Benzene Derivatives

Abstract

To provide a compound having a neural protecting and / or repairing effect.SOLUTION: A compound represented by general formula (I) or a salt thereof has a potent neural protecting and / or repairing effect and, therefore, is usable as a therapeutic agent for neurological disorders (for example, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, periarteritis nodosa, allergic angiitis, diabetic peripheral neuropathy, entrapment neuropathy, peripheral neuropathy associated with chemotherapeutic drug administration).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a compound represented by the following general formula (I):

[0002] [ka]

[0003] (wherein all symbols have the same meaning as described below) or a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention). [Background technology]

[0004] The nervous system is broadly divided into the central nervous system and the peripheral nervous system, and the peripheral nervous system in particular connects the brain and spinal cord with the periphery of the body and is responsible for nerve transmission. The peripheral nervous system can be classified into the somatic nervous system (cerebrospinal nervous system) and the autonomic nervous system. The somatic nervous system can be further divided into the cranial nerves and the spinal nerves. In addition, when classifying the somatic nervous system functionally, those that transmit nerve signals (excitation) generated by sensory receptors to the central nerves are classified as afferent or sensory nerve fibers, while those that transmit nerve signals from the brain and spinal cord to effector organs such as muscles and glands are classified as efferent or motor nerve fibers. The cranial nerves are peripheral nerves that emerge from the brain, and there are 12 known pairs, some of which are sensory, some are motor, and some are mixed nerve fibers. The first to twelfth nerve pairs are called the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and hypoglossal nerve, respectively. Of these, the olfactory nerve, optic nerve, trigeminal nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, and vagus nerve are known to be composed of sensory or mixed nerve fibers. The spinal nerves are peripheral nerves that originate from the spinal cord, and 31 pairs are known to exist on the left and right sides, including 8 pairs of cervical nerves, 12 pairs of thoracic nerves, 5 pairs of lumbar nerves, 5 pairs of sacral nerves, and 1 pair of coccygeal nerves. All spinal nerves are composed of mixed nerve fibers, and include sensory fibers (posterior roots) that go to the skin, etc., and motor fibers (anterior roots) that go to skeletal muscles.

[0005] Sensory nerve fibers, i.e., sensory nerves, have the function of accurately transmitting stimuli such as light, sound, temperature, and touch received by sensory receptors such as the visual, auditory, olfactory, and gustatory organs and the skin to the central nervous system. The nerve signals transmitted to the central nervous system are finally transmitted to each sensory area of ​​the cerebral cortex, such as the visual and auditory areas, and the sensations are recognized normally. However, these sensory nerves may be invaded by, for example, viral infection, tumor, cancer, diabetes, ischemia, trauma, compression, drugs, radiation therapy, etc., causing various nerve disorders such as cell death and demyelination. As a result, accurate nerve transmission cannot be performed in the damaged sensory nerves, and diseases such as hearing loss and neuropathic pain develop. In addition to these, there is peripheral neuropathy in which not only specific sensory nerves but also various peripheral nerves including sensory nerves are simultaneously damaged due to, for example, metabolic diseases, autoimmune diseases, trauma, drug poisoning, etc. This disease can affect a single nerve, two or more nerves in separate areas, or multiple nerves simultaneously. Symptoms are very complex and varied, including peripheral tingling, numbness, burning sensation, decreased joint proprioception, decreased vibration sense, pain (including neuropathic pain), abnormal sensations, and chills or hot flashes.

[0006] However, because the mechanisms of the onset of the above-mentioned peripheral nervous system diseases are unknown or they are caused by physical damage to the nerves, their treatment is primarily symptomatic, with the aim of alleviating symptoms, and there are almost no known clinically useful drugs that act directly on the damaged nervous system to provide fundamental treatment. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide compounds having neuroprotective and / or restorative activity. [Means for solving the problem]

[0008] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have discovered that a compound represented by the following general formula (I) has strong neuroprotective and / or restorative effects, and have completed the present invention. That is, the present invention provides [1] General formula (I)

[0009] [ka]

[0010] [In the formula, R 1 is (1)-R 11 -COOR 12 , (2)-R 13 -CONR 14 R 15 , (3)-R 17 -CN, (4)-R 18 -CONHS(O)2-R 19 , (5)-R 20 -CycD, or

[0011] [ka]

[0012] (In the group, ring 1 represents a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle, R 101 represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group; n represents an integer from 0 to 3; when n is 2 or more, a plurality of R 101 may be the same or different. R 11 , R 13 , R 16 , R 17 , R 18 , and R 20each independently represents (1) a C1-6 alkylene group optionally substituted with 1 to 3 halogen atoms, (2) a C2-6 alkenylene group optionally substituted with 1 to 3 halogen atoms, or (3) a C2-6 alkynylene group optionally substituted with 1 to 3 halogen atoms, in which when the alkylene group, alkenylene group or alkynylene group is a branched chain, two C1-2 alkyl groups branched from the same carbon atom may be joined together to form a C3-5 saturated carbocyclic ring, R 12 , R 14 , R 15 and R 19 each independently represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, CycD represents triazole or tetrazole; R 2 represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group; p represents an integer from 0 to 3; when p is 2 or more, a plurality of R 2 may be the same or different, X represents (1) CH2 or (2) an oxygen atom; L 1 (1) 1 to 4 R L1a (2) a linear C3-7 alkylene group optionally substituted with 1 to 4 R L1a (3) a linear C3-7 alkenylene group optionally substituted with 1 to 4 R L1a or (4) (1 to 2 R L1a A straight-chain C1-3 alkylene group optionally substituted with 1-2 R L1a a straight-chain C1-3 alkylene group which may be substituted with R L1a represents (1) a halogen atom, (2) a hydroxyl group, (3) an oxo group, or (4) a C1-2 alkyl group; R L1a When there are two or more, multiple R L1a may be the same or different, and two R L1aare each a C1-2 alkyl group, the C1-2 alkyl group may form a C3-5 saturated carbocyclic ring together with the carbon atom to which it is attached,

[0013] [ka]

[0014] represents a single bond, a double bond or a triple bond, R 3 represents (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-2 alkyl group, or (5) a methylidene group; and q represents an integer of 0 to 2;

[0015] [ka]

[0016] When is a single bond and q is 2, multiple R 3 may be the same or different, and at least one R 3 When is a methyl group, the adjacent L 1 together with the carbon atom in to form a cyclopropane, CycA represents (1) a C5-10 monocyclic or bicyclic carbocycle, or (2) a 5-10 membered monocyclic or bicyclic heterocycle; R 4 represents (1) a halogen atom, (2) a hydroxyl group, (3) a C1-4 alkyl group, (4) a C1-4 haloalkyl group, (5) a C1-4 alkoxy group, (6) a C1-4 haloalkoxy group, (7) a cyano group, or (8) a -SO2-C1-2 alkyl group; r represents an integer from 0 to 6; when r is 2 or more, multiple R 4 may be the same or different, L 2 -R 31 -L 3 -R 32 - represents L 3 is (1)-NR 201 -S(O)-, (2)-NR 202-S(O)2-, (3)-NR 203 -C(O)-, (4)-CR 204 (OH)-, (5)-NR 205 -, (6) -S(O)-, or (7) -S(O)2-; R 201 , R 202 , R 203 , R 204 , and R 205 each independently represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, in which the alkyl group or haloalkyl group is optionally substituted with (1) a hydroxyl group, (2) an oxo group, (3) a C3-6 monocyclic carbocyclic ring, or (4) a 3-6 membered monocyclic heterocyclic ring; R 31 and R 32 each independently represents (1) a bond, or (2) a C1-3 alkylene group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an oxo group, CycB represents (1) a C5-10 monocyclic or bicyclic carbocycle, or (2) a 5-10 membered monocyclic or bicyclic heterocycle; R 5 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 haloalkyl group, (6) a C2-6 haloalkenyl group, (7) a C2-6 haloalkynyl group, (8) a C1-6 alkoxy group, or (9) a C1-6 haloalkoxy group; t represents an integer from 0 to 6; when t is 2 or greater, multiple R 5 may be the same or different.] or a salt thereof, [2] In general formula (I),

[0017] [ka]

[0018] (1) = CH-(1 to 2 R L1a (2)-(a linear C2-6 alkylene group optionally substituted with 1 to 2 R L1a(3)-(a linear C3-7 alkylene group optionally substituted with 1 to 2 R L1a A straight-chain C1-3 alkylene group optionally substituted with 1-2 R L1a (In (1) to (3), R is a straight-chain C1-3 alkylene group which may be substituted with L1a has the same meaning as in [1]), the compound of [1] or a salt thereof, [3] R 1 -R 11 -COOR 12 The compound or salt thereof according to any one of the above [1] or [2], [4] L 2 But (1)-NR 202 -S(O)2-, or (2)-CR 204 The compound according to any one of the above [1] to [3], wherein (OH)-CH2-, or a salt thereof. [5] The compound or salt thereof according to any one of [1] to [4] above, wherein CycA is a C5-6 monocyclic carbocyclic ring. [6] The compound or salt thereof according to any one of [1] to [5] above, wherein CycB is a C5-6 monocyclic carbocyclic ring. [7] The general formula (I) is represented by the general formula (I-1)

[0019] [ka]

[0020] [In the formula, R 11-1 represents a C2-4 alkylene group, L 1-1 1 to 2 R L1a represents a linear C3-4 alkylene group which may be substituted with 1 and CycB 1 each independently represents a C5-6 monocyclic carbocyclic ring; L 2-1 represents (1) -NH-S(O)2-, or (2) -CH(OH)-CH2-, and other symbols have the same meanings as in the above [1].], [8] The compound or salt thereof according to any one of the above [1] to [7], wherein X is an oxygen atom. [9] (1) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (2) 3-[2-[(3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid, (3) 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid, (4) 3-[2-[(E,3R)-5-[4-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (5) 3-[2-[(E,3R)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (6) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (7) 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]butanoic acid, (8) 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid, (9) (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid, (10) (S)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid, (11) 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid, (12) 3-[2-[5-[3-(benzenesulfonamido)phenyl]pentoxy]phenyl]propanoic acid, (13) 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid, (14) 3-[2-[(3S)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid, (15) 3-[2-[2-[2-[3-(benzenesulfonamido)phenyl]ethoxy]ethoxy]phenyl]propanoic acid, (16) 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid, or (17) The compound or salt thereof according to the above [1], which is 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid or a salt thereof.

[10] A pharmaceutical composition comprising the compound represented by formula (I) or a salt thereof according to claim 1.

[11] A Schwann cell differentiation promoter comprising the compound represented by the general formula (I) or a salt thereof according to [1] above.

[12] A preventive and / or therapeutic agent for nerve disorders, comprising the compound represented by the general formula (I) or a salt thereof according to [1] above.

[13] The agent according to the above

[12] , wherein the neuropathy is peripheral neuropathy.

[14] The agent according to the above

[13] , wherein the peripheral neuropathy is chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, entrapment neuropathy, peripheral neuropathy associated with chemotherapy, or peripheral neuropathy associated with Charcot-Marie-Tooth disease.

[15] A method for preventing and / or treating a nerve disorder, comprising administering to a mammal an effective amount of the compound represented by the general formula (I) described in [1] above or a salt thereof.

[16] A compound represented by the general formula (I) or a salt thereof according to the above [1] for use in the prevention and / or treatment of a neurological disorder,

[17] Use of the compound represented by the general formula (I) or a salt thereof according to the above [1] for the manufacture of an agent for the prophylaxis and / or treatment of a neuropathy.

[18] A pharmaceutical composition for neuroprotection and / or repair, comprising the compound represented by the general formula (I) or a salt thereof according to [1] above.

[19] The pharmaceutical composition according to

[18] above, wherein the neuroprotection and / or repair is neuroprotection and / or repair mediated by glial cells (e.g., microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.); or

[20] The pharmaceutical composition according to the above

[19] , wherein the glial cell-mediated neuroprotection and / or repair is neuroprotection and / or repair by promoting myelination by Schwann cells. Regarding. Effect of the Invention

[0021] The compounds of the present invention have potent neuroprotective and / or repair effects and are therefore useful in the treatment of neuropathies, such as peripheral neuropathy. [Brief description of the drawings]

[0022] [Figure 1] This shows the nociceptive threshold when the compounds of Examples 11, 36, 37 and 84 were administered at a dose of 0.3 mg / kg in the streptozotocin model (the vertical axis shows the nociceptive threshold, and the horizontal axis shows the number of days after streptozotocin administration). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention will be described in detail below.

[0024] In the present invention, the 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle refers to a monocyclic saturated heterocycle containing at least one nitrogen atom, and examples thereof include aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, morpholine, and thiomorpholine.

[0025] In the present invention, the halogen atom means fluorine, chlorine, bromine, iodine, or the like.

[0026] In the present invention, C1-4 alkyl groups include linear or branched C1-4 alkyl groups, for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert-butyl.

[0027] In the present invention, the C1-4 haloalkyl group refers to a linear or branched C1-4 alkyl group substituted with one or more halogen atoms, and examples thereof include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, and 4-bromobutyl.

[0028] In the present invention, the C1-6 alkylene group includes linear or branched C1-6 alkylene groups, such as methylene, ethylene, propylene, butylene, pentylene, hexanylene, or isomers thereof.

[0029] In the present invention, the C2-6 alkenylene group includes linear or branched C2-6 alkenylene, for example, ethenylene, propenylene, butenylene, pentenylene, hexenylene, or isomers thereof.

[0030] In the present invention, the C2-6 alkynylene group includes linear or branched C2-6 alkynylene groups, such as ethynylene, propynylene, butynylene, pentynylene, hexynylene, or isomers thereof.

[0031] In the present invention, examples of the linear C3-7 alkylene group include propylene, butylene, pentylene, hexanylene, and heptanylene.

[0032] In the present invention, examples of the linear C3-7 alkenylene group include propenylene, butenylene, pentenylene, hexenylene, heptenylene, and isomers thereof.

[0033] In the present invention, examples of the straight-chain C3-7 alkynylene group include propynylene, butynylene, pentynylene, hexynylene, and isomers thereof.

[0034] In the present invention, a C1-2 alkyl group refers to methyl or ethyl.

[0035] In the present invention, examples of the C3-5 saturated carbocyclic ring include cyclopropane, cyclobutane, and cyclopentane.

[0036] In the present invention, examples of the C5-10 monocyclic or bicyclic carbon ring include cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene.

[0037] In the present invention, the 5-10 membered monocyclic or bicyclic heterocycle refers to a 5-10 membered monocyclic or bicyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, Oxadiazepine, thiadiazole, thiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine , imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, Tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,Tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiaziazine, tetrahydrothiaziazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiazepine, perhydrothiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzo Thiophene, Perhydroisobenzothiophene, Dihydroindazole, Perhydroindazole, Dihydroquinoline, Tetrahydroquinoline, Perhydroquinoline, Dihydroisoquinoline, Tetrahydroisoquinoline, Perhydroisoquinoline, Dihydrophthalazine, Tetrahydrophthalazine, Perhydrophthalazine, Dihydronaphthyridine, Tetrahydronaphthyridine, Perhydronaphthyridine, Dihydroquinoxaline, Tetrahydroquinoxaline, Perhydroquinoxaline, Dihydroquinazoline, Tetrahydroquinazoline, Perhi Examples of the dihydroquinazoline include dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxindan, benzodioxane, chroman, benzodithiolane, and benzodithiane.

[0038] In the present invention, the C1-4 alkoxy group includes linear or branched C1-4 alkoxy groups, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0039] In the present invention, the C1-4 haloalkoxy group refers to a linear or branched C1-4 alkoxy group substituted with one or more halogen atoms, and examples thereof include trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy, and 1-chlorobutoxy.

[0040] In the present invention, examples of the C3-6 monocyclic carbocyclic ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

[0041] In the present invention, the 3- to 6-membered monocyclic heterocycle refers to a 3- to 6-membered monocyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, and azo. Diridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, oxirane, oxetane, dihydrofuran, tetrahydrofuran Ran, dihydropyran, tetrahydropyran, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane.

[0042] In the present invention, the 5- to 6-membered monocyclic heterocycle refers to a 5- to 6-membered monocyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, Thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyridine Lan, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane.

[0043] In the present invention, the 5- to 6-membered monocyclic aromatic heterocycle refers to a 5- to 6-membered monocyclic aromatic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, and thiadiazole.

[0044] In the present invention, the C1-3 alkylene group includes linear or branched C1-3 alkylene groups, such as methylene, ethylene, propylene, or isomers thereof.

[0045] In the present invention, the C1-6 alkyl group includes linear or branched C1-6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or isomers thereof.

[0046] In the present invention, C2-6 alkenyl groups include linear or branched C2-6 alkenyl groups, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, or isomers thereof.

[0047] In the present invention, the C2-6 alkynyl group includes linear or branched C2-6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, or isomers thereof.

[0048] In the present invention, the C1-6 haloalkyl group refers to a linear or branched C1-6 alkyl group substituted with one or more halogen atoms, and examples thereof include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, 1-fluoropentane, and 2-chlorohexane.

[0049] In the present invention, the C2-6 haloalkenyl group refers to a linear or branched C2-6 alkenyl group substituted with one or more halogen atoms, and examples thereof include 1-fluoroethenyl, 2-fluoroethenyl, 2-chloroethenyl, pentafluoroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl, 1-fluoropentenyl, and 2-chlorohexenyl.

[0050] In the present invention, the C2-6 haloalkynyl group refers to a linear or branched C2-6 alkynyl group substituted with one or more halogen atoms, and examples thereof include 1-fluoroethynyl, 2-fluoroethynyl, 2-chloroethynyl, pentafluoroethynyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl, 1-fluoropentynyl, and 2-chlorohexynyl.

[0051] In the present invention, the C1-6 alkoxy group includes linear or branched C1-6 alkoxy groups, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, and isohexyloxy.

[0052] In the present invention, the C1-6 haloalkoxy group refers to a linear or branched C1-6 alkoxy group substituted with one or more halogen atoms, and examples thereof include trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy, 1-chlorobutoxy, 2-fluoropentoxy, and 3-chlorohexyloxy.

[0053] In the present invention, examples of the linear C2-6 alkylene group include ethylene, propylene, butylene, pentylene, and hexanylene.

[0054] In the present invention, examples of the linear C3-7 alkylene group include propylene, butylene, pentylene, hexanylene, and heptanylene.

[0055] In the present invention, examples of the linear C1-3 alkylene group include methylene, ethylene and propylene.

[0056] In the present invention, examples of the C5-6 monocyclic carbocyclic ring include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

[0057] In the present invention, the C2-4 alkylene group includes linear or branched C2-4 alkylene groups, such as ethylene, propylene, butylene, or isomers thereof.

[0058] In the present invention, the C3-4 alkylene group includes linear or branched C3-4 alkylene groups, such as propylene, butylene, or isomers thereof.

[0059] In the present invention,

[0060] [ka]

[0061] means a single bond, a double bond or a triple bond, and in the case of a double bond, includes a cis form or a trans form.

[0062] In the present invention, L 3 The bond direction of is not limited. For example, L 3 Ga-NR 202 In the case of -S(O)2-, L 2 -R 31 -NR 202 -S(O)2-R 32 But, -R 31 -S(O)2-NR 202 -R 32 But that's okay.

[0063] In the present invention, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene and alkoxy groups include straight or branched chain groups, unless otherwise specified.

[0064] In the present invention, R 3 When represents a methylidene group, the partial structure of the general formula (I) is represented by the formula

[0065] [ka]

[0066] [wherein all symbols have the same meanings as above] is represented by the following structure:

[0067] [ka]

[0068] This means to take

[0069] The compound of the present invention is a compound represented by the following general formula (I) or a salt thereof, in which the number of atoms between CycA and the benzene ring is 5 or more.

[0070] [ka]

[0071] In the present invention, R 1 As for -R 11 -COOR 12 is preferred, -R 11 -COOH is more preferred. 11 is preferably a C1-6 alkylene group optionally substituted with 1 to 3 halogen atoms, and more preferably a C2-4 alkylene group optionally substituted with 1 to 3 halogen atoms.

[0072] In the present invention, R 1 but

[0073] [ka]

[0074] When the formula is represented by the formula (I), ring 1 is more preferably a 6-membered nitrogen-containing monocyclic saturated heterocycle, and further preferably morpholine.

[0075] In the present invention, R 101 is preferably a hydrogen atom.

[0076] In the present invention, R 11 , R 13 , R 16 , R 17 , R 18 and R 20 is preferably a C1-6 alkylene group optionally substituted with 1 to 3 halogen atoms, and more preferably a C2-4 alkylene group optionally substituted with 1 to 3 halogen atoms.

[0077] In the present invention, R12 , R 14 , R 15 and R 19 Each of these is preferably a hydrogen atom.

[0078] In the present invention, R 2 is preferably a halogen atom or a C1-4 alkyl group.

[0079] In the present invention, X is preferably an oxygen atom.

[0080] In the present invention, L 1 (1) 1 to 4 R L1a or (2) (1 to 2 R L1a A straight-chain C1-3 alkylene group optionally substituted with 1-2 R L1a A straight-chain C1-3 alkylene group which may be substituted with 1 to 4 R L1a A linear C3-7 alkylene group which may be substituted with is more preferred.

[0081] In the present invention,

[0082] [ka]

[0083] is preferably a single bond or a double bond.

[0084] In the present invention,

[0085] [ka]

[0086] As for the following: (1) = CH-(1 to 3 R L1a (2)-(a linear C2-6 alkylene group optionally substituted with 1 to 3 R L1a(3)-(a linear C3-7 alkylene group optionally substituted with 1 to 2 R L1a A straight-chain C1-3 alkylene group optionally substituted with 1-2 R L1a A straight-chain C1-3 alkylene group which may be substituted with L1a has the same meaning as above), (1) = CH-(1 to 3 R L1a (2)-(a linear C2-6 alkylene group optionally substituted with 1 to 3 R L1a A straight-chain C3-7 alkylene group which may be substituted with L1a has the same meaning as above), (1) = CH-(1 to 3 R L1a (2)-(a straight-chain C3 alkylene group optionally substituted with 1 to 3 R L1a (In (1) to (2), R L1a has the same meaning as above) is more preferable.

[0087] In the present invention, R L1a is preferably a hydroxyl group, a halogen atom or an oxo group, more preferably a hydroxyl group.

[0088] In the present invention, R 3 A hydrogen atom is preferable.

[0089] In the present invention, CycA is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5- to 10-membered monocyclic or bicyclic heterocycle, more preferably benzene or a 5- to 6-membered monocyclic aromatic heterocycle.

[0090] In the present invention, CycA is preferably benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline, more preferably benzene, isoindoline or tetrahydroquinoline, and even more preferably benzene.

[0091] In the present invention, R 4 is preferably a halogen atom, a C1-4 alkyl group or a C1-4 haloalkyl group, more preferably a halogen atom, a methyl group or a trihalomethyl group.

[0092] In the present invention, L 3 As for -NR 201 -S(O)2- or -CR 204 (OH) is preferred.

[0093] In the present invention, L 2 As for -NR 201 -S(O)2- or -CR 204 (OH)-CH2- is preferred.

[0094] In the present invention, R 201 , R 202 , R 203 , R 204 , and R 205 are preferably a hydrogen atom, a C1-4 alkyl group, a C1-4 alkyl group substituted with a hydroxyl group, a C1-4 alkyl group substituted with a C3-6 monocyclic carbocycle, or a C1-4 alkyl group substituted with a 3-6-membered monocyclic heterocycle, and more preferably a hydrogen atom. Of these, the C1-4 alkyl group substituted with a C3-6 monocyclic carbocycle is preferably a C1-4 alkyl group substituted with cyclopropane or benzene, and the C1-4 alkyl group substituted with a 3-6-membered monocyclic heterocycle is preferably a C1-4 alkyl group substituted with oxetane, tetrahydrofuran, or tetrahydropyran.

[0095] In the present invention, R 31 is preferably a bond or a C1-3 alkylene group, more preferably a bond.

[0096] In the present invention, R 32 is preferably a bond or a C1-3 alkylene group, more preferably a C1-3 alkylene group.

