RU2811803C9 - Benzene derivative - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, which can be used for the treatment and/or prevention of peripheral neuropathy and/or central neuropathy:

[Formula 1]

where: R¹ is (1) -R¹¹-COOR¹², (2) -R¹³-CONR¹⁴R¹⁵, (3) -R¹⁷-CN, (4) -R¹⁸-CONHS(O)₂-R¹⁹, (5) -R²⁰-CycD, or

[Formula 2]

(where: ring 1 represents morpholine and n represents the integer 0); R² represents (1) a halogen atom or (2) a C1-4 alkyl group, and p is an integer from 0 or 1; X represents either (1) CH₂ or (2) an oxygen atom; L¹ represents (1) a linear C3-7 alkylene group, which may be substituted by 1-2 R^L1a, or (4) (a linear C1-3 alkylene group)-O-(a linear C1-3 alkylene group); R³ represents either (1) a hydrogen atom, (2) a halogen atom, or (4) a C1-2 alkyl group, and q represents an integer from 0 to 2, wherein: when

[Formula 4]

represents a single bond and q is 2, the set of R³ may be the same or different from each other; and when at least one of R³ is a methyl group, the methyl group can form cyclopropane in combination with a carbon atom in adjacent L¹ ; CycA is (1) a C6 monocyclic carbocyclic ring or (2) a 5–10 membered monocyclic or bicyclic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom; R⁴ represents (1) a halogen atom, (2) a hydroxyl group, (3) a C1-4 alkyl group, (4) a C1-4 haloalkyl group; (7) a cyano group or (8) a -SO₂-C1-2 alkyl group, and r is an integer from 0 to 3, wherein when r is 2 or more, the plurality of R⁴ may be the same or different from each other; L² represents -R³¹-L³-R³²-; CycB is (1) a C5-6 monocyclic ring or (2) a 5–10 membered monocyclic or bicyclic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom; and R⁵ represents either (1) a halogen atom, (2) a C1-6 alkyl group, (5) a C1-6 haloalkyl group, or (8) a C1-6 alkoxy group, and t represents the integer 0 or 1, and R¹¹–R²⁰, R³¹, R³², L³, CycD have the meanings specified in the claims.

EFFECT: production of a compound with neuroprotective and/or neurorestorative activity.

20 cl, 1 dwg, 2 tbl, 273 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001]

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

[0002]

[Formula 1]

[0003]

(wherein all symbols have the same meaning as described below) or a salt thereof (wherein the compound or a salt thereof is sometimes referred to hereinafter as a “compound of the present invention”).

BACKGROUND OF THE ART

[0004]

Nervous systems are roughly divided into central nervous systems and peripheral nervous systems. In particular, the peripheral nervous systems provide communication between the brain and spinal cord and peripheral areas of the body and are therefore involved in neurotransmission. The peripheral nervous systems are divided into somatic nervous systems (cerebrospinal nervous systems) and autonomic nervous systems. The somatic nervous systems are divided into cranial nerves and spinal nerves. In terms of function, the somatic nervous systems are classified as follows: the fibers that transmit the nerve signal (excitation) generated by the sensory receptor to the central nerves are divided into afferent or sensory nerve fibers, while the fibers that transmit the nerve signal directed from the brain and spinal brain to effector organs such as muscles and glands, are divided into efferent or motor nerve fibers. Cranial nerves are peripheral nerves that arise from the brain, and there are 12 known pairs of them. Among the cranial nerves, some are composed of sensory nerve fibers; some are composed of motor nerve fibers; and some are composed of 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, auditory nerve, glossopharyngeal nerve, vagus nerve, accessory nerve and hypoglossal nerve, respectively. Among these nerves, the olfactory nerve, optic nerve, trigeminal nerve, facial nerve, auditory nerve, glossopharyngeal nerve and vagus nerve are known as nerves consisting of sensory or mixed nerve fibers. Spinal nerves are peripheral nerves that arise from the spinal cord, and of these, there are 31 known corresponding pairs, including 8 pairs of cervical nerves, 12 pairs of thoracic nerves, 5 pairs of lumbar nerves, 5 pairs of sacral nerves, and one pair of coccygeal nerves. All spinal nerves are composed of mixed nerve fibers, each containing a sensory fiber (dorsal root) that runs toward the skin or the like, and a motor fiber (ventral root) that runs toward the skeletal muscle.

[0005]

Sensory nerve fibers, i.e. sensory nerves take on the function of accurately transmitting stimuli such as light, sound, temperature and touch perceived by sensory receptors such as the optical organ, hearing organ, olfactory organ, taste organ and skin to the central nervous system. The nerve signal transmitted to the central nervous system is ultimately transmitted to each sensory area of the cerebral cortex, such as the visual area, auditory area and the like, and as a result, the sensation is usually recognized. However, in these sensory nerves, axons, myelin sheaths, Schwann cells or the like can be damaged by viral infection, tumor, cancer, diabetes, ischemia, trauma, compression, drug, radiation therapy or the like, sometimes causing various neuropathies including cell death and demyelination. As a result, proper neurotransmission does not occur in the sensory nerve, which becomes compromised, leading to the development of diseases such as hearing loss and neuropathic pain. In addition to these disorders, peripheral neuropathy is also known in which various peripheral nerves, including sensory nerves, are damaged simultaneously with a particular sensory nerve as a result of the manifestation of a disease such as a metabolic disease and an autoimmune disease, trauma, drug poisoning or the like. In this condition, a single nerve may be damaged, two or more nerves in different areas may be damaged, or many nerves may be damaged at the same time. Symptoms of this disease include peripheral pain, numbness, burning sensation, decreased joint proprioception, decreased sensitivity to vibration, pain (including neuropathic pain), abnormal sensations, cold, hot flashes and the like, and are thus very complex and diverse.

[0006]

However, since the above-mentioned peripheral nerve diseases have not been studied in terms of the mechanisms of their development or are physical damage to the nerves, symptomatic therapy for symptomatic relief or the like is mainly carried out for the medical treatment of these diseases. There are very few known chemicals that are clinically useful as a means of targeting damaged nervous systems directly.

SUMMARY OF THE INVENTION

TECHNICAL CHALLENGES

[0007]

The present invention solves the problem of obtaining a compound having neuroprotective and/or neurorestorative activity.

SOLUTIONS TO PROBLEMS

[0008]

The inventors of the present invention have conducted extensive and intensive research to solve the problem. As a result, it was found that the compound represented by the general formula (I) has strong neuroprotective and/or neurorestorative activity. This discovery led to the implementation of the present invention.

The present invention meets the following points:

[1] a compound represented by the general formula (I):

[0009]

[Formula 2]

[0010]

[Where:

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

[0011]

[Formula 3]

[0012]

(where: ring 1 is a 3-6 membered nitrogen containing monocyclic saturated heterocyclic ring; R ¹⁰¹ is (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, and n is an integer from 0 to 3, wherein when n is 2 or more, the set R ¹⁰¹ may be the same or different from each other);

each of R ¹¹ , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ²⁰ independently represents (1) a C1-6 alkylene group which may be substituted by 1-3 halogen atoms, (2) a C2-6 alkenylene group, which may be substituted by 1 to 3 halogen atoms, or (3) a C2-6 alkynylene group which may be substituted by 1 to 3 halogen atoms, wherein when the alkylene group, alkenylene group or alkynylene group is a branched chain, two C1- 2 alkyl groups branched from one carbon atom can together form a C3-5 saturated carbocyclic ring;

each of R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁹ independently represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group;

CycD is a triazole or tetrazole;

R ² represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, and p represents an integer from 0 to 3, wherein when p is 2 or more, the plurality of R ² may be the same or different from each other;

X represents (1) CH ₂ or (2) an oxygen atom;

L ¹ represents (1) a linear C3-7 alkylene group which may be substituted by 1-4 R ^L1a , (2) a linear C3-7 alkenylene group which may be substituted by 1-4 R ^L1a , (3) a linear C3- 7 alkynylene group, which may be substituted by 1-4 R ^L1a , or (4) (linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-O-(linear C1-3 alkylene group, which may be substituted 1-2 R ^L1a );

R ^L1a represents (1) a halogen atom, (2) a hydroxyl group, (3) an oxo group, or (4) a C1-2 alkyl group, wherein: when at least two R ^L1a are present, the plurality of R ^L1a may be the same or different from each other; and when each of the two R ^L1a bonded to one carbon atom is a C1-2 alkyl group, the C1-2 alkyl group may form a C3-5 saturated carbocyclic ring together with the carbon atom to which the C1-2 alkyl group is attached;

[0013]

[Formula 4]

[0014]

represents a single bond, double bond 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, wherein: When

[0015]

[Formula 5]

