JP7384179B2 - Pharmaceutical composition containing benzene derivative - Google Patents

Description

The present disclosure relates to the following general formula (I)

(In the formula, all symbols have the same meanings as below.)
The present invention relates to a pharmaceutical composition containing the compound represented by the above or a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention).

The nervous system is broadly divided into the central nervous system and the peripheral nervous system, with the peripheral nervous system being responsible for communicating nerve transmission between the brain and spinal cord and the periphery of the body. The peripheral nervous system can be classified into the somatic nervous system (cerebrospinal nervous system) and the autonomic nervous system. Furthermore, the somatic nervous system is divided into cranial nerves and spinal nerves. Furthermore, when the somatic nervous system is functionally classified, those that transmit nerve signals (excitation) generated from sensory receptors to the central nervous system are classified as afferent or sensory nerve fibers; Those that transmit nerve signals from the spinal cord to effect organs such as muscles and glands are classified as efferent or motile nerve fibers. Cranial nerves are peripheral nerves that exit from the brain and are known in 12 pairs, some consisting of sensory, some motor, and some 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, cochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and hypoglossal nerve, respectively. Among these, known nerves consisting of sensory or mixed nerve fibers include the olfactory nerve, optic nerve, trigeminal nerve, facial nerve, cochlear nerve, glossopharyngeal nerve, and vagus nerve. Spinal nerves are peripheral nerves that originate from the spinal cord, and 31 pairs are known on the left and right, 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, including sensory fibers (dorsal roots) that go to the skin and motor fibers (ventral roots) that go to skeletal muscles.

Sensory nerve fibers, or sensory nerves, have the function of accurately transmitting stimuli such as light, sound, temperature, and touch received by sensory receptors such as visual, auditory, olfactory, and gustatory organs, and the skin to the central nervous system. is in charge of The nerve signals transmitted to the central nervous system are ultimately transmitted to each sensory area of the cerebral cortex, such as the visual cortex and the auditory cortex, so that sensations are normally recognized. However, these sensory nerves can be affected by axons, myelin sheaths, or Schwann cells due to viral infections, tumors, cancer, diabetes, ischemia, trauma, compression, drugs, radiation therapy, etc., resulting in cell death or withdrawal. Various neurological disorders such as spinal cord may be caused. As a result, accurate nerve transmission is not carried out in the damaged sensory nerves, leading to the development of diseases such as hearing loss and neuropathic pain. In addition to these, there are peripheral neuropathies in which not only specific sensory nerves but also various peripheral nerves including sensory nerves are simultaneously damaged due to causes such as metabolic diseases, autoimmune diseases, trauma, drug addiction, etc. be. The disease may affect a single nerve, two or more nerves in separate areas, or multiple nerves simultaneously. Symptoms are extremely complex and include tingling, numbness, burning in the periphery, decreased joint proprioception, decreased vibration sensation, pain (including neuropathic pain), paresthesia, coldness or hot flashes, etc. It's wide-ranging.

However, since the mechanisms of peripheral nervous system diseases mentioned above are unknown or physical damage to the nerves occurs, their treatment mainly involves symptomatic treatment aimed at improving symptoms. There are currently few clinically useful drugs known that act directly on the affected nervous system to provide a fundamental treatment.

An object of the present invention is to provide a pharmaceutical composition containing a compound having neuroprotective and/or repair action.

As a result of intensive studies to solve the above problems, the present inventors have found that a pharmaceutical composition containing a compound represented by the general formula (I) shown below or a salt thereof has a strong neuroprotective and/or restorative effect. It was found that
That is, in one aspect of the present invention,
[1] General formula (I)

[Wherein, 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

(In the group, ring1 represents a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle, and ^R101 is (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, and when n is 2 or more, multiple R ¹⁰¹ may be the same or different.),
R ¹¹ , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ²⁰ each independently represent (1) a C1-6 alkylene group optionally substituted with 1 to 3 halogen atoms, (2 ) represents a C2-6 alkenylene group optionally substituted with 1 to 3 halogen atoms, or (3) represents a C2-6 alkynylene group optionally substituted with 1 to 3 halogen atoms; 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 join together to form a C3-5 saturated carbocycle,
R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁹ each independently represent (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, and when p is 2 or more, multiple R ² may be the same or different,
X represents (1) CH ₂ or (2) oxygen atom,
L ¹ is (1) a linear C3-7 alkylene group optionally substituted with 1 to 4 R ^L1a , (2) a linear C3-7 alkylene group optionally substituted with 1 to 4 R ^L1a ; C3-7 alkenylene group, (3) a linear C3-7 alkynylene group optionally substituted with 1 to 4 R ^L1a , or (4) (even if substituted with 1 to 2 R ^L1a ) represents a good linear C1-3 alkylene group) -O- (a straight-chain C1-3 alkylene group optionally substituted with 1 to 2 R ^L1a ),
R ^L1a represents (1) a halogen atom, (2) a hydroxyl group, (3) an oxo group, or (4) a C1-2 alkyl group, and when R ^L1a is two or more, multiple R ^L1a may be the same or different. Furthermore, when two R ^L1a bonded to the same carbon atom are each a C1-2 alkyl group, the C1-2 alkyl group together with the bonded carbon atom forms a C3-5 saturated carbocyclic ring. may be formed,

represents a single, double or 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 from 0 to 2;

is a single bond and q is 2, multiple R ³ may be the same or different, and if at least one R ³ is a methyl group, together with the adjacent carbon atoms in L ¹ May form cyclopropane,
CycA represents (1) a C5-10 monocyclic or bicyclic carbocycle, or (2) a 5-10 membered monocyclic or bicyclic heterocycle,
R ⁴ is (1) halogen atom, (2) hydroxyl group, (3) C1-4 alkyl group, (4) C1-4 haloalkyl group, (5) C1-4 alkoxy group, (6) C1-4 haloalkoxy group, (7) cyano group, or (8) -SO ₂ -C1-2 alkyl group, r represents an integer from 0 to 6, and when r is 2 or more, multiple R ^4s are the same or different. It's okay,
L ² represents -R ³¹ -L ³ -R ³² -,
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 represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, and The alkyl group or haloalkyl group is substituted with (1) a hydroxyl group, (2) an oxo group, (3) a C3-6 monocyclic carbocycle, or (4) a 3-6 membered monocyclic heterocycle. It's okay,
R ³¹ and R ³² may each be independently substituted with (1) a bond, or (2) 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an oxo group. Represents a C1-3 alkylene group,
CycB represents (1) a C5-10 monocyclic or bicyclic carbocycle, or (2) a 5-10 membered monocyclic or bicyclic heterocycle,
R ⁵ is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 haloalkyl group, (6) C2 -6 haloalkenyl group, (7) C2-6 haloalkynyl group, (8) C1-6 alkoxy group, or (9) C1-6 haloalkoxy group, t represents an integer from 0 to 6, and t When the number is 2 or more, the plurality of R ⁵ 's may be the same or different. ] A pharmaceutical composition containing a compound or a salt thereof,
[1-1] The pharmaceutical composition according to [1] above, further comprising a pharmaceutically acceptable carrier;
[2] In general formula (I),

is, (1)=CH-(linear C2-6 alkylene group optionally substituted with 1 to 2 R ^L1a )-, (2) -(substituted with 1 to 2 R ^L1a ) a linear C3-7 alkylene group which may be substituted with 1 to 2 ^R (In (1) to (3), R ^L1a has the same meaning as described in [1] above) ^, [1] The pharmaceutical composition described,
[3] The pharmaceutical composition according to any one of [1] or [2] above, wherein R ¹ is -R ¹¹ -COOR ¹² ;
[4] Any one of the above [1] to [3], wherein L ² is (1) -NR ²⁰² -S(O) ₂ - or (2) -CR ²⁰⁴ (OH) -CH ₂ - a pharmaceutical composition of
[5] The pharmaceutical composition according to any one of [1] to [4] above, wherein CycA is a C5-6 monocyclic carbocycle;
[6] The pharmaceutical composition according to any one of [1] to [5] above, wherein CycB is a C5-6 monocyclic carbocycle;
[7] General formula (I) is general formula (I-1)

[In the formula, R ^11-1 represents a C2-4 alkylene group, L ^1-1 represents a linear C3-4 alkylene group optionally substituted with 1 to 2 R ^L1a , CycA ¹ and CycB ¹ each independently represents a C5-6 monocyclic carbocycle, and L ^2-1 is (1) -NH-S(O) ₂ - or (2) -CH(OH)-CH ₂ -, and other symbols have the same meanings as [1] above. ] The pharmaceutical composition according to any one of [1] to [6] above,
[8] The pharmaceutical composition according to any one of [1] to [7] above, wherein X is an oxygen atom;
[9] The compound represented by general formula (I) or a salt thereof is
(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) 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid The pharmaceutical composition according to [1] above, which is amido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid or a salt thereof;
[10] The pharmaceutical composition according to any one of [1] to [9] above, for neuroprotection and/or repair;
[11] The above-mentioned [10], 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.) ] The pharmaceutical composition described in
[12] The pharmaceutical composition according to [11] above, wherein the neuroprotection and/or repair mediated by glial cells is neuroprotection and/or repair by promoting myelination of Schwann cells.
[13] The pharmaceutical composition according to any one of [1] to [12] above, which is a preventive and/or therapeutic agent for neuropathy;
[14] The pharmaceutical composition according to [13] above, wherein the neuropathy is peripheral neuropathy;
[15] Peripheral neuropathy is associated with chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, or chemotherapy drug administration. The pharmaceutical composition according to [14] above, which is peripheral neuropathy or peripheral neuropathy associated with Charcot-Marie-Tooth disease;
[2-1] A Schwann cell differentiation promoter containing the compound represented by the general formula (I) or a salt thereof according to [1] above,
[2-1-1] Schwann cell differentiation promoter containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof ,
[2-2] A neuroprotective and/or restorative agent containing a compound represented by the general formula (I) or a salt thereof according to [1] above,
[2-2-1] Neuroprotective and/or containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof repair agent,
[2-2-2] 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.) , the agent according to any one of [2-2] or [2-2-1] above,
[2-2-3] The agent according to [2-2-2] above, wherein the neuroprotection and/or repair via glial cells is neuroprotection and/or repair by promoting myelination of Schwann cells;
[2-3] A preventive and/or therapeutic agent for neurological disorders containing the compound represented by the general formula (I) or a salt thereof according to [1] above,
[2-3-1] Prevention of neurological disorders containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or its salts and /or therapeutic agent,
[2-3-2] The agent according to any one of [2-3] or [2-3-1] above, wherein the neuropathy is peripheral neuropathy;
[2-3-3] Peripheral neuropathy is caused by chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, chemotherapy The agent according to [2-3-2] above, which is peripheral neuropathy associated with drug administration or peripheral neuropathy associated with Charcot-Marie-Tooth disease;
Regarding etc.

Pharmaceutical compositions containing the compounds of the present invention have strong neuroprotective and/or restorative effects and are therefore useful for treating neuropathies, such as peripheral neuropathies.

In the streptozotocin model, the nociceptive thresholds are shown when the compounds of Examples 11, 36, 37, and 84 were administered at a dose of 0.3 mg/kg (the vertical axis represents the nociceptive threshold, and the horizontal axis represents the nociceptive threshold after streptozotocin administration. (Represents the number of days that have passed.)

The present invention will be explained in detail below.
In the present invention, a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle refers to a monocyclic saturated heterocycle containing at least one nitrogen atom, such as aziridine, azetidine, pyrrolidine, imidazolidine, Triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydroxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydro Examples include oxadiazole (oxadiazolidine), tetrahydroxazine, tetrahydroxadiazine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, morpholine, and thiomorpholine.

In the present invention, the halogen atom means fluorine, chlorine, bromine, iodine, etc.

In the present invention, the C1-4 alkyl group includes straight-chain or branched C1-4 alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert. -butyl.

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

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. It will be done.

In the present invention, the C2-6 alkenylene group includes linear or branched C2-6 alkenylene groups, such as ethenylene, propenylene, butenylene, pentenylene, hexenylene, or isomers thereof. .

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. .

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

In the present invention, the linear C3-7 alkenylene group includes, for example, propenylene, butenylene, pentenylene, hexenylene, heptenylene, or isomers thereof.

In the present invention, the linear C3-7 alkynylene group includes, for example, propynylene, butynylene, pentynylene, hexynylene, or isomers thereof.

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

In the present invention, examples of the C3-5 saturated carbon ring include cyclopropane, cyclobutane, and cyclopentane.

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

In the present invention, a 5- to 10-membered monocyclic or bicyclic heterocycle refers to a 5- to 10-membered monocyclic or bicyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom, and a sulfur atom. Refers to a ring such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole, isothiazole, Furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, Quinoline, isoquinoline, quinolidine, 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, Dihydroxepin, Tetrahydroxepine, Perhydroxepine, Dihydrothiophene, Tetrahydrothiophene , dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine) ), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine Zine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine, perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydro Thiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathian, indoline , isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, Tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, Dihydroquinazoline, Tetrahydroquinazoline, Perhydroquinazoline, Dihydrocinnoline, Tetrahydrocinnoline, Perhydrocinnoline, Benzoxathian, Dihydrobenzoxazine, Dihydrobenzothiazine, Pyrazinomorpholine, Dihydrobenzoxazole, Perhydrobenzoxazole, Dihydro Examples include benzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxindane, benzodioxane, chroman, benzodithiolane, and benzodithiane.

In the present invention, the C1-4 alkoxy group includes linear or branched C1-4 alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec -butoxy and tert-butoxy.

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

In the present invention, examples of the C3-6 monocyclic carbocycle include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

In the present invention, a 3- to 6-membered monocyclic heterocycle refers to a 3- to 6-membered monocyclic heterocycle containing a hetero atom selected from an oxygen atom, a nitrogen atom, and a sulfur atom, such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, Aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, Dihydropyridazine, tetrahydropyridazine, perhydropyridazine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, tetrahydroxazole (oxazolidine) ), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxazi Azole (Oxadiazolidine), Dihydroxazine, Tetrahydroxazine, Dihydroxadiazine, Tetrahydroxadiazine, Dihydrothiadiazole, Tetrahydrothiadiazole (Thiadiazolidine), Dihydrothiazine, Tetrahydrothiazine, Dihydrothiadiazine, Tetrahydrothiadiazine Examples include gin, morpholine, thiomorpholine, oxathian, dioxolane, dioxane, dithiolane, and dithiane.

In the present invention, a 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, such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazane, 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, tetrahydro Pyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine) ), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine , dihydroxadiazine, tetrahydroxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathian, dioxolane, dioxane , dithiolane, and dithiane.

In the present invention, a 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, Examples include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, and thiadiazole.

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.

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- Mention may be made of butyl, tert-butyl, pentyl, hexyl, or isomers thereof.

In the present invention, the C2-6 alkenyl group includes linear or branched C2-6 alkenyl groups, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, or isomers thereof. .

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. .

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

In the present invention, the C2-6 haloalkenyl group refers to a group in which a linear or branched C2-6 alkenyl group is substituted with one or more halogen atoms, such as 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.

In the present invention, the C2-6 haloalkynyl group refers to a group in which a linear or branched C2-6 alkynyl group is substituted with one or more halogen atoms, such as 1-fluoroethynyl, 2-fluoroethynyl, -Fluoroethynyl, 2-chloroethynyl, pentafluoroethynyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl, 1- Examples include fluoropentynyl and 2-chlorohexynyl.

In the present invention, the C1-6 alkoxy group includes linear or branched C1-6 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, Examples include n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, and isohexyloxy.