[0097] In the present invention, CycB is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5- or 6-membered monocyclic heterocycle, more preferably benzene or a 5- or 6-membered monocyclic aromatic heterocycle.

[0098] In the present invention, CycB is preferably cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran, and more preferably benzene.

[0099] In the present invention, R 5 is preferably a halogen atom, a C1-4 alkyl group, a C1-4 haloalkyl group or a C1-4 alkoxy group, more preferably a halogen atom, a C1-4 alkyl group, a trihalomethyl group or a C1-4 alkoxy group.

[0100] In the present invention, r and t each preferably represent an integer of 0 to 3, and more preferably an integer of 0 to 2.

[0101] In the present invention, the partial structure in general formula (I)

[0102] [ka]

[0103] [wherein all symbols have the same meanings as above] may have the following structure:

[0104] [ka]

[0105] is preferred,

[0106] [ka]

[0107] is more preferred.

[0108] In the present invention, the formula (I) which is a partial structure

[0109] [ka]

[0110] [wherein all symbols have the same meanings as above] is

[0111] [ka]

[0112] [In the formula, all symbols have the same meanings as defined above.] is preferred.

[0113] In the present invention, the formula (I) which is a partial structure

[0114] [ka]

[0115] [wherein all symbols have the same meanings as above] is

[0116] [ka]

[0117] [In the formula, all symbols have the same meanings as defined above.] is preferred.

[0118] In the present invention, an embodiment of the general formula (I) is the general formula (Ii)

[0119] [ka]

[0120] [In the formula, L 1-i (1) 1 to 3 R L1aor (2) -O-(1 to 2 R L1a represents a straight-chain C1-3 alkylene group which may be substituted by -, and the other symbols have the same meanings as above.

[0121] In the present invention, an embodiment of the general formula (Ii) is the general formula (I-ii)

[0122] [ka]

[0123] [In the formula, L 1-ii 1 to 3 R L1a represents a linear C2-4 alkylene group which may be substituted by, and the other symbols have the same meanings as above. General formula (I-iii)

[0124] [ka]

[0125] [In the formula, L 1-iii (1) 1 to 3 R L1a or (2) -O-(1 to 2 R L1a (a)-, a straight-chain C1-3 alkylene group which may be substituted with (a)-, and the other symbols have the same meanings as above.], or General formula (I-iv)

[0126] [ka]

[0127] [In the formula, L 1-iv 1 to 3 R L1a represents a linear C2-4 alkylene group which may be substituted by, and the other symbols have the same meanings as above.

[0128] In one embodiment, the compound represented by formula (Ii), (I-ii), (I-iii) or (I-iv) or a salt thereof is (1)R 11 is a C2-4 alkylene group, (2) X is an oxygen atom, (3)R L1a is a hydroxyl group, (4) CycA is (i) a C5-6 monocyclic carbocycle or a 5-10 membered monocyclic or bicyclic heterocycle, (ii) benzene or a 5-6 membered monocyclic aromatic heterocycle, (iii) a C5-6 monocyclic carbocycle, or (iv) benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline, (5) CycB is (i) a C5-6 monocyclic carbocycle or a 5- to 6-membered monocyclic heterocycle, (ii) benzene or a 5- to 6-membered monocyclic aromatic heterocycle, (iii) a C5-6 monocyclic carbocycle, or (iv) cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran, (6) L 2 Ga-NR 201 -S(O)2- or -CR 204 (OH)-CH2-, or (7)R 11 , X, R L1a , CycA, CycB and L 2 The symbol other than the above-mentioned group (for example, a group represented by "preferable", "more preferred" or "further preferred"), (8) Compounds or salts thereof that are combinations of two or more of the definitions described in (1) to (7) above. In the present invention, the compound represented by the general formula (Ii), (I-ii), (I-iii) or (I-iv) or a salt thereof is preferably (1) X is an oxygen atom, and L 2 Ga-NR 201 -S(O)2- or -CR 204 A compound represented by the formula (OH)-CH2- or a salt thereof, (2) X is an oxygen atom, and L 2 Ga-NR 201 -S(O)2- or -CR 204a compound or a salt thereof, wherein (OH)-CH2- and CycA and CycB are C5-6 monocyclic carbocycles; (3)R 11 is a C2-4 alkylene group, X is an oxygen atom, and L 2 Ga-NR 201 -S(O)2- or -CR 204 (OH)-CH2-, and CycA and CycB are C5-6 monocyclic carbocycles, or a salt thereof; or (4) X is an oxygen atom and R L1a is a hydroxyl group, and L 2 Ga-NR 201 -S(O)2- or -CR 204 (OH)-CH2-, and CycA and CycB are C5-6 monocyclic carbocycles, or a salt thereof.

[0129] In the present invention, another embodiment of the general formula (I) is the general formula (I-1)

[0130] [ka]

[0131] [wherein all symbols have the same meanings as defined above]. In the present invention, the general formula (I-1) is represented by the general formula (I-1-A):

[0132] [ka]

[0133] [In the formula, L 1-2 represents a linear C2-3 alkylene group, and the other symbols have the same meanings as above. General formula (I-1-B)

[0134] [ka]

[0135] [In the formula, all symbols have the same meaning as above.] General formula (I-1-C)

[0136] [ka]

[0137] [In the formula, all symbols have the same meaning as above.] Or general formula (I-1-D)

[0138] [ka]

[0139] [In the formula, all symbols have the same meanings as defined above.] is preferred.

[0140] In one embodiment, the compound represented by formula (I-1-A), (I-1-B), (I-1-C) or (I-1-D) or a salt thereof is (1) X is an oxygen atom, (2) CycA 1 benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline, (3) CycB 1 is cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran; (4) X, CycA 1 and CycB 1 The symbol other than the above-mentioned group (for example, a group represented by "preferable", "more preferred" or "further preferred"), (5) A combination of two or more of the definitions in (1) to (4) above. or a salt thereof.

[0141] [Isomers] In the present invention, unless otherwise specified, the symbols

[0142] [ka]

[0143] indicates that the bond is on the other side of the paper (i.e., α-configuration),

[0144] [ka]

[0145] indicates that the molecule is bonded to the front side of the paper (i.e., the β configuration),

[0146] [ka]

[0147] represents a mixture of α and β configurations in any ratio.

[0148] In the present invention, all isomers are included unless otherwise specified. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene, and alkenylidene include straight-chain and branched-chain isomers. Furthermore, isomers (E, Z, cis, trans) in double bonds, rings, and condensed rings, isomers due to the presence of asymmetric carbons, etc. (R, S, α, β configurations, enantiomers, diastereomers), optically active isomers having optical rotation (D, L, d, l), polar isomers (high polarity, low polarity) by chromatographic separation, equilibrium compounds, rotational isomers, mixtures of these in any ratio, and racemic mixtures are all included in the present invention.

[0149] Furthermore, the optically active compound of the present invention need not necessarily be 100% pure, but may contain less than 50% of other optical isomers.

[0150] In the present invention, all references to the compounds of the present invention include the compounds represented by the general formula (I), salts thereof, N-oxides thereof, solvates thereof, or co-crystals thereof, or the N-oxides of the salts of the compounds represented by the general formula (I), solvates thereof, or co-crystals thereof.

[0151] The compound represented by the general formula (I) can be converted into a corresponding salt by a known method. The salt is preferably water-soluble. The salt is preferably a pharma- ceutically acceptable salt. Examples of such salts include salts of alkali metals (lithium, potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), salts of other metals (silver, zinc, etc.), ammonium salts, salts of pharma- ceutically acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-2- ... -phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc.), acid addition salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, napadisilate, glucuronate, gluconate, etc.) and the like).

[0152] The compound represented by formula (I) or its pharma- ceutically acceptable salt may exist in a non-solvated form or in a solvated form with a pharma-ceutically acceptable solvent such as water or ethanol. The solvate is preferably low toxic and water soluble, more preferably a hydrate. The compound represented by formula (I) or its salt may be converted into a solvate by a known method.

[0153] The N-oxide of the compound represented by the general formula (I) refers to a compound in which the nitrogen atom of the compound represented by the general formula (I) is oxidized. The N-oxide of the compound represented by the general formula (I) may further be in the form of the above-mentioned alkaline (earth) metal salt, ammonium salt, organic amine salt, or acid addition salt.

[0154] The compound of formula (I) or a pharma- ceutically acceptable salt thereof may exist in the form of a co-crystal formed with a suitable co-crystal former. The co-crystal is preferably a pharma- ceutically acceptable one formed with a pharma- ceutical acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different types of intermolecular interactions. A co-crystal may also be a complex of a neutral molecule and a salt. A co-crystal may be prepared by known methods, for example, by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include organic acids (such as malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, and isonicotinic acid), organic amines (such as imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, 4-(2-hydroxyethyl)morpholine, N-methyl-D-glucamine, glycine, histidine, and proline), and other organic compounds (such as caffeine and saccharin).

[0155] A prodrug of a compound represented by general formula (I) refers to a compound that is converted into a compound represented by general formula (I) in vivo by a reaction caused by an enzyme, gastric acid, or the like. Examples of prodrugs of a compound represented by general formula (I) include, when the compound represented by general formula (I) has an amino group, compounds in which the amino group has been acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of a compound represented by general formula (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when the compound represented by general formula (I) has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of a compound represented by general formula (I) has been acetylated, paclitaxelated, or the like). lumitoyl, propanoyl, pivaloyl, succinyl, fumarylate, alanylate, dimethylaminomethylcarbonylated compounds, etc.; when the compound represented by the general formula (I) has a carboxy group, the carboxy group is esterified or amidated (for example, the carboxy group of the compound represented by the general formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compounds, etc.). These compounds can be produced by a method known per se. In addition, the prodrug of the compound represented by the general formula (I) may be a solvate. The prodrug of the compound represented by the general formula (I) may be converted to the compound represented by the general formula (I) under physiological conditions as described in "Drug Development", Vol. 7, "Molecular Design", pp. 163-198, published by Hirokawa Publishing Co., Ltd. in 1990. Furthermore, the compound represented by the general formula (I) may be a prodrug containing an isotope (e.g., 2 H, 3 H, 11 C. 13 C. 14C. 13 N, 15 N, 15 O. 17 O. 18 O. 35 S, 18 F, 36 Cl, 123 I, 125 I, etc.) may be used.

[0156] [Method of producing the compound of the present invention] The compound of the present invention can be produced by appropriately modifying and combining known methods, for example, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) or the methods shown in the Examples.

[0157] Among the compounds represented by general formula (I), those represented by general formula (IA)

[0158] [ka]

[0159] (In the formula, L 1M (1) 1 to 4 R L1a (2) a linear C2-6 alkylene group optionally substituted with 1 to 4 R L1a (3) a straight-chain C2-6 alkenylene group optionally substituted with 1 to 4 R L1a or (4) (1 to 2 R L1a A straight-chain C1-3 alkylene group optionally substituted with 1-2 R L1a The compound represented by the formula (I) can be produced by the method shown in the following reaction scheme 1.

[0160] [ka]

[0161] (In the formula, Hal represents a halogen atom, and the other symbols have the same meanings as above.)

[0162] In the reaction scheme 1, reaction 1-1 can be carried out by subjecting a compound represented by general formula (A-1) to a nucleophilic addition reaction using 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. This nucleophilic addition reaction is known, and is carried out, for example, in an organic solvent (hexane, heptane, octane, benzene, toluene, tetrahydrofuran (hereinafter abbreviated as THF), dioxane, dimethoxyethane, diethyl ether, or a mixture of two or more of them, etc.) or under solvent-free conditions at a temperature of 0 to 120°C. In addition, the reaction can be carried out in the presence of a catalyst for the purpose of promoting the reaction. Examples of the catalyst include formic acid, acetic acid, benzoic acid, 4-dimethylaminobenzoic acid, Schwartz's reagent (CAS registration number: 37342-97-5), etc.

[0163] In reaction scheme 1, reaction 1-2 can be carried out by subjecting a compound represented by general formula (A-2) and a compound represented by general formula (A-3) to Suzuki coupling reaction. This Suzuki coupling reaction is known, and can be carried out, for example, in an organic solvent (toluene, benzene, N,N-dimethylformamide (hereinafter abbreviated as DMF), THF, methanol, ethanol, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide, etc.), or water, or a mixed solvent of two or more thereof, in the presence of a palladium catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), dichlorobis(triphenylphosphine)palladium (Cl2Pd(PPh3)2), palladium acetate (Pd(OAc)2), bis(tri-tert-butylphosphine)palladium(0) (Pd(tBu3P)2), etc.), in the presence of a base (sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.), at room temperature to 120°C.

[0164] Furthermore, by subjecting a compound represented by general formula (IA) to a reduction reaction, a compound represented by general formula (IB)

[0165] [ka]

[0166] (wherein all symbols have the same meaning as above) can be produced. This reduction reaction is known and can be carried out by the following methods. For example, (1) reduction reaction using a metal, (2) diimide reduction reaction, etc. can be mentioned. (1) Reduction reaction using a metal is carried out, for example, in an organic solvent (for example, THF, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, DMF, ethyl acetate, acetic acid, water, or a mixed solvent of two or more thereof, etc.) in the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, ruthenium chloride, etc.), in the presence or absence of an acid (hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid (hereinafter abbreviated as TFA), formic acid, etc.), under a hydrogen atmosphere under normal pressure or pressure, at 0 to 200°C. (2) The diimide reduction reaction can be carried out, for example, in an organic solvent (toluene, benzene, DMF, THF, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide, methanol, ethanol, or a mixed solvent of two or more of these, etc.) in the presence or absence of a hydrazine compound (hydrazine, hydrazine monohydrate, tosylhydrazine, etc.) and a base (sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, etc.) at 0 to 120°C.

[0167] Among the compounds represented by general formula (I), those represented by general formula (IC)

[0168] [ka]

[0169] The compound represented by the formula (wherein the symbols have the same meanings as defined above) can be prepared by the method shown in the following reaction scheme 2.

[0170] [ka]

[0171] (In the formula, all symbols have the same meanings as above.)

[0172] In the reaction scheme 2, the reaction 2-1 can be carried out by subjecting the compound represented by the general formula (A-1) and the compound represented by the general formula (A-3) to the Sonogashira reaction. The Sonogashira reaction is known, and can be carried out, for example, in an organic solvent (ethyl acetate, isopropyl acetate, benzene, toluene, xylene, heptane, cyclohexane, THF, dioxane, dimethoxyethane, ethanol, 2-propanol, polyethylene glycol, dimethyl sulfoxide, DMF, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, methylene chloride, chloroform, acetone, acetonitrile), or water, or a mixture of two or more of them, or under a solvent-free condition, in a base (diethylamine, triethylamine, propylamine, diisopropylamine, diisopropylethylamine, dibutylamine, tributylamine, pyrrolidine, piperidine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]octane, pyridine, sodium hydroxide, The reaction is carried out in the presence of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, potassium fluoride, etc., in the presence of a catalyst (a palladium catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), dichlorobis(triphenylphosphine)palladium (Cl2Pd(PPh3)2), palladium acetate (Pd(OAc)2), bis(tri-tert-butylphosphine)palladium(0) (Pd(tBu3P)2), etc.), or a mixture of these with a copper catalyst (copper(I) iodide, etc.), etc.), in the presence or absence of a phase transfer catalyst (e.g., tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium acetate, etc.), at room temperature to 120°C.

[0173] Among the compounds represented by the general formula (A-3) in reaction schemes 1 and 2, the compound represented by the general formula (A-3-1)

[0174] [ka]

[0175] The compound represented by the formula: (wherein all symbols have the same meaning as defined above) can be prepared by the method shown in the following reaction scheme 3.

[0176] [ka]

[0177] (In the formula, all symbols have the same meaning as above.)

[0178] In the reaction scheme 3, reaction 3-1 can be carried out by subjecting a compound represented by general formula (A-3-1a) and a compound represented by general formula (A-3-1b) to a sulfonamidation reaction. This sulfonamidation reaction is known, and can be carried out, for example, in an organic solvent (ethyl acetate, isopropyl acetate, benzene, toluene, xylene, heptane, cyclohexane, THF, dioxane, dimethoxyethane, ethanol, 2-propanol, dimethyl sulfoxide, DMF, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, methylene chloride, chloroform, acetone, acetonitrile, or a mixture of two or more thereof, etc.) or under solvent-free conditions, in the presence or absence of a base (diisopropylethylamine, pyridine, triethylamine, dimethylaniline, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, etc.), in the presence or absence of a catalyst (4-dimethylaminopyridine, etc.), at 0 to 120°C.

[0179] In the reaction scheme 3, reaction 3-2 can be carried out by subjecting a compound represented by general formula (A-3-1c) and a compound represented by general formula (A-3-1d) to an alkylation reaction, or by subjecting a compound represented by general formula (A-3-1c) and a compound represented by general formula (A-3-1e) to a Mitsunobu reaction. This alkylation reaction is known, and can be carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, acetonitrile, water, or a mixed solvent of two or more of them, etc.) in the presence of a base (sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, etc.) at 0 to 100°C. This Mitsunobu reaction is known and can be carried out, for example, by reacting in an organic solvent (dichloromethane, diethyl ether, THF, acetonitrile, benzene, toluene, etc.) in the presence of an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.) at 0 to 80°C.

[0180] Among the compounds represented by the general formula (A-3) in reaction schemes 1 and 2, the compound represented by the general formula (A-3-2)

[0181] [ka]

[0182] (wherein all symbols have the same meanings as defined above) can be prepared by the method shown in the following reaction scheme 4.

[0183] [ka]

[0184] (In the formula, all symbols have the same meaning as above.)

[0185] In reaction scheme 4, reaction 4-1 is carried out by reacting a compound represented by general formula (A-3-2a) in an organic solvent (e.g., THF, dimethoxyethane, toluene, dichloromethane, diethyl ether, dioxane, methanol, etc.) with or without cerium chloride using a reducing agent (e.g., sodium borohydride, zinc borohydride, etc.) at -20 to 50°C. In addition, when only one stereoisomer is to be selectively produced, the reaction is carried out at a temperature of -100 to 50°C using an asymmetric reducing agent (e.g., chlorodiisopinocamphenylborane, etc.) or a combination of an asymmetric auxiliary and a reducing agent ((R)-2-methyl-CBS-oxazaborolidine and boron hydride·THF complex or borane dimethylsulfide complex, (S)-(-)-binaphthol and lithium aluminum hydride, etc.).

[0186] In the case where a protecting group is present in the compound represented by each general formula in Reaction Scheme 1, Reaction Scheme 2, Reaction Scheme 3, or Reaction Scheme 4, a deprotection reaction can be carried out as necessary. The deprotection reaction of the protecting group is known and can be carried out by the following methods. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenolysis, (4) deprotection reaction of a silyl group, (5) deprotection reaction using a metal, (6) deprotection reaction using a metal complex, etc. can be mentioned.

[0187] To explain these methods in detail, (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, THF, dioxane, etc.) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.), or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an aqueous solution thereof, or a mixture thereof, at 0 to 40°C. (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0 to 100°C. (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., an ether (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), an alcohol (e.g., methanol, ethanol, etc.), a benzene (e.g., benzene, toluene, etc.), a ketone (e.g., acetone, methyl ethyl ketone, etc.), a nitrile (e.g., acetonitrile, etc.), an amide (e.g., DMF, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.), under normal or increased pressure in a hydrogen atmosphere or in the presence of ammonium formate, at 0 to 200°C. (4) The deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (e.g., THF, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40° C. Also, for example, it is carried out in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.) at −10 to 100° C. (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution of pH 4.2 to 7.2, or a mixture of such a solution with an organic solvent such as THF) in the presence of zinc powder at 0 to 40° C., if necessary, with ultrasonication. (6) The deprotection reaction using a metal complex is carried out, for example, in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof in the presence of a trapping reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.) in the presence or absence of a phosphine-based reagent (e.g., triphenylphosphine, etc.) using a metal complex (e.g., tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.) at 0-40°C.

[0188] 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, 1999.

[0189] Examples of the protecting group for a hydroxyl group include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, a 2-tetrahydropyranyl (THP) group, a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a t-butyldimethylsilyl (TBDMS) group, a t-butyldiphenylsilyl (TBDPS) group, an acetyl (Ac) group, a pivaloyl group, a benzoyl group, a benzyl (Bn) group, a p-methoxybenzyl group, an allyloxycarbonyl (Alloc) group, and a 2,2,2-trichloroethoxycarbonyl (Troc) group.

[0190] Examples of the protecting group for an amino group include a benzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl (Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, a trifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl (Bn) group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, and a 2-(trimethylsilyl)ethoxymethyl (SEM) group.

[0191] The protecting groups for the hydroxyl and amino groups are not particularly limited as long as they can be easily and selectively removed, in addition to the above-mentioned groups. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 can be used.

[0192] In each reaction in the present specification, the compounds used as starting materials, for example, the compounds represented by the general formulae (A-1), (A-3), (A-3-1a) and (A-3-1b), are either known or can be easily produced by known methods.

[0193] In each reaction in the present specification, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.

[0194] In each reaction herein, a solid-phase supported reagent supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0195] In each reaction in the present specification, the reaction product can be purified by a conventional purification method, for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin or column chromatography, washing, recrystallization, etc. Purification may be carried out for each reaction or after completion of some reactions.

[0196] [toxicity] The toxicity of the compound of the present invention is sufficiently low, and it can be safely used as a pharmaceutical.

[0197] [Application to pharmaceuticals] The compounds of the present invention have neuroprotective and / or restorative properties. In one embodiment, the compound of the present invention has a highly sustained neuroprotective and / or restorative effect. The compounds of the present invention are therefore useful, for example, in the treatment of diseases involving neurological disorders.

[0198] In the present invention, examples of the neuroprotective and / or repairing effect include the neuroprotective and / or repairing effect mediated by glial cells (e.g., microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.). Examples of the neuroprotective and / or repairing effect mediated by glial cells include the myelination promoting effect of Schwann cells.

[0199] In the present invention, neuropathy includes peripheral neuropathy and central neuropathy. Examples of diseases accompanied by peripheral neuropathy include diabetic neuropathy, metabolic peripheral neuropathy associated with uremia, peripheral neuropathy associated with vitamin B deficiency, peripheral neuropathy associated with infectious diseases such as diphtheria, botulinum food poisoning, and herpes virus (shingles), anticonvulsant phenytoin, antibacterial drugs (chloramphenicol, nitrofurantoin, sulfonamide drugs, etc.), chemotherapy drugs (taxanes: paclitaxel, docetaxel, etc., platinum preparations: oxaliplatin, cisplatin, carboplatin, nedaplatin, etc., vinca alkaloids: vinblastine, vincristine, vindesine, etc.), and drug-induced peripheral neuropathy associated with administration of sedatives (barbital, hexobarbital, etc.), chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, and entrapment nerve injury. peripheral neuropathy associated with allergies such as periarteritis nodosa, allergic vasculitis, and systemic lupus erythematosus; toxic peripheral neuropathy associated with heavy metals such as lead, mercury, arsenic, and thallium; organic solvents such as paint thinner; organophosphate insecticides; and toxic substances such as triorthocresyl phosphate (TOCP). toxic peripheral neuropathy associated with cancer compression of the nerves. peripheral neuropathy associated with hereditary diseases (such as hypothyroidism, renal failure, Charcot-Marie-Tooth disease, Refsum disease, porphyria, Fabry disease, and hereditary neuropathy with liability to pressure palsies).

[0200] Examples of diseases accompanied by central nervous system disorders include infectious neurological disorders such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, dystonia, prion disease, multiple system atrophy, spinocerebellar degeneration, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal-bulbar muscular atrophy, spinal muscular atrophy, spastic paraplegia, syringomyelia, multiple sclerosis, neuromyelitis optica, concentric sclerosis, acute disseminated encephalomyelitis, inflammatory widespread sclerosis, subacute sclerotic panencephalitis, and progressive multifocal leukoencephalopathy, toxic / metabolic neurological disorders such as hypoxic encephalopathy and central pontine myelinopathy, and vascular neurological disorders such as Binswanger's disease.