[0016]

represents a single bond, and q is equal to 2, the set of R ³ may be the same or different from each other; and when at least one of R ³ is a methyl group, the methyl group can form cyclopropane in combination with a carbon atom in adjacent L ¹ ;

CycA is (1) a C5-10 monocyclic or bicyclic carbocyclic ring or (2) a 5-10 membered monocyclic or bicyclic heterocyclic ring;

R ⁴ represents (1) a halogen atom, (2) a hydroxyl group, (3) a C1-4 alkyl group, (4) a C1-4 haloalkyl group; (5) C1-4 alkoxy group; (6) a C1-4 haloalkoxy group, (7) a cyano group or (8)-SO ₂ -(C1-2 alkyl group) and r is an integer from 0 to 6, wherein when r is 2 or more, the set R ⁴ may be the same or different from each other;

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 -;

each of R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ and R ²⁰⁵ independently represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, wherein the alkyl group or haloalkyl group may be substituted with (1) a hydroxyl group, (2) an oxo group, (3) a C3-6 monocyclic carbocyclic ring, or (4) a 3-6 membered monocyclic heterocyclic ring;

each of R ³¹ and R ³² independently represents (1) a bond or (2) a C1-3 alkylene group which may be substituted by 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxyl group and an oxo group;

CycB is (1) a C5-10 monocyclic or bicyclic carbocyclic ring or (2) a 5-10 membered monocyclic or bicyclic heterocyclic ring; And

R ⁵ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 haloalkyl group, (6) C2 -6 haloalkenyl group, (7) C2-6 haloalkynyl group, (8) C1-6 alkoxy group or (9) C1-6 haloalkoxy group, and t represents an integer from 0 to 6, wherein when t is 2 or more, the plurality of R ⁵ may be the same or different from each other], or a salt thereof;

[2] a compound or a salt thereof according to claim [1], where in the general formula (I), the group is:

[0017]

[Formula 6]

[0018]

is (1) =CH-(linear C2-6 alkylene group which may be substituted by 1-2 R ^L1a )-, (2) -(linear C3-7 alkylene group which may be substituted by 1-2 R ^L1a ) -, or (3) -(linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-O-(linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-, (in (1)-(3) R ^L1a has the same meaning as in paragraph [1]);

[3] a compound or a salt thereof according to claim [1] or item [2], where R ¹ represents -R ¹¹ -COOR ¹² ;

[4] a compound or a salt thereof according to any one of claims [1]-[3], where L ² represents (1) -NR ²⁰² -S(O) ₂ - or (2) -CR ²⁰⁴ (OH) -CH ₂ -;

[5] a compound or a salt thereof according to any one of claims [1]-[4], where CycA is a C5-6 monocyclic carbocyclic ring;

[6] a compound or a salt thereof according to any one of claims [1]-[5], where CycB represents a C5-6 monocyclic carbocyclic ring;

[7] a compound or a salt thereof according to any one of claims [1] to [6], wherein the general formula (I) is the general formula (I-1):

[0019]

[Formula 7]

[0020]

[where: R ^11-1 represents a C2-4 alkylene group; L ^1-1 represents a linear C3-4 alkylene group which may be substituted by 1-2 R ^L1a ; CycA ¹ and CycB ¹ are each independently a C5-6 monocyclic carbocyclic ring; L ^2-1 is (1) -NH-S(O) ₂ - or (2) -CH(OH)-CH ₂ -; and other symbols have the same meaning as specified in paragraph [1]];

[8] a compound or a salt thereof according to any one of claims [1]-[7], where X represents an oxygen atom;

[9] a compound or a salt thereof according to claim [1], wherein the compound 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]-3,3-difluoropentoxy]phenyl]propanoic acid, or

their salt;

[10] a pharmaceutical composition containing a compound represented by the general formula (I) or a salt thereof according to claim 1;

[11] an agent for promoting Schwann cell differentiation, containing the compound represented by the general formula (I) or a salt thereof according to claim [1];

[12] a preventive and/or therapeutic agent for neuropathy containing a compound represented by the general formula (I) or a salt thereof according to claim [1];

[13] the agent according to claim [12], wherein the neuropathy is peripheral neuropathy;

[14] the agent according to claim [13], wherein the peripheral neuropathy is chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, compressive neuropathy, chemotherapy drug-associated peripheral neuropathy, or peripheral neuropathy associated with Charcot-Marie-Tooth disease;

[15] a method for the prevention and/or treatment of neuropathy, comprising administering an effective amount of a compound represented by the general formula (I) or a salt thereof according to claim [1] mammal;

[16] a compound represented by the general formula (I), or a salt thereof according to claim [1], which is used for the prevention and/or treatment of neuropathy;

[17] use of a compound represented by the general formula (I) or a salt thereof according to claim [1] to obtain a prophylactic and/or therapeutic agent for neuropathy;

[18] a pharmaceutical composition for protecting and/or restoring a nerve, which contains a compound represented by the general formula (I) or a salt thereof according to claim [1];

[19] the pharmaceutical composition according to claim [18], wherein protecting and/or restoring the nerve is protecting and/or restoring the nerve through a glial cell (eg, microglia, astrocyte, oligodendrocyte, ependymocyte, Schwann cell, satellite cell);

[20] the pharmaceutical composition according to claim [19], wherein the protection and/or repair of the nerve through the glial cell is the protection and/or repair of the nerve by stimulating myelination of the Schwann cell; or the like.

USEFUL EFFECTS OF THE INVENTION

[0021]

The compound of the present invention has potent neuroprotective and/or neurorestorative activity and therefore can be used for the treatment of neuropathy such as peripheral neuropathy.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]

Figure 1 shows nociceptive thresholds in streptozotocin models that were obtained when compounds of Examples 11, 36, 37 and 84 were each administered at a dose of 0.3 mg/kg (the vertical axis represents the nociceptive threshold and the horizontal axis represents the amount days elapsed after the administration of streptozotocin).

DESCRIPTION OF IMPLEMENTATION OPTIONS

[0023]

Next, the present invention will be described in detail.

[0024]

The term "3-6 membered nitrogen-containing monocyclic saturated heterocyclic ring" as used herein refers to a monocyclic saturated heterocyclic ring containing at least one nitrogen atom, and examples thereof include aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isooxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, azine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, morpholine and thiomorpholine.

[0025]

The term “halogen atom” as used herein refers to fluorine, chlorine, bromine, iodine or the like.

[0026]

The term "C1-4 alkyl group" as used herein includes a linear or branched C1-4 alkyl group, and examples thereof include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.

[0027]

The term “C1-4 haloalkyl group” as used herein refers to a group having such a structure that a linear or branched C1-4 alkyl group is substituted by at least one halogen atom, and examples thereof include fluoromethyl, chloromethyl, bromomethyl, iodomethyl , difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl and 4-bromobutyl.

[0028]

The term "C1-6 alkylene group" as used herein includes a linear or branched C1-6 alkylene group, and examples thereof include methylene, ethylene, propylene, butylene, pentylene, hexanylene and isomers thereof.

[0029]

The term “C2-6 alkenylene group” as used herein includes a linear or branched C2-6 alkenylene group, and examples thereof include ethenylene, propenylene, butenylene, pentenylene, hexenylene and isomers thereof.

[0030]

The term “C2-6 alkynylene group” as used herein includes linear or branched C2-6 alkynylene, and examples thereof include ethynylene, propynylene, butynylene, pentynylene, hexynylene and isomers thereof.

[0031]

The term "linear C3-7 alkylene group" as used herein includes, for example, propylene, butylene, pentylene, hexanylene and heptanylene.

[0032]

The term "linear C3-7 alkenylene group" as used herein includes, for example, propenylene, butenylene, pentenylene, hexenylene, heptenylene, and isomers thereof.

[0033]

The term “linear C3-7 alkynylene group” as used herein includes, for example, propynylene, butynylene, pentynylene, hexynylene, and isomers thereof.

[0034]

The term "C1-2 alkyl group" as used herein refers to methyl or ethyl.

[0035]

The term "C3-5 saturated carbocyclic ring" as used herein includes, for example, cyclopropane, cyclobutane and cyclopentane.

[0036]

The term "C5-10 monocyclic or bicyclic carbocyclic ring" as used herein includes, for example, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene , pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene and perhydronaphthalene.

[0037]

The term “5-10 membered monocyclic or bicyclic heterocyclic ring” as used herein refers to a 5-10 membered monocyclic or bicyclic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, tiepine, oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolysine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolysine, purine, phthalazine, naphthyridine, , quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, zine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, hydroxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisooxazole, tetrahydroisooxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazoles) din), dihydrooxazine, tetrahydroxazine, dihydrooxadiazine, tetrahydroxadiazine, dihydrooxazepine, tetrahydroxazepine , perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, zepin, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathian, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, tetrahydroisoquinoline, perhydroisoquinoline, , tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzooxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzooxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, dioxolane, san, dithiolane, dithian, dioxaindane, benzodioxane, chroman, benzodithiolane and benzodithiane.

