COMPOSTO TRICÍCLICO

Abstract

To provide a compound having EP3 agonist activity. A compound represented by general formula (I) (in the formula, all symbols are as defined in the description) or a salt thereof has strong EP3 agonist activity and can therefore be used as an EP3 agonist.

Description

[001] This disclosure refers to a compound represented by the following general formula (I): R1 (where all symbols represent the same meaning as described below) or a salt thereof (hereinafter, the compound of the present invention may be abbreviated as the present compound). BACKGROUND OF THE TECHNIQUE

[002] Prostaglandin is known as a metabolite in the arachidonic acid cascade, and its effect is known to have a cytoprotective effect, uterine contraction, pain-generating effect, promotion of peristaltic movement of the digestive tract, arousal effect, suppression of gastric acid secretion, blood pressure-lowering effect, diuretic effect, and the like. It is also known that there are PGE (prostaglandin E) receptors with different functions for each subtype. There are approximately four known subtypes currently, designated EP1, EP2, EP3, and EP4 (Unpatented Literature 1).

[003] Unpatented Literature 2 and Unpatented Literature 3 are known, which refer to a tricyclic compound. LIST OF QUOTES Unpatented Literature Petition 870250079778, dated 05 / 09 / 2025, pp. 243 / 481 2 / 226

[004] Non-Patented Literature 1: Journal of Biological Chemistry, vol. 282, no. 16, pp. 11613-11617

[005] Non-Patented Literature 2: Phytochemistry, vol. 16, no. 4, pp. 494-495

[006] Non-Patented Literature 3: Journal of Organic Chemistry, vol. 64, no. 17, pp. 6380-6386 SUMMARY OF THE INVENTION TECHNICAL PROBLEM

[007] One of the objectives of the present invention is to provide a compound with EP3 agonist activity. SOLUTION TO THE PROBLEM

[008] As a result of intensive studies to solve the above problems, the present inventors discovered that a compound shown below has a potent EP3 agonist activity.

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

[010] (1) A compound represented by the general formula (I) or a salt thereof: R1 in what R1 represents COOH, COOR11, CONHSO2R12or tetrazolyl, R11 represents C1-6 alkyl, Petition 870250079778, dated 05 / 09 / 2025, pp. 244 / 481 3 / 226 R12 represents C1-6 alkyl or phenyl, and the phenyl is optionally substituted by 1 to 5 (1) halogen atoms or (2) C1-4 alkyl groups, X1, X2 and X3 each independently represent N, CH or CR21, a plurality of R21s independently represent (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) -(CH2)t-(saturated C3-4 carbocycle) or (5) vinyl optionally substituted with 1 to 3 halogen atoms, t represents an integer from 0 or 1, R6 represents (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl OR (4) -(CH2)q (saturated C3-4 carbocycle), q represents an integer from 0 or 1, p represents an integer from 0 to 3, a plurality of R6s can form a saturated C3-4 carbocycle optionally substituted by 1 to 6 halogen atoms together with a carbon atom to which each R6 is attached, Y represents an oxygen atom or a sulfur atom. R2 and R3 each independently represent (1) a hydrogen atom, (2) a halogen, (3) a C1-4 alkyl or (4) a C1-4 haloalkyl, R2e R3 can form a saturated C3-4 carbocycle, optionally substituted by 1 to 6 halogen atoms, along with a carbon atom to which R2e Petition 870250079778, dated 05 / 09 / 2025, pages 245 / 481 4 / 226 R3s are connected, Z represents CHR10, or an oxygen atom. R10 represents a hydrogen atom, halogen atom, hydroxyl group, or methoxy group. L represents -CH2-, -CHRL1-, -CRL2RL3- or -C(=CH2)-, RL1 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, RL2 and RL3 each independently represent (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) C2-4 alkenyl, (5) C2-4 haloalkenyl, (6) C2-4 alkynyl, (7) C2-4 haloalkynyl or (8) a hydroxyl group, or RL2 and RL3 can form (1) a saturated C3-6 carbocycle optionally substituted by 1 to 10 halogen atoms or (2) a saturated 3- to 6-membered heterocycle optionally substituted by 1 to 8 halogen atoms, together with a carbon atom to which RL2 and RL3 are attached. R4 represents (1) C3-7 alkyl optionally substituted by 1 to 5 R41s, (2) C3-7 alkenyl optionally substituted by 1 to 5 R42s, (3) C3-7 alkynyl optionally substituted by 1 to 5 R43s, (4) C2-6 alkoxy optionally substituted by 1 to 5 R44s, (5) Cyc1 or (6) -O-Cyc1, where R4 represents a C3-7 alkyl optionally substituted by 1 to 5 R41s, one carbon atom of the C3-7 alkyl may be substituted by an oxygen atom, R41, R42, R43 and R44 each independently represent (1) a halogen, (2) a C3-6 carbocycle or (3) a 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and the 3- to 6-membered heterocycle are optionally substituted by 1 to 10 (1) halogen atoms or (2) C1-2 alkyl groups, Cyc1 represents (1) a C5-10 carbocycle optionally substituted by 1 to 5 R51s or (2) a 5 to 10 membered heterocycle optionally substituted by 1 to 5 Petition 870250079778, dated 05 / 09 / 2025, pp. 246 / 481 5 / 226 R52s, R51 and R52 each independently represent (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) a hydroxyl group, (11) a saturated C3-6 carbocycle or (12) a saturated 3- to 6-membered heterocycle, RL1 and R51 can form (1) a saturated C3-6 carbocycle or (2) a saturated 3- to 6-membered heterocycle, together with a carbon atom to which RL1 and R51 are attached. R5 represents a hydrogen atom or a hydroxyl group, where a plurality of R6s, R41s, R42s, R43s, R44s, R51s and R52s may be the same or different, representing a single bond or a double bond, provided that adjacent groups are not simultaneously double bonds. represents a connection beyond the surface of the sheet (i.e., an α configuration), represents a connection at the front of the sheet surface (i.e., a β configuration), in which When bonded to an asymmetric atom, it represents the α configuration, the β configuration, or a mixture of them in any ratio, unless otherwise indicated.

[011] (2) The compound or salt thereof, according to (1), in which X1, X2 and X3 are each independently CH or CR21. Petition 870250079778, dated 05 / 09 / 2025, pp. 247 / 481 6 / 226

[012] (3) The compound or salt thereof, according to (1) or (2), in which Y is an oxygen atom.

[013] (4) The compound or salt thereof, according to any one of (1) to (3), in which R4 is C3-7 alkyl optionally substituted by 1 to 3 R41s, C3-7 alkenyl optionally substituted by 1 to 3 R42s or Cyc1.

[014] (5) The compound or salt thereof, according to any one of (1) to (4), in which Z is CHR10 and R10 is a hydroxyl group.

[015] (6) The compound or salt thereof, according to any one of (1) to (5), in which R1 is COOH.

[016] (7) The compound or salt thereof, according to (1), in which the general formula (I) is represented by the general formula (I-3) wherein L10 represents -CHRL1- or CRL2RL3-, R4a represents C3-7 alkyl optionally substituted with 1 to 3 R41s, C3-7 alkenyl optionally substituted with 1 to 3 R42s, or Cyc1, and the other symbols represent the same meaning described above.

[017] (8) The compound or salt thereof, according to (1), wherein the compound represented by the general formula (I) or salt thereof is (1) (1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (2) (1R,2R,3aS,10aR)-5-fluoro-1-[(1E)-4-(2-fluorophenyl)-3-hydroxy-1 Petition 870250079778, dated 05 / 09 / 2025, pp. 248 / 481 7 / 226 penten-1 -il]-2-hidróxi-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (3) ácido (1 R,2R,3aS, 10aR)-1 -{(1 Ε,3ξ)-3-[1 -(4-fluorofenil)ciclobutil]-3-hidróxi1 -propen-1 -il}-2-hidróxi-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina6-carboxílico, (4) ácido (1 R,2R,3aS,10aR)-1 -{(1 E^)-3-[1 -(2,5-difluorophenyl)cyclobutyl]-3hidróxi-1-propen-1-il}-2-hidróxi-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]ciclopenta[f]oxepina-6-carboxílico, (5) ácido (1 R,2R,3aS,10aR)-5-chloro-1 -[(1 E,3U-4-(2,6-difluorophenyl)-4,4difluoro-3-hidróxi-1 -buten-1 -il]-2-hidróxi-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (6) acid (1 R,2R,3aS, 10aR)-1 -{(1 E,3U-3-[1 -(4-fluorofenil)ciclobutil]-3-hidróxi1 -propen-1 -il}-2-hidróxi-5-metil-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]ciclopenta[f]oxepina-6-carboxylico, (7) ácido (1 R,2R,3aS, 10aR)-1 -[(1 E,3^)-4-etil-3-hidróxi-7-metil-1 -octen-1 -il]2-hidróxi-5-metil-2,3,3a,9,10,10a-hexa-hydro-1H-benzo[b]cyclopenta[f]oxepine-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-hexa-hydro-1Hbenzo[b]cyclopenta[f]oxepine-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-hexa-hydro-1 Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (10) (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^)-4-hydroxy-4,7-dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid, (11) (1 R,3aS,10aR)-5-fluoro-1 -[(1 E,3U-3-hydroxy-4-methyl-4-phenyl-1, Petition 870250079778, dated 05 / 09 / 2025, pp. 249 / 481 8 / 226 penten-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (12) ácido (1 R,3aS,10aR)-1 -{(1 Ε,3ξ)-3-[1 -(2-fluorofenil)ciclobutil]-3-hidróxi-1 propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (13) ácido (1 R,3aS,10aR)-5-cloro-1 -{(1 E,3^-3-[1 -(2-fluorofenil)ciclobutil]-3hidróxi-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (14) ácido (1 R,3aS, 10aR)-5-cloro-1 -[(1 E^)-3-hidróxi-6-metóxi-4-metileno-1 hexen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (15) ácido (1 R,3aS, 10aR)-5-cloro-1 -[(1 E,3^4S)-4-etil-3-hidróxi-1 -octen-1 -il]2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6-carboxílico, (16) ácido (1 R,3aS,10aR)-5-cloro-1 -[(1 E^)-3-hidróxi-3-(3-fenil-3-oxetanil)-1 propen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (17) ácido (1 R,2R,3aS, 10aR)-2,5-difluoro-1 -[(1 E^)-3-hidróxi-4-metil-4-fenil1 -penten-il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6-carboxílico, (18) ácido (1 R,2R,3aS,10aR)-2,5-difluoro-1 -[(1 E^)-3-hidróxi-3-(3-fenil-3oxetanil)-1 -propen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina6-carboxílico, (19) ácido (1R,2R,3aS,10aR)-2-cloro-5-fluoro-1-{(1E^)-3-[3-(2-fluorofenil)-3oxetanil]-3-hidróxi-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]ciclopenta[f]oxepina-6-carboxílico, (20) ácido (1 R,2R,3aS, 10aR)-2-cloro-5-fluoro-1 -{(1 E,3^-3-hidróxi-3-[^)-2fenil-2-oxetanil]-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 H-, Petition 870250079778, 05 / 09 / 2025, pág. 250 / 481 9 / 226 benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (21) (1R,3aR,10aR)-1-[(1E,3^4S)-3-hydroxy-4-methyl-1-octen-1-yl]-5-methyl-1,3,3a,9,10,10a-hexahydrofuro[3,4-b][1]benzoxepine-6-carboxylic acid, (22) (1R,3aR,10aR)-1-[(1E^)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen1-yl]-5-methyl-1,3,3a,9,10,10a-hexahydrofuro[3,4-b][1]benzoxepine-6-carboxylic acid, (23) (1R,2R,3aS, 10aR)-5-fluoro-2-hydroxy-1-{(1 E^)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexa-hydro-1 Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, or (24) (1 R,2R,3aS, 10aR)-2-hydroxy-1-[(1 E,3R)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexa-hydro-1 Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, or a salt thereof.

[018] (9) A pharmaceutical composition containing the compound or a salt thereof, according to any one of (1) to (8).

[019] (10) An EP3 agonist containing the compound or its salt, according to any one of (1) to (8).

[020] (11) The pharmaceutical composition according to (9) or the EP3 agonist according to (10), for use in the prevention and / or treatment of a disease such as myocardial infarction, dysuria or glaucoma.

[021] (12) An agent for preventing and / or treating a kidney disease, containing the compound or the salt thereof, according to any one of (1) to (8).

[022] (13) The agent according to (12), in which kidney disease is chronic kidney disease.

[023] (14) The agent according to (13), in which chronic kidney disease is diabetic kidney disease, nephrosclerosis, IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative nephritis, lupus nephritis, minimal change nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, Petition 870250079778, dated 05 / 09 / 2025, pp. 251 / 481 10 / 226 Alport syndrome or polycystic kidney disease.

[024] (15) The agent according to (12), in which kidney disease is acute kidney damage.

[025] (16) The agent according to (15), in which acute kidney injury is acute kidney injury associated with organ surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis, contrast nephropathy or drug-induced kidney injury.

[026] (17) A method for preventing and / or treating kidney disease, characterized by administering an effective amount of the compound or its salt, according to any one of (1) to (8), to a mammal (preferably a patient who needs it).

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

[028] (19) Use of the compound or its salt, according to any one of (1) to (8), to produce a preventive and / or therapeutic agent for a kidney disease.

[029] (20) The pharmaceutical composition according to (9) or the EP3 agonist according to (10), for use in the prevention and / or treatment of a renal disease.

[030] (21) The pharmaceutical composition according to (9) or the EP3 agonist according to (10) to produce an agent to prevent and / or treat a kidney disease.

[031] (22) A method for producing the compound or the salt thereof, according to any one of (1) to (8), including the step of: submit a compound represented by the general formula (I') Petition 870250079778, dated 05 / 09 / 2025, pp. 252 / 481 11 / 226 in which: T10 is a hydrogen atom or R11, T20 is a hydrogen atom or a protecting group for a hydroxyl group, T10 and T20 are not simultaneously a hydrogen atom, and the other symbols represent the same meaning defined in the general formula (I) to a hydrolysis reaction and / or a deprotection reaction.

[032] (23) The production method according to (22), for producing a compound of general formula (I) (R1= COOH, Z = CHR10, R10= a hydroxyl group) or a salt thereof, including the step of (A) subjecting the compound represented by general formula (I') (T10= R11, T20= a hydrogen) to a hydrolysis reaction. ADVANTAGEOUS EFFECTS OF THE INVENTION

[033] Because the present compound has a potent EP3 agonist activity, it is useful as a preventive and / or therapeutic agent for kidney disease and other diseases that relate to the EP3 receptor. DESCRIPTION OF THE MODALITIES

[034] A detailed description of the present invention follows.

[035] In the present invention, C1-6 alkyl includes linear or branched C1-6 alkyl, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl and their isomers.

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

[037] In the present invention, C1-4 alkyl includes linear or branched C1-4 alkyl, Petition 870250079778, dated 05 / 09 / 2025, pp. 253 / 481 12 / 226 including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and their isomers.

[038] In the present invention, C1-2 alkyl means methyl or ethyl.

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

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

[041] In the present invention, C2-4 alkenyl includes linear or branched C2-4 alkenyl, including ethenyl, propenyl, butenyl and their isomers.

[042] In the present invention, C2-4 haloalkenyl refers to a group in which any hydrogen atom of a linear or branched C2-4 alkenyl group is replaced by one or more halogen atoms, including 1-fluoroethenyl, 2-fluoroethenyl, 2-chloroethenyl, trifluoroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl and their isomers.

[043] In the present invention, C2-4 alkynyl includes linear or branched C2-4 alkynyl groups, including ethinyl, propynyl, butynyl and their isomers.

[044] In the present invention, C2-4 haloalkynyl refers to a group in which any hydrogen atom of a linear or branched C2-4 alkynyl group is replaced by one or more halogen atoms, including 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl and their isomers.

[045] In the present invention, examples of a saturated C3-6 carbocycle include cyclopropane, cyclobutane, cyclopentane and cyclohexane. Petition 870250079778, dated 05 / 09 / 2025, pp. 254 / 481 13 / 226

[046] In the present invention, a saturated 3- to 6-membered heterocycle refers to saturated 3- to 6-membered heterocycles containing a heteroatom selected from among an oxygen atom, a nitrogen atom and a sulfur atom, including 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, tetrahydro-oxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothidiazine, morpholine, thiomorpholine, oxatane, dioxolane, dioxane, dithiolane and dithiane.

[047] In the present invention, C3-7 alkyl includes straight or branched C3-7 alkyl, including 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, 1ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 1-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylpentyl, 1,3dimethylpentyl, 1,4-dimethylpentyl, 1-ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl, 1,1,3-trimethylbutyl, 1,1-diethylpropyl, 2-methyl-hexyl, 3-methyl-hexyl, 4-methyl-hexyl, 5-methyl-hexyl, 3-ethylpentyl are all isomers.

[048] In the present invention, C3-5 alkyl includes linear or branched C3-5 alkyl, including 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 their isomers. Petition 870250079778, dated 05 / 09 / 2025, pages 255 / 481 14 / 226

[049] In the present invention, C3-7 alkenyl includes linear or branched C3-7 alkenyl, including 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-1methylpropenyl, 1-ethyl-2-methylpropenyl, 1,1-dimethylbutenyl, 1,2-dimethylbutenyl, 1,3dimethylbutenyl, 2-methylpentenyl, 3-methylpentenyl, 4-methylpentenyl, 2,3dimethylbutenyl, 1-methylhexenyl, 1-ethylpentenyl, 2-ethylpentenyl, 1-propylbutenyl, 2methyl-3-hexenyl, 1,2-dimethylpentenyl, 1,3-dimethylpentenyl, 1,4-dimethylpentenyl, 1-ethyl1-methylbutenyl, 1-methyl-2-ethylbutenyl, 1-ethyl-2-methylbutenyl, 1-ethyl-3-methylbutenyl, 1,1-dimethylpentenyl, 1,1,3-trimethylbutenyl, 1,1-diethylpropenyl, 2-methyl-hexenyl, 3-methylhexenyl, 4-methyl-hexenyl, 5-methyl-hexenyl, 3-ethylpentenyl are all isomers.

[050] In the present invention, C3-5 alkenyl includes linear or branched C3-5 alkenyl, including propenyl, butenyl, pentenyl, isopropenyl, isobutenyl, 1-methylbutenyl, 1-ethylpropenyl, 1,1-dimethylpropenyl, 1,2-dimethylpropenyl, 2-methylbutenyl, 3-methylbutenyl and their isomers.

[051] In the present invention, C3-7 alkynyl includes linear or branched C3-7 alkynyl, including propynyl, butyl, pentynyl, hexynyl, heptynyl, 1-methylbutynyl, 1-ethylpropynyl, 1,1-dimethylpropynyl, 2-methylbutynyl, 3-methylbutynyl, 1-methylpentynyl, 1-ethylbutynyl, 2-ethylbutynyl, 1-ethyl-1-methylpropynyl, 1,1-dimethylbutynyl, 1,2-dimethylbutynyl, 2-methylpentynyl, 3-methylpentynyl, 4-methylpentynyl, 1-methyl-hexynyl, 1-ethylpentynyl, 2-ethylpentynyl, 1-propylbutynyl, 2-methyl-3-hexynyl, 1,2-dimethylpentynyl, 1,3dimethylpentynyl, 1,4-dimethylpentynyl, 1-ethyl-1-methylbutynyl, 1-methyl-2-ethylbutynyl, 1-ethyl-2methylbutynila, 1,1-dimethylpentinila, 1,1-diethylpropynila, 2-methyl-hexinila, 3-metil-hexinila, 4-metil-hexinila, 5-metil-hexinila, 3-etilpentinila e seus isomeros.

[052] In the present invention, the C2-6 alkoxy includes linear or branched C2-6 alkoxy groups, including ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy and iso-hexyloxy. Petition 870250079778, dated 05 / 09 / 2025, pp. 256 / 481 15 / 226

[053] In the present invention, the C1-4 alkoxy includes linear or branched C1-4 alkoxy groups, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy and their isomers.

[054] In the present invention, C1-4 haloalkoxy refers to a group in which any hydrogen atom of a linear or branched C1-4 alkoxy group is replaced by one or more halogen atoms, including 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.

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

[056] In the present invention, a 3- to 6-membered heterocycle refers to a 3- to 6-membered heterocycle containing a heteroatom selected from among an oxygen atom, a nitrogen atom and a sulfur atom, including pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, thiadiazole, thiazine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazolidine, tetrazoline, tetrazolidine, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydrophyran, thiran, thiethane, dihydrothiophene, tetrahydrothiophene,di-hidrotiopirano, tetra-hidrotiopirano, di-hidro-oxazol, tetra-hidro-oxazol (oxazolidina), di-hidroisoxazol, tetra-hidroisoxazol (isoxazolidina), di-hidrotiazol, tetra-hidrotiazol (tiazolidine), di-hidroisotiazol, tetra-hidroisotiazol (isotiazolidine), di-hidrofurazan, tetra-hidrofurazan, di-hidro-oxadiazol, tetra-hidro, Petition 870250079778, dated 05 / 09 / 2025, p. 257 / 481 16 / 226 oxadiazol (oxadiazolidina), di-hidro-oxazina, tetra-hidro-oxazina, di-hidro-oxadiazina, di-hidrotiadiazol, tetra-hidrotiadiazol (tiadiazolidina), di-hidrotiazina, tetra-hidrotiazina, di-hidrotiadiazina, tetra-hidrotiadiazina, morfolina, tiomorfolina, oxatano, dioxolano, dioxano, ditiolano e ditiano.

[057] In the present invention, examples of a C5-10 carbocycle include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentanelene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, spiro[4,4]nonane and spiro[4,5]decane.

[058] In the present invention, a 5- to 10-membered heterocycle refers to a 5- to 10-membered heterocycle containing a heteroatom selected from among an oxygen atom, a nitrogen atom and a sulfur atom, including pyrrole, imidazole triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, tiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinoline, benzoxazole, benzothiazole, benzodiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, 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, perPetition 870250079778, of 05 / 09 / 2025, pág. 258 / 481, 17 / 226 hydrodiazepine, di-hydrofurano, tetra-hydrofurano, di-hydropyrano, tetra-hydropyrano, dihydro-oxepine, tetra-hydro-oxepine, per-hydro-oxepine, di-hydrothiopheno, tetrahydrothiopheno, di-hydrothiopirano, tetra-hydrothiopirano, di-hydrothiopirano, tetra-hydrothiopirano, di-hydrothiopirano, tetra-hydrothiopirano, per-hydrothiopirano, di-hydro-oxazole, tetra-hydro-oxazole (oxazolidine), di-hydroisoxazole, tetra-hydroisoxazole (isoxazolidine), di-hydrothiazole, tetra-hydrothiazole (thiazolidine), dihydroisothiazole, tetra-hydroisothiazole (isothiazolidine), di-hydrofurazan, tetra-hydrofurazan, di-hydro-oxadiazole, tetra-hydro-oxadiazole (oxadiazolidine), di-hydro-oxazine, tetra-hydrooxazine, di-hydro-oxadiazine, tetra-hydro-oxadiazine, di-hydro-oxazepina, tetra-hydrooxazepina, per-hydro-oxazepina, di-hydro-oxadiazepina, tetra-hydro-oxadiazepina, perhydro-oxadiazepina, di-hydrothiadiazole, tetra-hydrothiadiazole (thiadiazolidine), dihydrothiazine, tetra-hydrothiazine, di-hydrothiadiazine, tetra-hydrothiadiazine, dihydrothiazepina, tetra-hydrothiazepina,per-hydrotiazepine, di-hydrotiadiazepine, tetrahydrotiadiazepine, per-hydrotiadiazepine, morpholina, thiomorpholina, oxatino, indoline, isoindoline, di-hydrobenzofurano, per-hydrobenzofurano, di-hydroisobenzofurano, perhydroisobenzofurano, di-hydrobenzothiopheno, per-hydrobenzothiopheno, dihydroisobenzothiopheno, per-hydroisobenzothiopheno, di-hydroindazole, per-hydroindazole, dihydroquinoline, tetra-hydroquinoline, per-hydroquinoline, di-hydroisoquinoline, tetrahydroisoquinoline, per-hydroisoquinoline, di-hydrophthalazine, tetra-hydrophthalazine, perhydrohthalazine, di-hydronaphtharidine, tetra-hydronaphtharidine, per-hydronaphtharidine, dihydroquinoxaline, tetra-hydroquinoxaline, per-hydroquinoxaline, di-hydroquinazoline, tetra-hydroquinazoline, per-hydroquinazoline, di-hydroquinoline, tetra-hydroquinoline, perhydroquinoline, benzoxatiane, di-hydrobenzoxazine, di-hydrobenzothiazine, pyrazinomorfoline, di-hydrobenzoxazole, per-hydrobenzoxazole, di-hydrobenzothiazole, perhydrobenzothiazole, di-hydrobenzoimidazole,perhydrobenzoimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxaindane, benzodioxane, chromane, benzodithiolane, benzodithiolane, azaespiro[4,4]nonane, oxazaespiro[4,4]nonane, dioxaespiro[4,4]nonane, azaespiro[4,5]decane, tiaaspiro[4,5]decane, Petition 870250079778, dated 05 / 09 / 2025, pp. 259 / 481 18 / 226 dithiaespiro[4,5]decane, dioxaespiro[4,5]decane and oxazaespiro[4,5]decane.

[059] In the present invention, examples of a C5-6 carbocycle include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene and benzene.

[060] Na presente invenção, um heterociclo de 5 a 6 membros inclui isoxazol, isothiazol, imidazol, imidazolidina, imidazolina, oxadiazina, oxadiazol, oxazina, oxazol, oxatano, dioxano, dioxolano, ditiano, dithiolano, di-hydroisoxazol, di-hydroisothiazol, dihydro-oxadiazine, di-hydro-oxadiazol, di-hydro-oxadiazine, di-hydro-oxazina, di-hydrooxazol, di-hydrothiadiazine, di-hydrothiadiazine, di-hydrothiazine, di-hydrothiazol, dihydrothiopirano, di-hydrothiopheno, di-hydropyrazine, di-hydropyrazine, di-hydropyridine, dihydropyridazine, di-hydropyrimidine, di-hydrofurazan, di-hydrofurano, thiadiazine, thiadiazole, thiazine, thiazole, thiopyrano, thiopheno, thiomorpholine, tetrazole, tetrazolidine, tetrazoline, tetrahydroisoxazole (isoxazolidine), tetra-hydroisothiazole (isothiazolidineine), tetra-hydrooxadiazine, tetra-hydro-oxadiazole (oxadiazolidine), tetra-hydro-oxazine, tetra-hydrothiadiazine (oxazolidine), tetra-hydrothiadiazine, tetra-hydrothiadiazine, tetra-hydrothiadiazole (thiadiazolidine), tetra-hydrothiazine,tetrahydrothiazole (thiazolidine), tetrahydrothiopyran, tetrahydrothiophene, tetrahydropyrazine, tetrahydropyran, tetrahydropyridine, tetrahydropyridazine, tetrahydropyrimidine, tetrahydrofurazan, tetrahydrofuran, triazole, triazolidine, triazoline, perhydropyridazine, perhydropyrimidine, piperazine, piperidine, pyrazine, pyrazole, pyrazolidine, pyrazoline, pyran, pyridine, pyridazine, pyrimidine, pyrrole, pyrrolidine, pyrroline, furazan, furan and morpholine.

[061] In the present invention, the following partial structure in each general formula represents Petition 870250079778, dated 05 / 09 / 2025, pp. 260 / 481 19 / 226 The partial structure includes, for example,

[062] In the present invention, R1 is preferably COOH.

[063] In the present invention, R11 is preferably C1-2 alkyl.

[064] In the present invention, R12 is preferably C1-6 alkyl, more preferably C1-2 alkyl, and even more preferably methyl.

[065] In the present invention, X1 is preferably CH or CR21, and more preferably CR21.

[066] In the present invention, X2 is preferably CH or CR21, and more preferably CH.

[067] In the present invention, X3 is preferably CH or CR21, and more Petition 870250079778, dated 05 / 09 / 2025, pp. 261 / 481 20 / 226 preferably CH.

[068] In the present invention, R21 is preferably (1) halogen, (2) alkyl C1-4, or (3) vinyl, and more preferably halogen or methyl.

[069] In the present invention, the following partial structure in general formula (I) preferably more preferably even more preferably and, in particular, preferably

[070] In the present invention, R6 is preferably a C1-4 alkyl, and more Petition 870250079778, dated 05 / 09 / 2025, pp. 262 / 481 21 / 226 preferably methyl.

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

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

[073] In the present invention, R2 is preferably a hydrogen atom.

[074] In the present invention, R3 is preferably a hydrogen atom.

[075] In the present invention, Z is preferably CHR10.

[076] In the present invention, R10 is preferably a hydroxyl group.

[077] In the present invention, L is preferably -CHRL1- or -CRL2RL3-, and more preferably -CRL2RL3-.

[078] In the present invention, L is preferably and, preferably

[079] In the present invention, RL1 is preferably (1) halogen, (2) alkyl Petition 870250079778, dated 05 / 09 / 2025, pp. 263 / 481 22 / 226 C1-4 or (3) C1-4 haloalkyl, more preferably C1-4 alkyl and even more preferably methyl or ethyl.

[080] In the present invention, RL2 is preferably (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl or (4) a hydroxyl group, and more preferably C1-4 alkyl or a hydroxyl group.