[0201] In the present invention, an embodiment of the prevention and / or treatment of peripheral neuropathy includes the prevention and / or treatment of peripheral neuropathic pain.

[0202] The combination of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are combined in one preparation, or in the form of separate preparations. When the separate preparations are administered, simultaneous administration and administration with a time lag are included. In addition, administration with a time lag may be such that the compound of the present invention is administered first and the other drug is administered later, or the other drug is administered first and the compound of the present invention is administered later. The administration methods of each may be the same or different.

[0203] There are no particular limitations on the diseases for which the above-mentioned concomitant drugs can exert preventive and / or therapeutic effects, so long as they complement and / or enhance the preventive and / or therapeutic effects of the compound of the present invention.

[0204] Other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention against diseases accompanied by neurological disorders include, for example, aldose reductase inhibitors, vitamins, and brain protective drugs.Aldose reductase inhibitors include epalrestat.Vitamins include mecobalamin, etc.Cerebral protective drugs include edaravone.

[0205] Furthermore, concomitant drugs to be combined with the compound of the present invention include not only those that have been discovered so far but also those that will be discovered in the future.

[0206] The compound of the present invention is usually administered systemically or locally, orally or parenterally. Examples of oral preparations include liquid preparations for internal use (e.g., elixirs, syrups, pharma- ceutically acceptable solutions, suspensions, emulsions), solid preparations for internal use (e.g., tablets (including sublingual tablets and oral disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and lozenges). Examples of parenteral preparations include liquid preparations (e.g., injections (intravitreal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops, etc.), eye drops (e.g., aqueous eye drops (aqueous eye drops, aqueous suspension eye drops, viscous eye drops, solubilized eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspension eye drops, etc.)), etc.), topical preparations (e.g., ointments (ophthalmic ointments, etc.)), ear drops, etc. These preparations may be release-controlled preparations such as immediate-release preparations and sustained-release preparations. These preparations can be produced by known methods, for example, methods described in the Japanese Pharmacopoeia.

[0207] Oral liquid preparations for internal use are produced, for example, by dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (e.g., purified water, ethanol or a mixture thereof, etc.) The liquid preparation may further contain a wetting agent, a suspending agent, an emulsifying agent, a sweetener, a flavoring agent, an aromatic agent, a preservative, a buffering agent, etc.

[0208] Oral solid preparations for internal use are prepared by mixing the active ingredient with excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), disintegrants (e.g., calcium cellulose glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, solubilizers (glutamic acid, aspartic acid, etc.), etc. according to conventional methods. If necessary, the solid preparations may be coated with a coating agent (e.g., sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers.

[0209] External preparations as parenteral agents are prepared by known methods or commonly used formulations. For example, ointments are prepared by triturating or melting the active ingredient in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid esters, myristic acid esters, palmitic acid esters, stearic acid esters, oleic acid esters, etc.), waxes (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate esters, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), and the like are suitable. The composition may be used alone or in combination of two or more of the following: organic solvents (e.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (e.g., mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and rash prevention agents. The composition may further contain moisturizers, preservatives, stabilizers, antioxidants, fragrances, etc.

[0210] Injectables as parenteral preparations include solutions, suspensions, emulsions, and solid injectables that are dissolved or suspended in a solvent when used. Injectables are used, for example, by dissolving, suspending, or emulsifying the active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, the injectables may contain stabilizers, dissolving aids (e.g., glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifying agents, soothing agents, buffering agents, preservatives, etc. These are sterilized in the final process or produced by an aseptic operation method. Also, a sterile solid preparation, for example, a lyophilized product, can be produced and dissolved in sterilized or sterile distilled water for injection or other solvent before use.

[0211] To use the compound of the present invention or the combination of the compound of the present invention and other drugs for the above purpose, it is usually administered systemically or locally, orally or parenterally.The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, it is orally administered once to several times a day in the range of 1ng to 1000mg per dose per adult, or it is parenterally administered once to several times a day in the range of 0.1ng to 10mg per dose per adult, or it is continuously administered intravenously for 1 to 24 hours a day.Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases a smaller dosage than the above dosage is sufficient, and in other cases it is necessary to administer it beyond the range. EXAMPLES

[0212] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these.

[0213] The solvents in parentheses shown in the chromatographic separations and TLCs indicate the eluting or developing solvents used, and the ratios are by volume. The conditions used in the LC / MS analysis in the following examples are as follows: Column: YMC Triart C18, 2.0 mm x 30 mm, 1.9 μm; Flow rate: 1.0 mL / min; Temperature: 30°C; Mobile phase A: 0.1% TFA aqueous solution; Mobile phase B: 0.1% TFA acetonitrile solution; Gradient (ratio of mobile phase A:mobile phase B is listed): 0 to 0.10 min (95:5), 0.10 to 1.20 min (95:5 to 5:95), 1.20 to 1.50 min (5:95). The solvent used in the NMR measurements is shown in parentheses. The names of compounds used in this specification are generally determined using ACD / Name (registered trademark) of Advanced Chemistry Development, Inc., a computer program that determines names according to the IUPAC rules, or are determined according to the IUPAC nomenclature method.

[0214] Example 1: Isopropyl 3-(2-hydroxyphenyl)propanoate To a solution of 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL), sulfuric acid (0.26 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. It was washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (73.2 g) having the following physical properties. 1 H-NMR (CDCl3): δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35.

[0215] Example 2: Isopropyl 3-(2-(2-(1,3-dioxan-2-yl)ethoxy)phenyl)propanoate To a solution of the compound (2.00 g) produced in Example 1 and 2-(2-bromoethyl)-1,3-dioxane (2.43 g) in DMF (4 mL), potassium phosphate (2.85 g) was added, and the reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→4:1) to obtain the title compound (2.73 g) having the following physical properties. TLC: Rf 0.57 (hexane:ethyl acetate=2:1).

[0216] Example 3: Isopropyl 3-(2-(3-oxopropoxy)phenyl)propanoate A solution of the compound (500 mg) produced in Example 2 and lutidine (0.40 mL) in dichloromethane (1.5 mL) was cooled to -15°C, and trimethylsilyl trifluoromethanesulfonate (0.42 mL) was added. The reaction mixture was stirred at 0°C for 2 hours. Ice (10 g) was added to the reaction solution, and the mixture was stirred at 0°C for 15 minutes. Water and ethyl acetate were added, and the mixture was stirred at 0°C for 20 hours. The reaction mixture was poured into 1M hydrochloric acid and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (443 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 1.20, 2.50-2.55, 2.93-2.96, 4.33, 4.98, 6.85-6.92, 7.14-7.19, 9.90.

[0217] Example 4: Isopropyl 3-(2-((3-hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)oxy)phenyl)propanoate A solution of trimethylsilylacetylene (5.0 mL) in THF (70 mL) was cooled to -70°C, n-butyllithium (1.6 M hexane solution, 20 mL) was added, and the reaction mixture was stirred at -70°C for 30 minutes. A solution of the compound (7.15 g) produced in Example 3 in THF (10 mL) was added dropwise, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 → 7:3) to obtain the title compound (1.8 g) having the following physical properties. 1 H-NMR(CDCl3):δ 0.17, 1.19, 2.22-2.33, 2.56, 2.87-2.98, 4.09-4.23, 4.70, 3.60-4.93-5.03, 6.86-6.91, 7.14-7.18.

[0218] Example 5: Isopropyl 3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate A solution of the compound (6.89 g) produced in Example 4 in THF (38 mL) was cooled to 0° C., and tetrabutylammonium fluoride (hereinafter abbreviated as TBAF) (1.0 M THF solution, 7.3 mL) was added. The reaction mixture was stirred at 0° C. for 10 minutes. The reaction mixture was poured into 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:1) to obtain the title compound (5.06 g) having the following physical properties. 1 H-NMR(CDCl3): δ 1.19, 2.20-2.26, 2.43, 2.50-2.59, 2.87-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.

[0219] Example 6:Isopropyl (R)-3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate Vinyl acetate (4 mL) was added to a solution of the compound (1.2 g) produced in Example 5 in heptane (24 mL). CHIRAZYME L-5 CA (trade name) (0.4 g) was added, and the reaction mixture was stirred at 45°C for 9 hours. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:1) to obtain the title compound (0.54 g, >99% ee) having the following physical properties. The compound obtained was analyzed by high performance liquid chromatography (column used: Daicel Corporation CHIRALPAK-IB (4.6 mm x 250 mm), mobile phase: hexane:2-propanol=95:5, flow rate: 1 mL / min, wavelength: 254 nm, column temperature: 40°C), and the retention time was 10.6 minutes. 1 H-NMR(CDCl3): δ 1.19, 2.20-2.26, 2.41, 2.50-2.59, 2.90-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.

[0220] Example 7: Isopropyl (R)-3-(2-((3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl)propanoate A solution of the compound (500 mg) produced in Example 6 in DMF (3.4 mL) was cooled to 0°C, and chlorotrimethylsilane (0.24 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 9:1) to obtain the title compound (600 mg) having the following physical properties. 1H-NMR(CDCl3): δ 0.17, 1.21, 2.18, 2.43, 2.54-2.59, 2.90-2.95, 4.06-4.15, 4.67, 4.99, 6.83-6.89, 7.14-7.20.

[0221] Example 8: Isopropyl (R,E)-3-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((trimethylsilyl)oxy)pent-4-en-1-yl)oxy)phenyl)propanoate To a solution of the compound (2.45 g) produced in Example 7 in heptane (6 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.09 g) and 4-dimethylaminobenzoic acid (53.9 mg) were added and stirred at 100°C for 13 hours. The reaction solution was cooled to room temperature and then concentrated. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1 → 3:1) to obtain the title compound (1.45 g) having the following physical properties. HPLC retention time (min): 1.14.

[0222] Example 9: N-(3-bromophenyl)benzenesulfonamide To a solution of 3-bromoaniline (1.02 g) in dichloromethane (20 mL), pyridine (0.95 mL), N,N-dimethylaminopyridine (hereinafter abbreviated as DMAP) (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added at 0° C. and stirred at room temperature for 2 hours. After concentrating the reaction solution, the residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to obtain the title compound (1.96 g) having the following physical properties. HPLC retention time (min): 0.98.

[0223] Example 10: Propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate To a solution of the compound (2.00 g) produced in Example 8 in THF (18 mL), the compound (1.18 g) produced in Example 9, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS registration number: 1310584-14-5) (0.30 g) and 2M tripotassium phosphate aqueous solution (5.7 mL) were added and stirred at 60°C for 2 hours. After cooling the reaction solution to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. TBAF (1.0M THF solution, 6.3 mL) was added to the obtained residue in THF (6 mL) and stirred at room temperature for 1 hour. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to give the title compound (1.41 g) having the following physical properties: HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 1.21, 2.05-2.17, 2.21, 2.57-2.61, 2.91-2.95, 4.11-4.19, 4.62, 5.02, 6.25, 6.55, 6.72, 6.85-6.91, 6.99, 7.09-7.22, 7.41-7.45, 7.53, 7.75-7.78.

[0224] Example 11: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

[0225] [ka]

[0226] To a solution of the compound (680 mg) produced in Example 10 in THF (5 mL) and methanol (1 mL), 1M aqueous lithium hydroxide solution (5 mL) was added and stirred at 30° C. for 18 hours. 1M hydrochloric acid was added to make the mixture acidic, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (600 mg) having the following physical properties. HPLC retention time (min): 0.93; 1 H-NMR(CD3OD):δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45-7.50, 7.56, 7.75-7.78.

[0227] Example 12 (1) to (13) The following example compounds were obtained by subjecting the compound to the same procedure as in Example 10→Example 11, except that the corresponding halide compound was used in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10.

[0228] Example 12(1): 3-[2-[(E,3R)-5-(3-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.95; 1 H-NMR(CD3OD):δ 2.10-2.15, 2.59-2.63, 2.93-2.97, 4.13, 4.21, 4.60, 6.39, 6.67, 6.86, 6.95, 7.16, 7.24, 7.33, 7.52-7.63, 7.81, 7.95-7.97.

[0229] Example 12(2): 3-[2-[(E,3R)-5-[4-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

[0230] [ka]

[0231] HPLC retention time (min): 0.92; MS(ESI,Pos.):464(M+H-H2O) + .

[0232] Example 12(3): 3-[2-[(E,3R)-5-(4-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.95; 1 H-NMR(CD3OD):δ 2.10-2.14, 2.58-2.63, 2.93-2.97, 4.13, 4.20, 4.58, 6.32, 6.64, 6.86, 6.95, 7.15-7.20, 7.44-7.55, 7.60, 7.67-7.71, 7.93-7.97.

[0233] Example 12(4): 3-[2-[(E,3R)-5-[2-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94; MS(ESI,Pos.):464(M+H-H2O) + .

[0234] Example 12(5): 3-[2-[(E,3R)-5-(2-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.89; MS(ESI,Pos.):428(M+H-H2O) + .

[0235] Example 12(6): 3-[2-[(E,3R)-5-[3-(benzylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.85; 1H-NMR(CD3OD):δ 2.05-2.10, 2.57-2.61, 2.92-2.95, 4.10, 4.17, 4.33, 4.52, 6.19, 6.49-6.56, 6.69-6.71, 6.85, 6.93, 7.04, 7.15-7.24, 7.29-7.33, 7.37-7.39.

[0236] Example 12(7): 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylsulfamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94; MS(ESI,Pos.):464(M+H-H2O) + .

[0237] Example 12(8): 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylcarbamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.95; MS(ESI,Pos.):428(M+H-H2O) + .

[0238] Example 12(9): 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96; 1 H-NMR (CD3OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.62, 6.86, 6.94, 7.10-7.31.

[0239] Example 12(10): 3-[2-[(E,3R)-5-[3-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.93; MS(ESI,Pos.):478(M+H-H2O) + .

[0240] Example 12(11): 3-[2-[(E,3R)-5-[2-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97; 1 H-NMR(CDCl3):δ 1.99-2.07, 2.11-2.19, 2.68-2.72, 2.95-3.08, 4.12-4.26, 4.73-4.78, 6.12, 6.59, 6.86-6.92, 7.04-7.11, 7.16-7.23, 7.33-7.38, 7.44-7.48, 7.64-7.67.

[0241] Example 12(12): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2-methylindol-4-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10; MS(ESI,Pos.):502(M+H-H2O) + .

[0242] Example 12(13): 3-[2-[(E,3R)-3-hydroxy-5-[3-(2-hydroxy-1-phenylpropan-2-yl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 2.10-2.15, 2.65-2.68, 2.94-3.14, 4.12-4.22, 4.62, 6.28, 6.64, 6.86-6.91, 7.00-7.02, 7.15-7.28, 7.44.

[0243] Examples 13(1) to (19) The following example compounds were obtained by carrying out the same operations as in Example 9→Example 10→Example 11, using the corresponding amine compounds instead of 3-bromoaniline used in Example 9.

[0244] Example 13(1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

[0245] [ka]

[0246] HPLC retention time (min): 0.94; 1 H-NMR(CD3OD):δ 1.96, 2.07-2.12, 2.56-2.60, 2.90-2.94, 4.10, 4.18, 4.57, 6.12, 6.78, 6.84-6.93, 7.04, 7.15-7.20, 7.36, 7.47-7.51, 7.60, 7.65-7.67.

[0247] Example 13(2): 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.95; 1 H-NMR(CD3OD):δ 2.05-2.11, 2.19, 2.56-2.60, 2.91-2.95, 4.09, 4.19, 4.56, 6.01, 6.76, 6.84-6.94, 6.99, 7.12-7.20, 7.44-7.48, 7.56, 7.73-7.75.

[0248] Example 13(3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96; 1 H-NMR(CD3OD):δ 1.93-1.98, 2.12, 2.45-2.49, 2.79-2.83, 3.98, 4.05, 4.41, 6.09, 6.37, 6.69, 6.74, 6.80-6.83, 7.03-7.08, 7.34-7.38, 7.44, 7.63-7.66.

[0249] Example 13(4): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94; 1 H-NMR(CD3OD):δ 1.89-1.97, 1.91, 2.46-2.50, 2.81-2.84, 3.98, 4.06, 4.40, 5.98, 6.37, 6.75, 6.83, 6.90, 6.97, 7.04-7.09, 7.34-7.38, 7.46, 7.56-7.58.

[0250] Example 13(5): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94; 1 H-NMR(CD3OD):δ 2.03-2.09, 2.55-2.59, 2.89-2.93, 4.09, 4.16, 4.53, 6.36, 6.63, 6.86, 6.92, 7.06, 7.15-7.19, 7.30-7.37, 7.45-7.49, 7.57, 7.75-7.77.

[0251] Example 13(6): 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94; 1H-NMR(CD3OD):δ 1.90-2.01, 2.45-2.49, 2.79-2.83, 3.99, 4.07, 4.43, 6.17, 6.56, 6.75, 6.81-6.88, 7.03-7.09, 7.34-7.38, 7.45, 7.60-7.63.

[0252] Example 13(7): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96; 1 H-NMR(CD3OD):δ 1.92-1.98, 2.44-2.48, 2.78-2.82, 3.98, 4.06, 4.42, 6.17, 6.39, 6.68, 6.70-6.82, 7.03-7.08, 7.37-7.41, 7.47, 7.68-7.71.

[0253] Example 13(8): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.92; 1 H-NMR(CD3OD):δ 1.95-2.00, 2.45-2.49, 2.81-2.84, 4.00, 4.07, 4.44, 6.10, 6.45, 6.75, 6.81-6.86, 7.04-7.10, 7.34-7.39, 7.47, 7.64-7.66.

[0254] Example 13(9): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.95; 1H-NMR(CD3OD):δ 1.94-2.00, 2.43-2.47, 2.78-2.82, 3.99, 4.06, 4.45, 6.08, 6.74, 6.79-6.85, 7.03-7.10, 7.32-7.43, 7.50, 7.58-7.60.

[0255] Example 13(10): 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.99; 1 H-NMR(CD3OD):δ 1.94-2.00, 2.43-2.47, 2.79-2.83, 3.99, 4.07, 4.47, 6.09, 6.73-6.82, 7.04-7.08, 7.27, 7.38-7.42, 7.48, 7.73-7.76.

[0256] Example 13(11): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.99; 1 H-NMR(CD3OD):δ 1.91-2.03, 2.42-2.46, 2.79-2.83, 3.99, 4.07, 4.46, 6.25,6.49, 6.74, 6.81, 7.03-7.07, 7.16, 7.22-7.26, 7.37-7.41, 7.47, 7.67-7.70.

[0257] Example 13(12): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97; 1H-NMR(CD3OD):δ 1.94-2.00, 2.46-2.50, 2.80-2.84, 4.00, 4.08, 4.46, 6.19, 6.49, 6.76, 6.84, 7.05-7.10, 7.24, 7.28, 7.39-7.52, 7.67-7.70.

[0258] Example 13(13): 3-[2-[(E,3R)-5-[6-(benzenesulfonamido)pyridin-2-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.85; 1 H-NMR(CD3OD):δ 1.92-2.00, 2.45-2.49, 2.79-2.83, 3.96-4.10, 4.47, 6.42, 6.64, 6.75, 6.79-6.83, 6.88, 7.03-7.08, 7.36-7.49, 7.85-7.88.

[0259] Example 13(14): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-6-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 2.11-2.16, 2.59-2.63, 2.82-2.86, 2.94-2.98, 3.94-3.98, 4.14, 4.22, 4.60, 6.34, 6.66, 6.87, 6.96, 7.05-7.09, 7.16-7.21, 7.48-7.52, 7.63, 7.66, 7.78-7.81.

[0260] Example 13(15): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-4-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1H-NMR(CD3OD):δ 2.04-2.09, 2.51-2.55, 2.70-2.89, 3.89-3.96, 4.08, 4.14, 4.53, 6.23, 6.50, 6.83, 6.90, 7.08-7.19, 7.48-7.53, 7.63, 7.78-7.81.

[0261] Example 13(16): 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-1,3-dihydroisoindol-5-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 2.06-2.10, 2.55-2.59, 2.89-2.93, 4.10, 4.17, 4.54, 4.60, 6.31, 6.60, 6.85, 6.92, 7.13-7.18, 7.28-7.30, 7.58-7.68, 7.90-7.93.

[0262] Example 13(17): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-7-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 1.59-1.66, 2.10-2.15, 2.40-2.43, 2.59-2.63, 2.93-2.97, 3.82-3.85, 4.14, 4.21, 4.59, 6.31, 6.62, 6.86, 6.94-7.01, 7.16-7.21, 7.45-7.49, 7.59-7.63, 7.79.

[0263] Example 13(18): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-5-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 1.50-1.57, 2.01-2.15, 2.19-2.37, 2.53-2.57, 2.88-2.92, 3.75-3.78, 4.07, 4.16, 4.56, 6.12, 6.67, 6.84, 6.90, 7.13-7.21, 7.32, 7.45-7.49, 7.56-7.65.

[0264] Example 13(19): 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinolin-7-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 2.07-2.12, 2.57-2.61, 2.87-2.95, 3.36-3.39, 4.11, 4.18, 4.25, 4.55, 6.29, 6.57, 6.85, 6.93, 7.05, 7.14-7.19, 7.23, 7.59-7.70, 7.87-7.89.

[0265] Example 14: N-(3-bromophenyl)-N-(oxetan-2-ylmethyl)benzenesulfonamide To a solution of the compound (313 mg) produced in Example 9 in THF (2 mL), oxetan-2-ylmethanol (132 mg), triphenylphosphine (394 mg), and diethyl azodicarboxylate (40% solution in toluene, 0.68 mL) were added and stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 → 1:1) to obtain the title compound (381 mg) having the following physical properties. TLC: Rf 0.34 (hexane:ethyl acetate=2:1)

[0266] Example 15: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 10→Example 11, except that the compound prepared in Example 14 was used in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. HPLC retention time (min): 0.95; 1 H-NMR(CD3OD):δ 2.06-2.10, 2.48-2.69, 2.91-2.95, 3.80, 4.00, 4.10, 4.18, 4.47-4.64, 4.83, 6.21, 6.55, 6.87, 6.94-6.96, 7.03, 7.17-7.21, 7.27, 7.38, 7.50-7.54, 7.60-7.65.

[0267] Example 16 (1) to (8) The following example compounds were obtained by carrying out the same operations as in Example 14→Example 10→Example 11, using the corresponding alcohol compound instead of oxetan-2-ylmethanol used in Example 14, and the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10.

[0268] Example 16(1): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94; 1 H-NMR(CD3OD):δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.04, 3.95, 4.10, 4.18, 4.36-4.40, 4.55, 4.63-4.67, 6.22, 6.55, 6.85-6.97, 7.16-7.21, 7.29, 7.40, 7.52-7.56, 7.62-7.67.

[0269] Example 16(2):3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 1.72, 1.84-1.99, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.57, 3.66-3.80, 3.89, 4.10, 4.18, 4.55, 6.22, 6.56, 6.87, 6.94-6.97, 7.05, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.64.

[0270] Example 16(3): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97; 1 H-NMR(CD3OD):δ 1.74, 1.95, 2.06-2.11, 2.25, 2.57-2.61, 2.91-2.95, 3.57-3.61, 3.67-3.73, 3.87, 4.10, 4.19, 4.55, 6.23, 6.56, 6.87, 6.94-6.96, 7.02, 7.16-7.21, 7.30, 7.41, 7.50-7.54, 7.57-7.65.

[0271] Example 16(4): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10; 1H-NMR(CD3OD):δ 1.26, 1.39-1.55, 1.68, 1.82, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.23-3.30, 3.51, 3.70, 3.87, 4.10, 4.18, 4.55, 6.20, 6.56, 6.87, 6.93-6.96, 7.02, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.63.

[0272] Example 16(5): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(propan-2-yl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.31 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 1.04, 1.98-2.21, 2.67, 2.89-3.01, 4.10-4.24, 4.55-4.66, 6.22, 6.59, 6.85-6.92, 7.07, 7.16-7.28, 7.38-7.57, 7.76.