[0038]

The term “C1-4 alkoxy group” as used herein includes a linear or branched C1-4 alkoxy group, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy.

[0039]

The term "C1-4 haloalkoxy group" as used herein includes a group having such a structure that a linear or branched C1-4 alkoxy group is substituted by at least one halogen atom, and examples thereof include trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy and 1- chlorobutoxy.

[0040]

The term "C3-6 monocyclic carbocyclic ring" as used herein includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene and benzene.

[0041]

The term "3-6 membered monocyclic heterocyclic ring" used in this specification refers to a 3-6 membered monocyclic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isooxazole, thiazole, isothiazole, furazan, 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, hydropyridazine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisooxazole, tetrahydroisoxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (dihydroisothiazole), tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, oxathiane, dioxolane, dioxane, dithiolane and dithiane.

[0042]

The term "5-6 membered monocyclic heterocyclic ring" used in this specification refers to a 5-6 membered monocyclic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, ran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisooxazole, tetrahydroisoxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, , tetrahydroxadiazole (oxadiazolidine), dihydrooxazine, tetrahydroxazine, dihydrooxadiazine, tetrahydroxadiazine , dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane and dithiane.

[0043]

The term "5-6 membered monocyclic aromatic heterocyclic ring" used in this specification refers to a 5-6 membered monocyclic aromatic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, and examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole and thiadiazole.

[0044]

The term "C1-3 alkylene group" as used herein includes a linear or branched C1-3 alkylene group, and examples thereof include methylene, ethylene, propylene and isomers thereof.

[0045]

The term "C1-6 alkyl group" as used herein includes a linear or branched C1-6 alkyl group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl and their isomers.

[0046]

The term “C2-6 alkenyl group” as used herein includes a linear or branched C2-6 alkenyl group, and examples thereof include ethenyl, propenyl, butenyl, pentenyl, hexenyl and isomers thereof.

[0047]

The term “C2-6 alkynyl group” as used herein refers to a linear or branched C2-6 alkynyl group, and examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and isomers thereof.

[0048]

The term "C1-6 haloalkyl group" as used herein refers to a group having such a structure that the linear or branched C1-6 alkyl group is substituted by at least one halogen atom, and examples thereof include fluoromethyl, chloromethyl, bromomethyl, iodomethyl , difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, 1-fluoropentane and 2-chlorohexane.

[0049]

The term “C2-6 haloalkenyl group” as used herein refers to a group having such a structure that a linear or branched C2-6 alkenyl group is substituted with at least one halogen atom, and examples thereof include 1-fluoroethenyl, 2-fluoroethenyl , 2-chloroethenyl, pentafluoroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl, 1-fluoropentenyl and 2-chlorohexenyl.

[0050]

The term “C2-6 haloalkynyl group” as used herein refers to a group having such a structure that a linear or branched C2-6 alkynyl group is substituted by at least one halogen atom, and examples thereof include 1-fluoroethynyl, 2-fluoroethynyl , 2-chloroethynyl, pentafluoroethynyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl, 1-fluoropentinyl and 2-chlorhexynyl.

[0051]

The term "C1-6 alkoxy group" as used herein includes a linear or branched C1-6 alkoxy group, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy and isohexyloxy.

[0052]

The term “C1-6 haloalkoxy group” as used herein refers to a group having such a structure that the linear or branched C1-6 alkoxy group is replaced by at least one halogen atom, and examples thereof include trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy , iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy, 1 -chlorobutoxy, 2-fluoropentoxy and 3-chlorohexyloxy.

[0053]

The term "linear C2-6 alkylene group" as used herein includes, for example, ethylene, propylene, butylene, pentylene and hexanylene.

[0054]

The term "linear C3-7 alkylene group" as used herein includes, for example, propylene, butylene, pentylene, hexanylene and heptanylene.

[0055]

The term "linear C1-3 alkylene group" as used herein includes, for example, methylene, ethylene and propylene.

[0056]

The term "C5-6 monocyclic carbocyclic ring" as used herein includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene and benzene.

[0057]

The term “C2-4 alkylene group” as used herein includes a linear or branched C2-4 alkylene group, and examples thereof include ethylene, propylene, butylene and isomers thereof.

[0058]

The term “C3-4 alkylene group” as used herein includes a linear or branched C3-4 alkylene group, and examples thereof include propylene, butylene and isomers thereof.

[0059]

In the present invention,

[0060]

[Formula 8]

[0061]

refers to a single, double or triple bond. In the case where the symbol represents a double bond, the double bond includes its cis form and its trans form.

[0062]

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

[0063]

In the present invention, each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene and alkoxy groups includes both their linear and branched forms, unless otherwise indicated.

[0064]

In the present invention, in the case where R ³ represents a methylidene group, it means that the formula is:

[0065]

[Formula 9]

[0066]

[where all symbols have the same meaning as above], which is a fragment of the structure of the general formula (I), has the structure shown below:

[0067]

[Formula 10]

[0068]

[0069]

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

[0070]

[Formula 11]

[0071]

In the present invention, R ¹ is preferably -R ¹¹ -COOR ¹² , more preferably -R ¹¹ -COOH. R ¹¹ preferably represents a C1-6 alkylene group which may be substituted by 1-3 halogen atoms, more preferably a C2-4 alkylene group which may be substituted by 1-3 halogen atoms.

[0072]

In the present invention, in the case where R ¹ represents a group:

[0073]

[Formula 12]

,

[0074]

ring 1 is more preferably a 6-membered nitrogen-containing monocyclic saturated heterocyclic ring, even more preferably a morpholine.

[0075]

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

[0076]

In the present invention, each of R ¹¹ , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ²⁰ preferably represents a C1-6 alkylene group which may be substituted by 1 to 3 halogen atoms, more preferably a C2-4 alkylene group which may be replaced. 1-3 halogen atoms.

[0077]

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

[0078]

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

[0079]

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

[0080]

In the present invention, L ¹ is preferably (1) a linear C3-7 alkylene group which may be substituted by 1-4 R ^L1a , or (2) a (linear C1-3 alkylene group which may be substituted by 1-2 R ^L1a ) -O-(a linear C1-3 alkylene group which may be substituted by 1-2 R ^L1a ), more preferably a linear C3-7 alkylene group which may be substituted by 1-4 R ^L1a .

[0081]

In the present invention,

[0082]

[Formula 13]

[0083]

preferably represents a single or double bond.

[0084]

In the present invention,

[0085]

[Formula 14]

[0086]

represents

preferably (1) =CH-(linear C2-6 alkylene group which may be substituted by 1-3 R ^L1a )-, (2) -(linear C3-7 alkylene group which may be substituted by 1-3 R ^L1a )- , or (3) -(linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-O-(linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-, (in ( 1)-(3) R ^L1a has the same meaning as above),

more preferably (1) =CH-(linear C2-6 alkylene group which may be substituted by 1-3 R ^L1a )- or (2) -(linear C3-7 alkylene group which may be substituted by 1-3 R ^L1a ) - (in (1)-(2) R ^L1a has the same meaning as above),

even more preferably (1) =CH-(linear C3 alkylene group which may be substituted by 1-3 R ^L1a )- or (2) -(linear C4 alkylene group which may be substituted by 1-3 R ^L1a )- (in (1)-(2) R ^L1a has the same meaning as above).

[0087]

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

[0088]

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

[0089]

In the present invention, CycA is preferably (1) a C5-6 monocyclic carbocyclic ring or (2) a 5-10 membered monocyclic or bicyclic heterocyclic ring, even more preferably a benzene or a 5-6 membered monocyclic aromatic heterocyclic ring.

[0090]

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

[0091]

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

[0092]

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

[0093]

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

[0094]

In the present invention, each of ^R201 , ^R202 , ^R203 , ^R204 and ^R205 preferably represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkyl group that is substituted with a hydroxyl group, a C1-4 alkyl group that is substituted A C3-6 monocyclic carbocyclic ring or a C1-4 alkyl group that is substituted with a 3-6 membered monocyclic heterocyclic ring, more preferably a hydrogen atom. A C1-4 alkyl group which is substituted with a C3-6 monocyclic carbocyclic ring is preferably a C1-4 alkyl group which is substituted with cyclopropane or benzene, and a C1-4 alkyl group which is substituted with a 3-6 membered monocyclic heterocyclic ring is preferably is a C1-4 alkyl group which is substituted with oxetane, tetrahydrofuran or tetrahydropyran.