[081] In the present invention, RL3 is preferably (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl or (4) a hydroxyl group and, more preferably, halogen or a hydroxyl group.

[082] In the present invention, when RL2 and RL3 form a ring together with the carbon atom to which they are attached, the ring is preferably a saturated C3-6 carbocycle, more preferably a saturated C3-4 carbocycle, and even more preferably cyclobutane.

[083] In the present invention, R4 is preferably (1) C3-7 alkyl optionally substituted by 1 to 5 R41s, (2) C3-7 alkenyl optionally substituted by 1 to 5 R42s, or (3) Cyc1. R4 is preferably (1) C3-7 alkyl optionally substituted by 1 to 3 R41s, (2) C3-7 alkenyl optionally substituted by 1 to 3 R42s, or (3) Cyc1. R4 is, more preferably, (1) C3-5 alkyl optionally substituted by 1 to 3 R41s, (2) C3-5 alkenyl optionally substituted by 1 to 3 R42s, or (3) Cyc1.

[084] In the present invention, R41 and R42 are each independently preferably halogen.

[085] In the present invention, Cyc1 is preferably (1) a C5-6 carbocycle optionally substituted with 1 to 5 R51s or (2) a 5 to 6 membered heterocycle optionally substituted with 1 to 5 R52s, more preferably (1) phenyl optionally substituted with 1 to 5 R51s, (2) thiophene optionally substituted with 1 to 3 R52s or (3) pyridine optionally substituted with 1 to 4 R52s, even more preferably phenyl optionally substituted with 1 to 5 R51s and, particularly, preferably phenyl optionally substituted with 1 to 3 halogen atoms. Petition 870250079778, dated 05 / 09 / 2025, pp. 264 / 481 23 / 226

[086] In the present invention, Cyc1 is also preferably (where r represents an integer from 0 to 5, and the other symbols have the same meaning described above) and, more preferably R71 (where R71 represents (1) halogen or (2) C1-4 alkyl, R72 represents (1) halogen or (2) C1-4 alkyl, and es represents an integer of 0 or 1).

[087] In the present invention, R71 is preferably a halogen.

[088] In the present invention, R72 is preferably a halogen.

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

[090] In the present invention, R51 is preferably (1) halogen, (2) C1-4 alkyl, or (3) C1-4 haloalkyl, and more preferably halogen.

[091] In the present invention, R52 is preferably (1) halogen, (2) C1-4 alkyl or (3) C1-4 haloalkyl and, more preferably, halogen.

[092] In the present invention, an aspect of a compound represented by general formula (I) is a compound represented by general formula (I-1): Petition 870250079778, dated 05 / 09 / 2025, pages 265 / 481 24 / 226 (where all symbols represent the same meaning described above), and an aspect of a compound represented by the general formula (I-1) is a compound represented by the general formula (I-2): (where all symbols represent the same meaning described above), and an aspect of the compound represented by the general formula (I-2) is a compound represented by the general formula (I-3): (where L10 represents -CHRL1- or -CRL2RL3-, R4a represents C3-7 alkyl optionally substituted with 1 to 3 R41s, C3-7 alkenyl optionally substituted with 1 to 3 R42s, or Cyc1, and the other symbols represent the same meaning described above).

[093] Another aspect of the compound represented by the general formula (I) is a compound represented by the general formula (I-4): Petition 870250079778, dated 05 / 09 / 2025, pp. 266 / 481 25 / 226 (where all symbols represent the same meaning described above), and an aspect of the compound represented by the general formula (I-4) is a compound represented by the general formula (I-5): (where all symbols represent the same meaning described above).

[094] Another aspect of the compound represented by the general formula (I) is a compound represented by the general formula (I-6): R1 Petition 870250079778, dated 05 / 09 / 2025, pp. 267 / 481 26 / 226 (where all symbols represent the same meaning described above), and an aspect of the compound represented by the general formula (I-6) is a compound represented by the general formula (I-7): (where all symbols represent the same meaning described above).

[095] In the present invention, an embodiment of the compound represented by general formula (I) or a salt thereof is (1) (1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-Hbenzo[b]cyclopenta[f]oxepine-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-1-Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (3) (1R,2R,3aS,10aR)-1-{(1E,3^-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]oxepine-6-carboxylic acid, (4) (1R,2R,3aS,10aR)-1-{(1E^)-3-[1 -(2,5-difluorophenyl)cyclobutyl]-3hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (5) (1R,2R,3aS,10aR)-5-chloro-1 -[(1 E,3^-4-(2,6-difluorophenyl)-4,4difluoro-3-hydroxy-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H- Petition 870250079778, dated 05 / 09 / 2025, pp. 268 / 481 27 / 226 benzo[b]cyclopenta[f]oxepine-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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (7) (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-ethyl-3-hydroxy-7-methyl-1-octen-1-yl]2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepine-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-1-Hbenzo[b]cyclopenta[f]oxepine-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-1- Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid, (10) (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^)-4-hydroxy-4,7-dimethyl-1octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid, (11) (1R,3aS,10aR)-5-fluoro-1-[(1E,3^-3-hidróxi-4-metil-4-fenil-1 - penten-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (12) ácido (1 R,3aS,10aR)-1 -{(1 E,3^-3-[1 -(2-fluorofenil)ciclobutil]-3-hidróxi-1 propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (13) ácido (1 R,3aS,10aR)-5-cloro-1 -{(1 E,3^-3-[1 -(2-fluorofenil)ciclobutil]-3hidróxi-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (14) ácido (1 R,3aS, 10aR)-5-cloro-1 -[(1 E^)-3-hidróxi-6-metóxi-4-metileno-1 hexen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6-, Petition 870250079778, 05 / 09 / 2025, pág. 269 / 481 28 / 226 carboxylic acid, (15) (1 R,3aS, 10aR)-5-cloro-1 -[(1 E,3^4S)-4-ethyl-3-hydroxy-1 -octen-1 -yl]2,3,3a,9,10,10a-hexa-hydro-1 H-benzo[b]cyclopenta[f]oxepina-6-carboxylic acid, (16) (1 R,3aS,10aR)-5-cloro-1 -[(1 E^)-3-hydroxy-3-(3-phenyl-3-oxetanil)-1 propen-1 -yl]-2,3,3a,9,10,10a-hexa-hydro-1 H-benzo[b]cyclopenta[f]oxepina-6-carboxylic acid, (17) ácido (1 R,2R,3aS, 10aR)-2,5-difluoro-1 -[(1 E^)-3-hidróxi-4-metil-4-fenil1 -penten-il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6-carboxílico, (18) ácido (1 R,2R,3aS,10aR)-2,5-difluoro-1 -[(1 E^)-3-hidróxi-3-(3-fenil-3oxetanil)-1 -propen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina6-carboxílico, (19) ácido (1R,2R,3aS,10aR)-2-cloro-5-fluoro-1-{(1E^)-3-[3-(2-fluorofenil)-3oxetanil]-3-hidróxi-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]ciclopenta[f]oxepina-6-carboxílico, (20) ácido (1 R,2R,3aS, 10aR)-2-cloro-5-fluoro-1 -{(1 E,3^-3-hidróxi-3-[^)-2fenil-2-oxetanil]-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (21) (1R,3aR,10aR)-1-[(1E,3^4S)-3-hydroxy-4-methyl-1-octen-1-yl]-5-methyl-1,3,3a,9,10,10a-hexa-hydrofuro[3,4-b][1]benzoxepine-6-carboxylic acid, (22) (1R,3aR,10aR)-1-[(1E^)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen1-yl]-5-methyl-1,3,3a,9,10,10a-hexa-hydrofuro[3,4-b][1]benzoxepine-6-carboxylic acid, (23) (1 R,2R,3aS, 10aR)-5-fluoro-2-hydroxy-1 -{(1 E^)-3-hydroxy-3-[1 -(2methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1 Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or (24) acid (1 R,2R,3aS, 10aR)-2-hydroxy-1 -[(1 E,3R)-3-hydroxy-3-(1 phenylcyclopropyl)-1 -propen-1 -yl]-2,3,3a,9,10,10a-hexahydro-1 H-, Petition 870250079778, dated 05 / 09 / 2025, pages 270 / 481 29 / 226 benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, or a salt thereof. [Isomer]

[096] In the present invention, X represents a bond beyond the surface of the sheet (i.e., α configuration), and represents a bond in front of the surface of the sheet (i.e., β configuration).

[097] In the present invention, linked to an asymmetric atom represents the α configuration, the β configuration, or a mixture thereof in any ratio, unless otherwise indicated.

[098] In the present invention, When bonded to an asymmetric atom, it represents the α configuration or the β configuration.

[099] Furthermore, the description of ξ in the chemical name indicates that the configuration of a substituent attached to an asymmetric atom is either the α configuration or the β configuration (IUPAC. Compendium of Chemical Terminology, 2nd ed. (the “Gold Book”). Compiled by A.D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by S.J. Chalk. ISBN 0-9678550-9-8. https: / / doi.org / 10,1351 / goldbook.).

[0100] For example, the chemical name of Example 7-3 and Example 7-4 is (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^^)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pages 271 / 481 30 / 226 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid or (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3^4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, or represents (1R,2R,3aS,10aR)-2-hydroxy-1 -[(1 E,3R,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (1 R,2R,3aS,10aR)-2-hydroxy-1-[(1 E,3S,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (1 R,2R,3aS,10aR)-2-hydroxy-1-[(1 E,3R,4S)-3-hydroxy-4-(trifluoromethyl)-1 octen-1 -yl]-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid, or (1R,2R,3aS,10aR)-2-hydroxy-1 -[(1E,3S,4S)-3-hydroxy-4-(trifluoromethyl)-1 octen-1 -il]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid.,

[0101] For example, in a certain aspect, when Example 7-3 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexa-hydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, Example 7-4 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexa-hydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid. In another aspect, when Example 7-3 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4S)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, Example 7-4 represents (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4R)-3-hydroxy-4-(trifluoromethyl)-1-octen-1-yl]2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid. Petition 870250079778, dated 05 / 09 / 2025, pp. 272 / 481 31 / 226

[0102] As will be evident to those skilled in the art, the other compound present in which the configuration of a substituent attached to an asymmetric atom is represented by ξ can be interpreted in the same way.

[0103] In the present invention, all isomers encompass the above interpretation. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene, and alkenylidene include linear and branched forms. Furthermore, isomers with a double bond, a ring, and a fused ring (E, Z, cis, and trans isomers), isomers due to the presence of asymmetric carbon or similar (R, S forms, α, β configuration, enantiomer, diastereomer), optically active materials with optical rotation (D, L, d, l forms), polar materials caused by chromatographic separation (high-polarity material, low-polarity material), equilibrium compounds, rotational isomers, mixtures thereof in any arbitrary proportion, racemic mixtures, and tautomers are all included in the present invention.

[0104] The optically active compounds of the present invention are not only 100% pure, but may contain less than 50% of other optical isomers.

[0105] In the present invention, all references to the present compound include a compound represented by general formula (I) and the like, a salt thereof, a solvate (e.g., hydrate) thereof, an N-oxide thereof or a cocrystal thereof, or a solvate (e.g., hydrate) of the salt of the compound represented by general formula (I) and the like or a cocrystal thereof.

[0106] The compound represented by the general formula (I) and similar compounds is converted into a corresponding salt by a known method. The salt is preferably soluble in water. The salt is also preferably a pharmaceutically acceptable salt. These salts include salts of alkali metals (lithium, potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), salts of other metals (silver, zinc, etc.), ammonium salts (tetramethylammonium salts), salts of Petition 870250079778, dated 05 / 09 / 2025, pp. 273 / 481 32 / 226 pharmaceutically acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-2-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc.), salts of acid adducts (salts of inorganic acids (hydrochloride, hydrobromide, iodide, sulfate, phosphate, nitrate, etc.), salts of organic acids (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluene sulfonate, isethionate, napadisylate, glucuronate, gluconate etc.) etc.).

[0107] The compound represented by general formula (I) and similar compounds, or a salt thereof, may exist in an unsolvated form or may exist in a solvated form with a pharmaceutically acceptable solvent, such as water or ethanol. The solvent is preferably low toxicity and soluble in water, and more preferably a hydrate. The compound represented by general formula (I) and similar compounds, or a salt thereof, may be converted into a solvent by a known method.

[0108] The N-oxide of the compound represented by general formula (I) and similar compounds represents a compound obtained by the oxidation of a nitrogen atom of the compound represented by general formula (I) and similar compounds. In addition, the N-oxide of the compound represented by general formula (I) and similar compounds may also be the alkali (earth) metal salt, the ammonium salt, the organic amine salt, or the acid adduct salt described above.

[0109] The compound represented by general formula (I) and similar forms, or a salt thereof, may exist in a form in which a cocrystal is formed with an appropriate cocrystal-forming agent. The cocrystal is preferably a pharmaceutically acceptable cocrystal formed with a cocrystal-forming agent. Petition 870250079778, dated 05 / 09 / 2025, pp. 274 / 481 33 / 226 pharmaceutically acceptable. A cocrystal is normally defined as a crystal formed by the interaction between two or more different molecules. A cocrystal can also be a complex of a neutral molecule and a salt. Cocrystals can be prepared by known methods, for example, melt crystallization, recrystallization from a solvent, or physical grinding of components together. Suitable cocrystal forming agents include organic acids (malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, isonicotinic acid, etc.), organic amines (imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzylphenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, 4-(2-hydroxyethyl)morpholine, N-methyl-D-glucamine, glycine, histidine, proline, etc.) and other organic compounds (caffeine, saccharin, etc.).

[0110] A prodrug of the compound represented by general formula (I) and similar refers to a compound that is converted into the compound represented by general formula (I) and similar by means of a reaction with an enzyme, gastric acid or similar in a living body.The prodrug of the compound represented by general formula (I) and similar compounds includes a compound that, when the compound represented by general formula (I) and similar compounds has an amino group, the amino group is acylated, alkylated or phosphorylated (for example, a compound having the amino group of the compound represented by general formula (I) and similar compounds eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivalyloxymethylated, acetoxymethylated, tert-butylated or similar); a compound whereby the compound represented by general formula (I) and similar forms has a hydroxyl group, the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, a compound having the hydroxyl group of the compound represented by general formula (I) and similar forms acetylated, palmitoylated, propanoylated, pivaloylated, succinylated,). Petition 870250079778, dated 05 / 09 / 2025, pp. 275 / 481 34 / 226 fumilated, alanylated, dimethylaminomethylcarbonylated or similar); and a compound whereby, when the compound represented by general formula (I) and similar has a carboxy group, the carboxy group is esterified or amidated (for example, a compound having the carboxy group of the compound represented by general formula (I) and similar ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-esterified, cyclohexyloxycarbonylethyl-esterified, methylamidated or similar). These compounds may be produced by a method known per se. The prodrug of the compound represented by general formula (I) and similar may be a solvent.Furthermore, the prodrug of the compound represented by general formula (I) and similar compounds may be that which transforms into the compound represented by general formula (I) and similar compounds under physiological conditions, as described in “Molecular Design”, pp. 163 to 198 in “Pharmaceutical research and development”, vol. 7, published by Hirokawa Shoten, 1990. Additionally, the compound represented by general formula (I) and similar compounds may be labeled with an isotope (e.g., 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 35S, 18F, 36Cl, 123I, 125I or similar compounds) or similar compounds. [Method for Producing the Compound Gift]

[0111] The present compound can be produced through appropriate improvement and the use of known methods, for example, a method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), a method shown in Examples, and similar methods in combination.

[0112] Among the compounds represented by general formula (I), the compounds represented by general formula (IA) Petition 870250079778, dated 05 / 09 / 2025, pp. 276 / 481 35 / 226 (where all symbols represent the same meaning described above) can be produced by the following Reaction Scheme 1. Reaction scheme 1 (where T represents a protecting group for a hydroxyl group, R101s each independently represents C1-6 alkyl, and the other symbols represent the same meaning described above).

[0113] In Reaction Scheme 1, Reaction 1 is known and is carried out, for example, by the reaction of a compound represented by the general formula (A1) with a compound represented by the general formula (A2) in an organic solvent (by Petition 870250079778, dated 05 / 09 / 2025, pp. 277 / 481 36 / 226 example, tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), dioxane, acetonitrile, ethanol or dichloromethane), water or a mixture thereof, in the presence of a base (for example, sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium tert-butoxide, potassium carbonate or tertiary amine + lithium chloride) at temperatures from -20 to 70 °C.

[0114] In Reaction Scheme 1, Reaction 2 is known and is carried out by reacting the compound represented by the general formula (A3) obtained in Reaction 1 in an organic solvent (e.g., THF, DME, toluene, dichloromethane, diethyl ether and dioxane) in the presence or absence of cerium chloride using a reducing agent (e.g., sodium borohydride or zinc borohydride) at temperatures from -20 to 50 °C. When only one stereoisomer is selectively produced, production is carried out using an asymmetric reducing agent (e.g., chlorodiisopinocamphenylborane) or a combination of an asymmetric auxiliary and a reducing agent ((R)-2-methyl-CBS-oxazaborolidine and a borohydride / tetrahydrofuran complex or a dimethylborane sulfide, (S)-(-)-bainaphthol and lithium aluminum hydride complex, or similar) at temperatures of -100 to 50 °C.

[0115] In Reaction Scheme 1, a deprotection reaction of a protecting group is known and can be carried out by the following method. Examples of the method include (1) a deprotection reaction by alkaline hydrolysis, (2) a deprotection reaction under acidic conditions, (3) a deprotection reaction by hydrogenolysis, (4) a deprotection reaction of a silyl group, (5) a deprotection reaction carried out using a metal, and (6) a deprotection reaction carried out using a metal complex.

[0116] These methods are specifically described below: (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane or the like) using an alkali metal hydroxide (e.g., hydroxide of Petition 870250079778, dated 05 / 09 / 2025, pages 278 / 481 37 / 226 sodium, potassium hydroxide, lithium hydroxide or similar), an alkaline earth metal hydroxide (for example, barium hydroxide, calcium hydroxide or similar), a carbonate (for example, sodium carbonate, potassium carbonate or similar), an aqueous solution thereof or a mixture thereof at 0 to 40 °C. (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole or the like), an organic acid (for example, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosilic acid or the like), or an inorganic acid (for example, hydrochloric acid, sulfuric acid or the like) or a mixture thereof (for example, hydrogen bromide / acetic acid or the like), in the presence or absence of 2,2,2-trifluoroethanol, from 0 to 100 °C. (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (for example, an ether-based solvent (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether or the like), an alcohol-based solvent (e.g., methanol, ethanol or the like), a benzene-based solvent (e.g., benzene, toluene or the like), a ketone-based solvent (e.g., acetone, methyl ethyl ketone or the like), a nitrile-based solvent (e.g., acetonitrile or the like), an amide-based solvent (e.g., N,N-dimethylformamide or the like), water, ethyl acetate, acetic acid or a mixed solvent of two or more of these solvents or the like), in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, Raney nickel or the like), in a hydrogen atmosphere under normal pressure or pressure, or in the presence of ammonium formate from 0 to 200 °C. (4) The deprotection reaction of a silyl group is carried out, for example, in Petition 870250079778, dated 05 / 09 / 2025, pp. 279 / 481 38 / 226 an organic solvent (e.g., tetrahydrofuran, acetonitrile, or similar) miscible with water using tetrabutylammonium fluoride at 0 to 40 °C. Alternatively, for example, the reaction is carried out in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosilic acid, or similar), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, or similar), or a mixture thereof (e.g., hydrogen bromide / acetic acid or similar) at -10 to 100 °C. (5) The deprotection reaction carried out with a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution with a pH of 4.2 to 7.2 or a mixture of these solutions with an organic solvent, such as tetrahydrofuran) in the presence of zinc powder, applying ultrasonic waves, if necessary, from 0 to 40 °C. (6) The deprotection reaction carried out using a metal complex is performed, for example, in an organic solvent (e.g., dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol or the like), water, or a mixture thereof, in the presence of a trap reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine or the like), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid or the like) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate or the like), in the presence or absence of a phosphine-based reagent (e.g., triphenylphosphine or the like), using a metal complex (e.g., tetracistriphenylphosphine palladium(0), dichloride of bis(triphenylphosphine)palladium(II), palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride or similar) from 0 to 40 °C.

[0117] In addition to the above, the deprotection reaction can be carried out, for example, by the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014. Petition 870250079778, dated 05 / 09 / 2025, pp. 280 / 481 39 / 226

[0118] Examples of protecting groups of a hydroxyl group (including T described in Reaction Scheme 1) include a methyl group, a trityl group, a methoxymethyl group (MOM), a 1-ethoxyethyl group (EE), a methoxyethyl group (MEM), a 2-tetrahydropyranyl group (THP), a trimethylsilyl group (TMS), a triethylsilyl group (TES), a t-butyldimethylsilyl group (TBDMS), a t-butyldiphenylsilyl group (TBDPS), an acetyl group (Ac), a pivaloyl group, a benzoyl group, a p-phenylbenzoyl group, a benzyl group (Bn), a p-methoxybenzyl group, an allyloxycarbonyl group (Alloc), a 2,2,2-trichloroethoxycarbonyl group (Troc) and the like.

[0119] Examples of protecting groups for an amino group include a benzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl group (Alloc), a 1-methyl-1-(4-biphenyl)ethoxycarbonyl group (Bpoc), a trifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl group (Bn), a p-methoxybenzyl group, a benzyloxymethyl group (BOM), a 2-(trimethylsilyl)ethoxymethyl group (SEM) and the like.

[0120] The protecting group of a hydroxyl group is preferably a 2-tetrahydropyranyl (THP) group or a tert-butyldimethylsilyl (TBDMS) group.

[0121] In addition to the groups described above, the protective group of a hydroxyl group is not particularly limited, provided it is a group that can be easily and selectively separated. For example, the groups described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 2014, are used.

[0122] Among the compounds represented by general formula (I), the compounds represented by general formula (IB) Petition 870250079778, dated 05 / 09 / 2025, pages 281 / 481 40 / 226 HOOC (where all symbols represent the same meaning described above) can be produced by subjecting the compounds represented by the general formula (IA) to a hydrolysis reaction.

[0123] This hydrolysis reaction (deprotection reaction of a carboxyl group) is known, and examples include the alkaline hydrolysis described above.

[0124] If necessary, the reaction can be followed by a known method to convert the compound into a desired salt or solvent (e.g., hydrate).

[0125] The compound represented by the general formula (A1) in Reaction Scheme 1 can be produced by Reaction Scheme 2 below. Petition 870250079778, dated 05 / 09 / 2025, pages 282 / 481 41 / 226 (where T1 represents a protecting group for a hydroxyl group, R102 represents a hydrogen, phenyl, or substituted phenyl atom (e.g., 4-fluorophenyl or similar), R103 represents a halogen or COOR11 atom, and the other symbols represent the same meaning described above. The group of Petition 870250079778, dated 05 / 09 / 2025, pages 283 / 481 42 / 226 protection for a hydroxyl group represented by T1 is the same as the protecting group T described above).

[0126] In Reaction Scheme 2, a compound represented by the general formula (A7) can be produced by subjecting a compound represented by the general formula (A6) to a protection reaction. For example, the reaction is carried out using a base (e.g., imidazole or similar) and a silane compound (e.g., trimethylsilane chloride (TESCl), tert-butyldimethylsilane chloride (TBSCl), tert-butyldiphenylsilane chloride (TBDPSCl) or similar) in an organic solvent (e.g., DMF or similar) at temperatures from -100 to 50 °C.

[0127] In Reaction Scheme 2, a compound represented by the general formula (A8) can be produced by subjecting a compound represented by the general formula (A7) to a reduction reaction. For example, the reaction is carried out using a reducing agent (e.g., diisobutylaluminum hydride (DIBAL), lithium aluminum hydride or similar) in an organic solvent (e.g., toluene, ethanol, tetrahydrofuran, hexane or similar) at -78 to 80 °C.

[0128] In Reaction Scheme 2, Reaction 3 is known and is carried out, for example, using a Wittig reagent (e.g., methyltriphenylphosphonium bromide or similar) in an organic solvent (e.g., anhydrous toluene, dimethoxyethane, tetrahydrofuran or similar) in the presence of a base (e.g., lithium hexamethyldisilazane (LHMDS), lithium diisopropylamide (LDA), butyllithium, potassium tert-butoxide, sodium hydride or similar) at temperatures of 78 to 50 °C.

[0129] In Reaction Scheme 2, Reaction 4 is known and is carried out, for example, using a ruthenium catalyst (e.g., tris(triphenylphosphine)ruthenium(II) carbonyl chlorohydride, a metathesis catalyst or the like) or a cobalt catalyst (e.g., a Jacobsen catalyst or the like) in a solvent Petition 870250079778, dated 05 / 09 / 2025, pp. 284 / 481 43 / 226 organic (e.g., anhydrous toluene, benzene, 1,4-dioxane, dimethoxyethane, methanol or similar) at temperatures of 20 to 100 °C.

[0130] In Reaction Scheme 2, the Mitsunobu reaction in Reaction 5 and Reaction 7 is known and is 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 in the presence of (2) an ilide compound (cyanomethylene tributylphosphorane, cyanomethylene trimethylphosphorane) from 0 to 100 °C.

[0131] In Reaction Scheme 2, Reaction 6 is known and is carried out, for example, using an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide or similar), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide or similar), a carbonate (sodium carbonate, potassium carbonate or similar), an aqueous solution or a mixture thereof in an organic solvent (methanol, tetrahydrofuran, dioxane or similar) at temperatures from 0 to 100 °C.

[0132] In Reaction Scheme 2, Reaction 8 is known and is carried out, for example, using a metathesis catalyst (e.g., bis(tert-butoxide) of 2,6-diisopropylphenylimide neophyllidenemorbidene(VI), bis(hexafluoro tert-butoxide) of 2,6-diisopropylphenylimide neophyllidenemorbidene(VI) or the like) in an organic solvent (e.g., toluene, dichloromethane, dichloroethane or the like) at temperatures of 20 to 80 °C.

[0133] In Reaction Scheme 2, Reaction 9 is known and is carried out, for example, in an organic solvent (e.g., toluene, THF, DMF or similar) in the presence of a nucleophilic agent (e.g., alcohol or similar) and a Petition 870250079778, dated 05 / 09 / 2025, pp. 285 / 481 44 / 226 palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium (Pd(P(t-Bu)3)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2) or similar) under carbon monoxide flow at temperatures of 50 to 100 °C.

[0134] In Reaction Scheme 2, Reaction 10 is known and is carried out by means of (1) a reaction carried out with a metallic catalyst (e.g., palladium carbonate, platinum oxide, rhodium-alumina, Raney nickel, a Wilkinson complex, a ruthenium catalyst, an iridium catalyst or the like) in an organic solvent (e.g., methanol, ethanol, ethyl acetate, dichloromethane, dichloroethane or the like), for example, using hydrogen gas under atmospheric pressure or high pressure at 0 °C to 80 °C, or (2) a reaction carried out with a reducing agent (e.g., sodium borohydride or the like) in an organic solvent (e.g., methanol, ethanol or the like) in the presence or absence of cerium chloride or the like as an additive between -40 °C and 80 °C.

[0135] In Reaction Scheme 2, a compound represented by the general formula (A18) can be produced by subjecting a compound represented by the general formula (A17) to the deprotection reaction.

[0136] In Reaction Scheme 2, the compound represented by the general formula (A1) can be produced by subjecting a compound represented by the general formula (A18) to an oxidation reaction. Examples of the oxidation reaction include (1) a method carried out with the oxidation of DMSO (e.g., Swern oxidation), (2) a method carried out using a Dess-Martin reagent, (3) a method carried out with a TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) reagent. Petition 870250079778, dated 05 / 09 / 2025, pp. 286 / 481 45 / 226 and similar.

[0137] As a specific example, the method carried out with the oxidation of DMSO is carried out, for example, by reacting an alcohol compound in an organic solvent (e.g., chloroform, dichloromethane, ethyl acetate or the like) in the presence of an activating agent (e.g., oxalyl chloride, acetic anhydride, pyridine-sulfur trioxide complex or the like) and an oxidizing agent (e.g., dimethyl sulfoxide (DMSO) or the like), and further reacting the alcohol compound with a tertiary amine (e.g., triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, diazabicyclo[5,4,0]undec-7ene or the like) at -78 to 40 °C.

[0138] In each reaction of this descriptive report, the compound with a chiral center may be a compound of a desired optical isomer fractionated by means of optical resolution using a conventional method (e.g., a method performed using an optical resolution column).

[0139] In Reaction Scheme 2, Reaction 4 and / or Reaction 9 may be appropriately omitted, depending on the compound to be obtained or the intermediate to be used.

[0140] Among the compounds represented by the general formula (I), the compounds represented by the general formula (IC) R11OOC (where all symbols represent the same meaning described above) can be produced by the following Reaction Scheme 3. Petition 870250079778, dated 05 / 09 / 2025, pages 287 / 481 46 / 226 Reaction scheme 3 HO (where all symbols represent the same meaning described above).

[0141] In Reaction Scheme 3, Reaction 11 is known and is carried out, for example, by the reaction of the compound represented by the general formula (A1) with a compound represented by the general formula (A19) in an organic solvent (for example, tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), toluene or similar) in the presence of a base (for example, potassium hexamethyldisylazide, lithium diisopropylamide, butyllithium or similar) at temperatures from 100 to -20 °C.

[0142] In Reaction Scheme 3, a deprotection reaction of a protecting group is known and can be carried out by the deprotection reaction method described above.