[0273] Example 16(6): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.34 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 0.91, 1.57, 2.08-2.15, 2.67, 2.97, 3.30, 4.10-4.24, 4.62, 6.20, 6.57, 6.83-6.92, 7.08, 7.16-7.25, 7.31, 7.40-7.47, 7.51-7.60.

[0274] Example 16(7): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(cyclopropylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.79 (ethyl acetate); 1 H-NMR(CDCl3):δ 0.09-0.13, 0.38-0.43, 0.80-0.90, 2.09-2.18, 2.67, 2.97, 3.42, 4.11-4.23, 4.63, 6.22, 6.58, 6.86-6.93, 7.14-7.26, 7.33, 7.44, 7.55, 7.63.

[0275] Example 16(8): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-phenylethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.74 (ethyl acetate); 1 H-NMR(CDCl3):δ 2.07-2.21, 2.64-2.71, 2.74-2.81, 2.94-3.01, 3.72-3.80, 4.11-4.24, 4.63, 6.22, 6.59, 6.81-6.93, 7.09-7.26, 7.31-7.45, 7.51-7.60.

[0276] Example 17: N-(3-bromophenyl)-N-(2-oxopropyl)benzenesulfonamide To a solution of the compound (1.00 g) produced in Example 9 in DMF (6 mL), sodium hydride (60% in mineral oil, 141 mg) was added under ice cooling, and the mixture was stirred at room temperature. After 30 minutes, chloroacetone (0.52 mL) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20 → 50:50) to obtain the title compound (1.10 g) having the following physical properties. TLC: Rf 0.42 (hexane:ethyl acetate=2:1)

[0277] Example 18:N-(3-bromophenyl)-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide Methylmagnesium bromide (0.95M THF solution, 1.0mL) was added to a solution of the compound (313mg) produced in Example 17 in THF (3mL) under ice cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50) to obtain the title compound (50mg) having the following physical properties. TLC: Rf 0.58 (hexane:ethyl acetate=1:1).

[0278] Example 19: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl-(2-hydroxy-2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 10→Example 11, except that the compound prepared in Example 18 was used in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. HPLC retention time (min): 0.93; 1 H-NMR(CD3OD):δ 1.18, 2.06-2.10, 2.58-2.62, 2.92-2.96, 3.66, 4.10, 4.18, 4.54, 6.20, 6.55, 6.87, 6.95, 6.99, 7.05, 7.17-7.21, 7.25, 7.35, 7.46-7.54, 7.60.

[0279] Example 20(1) to (4) The following example compounds were obtained by carrying out the same operations as in Example 17→Example 10→Example 11, using the corresponding halide compound instead of chloroacetone used in Example 17 and the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10.

[0280] Example 20(1): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(methyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.99; 1 H-NMR(CDCl3):δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.20, 4.10, 4.19, 4.55, 6.24, 6.57, 6.87, 6.93-7.00, 7.08, 7.17-7.20, 7.27, 7.36, 7.50-7.56, 7.63.

[0281] Example 20(2): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(ethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.01; 1 H-NMR(CDCl3):δ 1.07, 2.06-2.11, 2.57-2.61, 2.92-2.96, 3.66, 4.11, 4.19, 4.55, 6.22, 6.57, 6.87, 6.92-6.96, 7.01, 7.16-7.21, 7.29, 7.39, 7.50-7.54, 7.59-7.65.

[0282] Example 20(3): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(benzyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.07; 1H-NMR(CDCl3):δ 2.04-2.09, 2.57-2.61, 2.91-2.95, 4.08, 4.16, 4.52, 4.80, 6.14, 6.48, 6.85-6.89, 6.93-6.96, 7.14-7.28, 7.54-7.58, 7.63-7.69.

[0283] Example 20(4): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2,2,2-trifluoroethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.49 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 2.08-2.17, 2.62-2.70, 2.94-3.00, 4.11-4.26, 4.62, 6.21, 6.57, 6.83-6.93, 7.10, 7.17-7.25, 7.36, 7.47, 7.57-7.63.

[0284] Example 21: (R)-1-(3-bromophenyl)-2-phenylethan-1-ol To a solution of 1-(3-bromophenyl)-2-phenylethanone (CAS reg. no.: 40396-53-0) (2.00 g) in THF (70 mL), (R)-methyloxazaborolidine (1.0 M toluene solution, 3.6 mL) and borane dimethylsulfide (2.0 M THF solution, 3.6 mL) were added at -20°C and stirred at the same temperature for 1 hour. Methanol (1 mL) was added to the reaction solution at -20°C and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 → 2:1) to obtain the title compound (1.91 g, 96% ee) with the following physical properties. The compound obtained was analyzed by SFC (column used: Daicel CHIRALPAK-IA (10 mm x 250 mm), mobile phase: CO2:acetonitrile:methanol = 90:9:1, flow rate: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35°C), and the retention time was 5.6 minutes. HPLC retention time (min): 1.08.

[0285] Example 22: Isopropyl 3-(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate The title compound having the following physical properties was obtained by using the compound prepared in Example 21 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 and carrying out the same procedure as in Example 10. HPLC retention time (min): 1.21.

[0286] Example 23: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 22 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 0.95; 1 H-NMR (CD3OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.28, 6.62, 6.86, 6.94, 7.10-7.31.

[0287] Example 24: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 21→Example 10→Example 11, using (S)-methyloxazaborolidine instead of (R)-methyloxazaborolidine used in Example 21, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. HPLC retention time (min): 0.97; 1 H-NMR (CD3OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.61, 6.86, 6.94, 7.10-7.31.

[0288] Example 25: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2R)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 21→Example 10→Example 11, using 2-(3-bromophenyl)-1-phenylethanone (CAS registration number: 27798-44-3) instead of 1-(3-bromophenyl)-2-phenylethanone used in Example 21, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. HPLC retention time (min): 0.99; 1 H-NMR(CDCl3):δ 2.10-2.15, 2.64-2.68, 2.94-3.05, 4.10-4.21, 4.59-4.64, 4.92, 6.27, 6.61, 6.86-6.91, 7.05-7.24, 7.27-7.37.

[0289] Example 26: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2S)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operation as in Example 25, using (S)-methyloxazaborolidine instead of (R)-methyloxazaborolidine used in Example 25, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. HPLC retention time (min): 0.98; 1 H-NMR(CDCl3):δ 2.10-2.15, 2.63-2.67, 2.94-3.05, 4.10-4.22, 4.59-4.64, 4.91, 6.27, 6.61, 6.86-6.91, 7.06-7.08, 7.14-7.24, 7.28-7.38.

[0290] Example 27: 1-(3-bromophenyl)-3-phenylpropan-1-ol A solution of 3-bromobenzaldehyde (500 mg) in THF (13.5 mL) was cooled to 0° C., phenylmagnesium chloride (1.0 M in THF, 3.5 mL) was added, and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with methyl tert-butyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→2:1) to give the title compound (610 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 1.85, 1.98-2.15, 2.65-2.80, 4.65-4.69, 7.18-7.31, 7.39-7.42, 7.51.

[0291] Example 28: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-3-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 10→Example 11, except that the compound prepared in Example 27 was used in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. HPLC retention time (min): 1.00; 1 H-NMR (CD3OD): δ 1.82-2.03, 2.36-2.40, 2.47-2.63, 2.81-2.85, 3.96-4.09, 4.46-4.51, 6.22, 6.54, 6.69-6.79, 6.98-7.29.

[0292] Example 29: 1-(3-bromophenyl)-2-methyl-2-phenylpropan-1-ol To a solution of 1-(3-bromophenyl)-2-phenyl-ethanone (CAS reg. no.: 40396-53-0) (220 mg) in toluene (0.4 mL), potassium hydroxide (179 mg), 18-crown-6-ether (4 mg) and methyl iodide (0.29 mL) were added, and the reaction mixture was stirred at 70°C for 4 hours. Water was added to the reaction mixture, and it was extracted with 2-methoxy-2-methylpropane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To a solution of the residue obtained in methanol (1.5 mL), sodium borohydride (61 mg) was added, and the reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (129 mg) having the following physical properties. HPLC retention time (min): 1.15 (conditions).

[0293] Example 30: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-methyl-2-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10, the compound prepared in Example 29 was used and the same procedure as in Example 10→Example 11 was carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 2.08-2.13, 2.64-2.68, 2.94-2.97, 4.08-4.21, 4.59, 4.75, 6.15, 6.56, 6.86-6.91, 6.97-7.00, 7.09, 7.15-7.25, 7.30-7.38.

[0294] Example 31: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanamide Triethylamine (0.021 mL) and isobutyl chloroformate (0.016 mL) were added to a solution of the compound (50 mg) produced in Example 11 in THF (1 mL) under ice cooling, and the reaction mixture was stirred at 0° C. for 10 minutes. Ammonia (0.5 M 1,4-dioxane solution, 0.4 mL) was added at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to obtain the title compound (38 mg) having the following physical properties. HPLC retention time (min): 0.88; 1 H-NMR(CDCl3):δ 2.09-2.21, 2.54-2.63, 3.01, 4.13-4.23, 4.59, 5.70, 6.36, 6.54, 6.87-6.94, 7.00-7.22, 7.40-7.53, 7.79-7.82, 7.93.

[0295] Example 32(1) to (3) The following example compounds were obtained by carrying out the same procedure as in Example 31, except that the corresponding amine compounds were used in place of the ammonia used in Example 31.

[0296] Example 32(1): N-[3-[(E,3R)-3-hydroxy-5-[2-(3-morpholin-4-yl-3-oxopropyl)phenoxy]pent-1-enyl]phenyl]benzenesulfonamide HPLC retention time (min): 0.94; 1 H-NMR(CDCl3):δ 2.09-2.19, 2.60-2.65, 2.92-2.99, 3.41, 3.50-3.70, 4.09-4.23, 4.57, 6.30, 6.52, 6.85-6.91, 7.02-7.20, 7.40-7.56, 7.78-7.81.

[0297] Example 32(2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N,N-dimethylpropanamide HPLC retention time (min): 0.95; 1 H-NMR(CDCl3):δ 2.09-2.19, 2.60-2.65, 2.86-3.03, 4.09-4.22, 4.55, 6.33, 6.51, 6.84-6.91, 6.98-7.00, 7.12-7.20, 7.23-7.26, 7.40-7.52, 7.78-7.83, 7.98.

[0298] Example 32(3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N-methylpropanamide HPLC retention time (min): 0.90; 1 H-NMR(CDCl3):δ 2.07-2.19, 2.41-2.53, 2.82, 2.93-2.97, 4.10-4.22, 4.60, 5.58, 6.31, 6.54, 6.86-6.90, 7.02-7.20, 7.40-7.54, 7.78.

[0299] Example 33: 3-[2-[(3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid

[0300] [ka]

[0301] To a solution of the compound (1.1 g) produced in Example 11 in methanol (10 mL), 5% palladium-carbon (200 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→ethyl acetate:methanol=95:5) to give the title compound (1.05 g) having the following physical properties. TLC: Rf 0.30 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.

[0302] Example 34: 3-[2-[(3S)-5-[3-(benzylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid The following example compounds were obtained by carrying out the same operations as in Example 33 using the compound prepared in Example 12(6) instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33. HPLC retention time (min): 0.81; 1H-NMR(CD3OD):δ 1.74-1.90, 2.00, 2.51-2.55, 2.59, 2.70, 2.85-2.89, 3.85, 4.07-4.16, 4.31, 6.47-6.56, 6.85, 6.92, 7.00, 7.13-7.23, 7.28-7.32, 7.36-7.38.

[0303] Example 35: Isopropyl 3-(2-(((S)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pentyl)oxy)phenyl)propanoate To a solution of the compound (782 mg) produced in Example 22 in THF (10 mL), p-toluenesulfonylhydrazide (2.66 g) and sodium acetate (1.17 g) were added at room temperature, and the mixture was stirred at 80° C. for 19 hours. After cooling the reaction solution to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain the title compound (515 mg) having the following physical properties. HPLC retention time (min): 1.22.

[0304] Example 36: 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid

[0305] [ka]

[0306] The title compound having the following physical properties was obtained by using the compound prepared in Example 35 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 0.99; 1 H-NMR(CD3OD):δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.82, 6.85, 6.94, 7.08-7.23.

[0307] Example 37: 3-[2-[(3S)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid

[0308] [ka]

[0309] The title compound having the following physical properties was obtained by carrying out the same operations as in Example 21 → Example 10 → Example 35 → Example 11, using (S)-methyloxazaborolidine instead of (R)-methyloxazaborolidine used in Example 21, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. HPLC retention time (min): 0.99; 1 H-NMR(CD3OD):δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.81, 6.85, 6.94, 7.08-7.23.

[0310] Example 38: Isopropyl 3-(2-((3R)-3-hydroxy-3-(2-(3-(phenylsulfonamido)phenyl)cyclopropyl)propoxy)phenyl)propanoate A solution of the compound (50 mg) produced in Example 10 in dichloromethane (2 mL) was cooled to 0°C, diethylzinc (1M hexane solution, 0.5 mL) was added, followed by diiodomethane (128 mg), and the reaction mixture was stirred at 0°C for 1.5 hours. A saturated aqueous solution of ammonium chloride was added at 0°C, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 2:1) to obtain the title compound (15 mg) having the following physical properties. HPLC retention time (min): 1.10.

[0311] Example 39: 3-[2-[(3R)-3-[2-[3-(benzenesulfonamido)phenyl]cyclopropyl]-3-hydroxypropoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 38 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 0.92; 1 H-NMR(CD3OD):δ 0.85-0.92, 1.03-1.08, 1.72-1.75, 2.03-2.09, 2.57, 2.91, 4.06-4.15, 6.68-6.69, 6.73-6.75, 6.84-6.89, 7.06, 7.14-7.20, 7.44-7.57, 7.72-7.74.

[0312] Example 40: 5-((3-nitrobenzyl)sulfonyl)-1-phenyl-1H-tetrazole A solution of 5-[(3-nitrobenzyl)thio]-1-phenyl-1H-tetrazole [J.Org.Chem.(2001),80,pp.11611-11617] (8.50g) in acetonitrile (150mL) and ethanol (150mL) was cooled to 0℃, and a solution of ammonium molybdate tetrahydrate (3.35g) in hydrogen peroxide solution (35%, 26mL) was added dropwise over 10 minutes. The reaction mixture was stirred at 0℃ for 2 hours and at room temperature for 2.5 hours. The reaction mixture was cooled again to 0℃, and an aqueous solution of sodium thiosulfate (1M, 150mL) was added slowly over 20 minutes. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained oil was suspended in a mixed solvent of hexane and ethyl acetate, and a blue solid was collected by filtration. The solid was dissolved in dichloromethane, and the resulting solid was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (7.71 g) having the following physical properties. 1 H-NMR (CDCl3): δ 5.12, 7.46-7.64, 7.82, 8.27, 8.35.

[0313] Example 41: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-ol DMAP (0.73 g) and imidazole (6.08 g) were added to a solution of (R)-4-[(4-methoxybenzyl)oxy]butane-1,2-diol (CAS registration number: 213978-61-1) (13.5 g) in DMF (300 mL), and the reaction mixture was stirred at 0°C for 5 minutes. Chloro-tert-butyl-dimethylsilane (8.93 g) was added and stirred at room temperature overnight. After diluting the reaction mixture with ethyl acetate, the organic layer was washed with a saturated aqueous ammonium chloride solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (18.1 g) having the following physical properties. 1 H-NMR (CDCl3): δ 0.02, 0.83, 1.65-1.71, 2.73, 3.62-3.41, 3.74, 3.74-3.76, 4.39, 6.82, 7.18-7.21.

[0314] Example 42: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-yl benzoate A solution of the compound (5.60 g) produced in Example 41 and pyridine (27 mL) in dichloromethane (55 mL) was cooled to 0°C, and N,N-diisopropylethylamine (27 mL) and DMAP (0.2 g) were added. Benzyl chloride (2.5 mL) was added to the reaction solution, and the mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The resulting residue was poured into ethyl acetate, and the organic layer was washed with 1M hydrochloric acid and saturated sodium bicarbonate water, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 7:3) to obtain the title compound (6.31 g) having the following physical properties. 1 H-NMR(CDCl3):δ 0.00, 0.01, 0.85, 2.02-2.08, 3.53-3.57, 3.76, 3.79, 4.40, 5.27-5.30, 6.81, 7.21, 7.42, 7.53-7.56, 8.01.

[0315] Example 43: (R)-1-Hydroxy-4-((4-methoxybenzyl)oxy)butan-2-yl benzoate A solution of the compound (6.31 g) produced in Example 42 in THF (170 mL) was cooled to 0°C, and acetic acid (3.6 mL) and tetrabutylammonium fluoride (1.0 M THF solution, 21.2 mL) were added and stirred at room temperature overnight. The resulting residue was poured into ethyl acetate, and the organic layer was washed with saturated aqueous ammonia and saturated aqueous sodium bicarbonate, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 1:1) to obtain the title compound (4.10 g) having the following physical properties. 1H-NMR(CDCl3):δ 2.06-2.09, 2.57, 3.54-3.65, 3.78, 3.80-3.86, 4.41-4.46, 5.27-5.30, 6.84, 7.23, 7.43, 7.56, 8.02.

[0316] Example 44: (R)-4-((4-Methoxybenzyl)oxy)-1-oxobutan-2-yl benzoate Pyridinium dichromate (10.6 g) and Molecular Sieves (trade name) (21.7 g) were suspended in dichloromethane (30 mL), and a dichloromethane solution (100 mL) of the compound (3.1 g) produced in Example 43 was added dropwise to the solution. After stirring at room temperature for 2.5 hours, the mixture was diluted with diethyl ether and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound having the following physical properties. 1 H-NMR (CDCl3): δ 2.27-2.40, 3.57-3.70, 3.76, 4.43, 5.40, 6.82, 7.15-7.24, 7.45, 7.60, 8.03, 9.64.

[0317] Example 45: (R,E)-5-((4-methoxybenzyl)oxy)-1-(3-nitrophenyl)pent-1-en-3-yl benzoate A solution of the compound (3.56 g) produced in Example 40 in THF (70 mL) was cooled to -70 ° C., and potassium hexamethyldisilazide (0.5 M toluene solution, 22.5 mL) was added. The reaction solution was stirred at -70 ° C. for 30 minutes, and a solution of the compound (3.09 g) produced in Example 44 in THF (20 mL) was added dropwise over 5 minutes, and the reaction solution was stirred at room temperature overnight. After diluting the reaction solution by adding ethyl acetate, the organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 10:0 → 1:1) to obtain the title compound (2.23 g) having the following physical properties. 1H-NMR (CDCl3): δ 2.11-2.24, 3.60, 3.75, 6.81, 7.22, 7.43-7.47, 7.56-7.63, 8.04-8.09, 8.21.

[0318] Example 46: (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate or (S,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.26 g) was added to a solution of the compound (2.23 g) produced in Example 45 in dichloromethane (100 mL) and phosphate buffer (pH 7, 100 mL) at room temperature, and the mixture was vigorously stirred at room temperature for 3.5 hours. The reaction mixture was poured into ethyl acetate, and the organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 1:4) to obtain a mixture of the title compounds (1.25 g). The mixture obtained was subjected to optical resolution using SFC (column used: Daicel Corporation CHIRALPAK-IA (20 mm x 250 mm), mobile phase: CO2:methanol = 90:10, flow rate: 100 mL / min, pressure: 120 bar, wavelength: 254 nm, column temperature: 35 °C). The optically active substances obtained under the optical resolution conditions were analyzed by SFC (column used: Daicel Corporation CHIRALPAK-IA (10 mm x 250 mm), mobile phase: CO2:methanol = 75:22.5:2.5, flow rate: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35°C), and the retention times of (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate and (S,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate were 5.4 minutes and 8.5 minutes, respectively. 1H-NMR(CDCl3): δ 2.04, 2.10-2.14, 3.77-3.82, 5.92-5.95, 6.47, 6.79, 7.46-7.51, 7.60, 7.68, 8.08-8.12, 8.26.

[0319] Example 47: Methyl 2-(2-hydroxyphenyl)-2-methylpropanoate To a solution of methyl 2-(2-hydroxyphenyl)acetate (CAS registration number: 22446-37-3) (1.5 g) in THF (120 mL), lithium diisopropylamide (2.0 M THF solution, 18 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction solution, methyl iodide (5.2 g) was added at -78°C, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, water (40 mL) and acetic acid (1 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue (1.8 g) was dissolved in THF (150 mL), and lithium diisopropylamide (2.0 M THF solution, 10 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction solution, methyl iodide (2.85 g) was added at -78°C, and the mixture was stirred at room temperature for 30 minutes. Water (40 mL) and acetic acid (1 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated saline, then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=7:1) to give the title compound (538 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 1.42, 3.51, 6.70-6.83, 7.05, 7.19, 9.49.

[0320] Example 48: Methyl 1-(2-hydroxybenzyl)cyclopropane-1-carboxylate Sodium bis(trimethylsilyl)amide (1.0M THF solution, 75mL) was added to a solution of cyclopropylcarbonitrile (CAS registration number: 5500-21-0) (3.35g) in THF (50mL) at room temperature, and the mixture was stirred for 20 minutes. 1-(chloromethyl)-2-methoxybenzene (CAS registration number: 7035-02-1) (7.83g) was added to the reaction solution at room temperature, and the mixture was stirred for 3 hours under heating and reflux. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain a crude product of a nitrile compound (6.00g). Concentrated sulfuric acid (20mL) was added to a solution of the crude product of the obtained nitrile compound (4.50g) in methanol (50mL) at room temperature, and the mixture was stirred for 5 hours under heating and reflux. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The residue obtained was added with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product (3.20 g) of the ester compound. Boron tribromide (1.0 M dichloromethane solution, 18.2 mL) was added dropwise to a dichloromethane (30 mL) solution of the crude product (2.00 g) of the ester compound obtained at -10°C and stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, the residue obtained was purified by high performance liquid chromatography (mobile phase A (0.1% trifluoroacetic acid (hereinafter abbreviated as TFA) aqueous solution):mobile phase B (0.1% TFA / acetonitrile) = 95:5 → 5:95) to obtain the title compound (550 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 1.11, 1.39, 2.90, 3.67, 6.87, 6.99, 7.18, 8.45.

[0321] Example 49: Methyl 4-(2-hydroxyphenyl)-2,2-dimethylbutanoate To a solution of methyl 4-(2-hydroxyphenyl)butanoate (CAS registration number: 93108-07-7) (3.00 g) in THF (150 mL), lithium diisopropylamide solution (2.0 M THF solution, 22.5 mL) was added at -78 ° C. and stirred at the same temperature for 30 minutes. Methyl iodide (6.3 g) was added to the reaction solution at -78 ° C. and stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by high performance liquid chromatography (mobile phase A (0.1% TFA aqueous solution): mobile phase B (0.1% TFA / acetonitrile) = 95: 5 → 5: 95) to obtain the title compound (538 mg) with the following physical properties. 1 H-NMR (DMSO-d6): δ 1.17, 1.67-1.73, 2.38-2.43, 3.59, 6.66-6.76, 6.95-7.00, 9.19.

[0322] Example 50: Methyl 1-(2-methoxyphenethyl)cyclopropane-1-carboxylate Zinc (18.2 g) was added to a solution of bis(cyclopentadienyl)titanium(IV) dichloride (CAS registration number: 1271-19-8) (34.6 g) in THF (200 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A solution of methyl 2-(1-acetoxymethyl)-2-propenoate (CAS registration number: 30982-08-2) (11.0 g) and 1-(chloromethyl)-2-methoxybenzene (CAS registration number: 7035-02-1) (10.9 g) in THF (200 mL) was added to the reaction solution at room temperature, and the mixture was stirred overnight at the same temperature. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 → 2:1) to obtain a crude product (13.0 g) of the ester compound. Palladium (II) acetate and diazomethane (0.5M diethyl ether solution, 32.6mL) were added to a diethyl ether (100mL) solution of the crude product of the obtained ester compound (3.00g) under ice cooling, and the mixture was stirred at room temperature for 4 hours. Acetic acid (4mL) and water were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (3.00g) having the following physical properties. 1 H-NMR (DMSO-d6): δ 0.70, 1.21, 1.76-1.88, 2.76-2.87, 3.70, 3.83, 6.80-6.96, 7.11-7.32.