[0095]

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

[0096]

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

[0097]

In the present invention, CycB is preferably (1) a C5-6 monocyclic carbocyclic ring or (2) a 5-6 membered monocyclic heterocyclic ring, more preferably benzene or a 5-6 membered monocyclic aromatic heterocyclic ring.

[0098]

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

[0099]

In the present invention ^{, R5} preferably represents a halogen atom, a C1-4 alkyl group, a C1-4 haloalkyl group or a C1-4 alkoxy group, more preferably a halogen atom, a C1-4 alkoxy group, a trihalomethyl group or a C1-4 alkoxy group.

[0100]

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

[0101]

In the present invention, the group structure is:

[0102]

[Formula 15]

[0103]

[where all symbols have the same meaning as above] which is a fragment of the structure of the general formula (I), is preferably

[0104]

[Formula 16]

[0105]

more preferable

[0106]

[Formula 17]

[0107]

[0108]

In the present invention, the formula structure is:

[0109]

[Formula 18]

[0110]

[where all symbols have the same meaning as above] which is a fragment of the structure of the general formula (I), is preferably

[0111]

[Formula 19]

[0112]

[where all characters have the same meaning as above].

[0113]

In the present invention, the formula structure is:

[0114]

[Formula 20]

[0115]

[where all symbols have the same meaning as above] which is a fragment of the structure of the general formula (I), is preferably

[0116]

[Formula 21]

[0117]

[where all characters have the same meaning as above].

[0118]

In the present invention, one embodiment of the general formula (I) is the general formula (I-i):

[0119]

[Formula 22]

[0120]

[where L ^1-i represents (1) a linear C2-4 alkylene group, which may be substituted with 1-3 R ^L1a , or (2) an -O-(linear C1-3 alkylene group, which may be substituted with 1-2 R ^L1a )-; and other symbols have the same meaning as above].

[0121]

In the present invention, one embodiment of the general formula (I-i) is the general formula (I-ii):

[0122]

[Formula 23]

[0123]

[where L ^1-ii represents a linear C2-4 alkylene group which may be substituted by 1-3 R ^L1a ; and other characters have the same meaning as above];

general formula (I-iii):

[0124]

[Formula 24]

[0125]

[where L ^1-iii represents (1) a linear C2-4 alkylene group, which may be substituted by 1-3 R ^L1a , or (2) an -O-(linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-; and other characters have the same meaning as above]; or

general formula (I-iv):

[0126]

[Formula 25]

[0127]

[where L ^1-iv represents a linear C2-4 alkylene group which may be substituted by 1-3 R ^L1a ; and other symbols have the same meaning as above].

[0128]

One embodiment of the compound represented by the general formula (I-i), (I-ii), (I-iii) or (I-iv), or a salt thereof, is a compound in which:

(1) R ¹¹ represents a C2-4 alkylene group;

(2) X represents an oxygen atom;

(3) R ^L1a represents a hydroxyl group;

(4) CycA is (i) a C5-6 monocyclic carbocyclic ring or a 5-10 membered monocyclic or bicyclic heterocyclic ring, (ii) a benzene or a 5-6 membered monocyclic aromatic heterocyclic ring, (iii) a C5-6 monocyclic carbocyclic ring ring, or (iv) benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline;

(5) CycB is (i) a C5-6 monocyclic carbocyclic ring or a 5-6 membered monocyclic heterocyclic ring, (ii) a benzene or a 5-6 membered monocyclic aromatic heterocyclic ring, (iii) a C5-6 monocyclic carbocyclic ring , 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) symbols other than R ¹¹ , X, R ^L1a , CycA, CycB and L ² represent the above groups (for example, groups that are indicated above as “preferred”, “more preferred” or “even more preferred” groups) ; or

(8) a combination of two or more points (1)-(7) is satisfied,

or salt of the compound.

In the present invention, the compound represented by the general formula (I-i), (I-ii), (I-iii) or (I-iv), or a salt thereof, is preferably:

(1) a compound in which X represents an oxygen atom and L ² represents -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH)-CH ₂ -, or a salt thereof;

(2) a compound in which X is an oxygen atom, L ² is -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH)-CH ₂ -, and CycA and CycB are each C5-6 a monocyclic carbocyclic ring, or a salt thereof;

(3) a compound in which R ¹¹ represents a C2-4 alkylene group, X represents an oxygen atom, L ² represents -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH)-CH ₂ -, and CycA and CycB are each a C5-6 monocyclic carbocyclic ring, or a salt thereof; or

(4) a compound in which X represents an oxygen atom, R ^L1a represents a hydroxyl group, L ² represents -NR ²⁰¹ -S(O) ₂ - or -CR ²⁰⁴ (OH)-CH ₂ -, and each of CycA and CycB is a C5-6 monocyclic carbocyclic ring, or salt of the compound.

[0129]

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

[0130]

[Formula 26]

[0131]

[where all characters have the same meaning as above].

In the present invention, the general formula (I-1) is preferably the general formula (I-1-A):

[0132]

[Formula 27]

[0133]

[where L ^1-2 represents a linear C2-3 alkylene group; and other characters have the same meaning as above];

general formula (I-1-B):

[0134]

[Formula 28]

[0135]

[where all characters have the same meaning as above];

general formula (I-1-C):

[0136]

[Formula 29]

[0137]

[where all characters have the same meaning as above];

general formula (I-1-D):

[0138]

[Formula 30]

[0139]

[where all characters have the same meaning as above].

[0140]

Embodiments of the compound represented by the general formula (I-1-A), (I-1-B), (I-1-C) or (I-1-D), or a salt thereof, include:

(1) a compound in which X represents an oxygen atom, or a salt thereof;

(2) a compound in which CycA ¹ represents benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline, or a salt thereof;

(3) a compound in which CycB ¹ is cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran, or a salt thereof;

(4) a compound in which the groups other than X, CycA ¹ and CycB ¹ are the above groups (for example, the groups that are indicated above as “preferred”, “more preferred” or “even more preferred” groups), or its salt; And

(5) a compound in which the combination of two or more points (1)-(4) is satisfied, or a salt thereof.

[0141]

[Isomers]

In the present invention, as will be apparent to those skilled in the art, the symbol:

[0142]

[Formula 31]

[0143]

means that the connection is projected below the plane of the sheet (i.e. α-configuration), the symbol:

[0144]

[Formula 32]

[0145]

means that the bond projects above the plane of the sheet (i.e. β configuration), and the symbol:

[0146]

[Formula 33]

[0147]

means that the bond is a combination of an α-configuration and a β-configuration in an arbitrary ratio of components, unless otherwise noted.

[0148]

In the present invention, an isomer includes all of these isomers unless otherwise specified. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene and alkenylidene each include both their linear and branched forms. Additionally, isomer in a double bond, ring, or fused ring (E-, Z-, cis-, or trans-form), isomer due to the presence of an asymmetric carbon, or the like (R- or S-form, α- or β- configuration, enantiomer, diastereomer), optically active form having optical activity (D-, L-, d- or l-form), polar body (highly polar body, weakly polar body) obtained by chromatographic separation, equilibrium compound and rotating isomer, as well as their mixture and racemic mixture at an arbitrary ratio of components in the mixture are also included in the scope of the present invention.

[0149]

The optically active compound of the present invention may include its 100% pure form, as well as other optical isomers, each of which is less than 50% pure.

[0150]

In the present invention, all statements about the compound of the present invention include statements that relate to the compound represented by the general formula (I), or a salt, N-oxide, solvate or co-crystal thereof, or an N-oxide, solvate or co-crystal of a salt of the compound represented by the general formula ( I).

[0151]

The compound represented by the general formula (I) can be converted into the corresponding salt in a known manner. The salt is preferably water soluble. The salt is also preferably a pharmaceutically acceptable salt. Examples of the salt include an alkali metal salt (eg, lithium, potassium, sodium), an alkaline earth metal salt (eg, calcium, magnesium), another metal salt (eg, silver, zinc), ammonium salt, pharmaceutically acceptable organic amine salt (eg, tetramethylammonium , choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-2-phenethylamine, dinol, 2 -(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine), acid addition salt (for example, inorganic acid salt (hydrochloric acid salt, hydrobromic acid salt, hydroiodic acid salt , sulfuric acid salt, phosphoric acid salt, nitric acid salt, etc.), organic acid salt (acetic acid salt, trifluoroacetic acid salt, lactic acid salt, tartaric acid salt, oxalic acid salt, fumaric acid salt, maleic acid salt , benzoic acid salt, citric acid salt, methanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonic acid salt, toluenesulfonic acid salt, isethionic acid salt, napadisilic acid salt, glucuronic acid salt, gluconic acid salt, etc.) and the like) .