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

In the present invention, examples of the linear C2-6 alkylene group include ethylene, propylene, butylene, pentylene, and hexanylene.
In the present invention, examples of the linear C3-7 alkylene group include propylene, butylene, pentylene, hexanylene, and heptanylene.
In the present invention, examples of the linear C1-3 alkylene group include methylene, ethylene, and propylene.

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

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

In the present invention,

means a single bond, double bond or triple bond, and in the case of a double bond, the cis or trans form is included.

In the present invention, the bond direction of L ³ is not limited. For example, when L ³ is -NR ²⁰² -S(O) ₂ -, L ² is -R ³¹ -NR ²⁰² -S(O) ₂ - It may be R ³² or -R ³¹ -S(O) ₂ -NR ²⁰² -R ³² .

In the present invention, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene and alkoxy groups include straight or branched chains, unless otherwise stated.

In the present invention, when R ³ takes a methylidene group, the formula which is a partial structure in general formula (I)

[In the formula, all symbols have the same meanings as above. ] has the following structure

It means to take.

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 the CycA and benzene rings is 5 or more.

In the present invention, R ¹ is preferably -R ¹¹ -COOR ¹² , more preferably -R ¹¹ -COOH. Furthermore, R ¹¹ is preferably a C1-6 alkylene group which may be substituted with 1 to 3 halogen atoms, and a C2-4 alkylene group which may be substituted with 1 to 3 halogen atoms. More preferred.

In the present invention, R ¹ is

When this is the case, ring1 is more preferably a 6-membered nitrogen-containing monocyclic saturated heterocycle, and even more preferably morpholine.

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

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

In the present invention, each of R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁹ is preferably a hydrogen atom.

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

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

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

In the present invention,

A single bond or a double bond is preferable.

In the present invention,

as,
(1)=CH-(linear C2-6 alkylene group optionally substituted with 1 to 3 R ^L1a )-, (2)-(even if substituted with 1 to 3 R ^L1a ) a straight chain C3-7 alkylene group)-, or (3)-(a straight-chain C1-3 alkylene group optionally substituted with 1-2 R ^L1a )-O-(1-2 A linear C1-3 alkylene group optionally substituted with R ^L1a ) - (R ^L1a in (1) to (3) represents the same meaning as above) is preferable,
(1)=CH-(linear C2-6 alkylene group optionally substituted with 1 to 3 R ^L1a )-, or (2)-(substituted with 1 to 3 R ^L1a ) A linear C3-7 alkylene group)-(in (1) to (2), R ^L1a has the same meaning as above) is more preferable,
(1)=CH-(linear C3 alkylene group optionally substituted with 1 to 3 R ^L1a )-, or (2)-(optionally substituted with 1 to 3 R ^L1a ) More preferred is a linear C4 alkylene group) (in (1) to (2), R ^L1a has the same meaning as above).

In the present invention, R ^L1a is preferably a hydroxyl group, a halogen atom, or an oxo group, and more preferably a hydroxyl group.

In the present invention, R ³ is preferably a hydrogen atom.

In the present invention, CycA is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5-10 membered monocyclic or bicyclic heterocycle, such as benzene or a 5-6 membered monocyclic ring. More preferred are aromatic heterocycles.

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.

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

In the present invention, L ³ is preferably -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH).

In the present invention, L ² is preferably -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH)-CH ₂ -.

In the present invention, R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ , and R ²⁰⁵ are each a hydrogen atom, a C1-4 alkyl group, a C1-4 alkyl group substituted with a hydroxyl group, or a C3-6 monocyclic carbon A C1-4 alkyl group substituted with a ring or a C1-4 alkyl group substituted with a 3- to 6-membered monocyclic heterocycle is preferred, and a hydrogen atom is more preferred. Among 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; The substituted C1-4 alkyl group is preferably a C1-4 alkyl group substituted with oxetane, tetrahydrofuran, or tetrahydropyran.

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

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

In the present invention, CycB is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5-6 membered monocyclic heterocycle, such as benzene or a 5-6 membered monocyclic aromatic heterocycle. is even more preferable.

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

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; a halogen atom, a C1-4 alkyl group, a trihalomethyl group, or a C1-4 alkoxy group. is more preferable.

In the present invention, r and t are each preferably an integer of 0 to 3, more preferably an integer of 0 to 2.

In the present invention, a partial structure in general formula (I)

[In the formula, all symbols have the same meanings as above. ] The structure of

is preferable,

is more preferable.

In the present invention, the formula which is a partial structure in general formula (I)

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

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

In the present invention, the formula which is a partial structure in general formula (I)

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

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

In the present invention, as a certain embodiment of general formula (I), general formula (I-i)

[In the formula, L ^1-i is (1) a linear C2-4 alkylene group optionally substituted with 1 to 3 R ^L1a , or (2) -O-(1 to 2 R represents a linear C1-3 alkylene group optionally substituted with ^L1a , and the other symbols have the same meanings as above. ].

In the present invention, as a certain embodiment of general formula (I-i), general formula (I-ii)

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

General formula (I-iii)

[In the formula, L ^1-iii is (1) a linear C2-4 alkylene group optionally substituted with 1 to 3 R ^L1a , or (2) -O-(1 to 2 R ^L1a represents a straight-chain C1-3 alkylene group (optionally substituted with )-, and the other symbols have the same meanings as above. ],or

General formula (I-iv)

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

Certain embodiments of the compound represented by general formula (I-i), (I-ii), (I-iii) or (I-iv) or a salt thereof include:
(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) C5-6 monocyclic carbocycle, or (iv) benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline,
(5) CycB is (i) a C5-6 monocyclic carbocycle or a 5-6 membered monocyclic heterocycle, (ii) benzene or a 5-6 membered monocyclic aromatic heterocycle, (iii) C5-6 monocyclic carbocycle, or (iv) cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran,
(6) L ² is -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH)-CH ₂ -, or (7) R ¹¹ , X, R ^L1a , CycA, CycB and symbols other than L ² are the aforementioned groups (e.g., groups marked as "preferred", "more preferred" or "even more preferred"),
(8) Examples include compounds or salts thereof that are a combination of two or more of the definitions described in (1) to (7) above.

In the present invention, the compound represented by general formula (I-i), (I-ii), (I-iii) or (I-iv) or a salt thereof is preferably:
(1) A compound or a salt thereof in which X is an oxygen atom and L ² is -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH)-CH ₂ -,
(2) X is an oxygen atom, L ² is -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH) -CH ₂ -, and CycA and CycB are C5-6 monocyclic carbocycles. a compound or its salt,
(3) R ¹¹ is a C2-4 alkylene group, X is an oxygen atom, L ² is -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH) -CH ₂ -, and CycA and A compound or a salt thereof in which CycB is a C5-6 monocyclic carbocycle, or (4) X is an oxygen atom, R ^L1a is a hydroxyl group, and L ² is -NR ²⁰¹ -S(O) ₂ - or - CR ²⁰⁴ (OH)-CH ₂ -, and CycA and CycB are C5-6 monocyclic carbocycles, or salts thereof.

In the present invention, as another embodiment of general formula (I), general formula (I-1)

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

[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)

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

General formula (I-1-C)

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

or general formula (I-1-D)

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

Certain embodiments of the compound represented by general formula (I-1-A), (I-1-B), (I-1-C) or (I-1-D) or a salt thereof include:
(1) X is an oxygen atom,
(2) CycA ¹ is benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline,
(3) CycB ¹ is cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran,
(4) a group in which symbols other than X, CycA ¹ and CycB ¹ are as described above (e.g., a group designated as “preferable”, “more preferable” or “even more preferable”),
(5) Compounds or salts thereof that are a combination of two or more of the definitions described in (1) to (4) above are included.

[isomer]
In the present invention, unless otherwise specified, symbols will be used as is clear to those skilled in the art.

represents that it is connected to the other side of the paper (i.e. α configuration),

indicates that it is connected to the front side of the paper (i.e. β configuration),

represents a mixture of α configuration and β configuration at an arbitrary ratio.

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 chains. Furthermore, isomers in double bonds, rings, condensed rings (E, Z, cis, trans forms), isomers due to the presence of asymmetric carbon, etc. (R, S forms, α, β configurations, enantiomers, diastereomers) , optically active substances with optical rotation (D, L, d, l forms), polar forms (highly polar forms, low polar forms) obtained by chromatographic separation, equilibrium compounds, rotamers, mixtures of these in arbitrary proportions, All racemic mixtures are included in the invention.

Furthermore, the optically active compound in the present invention may not only be 100% pure but may also contain less than 50% of other optical isomers.

In the present invention, all references to the compound of the present invention refer to a compound represented by general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a co-crystal thereof, or a compound represented by general formula (I). It includes the N-oxide form of a salt of the compound, its solvate, or its co-crystal.

The compound represented by general formula (I) is converted into the corresponding salt by a known method. The salt is preferably water-soluble. Further, the salt is preferably a pharmaceutically acceptable salt. 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, and pharmaceutical salts. Acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris( hydroxymethyl)aminomethane, N-benzyl-2-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc.) salts, acids Adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartaric acid) salt, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, napadisylate, glucuronate, gluconate, etc.).

The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof may exist in an unsolvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. may exist. It is preferable that the solvate has low toxicity and water solubility, and hydrates are more preferable. The compound represented by general formula (I) and its salt can be converted into a solvate by a known method.

The N-oxide form 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. Further, the N-oxide form of the compound represented by the general formula (I) may further be the above-mentioned alkali (earth) metal salt, ammonium salt, organic amine salt, or acid adduct salt.

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

A prodrug of a compound represented by general formula (I) refers to a compound that converts into a compound represented by general formula (I) by reaction with enzymes, gastric acid, etc. in vivo. As prodrugs of the compound represented by general formula (I), for example, when the compound represented by general formula (I) has an amino group, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g. , the amino group of the compound represented by general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranyl pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated compounds, etc.); When the compound represented by general formula (I) has a hydroxyl group, the hydroxyl group (For example, the hydroxyl group of the compound represented by general formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonyl) When the compound represented by the general formula (I) has a carboxyl group, a compound in which the carboxyl group is esterified or amidated (for example, a carboxyl group of the compound represented by the general formula (I)); is ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidation compounds, etc.). These compounds can be produced by methods known per se. Further, the prodrug of the compound represented by general formula (I) may be a solvate. In addition, prodrugs of the compound represented by the general formula (I) can be prepared under physiological conditions as described in Hirokawa Shoten's 1990 "Pharmaceutical Development", Vol. It may be converted into a compound represented by (I). Furthermore, ^the compound represented by general formula (I) has isotopes (for example, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, 15 N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, ¹²⁵ I, etc.).

[Method for producing the compound of the present invention]
The compound of the present invention can be prepared by a known method, for example, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999), or the method shown in Examples. It can be manufactured by appropriately improving and using them in combination.

Among the compounds represented by general formula (I), general formula (IA)

(In the formula, L ^1M is (1) a linear C2-6 alkylene group optionally substituted with 1 to 4 R ^L1a , (2) optionally substituted with 1 to 4 R ^L1a a straight chain C2-6 alkynylene group, (3) a straight chain C2-6 alkynylene group optionally substituted with 1 to 4 R ^L1a , or (4) (substituted with 1 to 2 R ^L1a) -O- (straight chain C1-3 alkylene group optionally substituted with 1-2 R ^L1a ); other symbols are as above. ) can be produced by the method shown in Reaction Scheme 1 below.

(In the formula, Hal represents a halogen atom, and the other symbols have the same meanings as above.)
In reaction scheme 1, reaction 1-1 is a nucleophilic addition using a compound represented by general formula (A-1) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. This can be done by subjecting it to a reaction. This nucleophilic addition reaction is known, and examples include organic solvents (hexane, heptane, octane, benzene, toluene, tetrahydrofuran (hereinafter abbreviated as THF), dioxane, dimethoxyethane, diethyl ether, or a mixed solvent of two or more thereof). ) or under solvent-free conditions at temperatures of 0 to 120°C. Moreover, for the purpose of promoting the reaction, it can also be carried out in the presence of a catalyst. Examples of the catalyst include formic acid, acetic acid, benzoic acid, 4-dimethylaminobenzoic acid, Schwartz's reagent (CAS registration number: 37342-97-5), and the like.

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 a Suzuki coupling reaction. can. This Suzuki coupling reaction is known, and examples include organic solvents (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, using a palladium catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), dichlorobis(triphenylphosphine)palladium (Cl ₂ Pd(PPh ₃ )). ₂ ), palladium acetate (Pd(OAc) ₂ ), bis(tri-tert-butylphosphine)palladium(0) (Pd(tBu3P)2), etc.) in the presence of bases (sodium hydroxide, potassium hydroxide, triethylamine). , sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) at room temperature to 120°C. .

Furthermore, by subjecting to a reduction reaction using a compound represented by general formula (IA), general formula (IB) can be obtained.

A compound represented by the formula (in which all symbols have the same meanings as above) can be produced. This reduction reaction is known and can be carried out by the following method. Examples include (1) a reduction reaction using a metal, (2) a diimide reduction reaction, and the like. (1) The reduction reaction using a metal can be carried out using, for example, an organic solvent (such as 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) 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 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.), It is carried out at 0 to 200° C. under a hydrogen atmosphere under normal pressure or pressurization. (2) The diimide reduction reaction is performed, for example, by using a hydrazine compound in an organic solvent (toluene, benzene, DMF, THF, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide, methanol, ethanol, or a mixed solvent of two or more thereof). (hydrazine, hydrazine monohydrate, tosylhydrazine, etc.) and a base (sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.) in the presence or absence of 0 to 120°C. It can be done with

Among the compounds represented by general formula (I), general formula (IC)

The compound represented by (the symbols in the formula have the same meanings as above) can be produced by the method shown in Reaction Scheme 2 below.

(In the formula, all symbols have the same meanings as above.)
In reaction scheme 2, reaction 2-1 can be carried out by subjecting a compound represented by general formula (A-1) and a compound represented by general formula (A-3) to a Sonogashira reaction. This Sonogashira reaction is known, and examples include organic solvents (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), water, or a mixed solvent of two or more thereof, or under solvent-free conditions with a base (diethylamine, Triethylamine, propylamine, diisopropylamine, diisopropylethylamine, dibutylamine, tributylamine, pyrrolidine, piperidine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]octane, pyridine, sodium hydroxide, sodium bicarbonate, Sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, potassium fluoride, etc.) in the presence of a catalyst (palladium catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), dichlorobis(triphenyl) phosphine) palladium (Cl2Pd(PPh ₃ ) ₂ ), palladium acetate (Pd(OAc) ₂ ), bis(tri-tert-butylphosphine)palladium(0) (Pd(tBu ₃ P) ₂ ), etc.), or with them. In the presence of a phase transfer catalyst (e.g., tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium acetate, etc.) in the presence of a copper catalyst (such as a mixture with copper (I) iodide, etc.) The reaction is carried out at room temperature to 120° C. under or in the absence of the reaction.

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

The compound represented by (wherein all symbols have the same meanings as above) can be produced by the method shown in Reaction Scheme 3 below.

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

In reaction scheme 3, reaction 3-1 is 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. Can be done. This sulfonamidation reaction is known, and examples include organic solvents (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 mixed solvent of two or more thereof) or under solvent-free conditions. 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.), The reaction is carried out at 0 to 120°C.

In reaction scheme 3, reaction 3-2 involves 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 This can be carried out by subjecting a compound represented by (A-3-1c) and a compound represented by general formula (A-3-1e) to a Mitsunobu reaction. This alkylation reaction is known, and for example, a base is (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 for example, an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-(azodicarboxylate), carbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.) at 0 to 80 °C. This is done by reacting.