[0143] Among the compounds represented by the general formula (I), the compounds represented by the general formula (ID) Petition 870250079778, dated 05 / 09 / 2025, pages 288 / 481 47 / 226 HOOC R4 (where all symbols represent the same meaning described above) can be produced by subjecting the compounds represented by the general formula (IC) to a hydrolysis reaction.

[0144] This hydrolysis reaction (deprotection reaction of a carboxyl group) is known, and examples include the alkaline hydrolysis described above.

[0145] If necessary, the reaction can be followed by a known method to convert the compound into a desired salt.

[0146] In each of the reactions in this document, the compounds used as starting materials, for example, the compounds represented by general formula (A2), general formula (A6), general formula (A10-1), general formula (A13) and general formula (A19) are known or can be easily produced by known methods.

[0147] In each of the reactions in this document, a reaction involving heating can be carried out using a water bath, an oil bath, a sand bath, or a microwave, as will be evident to those skilled in the art.

[0148] In each of the reactions in this document, a solid-phase supported reagent supported on a high molecular weight polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like) can be used appropriately.

[0149] In each of the reactions in this document, the reaction product can be purified by common purification methods, for example, distillation under normal or reduced pressure, high-performance liquid chromatography performed with Petition 870250079778, dated 05 / 09 / 2025, pages 289 / 481 48 / 226 silica gel or magnesium silicate, thin-layer chromatography, ion-exchange resin, stripping resin or column chromatography, washing, recrystallization or similar. Purification can be performed for each reaction or can be performed after the completion of some reactions.

[0150] Specific aspects of the production method of the present compound include the following.

[0151] A method for producing a compound of general formula (I) or a salt thereof, including the step of: submit a compound represented by the general formula (I') [in which: T10 is a hydrogen atom or R11, T20 is a hydrogen atom or a protecting group for a hydroxyl group, T10 and T20 are not simultaneously a hydrogen atom, and the other symbols represent the same meaning defined in the general formula (I)] to a hydrolysis reaction and / or a deprotection reaction.

[0152] The protecting group for a hydroxyl group represented by T20 is the same as the T protecting group described above.

[0153] The hydrolysis reaction (deprotection reaction of a carboxyl group) when T10 is R11 is known, and examples include alkaline hydrolysis.

[0154] When T20 is a protecting group for a hydroxyl group, the deprotection reaction for it can be carried out by a known method. Examples of Petition 870250079778, dated 05 / 09 / 2025, pages 290 / 481 49 / 226 methods include (1) a deprotection reaction by alkaline hydrolysis, (2) a deprotection reaction under acidic conditions, (3) a deprotection reaction by hydrogenolysis, (4) a deprotection reaction of a silyl group, (5) a deprotection reaction carried out with a metal, and (6) a deprotection reaction carried out with a metal complex. Details have been described above.

[0155] If necessary, these reactions can be followed by a known method to convert the compound into a desired salt.

[0156] In the above production method, the hydrolysis reaction can be (A) a step in which a compound represented by the general formula (I') (T10= R11, T20= a hydrogen atom) is subjected to a hydrolysis reaction and, in that case, the compound of the general formula (I) (R1= COOH, Z = CHR10, R10= a hydroxyl group) or a salt thereof can be produced. [Toxicity]

[0157] The toxicity of the present compound is low enough that the preventive and / or therapeutic agent can be safely used as a pharmaceutical product. [Application to Pharmaceutical Products]

[0158] The present compound can be used as an EP3 agonist with EP3 agonist activity.

[0159] Because the present compound has EP3 agonist activity, it is considered useful for the treatment and / or prevention of diseases such as kidney disease (e.g., chronic kidney disease or acute kidney injury), myocardial infarction, dysuria, and glaucoma.

[0160] This compound is useful, for example, for the treatment and / or prevention of kidney disease. Certain aspects of kidney disease are chronic kidney disease and acute kidney injury.

[0161] In a preferred embodiment, chronic kidney disease is, by Petition 870250079778, dated 05 / 09 / 2025, pages 291 / 481 50 / 226 For example, chronic kidney disease based on lifestyle diseases, chronic glomerulonephritis, nephrotic syndrome, or hereditary kidney disease. Among these, chronic kidney disease based on lifestyle diseases includes diabetic kidney disease 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.

[0162] Other forms of chronic kidney disease include, for example, chronic symptoms of renal failure and / or renal insufficiency, renal hypoperfusion, hypertensive nephrosclerosis, immune renal damage, and pyelonephritis.

[0163] Other forms of chronic kidney disease include, for example, dehydration through forced diuresis after partial kidney resection, uncontrolled elevation of blood pressure with malignant hypertension, urinary tract obstruction and infections and amyloidosis and systemic diseases involving the glomeruli, for example, rheumatoid systemic immunological disorders, chronic renal failure, for example, in lupus erythematosus, and renal artery stenosis, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, chronic interstitial kidney damage induced by X-ray contrast agents and induced by drugs, and chronic renal failure due to metabolic syndrome and dyslipidemia.

[0164] 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 disorders, glomerular and tubular proteinuria, abnormal reduction of Petition 870250079778, dated 05 / 09 / 2025, pages 292 / 481 51 / 226 renal edema, hematuria, creatinine and / or water excretion, abnormal elevation of blood concentrations of urea, nitrogen, potassium and / or creatinine, nitrogen, potassium and / or creatinine, alteration in the activity of a renal enzyme, for example, glutamyl synthase, alteration in the osmolar concentration of urine or in the volume of urine, elevation of microalbuminuria, evident albuminuria, glomerular and arteriolar lesions, tubular dilation and hyperphosphatemia.

[0165] In a preferred embodiment, acute kidney injury is, for example, acute kidney injury accompanied by ischemic reperfusion injury or drug-induced kidney injury (antimicrobials, anticancer agents, etc.). Among these, acute kidney injury accompanied by ischemic reperfusion injury includes acute kidney injury associated with organ surgery, such as cardiac surgery, liver surgery or lung surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis and contrast nephropathy.

[0166] Other types of acute kidney injury include, for example, partial kidney resection, dehydration through forced diuresis, uncontrolled elevation of blood pressure with malignant hypertension, urinary tract obstruction and infections, amyloidosis and systemic diseases involving the glomeruli, for example, systemic immunological rheumatoid diseases, for example, in lupus erythematosus, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, as well as acute interstitial kidney damage induced by X-ray contrast agents and drugs.

[0167] Preferred examples of kidney diseases to be treated and / or prevented with the use of this compound include diabetic kidney disease, IgA nephropathy, Alport syndrome and autosomal dominant polycystic kidney disease.

[0168] The present compound can be administered as a drug. Petition 870250079778, dated 05 / 09 / 2025, pp. 293 / 481 52 / 226 concomitant in combination with another agent for 1) Supplementing and / or intensifying the preventive and / or therapeutic effect of the compound, 2) improvement of kinetics and absorption and reduction of compound dosage, and / or 3) Reduction of the compound's side effects

[0169] The concomitant drug of the present compound and another drug may be administered in the form of a compounding agent in which both components are combined in one formulation, or it may be administered in the form of separate formulations. When administration is carried out in these separate formulations, simultaneous administration or administration with a time difference is included. Furthermore, with regard to administration with a time difference, the present compound may be administered first, and the other drug may be administered afterward, or the other drug may be administered first, and the present compound may be administered afterward. The respective methods of administration may be the same or different.

[0170] The disease in which a therapeutic and / or preventive effect is exhibited by the concomitant drug is not particularly limited, provided that the concomitant drug complements and / or enhances the therapeutic and / or preventive effect of the present compound.

[0171] In addition, the concomitant drug obtained by combination with the present compound includes not only those that have been found to date, but also those that will be found in the future.

[0172] The pharmaceutical composition of the present invention contains the present compound and any pharmaceutically acceptable carrier. For use in preventing and / or treating the diseases mentioned above, the pharmaceutical composition containing the present compound is generally prepared by the formulation of the present Petition 870250079778, dated 05 / 09 / 2025, pp. 294 / 481 53 / 226 compound, which is an active ingredient, with a pharmaceutically acceptable carrier, such as various additives or solvents, and then administered systemically or topically in an oral or parenteral form. In this document, pharmaceutically acceptable carrier means a substance other than the active ingredient, a substance generally used for pharmaceutical formulation. Preferably, the pharmaceutically acceptable carrier does not have a pharmacological effect, is harmless, and does not interfere with the therapeutic effect of the active ingredient at the dosage of the formulation. The pharmaceutically acceptable carrier may also be used for the purpose of, for example, increasing the usefulness of the active ingredient and the formulation, facilitating formulation, stabilizing quality, or improving usability.Specifically, substances described in the “Iyakuhin Tenkazai Jiten (Japanese Directory of Pharmaceutical Excipients)” published in 2000 by Yakuji Nippo Limited (edited by the Japan International Council for Pharmaceutical Excipients) and similar substances may be appropriately selected depending on the purpose.

[0173] To use the present compound or the concomitant drug of the present compound and another drug for the above purpose, the present compound or the concomitant drug is generally administered systemically or locally, in an oral or parenteral form. The dosage varies according to age, body weight, symptom, therapeutic effect, method of administration, treatment time and the like, but is generally administered orally once to several times a day, in the range of 1 ng to 1000 mg per adult for each administration, or administered parenterally once to several times a day, in the range of 0.1 ng to 10 mg per adult for each administration, or administered continuously intravenously in the range of 1 hour to 24 hours per day. It is clear that, as described above, since the dosage varies according to various conditions, a smaller amount than the above dosage may be sufficient, or administration beyond the range may be necessary. Petition 870250079778, dated 05 / 09 / 2025, pp. 295 / 481 54 / 226

[0174] Examples of oral preparations include oral liquid preparations (e.g., elixirs, syrups, pharmaceutically acceptable water, suspensions, emulsions) and oral solid preparations (e.g., tablets (including sublingual tablets, orally disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules), powders, granules, lozenges). Examples of parenteral preparations include liquid preparations (e.g., injections (intravitreal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion, etc.), eye drops (e.g., aqueous eye drops (aqueous ophthalmic solution, aqueous suspended ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), non-aqueous eye drops (non-aqueous ophthalmic solution, non-aqueous suspended ophthalmic solution, etc.).External preparations (e.g., an ointment (eye ointment or similar)), ear drops, and the like. These formulations may be controlled-release formulations, such as rapid-release formulations and sustained-release formulations. These formulations may be produced by known methods, for example, a method described in the Japanese Pharmacopoeia.

[0175] An oral liquid preparation, such as an oral preparation, is produced, for example, by dissolving, suspending, or emulsifying an active ingredient in a commonly used diluent (e.g., purified water, ethanol, a mixture thereof, or similar). In addition, this liquid preparation may contain a humectant, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative, a buffering agent, or similar.

[0176] A solid oral preparation, such as an oral preparation, is prepared, for example, by mixing an active ingredient with an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch or the like), a Petition 870250079778, dated 05 / 09 / 2025, pages 296 / 481 55 / 226 binder (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate or similar), a disintegrant (e.g., calcium fiber glycolate or similar), a lubricant (e.g., magnesium stearate or similar), a stabilizer, a solubilizer (glutamic acid, aspartic acid or similar) or similar, followed by formulation according to a conventional method. If necessary, the preparation may be coated with a coating agent (e.g., white sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or similar), or it may be coated with two or more layers.

[0177] An external preparation, such as a parenteral preparation, is produced by a known method or by a commonly used formulation. For example, an ointment is produced by grinding or melting an active ingredient in a base. The ointment base is selected from those known or commonly used. For example, one or a mixture of two or more higher fatty acids or esters of higher fatty acids (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester or oleic acid ester), oleic acid ester or similar), a wax (e.g., beeswax, spermaceti wax, celesin or similar), a surfactant (e.g., polyoxyethylene alkyl ether phosphoric acid ester or similar), a higher alcohol (e.g., cetanol, stearyl alcohol, cetostearyl alcohol or similar),a silicone oil (e.g., dimethylpolysiloxane or similar), a hydrocarbon (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin or similar), a glycol (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol macrogol or similar), a vegetable oil (e.g., castor oil, olive oil, sesame oil, turpentine oil or similar), an animal oil (e.g., mink oil, egg yolk oil, Petition 870250079778, dated 05 / 09 / 2025, pages 297 / 481 56 / 226 squalane, squalene or similar), water, an absorption enhancer and an antipyretic agent. In addition, it may contain a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent or similar.

[0178] Injection as a parenteral agent includes a solution, a suspension, an emulsion, and a solid injection that is dissolved or suspended in a solvent at the time of use. The injection is used, for example, by dissolving, suspending, or emulsifying the active ingredient in a solvent. Solvents used include, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohol such as ethanol, etc., and a combination thereof. In addition, the injection may contain a stabilizer, a solubilizer (e.g., glutamic acid, aspartic acid, polysorbate 80 (trademark) or similar), a suspending agent, an emulsifying agent, a calming agent, a buffering agent, a preservative, an antioxidant, an isotonic agent, a pH adjusting agent, an excipient, or similar. These preparations are sterilized in the final step or produced by aseptic handling.In addition, it is also possible to produce a sterile solid preparation, for example, a lyophilized product, and dissolve the solid preparation in sterile distilled water or sterile water for injection or in another solvent before use. EXAMPLES

[0179] A detailed description of the present invention follows with reference to the Examples, but the present invention is not limited to them.

[0180] The solvent in parentheses shown at the chromatography separation point and in TLC indicates an elution solvent or developing solvent used, and the ratio represents a volume ratio.

[0181] The conditions used in the LC / MS analysis in the following examples are shown below. Column: YMC Triart C18, 2.0 mm x 30 mm, 1.9 μm; Flow rate: 1.0 mL / min; Temperature: 30 °C; Mobile phase A: aqueous solution of TFA (acid Petition 870250079778, dated 05 / 09 / 2025, pages 298 / 481 57 / 226 trifluoroacetic) at 0.1%; Mobile phase B: acetonitrile solution with TFA at 0.1%: gradient (ratio of mobile phase A : mobile phase B is described): 0 to 0.10 min (95 : 5), 0.10 to 1.20 min (95 : 5 to 5 : 95), 1.20 min to 1.50 min (5 : 95).

[0182] The parenthesis shown in the NMR section indicates a solvent used for the measurement.

[0183] The name of the compound used in this document is generally named using a computer program ACD / Name (registered trademark) from Advanced Chemistry Development, which performs naming in accordance with IUPAC nomenclature, or named in accordance with IUPAC nomenclature. Reference Example 1: (1R,2R,3S,4R)-3-({[dimethyl(2-methyl-2propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2yloxy)cyclopentylformate

[0184] To a solution of (1S,2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2prop-1-enyl-4-tetrahydropyran-2-yloxy-2-cyclopentanol (CAS No: 1262874-63-4, 7.2 g) in tetrahydrofuran (hereinafter, THF) (5.8 mL) were added triphenylphosphine (10 g) and formic acid (1.5 mL), followed by cooling to -30 °C. To the reaction solution was added diethyl azodicarboxylate (18 mL), followed by stirring for 3 hours under ice cooling. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 ^ 90:10) to yield the title compound (7.7 g) with the following physical properties.

[0185] TLC: Rf 0.85 (hexane : ethyl acetate = 2 : 1). Reference Example 2: (1R,2R,3S,4R)-3-({[dimethyl(2-methyl-2propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol

[0186] A solution of the compound (7.7 g) produced in Example Petition 870250079778, dated 05 / 09 / 2025, pp. 299 / 481 58 / 226 Reference 1 in ethanol (50 mL) was added to potassium carbonate (2.67 g), followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, followed by filtration and washing with ethyl acetate. The filtrate obtained was concentrated under reduced pressure, followed by dilution with ethyl acetate, addition of water, and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 ^ 85:15) to yield the title compound (6.0 g) with the following physical properties.

[0187] TLC: Rf 0.60 (hexane : ethyl acetate = 2 : 1). Example of Reference 3: 3-bromo-2-fluoro-6-vinylphenol

[0188] To a solution of methyltriphenylphosphonium bromide (2.45 g) in THF (12 mL) was added potassium t-butoxide (666 mg) at 0 °C, followed by stirring at room temperature for 1 hour. After cooling to 0 °C, a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (CAS No: 1427373-29-2, 1.0 g) in THF (15 mL) was added, followed by stirring at 0 °C for 1 h. To the reaction mixture was added a 1 N aqueous solution of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0^85:15) to yield the title compound (1.1 g) with the following physical properties.

[0189] TLC: Rf 0.44 (hexane : ethyl acetate = 6 : 4); 1H NMR (CDCle): δ 7.10, 7.03, 6.91, 5.82, 5.47, 5.38. Reference Example 4: {[(1S,2R,3S,5R)-3-(3-bromo-2-fluoro-6-vinylphenoxy)2-(1-propen-1-yl)-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]methoxy}(dimethyl)(2-methyl-2propanyl)silane Petition 870250079778, dated 05 / 09 / 2025, pp. 300 / 481 59 / 226

[0190] To a solution of the compound (1.7 g) produced in Reference Example 2 and the compound (1.0 g) produced in Reference Example 3 in THF (17 mL) was added triphenylphosphine (1.7 g), followed by cooling with ice. Diethyl azodicarboxylate (2.9 mL) was added to the reaction solution, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0^90:10) to yield the title compound (2.39 g) with the following physical properties.

[0191] TLC: Rf 0.79 (hexane : ethyl acetate = 9 : 1); NMR of 1H (CDCle): 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 to 0.07. Reference Example 5: {[(1S,2R,3aS,10aR)-6-bromo-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a, 10a-tetra-hydro-1 H-benzo[b]oxecyclopin-1[f] il]methoxy}(dimethyl)(2-methyl-2-propanyl)silane

[0192] A solution of the compound (2.39 g) produced in Reference Example 4 in toluene (83.7 mL) was stirred at 100 °C for 30 minutes under a nitrogen stream. Then, the temperature was reduced to 80 °C, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride (397 mg) was added, and the reaction solution was stirred at 80 °C for 100 minutes. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0^90:10) to yield the title compound (2.21 g) with the following physical properties.

[0193] TLC: Rf 0.64 (hexane : ethyl acetate = 9 : 1); 1H NMR (CDCle): δ 7.14, 6.81, 6.30, 6.02, 4.70, 4.21 - 4.28, 3.96 - 4.08, Petition 870250079778, dated 05 / 09 / 2025, pages 301 / 481 60 / 226 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. Example of Reference 6: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,10a-tetrahydro1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0194] To a solution of the compound (2.06 g) produced in Reference Example 5 in ethanol (12.4 mL) / dimethylformamide (hereinafter, DMF) (6.18 mL) was added diisopropylamine (1.69 mL). Under a stream of nitrogen, the dichloromethane adduct of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (319 mg) was added, followed by stirring 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 solution of ammonium chloride, and then extracted with a mixed solution of ethyl acetate / n-hexane. The organic layer was washed with saturated saline solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 ^ 75:25) to yield the title compound (1.65 g) with the following physical properties.

[0195] TLC: Rf 0.43 (hexane : ethyl acetate = 9 : 1); 1H NMR (CDCle): 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. Example of Reference 7: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0196] To a solution of the compound (1.65 g) produced in Reference Example 6 in ethanol (25.1 mL) 10% palladium carbonate (165 mg) was added, followed by stirring at room temperature for 3 hours under a stream of hydrogen. Petition 870250079778, dated 05 / 09 / 2025, pages 302 / 481 61 / 226 The reaction solution was diluted with ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was subjected to the next reaction without subsequent purification.

[0197] TLC: Rf 0.87 (hexane : ethyl acetate = 4 : 6); 1H NMR (CDCie): 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. Example of Reference 8: (1S,2R,3aS,10aR)-5-fluoro-1-(hydroxymethyl)-2-(tetrahydro-2H-pyrano-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0198] To a solution of the crude product produced in Reference Example 7 in THF (11.6 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (4.8 mL) at room temperature, followed by stirring at room temperature overnight. To the reaction solution was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 40:60^0:100) to yield the title compound (1.20 g) with the following physical properties.

[0199] TLC: Rf 0.36 (hexane : ethyl acetate = 4 : 6); 1H NMR (CDCle): 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. Example of Reference 9: (1R,2R,3aS,10aR)-5-fluoro-1-formyl-2-(tetrahydro2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl Petition 870250079778, dated 05 / 09 / 2025, pp. 303 / 481 62 / 226

[0200] To a solution of the compound (500 mg) produced in Reference Example 8 in dichloromethane (5 mL) were added dimethyl sulfoxide (hereinafter, DMSO) (1 mL) and triethylamine (854 μL). The reaction solution was cooled to 0 °C. A sulfur trioxide-pyridine complex (584 mg) was added to the reaction solution, followed by stirring at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to yield the title compound (446 mg) with the following physical properties.

[0201] TLC: Rf 0.40 (hexane : ethyl acetate = 2 : 1); 1H NMR (CDCie): 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. Example of Reference 10: (2S)-2-(2,4-difluorophenyl)propanoate methyl

[0202] 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 2 M solution of trimethylsilyldiadiazomethane in n-hexane (82.3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then stirred at room temperature for 30 min. Acetic acid was added to the reaction mixture, followed by concentration under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0^83:17) to yield the title compound (6.08 g) with the following physical properties.

[0203] TLC: Rf 0.50 (hexane : ethyl acetate = 5 : 1); 1H NMR (CDCle): δ 7.24 - 7.29, 6.78 - 6.86, 3.98, 3.69, 1.49. Example of Reference 11: dimethyl[(3S)-3-(2,4-difluorophenyl)-2-oxobutyl] Petition 870250079778, dated 05 / 09 / 2025, p. 304 / 481 63 / 226 phosphonate

[0204] To a solution of dimethyl methylphosphonate (7.85 g) in THF (50 mL) was added, dropwise, a 1.55 M n-butyllithium solution in n-hexane (38.9 mL) at -60 °C, followed by stirring at -78 °C for 1 hour. To the reaction mixture was added, dropwise, a solution of the compound (6.05 g) produced in Reference Example 10 in THF (50 mL) at -78 °C, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50^0:100) to yield the title compound (4.74 g) with the following physical properties.

[0205] TLC: Rf 0.41 (ethyl acetate); 1H 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. Example of Reference 12: (4S)-4-benzyl-3-[(2R)-2-(2,4-difluorophenyl)propanoyl]-1,3-oxazolidin-2-one

[0206] 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-benzyloxazolidine-2-one (CAS No: 180917-48-0, 1.43 g). In addition, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.54 g), 4-dimethylaminopyridine (131 mg) and triethylamine (1.5 mL) were added at 0 °C, followed by stirring at room temperature overnight. To the reaction mixture was added a 1 N aqueous solution of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10^65). Petition 870250079778, dated 05 / 09 / 2025, pages 305 / 481 64 / 226 : 35) to produce the title compound (1.13 g, high polarity material) with the following physical properties.

[0207] 1H NMR (CDCb): 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. Example of Reference 13: (2R)-2-(2,4-difluorophenyl)propanoic acid

[0208] To a solution of the compound (1.13 g) produced in Reference Example 12 in THF (15 mL) were added a 30% aqueous solution of hydrogen peroxide (2.8 mL) and an aqueous solution of lithium hydroxide (157 mg) (10 mL) at 0 °C, followed by stirring at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous solution of sodium thiosulfate, followed by the addition of a 1 N aqueous solution of hydrochloric acid and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20 ^ 60:40) to yield the title compound (861 mg) with the following physical properties.

[0209] 1H NMR (CDCle): δ 7.23 - 7.34, 6.76 - 6.92, 4.02, 1.51. Example of Reference 14: dimethyl[(3R)-3-(2,4-difluorophenyl)-2-oxobutyl]phosphonate

[0210] A procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11 was carried out using the compound (610 mg) produced in Reference Example 13 in place of (2S)-2-(2,4-difluorophenyl)propanoic acid to produce the title compound (614 mg) with the following physical properties.

[0211] 1H NMR (CDCb): δ 1.40, 2.94, 3.15, 3.72 - 3.83, 4.25, 6.80 - 6.93, 7.11 - 7.21. Example of Reference 15: (1 R,2R,3aS, 10aR)-1 -[(1 E,4S)-4-(2,4-difluorophenyl) Petition 870250079778, dated 05 / 09 / 2025, p. 306 / 481 65 / 226 Ethyl 3-oxo-1-penten-1-yl]-5-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylate

[0212] To a solution of the compound (80 mg) produced in Reference Example 9 in THF (1 mL) were added the compound (115 mg) produced in Reference Example 11, lithium chloride (18 mg) and triethylamine (60 μL), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1^75:25) to yield the title compound (117 mg) with the following physical properties.

[0213] 1H NMR (CDCle): 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. Example of Reference 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0214] To a solution of the compound (117 mg) produced in Reference Example 15 in methanol (2 mL) was added p-toluenesulfonic acid monohydrate (8 mg) at 0 °C, followed by stirring at room temperature for 1 hour. Triethylamine (14 μL) was added to the reaction mixture, followed by stirring at room temperature for 5 minutes. Then, cerium chloride (151 mg) and sodium tetrahydroboron (19 mg) were added at 0 °C, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated, followed by the addition of a 1 N aqueous hydrochloric acid solution and extraction with ethyl acetate. The organic layer was washed with saturated saline solution and dried over sulfate. Petition 870250079778, dated 05 / 09 / 2025, pp. 307 / 481 66 / 226 sodium and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane:ethyl acetate = 60:40 ^ 55:45) to produce a mixture containing two diastereomers.

[0215] TLC: Rf 0.45, 0.40 (hexane : ethyl acetate = 2 : 3); 1H NMR (CDCle): 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0216] The diastereomer mixture produced in Reference Example 16 was dissolved in dimethoxyethane (0.5 mL) / methanol (1 mL), followed by the addition of a 2 N aqueous sodium hydroxide solution (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of 1 N hydrochloric acid and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was separated into two diastereomers using an SFC column (CHIRALPAK ID, CO2 : Methanol = 82 : 18) to produce a high-polarity material (17.5 mg). The steric configuration was identified by single-crystal X-ray spectroscopy. Petition 870250079778, dated 05 / 09 / 2025, pages 308 / 481 67 / 226

[0217] HPLC retention time (min): 0.93; MS (ESI, Pos.): 445 (M+H-H2O)+; 1H 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. Example of Reference 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-yloxy)2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0218] To a solution of the compound (80 mg) produced in Reference Example 9 in THF (1 mL) were added the compound (115 mg) produced in Reference Example 14, lithium chloride (18 mg) and triethylamine (60 μL), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1^75:25) to yield the title compound (103 mg) with the following physical properties.

[0219] 1H NMR (CDCle): 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. Example of Reference 18: (1R,2R,3aS,10aR)-1-[(1E,3^4R)-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]oxepine-6-carboxylate ethyl

[0220] To a solution of the compound (103 mg) produced in Reference Example 17 in methanol (2 mL) was added p-toluenesulfonic acid monohydrate (7 mg) at 0 °C, followed by stirring at room temperature for 1 hour. To the reaction mixture was added triethylamine (13 μL), followed by stirring in Petition 870250079778, dated 05 / 09 / 2025, pages 309 / 481 68 / 226 at room temperature for 5 minutes. Then, cerium chloride (133 mg) and sodium tetrahydroboron (17 mg) were added at 0 °C, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by the addition of a 1 N aqueous hydrochloric acid solution and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane:ethyl acetate = 60:40 ^ 55:45) to be separated into two diastereomers, thus producing a high-polarity material (20.6 mg).

[0221] 1H NMR (CDCls): 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0222] To a solution of the compound (high polarity material: 20.6 mg) produced in Reference Example 18 in DME (0.5 mL) / methanol (1 mL) was added a 2 N aqueous solution of sodium hydroxide (0.5 mL), followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of 1 N hydrochloric acid and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to yield the title compound (14.6 mg) with the following physical properties.

[0223] HPLC retention time (min): 0.88; MS (ESI, Pos.): 445 (M+H-H2O)+; Petition 870250079778, dated 05 / 09 / 2025, p. 310 / 481 69 / 226 NMR of 1H (CD3OD): δ 7.39 − 7.46, 7.29 − 7.38, 6.88 − 6.96, 5.51, 5.29, 4.24 4.29, 4.12 − 4.919, 3.80, − 3.80, − 2.54 – 2.65, 2.44, 1.88, 1.64, 1.23 – 1.46. Reference Example 19 (1): (4S)-4-benzyl-3-[(2S)-2-(2fluorophenyl)propanyl]-1,3-oxazolidin-2-one Reference Example 19 (2): (4S)-4-benzyl-3-[(2R)-2-(2fluorophenyl)propanyl]-1,3-oxazolidin-2-one

[0224] A solution of 2-(2-fluorophenyl)propanoic acid (CAS No: 7304190-4, 2.5 g) in dichloromethane (49 mL) was added to (4S)-4-benzyloxazolidin-2-one (3.95 g). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.27 g), 4-dimethylaminopyridine (363 mg), and triethylamine (4.14 mL) were added at 0 °C, followed by stirring at room temperature overnight. A 1 N aqueous solution of hydrochloric acid was added to the reaction mixture, followed by extraction with dichloromethane and ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10^65:35) to yield the title compounds (low polarity material: 1.76 g, high polarity material: 2.93 g) with the following physical properties.

[0225] Low polarity material: 1H NMR (CDCle): 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.