[0152]

The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof may be present in unsolvated form or in a form solvated with a pharmaceutically acceptable solvent such as water and ethanol. The solvate is preferably low toxic and water soluble, and more preferably is a hydrate. The compound represented by the general formula (I) or a salt thereof can be converted into a solvate in a known manner.

[0153]

The N-oxide form of the compound represented by the general formula (I) is a compound obtained by oxidation of a nitrogen atom in the compound represented by the general formula (I). The N-oxide form of the compound represented by the general formula (I) may be in the form of the above-mentioned alkali (alkaline earth) metal salt, ammonium salt, organic amine salt or acid addition salt.

[0154]

The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof may be present in the form of a cocrystal with a suitable cocrystal-forming agent. The cocrystal is preferably a pharmaceutically acceptable cocrystal that is formed with a pharmaceutically acceptable cocrystal-forming agent. A cocrystal is usually defined as a crystal formed by at least two types of different intermolecular interactions. The cocrystal may be a complex of a neutral molecule and a salt. The cocrystal can be obtained by a known method, such as melt crystallization, recrystallization from a solvent, and physical grinding of all components together. Examples of suitable cocrystal forming agent include: organic acid (eg, malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, isonicotinic acid); organic amine (e.g. imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzylphenethylamine, dinol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, 4-(2-hydroxyethyl)morpholine, N- methyl-D-glucamine, glycine, histidine, proline); and other organic compounds (eg, caffeine, saccharin).

[0155]

The term “prodrug of the compound represented by the general formula (I)” refers to a compound that can be converted into the compound represented by the general formula (I) by reaction with an enzyme, gastric acid or the like in vivo . Examples of a prodrug of the compound represented by the general formula (I) include: in the case where the compound represented by the general formula (I) has an amino group, a compound having such a structure that the amino group in the corresponding compound is acylated, alkylated or phosphorylated (for example, a compound having such a structure that the amino group i of the compound represented by the general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-doxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated); in the case where the compound represented by the general formula (I) has a hydroxyl group, a compound having such a structure that the hydroxyl group in the corresponding compound is acylated, alkylated, phosphorylated or borated (for example, a compound having such a structure that the hydroxyl group in the corresponding compound represented by the general formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); and in the case where the compound represented by the general formula (I) has a carboxyl group, a compound having a structure such that the carboxyl group in the corresponding compound is esterified or amidated (for example, a compound having such a structure that the carbonyl group in the corresponding compound is represented by the general formula (I), is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonyl ethyl esterified or methyl amide ated). These compounds can be prepared by known methods. A prodrug of the compound represented by the general formula (I) may be a solvate. Alternatively, a prodrug of the compound represented by the general formula (I) may be a compound that can be converted to the compound represented by the general formula (I) under physiological conditions, as described in "Development of Pharmaceuticals", vol. 7, "Design of Molecules", pages: 163-198, 1990, Hirokawa-Shoten Ltd. In addition, the compound represented by the general formula (I) may be labeled with an isotope (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) or the like.

[0156]

[Production method of the compound of the present invention]

The compound of the present invention can be prepared by a suitably modified method of a known method, such as the method mentioned in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) and the methods specified in the "EXAMPLES" section, or by a combination of these methods.

[0157]

Among the compounds represented by the general formula (I), the compound represented by the general formula (I-A):

[0158]

[Formula 34]

[0159]

(where L ^1M represents (1) a linear C2-6 alkylene group which may be substituted by 1-4 R ^L1a , (2) a linear C2-6 alkenylene group which may be substituted by 1-4 R ^L1a , (3) a linear a C2-6 alkynylene group which may be substituted by 1-4 R ^L1a , or (4) (a linear C1-3 alkynylene group which may be substituted by 1-2 R ^L1a )-O-(a linear C1-3 alkylene group which may be substituted with 1-2 R ^L1a ); and other symbols have the same meaning as above) can be prepared by the method shown in the following Reaction Scheme 1.

[0160]

[Formula 35]

[0161]

(where Hal represents a halogen atom; and other symbols have the same meaning as above).

[0162]

In Reaction Scheme 1, reaction 1-1 can be achieved by carrying out a nucleophilic addition reaction using the compound represented by the general formula (A-1) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The nucleophilic addition reaction is known, and can be carried out, for example, in an organic solvent (for example, hexane, heptane, octane, benzene, toluene, tetrahydrofuran (hereinafter abbreviated as “THF”), dioxane, dimethoxyethane, diethyl ether, or a mixed solvent, consisting of two or more of these solvents), or under solvent-free conditions at a temperature of 0-120 °C. The reaction can also be carried out in the presence of a catalyst to speed up the reaction. Examples of the catalyst include formic acid, acetic acid, benzoic acid, 4-dimethylaminobenzoic acid and Schwartz's reagent (CAS registration number: 37342-97-5).

[0163]

In Reaction Scheme 1, reaction 1-2 can be achieved by performing a Suzuki coupling reaction using a compound represented by the general formula (A-2) and a compound represented by the general formula (A-3). The Suzuki reaction is known, and can be carried out, for example, in an organic solvent (for example, toluene, benzene, N,N-dimethylformamide (hereinafter abbreviated as “DMF”), THF, methanol, ethanol, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide ), water, a mixed solvent consisting of two or more of these solvents, or the like, in the presence of a palladium catalyst (for example, 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(tBu ₃ P) ₂ )) and in the presence of a base (for example, sodium hydroxide, hydroxide potassium, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride) at room temperature up to 120°C.

[0164]

Moreover, the compound represented by the general formula (I-B):

[0165]

[Formula 36]

[0166]

(wherein all symbols have the same meaning as above) can be obtained by performing a reduction reaction using the compound represented by the general formula (I-A). The reduction reaction is known and can be carried out in the following ways. For example, (1) a metal reduction reaction and (2) a diimide reduction reaction are mentioned. Reduction reaction (1) using a metal can be carried out, for example, in an organic solvent (for example, THF, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, DMF, ethyl acetate, acetic acid , water, or a mixed solvent consisting of two or more of these solvents), in the presence or absence of a hydrogenation catalyst (for example, palladium on carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum on carbon, nickel, Raney nickel , ruthenium chloride), in the presence or absence of acid (for example, 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), in a hydrogen atmosphere at atmospheric pressure or under pressure at 0-200 ° C. Diimide reduction reaction (2) can be carried out, for example, in an organic solvent (for example, toluene, benzene, DMF, THF, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide, methanol, ethanol, a mixed solvent consisting of two or more of these solvents), in the presence or absence of a hydrazine compound (eg hydrazine, hydrazine monohydrate, tosylhydrazine) and a base (eg sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate) at a temperature of 0°C to 120 °C.

[0167]

Among the compounds represented by the general formula (I), the compound represented by the general formula (I-C):

[0168]

[Formula 37]

[0169]

(where all symbols have the same meaning as above) can be prepared by the method shown in Reaction Scheme 2 below.

[0170]

[Formula 38]

[0171]

(where all characters have the same meaning as above).

[0172]

In Reaction Scheme 2, reaction 2-1 can be achieved by subjecting the compound represented by the general formula (A-1) and the compound represented by the general formula (A-3) to the Sonogashira reaction. The Sonogashira reaction is known and can be achieved, for example, by carrying out the reaction in an organic solvent (for example, 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, a mixed solvent consisting of two or more of these solvents, or the like, or in the absence of solvents, in the presence base (e.g. 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, carbonate potassium, cesium carbonate, sodium phosphate, potassium phosphate, potassium fluoride), in the presence of a catalyst (for example, a palladium catalyst (for example, 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(tBu ₃ P) ₂ )), mixtures of palladium catalyst and copper catalyst (for example, copper iodide (I)), with or without a phase transfer catalyst (e.g. tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium acetate) at room temperature up to 120°C.

[0173]

Among the compounds represented by the general formula (A-3) in Reaction Schemes 1 and 2, the compound represented by the general formula (A-3-1):

[0174]

[Formula 39]

[0175]

(where all symbols have the same meaning as above) can be prepared by the method shown in Reaction Scheme 3 below.

[0176]

[Formula 40]

[0177]

(where all characters have the same meaning as above).

[0178]

In Reaction Scheme 3, reaction 3-1 can be achieved by subjecting the compound represented by the general formula (A-3-1a) and the compound represented by the general formula (A-3-1b) to a sulfonamidation reaction. The sulfonamidation reaction is known and can be achieved, for example, by carrying out the reaction in an organic solvent (for example, 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, a mixed solvent consisting of two or more of these solvents) or under solvent-free conditions, with or without a base (e.g. diisopropylethylamine, pyridine, triethylamine, dimethylaniline, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate), in the presence or absence of a catalyst (e.g. 4-dimethylaminopyridine) at a temperature of 0-120 °C.