[0323] Example 51: Methyl 1-(2-hydroxyphenethyl)cyclopropane-1-carboxylate Boron tribromide (1.0M dichloromethane solution, 38.4mL) was added dropwise to a solution of the compound (3.00g) produced in Example 50 in dichloromethane (100mL) at -78°C, and the mixture was stirred at the same temperature for 5 hours. Methanol (30mL) and water were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (mobile phase A (0.5% ammonium bicarbonate aqueous solution):mobile phase B (acetonitrile) = 80:20 → 25:75) to obtain the title compound (515mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 0.73, 1.06, 1.67-1.79, 2.58-2.70, 3.58, 6.63-6.80, 6.95-7.01, 9.17.

[0324] Example 52: Ethyl (E)-3-(2-(benzyloxy)-5-fluorophenyl)acrylate Sodium hydride (60% in mineral oil, 1.80 g) was suspended in DMF (30 mL) and the solution was cooled to 0°C. Triethyl phosphonoacetate (10.0 g) was added and stirred at 0°C for 30 minutes, after which a solution of 2-benzyloxy-5-fluoro-benzaldehyde (CAS registration number: 312314-37-7) (8.70 g) in DMF (10 mL) was added dropwise and stirred at 0°C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (13.2 g) having the following physical properties. 1 H-NMR (CDCl3): δ 1.33, 4.24, 5.13, 6.47, 6.85-7.00, 7.21-7.41, 7.99-8.05.

[0325] Example 53: Ethyl 3-(5-fluoro-2-hydroxyphenyl)propanoate Palladium carbon (1.95 g) was added to a solution of the compound (11.0 g) produced in Example 52 in ethanol (18 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to obtain the title compound (5.8 g) having the following physical properties. 1 H-NMR (CDCl3): δ 1.24, 2.71, 2.86, 4.15, 6.77-6.83, 7.23.

[0326] Example 54: (R,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-nitrophenyl)pent-1-en-3-yl benzoate (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate (110 mg) prepared in Example 46, methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate (CAS registration number: 6236-69-7) (90 mg) and triphenylphosphine (130 mg) in THF (1 mL) were added with diisopropyl azodicarboxylate (hereinafter abbreviated as DIAD) (0.1 mL) and stirred overnight at room temperature. The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10:0 → 1:2) to obtain the title compound (200 mg) having the following physical properties. 1 H-NMR(CDCl3):δ 2.43-2.55, 3.78, 4.24, 5.94-5.98, 6.46-6.53, 6.82, 6.90, 6.96, 7.29-7.33, 7.44-7.51, 7.57-7.60, 7.68, 8.00, 8.07-8.10, 8.23-8.24.

[0327] Example 55:(R,E)-1-(3-aminophenyl)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)pent-1-en-3-yl benzoate Stannic chloride (310 mg) was added to an ethanol solution (7 mL) of the compound (160 mg) produced in Example 54, and the mixture was stirred at 70° C. for 3.5 hours. After the reaction solution was returned to room temperature, it was poured into ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→1:2) to obtain the title compound (120 mg) having the following physical properties. 1 H-NMR(CDCl3):δ 2.39-2.52, 3.66, 3.79, 4.20, 5.90, 6.28, 6.53, 6.57-6.59, 6.68, 6.73, 6.79, 6.89, 6.94, 7.09, 7.28-7.32, 7.42-7.47, 7.49-7.50, 7.54-7.58, 8.01, 8.05-8.07.

[0328] Example 56: (R,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-(phenylsulfonamido)phenyl)pent-1-en-3-yl benzoate A dichloromethane solution (1 mL) of the compound (60 mg) produced in Example 55 and pyridine (0.016 mL) was cooled to 0°C, phenylsulfonyl chloride (0.018 mL) was added, and the mixture was stirred overnight while returning to room temperature. 1M hydrochloric acid and saturated saline were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 1:1) to obtain the title compound (62 mg) having the following physical properties. 1H-NMR(CDCl3):δ 2.41-2.45, 3.87, 4.18-4.22, 5.84-5.88, 6.30-6.34, 6.51, 6.64, 6.89, 6.99, 7.05-7.19, 7.30-7.34, 7.38-7.50, 7.50-7.52, 7.56-7.59, 7.74-7.77, 8.04-8.07.

[0329] Example 57: (E)-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]prop-2-enoic acid A 1M lithium hydroxide aqueous solution (0.5mL) was added to a solution of the compound (62mg) produced in Example 56 in THF (1.5mL) and methanol (0.5mL), and the mixture was stirred at room temperature for 7 hours. 1M hydrochloric acid and saturated saline were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 10:0 → 9:1) to obtain the title compound (29mg) having the following physical properties. HPLC retention time (min): 0.89; 1 H-NMR(DMSO-d6):δ 1.91-2.04, 4.10-4.22, 4.36, 5.12, 6.21-6.25, 6.44, 6.55, 6.93-6.99, 7.08-7.11, 7.16, 7.36-7.40, 7.52-7.55, 7.58-7.61, 7.66-7.68, 7.75-7.77, 7.85, 10.27, 12.31.

[0330] Example 58: N-[3-[(E,3R)-5-[2-(2-cyanoethyl)phenoxy]-3-hydroxypent-1-enyl]phenyl]benzenesulfonamide Instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, the corresponding phenol compound was used and the same operations as in Example 54, Example 55, and Example 56 were carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 0.99; 1 H-NMR(CDCl3):δ 2.07-2.19, 2.60-2.65, 2.89-3.00, 4.10-4.23, 4.58, 6.24, 6.44, 6.56, 6.89-6.95, 7.10-7.27, 7.42-7.46, 7.52-7.56, 7.75-7.78.

[0331] Example 59: Methyl 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1-carboxylate The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54, Example 55, and Example 56, except that the phenol compound prepared in Example 51 was used in place of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 0.71, 1.22, 1.79-1.83, 2.07-2.15, 2.44, 2.77-2.81, 3.65, 4.10-4.23, 6.24, 6.44, 6.55, 6.83-6.94, 7.08-7.20, 7.41-7.45, 7.51-7.55, 7.75-7.77.

[0332] Example 60: Methyl 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoate The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54, Example 55, and Example 56, except that the phenol compound prepared in Example 49 was used in place of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 1.53, 1.56, 2.33-2.45, 3.63, 4.10-4.19, 5.95, 6.46, 6.71-6.91, 7.17-7.24, 7.45-7.52, 7.57-7.68.

[0333] Example 61(1) to (8) The following example compounds were obtained by carrying out the same operations as in Example 54 → Example 55 → Example 56 → Example 57, using the corresponding phenol compound instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54.

[0334] Example 61(1): (E)-3-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]prop-2-enoic acid HPLC retention time (min): 0.85; 1 H-NMR(DMSO-d6):δ 1.84-1.92, 4.06-4.17, 4.32-4.33, 5.07, 5.60-6.00, 6.10, 6.21, 6.37, 6.44, 6.94-6.97, 7.09-7.11, 7.16, 7.48-7.63, 7.75, 10.27, 12.15.

[0335] Example 61(2): 3-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.86; 1H-NMR(DMSO-d6):δ 1.80-1.84, 1.87-1.96, 2.48, 2.74, 3.95-4.01, 4.01-4.08, 4.28-4.34, 5.04, 6.21, 6.43, 6.82-6.94, 6.93-6.96, 7.08-7.13, 7.17, 7.51-7.56, 7.57-7.59, 7.75-7.78, 10.27, 12.04.

[0336] Example 61(3): (E)-3-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]prop-2-enoic acid HPLC retention time (min): 0.89; 1 H-NMR(DMSO-d6):δ 1.83-1.98, 4.06-4.17, 4.31-4.35, 5.06, 6.20-6.25, 6.44, 6.54, 6.94-6.99, 7.09-7.11, 7.17, 7.23-7.26, 7.31, 7.52-7.61, 7.75-7.77, 10.27, 12.35.

[0337] Example 61(4): 3-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.89; 1 H-NMR(DMSO-d6):δ 1.81-1.95, 2.51, 2.78, 4.31, 5.05, 6.21, 6.43, 6.73-6.79, 6.93-6.96, 7.09-7.10, 7.14-7.18, 7.52-7.55, 7.58-7.61, 7.75-7.78, 10.25, 12.10.

[0338] Example 61(5): 2-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid HPLC retention time (min): 0.93; 1 H-NMR(DMSO-d6):δ 1.44, 1.81-1.97, 3.99-4.10, 4.30-4.35, 5.05, 6.21, 6.44, 6.79-6.82, 6.84-6.85, 6.88-6.90, 6.93-6.96, 7.08-7.10, 7.16, 7.23, 7.51-7.55, 7.57-7.61, 7.75-7.78, 10.25, 12.30.

[0339] Example 61(6): 2-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid HPLC retention time (min): 0.92; 1 H-NMR(DMSO-d6):δ 1.44, 1.83-1.93, 3.99-4.08, 4.29-4.33, 5.04, 6.21, 6.42, 6.86-6.88, 6.93-6.95, 7.07-7.09, 7.16, 7.23-7.25, 7.51-7.55, 7.57-7.60, 7.75-7.77, 10.25, 12.30.

[0340] Example 61(7): 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]butanoic acid

[0341] [ka]

[0342] HPLC retention time (min): 0.95; 1 H-NMR(CDCl3):δ 1.92-2.00, 2.12, 2.28-2.42, 2.68-2.71, 4.07-4.20, 4.63, 6.85-6.96, 7.08-7.19, 7.40-7.59, 7.59-7.63, 7.75-7.77.

[0343] Example 61(8): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylpropanoic acid HPLC retention time (min): 0.95 1 H-NMR(CDCl3):δ 1.21, 2.05-2.15, 2.96, 4.07-4.15, 4.60, 6.23, 6.53, 6.85-7.00, 7.07-7.20, 7.40-7.63, 7.76-7.78.

[0344] Example 62: 2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54 → Example 55 → Example 56 → Example 57, using the phenol compound prepared in Example 47 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. HPLC retention time (min): 0.95; 1 H-NMR(CDCl3):δ 1.63-1.65, 2.09-2.14, 4.13-4.21, 4.58, 6.28, 6.52, 6.82-6.84, 7.00-7.06, 7.15-7.19, 7.40-7.62, 7.76-7.78.

[0345] Example 63: 1-[[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]methyl]cyclopropane-1-carboxylic acid Instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, the compound prepared in Example 48 was used, and the same procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 0.96; 1 H-NMR (CDCl3): δ 1.38-1.40, 2.11-2.16, 4.13-4.18, 4.58, 6.28, 6.54, 6.85-7.20, 7.38-7.52, 7.74-7.76.

[0346] Example 64: 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54 → Example 55 → Example 56 → Example 57, using the compound prepared in Example 49 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 1.28, 1.74-1.91, 2.08-2.17, 2.61, 4.01-4.16, 4.62, 6.22, 6.51, 6.81-7.17, 7.39-7.43, 7.48-7.53, 7.75-7.78.

[0347] Example 65: 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1-carboxylic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54 → Example 55 → Example 56 → Example 57, except that the phenol compound prepared in Example 51 was used in place of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 0.66-0.76, 1.19-1.30, 1.64-1.72, 1.79-1.88, 2.08-2.14, 2.75-2.89, 4.10-4.21, 4.65, 6.28, 6.55, 6.83-6.90, 6.96-7.00, 7.07-7.18, 7.35-7.39, 7.46-7.52, 7.73-7.76.

[0348] Example 66(1) to (3) The following example compounds were obtained by carrying out the same operations as in Example 1 → Example 54 → Example 55 → Example 56 → Example 57, using the corresponding lactone compound instead of 3,4-dihydrocoumarin used in Example 1.

[0349] Example 66(1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-bromophenyl]propanoic acid HPLC retention time (min): 0.99; 1 H-NMR(CD3OD):δ 2.06-2.10, 2.56-2.60, 2.88-2.92, 4.07-4.19, 4.51, 6.23, 6.53, 6.86-6.88, 6.97-7.00, 7.11-7.19, 7.29-7.32, 7.46-7.50, 7.54-7.58, 7.76-7.78.

[0350] Example 66(2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-methylphenyl]propanoic acid HPLC retention time (min): 0.98; 1 H-NMR(CD3OD):δ 1.92-1.96, 2.13, 2.42-2.46, 2.75-2.79, 3.63-4.03, 4.41, 6.11, 6.42, 6.69, 6.84-6.89, 6.99-7.06, 7.34-7.46, 7.64-7.66.

[0351] Example 66(3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-4-methylphenyl]propanoic acid HPLC retention time (min): 0.97; 1 H-NMR(CD3OD):δ 1.92-1.97, 2.18, 2.41-2.45, 2.74-2.78, 3.93-4.06, 4.42, 6.11, 6.41, 6.56, 6.64, 6.86-6.92, 7.00-7.07, 7.33-7.46, 7.64-7.66.

[0352] Example 67: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-fluorophenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54 → Example 55 → Example 56 → Example 57, except that the phenol compound prepared in Example 53 was used in place of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. HPLC retention time (min): 0.94; 1 H-NMR(CDCl3):δ 2.09-2.15, 2.67-2.71, 2.93-2.97, 4.10-4.15, 4.59, 6.27, 6.54, 6.77-6.80, 6.84-6.90, 6.95-7.00, 7.08-7.10, 7.16, 7.40-7.44, 7.50-7.55, 7.76-7.78.

[0353] Example 68(1) to (2) The following example compounds were obtained by carrying out the same operations as in Example 52 → Example 53 → Example 54 → Example 55 → Example 56 → Example 57, using the corresponding aldehyde compound instead of 2-benzyloxy-5-fluoro-benzaldehyde used in Example 52, and the corresponding phenol compound instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54.

[0354] Example 68(1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-6-fluorophenyl]propanoic acid HPLC retention time (min): 0.95; 1 H-NMR(CDCl3):δ 2.09-2.15, 2.61-2.65, 2.97-3.01, 4.10-4.17, 4.60, 6.26, 6.54, 6.65-6.70, 6.97-7.00, 7.05-7.18, 7.41-7.44, 7.50-7.54, 7.76-7.79.

[0355] Example 68(2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-3-fluorophenyl]propanoic acid HPLC retention time (min): 0.94; 1 H-NMR(CDCl3):δ 2.09-2.15, 2.69-2.73, 3.01-3.05, 4.22-4.24, 4.67, 6.30, 6.58, 6.95-7.01, 7.10-7.20, 7.42-7.45, 7.51-7.54, 7.77-7.79.

[0356] Example 69: 3-[2-[(E,3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54 → Example 55 → Example 56 → Example 57, using the compound prepared in Example 1 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, and (S,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate prepared in Example 54 instead of (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate used in Example 54. HPLC retention time (min): 0.93; 1 H-NMR(CD3OD):δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45-7.50, 7.56, 7.75-7.78.

[0357] Example 70: 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid

[0358] [ka]

[0359] The compound prepared in Example 69 was subjected to the same procedures as in Example 33 to give the title compound having the following physical properties. HPLC retention time (min): 0.93; 1 H-NMR (CD3OD): δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.

[0360] Example 71:Isopropyl (R,E)-3-(2-((5-(3-aminophenyl)-3-((trimethylsilyl)oxy)pent-4-en-1-yl)oxy)phenyl)propanoate To a solution of the compound (1.00 g) produced in Example 8 in THF (10 mL), 3-bromoaniline (421 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.30 g) and 2M tripotassium phosphate aqueous solution (5.7 mL) were added and stirred at 70°C for 19 hours. After cooling the reaction solution to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to obtain the title compound (515 mg) having the following physical properties. HPLC retention time (min): 0.82.

[0361] Example 72: Isopropyl (R,E)-3-(2-((5-(3-((4-fluorophenyl)sulfonamido)phenyl)-3-hydroxypent-4-en-1-yl)oxy)phenyl)propanoate To a solution of the compound (50 mg) produced in Example 71 in THF (1 mL), pyridine (0.018 mL), DMAP (2.7 mg) and 4-fluorobenzenesulfonyl chloride (CAS registration number: 349-88-2) (25.6 mg) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. TBAF (1.0 M THF solution, 0.27 mL) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (mobile phase A (0.1% TFA aqueous solution):mobile phase B (0.1% TFA / acetonitrile) = 90:0 → 10:90) to obtain the title compound (515 mg) having the following physical properties. HPLC retention time (min): 1.11.

[0362] Example 73:3-[2-[(E,3R)-5-[3-[(4-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11, the compound prepared in Example 72 was used and subjected to the same procedure as in Example 11 to obtain the title compound having the following physical properties. HPLC retention time (min): 0.94 1 H-NMR (CD3OD): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26, 6.55, 6.86, 6.93, 6.99, 7.13-7.25, 7.79-7.82.

[0363] Examples 74(1) to (21) The following example compounds were obtained by carrying out the same operations as in Example 72→Example 11, except that the corresponding sulfonyl compounds were used in place of 4-fluorobenzenesulfonyl chloride used in Example 72.

[0364] Example 74(1): 3-[2-[(E,3R)-5-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.98; 1 H-NMR(CD3OD):δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26, 6.55, 6.86, 6.93, 6.99, 7.13-7.21, 7.48-7.51, 7.71-7.75.

[0365] Example 74(2):3-[2-[(E,3R)-3-hydroxy-5-[3-[(4-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96; 1 H-NMR(CD3OD):δ 2.06-2.11, 2.37, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11-7.20, 7.27-7.30, 7.63-7.66.

[0366] Example 74(3): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[4-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.01; 1 H-NMR(CD3OD):δ 2.06-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.27, 6.55, 6.86, 6.93, 6.99, 7.15-7.22, 7.80-7.83, 7.93-7.95.

[0367] Example 74(4): 3-[2-[(E,3R)-5-[3-[(4-butylphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.08; 1 H-NMR(CD3OD):δ 0.93, 1.31-1.36, 1.55-1.63, 2.06-2.10, 2.57-2.67, 2.91-2.95, 4.11, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11-7.20, 7.28-7.30, 7.65-7.68.

[0368] Example 74(5):3-[2-[(E,3R)-5-[3-[(3-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.96; MS(ESI,Pos.):482(M+H-H2O) + .

[0369] Example 74(6): 3-[2-[(E,3R)-5-[3-[(3-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; MS(ESI,Pos.):498(M+H-H2O) + .

[0370] Example 74(7): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(3-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97; MS(ESI,Pos.):478(M+H-H2O) + .

[0371] Example 74(8): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[3-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; MS(ESI,Pos.):532(M+H-H2O) + .

[0372] Example 74(9): 3-[2-[(E,3R)-5-[3-[(2-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.94; MS(ESI,Pos.):482(M+H-H2O) + .

[0373] Example 74(10): 3-[2-[(E,3R)-5-[3-[(2-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97; MS(ESI,Pos.):498(M+H-H2O) + .

[0374] Example 74(11): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.97; MS(ESI,Pos.):478(M+H-H2O) + .

[0375] Example 74(12): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[2-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.99; MS(ESI,Pos.):532(M+H-H2O) + .

[0376] Example 74(13): 3-[2-[(E,3R)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

[0377] [ka]

[0378] HPLC retention time (min): 0.93; 1H-NMR(CD3OD):δ 1.60-1.67, 1.74-1.81, 1.90-2.05, 2.08-2.13, 2.58-2.62, 2.92-2.96, 3.56, 4.13, 4.20, 4.58, 6.35, 6.62, 6.86, 6.94, 7.14-7.20, 7.26-7.32.

[0379] Example 74(14): 3-[2-[(E,3R)-3-hydroxy-5-[3-(oxan-4-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.48 (ethyl acetate); 1 H-NMR(CDCl3):δ 1.88-2.00, 2.15-2.20, 2.63-2.74, 2.90-3.02, 3.22-3.35, 4.04, 4.17, 6.38, 6.60, 6.88, 7.13-7.28.

[0380] Example 74(15): 3-[2-[(E,3R)-5-[3-(benzylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.55 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 2.13-2.18, 2.67, 2.96, 4.13-4.22, 4.34, 4.64, 6.35, 6.61, 6.89, 6.96, 7.06, 7.13-7.36.

[0381] Example 74(16): 3-[2-[(E,3R)-3-hydroxy-5-[3-(pyridin-2-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.36 (ethyl acetate); 1H-NMR(CDCl3):δ 2.06-2.23, 2.72, 3.02, 4.16, 4.60, 6.31, 6.52, 6.86-6.93, 7.01, 7.10-7.22, 7.46, 7.85, 7.97, 8.41, 8.65.

[0382] Example 74(17): 3-[2-[(E,3R)-5-[3-(1-benzofuran-3-ylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.98; 1 H-NMR(CDCl3):δ 2.08-2.13, 2.69, 2.96, 4.11, 4.55-4.62, 6.21, 6.52, 684-6.92, 6.99-7.03, 7.09-7.19, 7.30-7.40, 7.50, 7.70, 8.05.

[0383] Example 74(18): 3-[2-[(E,3R)-5-[3-[(4-butoxyphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.40 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 0.95, 1.40-1.50, 1.68-1.79, 2.10-2.14, 2.68, 2.96, 3.93, 4.10-4.19, 4.60, 6.26, 6.52, 6.81-6.91, 6.97-7.09, 7.12-7.24, 7.68.

[0384] Example 74(19): 3-[2-[(E,3R)-3-hydroxy-5-[3-(thiophen-3-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.35 (hexane:ethyl acetate=1:2); 1H-NMR(CDCl3):δ 2.10-2.15, 2.68, 2.96, 4.09-4.20, 4.62, 6.27, 6.54, 6.84-6.92, 7.00-7.23, 7.27-7.32, 7.86.

[0385] Example 74(20): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-propylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.38 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 1.00, 1.64-1.74, 2.10-2.15, 2.70, 2.93-3.01, 4.10-4.19, 4.60, 6.26, 6.53, 6.85-6.92, 7.02-7.06, 7.10-7.24, 7.33, 7.45, 7.95.

[0386] Example 74(21): 3-[2-[(E,3R)-5-[3-[(3-butylphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid TLC: Rf 0.38 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 0.86, 1.18-1.28, 1.42-1.53, 2.08-2.14, 2.57, 2.69, 2.97, 4.10-4.21, 4.61, 6.25, 6.53, 6.84-6.92, 6.98, 7.04-7.21, 7.29-7.32, 7.55-7.60.

[0387] Example 75: 3-[2-[(3S)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid The following example compounds were obtained by carrying out the same operations as in Example 33 using the compound prepared in Example 74(13) instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33. HPLC retention time (min): 0.93; 1 H-NMR(CD3OD):δ 1.55-1.63, 1.74-2.07, 2.52-2.56, 2.73, 2.84, 2.85-2.89, 3.53, 3.89, 4.09-4.19, 6.85, 6.93, 7.02, 7.08-7.19, 7.23.

[0388] Example 76: Methyl (R,E)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Trimethylsilyldiazomethane (2.0M hexane solution, 2.6mL) was added to a solution of the compound (500mg) produced in Example 11 in methanol (10mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction solution under ice cooling, and the mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain the title compound (495mg) having the following physical properties. HPLC retention time (min): 1.03.

[0389] Example 77: Methyl 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopent-4-enoxy]phenyl]propanoate Manganese dioxide (868 mg) was added to a solution of the compound (495 mg) produced in Example 76 in dichloromethane (10 mL) at room temperature, and the mixture was stirred at the same temperature for 20 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain the title compound (439 mg) having the following physical properties. HPLC retention time (min): 1.10. 1 H-NMR(CDCl3):δ 2.59-2.63, 2.88-2.92, 3.08-3.11, 3.68, 4.31-4.34, 6.80, 6.85-6.92, 7.12, 7.18-7.34, 7.42-7.56, 7.77-7.80.