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

The compound represented by (in the formula, all symbols have the same meanings as above) can be produced by the method shown in Reaction Scheme 4 below.

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

In Reaction Scheme 4, Reaction 4-1 involves the reaction of a compound represented by general formula (A-3-2a) in an organic solvent (for example, THF, dimethoxyethane, toluene, dichloromethane, diethyl ether, dioxane, methanol, etc.) The reaction is carried out in the presence or absence of cerium chloride using a reducing agent (eg, sodium borohydride, zinc borohydride, etc.) at -20 to 50°C. In addition, when selectively producing only one stereoisomer, an asymmetric reducing agent (for example, chlorodiisopinocamphenylborane, etc.) or a combination of an asymmetric auxiliary and a reducing agent ((R)- (2-methyl-CBS-oxazaborolidine and borohydride/THF complex or borane dimethyl sulfide complex, (S)-(-)-binaphthol and lithium aluminum hydride, etc.) at a temperature of -100 to 50°C. It will be held in

When 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 performed as necessary. This deprotection reaction of the protecting group is known and can be carried out by the following method. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenolysis, (4) deprotection reaction of silyl group, (5) deprotection reaction of metal (6) deprotection reaction using a metal complex, and the like.

To explain these methods specifically,
(1) Deprotection reaction by alkaline hydrolysis is performed using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (e.g., methanol, THF, dioxane, etc.), It is carried out at 0 to 40°C using alkaline earth metal hydroxides (e.g. barium hydroxide, calcium hydroxide, etc.) or carbonates (e.g. sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof. It will be done.
(2) The deprotection reaction under acidic conditions is carried out in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.) with an organic acid (e.g., acetic acid, trifluoroacetic acid, etc.). , methanesulfonic acid, p-tosylic acid, etc.) or inorganic acids (e.g. hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (e.g. hydrogen bromide/acetic acid, etc.). The reaction is carried out at 0 to 100°C in the presence or absence of oxidation.
(3) The deprotection reaction by hydrolysis can be carried out using, for example, a solvent (e.g., ether type (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol type (e.g., methanol, ethanol, etc.), benzene type (e.g., benzene, toluene, etc.), ketone type (e.g., acetone, methyl ethyl ketone, etc.), nitrile type (e.g., acetonitrile, etc.), amide type (e.g., DMF, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc. ) in the presence of a catalyst (e.g. palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) at 0 to 200°C under a hydrogen atmosphere at normal or pressurized pressure or in the presence of ammonium formate. It is done.
(4) The deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (eg, THF, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40°C. Also, for example, organic acids (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or inorganic acids (e.g., hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (e.g., hydrogen bromide/acetic acid, etc.). ) at -10 to 100°C.
(5) The deprotection reaction using a metal can be carried out in the presence of powdered zinc in an acidic solvent (for example, acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of these solutions and an organic solvent such as THF). The process is carried out at 0 to 40°C, with ultrasonication applied if necessary.
(6) The deprotection reaction using a metal complex can be carried out using a trap reagent (for example, hydrogenation tributyltin, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (e.g. acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salts (e.g. sodium 2-ethylhexanoate, 2-ethylhexanoate, etc.) metal complexes (e.g., tetrakistriphenylphosphine palladium(0), bis(triphenylphosphine) dichloride) in the presence or absence of phosphine-based reagents (e.g., triphenylphosphine, etc.); Palladium(II), palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.) is used at 0 to 40°C.

In addition to the above, deprotection reactions can also be carried out, for example, by the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
Examples of protecting groups for hydroxyl groups include methyl group, trityl group, methoxymethyl (MOM) group, 1-ethoxyethyl (EE) group, methoxyethoxymethyl (MEM) group, 2-tetrahydropyranyl (THP) group, and trimethylsilyl group. (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, benzyl (Bn) group, Examples include p-methoxybenzyl group, allyloxycarbonyl (Alloc) group, and 2,2,2-trichloroethoxycarbonyl (Troc) group.

Examples of protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, and trifluoroacetyl group. , 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2-(trimethylsilyl)ethoxymethyl (SEM) group, and the like.
Protective groups for hydroxyl groups and amino groups are not particularly limited as long as they are groups that can be easily and selectively removed other than those mentioned above. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.

In each reaction in this specification, the compounds used as starting materials, for example, those represented by general formulas (A-1), (A-3), (A-3-1a), (A-3-1b) The compounds are known or can be easily prepared by known methods.

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

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

In each reaction herein, the reaction product can be purified by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by methods such as scavenger resin or column chromatography, washing, and recrystallization. Purification may be performed for each reaction or after completion of several reactions.

[toxicity]
The toxicity of the compounds of the present invention is sufficiently low, and they can be safely used as pharmaceuticals.

[Application to pharmaceuticals]
The compounds of the present invention have neuroprotective and/or repair effects.
In one embodiment, the compound of the present invention has a long-lasting neuroprotective and/or repair action.
Therefore, the compounds of the present invention are useful, for example, in the treatment of diseases accompanied by neurological disorders.

In the present invention, embodiments having neuroprotective and/or repair effects include neuroprotection and/or repair via glial cells (e.g., microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.). One example is the effect. Examples of the neuroprotective and/or repair action mediated by glial cells include the action of promoting Schwann cell differentiation (including the action of promoting myelination of Schwann cells).
In the present invention, neurological disorders include peripheral nerve disorders and central nervous disorders. Diseases associated with peripheral neuropathy include diabetic neuropathy, metabolic peripheral neuropathy associated with uremia, peripheral neuropathy associated with vitamin B deficiency, diphtheria, botulism food poisoning, and infectious diseases such as herpes virus (shingles). peripheral neuropathy associated with phenytoin, an anticonvulsant drug, antibiotics (chloramphenicol, nitrofurantoin, sulfonamides, etc.), chemotherapy drugs (taxanes: paclitaxel, docetaxel, etc., platinum drugs: oxaliplatin, cisplatin) , carboplatin, nedaplatin, vinca alkaloids: vinblastine, vincristine, vindesine, etc.), drug-induced peripheral neuropathy associated with administration of sedatives (barbital, hexobarbital, etc.), chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndromes, entrapment neuropathies (e.g., carpal tunnel syndrome, thoracic outlet syndrome, cubital tunnel syndrome, piriformis syndrome, tarsal tunnel syndrome, peroneal nerve entrapment disorder, etc.), and immune-related disorders such as multifocal motor neuropathies. Peripheral neuropathy, peripheral neuropathy associated with allergic diseases such as periarteritis nodosa, allergic vasculitis, and systemic lupus erythematosus, heavy metals such as lead, mercury, arsenic, and thallium, organic solvents such as thinner, and organophosphate pesticides. , toxic substances such as triorthocresyl phosphate (TOCP), toxic peripheral neuropathy associated with the intake of alcohol, peripheral neuropathy due to cancer compressing the nerves, genetic diseases (e.g. hypothyroidism, renal peripheral neuropathy associated with neuropathy, Charcot-Marie-Tooth disease, Refsum disease, porphyria, Fabry disease, hereditary pressure-fragile neuropathy, etc.).

Diseases associated with central nervous system disorders include, for example, Alzheimer's disease, Parkinson's disease, Lewy body dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, dystonia, and prion disease. disease, multiple system atrophy, spinocerebellar degeneration, amyotrophic lateral sclerosis, primary lateral sclerosis, spinobulbar muscular atrophy, spinal muscular atrophy, spastic paraplegia, syringomyelia, multiple Infectious neurological disorders such as sclerosis, neuromyelitis optica, concentric sclerosis, acute disseminated encephalomyelitis, inflammatory diffuse sclerosis, subacute sclerosis panencephalitis, progressive multifocal leukoencephalopathy, hypoxic encephalopathy, These include toxic and metabolic neuropathies such as central pontine myelinopathy, and vascular neuropathies such as Binswanger disease.

In the present invention, aspects of neuropathy include chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, and chemotherapy. Peripheral neuropathy associated with drug administration (including anticancer drugs) or peripheral neuropathy associated with Charcot-Marie-Tooth disease.

In the present invention, one embodiment of the prevention and/or treatment of peripheral neuropathy includes the prevention and/or treatment of subjective symptoms (numbness, pain) or vibration sensation abnormality associated with peripheral neuropathy; another embodiment is the prevention and/or treatment of peripheral neuropathy. Examples include the prevention and/or treatment of pain associated with peripheral neuropathy.

A combination drug containing the compound of the present invention and another drug may be administered in the form of a combination drug containing both components in one preparation, or may be administered in separate preparations. Administration in separate formulations includes simultaneous administration and staggered administration. In addition, in staggered administration, the compound of the present invention may be administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. The respective administration methods may be the same or different.

The diseases for which the above-mentioned concomitant drugs have a preventive and/or therapeutic effect are not particularly limited, as long as they complement and/or enhance the preventive and/or therapeutic effects of the compound of the present invention.

Examples of other drugs for supplementing and/or enhancing the prophylactic and/or therapeutic effects of the compound of the present invention against diseases accompanied by neurological disorders include, for example, aldose reductase inhibitors, vitamins, and brain protective drugs. Examples of aldose reductase inhibitors include epalrestat. Examples of vitamins include mecobalamin. Brain protective drugs include edaravone.

Furthermore, concomitant drugs that can be combined with the compound of the present invention include not only those that have been discovered to date but also those that will be discovered in the future.

The compound of the present invention is usually formulated as a suitable pharmaceutical composition with a pharmaceutically acceptable carrier, and then administered systemically or locally, orally or parenterally. Oral preparations include, for example, liquid preparations for internal use (e.g., elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for oral use (e.g., tablets (sublingual tablets, oral tablets), Examples include disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and troches). Parenteral preparations include, for example, liquid preparations (e.g., injections (intravitreal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, 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.)), external preparations (e.g. , ointment (eye ointment, etc.)), ear drops, etc. These formulations may be release controlled agents such as immediate release formulations and sustained release formulations. These preparations can be manufactured by known methods, for example, the method described in the Japanese Pharmacopoeia.

A liquid preparation for internal use as an oral preparation is produced, for example, by dissolving, suspending, or emulsifying the active ingredient in a commonly used diluent (eg, purified water, ethanol, or a mixture thereof). Furthermore, this liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative, a buffering agent, and the like.

Solid preparations for internal use as oral preparations include, for example, active ingredients combined with excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.) and binders (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, aluminum metasilicate). (magnesium acid, etc.), disintegrants (e.g., calcium glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, solubilizing agents (e.g., glutamic acid, aspartic acid, etc.), and then It is formulated according to the following. Further, if necessary, it may be coated with a coating agent (for example, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc.), or may be coated with two or more layers.

External preparations as parenteral preparations are manufactured by known methods or commonly used formulations. For example, ointments are prepared by blending or melting the active ingredient into a base. The ointment base is selected from those known or commonly used. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes. (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (e.g. , castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (for example, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and anti-rash agents, either alone or in combination of two or more. It is used as Furthermore, it may contain a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent, and the like.

Parenteral injections include solutions, suspensions, emulsions, and solid injections that are dissolved or suspended in a solvent before use. Injections are used, for example, by dissolving, suspending, or emulsifying the active ingredient in a solvent. Examples of the solvent used include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, this injection contains stabilizers, solubilizing agents (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifying agents, soothing agents, buffers, preservatives, etc. Good too. These are sterilized in the final step or manufactured using aseptic procedures. It is also possible to prepare a sterile solid preparation, such as a lyophilized product, and dissolve it in sterilized or sterile injection-grade distilled water or other solvent before use.

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

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

The solvent in parentheses shown at the point of chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the proportions represent volume ratios.
The conditions used in the LC/MS analysis in the following examples are shown below.
Column: YMC Triart C18, 2.0 mm x 30 mm, 1.9 μm; flow rate: 1.0 mL/min; temperature: 30°C; mobile phase A: 0.1% TFA aqueous solution; mobile phase B: 0.1% TFA acetonitrile Solution: Gradient (state the ratio of mobile phase A: mobile phase B): 0 to 0.10 minutes (95:5), 0.10 to 1.20 minutes (95:5 to 5:95), 1.20 minutes to 1.50 minutes (5:95).
The number in parentheses shown in the NMR section indicates the solvent used in the measurement.
The compound names used in this specification are generally named using ACD/Name (registered trademark) of Advanced Chemistry Development, a computer program that names according to IUPAC rules, or according to IUPAC nomenclature. This is what we named it.

Example 1: Isopropyl 3-(2-hydroxyphenyl)propanoate To a solution of 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL) was added sulfuric acid (0.26 mL), and the reaction mixture was heated at room temperature for 2 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (73.2 g) having the following physical properties.
^1H -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.

Example 2: Isopropyl 3-(2-(2-(1,3-dioxan-2-yl)ethoxy)phenyl)propanoate The compound prepared in Example 1 (2.00 g) and 2-(2-bromoethyl)- Potassium phosphate (2.85 g) was added to a solution of 1,3-dioxane (2.43 g) in DMF (4 mL), 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue 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).

Example 3: Isopropyl 3-(2-(3-oxopropoxy)phenyl)propanoate A solution of the compound prepared in Example 2 (500 mg) and lutidine (0.40 mL) in dichloromethane (1.5 mL) was cooled to -15°C. and trimethylsilyltrifluoromethanesulfonate (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 brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (443 mg) having the following physical properties.
^1H -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.

Example 4: A solution of isopropyl 3-(2-((3-hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)oxy)phenyl)propanoate trimethylsilylacetylene (5.0 mL) in THF (70 mL) After cooling to −70° C., n-butyllithium (1.6 M in hexane, 20 mL) was added, and the reaction mixture was stirred at −70° C. for 30 minutes. A solution of the compound prepared in Example 3 (7.15 g) 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 saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and 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.
^1H -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.

Example 5: Isopropyl 3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate A solution of the compound prepared in Example 4 (6.89 g) in THF (38 mL) was The mixture was cooled to 0.degree. 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 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and 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.
^1H -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.

Example 6: Isopropyl (R)-3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate The compound prepared in Example 5 (1.2 g) in heptane (24 mL) ) To the solution, vinyl acetate (4 mL) was added. CHIRAZYME L-5 CA (trade name) (0.4 g) was added, and the reaction mixture was stirred at 45° C. for 9 hours. After filtering the reaction mixture through Celite (trade name), the filtrate was 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 (0.54 g, >99% ee) having the following physical properties. . The obtained compound was subjected to 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, As a result of analysis at a column temperature of 40° C., the retention time was 10.6 minutes.
^1H -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.

Example 7: Isopropyl (R)-3-(2-((3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl)propanoate of the compound prepared in Example 6 (500 mg) The DMF (3.4 mL) solution 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue 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.

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 4,4,5,5-tetramethyl-1 was added to a solution of the compound prepared in Example 7 (2.45 g) in heptane (6 mL). , 3,2-dioxaborolane (2.09 g) and 4-dimethylaminobenzoic acid (53.9 mg) were added, and the mixture was stirred at 100° C. for 13 hours. The reaction solution was cooled to room temperature and then concentrated. The obtained residue 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.

Example 9: N-(3-Bromophenyl)benzenesulfonamide To a solution of 3-bromoaniline (1.02 g) in dichloromethane (20 mL) was added pyridine (0.95 mL), N,N-dimethylaminopyridine ( (hereinafter abbreviated as DMAP) (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, the resulting residue 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. Ta.
HPLC retention time (min): 0.98.