[0179]

In Reaction Scheme 3, Reaction 3-2 can be carried out by subjecting the compound represented by the general formula (A-3-1c) and the compound represented by the general formula (A-3-1d) to an alkylation reaction, or by subjecting the compound represented by the general formula ( A-3-1c), and the compound represented by the general formula (A-3-1e), Mitsunobu reaction. The alkylation reaction is known and can be achieved, for example, by carrying out the reaction in an organic solvent (for example, DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl tert-butyl ether, acetonitrile, water, a mixed solvent consisting of two or more of these solvents), in the presence of a base (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium bis(trimethylsilyl)amide, bis(trimethylsilyl)amide potassium, sodium bis(trimethylsilyl)amide) at temperatures from 0°C to 100°C. The Mitsunobu reaction is known and can be achieved, for example, by carrying out the reaction in an organic solvent (eg, dichloromethane, diethyl ether, THF, acetonitrile, benzene, toluene), in the presence of an azo compound (eg, diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-( azodicarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide)) and a phosphine compound (e.g. triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine) at a temperature of 0-80 °C.

[0180]

Among the compounds represented by the general formula (A-3) in Reaction Schemes 1 and 2, the compound represented by the general formula (A-3-2):

[0181]

[Formula 41]

[0182]

(where all symbols have the same meaning as above) can be prepared by the method shown in Reaction Scheme 4 below.

[0183]

[Formula 42]

[0184]

(where all characters have the same meaning as above).

[0185]

In Reaction Scheme 4, reaction 4-1 can be achieved, for example, by reacting the compound represented by the general formula (A-3-2a) in an organic solvent (for example, THF, dimethoxyethane, toluene, dichloromethane, diethyl ether, dioxane, methanol ) in the presence or absence of cerium chloride using a reducing agent (eg sodium borohydride, zinc borohydride) at a temperature of -20°C to 50°C. In the case where only one of the stereoisomers is to be produced selectively, the reaction is carried out using an asymmetric reducing agent (for example, chlorodiisopinocamphylborane) or a combination of a chiral auxiliary agent and a reducing agent (for example, (R)-2-methyl-CBS-oxazaborolidine and a borohydride-THF complex or borane-dimethylsulfide complex, (S)-(-)-binaphthol and lithium aluminum hydride) at temperatures from -100°C to 50°C.

[0186]

In reaction scheme 1, 2, 3 or 4, in the case where a protecting group is present in the compound represented by each of the general formulas, a deprotection reaction can be carried out as necessary. The deprotection reaction for a protecting group is known and can be carried out in the following ways. For example, mention may be made of (1) alkaline hydrolysis deprotection reaction, (2) acidic deprotection reaction, (3) hydrogenolysis deprotection reaction, (4) silyl group deprotection reaction, (5) metal deprotection reaction, and (6) deprotection reaction using a metal complex.

[0187]

These methods will be described in detail below.

(1) The alkaline hydrolysis deprotection reaction can be carried out, for example, in an organic solvent (for example, methanol, THF, dioxane), using an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide), an alkaline earth metal hydroxide (for example, barium hydroxide, calcium hydroxide), carbonate (e.g. sodium carbonate, potassium carbonate) or an aqueous solution or mixture thereof at a temperature of 0-40 °C.

(2) The deprotection reaction under acidic conditions can be carried out, for example, in an organic solvent (for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole), in an organic acid (for example, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid) or inorganic acid (e.g. hydrochloric acid, sulfuric acid) or mixtures thereof (e.g. hydrogen bromide/acetic acid) in the presence or absence of 2,2,2-trifluoroethanol at 0-100° C.

(3) The hydrogenolysis deprotection reaction can be carried out, for example, in a solvent (for example, an ether-type solvent (for example, THF, dioxane, dimethoxyethane, diethyl ether), an alcohol-type solvent (for example, methanol, ethanol), a benzene-type solvent (e.g. benzene, toluene), in a ketone type solvent (e.g. acetone, methyl ethyl ketone), in a nitrile type solvent (e.g. acetonitrile), in an amide type solvent (e.g. DMF), water, ethyl acetate, acetic acid or a mixed solvent, consisting of two or more of these solvents), in the presence of a catalyst (for example, palladium on carbon, palladium black, palladium hydroxide on carbon, platinum oxide, Raney nickel), under an atmosphere of hydrogen at atmospheric pressure or under pressure, or in the presence of ammonium formate at temperatures 0-200 °C.

(4) The deprotection reaction of the silyl group can be carried out, for example, in a water-miscible organic solvent (eg THF, acetonitrile) using tetrabutylammonium fluoride at a temperature of 0-40 °C. Alternatively, the deprotection reaction can also be carried out, for example, in an organic acid (eg acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid) or inorganic acid (eg hydrochloric acid, sulfuric acid) or a mixture thereof (eg , hydrogen bromide/acetic acid) at temperatures from -10°C to 100°C.

(5) The metal deprotection reaction can be carried out, for example, in an acidic solvent (for example, a mixed solution of acetic acid, a buffer solution having a pH value of 4.2 to 7.2, or a solution thereof with an organic solvent such as THF) , in the presence of zinc powder at a temperature of 0-40 °C, optionally using ultrasonic waves.

(6) The deprotection reaction using a metal complex can be carried out, for example, in an organic solvent (for example, dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol), water or a mixed solvent thereof in the presence of a trapping reagent (for example, tributyltin hydride , triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine), organic acid (e.g. acetic acid, formic acid, 2-ethylhexanoic acid) and/or organic acid salt (e.g. sodium 2-ethylhexanoate, potassium 2-ethylhexanoate), in the presence or in the absence of a phosphine-type reagent (e.g., triphenylphosphine), using a metal complex (e.g., tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, chlorotris(triphenylphosphine)rhodium(I) ) at a temperature of 0-40 °C.

[0188]

In addition to the above methods, the deprotection reaction can also be carried out, for example, by the method described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

[0189]

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

[0190]

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

[0191]

In addition to the above-mentioned protecting groups, the protecting group for the hydroxyl group or the amino group is not particularly limited as long as the protecting group can be easily and selectively separated. For example, the protecting groups mentioned in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999, can be used.

[0192]

In each of the reactions mentioned in the specification, a compound to be used as a starting raw material, for example, a compound represented by the general formulas (A-1), (A-3), (A-3-1a) and (A- 3-1b) is known or can be easily obtained by a known method.

[0193]

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

[0194]

Each of the reactions mentioned herein can also suitably use a solid-phase supported reagent supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol).

[0195]

In each of the reactions mentioned in the description, the reaction product can be purified by conventional purification methods such as atmospheric or reduced pressure distillation, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, absorbent resin, column chromatography, washing and recrystallization. Purification can be carried out for each reaction or can be carried out after completion of several reactions.

[0196]

[Toxicity]

The toxicity of the compound of the present invention is sufficiently low that it can be safely used as a medicine.

[0197]

[Pharmaceutical Application]

The compound of the present invention has neuroprotective and/or neurorestorative activity.

In one embodiment, the compound of the present invention has neuroprotective and/or neurorestorative activity having excellent stability.

In this regard, the compound of the present invention can be used, for example, for the treatment of a disease associated with neuropathy.

[0198]

In the present invention, one example of neuroprotective and/or neurorestorative activity is neuroprotective and/or neurorestorative activity through glial cells (such as microglia, astrocyte, oligodendrocyte, ependymocyte, Schwann cell, satellite cell). One example of neuroprotective and/or neurorestorative activity through glial cells is activity that promotes myelination of Schwann cells.

[0199]

In the present invention, neuropathy includes peripheral neuropathy and central neuropathy. Examples of disease associated with peripheral neuropathy include diabetic neuropathy, metabolic peripheral neuropathy associated with uremia, peripheral neuropathy associated with vitamin B deficiency, peripheral neuropathy associated with an infectious disease such as diphtheria, food botulism, herpes virus (herpes zoster) , drug-induced peripheral neuropathy associated with the administration of phenytoin, which is an anticonvulsant, an antimicrobial agent (for example, chloramphenicol, nitrofurantoin, a sulfonamide drug), a chemotherapy drug (taxane-based: paclitaxel, docetaxel, etc., platinum drugs: oxaliplatin, cisplatin , carboplatin, nedaplatin, etc., based on vinca alkaloids: vinblastine, vincristine, vindesine, etc.) or sedatives (for example, barbital, hexobarbital), chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, compressive neuropathy ( eg, carpal tunnel syndrome, superior thoracic outlet syndrome, cubital tunnel syndrome, piriformis syndrome, tarsal tunnel syndrome, peroneal nerve compression neuropathy), immunological peripheral neuropathy such as multifocal motor neuropathy, peripheral neuropathy associated with an allergic disease such as nodule periarteritis, allergic vasculitis and systemic lupus erythematosus, toxic peripheral neuropathy associated with ingestion of heavy metals such as lead, mercury, arsenic and thallium, organic solvent such as thinner, organic phosphorus insecticide, toxic substance such as triorthocresyl phosphate ( TOCP) or alcohol, peripheral neuropathy caused by nerve compression due to cancer, and peripheral neuropathy associated with a genetic disorder (eg, hypothyroidism, renal failure, Charcot-Marie-Tooth disease, Refsum disease, porphyria, Fabry disease, hereditary neuropathy with predisposition to compression paralysis).