[0390] Example 78: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopenta-4-enoxy]phenyl]propanoic acid Instead of methyl (R,E)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate used in Example 77, the compound prepared in Example 11 was used and subjected to the same procedure as in Example 77 to obtain the title compound having the following physical properties. HPLC retention time (min): 0.97; 1 H-NMR(CD3OD):δ 2.44-2.48, 2.81-2.85, 3.22, 3.25 ,4.33-4.37, 6.82, 6.86, 6.97, 7.14-7.21, 7.29, 7.33-7.39, 7.48-7.52, 7.56-7.63, 7.79-7.81.

[0391] Example 79: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3-oxopentoxy]phenyl]propanoic acid Instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33, the compound prepared in Example 78 was used and subjected to the same procedure as in Example 33 to obtain the title compound having the following physical properties. HPLC retention time (min): 0.97; 1 H-NMR (CD3OD): δ 2.47-2.51, 2.80-2.85, 2.88-2.91, 4.21-4.24, 6.85-6.95, 7.09-7.21, 7.44-7.48, 7.54, 7.74-7.76.

[0392] Example 80: 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]-3-oxopentoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 78→Example 79 using the compound prepared in Example 12(9) in place of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 78. HPLC retention time (min): 1.00; 1 H-NMR (CD3OD): δ 2.48-2.52, 2.80-2.96, 3.03-3.08, 4.25, 4.82, 6.85-6.94, 7.08-7.22.

[0393] Example 81: Isopropyl 3-(2-(pent-4-yn-1-yloxy)phenyl)propanoate Cesium carbonate (9.39 g) was added to a solution of the compound (3.00 g) produced in Example 1 in N,N-dimethylacetamide (25 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. 5-Chloro-1-pentyne (CAS registration number: 14267-92-6) (1.63 g) was added to the reaction solution at room temperature, and the mixture was stirred at 60°C for 3 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 1:0 → 5:1) to obtain the title compound (2.40 g) having the following physical properties. HPLC retention time (min): 1.13.

[0394] Example 82: Isopropyl (E)-3-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-1-yl)oxy)phenyl)propanoate To a solution of the compound (1.00 g) produced in Example 81 in heptane (2 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added at room temperature and stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→4:1) to obtain the title compound (503 mg) having the following physical properties. HPLC retention time (min): 1.38.

[0395] Example 83: Isopropyl (E)-3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate To a solution of the compound (180 mg) produced in Example 82 in THF (3 mL), the compound (168 mg) produced in Example 9, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.035 g) and 2M aqueous potassium phosphate solution (0.67 mL) were added and stirred at 60°C for 1 hour. After cooling the reaction solution to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=7:1→2:1) to obtain the title compound (113 mg) having the following physical properties. HPLC retention time (min): 1.24.

[0396] Example 84: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid

[0397] [ka]

[0398] To a solution of the compound (146 mg) produced in Example 83 in THF (0.5 mL) and methanol (0.1 mL), 1M aqueous lithium hydroxide solution (0.5 mL) was added and stirred at 50° C. for 8 hours. 1M hydrochloric acid was added to make the mixture acidic, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (105 mg) having the following physical properties. HPLC retention time (min): 1.10 1 H-NMR(CD3OD):δ 1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45-7.49, 7.55, 7.75-7.78.

[0399] Example 85: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid The following example compounds were obtained by subjecting the compound to the same procedure as in Example 83→Example 84, except that 1-(4-bromophenyl)-2-phenylethan-1-ol (CAS registration number: 20498-64-0) was used instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83. HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 1.97-2.03, 2.41-2.45, 2.67-2.71, 2.96-3.03, 4.04, 4.86-4.90, 6.23-6.30, 6.44, 6.83-6.89, 7.16-7.34.

[0400] Example 86: 3-[2-[(E)-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 21 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83 and carrying out the same operations as in Example 83→Example 84. HPLC retention time (min): 1.20; 1 H-NMR (CDCl3): δ 2.00, 2.43, 2.64-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.44, 6.83-6.89, 7.15-7.39.

[0401] Example 87: 3-[2-[(E)-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 21→Example 83→Example 84, using (S)-methyloxazaborolidine instead of (R)-methyloxazaborolidine used in Example 21, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83. HPLC retention time (min): 1.20; 1 H-NMR (CDCl3): δ 2.00, 2.44, 2.66-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.45, 6.83-8.89, 7.15-7.40.

[0402] Example 87(1) to (10) The title compound having the following physical properties was obtained by carrying out the same operations as in Example 9→Example 83→Example 84, using the corresponding amine compound instead of 3-bromoaniline used in Example 9.

[0403] Example 87(1): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.08; 1 H-NMR(CDCl3):δ 1.92-1.99, 2.36-2.42, 2.64-2.68, 2.93-2.97, 3.99, 5.98, 6.02, 6.58-6.65, 6.81, 6.88, 7.00, 7.15-7.20, 7.39-7.45, 7.51-7.56, 7.65, 7.70-7.73.

[0404] Example 87(2): 3-[2-[(E)-5-[5-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10; 1H-NMR(CDCl3):δ 1.97-2.04, 2.43-2.49, 2.74-2.78, 3.00-3.04, 4.04, 6.25-6.32, 6.66, 6.85, 6.91, 7.10-7.25, 7.44-7.48, 7.53-7.58, 7.84-7.87.

[0405] Example 87(3): 3-[2-[(E)-5-[3-(benzenesulfonamido)-5-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.11; 1 H-NMR(CDCl3):δ 1.96-2.02, 2.41-2.46, 2.72-2.76, 2.97-3.01, 4.03, 6.31-6.40, 6.84, 6.90, 7.15-7.25, 7.43-7.48, 7.52-7.57, 7.79-7.82.

[0406] Example 87(4): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 1.98-2.05, 2.45-2.50, 2.68-2.72, 2.97-3.01, 4.04, 6.36-6.47, 6.80-6.91, 7.15-7.22, 7.37-7.44, 7.51-7.55, 7.74-7.79.

[0407] Example 87(5): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2-cyanophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.01; 1H-NMR(CDCl3):δ 1.95-2.02, 2.44-2.49, 2.64-2.68, 2.93-2.97, 4.01, 6.44, 6.60, 6.82, 6.88, 7.15-7.20, 7.31-7.32, 7.42-7.50, 7.52-7.60, 7.82-7.85.

[0408] Example 87(6): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-cyanophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 1.98-2.04, 2.46-2.51, 2.57-2.61, 2.92-2.96, 4.04-4.07, 6.38-6.46, 6.87, 6.92, 7.16-7.20, 7.24, 7.34, 7.49-7.55, 7.60, 7.75-7.78.

[0409] Example 87(7): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2,4-dichlorophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.07; 1 H-NMR(CD3OD):δ 1.87-1.94, 2.36-2.41, 2.44-2.48, 2.81, 3.95, 6.25, 6.59, 6.74, 6.79, 7.03-7.08, 7.22, 7.39-7.43, 7.49-7.53, 7.67-7.70.

[0410] Example 87(8): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-methylsulfonylphenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10; 1H-NMR(CDCl3):δ 1.98-2.05, 2.46-2.50, 2.67-2.50, 2.77, 2.96-3.00, 4.03, 6.40-6.42, 6.84, 6.90, 7.16-7.22, 7.47-7.52, 7.58, 7.64, 7.71, 7.91-7.94.

[0411] Example 87(9): 3-[2-[(E)-5-[3-(benzenesulfonamido)-5-methylsulfonylphenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0.99; 1 H-NMR(CDCl3):δ 1.97-2.03, 2.44-2.49, 2.72-2.76, 2.97-3.03, 4.04, 6.36, 6.41-6.48, 6.84, 6.90, 7.15-7.22, 7.40, 7.45-7.49, 7.54-7.58, 7.77, 7.82-7.84.

[0412] Example 87(10): 3-[2-[(E)-5-[3-(benzenesulfonamidomethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 1.96-2.02, 2.39-2.44, 2.66-2.70, 2.93-2.97, 4.03, 4.12, 5.33, 6.24, 6.36, 6.83-6.90, 6.96-6.99, 7.14-7.21, 7.47-7.52, 7.54-7.59, 7.84-7.88.

[0413] Example 88(1) to (2) Instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83, the corresponding halide compound was used and the same operations as in Example 83 → Example 35 → Example 84 were carried out to obtain the title compound having the following physical properties.

[0414] Example 88(1): 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid TLC: Rf 0.61 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 1.47-1.55, 1.67-1.74, 1.79-1.85, 2.58, 2.65, 2.88, 2.97-3.07, 3.96, 4.89, 6.79-6.88, 7.09-7.33.

[0415] Example 88(2): 3-[2-[5-[4-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid HPLC retention time (min): 1.1; 1 H-NMR(CDCl3): δ 1.47-1.80, 2.48-2.56, 2.64-2.69, 2.82-2.88, 3.02-3.06, 3.95, 4.89-4.93, 6.79-6.87, 7.11-7.34.

[0416] Example 89: (R)-3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid, or (S)-3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid The compound produced in Example 88(1) was subjected to optical resolution using SFC (column used: Daicel Corporation CHIRALPAK-IF (10mm x 250mm), mobile phase: CO2: acetonitrile: methanol = 75: 22.5: 2.5, flow rate: 30mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.). The optically active substance of Example 88(1) obtained under the optical resolution conditions was analyzed by SFC (column used: Daicel Corporation CHIRALPAK-IF (10mm x 250mm), mobile phase: CO2: acetonitrile: methanol = 75: 22.5: 2.5, flow rate: 30mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.), and the retention times of the first peak and the second peak were 14.9 minutes and 19.1 minutes, respectively.

[0417] Example 90: 4-Bromo-N-methoxy-N-methylthiazole-2-carboxamide To a solution of 4-bromothiazole-2-carboxylic acid (1.0 g) in dichloromethane (9.6 mL), N,O-dimethylhydroxylamine hydrochloride (609 mg), diisopropylethylamine (2.5 mL), and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (2.4 g) were added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) ​​to obtain the title compound (1.0 g) having the following physical properties. TLC: Rf 0.3 (hexane:ethyl acetate=2:1).

[0418] Example 91: 1-(4-bromothiazol-2-yl)-2-phenylethan-1-one Benzylmagnesium bromide (0.1M diethyl ether solution, 40mL) was added to a solution of the compound (300mg) produced in Example 90 in diethyl ether (1mL) at 0°C and stirred at room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the title compound (181mg) having the following physical properties. TLC: Rf 0.7 (hexane:ethyl acetate=4:1).

[0419] Example 92: 3-[2-[(E)-5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-4-yl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 21→Example 83→Example 84, using the compound prepared in Example 91 instead of 1-(3-bromophenyl)-2-phenylethanone used in Example 21, (RS)-methyloxazaborolidine instead of (R)-methyloxazaborolidine used in Example 21, and the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83. HPLC retention time (min): 0.98; 1 H-NMR(DMSO-d6):δ 1.92-2.00, 2.41-2.48, 2.80-2.84, 2.85-2.90, 3.10-3.15, 4.01-4.06, 4.80-4.85, 5.83, 6.60-6.72, 6.85, 6.95, 7.14-7.18, 7.21-7.25.

[0420] Example 93: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by carrying out the same operations as in Example 90 → Example 91 → Example 21 (wherein (RS)-methyloxazaborolidine was used instead of (R)-methyloxazaborolidine) → Example 83 → Example 84, using 2-bromothiazole-4-carboxylic acid instead of 4-bromothiazole-2-carboxylic acid used in Example 90, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83. HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 1.98-2.05, 2.41-2.47, 2.66-2.70, 2.96-3.00, 3.08, 3.34, 4.03, 5.18, 6.42-6.46, 6.58, 6.62, 6.83-6.89, 6.93, 7.16-7.25, 7.27-7.34.

[0421] Example 94: 3-[2-[5-[5-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pentoxy]phenyl]propanoic acid The following example compounds were obtained by using the compound prepared in Example 93 instead of isopropyl 3-(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate used in Example 35, and subjecting the compound to the same procedure as in Example 35. HPLC retention time (min): 0.96; 1 H-NMR(CDCl3):δ 1.56-1.64, 1.80-1.90, 2.57-2.61, 2.94, 3.05, 3.09-3.11, 3.96, 5.14, 6.80, 6.86, 7.14-7.25, 7.29-7.33, 7.46.

[0422] Example 95: 3-[2-[5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-5-yl]pentoxy]phenyl]propanoic acid The following example compounds were obtained by using the compound prepared in Example 92 instead of isopropyl 3-(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate used in Example 35, and subjecting the compound to the same procedure as in Example 35. HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 1.51-1.59, 1.68-1.85, 2.57-2.61, 2.84, 2.90, 3.09, 3.27, 3.97, 5.14, 6.81, 6.86, 7.13-7.25, 7.28-7.32, 7.39.

[0423] Example 95(1): 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]-N-methylsulfonylpropanamide To a solution of the compound (100 mg) produced in Example 84 in DMF (1 mL), methanesulfonamide (102 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (124 mg) and DMAP (78.7 mg) were added and stirred at room temperature for 23 hours. 1M hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to give the title compound (80.7 mg) having the following physical properties. HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 1.97-2.04, 2.37-2.42, 2.64-2.67, 2.96-2.99, 3.19, 4.05, 6.22, 6.33, 6.73, 6.85-6.92, 7.06-7.08, 7.13-7.17, 7.21, 7.41-7.45, 7.50-7.54, 7.76-7.78.

[0424] Example 95(2):3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanamide The title compound having the following physical properties was obtained by using the compound prepared in Example 84 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 31 and carrying out the same operation as in Example 31. HPLC retention time (min): 0.98; 1 H-NMR(CDCl3):δ 1.95-2.02, 2.40-2.45, 2.60-2.64, 3.03-3.07, 4.04, 5.55, 5.82, 6.29, 6.34-6.41, 6.86, 6.89-6.95, 7.03-7.06, 7.11-7.22, 7.41-7.44, 7.49-7.53, 7.82-7.85, 8.25.

[0425] Example 95(3): N-[3-[(E)-5-[2-(2-cyanoethyl)phenoxy]pent-1-enyl]phenyl]benzenesulfonamide To a solution of the compound (100 mg) produced in Example 95(2) in THF (1 mL), pyridine (0.052 mL) and trifluoroacetic anhydride (67.8 mg) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Methanol and 1M aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to obtain the title compound (91.0 mg) having the following physical properties. HPLC retention time (min): 1.10; 1H-NMR(CDCl3):δ 1.95-2.02, 2.37-2.42, 2.61-2.65, 2.95-2.99, 4.03, 6.20, 6.34, 6.49, 6.84-6.94, 7.05-7.25, 7.41-7.46, 7.51-7.55, 7.75-7.78.

[0426] Example 95(4): N-[3-[(E)-5-[2-[2-(1H-tetrazol-5-yl)ethyl]phenoxy]pent-1-enyl]phenyl]benzenesulfonamide Trimethylsilyl azide (44.0 mg) and dibutyltin oxide (24.0 mg) were added to a toluene (0.5 mL) solution of the compound (43.0 mg) produced in Example 95(3), and the mixture was stirred overnight at 100° C. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate:methanol=50:50:3→0:100:3) to obtain the title compound (15.0 mg) having the following physical properties. HPLC retention time (min): 0.99; 1 H-NMR(CDCl3):δ 1.92-1.99, 2.34-2.39, 3.11-3.15, 3.30-3.34, 4.02, 6.20, 6.30, 6.83-6.90, 7.30-7.22, 7.39-7.43, 7.49-7.53, 7.76-7.78.

[0427] Example 95(5): Isobutyl (E)-(3-(5-(2-(3-amino-3-oxopropyl)phenoxy)pent-1-en-1-yl)phenyl)(phenylsulfonyl)carbamate Triethylamine (0.20 mL) and isobutyl chloroformate (110 mg) were added to a solution of the compound (100 mg) produced in Example 84 in THF (1 mL) under ice cooling, and the reaction mixture was stirred at room temperature for 10 minutes. Ammonia (28% aqueous solution, 0.5 mL) was added to the reaction solution under ice cooling, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1 → 0:1) to obtain the title compound (120 mg) having the following physical properties. HPLC retention time (min): 1.11.

[0428] Example 95(6): N-[3-[(E)-5-[2-[2-(1H-1,2,4-triazol-5-yl)ethyl]phenoxy]pent-1-enyl]phenyl]benzenesulfonamide To a solution of the compound (120 mg) produced in Example 95(5) in DMF (0.2 mL), N,N-dimethylformamide dimethyl acetal (0.5 mL) was added and stirred at 100°C for 4 hours. After concentrating the reaction solution under reduced pressure, acetic acid (1 mL) and hydrazine monohydrate (0.1 mL) were added and stirred at 100°C for 3 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). To a solution of the residue (48 mg) in methanol (1 mL), 2M aqueous sodium hydroxide solution (0.2 mL) was added and stirred at room temperature overnight. The reaction mixture was neutralized with 1M aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:methanol=50:50:3→0:100:3) to give the title compound (24.0 mg) having the following physical properties. HPLC retention time (min): 0.90; 1H-NMR(CDCl3):δ 1.95-2.02, 2.38-2.43, 3.08-3.18, 4.04, 6.22, 6.32, 6.84-6.89, 6.94-6.97, 7.02, 7.07-7.21, 7.39-7.43, 7.49-7.53, 7.67, 7.75-7.77, 8.04.

[0429] Example 96: Isopropyl (E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate The title compound having the following physical properties was obtained by subjecting the same operations as in Example 2 → Example 3 → Example 4 → Example 5 → Example 7 → Example 8 → Example 10 to the same target operations using 2-(3-bromopropyl)-1,3-dioxane instead of 2-(2-bromoethyl)-1,3-dioxane used in Example 2. TLC: Rf 0.43 (hexane:ethyl acetate=1:1).

[0430] Example 97: 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 96 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 0.96; 1 H-NMR(CDCl3):δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7.54, 7.66, 7.78-7.81.

[0431] Example 98: Isopropyl (R,E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate or isopropyl (S,E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate The compound produced in Example 96 was subjected to optical resolution using SFC (column used: Daicel Corporation CHIRALPAK-IC (20 mm x 250 mm), mobile phase: CO2:methanol = 85:15, flow rate: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.). The optically active substance of Example 96 obtained under the optical resolution conditions was analyzed by SFC (column used: Daicel Corporation CHIRALPAK-IC (10 mm x 250 mm), mobile phase: CO2:methanol = 85:15, flow rate: 30 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.), and the retention times of the first peak and the second peak were 13.6 minutes and 15.8 minutes, respectively.

[0432] Example 99: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid, or (S)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid Instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11, the optically active substance of the first peak prepared in Example 98 was used and subjected to the same operation as in Example 11 to obtain the title compound having the following physical properties. HPLC retention time (min): 0.96; 1H-NMR(CDCl3):δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7.54, 7.66, 7.78-7.81.

[0433] Example 100: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid, or (S)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid Instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11, the optically active substance of the second peak prepared in Example 98 was used, and the same operation as in Example 11 was carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 0.96; 1 H-NMR(CDCl3):δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7.54, 7.66, 7.78-7.81.

[0434] Example 101: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 97 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 and carrying out the same operations as in Example 33. HPLC retention time (min): 0.96; 1 H-NMR(CDCl3):δ 1.58-1.67, 1.72-2.00, 2.65-2.09, 2.93-3.07, 3.59-3.65, 3.95-4.05, 6.82-6.93, 6.98-7.01, 7.12-7.22, 7.40-7.45, 7.50-7.54, 7.77-7.80.

[0435] Example 102: (R)-3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid, or (S)-3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid The compound produced in Example 101 was subjected to optical resolution using SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: CO2: acetonitrile: methanol = 80: 18: 2, flow rate: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.). The optically active substance of Example 101 obtained under the optical resolution conditions was analyzed by SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: CO2: acetonitrile: methanol = 80: 18: 2, flow rate: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.), and the retention times of the first peak and the second peak were 9.6 minutes and 12.3 minutes, respectively.

[0436] Example 103: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 97 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 78 and carrying out the same operations as in Example 78→Example 79. TLC: Rf 0.45 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 2.01-2.10, 2.61-2.75, 2.83, 2.96, 3.96, 6.78-6.82, 6.86-6.91, 6.96, 7.10, 7.14-7.21, 7.42, 7.51, 7.68-7.84.

[0437] Example 104(1) to (2) The following example compounds were obtained by carrying out the same operations as in Example 81 → Example 82 → Example 83 → Example 84, using the corresponding phenol compound instead of isopropyl 3-(2-hydroxyphenyl)propanoate used in Example 81.

[0438] Example 104(1): 2-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]acetic acid HPLC retention time (min): 1.01; 1 H-NMR(CDCl3):δ 1.89-1.96, 2.33-2.38, 3.67, 4.01, 6.14, 6.29, 6.68, 6.85-6.94, 7.00-7.28, 7.39-7.43, 7.48-7.52, 7.74-7.77.

[0439] Example 104(2): 4-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]butanoic acid HPLC retention time (min): 1.07; 1 H-NMR(CDCl3):δ 1.93-2.00, 2.37-2.43, 2.70, 4.00, 6.21, 6.33, 6.82-6.92, 7.04-7.19, 7.40-7.44, 7.49-7.53, 7.75-7.78.

[0440] Example 105(1) to (3) The following example compounds were obtained by carrying out the same operations as in Example 81 → Example 82 → Example 83 → Example 84, using the corresponding halide compound instead of 5-chloro-1-pentyne used in Example 81.

[0441] Example 105(1): 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]but-3-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.01; 1 H-NMR(CD3OD):δ 2.52-2.56, 2.67-2.71, 2.88-2.92, 4.10-4.13, 6.31, 6.46, 6.86, 6.93-6.98, 7.09-7.20, 7.44-7.49, 7.52-7.57, 7.75-7.78.

[0442] Example 105(2): 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]hex-5-enoxy]phenyl]propanoic acid TLC: Rf 0.44 (hexane:ethyl acetate=1:1); 1 H-NMR(CDCl3):δ 1.65-1.76, 1.77-1.88, 2.25-2.31, 2.69-2.75, 2.99-3.05, 3.99, 6.18, 6.33, 6.83, 6.89, 6.95-7.00, 7.10-7.21, 7.44, 7.53, 7.67, 7.81.

[0443] Example 105(3): 3-[2-[(E)-7-[3-(benzenesulfonamido)phenyl]hept-6-enoxy]phenyl]propanoic acid TLC: Rf 0.44 (hexane:ethyl acetate=1:1); 1H-NMR(CDCl3):δ 1.61-1.73, 1.77-1.88, 2.27, 2.76-2.82, 3.02-3.07, 4.01, 6.29-6.33, 6.83-6.93, 7.08-7.23, 7.45, 7.53, 7.84, 8.75.

[0444] Example 106: Methyl 3-(2-((4-hydroxy-5-(3-(phenylsulfonamido)phenyl)pentyl)oxy)phenyl)propanoate The compound (200 mg) prepared in Example 84 was dissolved in ethyl acetate (1 mL). Methanol (1 mL) and trimethylsilyldiazomethane (2M hexane solution, 0.3 mL) were added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (2 mL). Saturated aqueous sodium bicarbonate solution (2 mL) and metachloroperbenzoic acid (171 mg) were added and stirred at room temperature for 5 hours. Saturated aqueous sodium thiosulfate solution was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL), 5% palladium-carbon (20 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→ethyl acetate) to obtain the title compound (53 mg) having the following physical properties. TLC: Rf 0.31 (hexane:ethyl acetate=1:1).

[0445] Example 107: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-hydroxypentoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 106 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. TLC: Rf 0.60 (ethyl acetate); 1 H-NMR(CDCl3):δ 1.50-1.68, 1.68-1.74, 1.77-2.00, 2.61-2.70, 2.72-2.79, 2.92-2.99, 3.87, 3.95-4.05, 6.82-7.03, 7.15-7.21, 7.38-7.45, 7.48-7.53, 7.77.