Example 10: Propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate in Example 8 The compound prepared in Example 9 (1.18 g) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1) were added to a solution of the prepared compound (2.00 g) in THF (18 mL). ,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS registration number: 1310584-14-5) (0.30 g) and 2M aqueous tripotassium phosphate solution (5.7 mL) was 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 then concentrated under reduced pressure. TBAF (1.0 M THF solution, 6.3 mL) was added to the resulting residue in THF (6 mL), and the mixture was stirred at room 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 then 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 (1.41 g) having the following physical properties.
HPLC retention time (min): 1.10;
^1H -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.

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

To a solution of the compound produced in Example 10 (680 mg) in THF (5 mL) and methanol (1 mL) was added 1M lithium hydroxide aqueous solution (5 mL), and the mixture was stirred at 30°C for 18 hours. The mixture was made acidic by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (600 mg) having the following physical properties.
HPLC retention time (min): 0.93;
^1H -NMR (CD ₃ OD): 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.

Example 12 (1) to (13)
By using a corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 and subjecting it to the same operation as in Example 10 → Example 11, the following examples were prepared. The compound was obtained.

Example 12 (1): 3-[2-[(E,3R)-5-(3-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0. 95;
^1H -NMR (CD ₃ OD): 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.

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

HPLC retention time (min): 0.92;
MS (ESI, Pos.): 464 (M+H- _H2O ) ⁺ .

Example 12 (3): 3-[2-[(E,3R)-5-(4-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 0. 95;
^1H -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.

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 ) ⁺ .

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 ) ⁺ .

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 (CD ₃ OD): 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.

Example 12 (7): 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylsulfamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time ( minute): 0.94;
MS (ESI, Pos.): 464 (M+H- _H2O ) ⁺ .

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 ) ⁺ .

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;
^1H -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.

Example 12 (10): 3-[2-[(E,3R)-5-[3-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time ( minute): 0.93;
MS (ESI, Pos.): 478 (M+H- _H2O ) ⁺ .

Example 12 (11): 3-[2-[(E,3R)-5-[2-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time ( minute): 0.97;
^1H -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, 7.1 6-7.23, 7.33-7.38, 7.44-7.48, 7.64-7.67.

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 ) ⁺ .

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;
^1H -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.

Example 13 (1) to (19)
By using the corresponding amine compound instead of 3-bromoaniline used in Example 9 and subjecting it to the same operations as in Example 9 → Example 10 → Example 11, the following example compounds were obtained. Ta.

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

HPLC retention time (min): 0.94;
^1H -NMR (CD ₃ OD): 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.

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;
^1H -NMR (CD ₃ OD): 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.

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;
^1H -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.

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;
^1H -NMR (CD ₃ OD): 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.

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;
^1H -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.

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 (CD ₃ OD): 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.

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;
^1H -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.

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;
^1H -NMR (CD ₃ OD): 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.
Example 13 (9): 3-[2-[(E,3R)-5-[3-(benzenesulfonamide

do)-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 .

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;
^1H -NMR (CD ₃ OD): 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 .

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;
^1H -NMR (CD ₃ OD): 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.

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 (CD ₃ OD): 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.

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;
^1H -NMR (CD ₃ OD): 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.

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;
^1H -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.

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 (CD ₃ OD): 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.

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;
^1H -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.

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;
^1H -NMR (CD ₃ OD): 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.

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;
^1H -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.

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;
^1H -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.

Example 14: N-(3-Bromophenyl)-N-(oxetan-2-ylmethyl)benzenesulfonamide To a solution of the compound prepared in Example 9 (313 mg) in THF (2 mL) was added oxetan-2-ylmethanol ( 132 mg), triphenylphosphine (394 mg), and diethyl azodicarboxylate (40% toluene solution, 0.68 mL) were added, and the mixture was 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)

Example 15: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Practice By using the compound prepared in Example 14 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 and performing the same operations as in Example 10→Example 11, the following results were obtained. The title compound having physical properties was obtained.
HPLC retention time (min): 0.95;
^1H -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.

Example 16 (1) to (8)
The experiment was carried out using a corresponding alcohol compound in place of oxetan-2-ylmethanol used in Example 14 and a corresponding halide compound in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. The following example compounds were obtained by performing the same operations as in Example 14→Example 10→Example 11.

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;
^1H -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.

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;
^1H -NMR (CD ₃ OD): 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.

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;
^1H -NMR (CD ₃ OD): 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.

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.

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);
^1H -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.

Example 16 (6): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propane Acid TLC: Rf 0.34 (hexane: ethyl acetate = 1:2);
^1H -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.

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);
^1H -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.

Example 16 (8): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-phenylethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propane Acid TLC: Rf 0.74 (ethyl acetate);
^1H -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, 7.09-7.2 6, 7.31- 7.45, 7.51-7.60.

Example 17: N-(3-bromophenyl)-N-(2-oxopropyl)benzenesulfonamide A solution of the compound prepared in Example 9 (1.00 g) in DMF (6 mL) was hydrogenated under ice cooling. Sodium (60% in mineral oil, 141 mg) was added and stirred at room temperature. After 30 minutes, chloroacetone (0.52 mL) was added and 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 brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue 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)

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

Example 19: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl-(2-hydroxy-2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl ] Propanoic acid Using the compound produced in Example 18 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10, subjecting the same objective operation to Example 10 → Example 11. The title compound having the following physical properties was obtained.
HPLC retention time (min): 0.93;
^1H -NMR (CD ₃ OD): 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, 7.1 7-7.21, 7.25 , 7.35, 7.46-7.54, 7.60.

Example 20 (1) to (4)
Using a corresponding halide compound in place of chloroacetone used in Example 17 and a corresponding halide compound in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10, Example 17 → Implementation The following example compounds were obtained by performing the same operations as in Example 10→Example 11.

Example 20(1): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(methyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention Time (minutes): 0.99;
^1H -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.

Example 20(2): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(ethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention Time (minutes): 1.01;
^1H -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.

Example 20(3): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(benzyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention Time (minutes): 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.

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);
^1H -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.

Example 21: (R)-1-(3-bromophenyl)-2-phenylethan-1-ol 1-(3-bromophenyl)-2-phenylethanone (CAS registration number: 40396-53-0) (2.00 g) in THF (70 mL) at -20°C were (R)-methyloxazaborolidine (1.0 M toluene solution, 3.6 mL) and borane dimethyl sulfide (2.0 M THF solution, 3. 6 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hour. Methanol (1 mL) was added to the reaction solution at -20°C, and the mixture was 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 (1.91 g, 96% ee) having the following physical properties. The obtained compound was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IA (10 mm x 250 mm), mobile phase: CO ₂ : acetonitrile: methanol = 90:9:1, flow rate: 30 mL/min, pressure: 100 bar, wavelength: As a result of analysis at 220 nm (column temperature: 35° C.), the retention time was 5.6 minutes.
HPLC retention time (min): 1.08.

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

Example 23: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid Propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 By using the compound produced in Example 22 instead and subjecting it to the same objective operations as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (min): 0.95;
^1H -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.

Example 24: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid: (S)-methyloxazaborolidine was used in place of (R)-methyloxazaborolidine used in Example 21, and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. Using the corresponding halide compound, the title compound having the following physical properties was obtained by performing the same operations as in Example 21 → Example 10 → Example 11.
HPLC retention time (min): 0.97;
^1H -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.

Example 25: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2R)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid 2-(3-bromophenyl)-1-phenylethanone (CAS registration number: 27798-44-3) was used instead of 1-(3-bromophenyl)-2-phenylethanone used in Example 21. , by using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10, and performing the same operation as in Example 21 → Example 10 → Example 11. , the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.99;
^1H -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, 7.27-7.3 7.

Example 26: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2S)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propane Acid: (S)-methyloxazaborolidine was used in place of (R)-methyloxazaborolidine used in Example 25, and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. The title compound having the following physical properties was obtained by carrying out the same operations as in Example 25 using the corresponding halide compound.
HPLC retention time (min): 0.98;
^1H -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, 7.14-7.2 4, 7.28- 7.38.

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., and phenylmagnesium chloride (1. 0M THF solution, 3.5 mL) was added and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into saturated ammonium chloride solution and extracted with methyl-tert-butyl ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→2:1) to obtain the title compound (610 mg) having the following physical properties.
^1H -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.

Example 28: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-3-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propanoic acid Example 10 By using the compound produced in Example 27 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 and performing the same operations as in Example 10 → Example 11, the following physical property values were obtained. The title compound was obtained.
HPLC retention time (min): 1.00;
^1H -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.

Example 29: 1-(3-bromophenyl)-2-methyl-2-phenylpropan-1-ol 1-(3-bromophenyl)-2-phenyl-ethanone (CAS registration number: 40396-53-0) (220 mg) in toluene (0.4 mL) were added potassium hydroxide (179 mg), 18-crown-6-ether (4 mg) and methyl iodide (0.29 mL), and the reaction mixture was heated at 70°C for 4 hours. Stirred. Water was added to the reaction mixture, and the mixture was extracted with 2-methoxy-2-methylpropane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Sodium borohydride (61 mg) was added to a solution of the obtained residue in methanol (1.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. 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 resulting residue 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).

Example 30: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-methyl-2-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propane Acid By using the compound produced in Example 29 instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10, and subjecting the operation to the same purpose as in Example 10 → Example 11. , the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.10;
^1H -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.

Example 31: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanamide Compound prepared in Example 11 ( Triethylamine (0.021 mL) and isobutyl chloroformate (0.016 mL) were added to a solution of 50 mg) in THF (1 mL) under ice cooling, and the reaction mixture was stirred at 0° C. for 10 minutes. Ammonia (0.5M 1,4-dioxane solution, 0.4 mL) was added at 0°C and 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;
^1H -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.

Example 32 (1) to (3)
The following example compounds were obtained by carrying out the same operations as in Example 31 using the corresponding amine compound instead of ammonia used in Example 31.

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;
^1H -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.

Example 32 (2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N,N-dimethylpropane Amide HPLC retention time (min): 0.95;
^1H -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, 7.23-7.2 6, 7.40- 7.52, 7.78-7.83, 7.98.

Example 32 (3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N-methylpropanamide HPLC Retention time (min): 0.90;
^1H -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.

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

To a solution of the compound prepared in Example 11 (1.1 g) in methanol (10 mL) was added 5% palladium-carbon (200 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After filtering the reaction solution, 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: methanol = 95:5) to obtain the following physical properties. The title compound (1.05g) was obtained.
TLC: Rf 0.30 (hexane: ethyl acetate = 1:2);
^1H -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.

Example 34: 3-[2-[(3S)-5-[3-(benzylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid 3-[2-[(E ,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid using the compound prepared in Example 12(6), Example 33 The following example compounds were obtained by performing the same operations as above.
HPLC retention time (min): 0.81;
^1H -NMR (CD ₃ OD): 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.

Example 35: Isopropyl 3-(2-(((S)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pentyl)oxy)phenyl)propanoate Example To a solution of the compound prepared in 22 (782 mg) in THF (10 mL) were added p-toluenesulfonyl hydrazide (2.66 g) and sodium acetate (1.17 g) 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 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 = 7:3→1:1) to obtain the title compound (515 mg) having the following physical properties.
HPLC retention time (min): 1.22.

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

Substitute for 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 35 was subjected to the same operations as in Example 11 to obtain the title compound having the following physical properties.
HPLC retention time (min): 0.99;
^1H -NMR (CD ₃ OD): 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 .

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

Corresponding to (S)-methyloxazaborolidine in place of (R)-methyloxazaborolidine used in Example 21 and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 10. Using the halide compound, the title compound having the following physical properties was obtained by performing the same operations as in Example 21 → Example 10 → Example 35 → Example 11.
HPLC retention time (min): 0.99;
^1H -NMR (CD ₃ OD): 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 .

Example 38: Isopropyl 3-(2-((3R)-3-hydroxy-3-(2-(3-(phenylsulfonamido)phenyl)cyclopropyl)propoxy)phenyl)propanoate Compound prepared in Example 10 ( A solution of 50 mg) in dichloromethane (2 mL) was cooled to 0°C, diethylzinc (1M solution in hexane, 0.5 mL) was added, followed by diiodomethane (128 mg), and the resulting reaction mixture was incubated at 0°C for 1.5 hours. Stirred. A saturated aqueous ammonium chloride solution 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue 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.

Example 39: 3-[2-[(3R)-3-[2-[3-(benzenesulfonamido)phenyl]cyclopropyl]-3-hydroxypropoxy]phenyl]propanoic acid Propane used in Example 11- Compound prepared in Example 38 in place of 2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical properties was obtained by carrying out the same operations as in Example 11.
HPLC retention time (min): 0.92;
^1H -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.

Example 40: 5-((3-nitrobenzyl)sulfonyl)-1-phenyl-1H-tetrazole 5-[(3-nitrobenzyl)thio]-1-phenyl-1H-tetrazole [J. Org. Chem. (2001), 80, pp. A solution of 11611-11617] (8.50 g) in acetonitrile (150 mL) and ethanol (150 mL) was cooled to 0°C, and a solution of ammonium molybdate tetrahydrate (3.35 g) in hydrogen peroxide (35%, 26 mL) was added. was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature for 2.5 hours. The reaction solution was again cooled to 0° C., and an aqueous sodium thiosulfate solution (1M, 150 mL) was slowly added 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained oil was suspended in a mixed solvent of hexane and ethyl acetate, and the blue solid was collected by filtration. The solid was dissolved in dichloromethane, the resulting solid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (7.71 g) having the following physical properties.
^1H -NMR ( _CDCl3 ): δ 5.12, 7.46-7.64, 7.82, 8.27, 8.35.

Example 41: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-ol (R)-4-[(4-methoxybenzyl) DMAP (0.73 g) and imidazole (6.08 g) were added to a solution of DMF (300 mL) of oxy]butane-1,2-diol (CAS registration number: 213978-61-1) (13.5 g), and reaction was started. The mixture was stirred at 0°C for 5 minutes. Chloro-tert-butyl-dimethylsilane (8.93 g) was added, and the mixture was stirred at room temperature overnight. After diluting the reaction solution with ethyl acetate, the organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (18.1 g) having the following physical properties. I got it.
^1H -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.

Example 42: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-yl benzoate Compound prepared in Example 41 (5.60 g) 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, stirred at room temperature overnight, and then concentrated under reduced pressure. The obtained residue was poured into ethyl acetate, and the organic layer was washed with 1M hydrochloric acid and saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained 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 physical properties shown below.
¹ H-NMR (CDCL ₃ ): δ 0.00, 0.01, 0.85, 2.02-2.08, 3.53-3.57, 3.53-3.57, 3.76, 4.40, 5.27-5.30, 5.27-5.30, 6.81, 7.42, 7.53-7.56, 8.01.

Example 43: (R)-1-hydroxy-4-((4-methoxybenzyl)oxy)butan-2-yl benzoate A solution of the compound prepared in Example 42 (6.31 g) in THF (170 mL) was heated at 0°C. Acetic acid (3.6 mL) and tetrabutylammonium fluoride (1.0 M THF solution, 21.2 mL) were added, and the mixture was stirred at room temperature overnight. The obtained 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 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 (4.10 g) having the physical properties shown below.
^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.

Example 44: (R)-4-((4-methoxybenzyl)oxy)-1-oxobutan-2-yl benzoate Pyridinium dichromate (10.6 g) and Molecular Sieve (trade name) (21.7 g) It was suspended in dichloromethane (30 mL), and a dichloromethane solution (100 mL) of the compound prepared in Example 43 (3.1 g) 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.
^1H -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.

Example 45: (R,E)-5-((4-methoxybenzyl)oxy)-1-(3-nitrophenyl)pent-1-en-3-yl benzoate Compound prepared in Example 40 (3. A solution of 56 g) in THF (70 mL) was cooled to -70°C, and potassium hexamethyldisilazide (0.5M solution in toluene, 22.5 mL) was added. The reaction solution was stirred at −70° C. for 30 minutes, a solution of the compound prepared in Example 44 (3.09 g) 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 with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to 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.