[0226] High polarity material: 1H NMR (CDCla): δ 7.23 - 7.34, 7.05 7.18, 5.25, 4.74, 4.09 - 4.22, 3.34, 2.63, 1.53. Example of Reference 20: dimethyl[(3S)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate

[0227] A procedure with a purpose similar to that of Reference Example 13 ^ Reference Example 10 ^ Reference Example 11 was carried out using the compound (low polarity material: 1.76 g) produced in Reference Example 19(1) in place of the compound produced in Reference Example 12 for Petition 870250079778, dated 05 / 09 / 2025, pages 311 / 481 70 / 226 produce the title compound (941 mg) with the following physical properties.

[0228] 1H NMR (CDCle): 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. Example of Reference 21: dimethyl[(3R)-3-(2-fluorophenyl)-2-oxobutyl]phosphonate

[0229] A procedure with a similar purpose to that of Example 13 ^ Example 10 ^ Example 11 was carried out using the compound (high polarity material: 2.93 g) produced in Reference Example 19 (2) in place of the compound produced in Reference Example 12 to produce the title compound (970 mg) with the following physical properties.

[0230] 1H NMR (CDCle): 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. Reference Example 22: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,4S)-4-(2fluorophenyl)-3-oxo-1-penten-1-yl]-2-(tetrahydro -2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-ethyl carboxylate

[0231] To a solution of the compound (80 mg) produced in Reference Example 9 in THF (1 mL) were added the compound (108 mg) produced in Reference Example 20, lithium chloride (18 mg) and triethylamine (60 μL), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1^75:25) to yield the title compound (105 mg) with the following physical properties.

[0232] TLC: Rf 0.65 (hexane : ethyl acetate = 2 : 1); 1H NMR (CDCle): 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, Petition 870250079778, dated 05 / 09 / 2025, pp. 312 / 481 71 / 226 2.50 - 2.74, 2.15, 1.98 - 2.11, 1.88, 1.72 - 1.84, 1.22 - 1.72. Example of Reference 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0233] To a solution of the compound (105 mg) produced in Reference Example 22 in methanol (2 mL) was added p-toluenesulfonic acid monohydrate (7 mg) at 0 °C, followed by stirring at room temperature for 1 hour. Triethylamine (13 μL) was added to the reaction mixture, followed by stirring at room temperature for 5 minutes. Then, cerium chloride (140 mg) and sodium tetrahydroboron (18 mg) were added at 0 °C, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by the addition of a 1 N aqueous hydrochloric acid solution and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane:ethyl acetate = 60:40 ^ 55:45) to be separated into two diastereomers, thus producing a highly polar material (18.6 mg).

[0234] 1H NMR (CDCls): 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 313 / 481 72 / 226

[0235] To a solution of the compound (high polarity material: 18.6 mg) produced in Reference Example 23 in dimethoxyethane (0.5 mL) / methanol (1 mL) was added a 2 N aqueous solution of sodium hydroxide (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, followed by the addition of 1 N hydrochloric acid and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the title compound (13.1 mg) with the following physical properties. The steric configuration was identified by single-crystal X-ray spectroscopy.

[0236] HPLC retention time (min): 0.91; MS (ESI, Pos.): 427 (M+H-H2O)+; 1H 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. Example of Reference 24: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,4R)-4-(2-fluorophenyl)-3-oxo-1-penten-1-yl]-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0237] To a solution of the compound (80 mg) produced in Reference Example 9 in THF (1 mL) were added the compound (108 mg) produced in Reference Example 21, lithium chloride (18 mg) and triethylamine (60 μL), followed by stirring at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and dried over sulfate. Petition 870250079778, dated 05 / 09 / 2025, pp. 314 / 481 73 / 226 of sodium and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1^75:25) to yield the title compound (114 mg) with the following physical properties.

[0238] TLC: Rf 0.65 (hexane : ethyl acetate = 2 : 1); 1H NMR (CDCl3): δ 7.45, 7.04 - 7.28, 6.71 - 6.85, 6.17 - 6.32, 4.63 - 4.66, 4.28 - 4.40, 4.04 - 4.10, 3.80 - 3.92, 3.49 - 3.59, 3.38 - 3.46, 3.27, 2.79 - 3.00, 2.52 2.70, 2.15, 1.99 - 2.05, 1.33 - 1.92. Example of Reference 25: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3^4R)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0239] To a solution of the compound (117 mg) produced in Reference Example 24 in methanol (2 mL) was added p-toluenesulfonic acid monohydrate (8 mg) at 0 °C, followed by stirring at room temperature for 1 hour. To the reaction mixture was added triethylamine (14 μL), followed by stirring at room temperature for 5 minutes. Then, cerium chloride (151 mg) and sodium tetrahydroboron (19 mg) were added at 0 °C, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by the addition of a 1 N aqueous hydrochloric acid solution and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, hexane:ethyl acetate = 60:40 ^ 55:45) to be separated into two diastereomers, thus producing a highly polar material (19 mg).

[0240] 1H NMR (CDCb): 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 Petition 870250079778, dated 05 / 09 / 2025, pages 315 / 481 74 / 226 - 2.06, 1.75, 1.62 - 1.70, 1.34 - 1.54. Example 4: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3^4R)-4-(2-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0241] To a solution of the compound (high polarity material: 19 mg) produced in Reference Example 25 in dimethoxyethane (0.5 mL) / methanol (1 mL) was added a 2 N aqueous solution of sodium hydroxide (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, followed by the addition of 1 N hydrochloric acid and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the title compound (14.1 mg) with the following physical properties.

[0242] HPLC retention time (min): 0.86; MS (ESI, Pos.): 427 (M+H-H2O)+; 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. Example of Reference 26: dimethyl{2-[1-(2-fluorophenyl)cyclobutyl]-2-oxoethyl}phosphonate

[0243] A procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11 was carried out using 1-(2-fluorophenyl)cyclobutanecarboxylic acid (CAS No: 151157-48-1, 10.4 g) in place of (2S)-2-(2,4-difluorophenyl)propanoic acid to produce the title compound (12.64 g) with the following physical properties.

[0244] 1H NMR (CDCla): 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. Petition 870250079778, dated 05 / 09 / 2025, pp. 316 / 481 75 / 226 Example of Reference 27: dimethyl[2-oxo-2-(1-phenylcyclopropyl)ethyl]phosphonate

[0245] A procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11 was carried out using 1-phenylcyclopropanecarboxylic acid (CAS No: 6120-95-2, 3.0 g) in place of (2S)-2-(2,4-difluorophenyl)propanoic acid to produce the title compound (2.6 g) with the following physical properties.

[0246] 1H NMR (CDCls): δ 7.30 - 7.42, 3.71 - 3.75, 3.05, 3.00, 1.71, 1.26 1.30. Example of Reference 28: (2,6-difluorophenyl)(difluoro)ethyl acetate

[0247] Ethyl bromodifluoroacetate (CAS No: 667-27-6, 2.5 mL) and activated copper (3.2 g) were added to a solution of 1,3-difluoro-2-iodobenzene (CAS No: 13697-89-7, 4.7 g) in DMSO (24 mL), followed by stirring at 65 °C for 20 hours. Methyl tert-butyl ether (hereinafter MTBE) was added to the reaction mixture to separate a layer of DMSO. Then, a saturated aqueous solution of ammonium chloride was added, followed by extraction with MTBE. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 ^ 93:7) to yield the title compound (3.31 g) with the following physical properties.

[0248] TLC: Rf 0.36 (hexane : ethyl acetate = 9 : 1); 1H NMR (CDCls): δ 7.42 - 7.50, 6.95 - 7.02, 4.39, 1.35. Example of Reference 29: dimethyl[3-(2,6-difluorophenyl)-3,3-difluoro-2-oxopropyl]phosphonate

[0249] A procedure with a purpose similar to that of Reference Example 11 was carried out using the compound (3.31 g) produced in Reference Example 28 in place of the compound produced in Reference Example 10 for Petition 870250079778, dated 05 / 09 / 2025, pp. 317 / 481 76 / 226 produce the title compound (4.02 g) with the following physical properties.

[0250] TLC: Rf 0.55 (ethyl acetate); 1H NMR (CDCle): δ 7.41 - 7.52, 6.98, 3.78 - 3.86, 3.43 - 3.54. Example 5: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E^)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0251] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 26 in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used.

[0252] HPLC retention time (min): 0.93; MS (ESI, Pos.): 453 (M-OH)+; 1H 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. Examples 5-1 to 5-21:

[0253] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using a corresponding phosphonate in place of the compound produced in Reference Example 14 to produce the following example compound. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used. The corresponding phosphonate is a known compound or was prepared from a known compound by subjecting it to a procedure with Petition 870250079778, dated 05 / 09 / 2025, pages 318 / 481 77 / 226 similar purpose to Reference Example 10 ^ Reference Example 11. Example 5-1: (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-[(1E,3^-3-hydroxy3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0254] HPLC retention time (min): 0.88; MS (ESI, Pos.): 421 (M+H-H2O)+; 1H 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. Example 5-2: (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0255] HPLC retention time (min): 0.94; MS (ESI, Pos.): 435 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.43, 7.25 - 7.30, 7.07 - 7.15, 6.95, 5.60, 5.32, 4.30, 4.11 - 4.15, 3.78 - 3.86, 3.03, 2.69 - 2.82, 2.50 - 2.64, 2.48, 1.91, 1.69 - 1.82, 1.63, 1.05 - 1.15, 0.73 - 0.80, 0.65. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0256] HPLC retention time (min): 0.99; MS (ESI, Pos.): 469, 471 (M+H-H2O, M+H+2-H2O)+; 1H 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. Example 5-4: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3^-4-(4-fluorophenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0257] HPLC retention time (min): 0.88; Petition 870250079778, dated 05 / 09 / 2025, pp. 319 / 481 78 / 226 MS (ESI, Pos.): 427 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.42, 7.28, 6.99 - 7.05, 6.94, 5.64, 5.46 - 5.52, 4.37, 4.17, 3.85 - 3.91, 3.05, 2.76 - 2.91,2.56 - 2.68, 1.85 - 1.97, 1.79, 1.27. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0258] HPLC retention time (min): 0.87; MS (ESI, Pos.): 427 (M+H-H2O)+; 1H 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. Example 5-6: (1R,2R,3aS,10aR)-5-fluoro-1-[(1E,3^)-4-(4-fluoro-2-methylphenyl)-3-hydroxy-1-penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0259] HPLC retention time (min): 0.94; MS (ESI, Pos.): 423 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.41 - 7.48, 7.24 - 7.33, 6.86 - 6.97, 5.69, 5.42 - 5.59, 4.38, 4.20, 3.85 - 3.92, 2.97 - 3.20, 2.82, 2.49 - 2.73, 2.38, 1.85 - 2.04, 1.69 - 1.85, 1.29 - 1.37, 1.22. Example 5-7: (1R,2R,3aS,10aR)-1-[(1E,3^)-4-(2-chloro-4-fluorophenyl)3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0260] HPLC retention time (min): 0.96; MS (ESI, Pos.): 461.463 (M-H2O, M+2-H2O)+; 1H 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. Example 5-8: (1R,2R,3aS,10aR)-1-[(1E,3^)-4-(2-chloro-4-fluorophenyl)] Petition 870250079778, dated 05 / 09 / 2025, page 320 / 481 79 / 226 3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-l-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0261] HPLC retention time (min): 0.93; MS (ESI, Pos.): 461.463 (M-H2O, M+2-H2O)+; 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. Example 5-9: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E^)-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]oxepine-6-carboxylic acid

[0262] HPLC retention time (min): 0.95; MS (ESI, Pos.): 453 (M-OH)+; 1H 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. Example 5-10: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3U-3-[1-(5-fluoro-2methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1 acid H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0263] HPLC retention time (min): 0.96; MS (ESI, Pos.): 453 (M-OH)+; 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. Example 5-11: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3U-3-[1-(3-fluoro-2methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1 acid H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0264] HPLC retention time (min): 0.95; 1H NMR (CD3OD): δ 7.42, 7.04 - 7.21, 6.88 - 7.02, 5.59, 5.34, 4.31,3.99 Petition 870250079778, dated 05 / 09 / 2025, pp. 321 / 481 80 / 226 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. Example 5-12: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3^-3-[1-(4-fluoro-2methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1 acid H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0265] HPLC retention time (min): 0.94; MS (ESI, Pos.): 453 (M+H-H2O)+, 435 (M+H-2H2O)+; 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. Example 5-13: (1R,2R,3aS,10aR)-1-[(1E,3^)-4-(2,3-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0266] HPLC retention time (min): 0.93; MS (ESI, Pos.): 445 (M-OH)+; 1H 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. Example 5-14: (1R,2R,3aS,10aR)-1-[(1E^^)-4-(2,3-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0267] HPLC retention time (min): 0.9; MS (ESI, Pos.): 445 (M-OH)+; 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. Example 5-15: (1R,2R,3aS,10aR)-1-[(1E,3ξ,4ξ)-4-(2,5-difluorophenyl)-3 Petition 870250079778, dated 05 / 09 / 2025, pp. 322 / 481 81 / 226 hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0268] HPLC retention time (min): 0.92; MS (ESI, Pos.): 445 (M-OH)+; 1H NMR (DMSO-d6): δ 13.07, 7.37, 7.18, 7.15, 7.02 - 7.08, 6.98, 5.35 - 5.51, 4.86, 4.79, 4.35, 4.09, 3.70, 3.06, 2.89 - 3.00, 2.74 - 2.86, 2.52 - 2.56, 2.33 - 2.45, 1.59 - 1.82, 1.12 - 1.25. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0269] HPLC retention time (min): 0.89; MS (ESI, Pos.): 445 (M-OH)+; 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0270] HPLC retention time (min): 0.9; MS (ESI, Pos.): 445 (M+H-H2O)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0271] HPLC retention time (min): 0.94; MS (ESI, Pos.): 445 (M+H-H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 323 / 481 82 / 226 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. Example 5-19: (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-[(1E^,4^-3hydroxy-4-(2,4,6-trifluorophenyl)-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0272] HPLC retention time (min): 0.95; MS (ESI, Pos.): 463 (M+H-H2O)+; 1H 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. Example 5-20: (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-5-fluoro-2-hydroxy-2,3,3a,9,10,10ahexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0273] HPLC retention time (min): 1.116; MS (ESI, Pos.): 471 (M+H-H2O)+, 453 (M+H-2H2O)+; 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. Example 5-21: (1R,2R,3aS,10aR)-5-fluoro-1-{(1E,3^-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0274] HPLC retention time (min): 1.102; MS (ESI, Pos.): 435 (M+H-2H2O)+; 1H 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. Example of Reference 30: (1R,2R,3aS,10aR)-1-[(1E)-4-(2,6-diforophenyl)-4,4 Petition 870250079778, dated 05 / 09 / 2025, pp. 324 / 481 83 / 226 difluoro-3-oxo-1 -buten-1 -yl]-5-fluoro-2-(tetra-hidro-2H-piran-2-ilóxi)-2,3,3a,9,10,10ahexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6-carboxylato de ethyla

[0275] To a solution of the compound (309 mg) produced in Reference Example 29 in THF (0.5 mL) was added sodium hydride (17.5 mg, 60% oil suspension), followed by stirring at room temperature for 2 hours. To the reaction mixture was added a solution of the compound (100 mg) produced in Reference Example 9 in THF (0.5 mL) and a solution of zinc chloride in 2-methyltetrahydrofuran (0.37 mL), followed by stirring at 50 °C overnight. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 ^ 80:20) to yield the title compound (114 mg) with the following physical properties.

[0276] TLC: Rf 0.43 (hexane : ethyl acetate = 7 : 3); 1H NMR (CDCle): 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0277] A procedure with a purpose similar to that of Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 30 in place of the compound produced in Reference Example 17 to produce the title compound exhibiting the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a procedure was used. Petition 870250079778, dated 05 / 09 / 2025, pp. 325 / 481 84 / 226 diastereomer separation.

[0278] HPLC retention time (min): 0.83; MS (ESI, Pos.): 467 (M-OH)+; 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. Examples 6-1 to 6-17:

[0279] A procedure with a purpose similar to that of Reference Example 30 ^ Reference Example 18 ^ Example 2 was carried out using a corresponding phosphonate in place of the compound produced in Reference Example 29 to produce the following example compound. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used. The corresponding phosphonate is a known compound or was prepared from a known compound by subjecting the compound to a procedure with a purpose similar to that of Reference Example 28 ^ Reference Example 29. Example 6-1: (1R,2R,3aS,10aR)-1-[(1E^)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0280] HPLC retention time (min): 0.86; MS (ESI, Pos.): 431 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.40 - 7.55, 6.79 - 7.03, 5.57 - 5.65, 4.41 - 4.56, 4.19 - 4.40, 3.84 - 3.91, 3.01, 2.74, 2.55 - 2.66, 1.89 - 1.96, 1.81, 1.63. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 326 / 481 85 / 226

[0281] HPLC retention time (min): 0.87; MS (ESI, Pos.): 449 (M-OH)+; 1H NMR (DMSO-d6): δ 12.88 - 13.32, 7.50 - 7.57, 7.28 - 7.40, 6.98, 5.84, 5.54, 5.45, 4.85, 4.37 - 4.51,4.32, 3.70, 2.71 - 3.02, 2.54 - 2.63, 2.35 - 2.47, 1.74. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0282] HPLC retention time (min): 0.9; MS (ESI, Pos.): 445 (M-OH)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0283] HPLC retention time (min): 0.92; MS (ESI, Pos.): 465 (M-OH)+; 1H NMR (DMSO-d6): δ 13.07, 7.46 - 7.57, 7.37, 6.99, 5.87, 5.51 - 5.60, 5.43, 4.85, 4.44, 4.33, 3.70, 2.90, 2.79, 2.53 - 2.64, 2.45, 1.65 - 1.81, 1.46 - 1.65. Example 6-5: (1R,2R,3aS,10aR)-1-[(1E,3^-4-(2,4-difluorophenyl)-4,4-difluoro-3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0284] HPLC retention time (min): 0.86; MS (ESI, Pos.): 467 (M+H-H2O)+; 1H 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. Example 6-6: (1R,2R,3aS,10aR)-1-[(1E,3^-4-(2-chlorophenyl)-4,4-difluoro] Petition 870250079778, dated 05 / 09 / 2025, p. 327 / 481 86 / 226 3-hydroxy-1-buten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0285] HPLC retention time (min): 0.86; MS (ESI, Pos.): 465 (M-OH)+; 1H NMR (DMSO-d6): δ 13.06, 7.44 - 7.62, 7.37, 6.98, 5.85, 5.46 - 5.62, 4.86, 4.77, 4.30, 3.66 - 3.75, 2.82 - 2.92, 2.68 - 2.74, 2.52 - 2.62, 2.45 - 2.46, 2.34 - 2.42, 1.63 - 1.75, 1.32 - 1.53. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0286] HPLC retention time (min): 0.87; MS (ESI, Pos.): 445 (M+H-H2O)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0287] HPLC retention time (min): 0.9; MS (ESI, Pos.): 463 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.36, 6.83 - 6.93, 5.46 - 5.60, 4.43, 4.20 - 4.25, 3.76, 3.23 - 3.27, 2.91,2.60 - 2.73, 2.43 - 2.55, 2.40, 1.43 - 1.85. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0288] HPLC retention time (min): 0.84; MS (ESI, Pos.): 467 (M+H-H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 328 / 481 87 / 226 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0289] HPLC retention time (min): 0.87; MS (ESI, Pos.): 463 (M-OH)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0290] HPLC retention time (min): 0.89; MS (ESI, Pos.): 463 (M-OH)+; 1H NMR (DMSO-d6): δ 12.88 - 13.22, 7.28 - 7.46, 7.16 - 7.22, 6.98, 5.85, 5.51 - 5.56, 4.85, 4.43 - 4.59, 4.31, 3.71, 2.82 - 2.92, 2.69 - 2.78, 2.52 - 2.60, 2.45, 2.26, 1.69, 1.37 - 1.60, 1.23. Example 6-12: (1R,2R,3aS,10aR)-1-[(1E,3U-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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0291] HPLC retention time (min): 0.88; MS (ESI, Pos.): 483 (M-OH)+; 1H 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. Example 6-13: (1R,2R,3aS,10aR)-1-[(1E,3U-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 Petition 870250079778, dated 05 / 09 / 2025, pp. 329 / 481 88 / 226 benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0292] HPLC retention time (min): 0.9; MS (ESI, Pos.): 463 (M+H-H2O)+; 1H 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. 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-1-Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0293] HPLC retention time (min): 0.9; MS (ESI, Pos.): 463 (M+H-H2O)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0294] HPLC retention time (min): 0.91; MS (ESI, Pos.): 463 (M+H-H2O)+; 1H 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. Example 6-16: (1R,2R,3aS,10aR)-1-[(1E,3^-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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0295] HPLC retention time (min): 0.92; MS (ESI, Pos.): 483 (M-OH)+; 1H NMR (DMSO-d6): δ 12.90 - 13.24, 7.63 - 7.69, 7.48 - 7.53, 7.39, 6.95 7.00, 5.98, 5.55, 4.86, 4.42 - 4.58, 4.28 - 4.38, 3.67, 2.85 - 2.96, 2.71 - 2.82, 2.54 Petition 870250079778, dated 05 / 09 / 2025, p. 330 / 481 89 / 226 2.63, 2.35 - 2.46, 1.66 - 1.78, 1.36 - 1.64. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0296] HPLC retention time (min): 0.86; MS (ESI, Pos.): 449 (M+H-H2O)+; 1H 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. Example of Reference 31: 5-bromo-2-vinylphenol

[0297] A procedure with a purpose similar to that of Reference Example 3 was carried out using 4-bromo-2-hydroxybenzaldehyde (CAS No: 22532-623) in place of 4-bromo-3-fluoro-2-hydroxybenzaldehyde to produce the title compound with the following physical properties.

[0298] 1H NMR (CDCls): δ 7.24, 7.05, 6.98 - 7.00, 6.80 - 6.92, 5.77, 5.71, 5.40, 5.09. Example of Reference 32: (1R,2R,3aS,10aR)-1-formyl-2-(tetrahydro-2Hpyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0299] A procedure with a purpose similar to that of Reference Example 4 ^ Reference Example 5 ^ Reference Example 6 ^ Reference Example 7 ^ Reference Example 8 ^ Reference Example 9 was carried out using the compound produced in Reference Example 31 in place of the compound produced in Reference Example 3 to produce the title compound with the following physical properties.

[0300] TLC: Rf 0.50 (hexane : ethyl acetate = 2 : 1); 1H NMR (CDCle): 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, Petition 870250079778, dated 05 / 09 / 2025, pp. 331 / 481 90 / 226 2.18 - 2.41, 1.98 - 2.15, 1.70 - 1.97, 1.59 - 1.70, 1.48 - 1.57, 1.39. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0301] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was performed using the compound produced in Reference Example 32 in place of the compound produced in Reference Example 9 and using the compound produced in Reference Example 27 in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties. The steric configuration was identified by single-crystal X-ray.

[0302] HPLC retention time (min): 0.91; MS (ESI, Pos.): 403 (M+H-H2O)+, 385 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.58, 7.48, 7.34 - 7.40, 7.22 - 7.29, 7.15 - 7.21, 5.53, 5.38, 4.30 - 4.35, 3.88, 3.77 - 3.85, 3.00, 2.80, 2.59, 2.42 - 2.51, 1.65 - 1.87, 0.87 1.00, 0.68 - 0.82. Examples 7-1 to 7-50:

[0303] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 32 in place of the compound produced in Reference Example 9 and using a corresponding phosphonate in place of the compound produced in Reference Example 14 to produce the following example compound. As the intermediate corresponding to the compound produced in Reference Example 18, a highly polar compound separated by a diastereomer separation procedure was used. The corresponding phosphonate is a known compound or was prepared from a known compound by subjecting the compound to a procedure with a purpose similar to that for Example 18. Petition 870250079778, dated 05 / 09 / 2025, pp. 332 / 481 91 / 226 Reference 10 ^ Example of Reference 11 or Example of Reference 28 ^ Example of Reference 29. Example 7-1: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S)-3-hydroxy-1-octen1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0304] MS (ESI, Pos.): 357 (M+H-H2O)+; 1H 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. Example 7-2: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3^-3-hydroxy-4(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0305] HPLC retention time (min): 0.97; MS (ESI, Pos.): 425 (M+H-H2O)+, 407 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.47, 7.39, 7.06, 5.51 - 5.63, 4.40 - 4.45, 4.28, 3.66 3.82, 2.84 - 2.96, 2.68 - 2.83, 2.40 - 2.62, 2.00 - 2.27, 1.70 - 1.93, 1.12 - 1.61, 0.84. Example 7-3: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^^)-3-hydroxy-4(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0306] HPLC retention time (min): 0.99; MS (ESI, Pos.): 425 (M+H-H2O)+, 407 (M+H-2H2O)+; 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. Example 7-4: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^^)-3-hydroxy-4(trifluoromethyl)-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0307] HPLC retention time (min): 0.99; MS (ESI, Pos.): 425 (M+H-H2O)+, 407 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.59, 7.51, 7.19, 5.60 - 5.75, 4.38 - 4.43, 3.90, 3.04, Petition 870250079778, dated 05 / 09 / 2025, pp. 333 / 481 92 / 226 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. Example 7-5: (1R,2R,3aS,10aR)-1-[(1E^)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0308] HPLC retention time (min): 0.86; MS (ESI, Pos.): 413 (M+H-H2O)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0309] HPLC retention time (min): 0.97; MS (ESI, Pos.): 417 (M+H-H2O)+; 1H NMR (CDCle): 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. Example 7-7: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4R)-3-hydroxy-4phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid

[0310] HPLC retention time (min): 0.92; MS (ESI, Pos.): 373 (M+H-2H2O)+; 1H 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. Example 7-8: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4S)-3-hydroxy-4phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 334 / 481 93 / 226

[0311] HPLC retention time (min): 0.92; MS (ESI, Pos.): 373 (M+H-2H2O)+; 1H 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0312] HPLC retention time (min): 0.99; MS (ESI, Pos.): 383 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.59, 7.51, 7.19, 5.50 - 5.67, 4.41, 3.86 - 3.94, 3.03, 2.89, 2.52 - 2.69, 1.83 - 1.98, 1.52, 1.24 - 1.43, 0.89 - 0.96, 0.50 - 0.58, 0.26 - 0.34. Example 7-10: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3S)-3-hydroxy-4-(3thienyl)-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid

[0313] HPLC retention time (min): 0.84; MS (ESI, Pos.): 383 (M+H-H2O)+; 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. Example 7-11: (1R,2R,3aS,10aR)-1-{(1E,3^)-3-[1-(2fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0314] HPLC retention time (min): 0.94; MS (ESI, Pos.): 421 (M+H-H2O); 1H NMR (DMSO-d6): δ 12.78, 7.48, 7.18 - 7.34, 7.03 - 7.11,5.40, 5.19, 4.80, 4.68, 4.22 - 4.31, 3.96, 3.56 - 3.66, 2.80 - 2.92, 2.67 - 2.79, 2.49, 2.19 - 2.28, 1.41 1.69, 0.88 - 1.03, 0.61 - 0.70, 0.50 - 0.58. Example 7-12: acid (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(3 Petition 870250079778, dated 05 / 09 / 2025, pp. 335 / 481 94 / 226 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

[0315] HPLC retention time (min): 0.94; MS (ESI, Pos.): 421 (M+H-H2O); 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. Example 7-13: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0316] HPLC retention time (min): 0.97; MS (ESI, Pos.): 435 (M+H-H2O)+, 417 (M+H-2H2O)+; 1H 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. Example 7-14: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(3fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0317] HPLC retention time (min): 0.97; MS (ESI, Pos.): 435 (M+H-H2O)+; 1H 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, Petition 870250079778, dated 05 / 09 / 2025, pp. 336 / 481 95 / 226 2.49, 2.11 - 2.35, 1.89 - 2.00, 1.58 - 1.77. Example 7-15: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4R)-3-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0318] HPLC retention time (min): 0.96; MS (ESI, Pos.): 371 (M+H-H2O)+, 353 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.57, 7.48, 7.16, 5.62, 5.49, 4.38, 3.83 - 3.92, 3.03, 2.84, 2.49 - 2.68, 1.79 - 1.96, 1.45 - 1.61, 1.21 - 1.41, 1.02 - 1.16, 0.86 - 0.96. Example 7-16: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^,4S)-3-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0319] HPLC retention time (min): 0.96; MS (ESI, Pos.): 371 (M+H-H2O)+, 353 (M+H-2H2O)+; 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. Example 7-17: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0320] HPLC retention time (min): 1.1; MS (ESI, Pos.): 417 (M+H-2H2O)+; 1H NMR (DMSO-d6): δ 12.80, 7.49, 7.33, 7.17 - 7.23, 7.01 - 7.12, 5.76, 5.28 - 5.39, 4.92, 4.68, 4.27 - 4.32, 4.16, 3.60 - 3.68, 2.83 - 2.92, 2.71 - 2.80, 2.52 - 2.55, 2.39 - 2.48, 1.91 - 2.08, 1.50 - 1.78. Example 7-18: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(3thienyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0321] HPLC retention time (min): 0.88; Petition 870250079778, dated 05 / 09 / 2025, pp. 337 / 481 96 / 226 MS (ESI, Pos.): 391 (M+H-2H2O)+; 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0322] HPLC retention time (min): 0.89; MS (ESI, Pos.): 409 (M+H-H2O)+, 391 (M+H-2H2O)+; 1H NMR (DMSO-d6): δ 12.80, 7.48, 7.32, 7.16 - 7.24, 7.04 - 7.10, 5.26 5.33, 5.14 - 5.21, 4.80, 4.70, 4.24 - 4.29, 3.94 - 4.00, 3.57 - 3.65, 2.64 - 2.82, 2.41 2.49, 2.18, 1.51 - 1.67, 1.34 - 1.44, 1.23. Example 7-20: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(2chlorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0323] HPLC retention time (min): 0.913; MS (ESI, Pos.): 437 (M+H-H2O); 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. Example 7-21: acid (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(2-chloro-6fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic

[0324] HPLC retention time (min): 0.915; MS (ESI, Pos.): 455 (M+H-H2O); 1H NMR (CD3OD): δ 7.58, 7.48, 7.16 - 7.27, 6.99 - 7.05, 5.65 - 5.75, 5.38, 5.25, 4.24 - 4.35, 3.70 - 3.84, 2.91 - 3.04, 2.67 - 2.84, 2.42 - 2.63, 1.76 - 1.88, 1.56 1.76, 1.43 - 1.52, 1.15 - 1.33, 0.81 - 0.92, 0.77, 0.62 - 0.73. Petition 870250079778, dated 05 / 09 / 2025, pp. 338 / 481 97 / 226 Example 7-22: (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,4difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1 H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0325] HPLC retention time (min): 0.885; MS (ESI, Pos.): 439 (M+H-H2O); 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. Example 7-23: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(3thienyl)cyclobutyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0326] HPLC retention time (min): 0.99; MS (ESI, Pos.): 405 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.60, 7.49, 7.32, 7.19, 7.09, 7.02, 5.36 - 5.47, 4.32 4.36, 4.23, 3.83, 2.99, 2.81, 2.39 - 2.65, 2.17 - 2.32, 1.61 - 1.99. Example 7-24: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(3chlorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0327] HPLC retention time (min): 0.97; MS (ESI, Pos.): 437 (M-OH)+; 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. Example 7-25: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(2-chlorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0328] HPLC retention time (min): 1.02; Petition 870250079778, dated 05 / 09 / 2025, pp. 339 / 481 98 / 226 MS (ESI, Pos.): 451 (M-OH)+; 1H NMR (DMSO-d6): δ 12.62 - 13.01, 7.48, 7.11 - 7.34, 5.17 - 5.60, 4.80 5.00, 4.71, 4.24 - 4.38, 3.55 - 3.72, 2.69 - 2.95, 2.57 - 2.63, 2.52 - 2.55, 2.39 - 2.46, 1.88 - 1.97, 1.67. Example 7-26: acid (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(2-fluoro-6methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1 H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0329] HPLC retention time (min): 0.94; MS (ESI, Pos.): 435 (M-OH)+; 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. Example 7-27: (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,6difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0330] HPLC retention time (min): 0.9; MS (ESI, Pos.): 439 (M-OH)+; 1H NMR (DMSO-d6): δ 12.68 - 13.15, 7.50, 7.27 - 7.39, 7.21, 6.96 - 7.04, 5.45 - 5.53, 5.20, 4.89, 4.69, 4.27, 3.93 - 3.99, 3.51 - 3.76, 2.69 - 2.93, 2.52 - 2.55, 2.44, 2.26, 1.62, 1.48, 1.00 - 1.11, 0.67, 0.49 - 0.58. Example 7-28: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^)-3-hydroxy-3-{1-[3(trifluoromethyl)phenyl]cyclopropyl}-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0331] HPLC retention time (min): 0.98; MS (ESI, Pos.): 471 (M-OH)+; 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, Petition 870250079778, dated 05 / 09 / 2025, pp. 340 / 481 99 / 226 2.34 - 2.46, 1.49 - 1.74, 0.62 - 1.01. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0332] HPLC retention time (min): 1; MS (ESI, Pos.): 487 (M-OH)+; 1H NMR (DMSO-d6): δ 12.68 - 12.97, 7.49, 7.32 - 7.41, 7.26, 7.19, 5.31 5.35, 4.94, 4.71, 4.27 - 4.34, 3.82, 3.58 - 3.71, 2.71 - 2.96, 2.55, 2.36 - 2.46, 2.19 2.31, 1.50 - 1.75, 0.62 - 0.99. Example 7-30: (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,5-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0333] HPLC retention time (min): 1.12; MS (ESI, Pos.): 435 (M+H-2H2O)+; 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. Example 7-31: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0334] HPLC retention time (min): 0.96; MS (ESI, Pos.): 417 (M+H-H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 341 / 481 100 / 226 1H NMR (CD3OD): δ 7.59, 7.49, 7.27, 7.07 - 7.20, 5.59, 5.32, 4.32, 4.12, 3.76 - 3.84, 3.35 - 3.43, 2.96 - 3.04, 2.80, 2.56 - 2.65, 2.48, 2.00, 1.69 - 1.88, 1.64, 1.32 - 1.36, 1.04 - 1.14, 0.74 - 0.79, 0.65. Example 7-32: (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,5difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1 H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0335] HPLC retention time (min): 0.93; MS (ESI, Pos.): 439 (M+H-H2O)+; 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. Example 7-33: (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0336] HPLC retention time (min): 0.99; MS (ESI, Pos.): 453 (M+H-H2O)+; 1H 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. Example 7-34: (1R,2R,3aS,10aR)-1-{(1E,3U-3-[1-(2-chloro-6-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0337] HPLC retention time (min): 1.03; MS (ESI, Pos.): 469, 471 (M-H2O, M+2-H2O)+; 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. Example 7-35: acid (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,6 Petition 870250079778, dated 05 / 09 / 2025, pp. 342 / 481 101 / 226 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

[0338] HPLC retention time (min): 0.99; MS (ESI, Pos.): 453 (M+H-H2O)+; 1H 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. Example 7-36: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(3methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0339] HPLC retention time (min): 0.95; MS (ESI, Pos.): 417 (M+H-H2O)+; 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. Example 7-37: (1R,2R,3aS,10aR)-1-{(1E^)-3-[1-(2,3-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0340] HPLC retention time (min): 0.98; MS (ESI, Pos.): 453 (M+H-H2O)+, 435 (M+H-2H2O)+; 1H 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. Example 7-38: acid (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(2-fluoro-3methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic

[0341] HPLC retention time (min): 0.96; MS (ESI, Pos.): 435 (M+H-H2O)+.417 (M-2H2O)+; 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 Petition 870250079778, dated 05 / 09 / 2025, pp. 343 / 481 102 / 226 2.29, 1.71 - 1.90, 1.56 - 1.71, 1.27 - 1.35, 0.96 - 1.06, 0.59 - 0.82. Example 7-39: acid (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(5-chloro-2fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1 H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0342] HPLC retention time (min): 0.96; MS (ESI, Pos.): 455, 457 (M+H-H2O)+,437, 439 (M+H-2H2O)+; 1H 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. Example 7-40: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(2-fluoro-5methylphenyl)cyclopropyl]-3-hydroxy-1-propen-1 acid -yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0343] HPLC retention time (min): 0.95; MS (ESI, Pos.): 435 (M+H-H2O)+, 417 (M+H-2H2O)+; 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. Example 7-41: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(3-methylphenyl)cyclobutyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0344] HPLC retention time (min): 1; MS (ESI, Pos.): 413 (M+H-2H2O)+; 1H 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. Example 7-42: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(3-methoxyphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 344 / 481 103 / 226

[0345] HPLC retention time (min): 0.89; MS (ESI, Pos.): 415 (M+H-2H2O)+; 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. Example 7-43: (1R,2R,3aS,10aR)-1-{(1E,3^-3-[1-(3-chlorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0346] HPLC retention time (min): 1.02; MS (ESI, Pos.): 451 (M-OH)+; 1H 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. Example 7-44: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(2-methylphenyl)cyclobutyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0347] HPLC retention time (min): 0.99; MS (ESI, Pos.): 413 (M+H-2H2O)+; 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. Example 7-45: (1R,2R,3aS,10aR)-1-[(1E,3^-4,4-difluoro-3-hydroxy-7-methyl-1-octen-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0348] HPLC retention time (min): 0.93; MS (ESI, Pos.): 407 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.57, 7.49, 7.13 - 7.18, 5.66 - 5.78, 4.80 - 4.83, 4.36 4.41, 4.16 - 4.24, 3.87 - 3.95, 3.26, 2.99 - 3.06, 2.79 - 2.89, 2.55 - 2.69, 1.79 - 2.02, Petition 870250079778, dated 05 / 09 / 2025, pp. 345 / 481 104 / 226 1.52 - 1.64, 1.35 - 1.47, 0.91 - 0.95, 0.93. Example 7-46: (1R,2R,3aS,10aR)-1-[(1E,3S)-6-cyclopropyl-3-hydroxy-1hexen-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid

[0349] HPLC retention time (min): 0.89; MS (ESI, Pos.): 369 (M+H-H2O)+, 351 (M+H-2H2O)+; 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. Example 7-47: (1R,2R,3aS,10aR)-1-[(1E,3S)-5-cyclobutyl-3-hydroxy-1penten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid

[0350] HPLC retention time (min): 0.91; MS (ESI, Pos.): 369 (M+H-H2O)+, 351 (M+H-2H2O)+; 1H 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0351] HPLC retention time (min): 0.86; MS (ESI, Pos.): 395 (M+H-H2O)+, 377 (M+H-2H2O)+; 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. 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]oxepine-6-carboxylic acid

[0352] HPLC retention time (min): 0.77; Petition 870250079778, dated 05 / 09 / 2025, pp. 346 / 481 105 / 226 MS (ESI, Pos.): 399 (M+Na)+; 1H 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. Example 7-50: (1R,2R,3aS,10aR)-1-[(1E,3^4S)-4-ethyl-3-hydroxy-1-octen1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0353] HPLC retention time (min): 1; MS (ESI, Pos.): 385 (M-OH)+; 1H NMR (DMSO-d6): δ 12.58 - 13.08, 7.48, 7.34, 7.18, 5.38 - 5.52, 4.75, 4.46, 4.34, 3.92, 3.71, 2.76 - 3.00, 2.54 - 2.62, 2.35 - 2.47, 1.66 - 1.82, 1.06 - 1.54, 0.80 - 0.90. Example of Reference 33: 3-bromo-2-chloro-6-vinylphenol

[0354] A procedure with a purpose similar to that of Reference Example 3 was carried out using 4-bromo-3-chloro-2-hydroxybenzaldehyde (CAS No: 1427438-98-9) in place of 4-bromo-3-fluoro-2-hydroxybenzaldehyde to produce the title compound with the following physical properties.

[0355] 1H NMR (CDCls): δ 7.23 - 7.28, 7.15 - 7.19, 6.89 - 6.97, 5.86, 5.80, 5.37. Example of Reference 34: (1R,2R,3aS,10aR)-5-chloro-1-formyl-2-(tetrahydro2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0356] A procedure with a purpose similar to that of Reference Example 4 ^ Reference Example 5 ^ Reference Example 6 ^ Reference Example 7 ^ Reference Example 8 ^ Reference Example 9 was performed using the compound produced in Reference Example 33 instead of the compound produced in Reference Example 3 to produce the title compound with the Petition 870250079778, dated 05 / 09 / 2025, pages 347 / 481 106 / 226 following physical properties.

[0357] 1H NMR (CDCle): 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid HOOC

[0358] A procedure with a purpose similar to that of Reference Example 30 ^ Reference Example 18 ^ Example 2 was performed using the compound produced in Reference Example 34 in place of the compound produced in Reference Example 9 to produce the title compound with the following physical properties. The steric configuration was identified by X-ray crystal.

[0359] HPLC retention time (min): 1.045; MS (ESI, Pos.): 523 (M+Na)+; 1H 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. Examples 8-1 to 8-8:

[0360] A procedure with a purpose similar to that of Reference Example 30 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 34 in place of the compound produced in Reference Example 9 and using a corresponding phosphonate in place of the compound produced in Reference Example 29 to produce the following compound Petition 870250079778, dated 05 / 09 / 2025, pages 348 / 481 Example 107 / 226. As the intermediate corresponding to the compound produced in Reference Example 18, a highly polar compound separated by a diastereomer separation procedure was used. The corresponding phosphonate is a known compound or was prepared from a known compound by subjecting the compound to a procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11 or Reference Example 28 ^ Reference Example 29. Example 8-1: (1R,2R,3aS,10aR)-5-chloro-1-[(1E^)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0361] HPLC retention time (min): 0.85; MS (ESI, Pos.): 447, 449 (M-H2O, M+2-H2O)+; 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. Example 8-2: (1R,2R,3aS,10aR)-5-chloro-2-hydroxy-1-[(1E^)-3-hydroxy-3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0362] HPLC retention time (min): 0.88; MS (ESI, Pos.): 437, 439 (M-H2O, M+2-H2O)+; 1H 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. Example 8-3: (1R,2R,3aS,10aR)-5-chloro-1-{(1E,3^-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0363] HPLC retention time (min): 1.117; MS (ESI, Pos.): 451 (M+H-2H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 349 / 481 108 / 226 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0364] HPLC retention time (min): 0.89; MS (ESI, Pos.): 443, 445 (M-H2O, M+2-H2O)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0365] HPLC retention time (min): 0.92; MS (ESI, Pos.): 443, 445 (M-H2O, M+2-H2O)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0366] HPLC retention time (min): 1.081; MS (ESI, Pos.): 425, 427 (M-2H2O, M+2-2H2O)+; 1H 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. Example 8-7: (1R,2R,3aS,10aR)-5-chloro-1-{(1E,3^-3-[1-(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexa-hydro-Petition 870250079778, dated 05 / 09 / 2025, page. 109 / 226 H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0367] HPLC retention time (min): 1.125; MS (ESI, Pos.): 469 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.39, 7.09 - 7.17, 6.86 - 6.92, 6.79 - 6.86, 5.49 - 5.56, 5.40 - 5.47, 4.32, 4.19, 3.83 - 3.90, 3.02 - 3.09, 2.51 - 2.68, 2.33 - 2.50, 2.05 - 2.13, 1.94 - 2.01, 1.71 - 1.89, 1.56 - 1.65. Example 8-8: (1R,2R,3aS,10aR)-5-chloro-1-{(1E,3^-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0368] HPLC retention time (min): 1.115; MS (ESI, Pos.): 469 (M+H-H2O)+; 1H 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. Example of Reference 35: Methyl 3-hydroxy-2-methyl-4-vinylbenzoate

[0369] 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, followed by stirring at 0 °C for 1 hour. A solution of methyl 4-formyl-3-hydroxy-2-methylbenzoate (CAS No: 1427361-42-9, 9.34 g) in THF (46.7 mL) was added, followed by stirring at 0 °C for 3 hours. To the reaction mixture were added a saturated aqueous solution of ammonium chloride and a 1 N aqueous solution of hydrochloric acid at 0 °C, followed by extraction with a mixed solvent of ethyl acetate / n-hexane. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 ^ 90:10 ^ 80:20 ^ 70:30) to yield the title compound (9.22 g) with the following physical properties. Petition 870250079778, dated 05 / 09 / 2025, pages 351 / 481 110 / 226

[0370] H NMR (CDCI3): δ 7.10 - 7.16, 7.00 - 7.07, 6.79 - 6.88, 5.69, 5.42, 5.17, 2.35. Example of Reference 36: 3-{[(1S,2R,3S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}2-methyl-4-vinylbenzoate

[0371] To a solution of the compound (7.0 g) produced in Reference Example 35 and the compound (13.5 g) produced in Reference Example 2 in THF (70 mL) was added triphenylphosphine (12.4 g), followed by cooling with ice. To the reaction solution was added a 2.2 M diethyl azodicarboxylate solution in toluene (22 mL), followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure. To the residue obtained was added MTBE : n-hexane (2 : 1, 150 mL), followed by stirring for 1 hour. The precipitate was filtered and then the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0^85:15) to yield the title compound (14.3 g) with the following physical properties.

[0372] 1H NMR (CDCle): 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. Example of Reference 37: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,10a-tetrahydro1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0373] A solution of the compound (14.3 g) produced in Reference Example 36 in toluene (200 mL) was stirred at 60 °C for 20 minutes under a stream of nitrogen to degas it. Heating was stopped, and tricyclohexylphosphine dichloride [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) (1.21 g) was added, followed by stirring at 85 °C overnight. Petition 870250079778, dated 05 / 09 / 2025, pp. 352 / 481 111 / 226 under a nitrogen stream. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 97:3 ^ 93:7) to yield the title compound (13.2 g) with the following physical properties.

[0374] 1H NMR (CDCle): 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. Example of Reference 38: (1S,2R,3aS,10aR)-1-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-methyl-2-(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0375] To a solution of the compound (13.2 g) produced in Reference Example 37 in ethyl acetate (132 mL) was added 10% palladium on carbon (1.32 g), followed by stirring at room temperature for 3 hours under a stream of hydrogen. The reaction solution was diluted with ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure. Subsequent purification was not performed, but the following reaction was carried out. Example of Reference 39: (1S,2R,3aS,10aR)-1-(hydroxymethyl)-5-methyl-2(tetrahydro-2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0376] A solution of the crude product produced in Reference Example 38 in THF (13.2 mL) was added to a 1 mol / L solution of tetrabutylammonium fluoride in THF (52.4 mL) at room temperature, followed by stirring at room temperature overnight. After confirming the completion of the reaction by TLC, the reaction solution was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane: Petition 870250079778, dated 05 / 09 / 2025, pages 353 / 481 112 / 226 ethyl acetate = 50 : 50 ^ 0 : 100, ethyl acetate : Methanol = 85 : 15) to produce the title compound (9.08 g) with the following physical properties.

[0377] 1H NMR (CDCie): 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. Example of Reference 40: (1R,2R,3aS,10aR)-1-formyl-5-methyl-2-(tetrahydro2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0378] To a solution of the compound (2.0 g) produced in Reference Example 39 in dichloromethane (20 mL) were added DMSO (10 mL) and triethylamine (3.57 mL), followed by cooling to 0 °C. To the reaction mixture was added a sulfur trioxide-pyridine complex (2.45 g), followed by stirring at room temperature for 2 hours. To the reaction mixture were added a saturated aqueous solution of ammonium chloride and a 1 N aqueous solution of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10^70:30^55:45) to yield the title compound (2.0 g) with the following physical properties.

[0379] 1H NMR (CDCls): 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0380] A procedure with a purpose similar to that of Example Petition 870250079778, dated 05 / 09 / 2025, pp. 354 / 481 113 / 226 Reference 17 ^ Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 40 in place of the compound produced in Reference Example 9 and using the compound produced in Reference Example 27 in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used.

[0381] HPLC retention time (min): 0.9; MS (ESI, Pos.): 417 (M+H-H2O)+; 1H 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. Examples 9-1 to 9-23:

[0382] A procedure with a purpose similar to that of Reference Example 30 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 40 in place of the compound produced in Reference Example 9 and using a corresponding phosphonate in place of the compound produced in Reference Example 29 to produce the following Example compound. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used. The corresponding phosphonate is a known compound or was prepared from a known compound by subjecting the compound to a procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11 or Reference Example 28 ^ Reference Example 29. Example 9-1: (1R,2R,3aS,10aR)-1-[(1E^)-4,4-difluoro-3-hydroxy-4 Petition 870250079778, dated 05 / 09 / 2025, pp. 355 / 481 114 / 226 phenyl-1-buten-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-l-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0383] HPLC retention time (min): 0.86; MS (ESI, Pos.): 427 (M+H-H2O)+; 1H 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. Example 9-2: (1R,2R,3aS,10aR)-1-{(1E,3^-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]oxepine-6-carboxylic acid

[0384] HPLC retention time (min): 0.97; MS (ESI, Pos.): 449 (M+H-H2O)+; 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0385] HPLC retention time (min): 0.9; MS (ESI, Pos.): 407 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.38, 6.98, 5.69 - 5.81, 4.15 - 4.26, 3.95 - 4.01, 3.08, 2.78, 2.60 - 2.68, 2.43, 1.85 - 2.02, 1.73, 1.34 - 1.56, 1.31. Example 9-4: (1R,2R,3aS,10aR)-1-{(1E^)-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]oxepine-6-carboxylic acid

[0386] HPLC retention time (min): 1.139; MS (ESI, Pos.): 507 (M+Na)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 356 / 481 115 / 226 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. Example 9-5: (1R,2R,3aS,10aR)-1-{(1E,3^-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]oxepine-6-carboxylic acid

[0387] HPLC retention time (min): 1.166; MS (ESI, Pos.): 489 (M+Na)+; 1H NMR (CD3OD): δ 7.47, 7.15, 6.97 - 7.04, 5.40 - 5.48, 5.31 - 5.38, 4.25, 4.05 - 4.13, 3.82 - 3.90, 3.00 - 3.09, 2.47 - 2.67, 2.25 - 2.43, 1.97 - 2.13, 1.74 - 1.93, 1.58 - 1.69. Example 9-6: (1R,2R,3aS,10aR)-1-{(1E^)-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]oxepine-6-carboxylic acid

[0388] HPLC retention time (min): 1.134; MS (ESI, Pos.): 507 (M+Na)+; 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 357 / 481 116 / 226

[0389] HPLC retention time (min): 1.117; MS (ESI, Pos.): 471 (M+Na)+; 1H NMR (CD3OD): δ 7.44 - 7.47, 7.25 - 7.30, 7.13 - 7.18, 6.99 - 7.02, 5.32 - 5.45, 4.25, 4.05 - 4.10, 3.82 - 3.89, 3.03, 2.51 - 2.66, 2.30 - 2.44, 2.01 - 2.09, 1.72 1.93, 1.60. Example 9-8: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^)-3-hydroxy-4-methyl4-(3-thienyl)-1-penten-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6 carboxylic acid

[0390] HPLC retention time (min): 1.083; MS (ESI, Pos.): 465 (M+Na)+; 1H NMR (CD3OD): δ 7.45, 7.29 - 7.32, 7.12 - 7.16, 7.07 - 7.10, 6.98, 5.45 5.52, 5.30 - 5.38, 4.05 - 4.12, 3.80 - 3.87, 2.94 - 3.03, 2.51 - 2.62, 2.41, 1.86 - 1.92, 1.63 - 1.73, 1.48 - 1.59, 1.26 - 1.35. Example 9-9: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E,3ξ)-3-hydroxy-3-[1-(3thienyl)cyclobutyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1 acid Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0391] HPLC retention time (min): 1.099; MS (ESI, Pos.): 477 (M+Na)+; 1H NMR (CD3OD): δ 7.46, 7.29 - 7.32, 7.06 - 7.08, 6.98 - 7.02, 5.34 - 5.45, 4.20 - 4.23, 4.06 - 4.10, 3.83 - 3.89, 2.97 - 3.05, 2.46 - 2.64, 2.35 - 2.44, 2.15 - 2.30, 1.83 - 1.99, 1.69 - 1.78, 1.53 - 1.62. Example 9-10: acid (1R,2R,3aS,10aR)-2-hydroxy-1 -{(1E^)-3-hydroxy-3-[1-(3thienyl)cyclopropyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1 Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0392] HPLC retention time (min): 1.064; MS (ESI, Pos.): 463 (M+Na)+; 1H NMR (CD3OD): δ 7.44 - 7.47, 7.25 - 7.29, 7.15 - 7.17, 7.09 - 7.12, 6.97 Petition 870250079778, dated 05 / 09 / 2025, pages 358 / 481 117 / 226 - 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. Example 9-11: (1R,2R,3aS,10aR)-1-[(1E,3^4S)-4-ethyl-3-hydroxy-1-octen1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0393] HPLC retention time (min): 1.151; MS (ESI, Pos.): 439 (M+Na)+; 1H NMR (CD3OD): δ 7.44, 6.98, 5.62 - 5.68, 5.46 - 5.53, 4.12 - 4.16, 4.03, 4.08, 3.89 - 3.95, 3.04 - 3.13, 2.57 - 2.76, 2.42, 1.81 - 1.97, 1.66 - 1.77, 1.52 - 1.63, 1.40 - 1.50, 1.20 - 1.39, 0.88 - 0.97. Example 9-12: (1R,2R,3aS,10aR)-1-[(1E,3ξ)-3-(1-butylcyclobutyl)-3-hydroxy-1-propen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0394] HPLC retention time (min): 1.185; MS (ESI, Pos.): 451 (M+Na)+; 1H NMR (CD3OD): δ 7.43 - 7.47, 6.96 - 7.00, 5.66 - 5.73, 5.50 - 5.57, 4.12 - 4.16, 3.90 - 3.98, 3.05 - 3.12, 2.57 - 2.78, 2.43, 2.05 - 2.15, 1.78 - 1.98, 1.58 - 1.75, 1.37 - 1.49, 1.28 - 1.37, 0.90 - 0.97, -0.03 - -0.01. Example 9-13: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,3U-3-hydroxy-4,4-dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0395] HPLC retention time (min): 1.168; MS (ESI, Pos.): 439 (M+Na)+; 1H NMR (CD3OD): δ 7.45, 6.98, 5.68 - 5.75, 5.46 - 5.52, 4.15, 3.89 - 3.95, 3.78, 3.05 - 3.13, 2.58 - 2.75, 2.43, 1.83 - 1.99, 1.72, 1.21 - 1.38, 0.85 - 0.95. Example 9-14: acid (1R,2R,3aS,10aR)-1-[(1E,3ξ,4R)-4-ethyl-3-hydroxy-1octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1HPetition 870250079778, from 05 / 09 / 2025, p. 359 / 481 118 / 226 benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0396] HPLC retention time (min): 1.169; MS (ESI, Pos.): 381 (M+H-2H2O)+; 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0397] HPLC retention time (min): 1.118; MS (ESI, Pos.): 437 (M+Na)+; 1H NMR (CD3OD): δ 7.46, 6.98, 5.60 - 5.68, 5.47 - 5.55, 4.12 - 4.17, 3.87 3.95, 3.04 - 3.14, 2.56 - 2.76, 2.43, 1.82 - 1.98, 1.67 - 1.77, 1.45 - 1.64, 1.25 - 1.42, 0.87 - 0.94, 0.48 - 0.57, 0.23 - 0.33. Example 9-16: acid (1R,2R,3aS,10aR)-2-hydroxy-1 -{(1E^)-3-hydroxy-3-[1-(3methylbutyl)cyclopropyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1 Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0398] HPLC retention time (min): 1.155; MS (ESI, Pos.): 451 (M+Na)+; 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. Example 9-17: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^)-3-hydroxy-4(trifluoromethyl)-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0399] HPLC retention time (min): 1.135; MS (ESI, Pos.): 479 (M+Na)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 360 / 481 119 / 226 1H NMR (CD3OD): δ 7.43, 6.97, 5.68 - 5.75, 5.57 - 5.65, 4.41 - 4.45, 4.13, 3.90 - 3.97, 3.03 - 3.12, 2.75, 2.57 - 2.65, 2.42, 2.18 - 2.31, 1.83 - 1.98, 1.57 - 1.75, 1.45, 1.28 - 1.41, 0.94. Example 9-18: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^)-3-hydroxy-4-methyl-4-phenoxy-1-penten-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0400] HPLC retention time (min): 1.085; MS (ESI, Pos.): 475 (M+Na)+; 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0401] HPLC retention time (min): 1.104; MS (ESI, Pos.): 487 (M+Na)+; 1H NMR (CD3OD): δ 7.45, 7.21 - 7.27, 6.99, 6.95, 6.88, 5.84 - 5.90, 5.59 5.66, 4.49, 4.14, 3.90 - 3.96, 3.13, 2.77, 2.57 - 2.67, 2.30 - 2.45, 1.81 - 1.99, 1.64 1.78. Example 9-20: (1R,2R,3aS,10aR)-1-[(1E^,4^-4-fluoro-3-hydroxy-4-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0402] HPLC retention time (min): 1.07; MS (ESI, Pos.): 443 (M+Na)+, 383 (M+H-H2O-HF)+; 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. Petition 870250079778, dated 05 / 09 / 2025, pp. 361 / 481 120 / 226 Example 9-21: (1R,2R,3aS,10aR)-1-[(1E^,4^-4-fluoro-3-hydroxy-4-methyl-1-octen-1-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0403] HPLC retention time (min): 1.067; MS (ESI, Pos.): 443 (M+Na)+, 383 (M+H-H2O-HF)+; 1H NMR (CD3OD): δ 7.41,6.97, 5.61 - 5.71,4.13 - 4.17, 4.05 - 4.11, 3.90 3.97, 3.04 - 3.12, 2.58 - 2.77, 2.41, 1.84 - 1.97, 1.57 - 1.76, 1.25 - 1.45, 0.91 - 0.97. Example 9-22: (1R,2R,3aS,10aR)-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(5methyl-3-thienyl)cyclobutyl]-1-propen-1-yl}-5-methyl-2,3,3a,9,10,10a-hexahydro-1 acid Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0404] HPLC retention time (min): 1.128; MS (ESI, Pos.): 491 (M+Na)+; 1H NMR (CD3OD): δ 7.46, 6.99, 6.76 - 6.80, 6.66, 5.35 - 5.45, 4.04 - 4.22, 3.82 - 3.90, 2.96 - 3.07, 2.52 - 2.67, 2.42, 2.08 - 2.28, 1.82 - 1.95, 1.74, 1.52 - 1.66. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0405] HPLC retention time (min): 1.094; MS (ESI, Pos.): 441 (M+Na)+; 1H NMR (CD3OD): δ 7.46, 6.99, 5.69 - 5.76, 5.47 - 5.55, 4.13 - 4.18, 3.89, 3.99, 3.42 - 3.53, 3.32 - 3.36, 3.28 - 3.34, 3.23, 3.05 - 3.14, 2.57 - 2.76, 2.43, 1.82 1.99, 1.69 - 1.79, 1.18, 0.87 - 0.95. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 362 / 481 121 / 226

[0406] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 40 in place of the compound produced in Reference Example 9 and using a corresponding phosphonate in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used. In addition, the diastereomer obtained by the procedure of Example 2 was separated using an SFC column (CHIRALPAK IG, CO2:2-propanol = 72:28) to produce a high-polarity material.A corresponding phosphonate was prepared using a procedure similar to that of Reference Example 11, using methyl 2-ethyl-5-methylhexanoate (CAS No: 1896760-61-4) in place of the compound produced in Reference Example 10.