[0200]

Examples of diseases associated with central neuropathy include Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, dystonia, prion disease, multiple system atrophy, spinal cerebellar ataxia, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal and bulbar muscular atrophy, spinal muscular atrophy, spastic paraplegia, syringomyelia, multiple sclerosis, neuromyelitis optica, concentric sclerosis, acute multiple encephalomyelitis, inflammatory diffuse sclerosis, subacute sclerosing panencephalitis, infectious neuropathy such as progressive multifocal leukoencephalopathy, toxic/metabolic neuropathy such as hypoxic-ischemic encephalopathy and central pontine myelinolysis, and vasculitic neuropathy such as Binswanger's disease.

[0201]

In the present invention, one example of the prevention and/or treatment of peripheral neuropathy is the prevention and/or treatment of peripheral neuropathic pain.

[0202]

As for a combination drug containing a compound of the present invention and another drug, the combination drug can be administered in the form of a mixed drug in which both components are mixed in one drug, or these drugs can be prepared separately and administered. In the case where drugs are prepared separately and administered, administration includes simultaneous administration and time-spaced administration. In the case of administration with a difference in time, it is possible to first administer the compound of the present invention and then administer another drug, or first administer the other drug and then administer the compound of the present invention. The method of administration of the compound of the present invention and the method of administration of another drug may be the same or may be different from each other.

[0203]

The disease for which the combination drug can have a prophylactic and/or therapeutic effect is not particularly limited, and any disease can be used as long as the prophylactic and/or therapeutic effect of the compound of the present invention can be complemented or enhanced for the disease.

[0204]

Examples of other drugs for complementing and/or enhancing the prophylactic and/or therapeutic effect of the compound of the present invention on a neuropathy-related disease include an aldose reductase inhibitory drug, a vitamin agent and a brain protective drug. An example of a drug that inhibits aldose reductase is epalrestat. An example of a vitamin supplement is mecobalamin. An example of a drug that protects the brain is edaravone.

[0205]

The concomitant drug used in combination with the compound of the present invention includes drugs that have been discovered to date as well as drugs that will be discovered in the future.

[0206]

Typically, the compound of the present invention is administered systemically or locally in the form of an oral or parenteral dosage form. Examples of the oral preparation include an internal liquid preparation (eg, elixir, syrup, pharmaceutically acceptable aqueous preparation, suspension, emulsion) and an internal solid preparation (eg, tablets (including sublingual and orodissolving tablets), pills , capsules (including hard capsules, soft capsules, gelatin capsules and microcapsules), powder, granule, lozenge). Examples of the parenteral drug include liquid drug (eg, injection solution (including intravitreal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), eye drops (including water-based eye drops (eg, water-based eye drop solution) water-based, water-based eye drop suspension, viscous eye drop solution, solubilized eye drop solution), anhydrous eye drops (e.g., anhydrous eye drop solution, anhydrous eye drop suspension)), topical preparation ( including ointment (eg, eye ointment)) and ear drops. These drugs can be controlled-release drugs, such as immediate-release drugs and sustained-release drugs. These drugs can be prepared by known methods, such as those described in the Japanese Pharmacopoeia. .

[0207]

An internal liquid preparation that is used as an oral preparation can be prepared, for example, by dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (eg, purified water, ethanol, a mixed solution thereof). The liquid preparation may further contain a humectant, a suspending agent, an emulsifying agent, a sweetener, a flavoring agent, a flavoring agent, a preservative, a buffering agent, and the like.

[0208]

The solid preparation for internal use, which is used as an oral preparation, can be prepared in accordance with a conventional method, for example, by mixing the active ingredient with an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch), a binder (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminum metasilicate), a disintegrant (eg calcium carboxymethylcellulose), a lubricant (eg magnesium stearate), a stabilizing agent, a solubilizing agent (glutamic acid, aspartic acid) and the like. If necessary, the solid preparation may be coated with a coating agent (eg, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate) or may be coated in two or more layers.

[0209]

The external preparation which is used as the parenteral preparation can be prepared by a known method or by using a commonly used composition. For example, an ointment may be prepared by grinding or melting the active ingredient into a base material. The ointment base may be selected from known or traditionally used substances. For example, one or two or more components selected from a higher fatty acid or a higher fatty acid ester (such as 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), wax (e.g. beeswax, spermaceti wax, ceresin wax), surfactant (e.g. polyoxyethylene alkyl ester phosphoric acid ester), higher alcohol (e.g. cetanol, stearyl alcohol, cetostearyl alcohol), silicone oil (e.g. dimethylpolysiloxane), hydrocarbon (e.g. hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin), glycol (e.g. ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol), vegetable oil ( eg castor oil, olive oil, sesame oil, turpentine oil), animal oil (eg mink oil, yolk oil, squalane, squalene), water, absorption accelerator and anti-rash agent, used alone or in mixed form. The ointment may further contain a humectant, a preservative, a stabilizing agent, an antioxidant, a flavoring agent, and the like.

[0210]

An injectable drug used as a parenteral drug includes a solid injectable drug that is dissolved or suspended in a solution, suspension, emulsion or solvent for immediate administration upon use. The injectable preparation is used in a form obtained, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent. Examples of the solvent used include distilled water for injection, saline solution, vegetable oil, alcohol such as propylene glycol, polyethylene glycol and ethanol, and a combination thereof. The injectable preparation may further contain a stabilizing agent, a solubilizing agent (eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), a suspending agent, an emulsifying agent, an analgesic, a buffering agent, a preservative, and the like. The injectable preparation is sterilized at the final stage or obtained in a sterile manner. Alternatively, it is also possible to prepare a sterile solid preparation, such as a lyophilized injection product, and dissolve the solid preparation in sterilized or germ-free distilled water for injection or other solvent prior to use.

[0211]

To use the compound of the present invention or a combination drug of the compound of the present invention and another drug for the above purposes, the compound of the present invention or combination drug is usually administered systemically or locally in an oral or parenteral dosage form. The dosage amount may vary depending on age, body weight, clinical conditions, therapeutic effects, routes of administration, treatment time periods, and the like, and is typically administered orally in a single dose or in multiple divided doses per day with a single dose ranging from 1 ng to 1000 mg per adult dose, or administered parenterally as a single dose or in multiple divided doses per day in amounts ranging from 0.1 ng to 10 mg per adult dose, or administered intravenously in a continuous manner over 1 to 24 hours per day per adult. As stated above, the dose varies depending on various factors. Accordingly, administration of a lesser amount than the above dosage amount may be sufficient, or it may be necessary to administer a greater amount than the above dosage amount.

EXAMPLES

[0212]

Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to these examples.

[0213]

The solvent mentioned in the section on chromatographic separation or shown in parentheses in the TLC data is the elution solvent or developing solvent used, where the ratio is expressed as volumetric.

The conditions used in the LC/MS analyzes in the following examples are shown below. Column: YMC Triart C18, 2.0 mm × 30 mm, 1.9 µm; flow rate: 1.0 ml/min; temperature: 30°C; mobile phase A: 0.1% aqueous TFA solution; mobile phase B: 0.1% TFA solution in acetonitrile; gradient (ratio (mobile phase A):(mobile phase B)): 0-0.10 min (95:5), 0.10-1.20 min (95:5 to 5:95), 1.20 -1.50 min (5:95).

The substance shown in parentheses in the NMR data is the solvent used for the measurement.

Each of the compounds used in the specification was named using the "ACD/Name" (registered trademark) computer program produced by Advanced Chemistry Development (which generally names in accordance with the IUPAC nomenclature rule) or was named in accordance with the IUPAC nomenclature method.

[0214]

Example 1: Isopropyl 3-(2-hydroxyphenyl)propanoate

Sulfuric acid (0.26 ml) was added to a solution of 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting the residue was diluted with ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The title compound (73.2 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06- 7.15, 7.35.

[0215]

Example 2: Isopropyl 3-(2-(2-(1,3-dioxan-2-yl)ethoxy)phenyl)propanoate

Potassium phosphate (2.85 g) was added to a solution of the compound obtained in Example 1 (2.00 g) and 2-(2-bromoethyl)-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 1 M hydrochloric acid and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 → 4:1). The title compound (2.73 g) was thereby obtained having the physical properties shown below.