Example 46: (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate, or (S,E)-5-hydroxy-1-(3-nitrophenyl) Phenyl)pent-1-en-3-yl benzoate 2,3-dichloro-5 was added to a solution of the compound prepared in Example 45 (2.23 g) in dichloromethane (100 mL) and phosphate buffer (pH 7, 100 mL) at room temperature. ,6-dicyano-1,4-benzoquinone (2.26 g) was added, 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:4) to obtain a mixture (1.25 g) of the title compound. The resulting mixture was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IA (20 mm x 250 mm), mobile phase: CO ₂ : methanol = 90:10, flow rate: 100 mL/min, pressure: 120 bar, wavelength: 254 nm, column temperature :35°C). The optically active substance obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IA (10 mm x 250 mm), mobile phase: CO ₂ : acetonitrile: methanol = 75:22.5:2.5, flow rate : 30 mL/min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35°C) As a result of analysis, (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-ene-3- The retention times for 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.

Example 47: Methyl 2-(2-hydroxyphenyl)-2-methylpropanoate Methyl 2-(2-hydroxyphenyl) acetate (CAS registration number: 22446-37-3) (1.5 g) in THF (120 mL) ) Lithium diisopropylamide (2.0M THF solution, 18 mL) was added to the solution at -78°C, and the mixture was stirred at the same temperature for 1.5 hours. Methyl iodide (5.2 g) was added to the reaction solution 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. After dissolving the obtained residue (1.8 g) in THF (150 mL), 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. Methyl iodide (2.85 g) was added to the reaction solution 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 a saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1) to obtain the title compound (538 mg) having the following physical properties.
^1H -NMR (DMSO- _d6 ): δ 1.42, 3.51, 6.70-6.83, 7.05, 7.19, 9.49.

Example 48: Methyl 1-(2-hydroxybenzyl)cyclopropane-1-carboxylate A solution of cyclopropylcarbonitrile (CAS Registration Number: 5500-21-0) (3.35 g) in THF (50 mL) at room temperature. Sodium bis(trimethylsilyl)amide (1.0 M THF solution, 75 mL) was added and stirred for 20 minutes. 1-(chloromethyl)-2-methoxybenzene (CAS registration number: 7035-02-1) (7.83 g) was added to the reaction solution at room temperature, and the mixture was stirred under heating under reflux for 3 hours. After cooling to room temperature, 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 then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a crude product (6.00 g) of a nitrile compound. To a solution of the obtained crude nitrile compound (4.50 g) in methanol (50 mL) was added concentrated sulfuric acid (20 mL) at room temperature, and the mixture was stirred under heating under reflux for 5 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure. Ice water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude ester compound (3.20 g). Boron tribromide (1.0 M dichloromethane solution, 18.2 mL) was added dropwise to a solution of the obtained crude ester compound (2.00 g) in dichloromethane (30 mL) at -10°C, and the mixture was stirred at room temperature for 1 hour. did. After concentrating the reaction solution under reduced pressure, the resulting residue was subjected to 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.
^1H -NMR ( _CDCl3 ): δ 1.11, 1.39, 2.90, 3.67, 6.87, 6.99, 7.18, 8.45.

Example 49: Methyl 4-(2-hydroxyphenyl)-2,2-dimethylbutanoate Methyl 4-(2-hydroxyphenyl)butanoate (CAS registration number: 93108-07-7) (3.00 g) in THF A lithium diisopropylamide solution (2.0 M THF solution, 22.5 mL) was added to the solution (150 mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (6.3 g) was added to the reaction solution at -78°C, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then 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) = 95:5 → 5:95). The title compound (538 mg) having the following physical property values was obtained.
^1H -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.

Example 50: Methyl 1-(2-methoxyphenethyl)cyclopropane-1-carboxylate bis(cyclopentadienyl)titanium(IV) dichloride (CAS registration number: 1271-19-8) (34.6 g) in THF Zinc (18.2 g) was added to the (200 mL) solution at room temperature, and the mixture was stirred at the same temperature for 1 hour. Add methyl 2-(1-acetoxymethyl)-2-propenoate (CAS registration number: 30982-08-2) (11.0 g) and 1-(chloromethyl)-2-methoxybenzene (CAS registration number) to the reaction solution at room temperature. A solution of No. 7035-02-1) (10.9 g) in THF (200 mL) was added, and the mixture was stirred at the same temperature overnight. Water was added to the reaction solution and extracted with diethyl ether. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1→2:1) to obtain a crude ester compound (13.0 g). To a solution of the crude product of the obtained ester compound (3.00 g) in diethyl ether (100 mL) were added palladium (II) acetate and diazomethane (0.5M solution in diethyl ether, 32.6 mL) under ice cooling, and the mixture was stirred at room temperature. Stirred for 4 hours. Acetic acid (4 mL) 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 (3.00 g) having the following physical properties.
^1H -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.

Example 51: Methyl 1-(2-hydroxyphenethyl)cyclopropane-1-carboxylate Boron tribromide (1 0M dichloromethane solution (38.4 mL) was added dropwise, and the mixture was stirred at the same temperature for 5 hours. Methanol (30 mL) 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 obtained 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 produce the following: The title compound (515 mg) having physical properties was obtained.
^1H -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.

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) to create a solution. Cooled to 0°C. After adding triethylphosphonoacetate (10.0 g) and stirring at 0°C for 30 minutes, 2-benzyloxy-5-fluoro-benzaldehyde (CAS registration number: 312314-37-7) (8.70 g) was added to DMF ( 10 mL) solution 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 brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (13.2 g) having the physical properties shown below.
^1H -NMR ( _CDCl3 ): δ 1.33, 4.24, 5.13, 6.47, 6.85-7.00, 7.21-7.41, 7.99-8.05.

Example 53: Ethyl 3-(5-fluoro-2-hydroxyphenyl)propanoate Palladium on carbon (1.95 g) was added to a solution of the compound prepared in Example 52 (11.0 g) in ethanol (18 mL), and a hydrogen atmosphere was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1→2:1) to obtain the title compound (5.8 g) having the physical properties shown below.
^1H -NMR ( _CDCl3 ): δ 1.24, 2.71, 2.86, 4.15, 6.77-6.83, 7.23.

Example 54: (R,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-nitrophenyl)penta-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)- Diisopropyl azodicarboxylate (hereinafter referred to as DIAD) was added to a solution of 3-(2-hydroxyphenyl)prop-2-enoate (CAS registration number: 6236-69-7) (90 mg) and triphenylphosphine (130 mg) in THF (1 mL). (abbreviation) (0.1 mL) was added, and the mixture was stirred at room temperature overnight. The residue was concentrated under reduced pressure and the resulting residue 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.
^1H -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.

Example 55: (R,E)-1-(3-aminophenyl)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)penta-1 -en-3-yl benzoate To an ethanol solution (7 mL) of the compound prepared in Example 54 (160 mg) was added stannic chloride (310 mg), 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 sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0→1:2) to obtain the title compound (120 mg) having the physical properties shown below.
^1H -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.

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 prepared in Example 55 (60 mg) and pyridine (0.016 mL) was cooled to 0°C, and phenylsulfonyl chloride (0.018 mL) was added. The mixture was stirred overnight while returning to room temperature. 1M hydrochloric acid and saturated brine were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and 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 (62 mg) having the physical properties shown below.
^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.

Example 57: (E)-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]prop-2-enoic acid A 1M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound produced in Example 56 (62 mg) in THF (1.5 mL) and methanol (0.5 mL), and the mixture was stirred at room temperature for 7 hours. 1M hydrochloric acid and saturated brine were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=10:0→9:1) to obtain the title compound (29 mg) having the physical properties shown below.
HPLC retention time (min): 0.89;
^1H -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.

Example 58: N-[3-[(E,3R)-5-[2-(2-cyanoethyl)phenoxy]-3-hydroxypent-1-enyl]phenyl]benzenesulfonamide Methyl used in Example 54 By using the corresponding phenol compound instead of (E)-3-(2-hydroxyphenyl)prop-2-enoate and performing the same operations as in Example 54 → Example 55 → Example 56, The title compound having the following physical properties was obtained.
HPLC retention time (min): 0.99;
^1H -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.

Example 59: Methyl 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1 -Carboxylate Using the phenol compound produced in Example 51 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54→Example 55→ By performing the same operations as in Example 56, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.10;
^1H -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.

Example 60: Methyl 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoate Using the phenol compound produced in Example 49 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Example 56 The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 1.10;
^1H -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.

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

Example 61 (1): (E)-3-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]proper-2 - Enoic acid HPLC retention time (min): 0.85;
^1H -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.

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.

Example 61 (3): (E)-3-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]proper-2 - Enoic acid HPLC retention time (min): 0.89;
^1H -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.

Example 61 (4): 3-[3-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid HPLC retention time (min ): 0.89;
^1H -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.

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;
^1H -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.

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;
^1H -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.

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

HPLC retention time (min): 0.95;
^1H -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, 7.7 5-7.77.

Example 61 (8): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylpropane Acid HPLC retention time (min): 0.95
^1H -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.

Example 62: 2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid in Example 54 Using the phenol compound produced in Example 47 instead of the used methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate, Example 54 → Example 55 → Example 56 → Example 57 The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 0.95;
^1H -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, 7.76-7.7 8.

Example 63: 1-[[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]methyl]cyclopropane-1-carboxylic acid Using the compound prepared in Example 48 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Example 56 → By performing the same operations as in Example 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.96;
^1H -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.

Example 64: 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoic acid Example Using the compound produced in Example 49 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Example 56 → Example By performing the same operations as in No. 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
^1H -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.

Example 65: 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1- Carboxylic acid Using the phenol compound produced in Example 51 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, Example 54 → Example 55 → Implementation By performing the same operations as in Example 56→Example 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
^1H -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, 6.83-6.9 0, 6.96- 7.00, 7.07-7.18, 7.35-7.39, 7.46-7.52, 7.73-7.76.

Example 66 (1) to (3)
Using the corresponding lactone compound instead of 3,4-dihydrocoumarin used in Example 1, the same objective operation as in Example 1 → Example 54 → Example 55 → Example 56 → Example 57 is performed. As a result, the following example compounds were obtained.

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;
^1H -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.

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;
^1H -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.

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;
^1H -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.

Example 67: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-fluorophenyl]propanoic acid in Example 54 Using the phenol compound produced in Example 53 instead of the methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used, Example 54 → Example 55 → Example 56 → Example 57 The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 0.94;
^1H -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, 7.08-7.1 0, 7.16, 7.40-7.44, 7.50-7.55, 7.76-7.78.

Example 68 (1)-(2)
In place of 2-benzyloxy-5-fluoro-benzaldehyde used in Example 52, the corresponding aldehyde compound was substituted for methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. The following example compounds were prepared by using the corresponding phenol compound instead and performing the same operations as in Example 52 → Example 53 → Example 54 → Example 55 → Example 56 → Example 57. Obtained.

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;
^1H -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, 7.41-7.4 4, 7.50- 7.54, 7.76-7.79.

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;
^1H -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, 7.51-7.5 4, 7.77- 7.79.

Example 69: 3-[2-[(E,3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Methyl used in Example 54 ( E)-3-(2-hydroxyphenyl)prop-2-enoate was replaced with the compound prepared in Example 1 (R,E)-5-hydroxy-1-(3-nitro) used in Example 54. (S,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate prepared in Example 54 was used instead of phenyl)pent-1-en-3-yl benzoate. The title compound having the following physical property values was obtained by performing the same operations as in Example 54 → Example 55 → Example 56 → Example 57.
HPLC retention time (min): 0.93;
^1H -NMR (CD ₃ OD): 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.

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

The compound produced in Example 69 was subjected to the same operations as in Example 33 to obtain the title compound having the following physical properties.
HPLC retention time (min): 0.93;
^1H -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.

Example 71: Isopropyl (R,E)-3-(2-((5-(3-aminophenyl)-3-((trimethylsilyl)oxy)pent-4-en-1-yl)oxy)phenyl)propanoate To a THF (10 mL) solution of the compound (1.00 g) produced in Example 8 were added 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 aqueous tripotassium phosphate solution (5.7 mL) were added, and the mixture was heated at 70°C for 19 min. Stir for 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 then 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.

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 prepared in Example 71 (50 mg) in THF (1 mL) was added pyridine (0.018 mL), DMAP (2.7 mg) and 4-fluorobenzenesulfonyl chloride (CAS registration number: 349) at room temperature. -88-2) (25.6 mg) was added, and the mixture was stirred at the same temperature for 16 hours. TBAF (1.0M 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 then 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). The title compound (515 mg) having the following physical properties was obtained.
HPLC retention time (min): 1.11.

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

Example 74 (1) to (21)
Using the corresponding sulfonyl compound instead of 4-fluorobenzenesulfonyl chloride used in Example 72, the following example compounds were obtained by performing the same operations as in Example 72→Example 11.

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;
^1H -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 .

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;
^1H -NMR (CD ₃ OD): 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.

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;
^1H -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 .

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;
^1H -NMR (CD ₃ OD): 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.

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 ) ⁺ .

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 ) ⁺ .

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 ) ⁺ .

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 ) ⁺ .

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 ) ⁺ .

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 ) ⁺ .

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 ) ⁺ .

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 ) ⁺ .

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

HPLC retention time (min): 0.93;
^1H -NMR (CD ₃ OD): 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.

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);
^1H -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.

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);
^1H -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.

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 .

Example 74 (17): 3-[2-[(E,3R)-5-[3-(1-benzofuran-3-ylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propane Acid HPLC retention time (min): 0.98;
^1H -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.

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);
^1H -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.

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.

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);
^1H -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.

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);
^1H -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.

Example 75: 3-[2-[(3S)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid 3-[2-[( Example 74 (13) was used in place of E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid. The following example compounds were obtained by carrying out the same operations as in No. 33.
HPLC retention time (min): 0.93;
^1H -NMR (CD ₃ OD): 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 .

Example 76: Methyl (R,E)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Practice To a solution of the compound prepared in Example 11 (500 mg) in methanol (10 mL) was added trimethylsilyldiazomethane (2.0 M hexane solution, 2.6 mL) 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:3→1:1) to obtain the title compound (495 mg) having the following physical properties.
HPLC retention time (min): 1.03.

Example 77: Methyl 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopent-4-enoxy]phenyl]propanoate of the compound prepared in Example 76 (495 mg) Manganese dioxide (868 mg) was added to a dichloromethane (10 mL) solution at room temperature, and the mixture was stirred at the same temperature for 20 hours. After filtering the reaction solution through Celite (trade name), the filtrate was concentrated under reduced pressure. The obtained residue 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.
^1H -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, 7.77-7.8 0.

Example 78: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopent-4-enoxy]phenyl]propanoic acid Methyl (R,E )-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate prepared in Example 11 By subjecting the compound to the same intended operations as in Example 77, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.97;
^1H -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.

Example 79: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3-oxopentoxy]phenyl]propanoic acid 3-[2-[(E,3R) used in Example 33 -5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]Propanoic acid was used for the same purpose as in Example 33, using the compound prepared in Example 78. By performing the operations, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.97;
^1H -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.

Example 80: 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]-3-oxopentoxy]phenyl]propanoic acid 3-[2-[ used in Example 78 (E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid was used in place of the compound prepared in Example 12(9). The title compound having the following physical properties was obtained by performing the same operations as in Example 78→Example 79.
HPLC retention time (min): 1.00;
^1H -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.