[0407] HPLC retention time (min): 1.196; MS (ESI, Pos.): 453 (M+Na)+; 1H NMR (CD3OD): δ 7.44, 6.98, 5.62 - 5.68, 5.46 - 5.53, 4.12 - 4.16, 4.03, 4.08, 3.89 - 3.95, 3.04 - 3.12, 2.57 - 2.76, 2.42, 1.81 - 1.97, 1.67 - 1.76, 1.40 - 1.61, 1.18 - 1.37, 0.88 - 0.94. Example of Reference 41: ethyl 6,7,7-trifluoro-3-hydroxy-3-methyl-6-heptenate

[0408] To a solution of lithium hexamethyldisylazide (1 mol / L toluene solution, 670 mL) in THF (270 mL) was added, dropwise, ethyl acetate (65.5 Petition 870250079778, dated 05 / 09 / 2025, pp. 363 / 481 The mixture was infused (122 / 226 mL) at -78 °C, followed by stirring 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, followed by stirring at -78 °C for 30 minutes. A saturated aqueous solution of ammonium chloride and water was added to the reaction mixture, followed by extraction with MTBE. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to yield the title compound (130 g) with the following physical properties.

[0409] 1H NMR (CDCla): δ 4.14 - 4.25, 3.68, 2.32 - 2.57, 1.65 - 1.85, 1.26 1.34, -0.06 - 0.20. Example of Reference 42: 6,7,7-trifluoro-3-hydroxy-3-methyl-6-heptenate

[0410] To a solution of the compound (130 g) produced in Reference Example 41 in ethanol (270 mL) was added a 5 N aqueous solution of sodium hydroxide (162 mL), followed by stirring at room temperature for 1 hour. MTBE was added to the reaction solution. The separated aqueous layer was acidified with a 5 N aqueous solution of hydrochloric acid and extracted with MTBE. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to yield the title compound (106 g) with the following physical properties.

[0411] 1H NMR (CDCla): δ 6.33, 3.24, 2.34 - 2.64, 1.70 - 1.93, 1.32. Example of Reference 43: (1R,2S)-2-hydroxy-1,2-diphenylethaneminium(3S)-6,7,7trifluoro-3-hydroxy-6-octenate

[0412] To a solution of the compound (106 g) produced in Reference Example 42 in 2-butanol (1.06 L) was added (1 S,2R)-diphenylethanolamine (106 g) at 80 °C, followed by stirring at room temperature for 4 hours. The precipitate was filtered and washed with n-heptane. The washing procedure was performed two more times to produce the title compound (56.94 g) with the following properties Petition 870250079778, dated 05 / 09 / 2025, pp. 364 / 481 123 / 226 physical.

[0413] 1H NMR (CDCI3): 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. Example of Reference 44: (3S)-6,7,7-trifluoro-3-methyl-6-heptene-1,3-diol

[0414] To the compound (56.4 g) produced in Reference Example 43, an aqueous solution of hydrochloric acid and ethyl acetate was added for extraction to produce a carboxylic acid form (24.0 g). The carboxylic acid form was dissolved in THF (340 mL). Then, triethylamine (15.8 mL) and isobutyl chloroform (14.7 mL) were added at -10 °C, followed by stirring for 30 minutes. To the filtrate obtained by filtering the precipitate at -10 °C, sodium borohydride (6.4 g) and water (10 mL) were added, followed by stirring at 0 °C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous solution of 1 N hydrochloric acid, water, and saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to yield the title compound (17.5 g) with the following physical properties.

[0415] 1H NMR (CDCle): δ 3.86 - 4.08, 2.65 - 2.82, 2.30 - 2.52, 1.64 - 1.86, 1.27. Example of Reference 45: (3S)-6,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-6-hepteno-3-ol

[0416] To a solution of the compound (17.5 g) produced in Reference Example 44 in toluene (71 mL) were added an aqueous solution of 5 N sodium hydroxide (71 mL) and tetrabutylammonium bromide (2.9 g). In addition, p-toluenesulfonyl chloride (18.6 g) was added at 0 °C, followed by stirring at 0 °C for 1 hour. 1-phenyl-1H-tetrazol-5-thiol (20.5 g) was added to the mixture, followed by stirring at 60 °C for 5 hours. The reaction solution was poured into ice water and Petition 870250079778, dated 05 / 09 / 2025, pp. 365 / 481 124 / 226 extracted with toluene. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 7:1^4:1) to yield the title compound (24.8 g) with the following physical properties.

[0417] 1H NMR (CDCla): 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. Example of Reference 46: (3S)-6,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-6-hepteno-3-ol

[0418] A mixture of sodium tungstate dihydrate (114 mg), benzenephosphonic acid (55 mg), and methyl tri-n-octylammonium chloride (140 mg) was added to an aqueous solution of hydrogen peroxide (30%), followed by stirring at room temperature for 15 minutes. A solution of the compound (24.8 g) produced in Reference Example 45 in toluene (70 mL) was added to the mixture, followed by stirring at 50 °C for 2 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to produce the title compound (26.7 g) exhibiting the following physical properties.

[0419] 1H NMR (CDCla): δ 7.55 - 7.73, 3.81 - 3.99, 2.32 - 2.51, 2.04 - 2.23, 1.71 - 1.85, 1.30. Example of Reference 47: 1-phenyl-5-({(3S)-6,7,7-trifluoro-3-methyl-3[(trimethylsilyl)oxy]-6-hepten-1-yl}sulfonyl)-1H-tetrazole

[0420] To a solution of the compound (5 g) produced in Reference Example 46 in DMF (30 mL) were added imidazole (2.6 g) and trimethylchlorosilane (2.4 mL) at room temperature for stirring. The reaction mixture was diluted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate and, in Petition 870250079778, dated 05 / 09 / 2025, pages 366 / 481 125 / 226 followed, filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was washed with n-hexane to produce the title compound (5.1 g) with the following physical properties.

[0421] H NMR (CDCb): 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. Example of Reference 48: (1R,2R,3aS,10aR)-5-methyl-2-(tetrahydro-2Hpyran-2-yloxy)-1-{(1E,4S)-7,8,8-trifluoro-4-methyl-4-[(trimethylsilyl)oxy]-1,7-octadien-1-yl}2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0422] To a solution of the compound (4.29 g) produced in Reference Example 47 in dimethoxyethane (19.2 mL) was added, dropwise, a 1 mol / L solution of potassium hexamethyldisylazide in THF (9.27 mL) at -78 °C, followed by stirring for 20 minutes. To the reaction mixture was added, dropwise, a solution of the compound (2.4 g) produced in Reference Example 40 in dimethoxyethane (16.8 mL) at -78 °C for 40 minutes, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium bicarbonate and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 90:10^80:20^70:30) to produce a crude product (2.11 g) containing the title compound.The product was not purified here for the next reaction. Example of Reference 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0423] To a solution of the crude product (2.11 g) produced in Reference Example 48 in methanol (21 mL) was added p-toluenesulfonic acid monohydrate (128 mg) at room temperature, followed by stirring at room temperature. Petition 870250079778, dated 05 / 09 / 2025, pp. 367 / 481 126 / 226 ambient for 2 hours. Triethylamine (0.47 mL) was added to the reaction solution, followed by concentration under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 70:30^30:70^0:100) to yield the title compound (1.49 g) with the following physical properties.

[0424] 1H NMR (CDCb): 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. Example 11: acid (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-7,8,8trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-2,3,3a,9,10,10a-hexahydro-1 Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0425] To a solution of the compound (1.49 g) produced in Reference Example 49 in THF (5 mL) / methanol (10 mL) was added a 2 N aqueous solution of sodium hydroxide (6.36 mL) at room temperature, followed by stirring at 40 °C overnight. The reaction solution was concentrated under reduced pressure, followed by the addition of a 2 N aqueous solution of hydrochloric acid under ice cooling and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was crystallized with ethyl acetate (14.5 mL) / n-hexane (5.8 mL) to produce the title compound (1.16 g) exhibiting the following physical properties.

[0426] HPLC retention time (min): 1.083; MS (ESI, Pos.): 477 (M+Na)+, 437 (M+H-H2O)+, 419 (M+H-2H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pages 368 / 481 127 / 226 1H 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. Example Reference 50: Ethyl 7,7,7-trifluoro-3-hydroxy-3-methyl-heptanoate

[0427] Diethyl ether (52 mL) was added to magnesium (1.53 g), and dibromoethane (0.45 mL) was added at room temperature for activation. In addition, bromotrifluorobutane (10 g) was added dropwise, followed by stirring at 50 °C to prepare an organometallic reagent. In a separate container, a solution of N-methoxy-N-methylacetamide (5.56 mL) in diethyl ether (45 mL) was cooled to -15 °C. The prepared organometallic reagent was added dropwise to this solution, followed by stirring for 90 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered to yield a ketone body (6,6,6-trifluorohexan-2-one) as a diethyl ether solution.

[0428] To a solution of lithium hexamethyldisylazide (1 mol / L THF solution, 62.8 mL) in THF (52 mL) was added dropwise ethyl acetate (6.14 mL) at -78 °C, followed by stirring at -78 °C for 25 minutes. To this was added dropwise a solution of the ketone body in diethyl ether over 20 minutes, followed by stirring at -78 °C for 50 minutes. To the reaction mixture was added a saturated aqueous solution of ammonium chloride and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 90:10^65:35) to yield the title compound (16.7 g) with the following physical properties.

[0429] 1H NMR (CDCle): δ 4.16 - 4.23, 3.61, 2.42 - 2.54, 2.02 - 2.17, 1.53 1.74, 1.29, 1.25. Petition 870250079778, dated 05 / 09 / 2025, pp. 369 / 481 128 / 226 Example of Reference 51: 7,7,7-trifluoro-3-hydroxy-3-methyl-heptanoate

[0430] To a solution of the compound (16.7 g) produced in Reference Example 50 in ethanol (130 mL) was added a 2 N aqueous solution of sodium hydroxide (52 mL), followed by stirring at room temperature for 1 hour. A 2 N aqueous solution of hydrochloric acid was added to the reaction solution to make the mixture acidic, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to yield the title compound (8.49 g) with the following physical properties.

[0431] H NMR (CDCle): δ 2.48 - 2.64, 2.02 - 2.21, 1.56 - 1.76, 1.31. Example of Reference 52: (1R)-1-phenylethanolamine(3S)-7,7,7trifluoro-3-hydroxy-3-methyl heptanoate

[0432] To a solution of the compound (8.49 g) produced in Reference Example 51 in ethyl acetate (50 mL) was added (R)-1-phenylethylamine (5 mL), followed by concentration to produce a crude crystal. Ethyl methyl ketone (65 mL) and n-heptane (130 mL) were added to the crude crystals obtained at 70 °C. The temperature was reduced to room temperature. The precipitate was filtered and washed with n-heptane. The washing procedure was performed two more times to produce the title compound (2.64 g) with the following physical properties.

[0433] 1H NMR (CDCle): 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. Example of Reference 53: (3S)-7,7,7-trifluoro-3-methyl-1,3-heptanediol

[0434] To the compound (2.64 g) produced in Reference Example 52, an aqueous solution of hydrochloric acid and ethyl acetate was added for extraction, followed by concentration under reduced pressure. The carboxylic acid obtained was dissolved in THF (40 mL). The solution was cooled to 0 °C and lithium aluminum hydride (0.3 g) was added, followed by stirring at 60 °C. The solution was cooled to 0 °C and Petition 870250079778, dated 05 / 09 / 2025, pp. 370 / 481 Water was added to 129 / 226, followed by stirring. The precipitate was removed by filtration and then the filtrate was concentrated under reduced pressure to produce the title compound (1.74 g) with the following physical properties.

[0435] 1H NMR (CDCla): δ 3.82 - 4.01, 2.41 - 2.61, 2.01 - 2.35, 1.76 - 1.89, 1.50 - 1.74. Example of Reference 54: (3S)-7,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)thio]-3-heptanol

[0436] To a solution of the compound (1.74 g) produced in Reference Example 53 in toluene (20 mL) were added an aqueous solution of 5 N sodium hydroxide (6.5 mL) and tetrabutylammonium bromide (254 mg). To the mixture was added p-Toluenesulfonyl chloride (1.65 g) at 0 °C, followed by stirring at 0 °C for 1 hour and 45 minutes. In addition, 1-phenyl-1H-tetrazol-5-thiol (1.69 g) was added, followed by stirring at 60 °C overnight. The reaction solution was extracted with MTBE. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 80:20^60:40^55:45) to yield the title compound (2.65 g) with the following physical properties.

[0437] 1H NMR (CDCla): δ 7.54 - 7.73, 3.85 - 3.94, 2.02 - 2.21, 1.53 - 1.73, 1.42 - 1.54, 1.28. Example of Reference 55: (3S)-7,7,7-trifluoro-3-methyl-1-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]-3-heptanol

[0438] To a solution of the compound (2.65 g) produced in Reference Example 54 in dichloromethane (35 mL) was added meta-chloroperbenzoic acid (4.5 g) at 0 °C, followed by stirring overnight. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and dried. Petition 870250079778, dated 05 / 09 / 2025, pages 371 / 481 130 / 226 on anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 80:20 ^ 75:25) to yield the title compound (2.76 g) with the following physical properties.

[0439] 1H NMR (CDCle): δ 7.54 - 7.73, 3.85 - 3.94, 2.02 - 2.21, 1.53 - 1.73, 1.42 - 1.54, 1.28. Example of Reference 56: 1-phenyl-5-({(3S)-7,7,7-trifluoro-3-methyl-3[(trimethylsilyl)oxy]heptyl}sulfonyl)-1H-tetrazole

[0440] A solution of the compound (2.76 g) produced in Reference Example 55 in DMF (25 mL) was cooled to 0 °C, and imidazole (1.44 g) and trimethylchlorosilane (1.34 mL) were added, followed by stirring at room temperature for 3.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate / n-hexane. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 95:5 ^ 85:15) to yield the title compound (2.88 g) with the following physical properties.

[0441] 1H NMR (CDCls): 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. Example of Reference 57: (1R,2R,3aS,10aR)-5-methyl-2-(tetrahydro-2Hpyrano-2-yloxy)-1-{(1E,4S)-8,8,8-trifluoro-4-methyl-4-[(trimethylsilyl)oxy]-1-octen-1-yl}2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0442] To a solution of the compound (3.95 g) produced in Reference Example 56 in dimethoxyethane (17.6 mL) was added dropwise a 1 M solution of potassium hexamethyldisylazide in THF (8.49 mL) at -78 °C, followed by stirring for 20 minutes. To the reaction mixture was added dropwise a solution of the compound (2.2 g) produced in Reference Example 40 in dimethoxyethane (15.4 mL) Petition 870250079778, dated 05 / 09 / 2025, pp. 372 / 481 The mixture was infused at -78 °C for 40 minutes, followed by stirring for 30 minutes. A saturated aqueous solution of sodium bicarbonate and water was added to the reaction mixture, followed by extraction with ethyl acetate / n-hexane. The organic layer was washed with saturated saline solution, dried by adding anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 97:3 ^ 90:10 ^ 80:20) to yield a crude product (3.53 g) containing the title compound. The product was not further purified for the next reaction. Example of Reference 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate methyl

[0443] To a solution of the crude product (3.53 g) produced in Reference Example 57 in methanol (35.3 mL) was added p-toluenesulfonic acid monohydrate (149 mg) at room temperature, followed by stirring for 3 hours. To the reaction solution was added triethylamine (0.55 mL), followed by concentration under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 50:50^30:70^0:100) to yield the title compound (1.80 g) with the following physical properties.

[0444] 1H NMR (CDCle): 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. Example 12: (1R,2R,3aS,10aR)-2-hydroxy-5-methyl-1-[(1E,4S)-8,8,8trifluoro-4-hydroxy-4-methyl-1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 373 / 481 132 / 226

[0445] To a solution of the compound (1.80 g) produced in Reference Example 58 in THF (6 mL)-methanol (12 mL) was added a 2 N aqueous solution of sodium hydroxide (6 mL) at room temperature, followed by stirring at 40 °C overnight. The reaction solution was concentrated under reduced pressure, followed by the addition of a 2 N aqueous solution of hydrochloric acid under ice cooling and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The crude product obtained (1.8 g) was washed with ethyl acetate / n-hexane to yield the title compound (1.51 g) exhibiting the following physical properties.

[0446] HPLC retention time (min): 1.088; MS (ESI, Pos.): 479 (M+Na)+, 421 (M+H-2H2O)+; 1H 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. Examples 12-1 to 12-4:

[0447] A procedure with a purpose similar to that of Reference Example 57 ^ Reference Example 58 ^ Example 12 was carried out using a corresponding tetrazolylsulfonyl compound in place of the compound produced in Reference Example 56 to produce the following Example compound. The corresponding tetrazolylsulfonyl compound is a known compound or was prepared from a known compound by subjecting the compound to a procedure with a purpose similar to that of Reference Example 50 ^ Example Petition 870250079778, dated 05 / 09 / 2025, pp. 374 / 481 133 / 226 Reference 51 ^ Example of Reference 52 ^ Example of Reference 53 ^ Example of Reference 54 ^ Example of Reference 55 ^ Example of Reference 56. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0448] HPLC retention time (min): 1.048; MS (ESI, Pos.): 423 (M+Na)+; 1H NMR (CD3OD): δ 7.46, 6.98, 5.80 - 5.90, 5.64 - 5.73, 5.32 - 5.42, 4.99 5.06, 4.90 - 4.96, 4.10 - 4.15, 3.86 - 3.94, 3.04 - 3.12, 2.55 - 2.74, 2.43, 2.25, 2.08 2.20, 1.89 - 2.01, 1.79 - 1.87, 1.66 - 1.76, 1.51 - 1.61, 1.18. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0449] HPLC retention time (min): 1.14; MS (ESI, Pos.): 439 (M+Na)+; 1H 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. Example 12-3: (1R,2R,3aS,10aR)-1-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-yl]-2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0450] HPLC retention time (min): 1.171; MS (ESI, Pos.): 451 (M+Na)+; 1H NMR (CD3OD): δ 7.44, 6.98, 5.65 - 5.73, 5.30 - 5.39, 4.13, 3.87 - 3.93, 3.04 - 3.13, 2.56 - 2.75, 2.42, 2.26, 1.78 - 2.00, 1.49 - 1.76, 1.29, 1.13 - 1.21. Example 12-4: (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E,4S)-4-hydroxy-4,7 Petition 870250079778, dated 05 / 09 / 2025, pp. 375 / 481 134 / 226 dimethyl-1,7-octadien-1-yl]-5-methyl-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0451] HPLC retention time (min): 1.113; MS (ESI, Pos.): 437 (M+Na)+; NMR de1H (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. Example 13: acid (1R,2R,3aS,10aR)-2-hidróxi-1-[(1E^)-4-hidróxi-4,7dimethyl-1-octen-1-yl]-5-methyl-2,3,3a,9,10,10a-hexa-hidro-1Hbenzo[b]ciclopenta[f]oxepina-6-carboxylico

[0452] A procedure for a purpose similar to that of Reference Example 57 ^ Reference Example 58 ^ Example 12 was carried out using a corresponding racemic compound in place of the compound produced in Reference Example 56 for separation into two diastereomers by means of an SFC column (CHIRALPAK IG, CO2 : Methanol = 69 : 31), thus producing the title compound (low polarity material) exhibiting the following physical properties. The corresponding racemic compound was prepared from a known compound by subjecting it to a procedure for a purpose similar to that of Reference Example 50 ^ Reference Example 51 ^ Reference Example 52 ^ Reference Example 53 ^ Reference Example 54 ^ Reference Example 55 ^ Reference Example 56.

[0453] HPLC retention time (min): 1.123; MS (ESI, Pos.): 439 (M+Na)+, 381 (M+H-2H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 376 / 481 135 / 226 1H NMR (CD3OD): δ 7.43, 6.97, 5.72, 5.31 - 5.39, 4.10 - 4.15, 3.86 - 3.94, 3.04 - 3.12, 2.56 - 2.74, 2.42, 2.17 - 2.28, 1.90 - 1.99, 1.78 - 1.87, 1.67 - 1.76, 1.46 1.55, 1.23 - 1.30, 1.15, 0.90 - 0.94. Example 13-1: acid (1R,2R,3aS,10aR)-1-[(1E,4ξ)-6-cyclobutyl-4-hidróxi-4methyl-1 -hexen-1 -yl]-2-hidróxi-5-methyl-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]ciclopenta[f]oxepina-6-carboxylico

[0454] A procedure for a purpose similar to that of Reference Example 57 ^ Reference Example 58 ^ Example 12 was carried out using a corresponding racemic compound in place of the compound produced in Reference Example 56 for separation into two diastereomers by means of an SFC column (CHIRALPAK IG, CO2 : 2-propanol = 70 : 30), thus producing the title compound (low polarity material) exhibiting the following physical properties. The corresponding racemic compound was prepared from a known compound by subjecting it to a procedure for a purpose similar to that of Reference Example 50 ^ Reference Example 51 ^ Reference Example 52 ^ Reference Example 53 ^ Reference Example 54 ^ Reference Example 55 ^ Reference Example 56.

[0455] HPLC retention time (min): 1.149; MS (ESI, Pos.): 451 (M+Na)+; 1H 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. Example of Reference 59: 5-bromo-4-fluoro-2-vinylphenol

[0456] A procedure with a purpose similar to that of Reference Example 3 was carried out using 4-bromo-5-fluoro-2-hydroxybenzaldehyde (CAS No: 1427405-76-2) in place of 4-bromo-3-fluoro-2-hydroxybenzaldehyde to produce the title compound with the following physical properties. Petition 870250079778, dated 05 / 09 / 2025, pp. 377 / 481 136 / 226

[0457] 1H NMR (CDCle): δ 7.15, 7.00, 6.79 - 6.88, 5.71 - 5.77, 5.41, 5.20 5.28. Example of Reference 60: (1R,2R,3aS,10aR)-7-fluoro-1-formyl-2-(tetrahydro2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0458] A procedure with a purpose similar to that of Reference Example 4 ^ Reference Example 5 ^ Reference Example 6 ^ Reference Example 7 ^ Reference Example 8 ^ Reference Example 9 was carried out using the compound produced in Reference Example 59 in place of the compound produced in Reference Example 3 to produce the title compound with the following physical properties.

[0459] 1H NMR (CDCle): 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. Example 14: (1R,2R,3aS,10aR)-7-fluoro-1-{(1E,3U-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0460] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 60 in place of the compound produced in Reference Example 9 and using the compound produced in Reference Example 26 in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties. As an intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used.

[0461] HPLC retention time (min): 0.97; Petition 870250079778, dated 05 / 09 / 2025, pp. 378 / 481 137 / 226 MS (ESI, Pos.): 453 (M-OH)+; 1H NMR (DMSO-d6): δ 13.04 - 13.20, 7.17 - 7.28, 7.01 - 7.14, 5.32, 4.93, 4.69, 4.22 - 4.27, 4.16, 3.59 - 3.72, 2.80 - 2.93, 2.68 - 2.77, 2.21 - 2.32, 1.46 - 1.81. Example of Reference 61: 5-bromo-3-fluoro-2-vinylphenol

[0462] A procedure with a purpose similar to that of Reference Example 3 was carried out using 4-bromo-2-fluoro-6-hydroxybenzaldehyde (CAS No: 1427438-90-1) in place of 4-bromo-3-fluoro-2-hydroxybenzaldehyde to produce the title compound with the following physical properties.

[0463] 1H NMR (CDCb): δ 6.79 - 6.90, 6.69, 5.79 - 5.97, 5.60 - 5.67. Example of Reference 62: (1R,2R,3aS,10aR)-8-fluoro-1-formyl-2-(tetrahydro2H-pyran-2-yloxy)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0464] A procedure with a purpose similar to that of Reference Example 4 ^ Reference Example 5 ^ Reference Example 6 ^ Reference Example 7 ^ Reference Example 8 ^ Reference Example 9 was carried out using the compound produced in Reference Example 61 in place of the compound produced in Reference Example 3 to produce the title compound with the following physical properties.

[0465] 1H NMR (CDCla): 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. Example 15: (1R,2R,3aS,10aR)-8-fluoro-2-hydroxy-1-[(1E,3^-3-hydroxy3-(1-phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0466] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was performed using the compound produced in Reference Example 62 instead of the compound produced Petition 870250079778, dated 05 / 09 / 2025, pp. 379 / 481 138 / 226 in Reference Example 9 and using the compound produced in Reference Example 27 in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used.

[0467] HPLC retention time (min); MS (ESI, Pos.): 403 (M+H-2H2O)+, 421 (M+H-H2O)+; 1H 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. Example of Reference 63: Ethyl 6-hydroxy-5-vinyl-2-pyridinecarboxylate

[0468] 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), tributylvinyltin (931 mg) and dichloromethane adduct of [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloride (160 mg), followed by stirring at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 ^ 100:0) to yield the title compound (170 mg) with the following physical properties.

[0469] TLC: Rf 0.52 (hexane : ethyl acetate = 3 : 7); 1H NMR (DMSO-d6): δ 11.50 - 12.12, 7.73, 7.02, 6.77, 6.24, 5.42, 4.30, 1.27 - 1.34. Reference Example 64: (6aR,7R,8R,9aS)-7-formyl-8-(tetrahydro-2Hpyran-2-yloxy)-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[6,7]oxepin[2,3-b]ethylpyridine-2carboxylate

[0470] A procedure with a purpose similar to that of Example Petition 870250079778, dated 05 / 09 / 2025, pp. 380 / 481 139 / 226 Reference 4 ^ Example of Reference 5 ^ Example of Reference 6 ^ Example of Reference 7 ^ Example of Reference 8 ^ Example of Reference 9 was carried out using the compound produced in Example of Reference 63 in place of the compound produced in Example of Reference 3 to produce the title compound with the following physical properties.

[0471] 1H NMR (CDCle): 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. Exemplo de Referência 65: (6aR,7R,8R,9aS)-7-{(1E,3^-3-[1-(2fluorofenil)ciclobutil]-3-hidróxi-1-propen-1-il}-8-hidróxi-6,6a,7,8,9,9a-hexa-hidro-5Hciclopenta[6,7]oxepina[2,3-b]piridina-2-carboxylato de ethyla

[0472] A procedure with a purpose similar to that of Reference Example 17 was carried out using the compound (45 mg) produced in Reference Example 64 in place of the compound produced in Reference Example 9 and using the compound (49 mg) produced in Reference Example 26 in place of the compound produced in Reference Example 14 to produce an enone form (21 mg). A solution of the enone form (21 mg) in THF (0.2 mL) was cooled to -15 °C. To this solution were added (S)-2-methyl-CBS-oxazaborolidine (0.037 mL, 1 mol / L toluene solution) and N,N-diethylaniline borane (0.013 mL), followed by stirring at -15 °C overnight. The completion of the reaction was confirmed by TLC, and the reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50^100:0) to produce a reduced form.A solution of the reduced form in methanol (0.2 mL) was cooled to 0 °C, and p-toluenesulfonic acid monohydrate (1.8 mg) was added, followed by stirring at room temperature for 2 hours. Triethylamine (0.022 mL) was added to the reaction solution, and then the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 50). Petition 870250079778, dated 05 / 09 / 2025, pages 381 / 481 140 / 226 : 50 ^ 100 : 0) to produce the title compound (7 mg) with the following physical properties.

[0473] 1H 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. 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-5Hcyclopenta[6,7]oxepin[2,3-b]pyridine-2-carboxylic acid

[0474] A procedure with a purpose similar to that of Example 2 was carried out using the compound produced in Reference Example 65 in place of the compound produced in Reference Example 18 to produce the title compound with the following physical properties.

[0475] HPLC retention time (min): 0.996; MS (ESI, Pos.): 454 (M+H)+; 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. Example of Reference 66: (2R,3R,3aR,11aS)-3-formyl-2-(tetrahydro-2Hpyran-2-yloxy)-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-ethyl carboxylate

[0476] A procedure with a purpose similar to that of Reference Example 4 ^ Reference Example 5 ^ Reference Example 6 ^ Reference Example 7 ^ Reference Example 8 ^ Reference Example 9 was carried out using (1R,2R,3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol (CAS No: 1262874-94-1) in place of the compound produced in Reference Example 2 and using the compound produced in Reference Example 31 in place of the compound produced in Reference Example 3 to produce the title compound with the following physical properties. Petition 870250079778, dated 05 / 09 / 2025, pp. 382 / 481 141 / 226

[0477] 1H NMR (CDCI3): 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. Example 17: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-1-octen1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0478] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 66 in place of the compound produced in Reference Example 9 and using dimethyl-2-oxo-heptyl phosphonate (CAS No: 36969-89-8) in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used.