[0446] Example 108: Ethyl 3-(2-(4-oxobutyl)phenyl)propanoate To a solution of ethyl 3-[2-(4-hydroxybutyl)phenyl]propanoate (CAS Registry Number: 864677-94-1) (0.56 g) in dichloromethane (9 mL), sodium hydrogen carbonate (0.56 g) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (CAS Registry Number: 87413-09-0) (1.13 g) were added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium thiosulfate, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (0.34 g) having the following physical properties. TLC: Rf 0.30 (hexane:ethyl acetate=4:1).

[0447] Example 109: 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid The compound prepared in Example 108 was used in place of isopropyl 3-(2-(3-oxopropoxy)phenyl)propanoate used in Example 4, and the same procedures as in Example 4, Example 5, Example 7, Example 8, Example 10, and Example 11 were carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 0.95; 1H-NMR(CDCl3):δ 1.60-1.79, 2.66-2.72, 2.97-3.01, 4.30-4.35, 6.16, 6.49, 6.98-7.07, 7.13-7.17, 7.40-7.53, 7.77-7.79.

[0448] Example 110: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid, or (S)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid

[0449] [ka]

[0450] The compound produced in Example 109 was subjected to optical resolution using SFC (column used: Daicel Corporation CHIRALPAK-IC (20 mm × 250 mm), mobile phase: CO2:methanol = 85:15, flow rate: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.). The optically active substance of Example 109 obtained under the optical resolution conditions was analyzed by SFC (column used: Daicel Corporation CHIRALPAK-IC (10 mm × 250 mm), mobile phase: CO2:methanol = 85:15, flow rate: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.), and the retention times of the first peak and the second peak were 12.4 minutes and 14.4 minutes, respectively.

[0451] Example 111: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexyl]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 109 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 and carrying out the same operation as in Example 33. HPLC retention time (min): 0.95; 1 H-NMR (CD3OD): δ 1.37-1.61, 2.39-2.58, 2.84, 6.79-6.81, 6.98-7.08, 7.30-7.42, 7.61-7.63.

[0452] Example 112: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid

[0453] [ka]

[0454] The title compound having the following physical properties was obtained by using the compound prepared in Example 109 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 78 and carrying out the same operations as in Example 78→Example 79. HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 1.75-1.83, 2.44-2.47, 2.54-2.61, 2.65-2.69, 2.75-2.79, 2.92-2.96, 6.90-6.94, 7.09-7.14, 7.18, 7.43-7.48, 7.54, 7.74-7.76.

[0455] Example 113: Isopropyl 3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate To a solution of the compound (1.5 g) produced in Example 81 and the compound (1.7 g) produced in Example 9 in DMF (6 mL), triethylamine (6 mL), bis(triphenylphosphine)palladium (II) dichloride (100 mg), and copper (I) iodide (50 mg) were added and stirred at 60°C overnight. Water was added to the reaction solution, and then it was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 → 0:1) to obtain the title compound (1.57 g) having the following physical properties. TLC: Rf 0.39 (hexane:ethyl acetate=2:1).

[0456] Example 114: 3-[2-[5-[3-(benzenesulfonamido)phenyl]pent-4-ynoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 113 in place of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 1.00; 1 H-NMR(CD3OD):δ 2.06-2.12, 2.55-2.59, 2.64-2.67, 2.92-2.96, 4.13-4.16, 6.87, 6.95, 7.03-7.07, 7.12-7.20, 7.45-7.50, 7.56, 7.74-7.77.

[0457] Example 115: Isopropyl (R)-3-(2-((5-(3-(phenylsulfonamido)phenyl)-3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl)propanoate The compound prepared in Example 7 was used in place of isopropyl 3-(2-(pent-4-yn-1-yloxy)phenyl)propanoate used in Example 113, and the same procedure as in Example 113 was carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 1.12.

[0458] Example 116: Isopropyl (R)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate To a solution of the compound (170 mg) produced in Example 115 in THF (1 mL), TBAF (1.0 M THF solution, 0.48 mL) was added at room temperature and stirred at the same temperature for 20 minutes. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→hexane:ethyl acetate=1:1) to obtain the title compound (82.8 mg) having the following physical properties. HPLC retention time (min): 1.12.

[0459] Example 117: 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-ynoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 116 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 0.93; 1 H-NMR (CD3OD): δ 2.19-2.30, 2.57-2.60, 2.91-2.95, 4.16-4.26, 4.85, 6.88, 6.96, 7.07-7.22, 7.46-7.51, 7.57, 7.75-7.77.

[0460] Example 118:3-[2-[5-[3-(benzenesulfonamido)phenyl]pentoxy]phenyl]propanoic acid

[0461] [ka]

[0462] The title compound having the following physical properties was obtained by using the compound prepared in Example 114 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 and carrying out the same operation as in Example 33. TLC: Rf 0.42 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 1.42-1.49, 1.58-1.65, 1.75-1.82, 2.55, 2.67, 2.95, 3.95, 6.80-6.97, 7.10-7.21, 7.27, 7.40, 7.49, 7.76.

[0463] Example 119: Isopropyl (Z)-3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Lindlar catalyst (containing 5% by weight of palladium) (10.0 mg) and quinoline (12.8 mg) were added to a solution of the compound (100 mg) produced in Example 113 in ethyl acetate (10 mL) at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere for 5 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain the title compound (92.3 mg) having the following physical properties. HPLC retention time (min): 1.23.

[0464] Example 120: 3-[2-[(Z)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 119 in place of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 1.10; 1 H-NMR(CD3OD):δ 1.89-1.95, 2.37-2.43, 2.49-2.53, 2.83-2.87, 3.97-4.00, 5.74, 6.38, 6.83-6.89, 6.96-7.02, 7.13-7.19, 7.41-7.45, 7.51, 7.72-7.76.

[0465] Example 121: 3-[2-[(Z,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Instead of isopropyl 3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate used in Example 119, the compound prepared in Example 116 was used and subjected to the same operation as in Example 119→Example 11 to obtain the title compound having the following physical properties. HPLC retention time (min): 0.92; 1 H-NMR(CD3OD):δ 2.00-2.07, 2.44-2.48, 2.77-2.80, 4.02, 4.11, 4.75, 5.72, 6.46 ,6.83-6.88, 6.92-7.04, 7.12-7.18, 7.42-7.47, 7.52, 7.74-7.77.

[0466] Example 122: Ethyl (E)-3-(2-(3-(benzyloxy)-2-hydroxypropoxy)phenyl)acrylate Benzyl glycidyl ether (6.57 g) was added to a solution of ethyl (E)-3-(2-hydroxyphenyl)prop-2-enoate (CAS Registry Number: 6236-62-0) (1.92 g) and diisopropylethylamine (0.69 mL) in hexamethylphosphoramide (20 mL), and the reaction mixture was stirred at 80° C. for 19 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) ​​to obtain the title compound (2.66 g) having the following physical properties. TLC: Rf 0.33 (hexane:ethyl acetate=2:1).

[0467] Example 123: Ethyl (E)-3-(2-(3-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)propoxy)phenyl)acrylate To a solution of the compound (300 mg) produced in Example 122 and imidazole (200 mg) in DMF (3 mL), tert-butyldimethylsilyl chloride (330 mg) was added at 0° C., and the reaction mixture was stirred at room temperature for 5 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (380 mg) having the following physical properties. TLC: Rf 0.41 (hexane:ethyl acetate=9:1).

[0468] Example 124: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-hydroxypropoxy)phenyl)propanoate A solution of the compound (380 mg) produced in Example 123 and 5% palladium carbon (50% wet, 180 mg) in ethanol (8 mL) was stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to obtain the title compound (290 mg) having the following physical properties. TLC: Rf 0.34 (hexane:ethyl acetate=4:1).

[0469] Example 125: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)propanoate To a solution of the compound (290 mg) produced in Example 124 and sodium bicarbonate (190 mg) in methylene chloride (3 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (390 mg) was added at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium thiosulfate, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (250 mg) having the following physical properties. TLC: Rf 0.40 (hexane:ethyl acetate=4:1).

[0470] Example 126: Ethyl (E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate The title compound having the following physical properties was obtained by using the compound prepared in Example 125 instead of (R)-4-((4-methoxybenzyl)oxy)-1-oxobutan-2-yl benzoate used in Example 45 and carrying out the same operations as in Example 45 → Example 55 → Example 56 → Example 116. TLC: Rf 0.43 (hexane:ethyl acetate=1:1).

[0471] Example 127: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid

[0472] [ka]

[0473] The title compound having the following physical properties was obtained by using the compound prepared in Example 126 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 0.95; 1 H-NMR(CDCl3):δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79.

[0474] Example 128: Ethyl (S,E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate or Ethyl (R,E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate The compound produced in Example 126 was subjected to optical resolution using SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: CO2: 2-propanol = 83: 17, flow rate: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.). The optically active substance of Example 126 obtained under the optical resolution conditions was analyzed by SFC (column used: Daicel Corporation CHIRALPAK-IB (10 mm x 250 mm), mobile phase: CO2: 2-propanol = 83: 17, flow rate: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.), and the retention times of the first peak and the second peak were 12.6 minutes and 14.6 minutes, respectively.

[0475] Example 129: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid Instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11, the optically active substance of the first peak prepared in Example 128 was used and subjected to the same operation as in Example 11 to obtain the title compound having the following physical properties. HPLC retention time (min): 0.95; 1 H-NMR(CDCl3):δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79.

[0476] Example 130: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid Instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11, the optically active substance of the second peak prepared in Example 128 was used and subjected to the same operation as in Example 11 to obtain the title compound having the following physical properties. HPLC retention time (min): 0.95; 1 H-NMR(CDCl3):δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79.

[0477] Example 131: N-(3-bromophenyl)-N-(phenylsulfonyl)benzenesulfonamide To a solution of 3-bromoaniline (500 mg) in dichloromethane (10 mL), triethylamine (1.6 mL), DMAP (177 mg), and benzenesulfonic anhydride (1.9 g) were added and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (950 mg) having the following physical properties. TLC: Rf 0.30 (hexane:ethyl acetate=4:1).

[0478] Example 132: N-(3-(4-hydroxybut-1-yn-1-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide To a solution of the compound (949 mg) produced in Example 131 in DMF (4 mL), triethylamine (1.5 mL), 3-butyn-1-ol (220 mg), copper iodide (40 mg), and bis(triphenylphosphine palladium) dichloride (147 mg) were added, and the mixture was stirred at 80°C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) ​​to give the title compound (771 mg) having the following physical properties. TLC: Rf 0.30 (hexane:ethyl acetate=2:1).

[0479] Example 133: N-(3-(4-hydroxybutyl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide A solution of the compound (600 mg) prepared in Example 132 and 20% palladium hydroxide on carbon (50% wet, 150 mg) in methanol (5 mL) was stirred for 9 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to obtain the title compound (575 mg) having the following physical properties. HPLC retention time (min): 1.00.

[0480] Example 134: 3-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid To a solution of the compound (45 mg) produced in Example 133 in THF (0.5 mL), methyl 3-(3-hydroxyphenyl)propanoate (22 mg), DIAD (82 mg), and triphenylphosphine (40 mg) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To a solution of the obtained residue in methanol (0.5 mL) and 1,2-dimethoxyethane (0.5 mL), 5N aqueous sodium hydroxide solution (0.4 mL) was added and stirred at 45° C. for 19 hours. To the reaction mixture, 2M hydrochloric acid was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (14 mg) having the following physical properties. HPLC retention time (min): 0.97; 1 H-NMR(CDCl3):δ 1.66-1.75, 2.61, 2.74, 2.94, 3.94, 6.71-6.73, 6.79-6.86, 6.91-7.00, 7.14, 7.21, 7.37-7.41, 7.47-7.52, 7.72-7.74.

[0481] Example 135(1) to (6) The following example compounds were obtained by subjecting the compound to the same procedure as in Example 134, except that the corresponding phenol compound was used in place of methyl 3-(3-hydroxyphenyl)propanoate used in Example 134.

[0482] Example 135(1): 3-[4-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid HPLC retention time (min): 0.96; 1 H-NMR (CD3OD): δ 1.64-1.74, 2.55-2.61, 2.86, 3.91, 6.80-6.84, 6.92-6.94, 7.11-7.15, 7.42-7.46, 7.50-7.54, 7.73-7.76.

[0483] Example 135(2): 4-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 1.77-1.83, 1.96-2.03, 2.48, 2.60, 2.71-2.75, 3.97, 6.82, 6.87-6.90, 7.05-7.07, 7.11-7.20, 7.39-7.43, 7.47-7.52, 7.78-7.81.

[0484] Example 135(3): 4-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid HPLC retention time (min): 0.99; 1 H-NMR(CDCl3):δ 1.70-1.74, 1.95-2.02, 2.40, 2.59, 2.65, 3.93, 6.71-6.78, 6.86, 6.93-6.95, 7.12-7.21, 7.39-7.43, 7.48-7.52, 7.74-7.77.

[0485] Example 135(4): 2-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]acetic acid HPLC retention time (min): 0.94; 1 H-NMR(CDCl3):δ 1.68-1.72, 2.57, 3.65, 3.96, 6.80-6.94, 7.13, 7.21-7.24, 7.37-7.42, 7.47-7.52, 7.74-7.77.

[0486] Example 135(5): 2-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]acetic acid HPLC retention time (min): 0.95; 1H-NMR(CDCl3):δ 1.74-1.77, 2.57-2.60, 3.66, 3.98, 6.83-6.86, 6.91-6.96, 7.11, 7.19-7.26, 7.36-7.43, 7.48-7.52, 7.75-7.78.

[0487] Example 135(6): 3-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid HPLC retention time (min): 0.99; 1 H-NMR(CDCl3):δ 1.70-1.86, 2.61, 2.66-2.70, 2.97-3.01, 3.97, 6.82, 6.87-6.91, 7.03-7.06, 7.12-7.21, 7.40-7.44, 7.48-7.53, 7.60, 7.78-7.81.

[0488] Example 136: Isopropyl (E)-3-(2-((5-(3-nitrophenyl)-3-oxopent-4-en-1-yl)oxy)phenyl)propanoate The title compound having the following physical properties was obtained by subjecting the same intended operation as in Example 10→Example 77, except that 3-bromonitrobenzene was used instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. TLC: Rf 0.43 (hexane:ethyl acetate=2:1).

[0489] Example 137: Isopropyl (E)-3-(2-((3,3-difluoro-5-(3-nitrophenyl)pent-4-en-1-yl)oxy)phenyl)propanoate The compound (205 mg) prepared in Example 136 was dissolved in dichloromethane (0.4 mL), bis(2-methoxyethyl)aminosulfur trifluoride (1.5 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→ethyl acetate) to obtain the title compound (29 mg) having the following physical properties. TLC: Rf 0.66 (hexane:ethyl acetate=2:1).

[0490] Example 138: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropent-4-enoxy]phenyl]propanoic acid Instead of (R,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-nitrophenyl)pent-1-en-3-yl benzoate used in Example 55, the compound prepared in Example 137 was used and subjected to the same operations as in Example 55 → Example 56 → Example 11 to obtain the title compound having the following physical properties. TLC: Rf 0.22 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3): δ 2.50-2.62, 2.72, 2.93, 4.20, 6.30, 6.80-6.95, 7.05, 7.12-7.25, 7.43, 7.53, 7.78, 7.89.

[0491] Example 139: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid

[0492] [ka]

[0493] The title compound having the following physical properties was obtained by using the compound prepared in Example 138 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 and carrying out the same operation as in Example 33. TLC: Rf 0.20 (hexane:ethyl acetate=1:2); 1 H-NMR(CDCl3):δ 2.14-2.47, 2.67-2.74, 2.76-2.84, 2.88-2.98, 4.13-4.21, 6.79-6.88, 6.89-7.07, 7.11-7.25, 7.42, 7.52, 7.79.

[0494] Example 140: (S)-5-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)thio)-1-phenyl-1H-tetrazole 2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (CAS Registry Number: 32233-43-5) (2.00 g) in THF (25 mL) was added with 1-phenyl-1H-tetrazole-5-thiol (CAS Registry Number: 86-93-1) (3.66 g), triphenylphosphine (5.38 g) and DIAD (1.10 g) at room temperature and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate = 7:1 → 2:1) to obtain the title compound (4.14 g) with the following physical properties. HPLC retention time (min): 0.97.

[0495] Example 141: (S)-5-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)sulfonyl)-1-phenyl-1H-tetrazole To a solution of the compound (4.14 g) produced in Example 140 in acetonitrile (15 mL) and ethanol (15 mL), ammonium molybdate tetrahydrate (1.57 g) and 30 wt% hydrogen peroxide solution (8.3 mL) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in 2,2-dimethoxypropane (8.3 mL), and p-toluenesulfonic acid monohydrate (129 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and saturated saline. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1 → 2:1) to obtain the title compound (3.96 g) having the following physical properties. HPLC retention time (min): 0.96.

[0496] Example 142: (S,E)-N-(3-(4,5-dihydroxypent-1-en-1-yl)phenyl)benzenesulfonamide To a solution of the compound (1.04 g) produced in Example 141 in 1,2-dimethoxyethane (15 mL), potassium bis(trimethylsilyl)amide (0.5 M toluene solution, 15.3 mL) was added at -78°C, and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution, a solution of N-(3-formylphenyl)benzenesulfonamide (CAS registration number: 151721-35-6) (800 mg) in 1,2-dimethoxyethane (5 mL) was added at -78°C, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10:1). The obtained residue was dissolved in methanol (3 mL), and then 2 M hydrochloric acid (3 mL) was added at room temperature, and the mixture was stirred at 50°C for 30 minutes. The reaction solution was cooled on ice, neutralized with 2M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give the title compound (675 mg) having the following physical properties. HPLC retention time (min): 0.73.

[0497] Example 143: (S,E)-1-Hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl benzoate To a solution of the compound (450 mg) produced in Example 142 and imidazole (131 mg) in DMF (5 mL), t-butyldimethylchlorosilane (0.7 M DMF solution, 2 mL) was added dropwise over 5 minutes under ice cooling, and the mixture was stirred at room temperature for 24 hours. After ice cooling the reaction solution, imidazole (131 mg) and t-butyldimethylchlorosilane (213 mg) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 mL), and pyridine (0.42 mL), benzoyl chloride (215 mg), and DMAP (15.7 mg) were added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After ice cooling the reaction solution, benzoyl chloride (215 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1→2:1). The resulting residue was dissolved in THF (3mL) and acetic acid (0.30mL), and then TBAF (1.0M THF solution 1.6mL) was added under ice cooling and stirred at room temperature for 12 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1→2:1) to obtain the title compound (292mg) having the following physical properties. HPLC retention time (min): 0.97.

[0498] Example 144: (S,E)-1-Iodo-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl benzoate Imidazole (68.6 mg) and triphenylphosphine (106 mg) were added to a solution of the compound (147 mg) produced in Example 143 in DMF (1 mL) at room temperature. Iodine (102 mg) was added to the reaction solution under ice cooling, and the mixture was stirred at 50° C. for 1.5 hours. After the reaction solution was ice-cooled, triphenylphosphine (26.0 mg) and iodine (25.0 mg) were added, and the mixture was stirred at 50° C. for 30 minutes. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=7:1→3:2) to obtain the title compound (121 mg) having the following physical properties. HPLC retention time (min): 1.20.

[0499] Example 145: (S,E)-1-(2-(3-isopropoxy-3-oxopropyl)phenoxy)-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl benzoate Sodium hydride (60% in mineral oil, 13.1 mg) was added to a solution of the compound (68.4 mg) produced in Example 1 in DMF (0.5 mL) under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A solution of the compound (60 mg) produced in Example 144 in DMF (0.5 mL) was added to the reaction solution at room temperature, and the mixture was stirred at 60° C. for 2 hours. After cooling the reaction solution to room temperature, the title compound (12.1 mg) having the following physical properties was obtained by purifying the mixture by silica gel column chromatography (hexane:ethyl acetate=7:1→3:2). HPLC retention time (min): 1.29.

[0500] Example 146: 3-[2-[(E,2S)-5-[3-(benzenesulfonamido)phenyl]-2-hydroxypent-4-enoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 145 instead of (R,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-(phenylsulfonamido)phenyl)pent-1-en-3-yl benzoate used in Example 57 and carrying out the same operations as in Example 57. HPLC retention time (min): 0.95 1 H-NMR(CD3OD):δ 2.50, 2.59-2.65, 2.95-2.99, 3.95-4.02, 4.09, 6.29, 6.43, 6.86-6.96, 7.08-7.10, 7.12-7.20, 7.44-7.48, 7.54, 7.75-7.77.

[0501] Example 147: 2-(3-Nitrophenethoxy)acetic acid A solution of 2-(3-nitrophenyl)ethanol (CAS registration number: 52022-77-2) (2.00 g) in DMF (4 mL) was cooled to 0°C, sodium hydride (60% in mineral oil, 0.7 g) was added, and the mixture was stirred at 0°C for 15 minutes. Isopropyl bromoacetate (2.6 g) was added dropwise, and the mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 2:1) to obtain an ester compound (1.80 g). The mixture was dissolved in methanol (15 mL), sodium hydroxide (2N aqueous solution, 10 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.15 g) having the following physical properties: 1 H-NMR (CDCl3): δ 3.05-3.07, 3.84-3.87, 4.14, 7.48, 7.58-7.60, 8.09-8.14.

[0502] Example 148: 2-(3-nitrophenethoxy)ethane-1-ol A solution of the compound (1.15 g) produced in Example 147 and 4-methylmorpholine (0.8 mL) in THF (10 mL) was cooled to 0°C, and isobutyl chloroformate (0.8 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes, and the resulting white solid was filtered. The filtrate was cooled to 0°C, sodium borohydride (1.15 g) was added, and the mixture was stirred at 0°C for 10 minutes, after which a small amount of water was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→1:1) to obtain the title compound (1.15 g) having the following physical properties. 1 H-NMR (CDCl3): δ 1.82, 3.00-3.03, 3.56-3.58, 3.69-3.78, 7.47, 7.56-7.58, 8.07-8.13.

[0503] Example 149: 3-[2-[2-[2-[3-(benzenesulfonamido)phenyl]ethoxy]ethoxy]phenyl]propanoic acid

[0504] [ka]

[0505] The title compound having the following physical properties was obtained by carrying out the same operations as in Example 54 → Example 55 → Example 56 → Example 11, using the compound prepared in Example 148 instead of the (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate used in Example 54, and the compound prepared in Example 1 instead of the methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. HPLC retention time (min): 0.99; 1H-NMR (DMSO-d6): δ 2.70-2.80, 3.17-3.18, 3.56-3.60, 3.68-3.71, 4.05-4.08, 6.84-6.96, 7.09-7.19, 7.50-7.60, 7.74-7.76.

[0506] Example 150: tert-Butyl (S)-2-(3-(1-hydroxy-2-phenylethyl)phenyl)acetate Bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (0.5M THF solution, 9mL) and bis(tri-tert-butylphosphine)palladium (76mg) were added to a solution of (1S)-1-(3-bromophenyl)-2-phenyl-ethanol (412mg) in THF (0.5mL) and stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (296mg) having the following physical properties. TLC: Rf 0.40 (hexane:ethyl acetate=4:1).

[0507] Example 151: tert-Butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)acetate 3,4-Dihydro-2H-pyran (239 mg) and pyridinium 4-toluenesulfonate (71 mg) were added to a solution of the compound (296 mg) produced in Example 150 in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (341 mg) having the following physical properties. TLC: Rf 0.60 (hexane:ethyl acetate=4:1).

[0508] Example 152: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)ethan-1-ol To a solution of the compound (341 mg) produced in Example 151 in THF (4 mL), water (0.15 mL) and lithium borohydride (187 mg) were added, and the mixture was stirred at 40° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (236 mg) having the following physical properties. TLC: Rf 0.50 (hexane:ethyl acetate=1:1).

[0509] Example 153: tert-Butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenethoxy)acetate To a solution of the compound (236 mg) produced in Example 152 in DMF (2 mL), tert-butyl bromoacetate (424 mg) and sodium hydride (60% in mineral oil, 87 mg) were added and stirred at room temperature for 2.5 hours. A saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (250 mg) having the following physical properties. TLC: Rf 0.60 (hexane:ethyl acetate=4:1).