Example 81: Isopropyl 3-(2-(pent-4-yn-1-yloxy)phenyl)propanoate The compound prepared in Example 1 (3.00 g) was added to a solution of N,N-dimethylacetamide (25 mL) at room temperature. Cesium carbonate (9.39 g) was added thereto, 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 extracted with diethyl ether. 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 = 1:0→5:1) to obtain the title compound (2.40 g) having the following physical properties.
HPLC retention time (min): 1.13.

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 prepared in Example 81 (1.00 g) in heptane (2 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1. 17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added, and the mixture was stirred at 100°C for 4 hours. The reaction solution was cooled to room temperature and then concentrated. The obtained residue 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.

Example 83: Isopropyl (E)-3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Compound prepared in Example 82 (180 mg) in THF (3 mL), the compound prepared in Example 9 (168 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [ 2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.035 g) and 2M aqueous tripotassium phosphate solution (0.67 mL) were added, and the mixture was 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 then concentrated under reduced pressure. The obtained residue 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.

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

A 1M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound produced in Example 83 (146 mg) in THF (0.5 mL) and methanol (0.1 mL), and the mixture was stirred at 50° C. for 8 hours. The mixture was made acidic by adding 1M hydrochloric acid and 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
^1H -NMR (CD ₃ OD): 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.

Example 85: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid N-( used in Example 83) Using 1-(4-bromophenyl)-2-phenylethan-1-ol (CAS registration number: 20498-64-0) in place of 3-bromophenyl)benzenesulfonamide, Example 83 → Example 84 The following example compounds were obtained by subjecting them to the same operations as above.
HPLC retention time (min): 1.10;
^1H -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.

Example 86: 3-[2-[(E)-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid Used in Example 83 By using the compound produced in Example 21 instead of the N-(3-bromophenyl)benzenesulfonamide obtained and subjecting it to the same operation as in Example 83 → Example 84, a product having the following physical property values was obtained. The title compound was obtained.
HPLC retention time (min): 1.20;
^1H -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.

Example 87: 3-[2-[(E)-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid Used in Example 21 (S)-methyloxazaborolidine was used in place of (R)-methyloxazaborolidine, and a corresponding halide compound was used in place of N-(3-bromophenyl)benzenesulfonamide used in Example 83. Then, the title compound having the following physical property values was obtained by subjecting it to the same operations as in Example 21→Example 83→Example 84.
HPLC retention time (min): 1.20;
^1H -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.

Example 87 (1) to (10)
By using the corresponding amine compound instead of 3-bromoaniline used in Example 9 and subjecting it to the same operation as in Example 9 → Example 83 → Example 84, a title having the following physical property values was obtained. The compound was obtained.

Example 87(1): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 1.08;
^1H -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.

Example 87 (2): 3-[2-[(E)-5-[5-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 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.

Example 87 (3): 3-[2-[(E)-5-[3-(benzenesulfonamido)-5-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 1.11;
^1H -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, 7.52-7.5 7, 7.79- 7.82.

Example 87 (4): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (minutes): 1.10;
^1H -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.

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.

Example 87 (6): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-cyanophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.00;
^1H -NMR (CD ₃ OD): 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.

Example 87 (7): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2,4-dichlorophenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min) :1.07;
^1H -NMR (CD ₃ OD): 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.

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.

Example 87 (9): 3-[2-[(E)-5-[3-(benzenesulfonamido)-5-methylsulfonylphenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min) :0.99;
^1H -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.

Example 87 (10): 3-[2-[(E)-5-[3-(benzenesulfonamidomethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.10 ;
^1H -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.

Example 88 (1)-(2)
By using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83, and subjecting it to the same objective operation as Example 83 → Example 35 → Example 84, The title compound having the following physical properties was obtained.

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);
^1H -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.

Example 88 (2): 3-[2-[5-[4-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid HPLC retention time (min): 1.1;
^1H -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.

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 SFC (column used: Daicel Corporation CHIRALPAK-IF (10 mm x 250 mm), Optical resolution was performed using a mobile phase: CO ₂ :acetonitrile:methanol=75:22.5:2.5, flow rate: 30 mL/min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35° C.). The optically active substance of Example 88 (1) obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IF (10 mm x 250 mm), mobile phase: CO ₂ :acetonitrile:methanol=75:22. As a result of analysis, the retention times of the first peak and second peak were 14.9 minutes and 19.5 minutes, respectively. It was 1 minute.

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) was added N,O-dimethylhydroxyl. Amine hydrochloride (609 mg), diisopropylethylamine (2.5 mL) and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (2.4 g) were added, and the mixture was 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).

Example 91: 1-(4-bromothiazol-2-yl)-2-phenylethan-1-one To a solution of the compound prepared in Example 90 (300 mg) in diethyl ether (1 mL) was added benzylmagnesium bromide (0. 1M diethyl ether solution (40 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. 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=8:1) to obtain the title compound (181 mg) having the following physical properties.
TLC: Rf 0.7 (hexane: ethyl acetate = 4:1).

Example 92: 3-[2-[(E)-5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-4-yl]pent-4-enoxy]phenyl]propanoic acid The compound prepared in Example 91 was used instead of 1-(3-bromophenyl)-2-phenylethanone used in Example 21, and the compound prepared in Example 91 was used instead of (R)-methyloxazaborolidine used in Example 21. Example 21 → Example 83 → Example 84 (RS)-methyloxazaborolidine was added using a corresponding halide compound in place of N-(3-bromophenyl)benzenesulfonamide used in Example 83. The title compound having the following physical properties was obtained by carrying out the same operations as above.
HPLC retention time (min): 0.98;
^1H -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.

Example 93: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pent-4-enoxy]phenyl]propanoic acid Corresponding to 2-bromothiazole-4-carboxylic acid in place of 4-bromothiazole-2-carboxylic acid used in Example 90 and in place of N-(3-bromophenyl)benzenesulfonamide used in Example 83. Example 90 → Example 91 → Example 21 (however, (RS)-methyloxazaborolidine was used instead of (R)-methyloxazaborolidine) → Example 83 → By performing the same operations as in Example 84, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
^1H -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.

Example 94: 3-[2-[5-[5-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pentoxy]phenyl]propanoic acid Isopropyl used in Example 35 3 -(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl ) Using the compound prepared in Example 93 instead of propanoate, the following example compound was obtained by subjecting it to the same operation as in Example 35.
HPLC retention time (min): 0.96;
^1H -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.

Example 95: 3-[2-[5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-5-yl]pentoxy]phenyl]propanoic acid Isopropyl used in Example 35 3 -(2-(((R,E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl ) Using the compound prepared in Example 92 instead of propanoate, the following example compound was obtained by subjecting it to the same operation as in Example 35.
HPLC retention time (min): 1.00;
^1H -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.

Example 95 (1): 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]-N-methylsulfonylpropanamide Produced in Example 84 Methanesulfonamide (102 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (124 mg) and DMAP (78.7 mg) were added to a solution of the compound (100 mg) in DMF (1 mL), and the mixture was stirred at room temperature. Stirred for 23 hours. 1M hydrochloric acid 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1→0:1) to obtain the title compound (80.7 mg) having the following physical properties. HPLC retention time (min): 1.00;
^1H -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.

Example 95 (2): 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanamide 3-[2- used in Example 31 Example 31 by using the compound prepared in Example 84 in place of [(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid. By subjecting it to the same operations as above, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.98;
^1H -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.

Example 95(3): N-[3-[(E)-5-[2-(2-cyanoethyl)phenoxy]pent-1-enyl]phenyl]benzenesulfonamide Compound produced in Example 95(2) (100 mg) in THF (1 mL) were added pyridine (0.052 mL) and trifluoroacetic anhydride (67.8 mg) 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 then concentrated under reduced pressure. The obtained residue 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.

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 at 100°C overnight. did. 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;
^1H -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, 7.49-7.5 3, 7.76- 7.78.

Example 95 (5): Isobutyl (E)-(3-(5-(2-(3-amino-3-oxopropyl)phenoxy)pent-1-en-1-yl)phenyl)(phenylsulfonyl)carbamate To a solution of the compound prepared in Example 84 (100 mg) in THF (1 mL) were added triethylamine (0.20 mL) and isobutyl chloroformate (110 mg) 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 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 then 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.

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 prepared in Example 95 (5) (120 mg) in DMF (0.2 mL) was added N,N-dimethylformamide dimethyl acetal (0.5 mL), and the mixture was stirred at 100°C for 4 hours. did. After the reaction solution was concentrated under reduced pressure, acetic acid (1 mL) and hydrazine monohydrate (0.1 mL) were added, and the mixture was stirred at 100°C for 3 hours. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). A 2M aqueous sodium hydroxide solution (0.2 mL) was added to a solution of the obtained residue (48 mg) in methanol (1 mL), and the mixture was 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 then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: methanol = 50:50:3 → 0:100:3) to obtain the title compound (24.0 mg) having the following physical properties. Ta.
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.

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

Example 97: 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid Propane-2- used in Example 11 Using the compound prepared in Example 96 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate By subjecting the mixture to the same operations as in Example 11, the title compound having the following physical properties was obtained.
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, 7.10-7.2 1, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.

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 in Example 96. The produced compound was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (20 mm x 250 mm), mobile phase: CO ₂ : methanol = 85:15, flow rate: 100 mL/min, pressure: 120 bar, wavelength: 220 nm, column temperature: Optical resolution was performed using a temperature of 35°C. The optically active substance of Example 96 obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (10 mm x 250 mm), mobile phase: CO ₂ : methanol = 85:15, flow rate: 30 mL/min , pressure: 120 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 13.6 minutes and 15.8 minutes, respectively.

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 Propan-2-yl 3-[ used in Example 11 Optically active compound of the first peak produced in Example 98 instead of 2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical property values was obtained by subjecting it to the same objective operations as in Example 11.
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, 7.10-7.2 1, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.

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 Propan-2-yl 3-[ used in Example 11 The optically active substance with the second peak produced in Example 98 instead of 2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical property values was obtained by subjecting it to the same objective operations as in Example 11.
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, 7.10-7.2 1, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.

Example 101: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid 3-[2-[(E,3R) used in Example 33 -5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid, using the compound prepared in Example 97, and the same objective operation as in Example 33. The title compound having the following physical properties was obtained.
HPLC retention time (min): 0.96;
^1H -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.

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 SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: Optical resolution was performed using CO ₂ :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 above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: CO ₂ :acetonitrile:methanol=80:18:2, flow rate : 100 mL/min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 9.6 minutes and 12.3 minutes, respectively.

Example 103: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexoxy]phenyl]propanoic acid 3-[2-[(E,3R)-5 used in Example 78 - [3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid was used for the same purpose as Example 78 → Example 79, using the compound prepared in Example 97 The title compound having the following physical properties was obtained.
TLC: Rf 0.45 (hexane: ethyl acetate = 1:2);
^1H -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.

Example 104 (1)-(2)
Using the corresponding phenol compound instead of isopropyl 3-(2-hydroxyphenyl)propanoate used in Example 81, the procedure was carried out for the same purpose as in Example 81 → Example 82 → Example 83 → Example 84. As a result, the following example compounds were obtained.

Example 104 (1): 2-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]acetic acid HPLC retention time (min): 1.01;
^1H -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.

Example 104 (2): 4-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]butanoic acid HPLC retention time (min): 1.07;
^1H -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.

Example 105 (1) to (3)
By using the corresponding halide compound instead of 5-chloro-1-pentyne used in Example 81, and subjecting it to the same objective operation as in Example 81 → Example 82 → Example 83 → Example 84, The following example compounds were obtained.

Example 105 (1): 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]but-3-enoxy]phenyl]propanoic acid HPLC retention time (min): 1.01;
^1H -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.

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);
^1H -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.

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.

Example 106: Methyl 3-(2-((4-hydroxy-5-(3-(phenylsulfonamido)phenyl)pentyl)oxy)phenyl)propanoate The compound prepared in Example 84 (200 mg) was added to ethyl acetate (1 mL). ) dissolved in Methanol (1 mL) and trimethylsilyldiazomethane (2M hexane solution, 0.3 mL) were added, and the mixture was 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. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, 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 under a hydrogen atmosphere for 3 hours. After filtering the reaction solution, 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) was obtained.
TLC: Rf 0.31 (hexane: ethyl acetate = 1:1).

Example 107: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-hydroxypentoxy]phenyl]propanoic acid Propan-2-yl 3-[2-[ used in Example 11) Same as Example 11, using the compound prepared in Example 106 instead of (E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate. By performing the desired operations, the title compound having the following physical properties was obtained.
TLC: Rf 0.60 (ethyl acetate);
^1H -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.

Example 108: Ethyl 3-(2-(4-oxobutyl)phenyl)propanoate Ethyl 3-[2-(4-hydroxybutyl)phenyl]propanoate (CAS Registration Number: 864677-94-1) (0.56 g) Sodium bicarbonate (0.56 g) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (CAS Registration No. :87413-09-0) (1.13 g) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue 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).

Example 109: 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid Isopropyl 3-( used in Example 4) Same as Example 4→Example 5→Example 7→Example 8→Example 10→Example 11 using the compound produced in Example 108 instead of 2-(3-oxopropoxy)phenyl)propanoate By subjecting it to the desired operation, the title compound having the following physical properties was obtained.
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.

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

The compound produced in Example 109 was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (20 mm x 250 mm), mobile phase: CO ₂ : 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 above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IC (10 mm x 250 mm), mobile phase: CO ₂ : methanol = 85:15, flow rate: 30 mL/min , pressure: 100 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 12.4 minutes and 14.4 minutes, respectively.

Example 111: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexyl]phenyl]propanoic acid 3-[2-[(E,3R)- used in Example 33 The same objective procedure as in Example 33 was carried out using the compound prepared in Example 109 in place of 5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid. As a result, the title compound having the following physical property values was obtained.
HPLC retention time (min): 0.95;
^1H -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.

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

Example 109 in place of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 78 By using the compound prepared in Example 78 and subjecting it to the same objective operations as in Example 79, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
^1H -NMR (CD ₃ OD): 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, 7.43-7.4 8, 7.54 , 7.74-7.76.

Example 113: Isopropyl 3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate Compound prepared in Example 81 (1.5 g ) and the compound prepared in Example 9 (1.7 g) in DMF (6 mL), triethylamine (6 mL), bis(triphenylphosphine)palladium(II) dichloride (100 mg), copper(I) iodide (50 mg). ) and stirred at 60°C overnight. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, 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).

Example 114: 3-[2-[5-[3-(benzenesulfonamido)phenyl]pent-4-inoxy]phenyl]propanoic acid Propan-2-yl 3-[2-[( The same procedure as in Example 11 was carried out using the compound prepared in Example 113 in place of E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate. By subjecting it to the intended operations, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.00;
^1H -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.

Example 115: Isopropyl (R)-3-(2-((5-(3-(phenylsulfonamido)phenyl)-3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl ) Propanoate The same purpose as in Example 113 was obtained by using the compound prepared in Example 7 instead of isopropyl 3-(2-(pent-4-yn-1-yloxy)phenyl)propanoate used in Example 113. By subjecting it to the operation, the title compound having the following physical properties was obtained.
HPLC retention time (min): 1.12.

Example 116: Isopropyl (R)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate Example 115 TBAF (1.0 M THF solution, 0.48 mL) was added to a THF (1 mL) solution of the compound (170 mg) prepared above at room temperature, and the mixture was 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.

Example 117: 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-inoxy]phenyl]propanoic acid Propane-2- used in Example 11 Using the compound prepared in Example 116 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate By subjecting the mixture to the same operations as in Example 11, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.93;
^1H -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.