[0479] TLC: Rf 0.37 (CHaCb / methanol, 9 / 1); MS (ESI, Pos.): 777 (2M+H)+; 1H NMR (CDCle): 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. Examples 17-1 to 17-31:

[0480] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using the compound produced in Reference Example 66 in place of the compound produced in Reference Example 9 and using a corresponding phosphonate in place of the compound produced in Reference Example 14 to produce the following example compound. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by Petition 870250079778, dated 05 / 09 / 2025, pages 383 / 481 142 / 226 a diastereomer separation procedure. The corresponding phosphonate is a known compound or was prepared from a known compound by subjecting the compound to a procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11. Example 17-1: (2R,3R,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-7-methyl-1octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0481] MS (ESI, Neg.): 401 (MH)-; 1H NMR (CDCle): 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. Example 17-2: (2R,3R,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-1-nonen-1yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0482] MS (ESI, Neg.): 401 (MH)-; NMR de1H (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. Exemplo 17-3: ácido (2R,3R,11aS)-3-[(1E,3S)-6-ciclopropil-3-hidróxi-1hexen-1-il]-2-hidróxi-1,2,3,3a,4,5,6,11a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9carboxílico

[0483] MS (ESI, Neg.): 399 (MH)-; NMR de1H (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. Example 17-4: acid (2R,3R,3aR,11aS)-2-hidróxi-3-[(1E^,4^-3-hidróxi-7methyl-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahidrobenzo[b]ciclopenta[g]oxocina-9-carboxylico

[0484] HPLC retention time (min): 1.01; MS (ESI, Pos.): 453 (M+H-H2O)+, 435 (M+H-2H2O)+; NMR de1H (CD3OD): δ 7.59 - 7.62, 7.17, 5.58 - 5.70, 4.58 - 4.63, 4.42, 3.82, Petition 870250079778, dated 05 / 09 / 2025, pages 384 / 481 143 / 226 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. Example 17-5: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E^,4R)-3-hydroxy-4methyl-1-octen-1-yl]-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9carboxylic acid

[0485] MS (ESI, Pos.): 385 (M+H-H2O)+, 367 (M+H-2H2O)+; 1H NMR (CDCls): 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. Example 17-6: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3S)-3-hydroxy-5-(2methylcyclopropyl)-1-penten-1-yl]-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0486] MS (ESI, Pos.): 365 (M+H-2H2O)+; MRI de1H (CDCie): 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. Exemplo 17-7: ácido (2R,3R,3aR,11aS)-2-hidróxi-3-[(1E^)-3-hidróxi-4-metil1 -octen-6-in-1 -il]-1,2,3,3a,4,5,6,11 a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9carboxílico

[0487] MS (ESI, Pos.): 381 (M+H-H2O)+, 363 (M+H-2H2O)+; MRI de1H (CDCie): 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. Exemplo 17-8: ácido (2R,3R,3aR,11aS)-2-hidróxi-3-[(1E^,4S)-3-hidróxi-4metil-1 -octen-1 -il]-1,2,3,3a,4,5,6,11 a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9carboxílico

[0488] MS (ESI, Pos.): 385 (M+H-H2O)+, 367 (M+H-2H2O)+; NMR de1H (DMSO-d6): δ 12.67 - 13.00, 7.44 - 7.50, 7.19, 5.36, 4.73, 4.55, Petition 870250079778, dated 05 / 09 / 2025, pages 385 / 481 144 / 226 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. Example 17-9: (2R,3R,3aR,11aS)-3-[(1E,3^-4,4-difluoro-3-hydroxy-1octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9carboxylic acid

[0489] MS (ESI, Pos.): 407 (M+H-H2O)+; 1H 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. Example 17-10: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E^)-3-hydroxy-4methylene-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9carboxylic acid

[0490] MS (ESI, Pos.): 383 (M+H-H2O)+, 365 (M+H-2H2O)+; 1H NMR (DMSO-d6): δ 12.73 - 12.95, 7.39 - 7.59, 7.20, 5.27 - 5.54, 5.00, 4.90, 4.66 - 4.82, 4.58, 4.35, 3.58 - 3.71,2.94, 2.81,2.51,2.07 - 2.33, 1.83 - 2.05, 1.64 - 1.83, 1.57, 1.45, 1.17 - 1.42, 0.85. Example 17-11: (2R,3R,3aR,11aS)-3-[(1E^^)-4-fluoro-3-hydroxy-4methyl-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0491] HPLC retention time (min): 0.95; MS (ESI, Pos.): 383 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.55 - 7.65, 7.17, 5.55 - 5.73, 4.60, 4.02, 3.83, 2.83 3.08, 2.56 - 2.83, 2.42, 1.86 - 2.07, 1.79, 1.43 - 1.63, 1.30 - 1.44, 1.26 - 1.28, 0.81 1.06. Example 17-12: (2R,3R,3aR,11aS)-3-[(1E^^)-4-fluoro-3-hydroxy-4methyl-1-octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 386 / 481 145 / 226

[0492] HPLC retention time (min): 0.95; MS (ESI, Pos.): 383 (M+H-2H2O)+; NMR de1H (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. Exemplo 17-13: ácido (2R,3R,3aR, 11 aS)-2-hidróxi-3-[(1 E^)-3-hidróxi-4-vinil1-octen-1-il]-1,2,3,3a,4,5,6,11a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9-carboxílico

[0493] MS (ESI, Pos.): 379 (M+H-2H2O)+; 1H 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. Example 17-14: acid (2R,3R,3aR,11aS)-3-[(1E,3^-4-fluoro-3-hidróxi-1octen-1 -il]-2-hidróxi-1,2,3,3a,4,5,6,11 a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9carboxylico

[0494] MS (FAB, Neg.): 405 (MH)-; 1H 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. Example 17-15: (2R,3R,3aR,11aS)-3-[(1E^,4S)-4-ethyl-3-hydroxy-1octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9carboxylic acid

[0495] HPLC retention time (min): 1.17; MS (ESI, Pos.): 381 (M+H-2H2O)+; 1H 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. Example 17-16: (2R,3R,3aR,11aS)-3-[(1E^,4R)-4-ethyl-3-hydroxy-1 Petition 870250079778, dated 05 / 09 / 2025, pp. 387 / 481 146 / 226 octen-1-yl]-2-hydroxy-1,2,3,3a,4,5,6,11 a-octa-hydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0496] MS (ESI, Pos.): 399 (M+H-H2O)+; 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. Example 17-17: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E^^)-3-hydroxy-4(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0497] HPLC retention time (min): 1.01; MS (ESI, Pos.): 439 (M+H-H2O)+, 421 (M+H-2H2O)+; 1H 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. Example 17-18: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E^^)-3-hydroxy-4(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0498] MS (ESI, Pos.): 439 (M+H-H2O), 421 (M+H-2H2O)+; NMR de1H (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. Example 17-19: acid (2R,3R,11aS)-2-hydroxi-3-[(1E,3S)-3-hydroxi-7-methyl1,7-octadien-1 -yl]-1,2,3,3a,4,5,6,11 a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9carboxylico

[0499] MS (ESI, Neg.): 399 (MH)-; NMR de1H (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. Example 17-20: acid (2R,3R,11aS)-2-hydroxi-3-[(1E,3S,6Z)-3-hydroxi-1,6 Petition 870250079778, 05 / 09 / 2025, pág. 388 / 481 147 / 226 octadien-1 -yl]-1,2,3,3a,4,5,6,11 a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9carboxílico

[0500] MS (ESI, Neg.): 385 (MH)-; NMR de1H (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. Exemplo 17-21: ácido (2R,3R,3aR,11aS)-3-[(1E,3ξ)-3-(1-butilciclopropil)-3hidróxi-1 -propen-1 -il]-2-hidróxi-1,2,3,3a,4,5,6,11 a-octahidrobenzo[b]ciclopenta[g]oxocina-9-carboxílico

[0501] MS (ESI, Pos.): 379 (M+H-2H2O)+; 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. Example 17-22: acid (2R,3R,3aR,11aS)-2-hydroxi-3-[(1E,3^-3-hidróxi-3-(1phenylcyclopropyl)-1 -propen-1 -il]-1,2,3,3a,4,5,6,11 a-octahidrobenzo[b]ciclopenta[g]oxocina-9-carboxylico

[0502] MS (ESI, Pos.): 399 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.56 - 7.62, 7.30 - 7.37, 7.12 - 7.24, 5.43 - 5.51, 5.30 - 5.38, 4.51 - 4.56, 3.88, 3.69 - 3.79, 2.88 - 2.96, 2.57 - 2.66, 2.21 - 2.31, 1.85 - 1.98, 1.27 - 1.70, 0.83 - 0.97, 0.65 - 0.79. Example 17-23: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3^-3-hydroxy-3-(1-phenylcyclobutyl)-1-propen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0503] HPLC retention time (min): 1; MS (ESI, Pos.): 431 (M+H); 1H NMR (CDCle): 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. Petition 870250079778, dated 05 / 09 / 2025, pp. 389 / 481 148 / 226 Example 17-24: (2R,3R,3aR,11aS)-3-{(1E,3^-3-[1-(2,5difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11 acid a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0504] HPLC retention time (min): 0.91; MS (ESI, Pos.): 453 (M+H-H2O)+, 435 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.56 - 7.61, 7.03 - 7.17, 6.89 - 6.99, 5.59, 5.41,4.50 4.57, 3.89, 3.72, 2.91,2.57 - 2.66, 2.22 - 2.31, 1.85 - 1.96, 1.55 - 1.71, 1.49, 1.38, 0.90 - 1.04, 0.74 - 0.79. Example 17-25: acid (2R,3R,3aR,11aS)-3-{(1E,3^-3-[1-(2,4difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0505] HPLC retention time (min): 1; MS (ESI, Pos.): 467 (M+H-H2O)+, 449 (M+H-2H2O)+; 1H 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. Example 17-26: acid (2R,3R,3aR,11aS)-3-{(1E,3^-3-[1-(2,5difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0506] HPLC retention time (min): 0.99; MS (ESI, Pos.): 467 (M+H-H2O)+, 449 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.56 - 7.62, 7.16, 6.91 - 6.97, 6.80 - 6.90, 5.43 - 5.51, 5.33 - 5.40, 4.50 - 4.56, 4.29, 3.71, 2.90, 2.44 - 2.66, 2.19 - 2.40, 1.98 - 2.09, 1.79 1.95, 1.43 - 1.67, 1.28 - 1.36. Example 17-27: acid (2R,3R,3aR,11aS)-3-{(1E,3^-3-[1-(2,6difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 390 / 481 149 / 226

[0507] HPLC retention time (min): 0.79; MS (ESI, Pos.): 467 (M+H-H2O)+, 449 (M+H-2H2O)+; 1H 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. Example 17-28: (2R,3R,3aR,11aS)-2-hydroxy-3-{(1E,3U-3-hydroxy-3-[1(3-methylphenyl)cyclopropyl]-1-propen-1-yl}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0508] HPLC retention time (min): 0.77; MS (ESI, Pos.): 431 (M+H-H2O)+, 413 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.56 - 7.61, 7.07 - 7.18, 6.97, 5.47, 5.34, 4.51 - 4.56, 3.86, 3.72, 3.33 - 3.37, 3.23 - 3.29, 2.92, 2.57 - 2.66, 2.17 - 2.36, 1.81 - 2.04, 1.47 1.72, 1.33 - 1.42, 0.82 - 0.97, 0.71 - 0.78, 0.63 - 0.69. Example 17-29: (2R,3R,3aR,11aS)-3-{(1E,3U-3-[1-(3-chlorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0509] HPLC retention time (min): 0.77; MS (ESI, Pos.): 452 (M+H-H2O)+, 434 (M+H-2H2O)+; 1H 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. Example 17-30: (2R,3R,3aR,11aS)-3-{(1E,3U-3-[1-(3fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0510] HPLC retention time (min): 0.78; MS (ESI, Pos.): 449 (M+H-H2O)+, 431 (M+H-2H2O)+; 1H NMR (CD3OD): δ 7.60, 7.57, 7.20 - 7.28, 7.16, 6.93, 6.82 - 6.88, 5.35 Petition 870250079778, dated 05 / 09 / 2025, pp. 391 / 481 150 / 226 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. Example 17-31: (2R,3R,3aR,11aS)-3-{(1E,3^-3-[1-(4fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2-hydroxy-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0511] HPLC retention time (min): 0.98; MS (ESI, Pos.): 450 (M+H-H2O)+; 1H 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. Example 18: (2R,3R,3aR,11aS)-10-fluoro-2-hydroxy-3-[(1E^)-3-hydroxy3-(1-phenoxycyclobutyl)-1-propen-1-yl]-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0512] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using a corresponding aldehyde form in place of the compound produced in Reference Example 9 and using a corresponding phosphonate in place of the compound produced in Reference Example 14 to produce the title compound exhibiting the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used. The corresponding aldehyde form was prepared by means of a procedure with a purpose similar to that of Reference Example 66, using the compound produced in Reference Example 3 in place of the compound produced in Reference Example 31.The corresponding phosphonate was prepared by means of a procedure similar to that of Reference Example 10 ^ Reference Example 11, using 1-phenoxycyclobutanecarboxylic acid (CAS No: 2287791-08-4) in place of (2S) acid. Petition 870250079778, dated 05 / 09 / 2025, p. 392 / 481. 151 / 226 2-(2,4-difluorophenyl)propanoic acid.

[0513] HPLC retention time (min): 1.107; MS (ESI, Pos.): 505 (M+Na)+; 1H NMR (CD3OD): δ 7.51 - 7.56, 7.22, 6.90 - 6.98, 6.83 - 6.88, 5.79 - 5.86, 5.55 - 5.62, 4.41 - 4.48, 3.76 - 3.84, 2.97 - 3.07, 2.76 - 2.86, 2.60 - 2.70, 2.23 - 2.51, 2.05 - 2.17, 1.92 - 2.03, 1.60 - 1.82, 1.45 - 1.57. Example 19: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,3^-3-hydroxy-3-(1phenoxycyclobutyl)-1-propen-1-yl]-10-methyl-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0514] A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using a corresponding aldehyde form in place of the compound produced in Reference Example 9 and using a corresponding phosphonate in place of the compound produced in Reference Example 14 to produce the title compound exhibiting the following physical properties. As the intermediate corresponding to the compound produced in Reference Example 18, a high-polarity compound separated by a diastereomer separation procedure was used. The corresponding aldehyde form was prepared by means of a procedure with a purpose similar to that of Reference Example 66, using the compound produced in Reference Example 35 in place of the compound produced in Reference Example 31.The corresponding phosphonate was prepared using a procedure similar to that in Reference Example 10 ^ Reference Example 11, using 1-phenoxycyclobutanecarboxylic acid in place of (2S)-2-(2,4-difluorophenyl)propanoic acid.

[0515] HPLC retention time (min): 1.134; MS (ESI, Pos.): 501 (M+Na)+; 1H NMR (CD3OD): δ 7.53, 7.22, 7.00, 6.93, 6.83 - 6.88, 5.80 - 5.86, 5.56 Petition 870250079778, dated 05 / 09 / 2025, pp. 393 / 481 152 / 226 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. Example 20: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E,4S)-7,8,8-trifluoro-4hydroxy-4-methyl-1,7-octadien-1-yl]-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0516] A procedure with a purpose similar to that of Reference Example 48 ^ Reference Example 49 ^ Example 11 was performed using the compound produced in Reference Example 66 in place of the compound produced in Reference Example 40 to produce the title compound exhibiting the following physical properties.

[0517] HPLC retention time (min): 0.94; MS (ESI, Pos.): 437 (M+H-H2O)+, 419 (M+H-2H2O)+; 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. Example 21: (2R,3R,3aR,11aS)-10-fluoro-2-hydroxy-3-[(1E,4S)-7,8,8trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]-1,2,3,3a,4,5,6,11 acid a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxylic acid

[0518] A procedure with a purpose similar to that of Reference Example 48 ^ Reference Example 49 ^ Example 11 was carried out using a corresponding aldehyde form in place of the compound produced in Reference Example 66 to produce the title compound exhibiting the following physical properties. The corresponding aldehyde form was prepared by means of a procedure with a purpose similar to that of Reference Example 66, using the compound produced in Reference Example 3 in place of the compound produced in Reference Example 31.

[0519] HPLC retention time (min): 1.079; Petition 870250079778, dated 05 / 09 / 2025, pp. 394 / 481 153 / 226 MS (ESI, Pos.): 495 (M+Na)+; 1H NMR (CD3OD): δ 7.50 - 7.55, 6.96, 5.61 - 5.69, 5.33 - 5.42, 4.41 - 4.46, 3.73 - 3.82, 2.96 - 3.06, 2.74 - 2.86, 2.60 - 2.69, 2.33 - 2.47, 2.17 - 2.30, 2.02 - 2.14, 1.88 - 2.02, 1.60 - 1.82, 1.44 - 1.57, 1.25 - 1.40, 1.17. Exemplo 22: ácido (2R,3R,3aR,5Z,11aS)-2-hidróxi-3-[(1E,3S)-3-hidróxi-1octen-1-il]-1,2,3,3a,4,11a-hexa-hidrobenzo[b]ciclopenta[g]oxocina-9-carboxílico

[0520] A procedure with a purpose similar to that of Reference Example 4 ^ Reference Example 5 ^ Reference Example 6 ^ Reference Example 8 ^ Reference Example 9 was carried out using (1R,2R,3S,4R)-2-allyl3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2yloxy)cyclopentanol (CAS No: 1262874-94-1) in place of the compound produced in Reference Example 2 and using the compound produced in Reference Example 31 in place of the compound produced in Reference Example 3 to produce an aldehyde form. A procedure with a purpose similar to that of Reference Example 17 ^ Reference Example 18 ^ Example 2 was carried out using the aldehyde form in place of the compound produced in Reference Example 9 and using dimethyl-2-oxo-heptyl phosphonate (CAS No: 36969-89-8) in place of the compound produced in Reference Example 14 to produce the title compound with the following physical properties.As the intermediate corresponding to the compound produced in Reference Example 18, a highly polar compound separated by a diastereomer separation procedure was used.

[0521] MS (ESI, Pos.): 351 (M+H-2H2O)+; 1H NMR (CDCls): 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. Example of Reference 67: (2R,3R,3aR,11aS)-2-hydroxy-3-[(1E^,4^-3hydroxy-4-(trifluoromethyl)-1-octen-1-yl]-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-methylcarboxylate Petition 870250079778, dated 05 / 09 / 2025, pp. 395 / 481 154 / 226

[0522] To a solution of the compound (125 mg) produced in Example 17-17 in methanol (1 mL) was added, dropwise, a 2 M solution of trimethylsilyldiadiazomethane in n-hexane (0.5 mL) at room temperature, with stirring until the reaction solution turned yellow. Acetic acid was added to the reaction mixture, followed by concentration under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to yield the title compound (126 mg). Reference Example 68: (2R,3R,3aR,11aS)-2-{[dimethyl(2-methyl-2propanyl)silyl]oxy}-3-[(1E^^)-3-hydroxy-4-(trifluoromethyl)-1-octen-1 -yl]1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-9-methyl carboxylate

[0523] To a solution of the compound produced in Reference Example 67 in dichloromethane (2 mL) were added triethylamine (0.22 mL) and N,N-dimethyl-4-aminopyridine (13 mg) at room temperature, followed by cooling with ice. In addition, tert-butyldiphenylchlorosilane (0.21 mL) was added, followed by stirring at room temperature for 2 days. Ethyl acetate was added to the reaction mixture for dilution. Then, saturated ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1) to yield the title compound (204 mg). Example of Reference 69: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-methylcarboxylate

[0524] To a solution of the compound produced in Reference Example 68 in dichloromethane (1.5 mL) was added 2,6-dimethylpyridine (0.1 mL) at temperature Petition 870250079778, dated 05 / 09 / 2025, pp. 396 / 481 155 / 226 ambient temperature, followed by cooling with ice. Tert-butyldimethylsilyl trifluoromethanesulfonate (0.1 mL) was added, followed by stirring at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture for dilution. Then, saturated ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1) to yield the title compound (174 mg). Example of Reference 70: (2R,3R,3aR,11aS)-3-[(1E,3^)-3{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocine-9-carboxylic acid

[0525] To a solution of the compound produced in Reference Example 69 in dimethoxyethane (1.5 mL)-methanol (1.5 mL) was added a 2 N aqueous solution of sodium hydroxide (0.5 mL) at room temperature, followed by stirring at 35 °C for 15 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of 1 N hydrochloric acid and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to yield the title compound (154 mg) with the following physical properties.

[0526] 1H NMR (CDCla): 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. Example 23: (2R,3R,3aR,11 aS)-2-hydroxy-3-[(1E,3^)-3-hydroxy-4(trifluoromethyl)-1-octen-1-yl]-N-(methylsulfonyl)-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9-carboxamide

[0527] A solution of the compound (40 mg) produced in Example Petition 870250079778, dated 05 / 09 / 2025, pp. 397 / 481 156 / 226 Reference 70 in DMF (1 mL) was added to methanesulfonamide (9.4 mg), N,N-dimethyl-4-aminopyridine (12 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg) at room temperature, followed by stirring at room temperature for 1 hour. To the reaction solution, THF (1 mL) and a 1 M tetra-n-butylammonium fluoride solution in THF (0.25 mL) were added at room temperature, and the reaction mixture was stirred at 45 °C for 15 hours. Saturated ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate : methanol = 5 : 1) to yield the title compound (2.5 mg) with the following physical properties.

[0528] HPLC retention time (min): 0.99; MS (ESI, Pos.): 516 (M+H-H2O)+; MRI de1H (CDCla): 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. Exemplo de Referência 71: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimetil(2metil-2-propanyl)silil]óxi}-4-(trifluorometil)-1-octen-1-il]-2-{[(2-metil-2-propanyl)(difenil)silil]óxi}-1,2,3,3a,4,5,6,11 a-octa-hidrobenzo[b]ciclopenta[g]oxocina-9carboxamida

[0529] To a solution of the compound (114 mg) produced in Reference Example 70 in DMF (1.1 mL), ammonium chloride (15 mg), 7-aza1-hydroxybenzotriazole (38 mg), diisopropylethylamine (0.1 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 mg) were added at room temperature, followed by stirring at room temperature for 15 hours. Ethyl acetate was added to the reaction mixture for dilution. Then, a saturated solution of ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was Petition 870250079778, dated 05 / 09 / 2025, pages 398 / 481 157 / 226 was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to yield the title compound (105 mg). Reference Example 72: (2R,3R,3aR,11aS)-3-[(1E,3ξ,4ξ)-3-{[dimethyl(2methyl-2-propanyl)silyl]oxy}-4-(trifluoromethyl)-1-octen-1-yl]-2-{[(2-methyl-2propanyl)(diphenyl)silyl]oxy}-1,2,3,3a,4,5,6,11 a-octahydrobenzo[b]cyclopenta[g]oxocin-9carbonitrile

[0530] The compound produced in Reference Example 71 was dissolved in a THF solution (2 mL), followed by the addition of pyridine (0.03 mL) at room temperature. The reaction solution was cooled with ice, followed by the addition of trifluoroacetic anhydride (0.03 mL) and stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture for dilution. Then, a saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to yield the title compound (99.7 mg) with the following physical properties.

[0531] 1H NMR (CDCle): 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. Example 24: (2R,3R,3aR,11 aS)-3-[(1 E^^)-3-hydroxy-4-(trifluoromethyl)-1 octen-1-yl]-9-(1 H-tetrazol-5-yl)-1,2,3,3a,4,5,6,11a-octahydrobenzo[b]cyclopenta[g]oxocin-2-ol

[0532] To a solution of the compound (99.7 mg) produced in Reference Example 72 in toluene (2 mL) were added dibutyltin oxide (38 mg) and azidotrimethylsilane (58 mg) at room temperature, followed by stirring at 95 °C for 15 hours. Ethyl acetate was added to the reaction mixture for dilution, and the Petition 870250079778, dated 05 / 09 / 2025, pp. 399 / 481 The resulting 158 / 226 solution was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1) to yield a tetrazole compound (98 mg). To a solution of the tetrazole compound obtained in THF (1 mL) was added 1 M tetra-n-butylammonium fluoride in THF (0.17 mL), followed by stirring at 35 °C for 15 hours. To the reaction mixture was added 1 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate:methanol = 3:1) to yield the title compound (35.2 mg) with the following physical properties.

[0533] HPLC retention time (min): 0.99; MS (ESI, Pos.): 463 (M+H-H2O)+; 1H 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. Example 24-1: (1 R,2R,3aS,10aR)-1 -[(1 E,3S)-3-hydroxy-1 -octen-1 -yl]-6-(1 Htetrazol-5-yl)-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepin-2-ol

[0534] A procedure with a purpose similar to that of Reference Example 67 ^ Reference Example 68 ^ Reference Example 69 ^ Reference Example 70 ^ Reference Example 71 ^ Reference Example 72 ^ Example 24 was carried out using the compound produced in Example 17 in place of the compound produced in Example 17-17 to produce the title compound with the following physical properties.

[0535] TLC: Rf 0.26 (CHaCb / methanol, 5 / 1) MS (APCI, Pos.): 381 (M-H2O)+; 1H 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. Petition 870250079778, dated 05 / 09 / 2025, pp. 400 / 481 159 / 226 Example of Reference 73: (1S,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0536] To a solution (50 mL) of the compound (8.3 g) produced in Reference Example 8 in dichloromethane, triethylamine (9.1 mL), tert-butyldiphenylchlorosilane (8.9 mL), and dimethylaminopyridine (0.31 g) were added at room temperature, followed by stirring at 35 °C for 3 hours. The reaction solution was poured into an aqueous solution of 1 N hydrochloric acid / ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was dissolved in methanol (50 mL), and p-toluenesulfonic acid monohydrate (378 mg) was added at room temperature, followed by stirring at room temperature for 1 hour. Triethylamine (3.0 mL) was added to the reaction solution, and the solvent was concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10^30:70) to yield the title compound (10.7 g) exhibiting the following physical properties.

[0537] H NMR (CDCla): 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. Example of Reference 74: (1S,2R,3aS,10aR)-5-fluoro-2-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10ahexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0538] To a solution (78 mL) of the compound (15.6 g) produced in Reference Example 73 in acetonitrile, triethylamine (12.8 mL), trimethylamine hydrochloride (344 mg), and p-toluenesulfonyl chloride (6.34 g) were added at room temperature, followed by stirring at room temperature for 3 hours. The solution of Petition 870250079778, dated 05 / 09 / 2025, pages 401 / 481 The 160 / 226 reaction was poured into a 1 N aqueous solution of hydrochloric acid / ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 90:10^70:30) to yield the title compound (20.2 g) exhibiting the following physical properties.

[0539] 1H NMR (CDCla): 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. Example of Reference 75: (1S,3aS,10aR)-5-fluoro-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0540] To a solution of the compound (20.2 g) produced in Reference Example 74 in dimethoxyethane (150 mL)-DMF (10 mL) were added water (15 mL), sodium iodide (16.6 g) and zinc (14.4 g) at room temperature, followed by stirring at 80 °C overnight. In addition, sodium iodide (4 g) and zinc (3.5 g) were added, followed by stirring at 80 °C for 5 hours. The reaction mixture was cooled to room temperature, followed by the addition of water and extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5^5:1) to yield the title compound (13.1 g) exhibiting the following physical properties.

[0541] 1H NMR (CDCla): 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. Petition 870250079778, dated 05 / 09 / 2025, pp. 402 / 481 161 / 226 Example of Reference 76: (1S,3aS,10aR)-5-fluoro-1-formyl-2,3,3a,9,10,10ahexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0542] A procedure with a purpose similar to that of Reference Example 8 ^ Reference Example 9 was carried out using the compound produced in Reference Example 75 in place of the compound produced in Reference Example 7 to produce the title compound which refers to the following physical properties.

[0543] 1H NMR (CDCle): 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. Example 25: (1R,3aS,10aR)-5-fluoro-1-{(1E^)-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0544] A procedure with a purpose similar to that of Reference Example 17 was carried out using the compound (70 mg) produced in Reference Example 76 in place of the compound produced in Reference Example 9 and using the compound (136 mg) produced in Reference Example 26 in place of the compound produced in Reference Example 14 to produce an enone form (97 mg). A solution of the enone form (97 mg) in THF (1 mL) was cooled to -15 °C. To this solution were added (S)-2-methyl-CBS-oxazaborolidine (1 mol / L toluene solution, 0.204 mL) and N,N-diethylaniline borane (0.073 mL), followed by stirring at -15 °C for 8 hours. Methanol and water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (Gold High Performance Silica manufactured by ISCO, n-hexane: ethyl acetate) to produce a reduced form. The reduced form was dissolved in methanol (1 mL) and dimethoxyethane (0.5 mL), followed by the addition of an aqueous solution of hydroxide. Petition 870250079778, dated 05 / 09 / 2025, pages 403 / 481 162 / 226 sodium 2 N (0.5 mL) and stirring overnight. After confirming the completion of the reaction by TLC, the reaction solution was concentrated, acidified with an aqueous solution of hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by an SFC column (CHIRALPAK IG, CO2:Methanol = 65:35) to yield the title compound (19 mg) with the following physical properties.

