92-2.06, 1.71-1.81,1.53, 0.91-1.04, 0.66-0.73, 0.53-0.61.

[1616] 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

[1617] [Chemical Formula 60]

[1618]

[1619] HPLC retention time (min): 1.035;

[1620] MS(ESI, Pos.):439(M+H-H2O)+,419(M+H-H2O-HF)+.;

[1621] 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.

[1622] 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

[1623] HPLC retention time (min): 1.053;

[1624] MS(ESI, Pos.):479(M+Na)+,439(M+H-H2O)+.;

[1625] 1 H-NMR(CD3OD): δ 7.24-7.49, 6.91-6.98, 5.40-5.57, 4.58-4.83, 4.43-4.52,4.13-4.28, 3.24-3.28, 3.12-3.20, 2.96-3.09, 2.81-2.95, 2.63-2.81, 2.43-2.61, 2.06-2.21, 1.75-1.87, 1.57-1.75.

[1626] Examples 29-1 to 29-4:

[1627] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Example 25, using the corresponding aldehyde instead of the compound prepared in Reference Example 76, and the corresponding phosphonate instead of the compound prepared in Reference Example 26. The corresponding aldehyde was prepared by performing the same procedures as in Reference Example 73 → Reference Example 77 → Reference Example 78 → Reference Example 79 → Reference Example 80, using the compound prepared in Reference Example 39 instead of the compound prepared in Reference Example 8. The corresponding phosphonate is a known compound or can be prepared from a known compound by performing the same procedures as in Reference Example 10 → Reference Example 11.

[1628] 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

[1629] HPLC retention time (min): 1.224;

[1630] MS (ESI, Pos.): 473 (M + Na) + .;

[1631] 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.

[1632] 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

[1633] HPLC retention time (min): 1.281;

[1634] MS(ESI, Pos.):453(M+Na)+,393(M+H-H2O-HF)+.;

[1635] 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.

[1636] 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

[1637] HPLC retention time (min): 1.217;

[1638] MS (ESI, Pos.): 491 (M + Na) + .;

[1639] 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.

[1640] 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

[1641] HPLC retention time (min): 1.193;

[1642] MS (ESI, Pos.): 479 (M + Na) + .;

[1643] 1 H-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.

[1644] 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

[1645] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Example 25 → Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23, 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 corresponding aldehyde was prepared by performing 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, using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 9. The corresponding phosphonate was prepared by performing the same procedures as in Reference Example 28 → Reference Example 29, using iodobenzene instead of 1,3-difluoro-2-iodobenzene.

[1646] HPLC retention time (min): 0.96;

[1647] MS (ESI, Pos.): 510 (M+H) +.;

[1648] 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.

[1649] 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]oxoctane-9-carboxylic acid

[1650] The title compound exhibiting the following physical property values ​​was obtained by performing the same procedures as in Example 25 → Reference Example 67 → Reference Example 68 → Reference Example 69 → Reference Example 70 → Example 23, 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. It should be noted that the corresponding aldehyde was prepared by performing 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, using (1R,2R,3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-oxy)cyclopentanol 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 corresponding phosphonate was prepared by performing the same procedures as in Reference Example 10 → Reference Example 11 using 1-phenylcyclobutanecarboxylic acid (CAS No.: 37828-19-6) instead of (2S)-2-(2,4-difluorophenyl)propionic acid.

[1651] MS(ESI, Pos.):433(M+H-H2O)+,413(M+H-H2O-HF)+.;

[1652] 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....