[0510] Example 154: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenethoxy)ethan-1-ol To a solution of the compound (250 mg) produced in Example 153 in THF (0.5 mL), water (0.1 mL) and lithium borohydride (123 mg) were added and stirred at 40° C. for 2.5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (107 mg) having the following physical properties. TLC: Rf 0.30 (hexane:ethyl acetate=1:1).

[0511] Example 155: Isopropyl (S)-3-(2-(2-(3-(1-hydroxy-2-phenylethyl)phenethoxy)ethoxy)phenyl)propanoate To a solution of the compound produced in Example 154 (107 mg) in dichloromethane (1 mL), the compound produced in Example 1 (90 mg), triphenylphosphine (114 mg) and 1,1-(azodicarbonyl)dipiperidine (110 mg) were added and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain an ester compound (181 mg). To a solution of the ester compound obtained (181 mg) in THF (0.6 mL), water (0.8 mL) and acetic acid (3.2 mL) were added and stirred at 50° C. for 7 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (97 mg) having the following physical properties. TLC: Rf 0.20 (hexane:ethyl acetate=4:1).

[0512] Example 156: 3-[2-[2-[2-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid The title compound having the following physical properties was obtained by using the compound prepared in Example 155 instead of propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 and carrying out the same operations as in Example 11. HPLC retention time (min): 1.10; 1 H-NMR(CDCl3):δ 2.59-2.63, 2.90-2.94, 3.00-3.03, 3.76-3.80, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 7.13-7.21, 7.22-7.32.

[0513] Example 157: 3-[2-[2-[2-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid Instead of (1S)-1-(3-bromophenyl)-2-phenyl-ethanol used in Example 150, the compound prepared in Example 21 was used, and the same operations as those in Example 150 → Example 151 → Example 152 → Example 153 → Example 154 → Example 155 → Example 11 were carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 1.00; 1 H-NMR(CDCl3):δ 2.58-2.62, 2.90-2.95, 2.99-3.06, 3.77-3.81, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 6.88, 7.13-7.21, 7.25-7.32.

[0514] Example 158: tert-Butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate A solution of methyl trans-3-[4-(tert-butoxycarbonylamino)cyclohexyl]propanoate (500 mg) in THF (5 mL) was cooled to 0°C, and a solution of lithium borohydride (72.8 mg) in THF (1 mL) was added, followed by stirring at room temperature for 15 minutes and at 50°C for 3.5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (429 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 0.95-1.28, 1.44, 1.53-1.60, 1.75-1.78, 1.98-2.01, 2.27-2.31, 3.36, 3.62, 4.36.

[0515] Example 159: tert-Butyl (trans-4-(3-oxopropyl)cyclohexyl)carbamate A solution of the compound (429 mg) produced in Example 158 in dichloromethane (8.3 mL) was cooled to 0°C, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (848 mg) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→1:1) to obtain the title compound (429 mg) having the following physical properties. 1 H-NMR(CDCl3): δ 0.96-1.28, 1.44, 1.53-1.60, 1.62-1.75, 1.98-2.01, 2.42-2.46, 3.36, 4.38.

[0516] Example 160: Ethyl (E)-5-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)pent-2-enoate A solution of ethyl diethylphosphonoacetate (747 mg) in THF (5 mL) was cooled to 0° C., sodium hydride (60% in mineral oil, 145 mg) was added, and the mixture was stirred at 0° C. for 15 minutes. A solution of the compound (429 mg) produced in Example 159 in THF (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→1:1) to obtain the title compound (270 mg) having the following physical properties. 1 H-NMR(CDCl3):δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00.

[0517] Example 161: Ethyl 5-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)pentanoate Palladium carbon (54 mg) was added to a solution of the compound (270 mg) produced in Example 160 in ethanol (10 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure to obtain the title compound (282 mg) having the following physical properties. 1 H-NMR(CDCl3):δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00.

[0518] Example 162: tert-Butyl (trans-4-(5-hydroxypentyl)cyclohexyl)carbamate A solution of the compound (282 mg) prepared in Example 161 in THF (5 mL) was cooled to 0° C., lithium borohydride (36 mg) was added, and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (270 mg) having the following physical properties. 1 H-NMR(CDCl3):δ 0.92-1.32, 1.44, 1.53-1.60, 1.73-1.78, 1.98-2.01, 2.26-2.31, 3.36, 3.64, 4.36.

[0519] Example 163: 5-(trans-4-aminocyclohexyl)pentan-1-ol hydrochloride Hydrogen chloride (4.0 M dioxane solution, 6 mL) was added to the compound prepared in Example 162 (140 mg), and the reaction mixture was stirred at room temperature for 1.5 hours and then concentrated to give the title compound (180 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 0.88-0.97, 1.15-1.42, 1.73-1.76, 1.90-1.93, 2.91, 3.36-3.75, 7.86.

[0520] Example 164: 5-(trans-4-(phenylsulfonamido)cyclohexyl)pentyl benzenesulfonate A solution of the compound (180 mg) prepared in Example 163, pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0°C, and DMAP (5 mg) was added. Benzenesulfonyl chloride (0.14 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (180 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 0.84-0.89, 1.07-1.83, 3.04-3.09, 3.98-4.27, 7.51-8.07.

[0521] Example 165: Isopropyl 3-(2-((5-(trans-4-(phenylsulfonamido)cyclohexyl)pentyl)oxy)phenyl)propanoate Cesium carbonate (377 mg) was added to a solution of the compound (180 mg) produced in Example 164 and 1-methyl-2-pyrrolidinone (2 mL), and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→2:1) to obtain the title compound (60 mg) having the following physical properties. 1 H-NMR(CDCl3):δ 0.83-0.92, 1.07-1.84, 2.53-2.57, 2.89-2.93, 3.04-3.12, 3.92-3.95, 4.26-4.27, 4.96-5.02, 6.79-6.86, 7.13-7.17, 7.48-7.59, 7.87-7.89.

[0522] Example 166: 3-[2-[5-[4-(benzenesulfonamido)cyclohexyl]pentoxy]phenyl]propanoic acid The ester compound prepared in Example 165 was used in place of the propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11, and the same procedure as in Example 11 was carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 1.20; 1 H-NMR(CDCl3):δ 0.83-0.92, 1.07-1.83, 2.64-2.68, 2.92-2.96, 3.05-3.13, 3.93-3.96, 4.42-4.43, 6.80-6.88, 7.14-7.20, 7.48-7.59, 7.87-7.89.

[0523] Biological experimental examples are shown below, and the effects of the compounds of the present invention were confirmed based on these experimental methods.

[0524] Biological Experiment Example 1: In vitro test using Schwann cells (Test Method) 1) Preparation of rat Schwann cells Dorsal root ganglia (DRG) from 0-2 day old neonatal rats were extracted in a clean bench and collected in DMEM. The tubes were centrifuged at 400g for 3 minutes at room temperature, the supernatant was removed, and 0.25% collagenase solution was added. The extracted DRG was dispersed and separated by incubation at 37°C for 30 minutes, then centrifuged at 400g for 3 minutes at room temperature, the supernatant was removed, and 0.25% Trypsin / EDTA and DNase I were added. After incubation at 37°C for 30 minutes, trypsin was inactivated with DMEM supplemented with 10% FBS (10% FBS-DMEM), and centrifuged at 400g for 3 minutes at room temperature. After removing the supernatant, 10% FBS-DMEM was added to prepare a cell suspension, which was then passed through a filter (diameter 70 μm). The number of cells in the cell suspension that had passed through the filter was counted, and the number of cells was 2.0 × 10 5 After adjusting the concentration to cells / mL, 100 μL / well of the cells were seeded onto a poly-D-lysine-coated 96-well black-clear plate and cultured statically in a CO2 incubator under conditions of 5% CO2, 95% air, and 37°C. 2) Compound addition The medium in the cell culture plate was removed by aspirating with an aspirator, and DMEM supplemented with 1% dialyzed FBS and 100 μmol / L dibutyryl cyclic AMP was added. Then, a solution of the compound of the present invention dissolved in DMSO was added, and the cells were statically cultured in a CO2 incubator under conditions of 5% CO2, 95% air, and 37°C. The final concentration of the compound of the present invention in the wells of the cell culture plate was 0.1, 0.3, 1, or 3 μmol / L. 3) Cell immunostaining Three days after compound treatment, formaldehyde was added to each well of the cell culture plate and left to stand at room temperature for 30 minutes or more. After removing the supernatant, 0.3% TritonX-100 solution was added and left to stand at room temperature for 20 minutes or more. After removing the supernatant, 5 μg / mL anti-myeline-associated glycoprotein antibody (anti-MAG antibody) solution was added and left to stand at room temperature for 60 minutes or more or at 4 ° C (tolerance range: 1 to 9 ° C) overnight. After washing three times with 0.1% TritonX-100 solution, 10 μg / mL Alexa fluor 488 anti-mouse IgG solution was added and left to stand at room temperature for 60 minutes or more or at 4 ° C overnight. After washing four times with 0.1% TritonX-100 solution, 1 μg / mL Hoechst33342 solution was added to stain the nuclei.

[0525] (Evaluation method) The MAG positive area and cell nuclei number of the fluorescent images were calculated, and the sum of 5 fields / well was used as the MAG positive area and cell nuclei number of each well. The MAG positive area of ​​each well was then divided by the number of cell nuclei (MAG / cell nuclei number) to calculate the Schwann cell differentiation promotion rate relative to the vehicle group using the following formula.

[0526]

number

[0527] (result) The Schwann cell differentiation promotion rate (% of vehicle value) when 0.3 or 3 μmol / L of the compound of the present invention solution was added relative to the vehicle group was as follows. From this, it is considered that the compound of the present invention has a strong neuroprotective and / or repairing effect.

[0528] [Table 1]

[0529] Biological Experimental Example 2: Experiment using streptozotocin-induced rat model In order to evaluate the therapeutic effect of the compound of the present invention on diabetic peripheral neuropathy, an in vivo test was carried out using a streptozotocin model. (Test Method) 1) Model creation method The tumor was generated by administering a single dose of 55 mg / kg of streptozotocin (hereinafter referred to as STZ) intravenously to rats. 2) Measurement of nociceptive threshold Before STZ administration, rats were placed in a transparent acrylic cage for measurement for at least 10 minutes at least once to acclimate them to the measurement environment. Eight von Frey filaments weighing 0.4, 0.6, 1, 2, 4, 6, 8, and 15 g were applied vertically to the plantar part of the hind paw from under the wire mesh floor. A quick escape reaction or a paw shaking reaction was considered a positive reaction (reaction). The compound of the present invention was orally administered once a day from 14 to 28 days after STZ administration at a dose of 0.03, 0.3, or 3 mg / kg. The nociceptive threshold was measured 2 hours after administration of the compound of the present invention before STZ administration, and on 14 days (the day administration of the compound of the present invention was started), 21 days (7 days after administration was started), 28 days (14 days after administration was started), and 35 days (7 days after withdrawal) after STZ administration.

[0530] (Evaluation method) The nociceptive threshold was measured using the up-down method according to the method of Chaplan et al. (J Neurosci Methods. 1994;53:55-63). The improvement rate of the nociceptive threshold was calculated using the following formula.

[0531]

number

[0532] (result) The results of the nociceptive threshold when the compound of the present invention was administered at a dose of 0.3 mg / kg are shown in Figure 1, and the improvement rate of the nociceptive threshold is shown in Table 2. All compounds showed a strong analgesic effect in peripheral neuropathy. For example, the compound of Example 11 showed an improvement in the nociceptive threshold from 7 days after the start of administration, and this effect continued even 7 days after the withdrawal, showing a sustained analgesic effect.

[0533] [Table 2]

[0534] Biological Experiment Example 3: Reactive Metabolite Measurement Test The complexes of the reactive metabolites of the compounds of the present invention with quaternary ammonium glutathione (QA-GSH) were semi-quantified by LC / MS / MS (Soglia JR et al., Chem. Res. Toxicol. 19(3), 480-490, 2006) to measure the amount of NADPH-dependent reactive metabolites. To 187.5 μL of 100 mM phosphate buffer (pH 7.4), 12.5 μL (final concentration: 1 mg / mL) of 20 mg / mL human liver microsomes (Xenotech), 25 μL (final concentration: 1 mmol / L) of 10 mmol / L QA-GSH, and 5 μL (final concentration of the compound of the present invention: 10 μmol / L) of 0.5 mmol / L solution of the compound of the present invention (DMSO: acetonitrile: water = 5: 38: 57) were added. After pre-incubation for 3 minutes in a water bath at 37 ° C, 20 μL (final concentration: 2 mmol / L) of 25 mmol / L NADPH was added to start the reaction. After 1 hour of reaction, 500 μL of IS-containing acetonitrile was mixed to stop the reaction. The complex of reactive metabolites and QA-GSH (QA-GS adduct) generated in the sample after the reaction was stopped was analyzed by LC / MS / MS. Measurements were performed with QA-GS adduct internal standards (IS).

[0535] The QA-GS adduct concentration was calculated using the following formula.

[0536]

number

[0537] (result) The QA-GS adduct concentrations of the compounds of the present invention were low. For example, the QA-GS adduct concentrations of the compounds of Examples 11, 36, 37, 74(13), 84 and 149 were all 200 nmol / L or less.

[0538] Biological Experimental Example 4: Hand-1EST Study The reproductive and developmental toxicity of the compound of the present invention was measured using POCA (registered trademark) Hand1-EST (DS Pharma Biomedical Co., Ltd.), which uses the number of viable cells and differentiation efficiency during the differentiation process of mouse ES cells into cardiac muscle as indicators (Le Coz F et al., J. Toxicol., 40(2):251-61.2015).

[0539] A 1000 mg / mL DMSO solution of the compound of the present invention was prepared. The 1000 mg / mL DMSO solution of the compound of the present invention was diluted with cardiac differentiation medium to prepare a 1000 μg / mL solution of the compound of the present invention (final DMSO concentration 0.1%). While visually checking for the presence or absence of precipitate, the solution was serially diluted 3-fold with cardiac differentiation medium (final DMSO concentration 0.1%), and the concentration without precipitate was recorded as the maximum solubility.

[0540] The thawed Hand1-ES cells (mouse ES cells transformed with the promoter region of the cardiac differentiation marker Hand1 gene and the luciferase gene downstream of it using pGL4.17 as a vector) were suspended in undifferentiated maintenance medium, seeded on a gelatin-coated 60 mm dish, and cultured for 2-3 days. After 2-3 days of culture, trypsinized Hand1-ES cells were seeded on a gelatin-coated 60 mm dish at 2 × 10 6The cells were passaged at 750 cells / 5mL and cultured overnight. Then, trypsinized Hand1-ES cells were suspended in cardiac differentiation medium, seeded on a PrimeSurface (registered trademark) U-bottom 96-well plate at 750 cells / 50μL / well, and cultured for 2 hours. After 2 hours, 50μL of cardiac differentiation medium containing the compound of the present invention or the positive control 5-FU was added (final concentration of the compound of the present invention: 1000, 333, 111, 37.0, 12.3, 4.12 and 1.37μg / mL, final concentration of 5-FU: 1, 0.333, 0.111, 0.0370, 0.0123, 0.00412 and 0.00137μg / mL, final concentration of DMSO: 0.1%), and cultured for 5 days. After exposure to the compound of the present invention or 5-FU for 5 days, CellTiter-Fluor (registered trademark) (Promega) was added to measure the number of viable cells, and fluorescence at an excitation wavelength of Ex 390 nm and a fluorescence wavelength of Em 505 nm was measured using a SpectraMax M5e plate reader (Molecular Devices). Furthermore, Steady-Glo (registered trademark) (Promega) was added to measure differentiation efficiency, and luminescence was measured using a SpectraMax M5e plate reader. The determined maximum solubility, 50% inhibitory concentration of viable cell count, and 50% inhibitory concentration of differentiation efficiency were input into the dedicated analysis software POCA Hand1-EST Analysis Software to determine the teratogenic risk. The criteria for determination were a probability of less than 0.52 as low risk and 0.52 or more as high risk (Nagahori et al., Toxicology Letters 259, 44-51).

[0541] (result) Among the compounds of the present invention, for example, the compounds of Examples 84, 86 and 87 had a probability of less than 0.52, and were considered to have a low risk of teratogenicity.

[0542] [Formulation example] Formulation Example 1 The following ingredients are mixed by a conventional method and compressed into tablets to obtain 10,000 tablets, each containing 10 mg of active ingredient. 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid…100g Calcium carboxymethylcellulose … 20g Magnesium stearate … 10g · Microcrystalline cellulose … 870g

[0543] Formulation Example 2 The following ingredients are mixed in the usual way, filtered through a dust filter, filled into ampoules at 5ml each, and sterilized by heating in an autoclave to obtain 10,000 ampoules, each containing 20mg of active ingredient. 200g 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Mannitol … 20g ·Distilled water … 50L [Industrial Applicability]

[0544] The compound of the present invention has a strong neuroprotective and / or restorative effect and is therefore useful for the prevention and / or treatment of diseases accompanied by neurological disorders.

Claims

1. General formula (I) 【Chemistry 1】 [In the formula, R １ is (1)-R １１ -COOR １２ , (2)-R １３ -CONR １４ R １５ , (3)-R １７ -CN, (4)-R １８ -CONHS (O) ２ -R １９ , (5)-R ２０ - CycD, or 【Chemistry 2】 (In the group, ring 1 represents a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle, R １０１ represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group; n represents an integer of 0 to 3; when n is 2 or more, a plurality of R １０１ may be the same or different; R １１ , R １３ , R １６ , R １７ , R １８ , and R ２０ each independently represents (1) a C1-6 alkylene group optionally substituted with 1 to 3 halogen atoms, (2) a C2-6 alkenylene group optionally substituted with 1 to 3 halogen atoms, or (3) a C2-6 alkynylene group optionally substituted with 1 to 3 halogen atoms, in which when the alkylene group, alkenylene group or alkynylene group is branched, two C1-2 alkyl groups branched from the same carbon atom may be joined together to form a C3-5 saturated carbocyclic ring, R １２ , R １４ , R １５ and R １９ each independently represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group; CycD represents triazole or tetrazole; R ２ represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group; p represents an integer of 0 to 3; when p is 2 or more, a plurality of R ２ may be the same or different, X is (1) CH ２ or (2) an oxygen atom, L １ (1) 1 to 4 R Ｌ１ａ (2) a straight-chain C3-7 alkylene group optionally substituted with 1 to 4 R Ｌ１ａ (3) a straight-chain C3-7 alkenylene group optionally substituted with 1 to 4 R Ｌ１ａ or (4) a straight-chain C alkynylene group optionally substituted with (1 to 2 R Ｌ１ａ a straight-chain C1-3 alkylene group optionally substituted with 1 to 2 R Ｌ１ａ a straight-chain C1-3 alkylene group which may be substituted by R Ｌ１ａ represents (1) a halogen atom, (2) a hydroxyl group, (3) an oxo group, or (4) a C1-2 alkyl group; R Ｌ１ａ When there are two or more R Ｌ１ａ may be the same or different, and two R Ｌ１ａ are each a C1-2 alkyl group, said C1-2 alkyl group together with the carbon atom to which it is attached may form a C3-5 saturated carbocyclic ring; 【Chemistry 3】 represents a single bond, a double bond or a triple bond, R ３ represents (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-2 alkyl group, or (5) a methylidene group; and q represents an integer of 0 to 2; 【Chemistry 4】 When q is a single bond and q is 2, multiple R ３ may be the same or different, and at least one R ３ When is a methyl group, the adjacent L １ together with the carbon atom in to form a cyclopropane, CycA represents (1) a C5-6 monocyclic carbocycle, (2) a 5- to 6-membered monocyclic aromatic heterocycle, (3) isoindoline, or (4) tetrahydroquinoline; R ４ is (1) a halogen atom, (2) a hydroxyl group, (3) a C1-4 alkyl group, (4) a C1-4 haloalkyl group, (5) a C1-4 alkoxy group, (6) a C1-4 haloalkoxy group, (7) a cyano group, or (8) -SO ２ represents a -C1-2 alkyl group, r represents an integer from 0 to 6, and when r is 2 or more, a plurality of R ４ may be the same or different, L ２ is -R ３１ -L ３ -R ３２ - represents L ３ is (1)-NR ２０１ -S(O)-, (2)-NR ２０２ -S (O) ２ -, (3)-NR ２０３ -C(O)-, (4)-CR ２０４ (OH)-, (5)-NR ２０５ -(6) -S(O)-, or (7) -S(O) ２ - represents R ２０１ , R ２０２ , R ２０３ , R ２０４ , and R ２０５ each independently represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, in which the alkyl group or haloalkyl group is optionally substituted by (1) a hydroxyl group, (2) an oxo group, (3) a C3-6 monocyclic carbocyclic ring, or (4) a 3-6 membered monocyclic heterocyclic ring; R ３１ and R ３２ each independently represents (1) a bond, or (2) a C1-3 alkylene group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an oxo group, CycB represents (1) a C5-6 monocyclic carbocycle, (2) a 5- to 6-membered monocyclic aromatic heterocycle, (3) benzofuran, or (4) a 5- to 6-membered monocyclic heterocycle; R ５ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 haloalkyl group, (6) a C2-6 haloalkenyl group, (7) a C2-6 haloalkynyl group, (8) a C1-6 alkoxy group, or (9) a C1-6 haloalkoxy group; t represents an integer of 0 to 6; when t is 2 or more, a plurality of R ５ may be the same or different.] or a salt thereof (with the proviso that the compound of formula (I) does not include 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]penta-4-enoxy]phenyl]propanoic acid).

2. In general formula (I), 【Chemistry 5】 (1) = CH-(1 to 2 R Ｌ１ａ (1)-(a linear C2-6 alkylene group optionally substituted with 1 to 2 R Ｌ１ａ (3) -(a linear C3-7 alkylene group optionally substituted with 1 to 2 R Ｌ１ａ a straight-chain C1-3 alkylene group optionally substituted with 1 to 2 R Ｌ１ａ (In (1) to (3), R Ｌ１ａ has the same meaning as in claim 1), the compound according to claim 1 or a salt thereof.

3. R １ Ga-R １１ -COOR １２ 3. The compound according to claim 1 or 2, wherein:

4. L 2 But (1)-NR ２０２ -S (O) ２ -, or (2) -CR ２０４ (OH)-CH ２ The compound or salt thereof according to any one of claims 1 to 3, wherein

5. The compound or salt thereof according to any one of claims 1 to 4, wherein CycA is a C5-6 monocyclic carbocyclic ring.

6. The compound or salt thereof according to any one of claims 1 to 5, wherein CycB is a C5-6 monocyclic carbocyclic ring.

7. The general formula (I) is represented by the general formula (I-1) 【Chemistry 6】 [In the formula, R １１－１ represents a C2-4 alkylene group; L １－１ is 1 to 2 R Ｌ１ａ represents a linear C3-4 alkylene group optionally substituted with 1 and CycB 1 each independently represents a C5-6 monocyclic carbocyclic ring; L ２－１ is (1)-NH-S(O) 2 -, or (2) -CH(OH)-CH ２ -, and other symbols have the same meanings as in claim 1. The compound or salt thereof according to any one of claims 1 to 6.

8. The compound or salt thereof according to any one of claims 1 to 7, wherein X is an oxygen atom.

9. (1) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (2) 3-[2-[(3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid, (3) 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid, (4) 3-[2-[(E,3R)-5-[4-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (5) 3-[2-[(E,3R)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (6) 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-methylphenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, (7) 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]butanoic acid, (8) 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid, (9) (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid, (10) (S)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid, (11) 3-[2-[5-[3-(benzenesulfonamido)phenyl]pentoxy]phenyl]propanoic acid, (12) 3-[2-[(3S)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid, (13) 3-[2-[(3S)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pentoxy]phenyl]propanoic acid, (14) 3-[2-[2-[2-[3-(benzenesulfonamido)phenyl]ethoxy]ethoxy]phenyl]propanoic acid, (15) 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid, or (16) The compound or salt according to claim 1, which is 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid or a salt thereof.

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