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

Example 114 instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 Using the compound prepared in Example 33, the title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 33.
TLC: Rf 0.42 (hexane: ethyl acetate = 1:2);
^1H -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.

Example 119: Isopropyl (Z)-3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Compound prepared in Example 113 (100 mg) in ethyl acetate (10 mL) at room temperature were added Lindlar catalyst (containing 5% by weight of palladium) (10.0 mg) and quinoline (12.8 mg), 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.

Example 120: 3-[2-[(Z)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid Propan-2-yl 3-[ used in Example 11 Using the compound prepared in Example 119 in place of 2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate, Example The title compound having the following physical properties was obtained by subjecting it to the same operation as in No. 11.
HPLC retention time (min): 1.10;
^1H -NMR (CD ₃ OD): 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.

Example 121: 3-[2-[(Z,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid Isopropyl used in Example 119 3 Example 119 using the compound prepared in Example 116 in place of -(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate →The title compound having the following physical properties was obtained by subjecting it to the same operations as in Example 11.
HPLC retention time (min): 0.92;
^1H -NMR (CD ₃ OD): 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.

Example 122: Ethyl (E)-3-(2-(3-(benzyloxy)-2-hydroxypropoxy)phenyl)acrylate Ethyl (E)-3-(2-hydroxyphenyl)prop-2-enoate (CAS Benzyl glycidyl ether (6.57 g) was added to a solution of Registration Number: 6236-62-0) (1.92 g) and diisopropylethylamine (0.69 mL) in hexamethylphosphoramide (20 mL), and the reaction mixture was heated at 80°C. The mixture was stirred for 19 hours. After cooling the reaction solution to room temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue 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).

Example 123: Ethyl (E)-3-(2-(3-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)propoxy)phenyl)acrylate Compound prepared in Example 122 (300 mg) and To a solution of imidazole (200 mg) in DMF (3 mL) was added tert-butyldimethylsilyl chloride (330 mg) 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 brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue 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).

Example 124: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-hydroxypropoxy)phenyl)propanoate The compound prepared in Example 123 (380 mg) and 5% palladium on carbon (50% A solution of 180 mg) in ethanol (8 mL) was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. After filtering the reaction mixture through Celite (trade name), 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).

Example 125: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)propanoate The compound prepared in Example 124 (290 mg) and sodium hydrogen carbonate (190 mg) 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (390 mg) was added to a methylene chloride (3 mL) solution at 0°C, and the reaction mixture was Stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue 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).

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

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

Substitute for propan-2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11 By using the compound produced in Example 126 and subjecting it to the same objective operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (min): 0.95;
^1H -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.

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 in Example 126 The produced compound was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IB (20 mm x 250 mm), mobile phase: CO ₂ :2-propanol = 83:17, flow rate: 100 mL/min, pressure: 120 bar, wavelength: 220 nm, column Optical resolution was performed using a temperature of 35°C. The optically active substance of Example 126 obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IB (10 mm x 250 mm), mobile phase: CO ₂ :2-propanol = 83:17, flow rate: 30 mL /min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35°C), the retention times of the first peak and second peak were 12.6 minutes and 14.6 minutes, respectively.

Example 129: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid Propane-2- used in Example 11 The first peak prepared in Example 128 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 11 using the optically active form of .
HPLC retention time (min): 0.95;
^1H -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.

Example 130: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid Propane-2- used in Example 11 The second peak prepared in Example 128 instead of yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 11 using the optically active form of .
HPLC retention time (min): 0.95;
^1H -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.

Example 131: N-(3-bromophenyl)-N-(phenylsulfonyl)benzenesulfonamide To a solution of 3-bromoaniline (500 mg) in dichloromethane (10 mL) is added triethylamine (1.6 mL) and DMAP (177 mg) and benzene. Sulfonic anhydride (1.9 g) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with dichloromethane. 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 = 4:1) to obtain the title compound (950 mg) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 4:1).

Example 132: N-(3-(4-hydroxybut-1-yn-1-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide The compound prepared in Example 131 (949 mg) 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 to the solution, and the mixture was stirred at 80° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (771 mg) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 2:1).

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

Example 134: 3-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid To a solution of the compound prepared in Example 133 (45 mg) in THF (0.5 mL) was added 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. A 5N aqueous sodium hydroxide solution (0.4 mL) was added to a solution of the obtained residue in methanol (0.5 mL) and 1,2-dimethoxyethane (0.5 mL), and the mixture was stirred at 45° C. for 19 hours. 2M hydrochloric acid 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 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;
^1H -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.

Example 135 (1) to (6)
The following example compound was obtained by subjecting it to the same operation as in Example 134, using the corresponding phenol compound instead of methyl 3-(3-hydroxyphenyl)propanoate used in Example 134.

Example 135 (1): 3-[4-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid HPLC retention time (min): 0.96;
^1H -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.

Example 135 (2): 4-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid HPLC retention time (min): 1.00;
^1H -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.

Example 135 (3): 4-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid HPLC retention time (min): 0.99;
^1H -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.

Example 135 (4): 2-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]acetic acid HPLC retention time (min): 0.94;
^1H -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.

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, 7.75-7.7 8.

Example 135 (6): 3-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid HPLC retention time (min): 0.99;
^1H -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, 7.48-7.5 3, 7.60, 7.78-7.81.

Example 136: Isopropyl (E)-3-(2-((5-(3-nitrophenyl)-3-oxopent-4-en-1-yl)oxy)phenyl)propanoate N- used in Example 10 By using 3-bromonitrobenzene in place of (3-bromophenyl)benzenesulfonamide and subjecting it to the same operations as in Example 10→Example 77, the title compound having the following physical properties was obtained.
TLC: Rf 0.43 (hexane: ethyl acetate = 2:1).

Example 137: Isopropyl (E)-3-(2-((3,3-difluoro-5-(3-nitrophenyl)pent-4-en-1-yl)oxy)phenyl)propanoate Prepared in Example 136 The obtained compound (205 mg) 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 sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue 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).

Example 138: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropent-4-enoxy]phenyl]propanoic acid used in Example 55 (R ,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-nitrophenyl)pent-1-en-3-yl By using the compound produced in Example 137 instead of benzoate and subjecting it to the same operations as in Example 55 → Example 56 → Example 11, the title compound having the following physical properties was obtained.
TLC: Rf 0.22 (hexane: ethyl acetate = 1:2);
^1H -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.

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

Example 138 in place of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33 Using the compound prepared in Example 33, the title compound having the following physical properties was obtained by subjecting it to the same objective operations as in Example 33.
TLC: Rf 0.20 (hexane: ethyl acetate = 1:2);
^1H -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, 7.7 9.

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

Example 141: (S)-5-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)sulfonyl)-1-phenyl-1H-tetrazole Compound prepared in Example 140 To a solution of (4.14 g) in acetonitrile (15 mL) and ethanol (15 mL), ammonium molybdate tetrahydrate (1.57 g) and 30% by weight hydrogen peroxide solution (8.3 mL) were added under ice cooling, and the mixture was heated to room temperature. The mixture was stirred for 16 hours. After concentrating the reaction solution under reduced pressure, the resulting aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. After dissolving the obtained residue in 2,2-dimethoxypropane (8.3 mL), 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 saturated aqueous sodium hydrogen carbonate solution and saturated brine. 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 = 7:1→2:1) to obtain the title compound (3.96 g) having the following physical properties.
HPLC retention time (min): 0.96.

Example 142: (S,E)-N-(3-(4,5-dihydroxypent-1-en-1-yl)phenyl)benzenesulfonamide 1 of the compound prepared in Example 141 (1.04 g) Potassium bis(trimethylsilyl)amide (0.5M toluene solution, 15.3 mL) was added to a solution of ,2-dimethoxyethane (15 mL) at -78°C, and the mixture was stirred at the same temperature for 10 minutes. A solution of N-(3-formylphenyl)benzenesulfonamide (CAS registration number: 151721-35-6) (800 mg) in 1,2-dimethoxyethane (5 mL) was added to the reaction solution at -78°C, and 1 Stir for 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 then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). After dissolving the obtained residue in methanol (3 mL), 2M 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 with ice, neutralized with a 2M aqueous sodium hydroxide solution, 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 = 1:0→9:1) to obtain the title compound (675 mg) having the following physical properties.
HPLC retention time (min): 0.73.

Example 143: (S,E)-1-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl benzoate The compound prepared in Example 142 (450 mg) and imidazole (131 mg) ) to a DMF (5 mL) solution under ice-cooling, t-butyldimethylchlorosilane (0.7M DMF solution, 2 mL) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 24 hours. After cooling the reaction solution with ice, 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 then concentrated under reduced pressure. After dissolving the obtained residue in dichloromethane (5 mL), 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 cooling the reaction solution with ice, benzoyl chloride (215 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→2:1). After dissolving the obtained residue in THF (3 mL) and acetic acid (0.30 mL), TBAF (1.6 mL of 1.0 M THF solution) was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→2:1) to obtain the title compound (292 mg) having the following physical properties.
HPLC retention time (min): 0.97.

Example 144: (S,E)-1-iodo-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl benzoate The compound prepared in Example 143 (147 mg) in DMF (1 mL) ) Imidazole (68.6 mg) and triphenylphosphine (106 mg) were added to the solution 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 cooling the reaction solution on ice, 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.

Example 145: (S,E)-1-(2-(3-isopropoxy-3-oxopropyl)phenoxy)-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-yl Benzoate To a solution of the compound prepared in Example 1 (68.4 mg) in DMF (0.5 mL) was added sodium hydride (60% in mineral oil, 13.1 mg) under ice cooling, and the mixture was stirred at room temperature for 15 minutes. . A solution of the compound prepared in Example 144 (60 mg) 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, it was purified by silica gel column chromatography (hexane:ethyl acetate = 7:1→3:2) to obtain the title compound (12.1 mg) having the following physical properties.
HPLC retention time (min): 1.29.

Example 146: 3-[2-[(E,2S)-5-[3-(benzenesulfonamido)phenyl]-2-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 57 (R ,E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-(phenylsulfonamido)phenyl)pent-1-ene By using the compound prepared in Example 145 in place of -3-yl benzoate and carrying out the same operation as in Example 57, the title compound having the following physical properties was obtained.
HPLC retention time (min): 0.95
^1H -NMR (CD ₃ OD): 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.

Example 147: A solution of 2-(3-nitrophenethoxy)acetic acid 2-(3-nitrophenyl)ethanol (CAS registration number: 52022-77-2) (2.00 g) in DMF (4 mL) was cooled to 0 °C. Then, 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue 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), added with sodium hydroxide (2N aqueous solution, 10 mL), and 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 brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.15 g) having the following physical properties.
^1H -NMR ( _CDCl3 ): δ 3.05-3.07, 3.84-3.87, 4.14, 7.48, 7.58-7.60, 8.09-8.14.

Example 148: 2-(3-nitrophenethoxy)ethane-1-ol A solution of the compound prepared in Example 147 (1.15 g) and 4-methylmorpholine (0.8 mL) in THF (10 mL) was heated to 0°C. After cooling, isobutyl chloroformate (0.8 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes, and the resulting white solid was collected by filtration. The filtrate was cooled to 0°C, sodium borohydride (1.15g) was added, and the mixture was stirred at 0°C for 10 minutes, then 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 brine, 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.
^1H -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.

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

In place of (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate used in Example 54, the compound prepared in Example 148 was used in Example 54. Using the compound prepared in Example 1 instead of the used methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate, Example 54→Example 55→Example 56→Example 11 By subjecting it to a similar operation, the title compound having the following physical properties was obtained.
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.

Example 150: tert-butyl (S)-2-(3-(1-hydroxy-2-phenylethyl)phenyl)acetate (1S)-1-(3-bromophenyl)-2-phenyl-ethanol (412 mg) To a THF (0.5 mL) solution were added bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (0.5 M THF solution, 9 mL) and bis(tri-tert-butylphosphine) palladium (76 mg). , and stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, saturated ammonium chloride aqueous solution was added, and the mixture was 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 = 4:1) to obtain the title compound (296 mg) having the following physical properties.
TLC: Rf 0.40 (hexane: ethyl acetate = 4:1).

Example 151: tert-butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)acetate Compound prepared in Example 150 ( 3,4-dihydro-2H-pyran (239 mg) and pyridinium 4-toluenesulfonate (71 mg) were added to a solution of 296 mg) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution 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 obtained residue 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).

Example 152: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)ethan-1-ol Compound prepared in Example 151 (341 mg) 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to obtain the title compound (236 mg) having the following physical properties.
TLC: Rf 0.50 (hexane: ethyl acetate = 1:1).

Example 153: tert-butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenetoxy)acetate Compound prepared in Example 152 ( Tert-butyl bromoacetate (424 mg) and sodium hydride (60% in mineral oil, 87 mg) were added to a solution of 236 mg) in DMF (2 mL), and the mixture was 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 obtained residue 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).

Example 154: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenetoxy)ethane-1-ol Compound prepared in Example 153 (250 mg) in THF (0.5 mL) were added water (0.1 mL) and lithium borohydride (123 mg), and the mixture was stirred at 40°C for 2.5 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 obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (107 mg) having the following physical properties.
TLC: Rf 0.30 (hexane: ethyl acetate = 1:1).

Example 155: Isopropyl (S)-3-(2-(2-(3-(1-hydroxy-2-phenylethyl)phenetoxy)ethoxy)phenyl)propanoate The compound prepared in Example 154 (107 mg) was dissolved in dichloromethane ( The compound prepared in Example 1 (90 mg), triphenylphosphine (114 mg) and 1,1-(azodicarbonyl)dipiperidine (110 mg) were added to the 1 mL) solution, and the mixture was stirred at room temperature for 1.5 hours. . The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain an ester compound (181 mg). To a solution of the obtained ester compound (181 mg) in THF (0.6 mL) were added water (0.8 mL) and acetic acid (3.2 mL), and the mixture was stirred at 50°C for 7 hours. A saturated aqueous sodium hydrogen carbonate 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 obtained residue 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).

Example 156: 3-[2-[2-[2-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid Propane used in Example 11 Compound prepared in Example 155 in place of 2-yl 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate The title compound having the following physical property values was obtained by subjecting it to the same objective operations as in Example 11.
HPLC retention time (min): 1.10;
^1H -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.

Example 157: 3-[2-[2-[2-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid used in Example 150 (1S )-1-(3-Bromophenyl)-2-phenyl-ethanol using the compound produced in Example 21, Example 150 → Example 151 → Example 152 → Example 153 → Example 154 → Example 155 was subjected to the same operation as in Example 11 to obtain the title compound having the following physical properties.
HPLC retention time (min): 1.00;
^1H -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, 7.25-7.3 2.

Example 158: A solution of tert-butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate methyl trans-3-[4-(tert-butoxycarbonylamino)cyclohexyl]propanoate (500 mg) in THF (5 mL) was The mixture was cooled to .degree. C., a solution of lithium borohydride (72.8 mg) in THF (1 mL) was added, and the mixture was stirred at room temperature for 15 minutes and at 50.degree. C. for 3.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (429 mg) having the following physical properties.
^1H -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.

Example 159: tert-butyl (trans-4-(3-oxopropyl)cyclohexyl)carbamate A solution of the compound prepared in Example 158 (429 mg) 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 the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, 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 (429 mg) having the following physical properties.
^1H -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.

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 heated to 0°C. After cooling, sodium hydride (60% in mineral oil, 145 mg) was added and stirred at 0° C. for 15 minutes. A solution of the compound prepared in Example 159 (429 mg) 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 brine, 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 (270 mg) having the following physical properties.
^1H -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, 6.91-7.0 0.