[0545] HPLC retention time (min): 1.09; MS (ESI, Pos.): 437 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.28 - 7.33, 6.97 - 7.12, 6.81 - 6.90, 5.26 - 5.39, 4.77, 4.20 - 4.26, 2.86 - 2.93, 2.35 - 2.64, 2.30, 1.80 - 2.07, 1.68 - 1.79, 1.51 - 1.68, 1.24 1.35. Examples 25-1 to 25-15:

[0546] A procedure with a purpose similar to that of Example 25 was carried out using a corresponding phosphonate in place of the compound produced in Reference Example 26 to produce the title compound exhibiting the following physical properties. In Example 25-6, the reduction reaction was carried out using (R)-2-methyl-CBS-oxazaborolidine in place of the (S)-2-methyl-CBS-oxazaborolidine used in Example 25. The corresponding phosphonate is a known compound or was prepared from a known compound by subjecting the compound to a procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11 or Reference Example 28 ^ Reference Example 29. Example 25-1: (1R,3aS,10aR)-5-fluoro-1-{(1E,3^-3-[1-(2fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0547] HPLC retention time (min): 1.05; MS (ESI, Pos.): 423 (M+H-H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 404 / 481 163 / 226 1H 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. Example 25-2: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl1-buten-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid

[0548] HPLC retention time (min): 0.97; MS (ESI, Pos.): 433 (M+H)+; 1H NMR (DMSO-d6): δ 13.12, 7.49 - 7.57, 7.42 - 7.48, 7.07, 5.87, 5.46 5.66, 4.40 - 4.54, 2.89 - 3.09, 2.74 - 2.87, 2.58 - 2.73, 2.13 - 2.23, 1.97 - 2.07, 1.70 1.93, 1.66, 1.33 - 1.45. Example 25-3: (1R,3aS,10aR)-1-[(1E,3^-4,4-difluoro-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0549] HPLC retention time (min): 1.01; MS (ESI, Pos.): 451 (M+H)+, 433 (M+H-H2O)+; 1H 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. 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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0550] HPLC retention time (min): 1.218; MS (ESI, Pos.): 429 (M-OH)+; 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. Petition 870250079778, dated 05 / 09 / 2025, pp. 405 / 481 164 / 226 Example 25-5: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-3-(1phenylcyclopropyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0551] HPLC retention time (min): 1.17; MS (ESI, Pos.): 405 (M+H-H2O)+; 1H 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. Example 25-6: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ,4S)-3-hydroxy-4-methyl1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid

[0552] HPLC retention time (min): 1.273; MS (ESI, Pos.): 373 (M-OH)+; 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. Example 25-7: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-4-methyl-4phenyl-1-penten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid HOOC

[0553] HPLC retention time (min): 1.212; MS (ESI, Pos.): 447 (M+Na)+; 1H NMR (CD3OD): δ 7.41 - 7.46, 7.36 - 7.41, 7.28, 7.12 - 7.19, 6.92, 5.25 Petition 870250079778, dated 05 / 09 / 2025, pp. 406 / 481 165 / 226 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. 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]oxepine-6-carboxylic acid

[0554] HPLC retention time (min): 1.27; MS (ESI, Pos.): 385 (M+H-H2O)+; 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. Example 25-9: (1R,3aS,10aR)-5-fluoro-1-[(1E,3ξ)-3-hydroxy-3-(3-phenyl-3oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin6-carboxylic acid

[0555] HPLC retention time (min): 1.089; MS (ESI, Pos.): 421 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.44 - 7.50, 7.36, 7.24 - 7.29, 7.08, 6.97, 5.49 - 5.57, 5.31 - 5.41, 4.97 - 5.03, 4.92, 4.50, 4.38, 2.98 - 3.07, 2.73 - 2.82, 2.60 - 2.70, 2.13 2.22, 1.93 - 2.09, 1.68 - 1.82, 1.38 - 1.49. 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]oxepin6-carboxylic acid

[0556] HPLC retention time (min): 1.18; MS (ESI, Pos.): 453 (M+Na)+, 413 (M+H-H2O)+; 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. Example 25-11: (1R,3aS,10aR)-5-fluoro-1-{(1E,3U-3-[1-(4 Petition 870250079778, dated 05 / 09 / 2025, pp. 407 / 481 166 / 226 fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0557] HPLC retention time (min): 1.23; MS (ESI, Pos.): 477 (M+Na)+; 1H 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. Example 25-12: (1R,3aS,10aR)-1-[(1E,3ξ)-3-(1-benzylcyclobutyl)-3hydroxy-1-propen-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0558] HPLC retention time (min): 1.276; MS (ESI, Pos.): 473 (M+Na)+; 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. 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-1-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0559] HPLC retention time (min): 1.095; MS (ESI, Pos.): 479 (M+Na)+; 1H 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. Example 25-14: (1R,3aS,10aR)-1-[(1E,3ξ)-5-ethoxy-3-hydroxy-4,4-dimethyl1-penten-1-yl]-5-fluoro-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin6-carboxylic acid

[0560] HPLC retention time (min): 1.173; Petition 870250079778, dated 05 / 09 / 2025, pp. 408 / 481 167 / 226 MS (ESI, Pos.): 429 (M+Na)+; 1H NMR (CD3OD): δ 7.41 - 7.48, 6.94, 5.59 - 5.66, 5.47 - 5.55, 4.39 - 4.45, 3.94, 3.41 - 3.52, 3.19 - 3.23, 3.02 - 3.11, 2.65 - 2.86, 2.06 - 2.25, 1.81 - 2.03, 1.43 1.55, 1.18, 0.89. 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-1-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0561] HPLC retention time (min): 1.071; MS (ESI, Pos.): 479 (M+Na)+; 1H 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. Example 26-1 to 26-23:

[0562] A procedure with a similar purpose to that of Example 25 was carried out using a corresponding aldehyde form in place of the compound produced in Reference Example 76 and using a corresponding phosphonate in place of the compound produced in Reference Example 26 to produce the title compound exhibiting the following physical properties. In Examples 26-1, 26-3, and 26-6, the reduction was carried out using (R)-2-methyl-CBS-oxazaborolidine instead of (S)-2-methyl-CBS-oxazaborolidine used in the reaction corresponding to Example 25. The corresponding aldehyde form was prepared by performing a procedure with a similar purpose to that of 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 a corresponding phenol form in place of the compound produced in Reference Example 3.The corresponding phosphonate is a known compound or was prepared from one. Petition 870250079778, dated 05 / 09 / 2025, pp. 409 / 481 168 / 226 known compound by subjecting the compound to a procedure with a purpose similar to that of Reference Example 10 ^ Reference Example 11 or Reference Example 28 ^ Reference Example 29. 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]oxepine-6-carboxylic acid

[0563] MS (FAB, Neg.): 357 (MH)-; 1H NMR (CDCle): 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. Example 26-2: (1R,3aS,10aR)-1-[(1E,3^-3-hydroxy-3-(1-phenylcyclobutyl)1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0564] MS (ESI, Pos.): 401 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.45 - 7.51, 7.36, 7.14 - 7.20, 7.02 - 7.10, 5.24 - 5.36, 5.12 - 5.22, 4.78, 4.25 - 4.29, 4.13, 2.85 - 2.93, 2.65 - 2.76, 2.38 - 2.51, 2.16 - 2.33, 1.86 - 2.10, 1.58 - 1.83, 1.15 - 1.36. Example 26-3: (1R,3aS,10aR)-1-[(1E,3^-3-hydroxy-4-phenoxy-1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0565] MS (ESI, Pos.): 377 (M+H-H2O)+; 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. Example 26-4: (1R,3aS,10aR)-1-[(1E^)-3-hydroxy-3-(1-phenylcyclopropyl)-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0566] MS (ESI, Pos.): 387 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.57 - 7.63, 7.48, 7.38, 7.25 - 7.30, 7.17 - 7.23, 5.36 5.49, 4.37 - 4.42, 3.85, 2.97 - 3.05, 2.77 - 2.85, 2.55 - 2.65, 2.13 - 2.23, 1.98 - 2.07, Petition 870250079778, dated 05 / 09 / 2025, pp. 410 / 481 169 / 226 1.69 - 1.95, 1.30 - 1.46, 0.95 - 1.00, 0.87 - 0.93, 0.77 - 0.83, 0.70 - 0.76.

[0567] Example 26-5: (1R,3aS,10aR)-1-{(1E,3^-3-[1-(4-fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid,

[0568] MS (ESI, Pos.): 405 (M+H-H2O)+; 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. 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]oxepine-6-carboxylic acid

[0569] HPLC retention time (min): 1.13; MS (ESI, Pos.): 409 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.57 - 7.62, 7.50, 7.19, 5.59 - 5.69, 4.41 - 4.48, 2.99 3.08, 2.77 - 2.91,2.71,2.17 - 2.30, 2.06 - 2.15, 1.81 - 2.00, 1.27 - 1.72, 0.89 - 0.99. Example 26-7: (1R,3aS,10aR)-1-{(1E,3^-3-[1-(4-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0570] HPLC retention time (min): 1,262; MS (ESI, Pos.): 419 (M+H-H2O)+; 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. Example 26-8: (1R,3aS,10aR)-1-{(1E^)-3-[1-(2-fluorophenyl)cyclopropyl]3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0571] HPLC retention time (min): 1.07; Petition 870250079778, dated 05 / 09 / 2025, pp. 411 / 481 170 / 226 MS (ESI, Pos.): 405 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.58 - 7.61, 7.48, 7.35 - 7.40, 7.22 - 7.26, 7.20, 7.08 7.12, 7.02, 5.48 - 5.56, 5.32 - 5.41,4.36 - 4.40, 3.99, 2.95 - 3.05, 2.81, 2.59, 2.15, 1.97 - 2.06, 1.86 - 1.96, 1.65 - 1.80, 1.30 - 1.43, 0.99 - 1.07, 0.76 - 0.83, 0.72. Example 26-9: (1R,3aS,10aR)-1-{(1E,3^-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0572] HPLC retention time (min): 1.14; MS (ESI, Pos.): 419 (M+H-H2O)+; 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. 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]oxepine-6-carboxylic acid

[0573] MS (ESI, Pos.): 437 (M+H)+; 1H NMR (CDCls): 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. Example 26-11: (1R,3aS,10aR)-1-{(1E^)-3-[1-(2,4-difluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0574] MS (ESI, Pos.): 437 (M+H-H2O)+; Petition 870250079778, dated 05 / 09 / 2025, pp. 412 / 481 171 / 226 1H NMR (CDCls): 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. Example 26-12: (1R,3aS,10aR)-1-{(1E^)-3-[1-(2,4difluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0575] MS (ESI, Pos.): 423 (M+H-H2O)+; 1H NMR (CDCla): 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. Example 26-13: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl1-buten-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid

[0576] HPLC retention time (min): 1.06; MS (ESI, Pos.): 397 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.40 - 7.58, 7.11 - 7.19, 5.42 - 5.61, 4.32 - 4.47, 2.84 - 3.00, 2.70 - 2.80, 2.59, 2.10 - 2.19, 1.82 - 2.08, 1.53 - 1.77, 1.26 - 1.47. Example 26-14: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-1octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0577] HPLC retention time (min): 1.04; MS (ESI, Pos.): 377 (M+H-H2O)+; 1H 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. Example 26-15: (1R,3aS, 10aR)-1-[(1E^)-3-hydroxy-4-methylene-1-octen1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0578] HPLC retention time (min): 1.06; Petition 870250079778, dated 05 / 09 / 2025, pp. 413 / 481 172 / 226 MS (ESI, Pos.): 353 (M+H-H2O)+; 1H 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. Example 26-16: (1R,3aS,10aR)-5-chloro-1-{(1E,3^-3-[1-(2fluorophenyl)cyclopropyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0579] HPLC retention time (min): 1.2; MS (ESI, Pos.): 439 (M+H-H2O)+; 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. Example 26-17: (1R,3aS,10aR)-5-chloro-1-{(1E,3^-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0580] HPLC retention time (min): 1.25; MS (ESI, Pos.): 453 (M+H-H2O)+; 1H 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. Example 26-18: (1R,3aS,10aR)-5-chloro-1-[(1E^)-3-hydroxy-4-methylene1-octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxylic acid Petition 870250079778, dated 05 / 09 / 2025, pp. 414 / 481 173 / 226

[0581] HPLC retention time (min): 1.255; MS (ESI, Pos.): 387 (M+H-H2O)+; 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. Example 26-19: (1R,3aS,10aR)-5-chloro-1-[(1E^)-3-hydroxy-6-methoxy-4-methylene-1-hexen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0582] HPLC retention time (min): 1.069; MS (ESI, Pos.): 389 (M-OH)+; 1H 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. Example 26-20: (1R,3aS,10aR)-5-chloro-1-[(1E^,4S)-4-ethyl-3-hydroxy-1octen-1-yl]-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0583] HPLC retention time (min): 1.301; MS (ESI, Pos.): 443 (M+Na)+, 403 (M+H-H2O)+; 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 Petition 870250079778, dated 05 / 09 / 2025, p. 415 / 481 174 / 226 0.88

[0584] Example 26-21: (1R,3aS,10aR)-5-chloro-1-[(1E^)-3-hydroxy-3-(3-phenyl-3-oxetanyl)-1-propen-1-yl]-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepin-6-carboxylic acid

[0585] HPLC retention time (min): 1.085; MS (ESI, Pos.): 477 (M+Na)+; 1H 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. 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-1-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0586] HPLC retention time (min): 1.278; MS (ESI, Pos.): 473 (M+Na)+; 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. Example 26-23: (1R,3aS,10aR)-8-fluoro-1-{(1E,3^-3-[1-(2-fluorophenyl)cyclobutyl]-3-hydroxy-1-propen-1-yl}-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid

[0587] MS (ESI, Pos,):437 (M+H-H2O)+; 1H NMR (CD3OD): δ 7.31 - 7.35, 7.31, 7.18 - 7.24, 7.08 - 7.17, 6.99, 5.38 Petition 870250079778, dated 05 / 09 / 2025, pp. 416 / 481 175 / 226 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. Example 27: (1R,3aS,10aR)-1-[(1E,3ξ)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten1-yl]-N-(methylsulfonyl)-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepin-6carboxamide

[0588] A procedure with a purpose similar to that of Reference Example 67 ^ Reference Example 68 ^ Reference Example 69 ^ Reference Example 70 ^ Example 23 was carried out using the compound produced in Example 26-13 in place of the compound produced in Example 17-17 to produce the title compound exhibiting the following physical properties.

[0589] HPLC retention time (min): 0.99; MS (ESI, Pos.): 492 (M+H)+; 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. Example of Reference 77: (1S,2S,3aS,10aR)-5-fluoro-2-hydroxy-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0590] To a solution of the compound (4.87 g) produced in Reference Example 73 in THF (39 mL) was added triphenylphosphine (4.54 g) at room temperature. The mixture was cooled to 0 °C, followed by the addition of formic acid (0.98 mL) and diethyl azodicarboxylate (2.2 mol / L toluene solution, 7.9 mL), and stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 100:0^80:20) to yield a formate ester form (4.53 g).

[0591] A solution of formate ester form (4.53 g) in ethanol (31.7 Petition 870250079778, dated 05 / 09 / 2025, pp. 417 / 481 Potassium carbonate (2.12 g) was added at room temperature (176 / 226 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with MTBE and then filtered. The filtrate was poured into a saturated aqueous solution of ammonium chloride / 1 N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 88:12 ^ 75:25) to yield the title compound (4.08 g) exhibiting the following physical properties. 592 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. Example of Reference 78: (1S,2R,3aS,10aR)-2,5-difluoro-1-({[(2-methyl-2-propanyl)(diphenyl)silyl]oxy}methyl)-2,3,3a,9,10,10a-hexahydro-1-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0593] A solution of the compound (6.0 g) produced in Reference Example 77 in MTBE (27 mL) was cooled to -78 °C, followed by the dropwise addition of bis(2-methoxyethyl)aminosulfide trifluoride (9.8 mL) and stirring at -78 °C. After confirming the disappearance of the raw material by TLC, the temperature was increased to -20 °C. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 93:7^86:14) to yield the title compound (2.59 g) exhibiting the following physical properties.

[0594] 1H NMR (CDCle): δ 7.61 - 7.68, 7.37 - 7.50, 6.86, 5.25 - 5.31, 5.11 Petition 870250079778, dated 05 / 09 / 2025, pages 418 / 481 177 / 226 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. Example of Reference 79: (1S,2R,3aS,10aR)-2,5-difluoro-1-(hydroxymethyl)2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0595] A procedure with a purpose similar to that of Reference Example 8 was carried out using the compound produced in Reference Example 78 in place of the compound produced in Reference Example 7 to produce the title compound exhibiting the following physical properties. 596 2.79, 2.48 - 2.66, 2.26 - 2.48, 2.01 2.12, 1.94, 1.44, 1.35 - 1.41. Example of Reference 80: (1S,2R,3aS,10aR)-2,5-difluoro-1-formyl-2,3,3a,9,10,10a-hexahydro-1H-benzo[b]cyclopenta[f]oxepine-6-carboxylate ethyl

[0597] To a solution of the compound (600 mg) produced in Reference Example 79 in dichloromethane (6 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin reagent, 1.17 g) at 0 °C, followed by stirring 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 residue obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate = 75:25 ^ 60:40) to yield the title compound (550 mg) with the following physical properties.

[0598] 1H NMR (CDCls): 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. Example 28: (1R,2R,3aS,10aR)-2,5-difluoro-1-[(1E^)-3-hydroxy-4-methyl-4-phenyl-1-penten-yl]-2,3,3a,9,10,1...

Claims

1. Compound CHARACTERIZED by the fact that it is represented by the general formula (I) or a salt thereof: R1 wherein R1 represents COOH, COOR11, CONHSO2R12 or tetrazolyl, R11 represents C1-6 alkyl, R12 represents C1-6 alkyl or phenyl, wherein the phenyl is optionally substituted by 1 to 5 (1) halogen atoms or (2) C1-4 alkyl groups, each X1, X2 and X3 independently represents N, CH or CR21, a plurality of R21 each independently represents (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) -(CH2)t-(saturated C3-4 carbocycle) or (5) vinyl optionally substituted by 1 to 3 halogen atoms, t represents an integer of 0 or 1, Petition 870250079778, dated 05 / 09 / 2025, p. 469 / 481 2 / 8 R6 represents (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl OR (4) -(CH2)q (saturated C3-4 carbocycle), q represents an integer from 0 or 1, p represents an integer from 0 to 3,A plurality of R6 can form a saturated C3-4 carbocycle optionally substituted by 1 to 6 halogen atoms together with a carbon atom to which each R6 is attached, Y represents an oxygen atom or a sulfur atom, R2 and R3 each independently represent (1) a hydrogen atom, (2) a halogen, (3) a C1-4 alkyl or (4) a C1-4 haloalkyl, R2 and R3 can form a saturated C3-4 carbocycle, optionally substituted by 1 to 6 halogen atoms, together with a carbon atom to which R2 and R3 are attached, Z represents CHR10 or an oxygen atom, R10 represents a hydrogen atom, a halogen, a hydroxyl group or a methoxy group, L represents -CH2-, -CHRL1-, -CRL2RL3- or -C(=CH2)-, RL1 represents (1) a halogen, (2) a C1-4 alkyl, (3) C1-4 haloalkyl, (4) C2-4 alkenyl, (5) C2-4 haloalkenyl, (6) C2-4 alkynyl or (7) C2-4 haloalkynyl, RL2 and RL3 each independently represent (1) halogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl,(4) C2-4 alkenyl, (5) C2-4 haloalkenyl, (6) C2-4 alkynyl, (7) C2-4 haloalkynyl or (8) a hydroxyl group, or RL2 and RL3 may form (1) a saturated C3-6 carbocycle optionally substituted by 1 to 10 halogen atoms or (2) a saturated heterocycle of 3 to 6 Petition 870250079778, dated 05 / 09 / 2025, p. 470 / 481 3 / 8 members optionally substituted by 1 to 8 halogen atoms, together with a carbon atom to which RL2 and RL3 are attached, R4 represents (1) C3-7 alkyl optionally substituted by 1 to 5 R41, (2) C3-7 alkenyl optionally substituted by 1 to 5 R42, (3) C3-7 alkynyl optionally substituted by 1 to 5 R43, (4) C2-6 alkoxy optionally substituted by 1 to 5 R44 or (5) Cyc1, R41, R42, R43 and R44 each independently represent (1) a halogen, (2) a C3-6 carbocycle or (3) a 3- to 6-membered heterocycle,wherein the C3-6 carbocycle and the 3- to 6-membered heterocycle are optionally substituted by 1 to 10 (1) halogen atoms or (2) C1-2 alkyl groups, Cyc1 represents (1) a C5-10 carbocycle optionally substituted by 1 to 5 R51 or (2) a 5- to 10-membered heterocycle optionally substituted by 1 to 5 R52, R51 and R52 each independently represent (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) a hydroxyl group, (11) a carbocycle saturated C3-6 or (12) a saturated 3- to 6-membered heterocycle, RL1 and R51 can form (1) a saturated C3-6 carbocycle or (2) a saturated 3- to 6-membered heterocycle, together with a carbon atom to which RL1 and R51 are attached, R5 represents a hydrogen atom or a hydroxyl group, wherein a plurality of R6, R41, R42, R43, R44, R51 and R52 may be the same or different,------ represents a single bond or a double bond, provided that adjacent ------ is not simultaneously a double bond, represents a bond beyond the surface of the sheet (i.e., an α configuration), Petition 870250079778, dated 05 / 09 / 2025, p. 471 / 481 4 / 8 r^P represents a bond in front of the surface of the sheet (i.e., a β configuration), wherein bonded to an asymmetric atom represents the α configuration, the β configuration, or a mixture of the α and β configurations in any ratio, unless otherwise indicated.

2. A compound or a salt thereof, according to claim 1, CHARACTERIZED in that X1, X2 and X3 are each independently CH or CR21.

3. A compound or salt thereof, according to claim 1 or 2, CHARACTERIZED in that Y is an oxygen atom.

4. Compound or salt thereof, according to any one of claims 1 to 3, CHARACTERIZED in that R4 is C3-7 alkyl optionally substituted by 1 to 3 R41, C3-7 alkenyl optionally substituted by 1 to 3 R42 or Cyc1.

5. A compound or a salt thereof, according to any one of claims 1 to 4, CHARACTERIZED in that Z is CHR10, and R10 is a hydroxyl group.

6. A compound or a salt thereof, according to any one of claims 1 to 5, CHARACTERIZED in that R1 is COOH.

7. Compound or salt thereof, according to claim 1, CHARACTERIZED in that the general formula (I) is represented by the general formula (I-3) Petition 870250079778, dated 05 / 09 / 2025, p. 472 / 481 5 / 8 where L10 represents -CHRL1- or -CRL2RL3-, R4a represents C3-7 alkyl optionally substituted with 1 to 3 R41, C3-7 alkenyl optionally substituted with 1 to 3 R42, or Cyc1, and other symbols represent meanings identical to those of claim 1.

8. Compound or salt thereof, according to claim 1, CHARACTERIZED in that the compound represented by the general formula (I) or salt thereof is (1) (1R,2R,3aS,10aR)-1-[(1E,3R,4S)-4-(2,4-difluorophenyl)-3-hydroxy-1-penten-1-yl]-5-fluoro-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1-Hbenzo[b]cyclopenta[f]oxepine-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-1-Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (3) (1R,2R,3aS,10aR)-1-{(1E,3^-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]oxepine-6-carboxylic acid, (4) (1R,2R,3aS,10aR)-1-{(1E^)-3-[1 -(2,5-difluorophenyl)cyclobutyl]-3hydroxy-1-propen-1-yl}-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (5) (1R,2R,3aS,10aR)-5-chloro-1-[(1E,3^-4-(2,6-difluorophenyl)-4,4difluoro-3-hydroxy-1-buten-1-yl]-2-hydroxy-2,3,3a,9,10,10a-hexahydro-1H- Petition 870250079778, dated 05 / 09 / 2025, page. 473 / 481 6 / 8 benzo[b]cyclopenta[f]oxepine-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-1Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (7) (1R,2R,3aS,10aR)-1-[(1E,3ξ)-4-ethyl-3-hydroxy-7-methyl-1-octen-1-yl]2-hydroxy-5-methyl-2,3,3a,9,10,10a-hexahydro-1 H-benzo[b]cyclopenta[f]oxepine-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-1-Hbenzo[b]cyclopenta[f]oxepine-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-1- Hbenzo[b]cyclopenta[f]oxepine-6-carboxylic acid, (10) (1R,2R,3aS,10aR)-2-hydroxy-1-[(1E^)-4-hydroxy-4,7-dimetil-1 octen-1 -il]-5-metil-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (11) ácido (1 R,3aS,10aR)-5-fluoro-1 -[(1 E,3U-3-hidróxi-4-metil-4-fenil-1 - penten-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (12) ácido (1 R,3aS,10aR)-1 -{(1 E,3U-3-[1 -(2-fluorofenil)ciclobutil]-3-hidróxi-1 propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (13) ácido (1 R,3aS,10aR)-5-cloro-1 -{(1 E,3U-3-[1 -(2-fluorofenil)ciclobutil]-3hidróxi-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (14) ácido (1 R,3aS, 10aR)-5-cloro-1 -[(1 E^)-3-hidróxi-6-metóxi-4-metileno-1 hexen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6- Petição 870250079778, de 05 / 09 / 2025, pág. 474 / 481 7 / 8 carboxyl, (15) acid (1 R,3aS, 10aR)-5-chloro-1 -[(1 E,3^4S)-4-ethyl-3-hidróxi-1 -octen-1 -il]2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]cyclopenta[f]oxepine-6-carboxylic acid,(16) ácido (1 R,3aS,10aR)-5-cloro-1 -[(1 E^)-3-hidróxi-3-(3-fenil-3-oxetanil)-1 propen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (17) ácido (1 R,2R,3aS, 10aR)-2,5-difluoro-1 -[(1 E^)-3-hidróxi-4-metil-4-fenil1 -penten-il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina-6carboxílico, (18) ácido (1 R,2R,3aS,10aR)-2,5-difluoro-1 -[(1 E^)-3-hidróxi-3-(3-fenil-3oxetanil)-1 -propen-1 -il]-2,3,3a,9,10,10a-hexa-hidro-1 H-benzo[b]ciclopenta[f]oxepina6-carboxílico, (19) ácido (1R,2R,3aS,10aR)-2-cloro-5-fluoro-1-{(1E^)-3-[3-(2-fluorofenil)-3oxetanil]-3-hidróxi-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]ciclopenta[f]oxepina-6-carboxílico, (20) ácido (1 R,2R,3aS, 10aR)-2-cloro-5-fluoro-1 -{(1 E,3^-3-hidróxi-3-[^)-2fenil-2-oxetanil]-1 -propen-1 -il}-2,3,3a,9,10,10a-hexa-hidro-1 Hbenzo[b]ciclopenta[f]oxepina-6-carboxylic acid, (21) ácido (1 R,3aR, 10aR)-1 -[(1 E,3^4S)-3-hidróxi-4-metil-1 -octen-1 -il]-5- metil-1,3,3a,9,10,10a-hexa-hydrofuro[3,4-b][1]benzoxepine-6-carboxylic acid, (22) (1R,3aR,10aR)-1-[(1E^)-3-hydroxy-3-(1-phenoxycyclobutyl)-1-propen-1-yl]-5-methyl-1,3,3a,9,10,10a-hexa-hydrofuro[3,4-b][1]benzoxepine-6-carboxylic acid, (23) (1R,2R,3aS,10aR)-5-fluoro-2-hydroxy-1-{(1E^)-3-hydroxy-3-[1-(2-methylphenyl)cyclopropyl]-1-propen-1-yl}-2,3,3a,9,10,10a-hexa-hydro-1 Hbenzo[b]cyclopenta[f]oxepine-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- Petition 870250079778, dated 05 / 09 / 2025, page 475 / 481 8 / 8 benzo[b]cyclopenta[f]oxepine-6-carboxylic acid, or a salt thereof., 9. Pharmaceutical composition, CHARACTERIZED in that it comprises the compound or a salt thereof, as defined in any one of claims 1 to 8.

10. EP3 agonist, CHARACTERIZED in that it comprises the compound or a salt thereof, as defined in any one of claims 1 to 8.

11. Use of the compound or a salt thereof, as defined in any one of claims 1 to 8, of the pharmaceutical composition, as defined in claim 9, or of the EP3 agonist, as defined in claim 9, CHARACTERIZED in that it is for the preparation of a medicament to prevent and / or treat a kidney disease.

12. Use, according to claim 11, CHARACTERIZED in that the kidney disease is a chronic kidney disease.

13. Use, according to claim 12, CHARACTERIZED in that chronic kidney disease is diabetic kidney disease, nephrosclerosis, IgA nephropathy, GBM nephritis, ANCA-associated nephritis, mesangial proliferative nephritis, lupus nephritis, minimal change nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, Alport syndrome, or polycystic kidney disease.

14. Use, according to claim 11, CHARACTERIZED in that the kidney disease is acute kidney damage.

15. Use, according to claim 14, _CHARACTERIZED in that_ acute kidney injury is acute kidney injury associated with organ surgery, acute kidney injury associated with sepsis, acute kidney injury associated with kidney transplantation, acute kidney injury associated with rhabdomyolysis, contrast nephropathy, or drug-induced kidney injury.