Claims

1. A compound represented by general formula (I) or a salt thereof, [Chemical Formula 1] ， Where, R 1 Indicates COOH, COOR 11 、CONHSO2R 12 or tetrazolyl, R 11 represents a C1~6 alkyl group, R 12 represents a C1-6 alkyl group or a phenyl group, the phenyl group being optionally substituted with 1 to 5 (1) halogen or (2) C1-4 alkyl groups, X 1 、X 2 and X 3 Each independently represents N, CH or CR 21 , Multiple R 21 Each independently represents (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) -(CH2) t -(C3~4 saturated carbocyclic ring) or (5) vinyl optionally substituted with 1~3 halogens, t represents an integer of 0 or 1, [Chemical Formula 2] ， The structure shown in Chemical Formula 2 represents the structure shown in Chemical Formula 3, [Chemical Formula 3] ， R 6 represents (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 from 0 to 3, Multiple R 6 Optionally, together with the carbon atoms to which they are bonded, they form a C3-4 saturated carbocyclic ring optionally 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, (3) a C1-4 alkyl group, or (4) a C1-4 haloalkyl group, R 2 and R 3 Optionally, together with the carbon atom to which it is bonded, it forms a C3-4 saturated carbocyclic ring optionally substituted with 1 to 6 halogens, Z stands for CHR 10 or oxygen atoms, R 10 represents a hydrogen atom, a halogen, 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 R L3 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) hydroxyl, or R L2 and R L3 Optionally, together with the carbon atom to which it is bonded, it forms (1) a C3-6 saturated carbocyclic ring optionally substituted with 1 to 10 halogens, or (2) a 3-6 membered saturated heterocyclic ring optionally substituted with 1 to 8 halogens, R 4 Indicates (1) optionally substituted with 1 to 5 R 41 C3~7 alkyl, (2) optionally substituted with 1~5 R 42 C3~7 alkenyl, (3) optionally substituted with 1~5 R 43 C3~7 alkynyl, (4) optionally substituted with 1~5 R 44 C2~6 alkoxy or (5)Cyc 1 , R 41 、R 42 、R 43 and R 44 Each independently represents (1) halogen, (2) C3-6 carbocycle or (3) 3-6 membered heterocycle, wherein the C3-6 carbocycle and 3-6 membered heterocycle are optionally substituted with 1 to 10 (1) halogen or (2) C1-2 alkyl groups, Cyc 1 Indicates (1) optionally substituted with 1 to 5 R 51 C5~10 carbon ring or (2) optionally substituted with 1~5 R 52 5-10 membered heterocyclic ring, R 51 and R 52 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, (8) C1-4 alkoxy, (9) C1-4 haloalkoxy, (10) hydroxy, (11) C3-6 saturated carbocyclic ring or (12) 3-6 membered saturated heterocyclic ring, R L1 and R 51 optionally together with the carbon atoms to which it is bonded, form (1) a C3-6 saturated carbocyclic ring or (2) a 3-6 membered saturated heterocyclic ring, R 5 represents a hydrogen atom or a hydroxyl group, Multiple R 6 、R 41 、R 42 、R 43 、R 44 、R 51 and R 52 can be the same as or different from each other, [Chemical Formula 4] ， The structure shown in Chemical Formula 4 represents a single bond or a double bond, wherein, The adjacent structures shown in Chemical Formula 5 do not have double bonds at the same time. [Chemical Formula 5] ， [Chemical Formula 6] ， The structure shown in Chemical Formula 6 indicates that the bond is formed on the opposite side of the paper (i.e., α configuration). [Chemical Formula 7] ， The structure shown in Chemical Formula 7 indicates that the bond is formed near the front side of the paper (i.e., β configuration). In the formula, the structure shown in Chemical Formula 8 bonded to an asymmetric atom represents an α configuration, a β configuration, or a mixture thereof in any ratio unless otherwise specified. [Chemical Formula 8] 。 2. The compound or salt thereof according to claim 1, wherein X 1 、X 2 and X 3 Each independently is CH or CR 21 .

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

4. The compound or salt thereof according to any one of claims 1 to 3, wherein R 4 is optionally substituted with 1 to 3 R 41 C3~7 alkyl, optionally substituted with 1~3 R 42 C3~7 alkenyl, or Cyc 1 .

5. The compound or salt thereof according to any one of claims 1 to 4, wherein Z is CHR 10 , R 10 It is a hydroxyl group.

6. The compound or salt thereof according to any one of claims 1 to 5, wherein R 1 is COOH.

7. The compound or salt thereof according to claim 1, wherein The general formula (I) is represented by the general formula (I-3), [Chemical Formula 9] ， Where, L 10 Indicates -CHR L1 -or-CR L2 R L3 -, R 4a Indicates optional substitution with 1 to 3 R 41 C3~7 alkyl, optionally substituted with 1~3 R 42 C3~7 alkenyl, or Cyc 1 , other symbols have the same meanings as in claim 1.

8. The compound or salt thereof according to claim 1, wherein The compound represented by general formula (I) or a salt thereof is the following compound or a salt thereof: (1)(1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (2) (1R,2R,3aS,10aR)-5-fluoro-1-[(1E)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (3) (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (4) (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2,5-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (5) (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-4-(2,6-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (6) (1R,2R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (7)(1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-ethyl-3-hydroxy-7-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (8) (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (9)(1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-8,8,8-trifluoro-4-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (10)(1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4ξ)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (11)(1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (12)(1R,3aS,10aR)-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (13)(1R,3aS,10aR)-5-chloro-1-{(1E,3ξ)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (14)(1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-6-methoxy-4-methylene-1-hexen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (15)(1R,3aS,10aR)-5-chloro-1-[(1E,3ξ,4S)-4-ethyl-3-hydroxy-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (16)(1R,3aS,10aR)-5-chloro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (17)(1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4-phenyl-1-pentenyl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (18) (1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (19)(1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-[3-(2-fluorophenyl)-3-oxetanyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (20)(1R,2R,3aS,10aR)-2-chloro-5-fluoro-1-{(1E,3ξ)-3-hydroxy-3-[(2ξ)-2-phenyl-2-oxetanyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (21)(1R,3aR,10aR)-1-[(1E,3ξ,4S)-3-hydroxy-4-methyl-1-octen-1-yl]-5-methyl-1,3,3a,9,10,10a-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. 9 . A pharmaceutical composition comprising the compound or salt thereof according to claim 1 . 10 . An EP3 agonist comprising the compound or a salt thereof according to claim 1 .

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