Example 161: Ethyl 5-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)pentanoate Palladium on carbon (54 mg) was added to a solution of the compound prepared in Example 160 (270 mg) in ethanol (10 mL), The mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. 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 physical properties shown below.
^1H -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, 6.91-7.0 0.

Example 162: tert-Butyl (trans-4-(5-hydroxypentyl)cyclohexyl)carbamate A solution of the compound prepared in Example 161 (282 mg) in THF (5 mL) was cooled to 0°C, and lithium borohydride (36 mg ) and stirred at 50°C for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (270 mg) having the following physical properties.
^1H -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.

Example 163: 5-(trans-4-aminocyclohexyl)pentan-1-ol hydrochloride Hydrogen chloride (4.0 M solution in dioxane, 6 mL) was added to the compound prepared in Example 162 (140 mg), and the reaction mixture was heated to room temperature. After stirring for 1.5 hours, the mixture was concentrated to obtain the title compound (180 mg) having the following physical properties.
^1H -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.

Example 164: 5-(trans-4-(phenylsulfonamido)cyclohexyl)pentyl benzenesulfonate A solution of the compound prepared in Example 163 (180 mg) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0 °C, and DMAP was added. (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 sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (180 mg) having the following physical properties.
^1H -NMR ( _CDCl3 ): δ 0.84-0.89, 1.07-1.83, 3.04-3.09, 3.98-4.27, 7.51-8.07.

Example 165: Isopropyl 3-(2-((5-(trans-4-(phenylsulfonamido)cyclohexyl)pentyl)oxy)phenyl)propanoate The compound prepared in Example 164 (180 mg) and 1-methyl-2- Cesium carbonate (377 mg) was added to the pyrrolidinone (2 mL) solution, 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue 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.
^1H -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.

Example 166: 3-[2-[5-[4-(benzenesulfonamido)cyclohexyl]pentoxy]phenyl]propanoic acid Propan-2-yl used in Example 11 3-[2-[(E,3R) -5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate using the ester compound prepared in Example 165, and the same objective operation as in Example 11. The title compound having the following physical properties was obtained.
HPLC retention time (min): 1.20;
^1H -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.

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

Biological experiment example 1: In vitro test using Schwann cells (test method)
1) Preparation of rat Schwann cells Dorsal root ganglia (hereinafter abbreviated as DRG) of newborn rats 0 to 2 days old were excised in a clean bench and collected in DMEM. The collected tube was centrifuged at 400 g for 3 minutes at room temperature, the supernatant was removed, and 0.25% collagenase solution was added. The excised DRG was dispersed and separated by incubation at 37° C. for 30 minutes, centrifuged at 400 g 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 400 g for 3 minutes at room temperature. After removing the supernatant, 10% FBS-DMEM was added to prepare a cell suspension, which was passed through a filter (70 μm in diameter). The cell number of the cell suspension passed through the filter was counted and adjusted to 2.0 × 10 ⁵ cells/mL, and then seeded at 100 μL/well on a poly-D-lysine coated 96-well black-clear plate. The cells were statically cultured in a CO ₂ incubator under conditions of 5% CO ₂ , 95% air, and 37°C.
2) Compound addition The medium in the cell culture plate was removed by suction using an aspirator, and DMEM containing 1% dialyzed FBS and 100 μmol/L dibutyryl cyclic AMP was added. Thereafter, a solution of the compound of the present invention dissolved in DMSO was added, and the mixture was statically cultured in a CO ₂ incubator under conditions of 5% CO ₂ , 95% Air, and 37° C. The final concentration of the compound of the present invention in the cell culture plate well was 0.1, 0.3, 1 or 3 μmol/L.
3) Cell immunostaining Formaldehyde was added to each well of the cell culture plate 3 days after compound treatment, and the plate was left standing at room temperature for 30 minutes or more. After removing the supernatant, 0.3% Triton After removing the supernatant, a 5 μg/mL anti-myeline-associated glycoprotein antibody (anti-MAG antibody) solution was added and allowed to stand at room temperature for 60 minutes or more or at 4° C. (acceptable range: 1 to 9° C.) overnight. After washing three times with 0.1% Triton After washing four times with 0.1% Triton X-100 solution, 1 μg/mL Hoechst 33342 solution was added to stain the nucleus.
(Evaluation method)
The MAG positive area and the number of cell nuclei in the fluorescence image were calculated, and the sum of 5 fields/well was defined as the MAG positive area and the number of cell nuclei in each well. Thereafter, the MAG positive area of each well divided by the number of cell nuclei (MAG/cell nucleus number) was calculated, and the Schwann cell differentiation promotion rate for the medium group was determined using the following formula.

(result)
The Schwann cell differentiation promotion rate (% of vehicle value) for the vehicle group when 0.3 or 3 μmol/L of the present invention compound solution was added was as follows. From this, it is thought that the compounds of the present invention have strong neuroprotective and/or repair effects.

Biological Experiment Example 2: Test using a 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 using a streptozotocin model was conducted.
(Test method)
1) Model Preparation Method A model was prepared by intravenously administering 55 mg/kg of streptozotocin (hereinafter abbreviated as STZ) to rats.
2) Measurement of nociceptive threshold Rats were placed in a transparent acrylic cage for measurement for 10 minutes or more at least once before STZ administration to acclimatize the rats to the measurement environment. Eight von Frey filaments of 0.4, 0.6, 1, 2, 4, 6, 8, 15 g were applied vertically to the plantar hind paw from beneath the wire mesh floor. A quick escape response or leg-shaking response was considered a positive response (response). The compound of the present invention was orally administered once a day from day 14 to day 28 after STZ administration, and the dose was 0.03, 0.3, or 3 mg/kg. In addition, the nociceptive threshold was measured before STZ administration, 14 days after STZ administration (the day on which the administration of the compound of the present invention was started), 21 days (7 days after the start of administration), 28 days (14 days after the start of administration), and 35 days after the administration of STZ (the day after the start of administration). 7 days after administration), measurements were taken 2 hours after administration of the compound of the present invention.
(Evaluation method)
Nociceptive thresholds were measured using the up-down method according to the method of Chaplan et al. (J Neurosci Methods. 1994; 53:55-63). In addition, the improvement rate of nociceptive threshold was calculated based on the following formula.

(result)
The nociceptive threshold results obtained when the compound of the present invention was administered at a dose of 0.3 mg/kg are shown in FIG. 1, and the nociceptive threshold improvement rate is shown in Table 2. A strong analgesic effect on peripheral neuropathy was observed in all compounds. Furthermore, for example, with the compound of Example 11, an improvement in nociceptive threshold was observed from 7 days after the start of administration, and this effect continued even 7 days after discontinuation of administration, indicating a sustained analgesic effect.

Biological Experiment Example 3: Reactive Metabolite Measurement Test The complex of the reactive metabolite of the compound of the present invention and quaternary ammonium glutathione (QA-GSH) was semi-quantitated by LC/MS/MS (Soglia JR et al. , Chem. Res. Toxicol. 19(3), 480-490, 2006), the amount of reactive metabolites dependent on NADPH was measured.

Add 12.5 μL of 20 mg/mL human liver microsomes (Xenotech) to 187.5 μL of 100 mM phosphate buffer (pH 7.4) (final concentration: 1 mg/mL), and 25 μL of 10 mmol/L QA-GSH (final concentration: 1 mmol/mL). L), 0.5 mmol/L 5 μL of a solution of the present compound (DMSO:acetonitrile:water = 5:38:57) (final concentration of the present compound: 10 μmol/L) was added. After preincubation for 3 minutes in a 37°C water bath, 20 μL of 25 mmol/L NADPH (final concentration: 2 mmol/L) was added to initiate the reaction. One hour after the reaction, 500 μL of acetonitrile containing QA-GS adduct internal standard substance (IS) was mixed to stop the reaction. A complex of reactive metabolites and QA-GSH (QA-GS adduct) produced in the sample after the reaction was stopped was analyzed by LC/MS/MS. Measurements were performed with a QA-GS adduct internal standard (IS).

The QA-GS adduct concentration was calculated from the following formula.

(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 below 200 nmol/L. .

Biological Experiment Example 4: Hand-1 EST test POCA (registered trademark) Hand1-EST (DS Pharma Biomedical Co., Ltd.) (Le Coz F et al., J. Toxicol., 40(2):251-61.2015).

A 1000 mg/mL DMSO solution of the compound of the present invention was prepared. A 1000 mg/mL DMSO solution of the compound of the present invention was diluted with myocardial differentiation medium to prepare a 1000 μg/mL solution of the compound of the present invention (final concentration of DMSO 0.1%). While visually checking for the presence of precipitates, the mixture was sequentially diluted 3 times with myocardial differentiation medium (DMSO final concentration 0.1%), and the concentration at which no precipitate was present was recorded as the maximum solubility.

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

(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.
[Formulation example]
Formulation example 1
The following ingredients are mixed in a conventional manner and then tableted to obtain 10,000 tablets each containing 10 mg of the active ingredient.
・3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid...100g
・Carboxymethylcellulose calcium...20g
・Magnesium stearate … 10g
・Microcrystalline cellulose...870g

Formulation example 2
The following components are mixed in a conventional manner, filtered through a dust removal filter, filled into ampoules of 5 ml each, and sterilized by heating in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient per ampoule.
・3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid...200g
・Mannitol…20g
・Distilled water…50L

A pharmaceutical composition containing 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 (38)

General formula (I-1)
[In the formula, R ^11-1 represents a C2-4 alkylene group, L ^1-1 represents a linear C3-4 alkylene group optionally substituted with 1 to 2 R ^L1a , CycA ¹ and CycB ¹ each independently represents a C5-6 monocyclic carbocycle, and L ^2-1 is (1) -NH-S(O) ₂ - or (2) -CH(OH)-CH ₂ - represents
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, and when p is 2 or more, multiple R ² may be the same or different,
X represents (1) CH ₂ or (2) oxygen atom,
R ^L1a represents (1) a halogen atom, (2) a hydroxyl group, (3) an oxo group, or (4) a C1-2 alkyl group, and when R L1a is two or more, multiple R L1a may be the ^same or ^different . Furthermore, when two R L1a bonded to the same carbon atom are each a C1-2 alkyl group, the C1-2 alkyl group together with the bonded carbon atom forms a C3-5 saturated carbocyclic ring ^. may be formed,
represents a single, double or 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 from 0 to 2;
is a single bond and q is 2, multiple R ³ may be the same or different, and when at least one R ³ is a methyl group, together with the adjacent carbon atoms in L ^1-1 to form cyclopropane,
R ⁴ is (1) halogen atom, (2) hydroxyl group, (3) C1-4 alkyl group, (4) C1-4 haloalkyl group, (5) C1-4 alkoxy group, (6) C1-4 haloalkoxy group, (7) cyano group, or (8) -SO ₂ -C1-2 alkyl group, r represents an integer from 0 to 6, and when r is 2 or more, multiple R ^4s are the same or different. It's okay,
R ⁵ is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 haloalkyl group, (6) C2 -6 haloalkenyl group, (7) C2-6 haloalkynyl group, (8) C1-6 alkoxy group, or (9) C1-6 haloalkoxy group, t represents an integer from 0 to 6, and t When 2 or more, the plurality of R5s ^may be the same or different,
R ¹² represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group . ]
A pharmaceutical composition containing a compound represented by or a salt thereof . The pharmaceutical composition according to claim 1 , wherein X is an oxygen atom. The compound represented by the general formula (I -1 ) or a salt thereof is
(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) 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-oxohexyl]phenyl]propanoic acid The pharmaceutical composition according to claim 1, which is amido)phenyl]-3,3-difluoropentoxy]phenyl]propanoic acid or a salt thereof. A pharmaceutical composition containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof. A pharmaceutical composition containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid. A pharmaceutical composition containing a compound having the following structure.
A pharmaceutical composition containing a salt of a compound having the following structure.
Pharmaceutical composition according to any one of claims 1 to 7 for neuroprotection and/or repair. The pharmaceutical composition according to claim 8 , wherein the neuroprotection and/or repair is glial cell-mediated neuroprotection and/or repair. The pharmaceutical composition according to claim 9 , wherein the glial cell-mediated neuroprotection and/or repair is neuroprotection and/or repair by promoting myelination of Schwann cells. The pharmaceutical composition according to any one of claims 1 to 10 , which is a preventive and/or therapeutic agent for neurological disorders. 12. The pharmaceutical composition according to claim 11 , wherein the neuropathy is peripheral neuropathy. Peripheral neuropathy is associated with chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, and Charcot-Marie-Tooth disease. Neuropathy, peripheral neuropathy associated with infection, drug-induced peripheral neuropathy associated with administration of anticonvulsants, antibiotics, chemotherapy drugs, or sedatives, multifocal motor neuropathy, or heavy metals, organic solvents, toxic substances, or The pharmaceutical composition according to claim 12 , which is a toxic peripheral neuropathy associated with alcohol intake. 14. The pharmaceutical composition according to claim 13 , wherein the drug-induced peripheral neuropathy is peripheral neuropathy associated with chemotherapy drug administration. The pharmaceutical composition according to claim 11 , wherein the neurological disorder is a central nervous system disorder. 16. The pharmaceutical composition according to claim 15 , wherein the central nervous system disorder is amyotrophic lateral sclerosis. A Schwann cell differentiation promoter comprising a compound represented by the general formula (I -1 ) according to claim 1 or a salt thereof. A Schwann cell differentiation promoter containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof. A Schwann cell differentiation promoter containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid. A Schwann cell differentiation promoting agent containing a compound having the following structure.
A Schwann cell differentiation promoter containing a salt of a compound having the following structure.
A neuroprotective and/or restorative agent containing the compound represented by the general formula (I -1 ) or a salt thereof according to claim 1. A neuroprotective and/or restorative agent containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof. A neuroprotective and/or restorative agent containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid. A neuroprotective and/or repair agent containing a compound having the following structure.
A neuroprotective and/or restorative agent containing a salt of a compound having the following structure.
The agent according to any one of claims 22 to 26 , wherein the neuroprotection and/or repair is glial cell-mediated neuroprotection and/or repair. 28. The agent according to claim 27 , wherein the glial cell-mediated neuroprotection and/or repair is neuroprotection and/or repair by promoting myelination of Schwann cells. A prophylactic and/or therapeutic agent for neurological disorders, comprising a compound represented by the general formula (I -1 ) or a salt thereof according to claim 1. A preventive and/or therapeutic agent for neurological disorders containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a salt thereof. A preventive and/or therapeutic agent for neurological disorders containing 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid. A preventive and/or therapeutic agent for neurological disorders containing a compound having the following structure.
A prophylactic and/or therapeutic agent for neurological disorders containing a salt of a compound having the following structure.
The agent according to any one of claims 29 to 33 , wherein the neuropathy is peripheral neuropathy. Peripheral neuropathy is associated with chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, and Charcot-Marie-Tooth disease. Neuropathy, peripheral neuropathy associated with infection, drug-induced peripheral neuropathy associated with administration of anticonvulsants, antibiotics, chemotherapy drugs, or sedatives, multifocal motor neuropathy, or heavy metals, organic solvents, toxic substances, or 35. The agent according to claim 34 , which is a toxic peripheral neuropathy associated with alcohol intake. 36. The agent according to claim 35 , wherein the drug-induced peripheral neuropathy is peripheral neuropathy associated with chemotherapy drug administration. The agent according to any one of claims 29 to 33 , wherein the neurological disorder is a central nervous system disorder. 38. The agent according to claim 37 , wherein the central nervous system disorder is amyotrophic lateral sclerosis.

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