TLC: Rf 0.57 (hexane:ethyl acetate=2:1).

[0216]

Example 3: Isopropyl 3-(2-(3-oxopropoxy)phenyl)propanoate

A solution of the compound obtained in Example 2 (500 mg) and lutidine (0.40 ml) in dichloromethane (1.5 ml) was cooled to -15°C and trimethylsilyl trifluoromethanesulfonate (0.42 ml) was added to the solution. The resulting reaction mixture was stirred at 0°C for 2 hours. Ice (10 g) was added to the reaction solution, and the resulting solution was stirred at 0°C for 15 minutes. Water and ethyl acetate were added to the solution, the resulting solution was stirred at 0°C for 20 hours, the resulting reaction mixture was poured into 1 M hydrochloric acid and ethyl acetate, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The title compound (443 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.20, 2.50-2.55, 2.93-2.96, 4.33, 4.98, 6.85-6.92, 7.14- 7.19, 9.90.

[0217]

Example 4: Isopropyl 3-(2-((3-hydroxy-5-(trimethylsilyl)pent-4-yn-1-yl)oxy)phenyl)propanoate

A solution of trimethylsilylacetylene (5.0 ml) in THF (70 ml) was cooled to -70°C, then n-butyllithium (1.6 M solution in hexane, 20 ml) was added to the solution, and the reaction mixture was stirred at -70°C within 30 min. A solution of the compound obtained in Example 3 (7.15 g) in THF (10 ml) was added dropwise to the solution, and the resulting reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the resulting solution was then extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 → 7:3). The title compound (1.8 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.17, 1.19, 2.22-2.33, 2.56, 2.87-2.98, 4.09-4.23, 4.70, 3.60-4.93-5.03, 6.86-6.91, 7.14-7.18.

[0218]

Example 5: Isopropyl 3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate

A solution of the compound obtained in Example 4 (6.89 g) in THF (38 ml) was cooled to 0°C, and tetrabutylammonium fluoride (hereinafter abbreviated as “TBAF”) (1.0 M solution in THF, 7.3 ml ) was further added to the solution. The reaction mixture was stirred at 0°C for 10 min. The reaction mixture was poured into 1 M hydrochloric acid and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 → 1:1). The title compound (5.06 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.19, 2.20-2.26, 2.43, 2.50-2.59, 2.87-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.

[0219]

Example 6: Isopropyl-(R)-3-(2-((3-hydroxypent-4-yn-1-yl)oxy)phenyl)propanoate

Vinyl acetate (4 ml) was added to a solution of the compound obtained in Example 5 (1.2 g) in heptane (24 ml). CHIRAZYME L-5 CA (trade name) (0.4 g) was added to the solution, and the resulting reaction mixture was stirred at 45°C for 9 hours. The reaction mixture was filtered through Celite (trade name) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 → 1:1) to give the title compound (0.54 g, >99% ee) having the physical properties shown below. The compound thus obtained was analyzed by high performance liquid chromatography (column used: Daicel Corporation, CHIRALPAK-IB (4.6 mm × 250 mm), mobile phase: hexane:2-propanol=95:5, flow rate: 1 ml/min , wavelength: 254 nm, column temperature: 40°C). As a result, the retention time was 10.6 minutes.

¹ H-NMR (CDCl ₃ ): δ 1.19, 2.20-2.26, 2.41, 2.50-2.59, 2.90-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.

[0220]

Example 7: Isopropyl-(R)-3-(2-((3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl)propanoate

A solution of the compound obtained in Example 6 (500 mg) in DMF (3.4 ml) was cooled to 0°C, and then chlorotrimethylsilane (0.24 ml) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 → 9:1). The title compound (600 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.17, 1.21, 2.18, 2.43, 2.54-2.59, 2.90-2.95, 4.06-4.15, 4.67, 4.99, 6.83-6.89, 7.14-7.20.

[0221]

Example 8: isopropyl-(R,E)-3-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3-((trimethylsilyl) hydroxy)pent-4-en-1-yl)oxy)phenyl)propanoate

4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (2.09 g) and 4-dimethylaminobenzoic acid (53.9 mg) were added to a solution of the compound obtained in Example 7 (2.45 g), in heptane (6 ml), and the resulting solution was stirred at 100°C for 13 hours. The reaction solution was cooled to room temperature and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 → 3:1). The title compound (1.45 g) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.14.

[0222]

Example 9: N-(3-bromophenyl)benzenesulfonamide

Pyridine (0.95 ml), N,N-dimethylaminopyridine (hereinafter abbreviated as "DMAP") (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added to a solution of 3-bromoaniline (1.02 g) in dichloromethane ( 20 ml) at 0°C, and the resulting solution was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the resulting residue was then purified by silica gel column chromatography (hexane:ethyl acetate=9:1 → 2:1). The title compound (1.96 g) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.98.

[0223]

Example 10: Propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoate

Compound obtained in Example 9 (1.18 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1' -biphenyl)]palladium(II) (CAS registration number: 1310584-14-5) (0.30 g) and 2 M aqueous solution of tripotassium phosphate (5.7 ml) were added to the solution of the compound obtained in Example 8 (2.00 d), in THF (18 ml), and the resulting solution was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature, then water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. TBAF (1.0 M solution in THF, 6.3 ml) was added to a solution of the resulting residue in THF (6 ml), and the solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the resulting solution 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 → 2:1). The title compound (1.41 g) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.21, 2.05-2.17, 2.21, 2.57-2.61, 2.91-2.95, 4.11-4.19, 4.62, 5.02, 6.25, 6.55, 6.72, 6.85-6.91, 6.99, 7.09-7.22, 7.41-7.45, 7, 53, 7.75-7.78.

[0224]

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

[0225]

[Formula 43]

[0226]

A 1M aqueous solution of lithium hydroxide (5 ml) was added to a solution of the compound obtained in Example 10 (680 mg) in THF (5 ml) and methanol (1 ml), and the resulting solution was stirred at 30°C for 18 hours. 1 M hydrochloric acid was added to the solution to make the solution acidic, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The title compound (600 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.93;

¹ H-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.

[0227]

Examples 12 (1) - (13)

The same prescribed procedures were carried out as in Example 10 → Example 11, using the corresponding halide compounds instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 10. The following example compounds were thereby obtained.

[0228]

Example 12(1): 3-[2-[(E,3R)-5-(3-benzamidophenyl)-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.95;

¹ H-NMR (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.

[0229]

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

[0230]

[Formula 44]

[0231]

HPLC retention time (min): 0.92;

MS (ESI, positive): 464 (M+HH ₂ O) ⁺ .

[0232]

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

HPLC retention time (min): 0.95;

¹ H-NMR (CD ₃ OD): δ 2.10-2.14, 2.58-2.63, 2.93-2.97, 4.13, 4.20, 4.58, 6.32 , 6.64, 6.86, 6.95, 7.15-7.20, 7.44-7.55, 7.60, 7.67-7.71, 7.93-7.97.

[0233]

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

HPLC retention time (min): 0.94;

MS (ESI, positive): 464 (M+HH ₂ O) ⁺ .

[0234]

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

HPLC retention time (min): 0.89;

MS (ESI, positive): 428 (M+HH ₂ O) ⁺ .

[0235]

Example 12(6): 3-[2-[(E,3R)-5-[3-(benzylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.85;

¹ H-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.

[0236]

Example 12(7): 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylsulfamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.94;

MS (ESI, positive): 464 (M+HH ₂ O) ⁺ .

[0237]

Example 12(8): 3-[2-[(E,3R)-3-hydroxy-5-[3-(phenylcarbamoyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.95;

MS (ESI, positive): 428 (M+HH ₂ O) ⁺ .

[0238]

Example 12(9): 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.96;

¹ H-NMR (CD ₃ OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56 , 4.84, 6.27, 6.62, 6.86, 6.94, 7.10-7.31.

[0239]

Example 12(10): 3-[2-[(E,3R)-5-[3-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.93;

MS (ESI, positive): 478 (M+HH ₂ O) ⁺ .

[0240]

Example 12(11): 3-[2-[(E,3R)-5-[2-(benzenesulfonamidomethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.97;

¹ H-NMR (CDCl ₃ ): δ 1.99-2.07, 2.11-2.19, 2.68-2.72, 2.95-3.08, 4.12-4.26, 4.73-4.78, 6.12, 6.59, 6.86-6.92, 7.04-7.11, 7.16-7.23, 7.33-7.38, 7, 44-7.48, 7.64-7.67.

[0241]

Example 12(12): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2-methylindol-4-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.10;

MS (ESI, positive): 502 (M+HH ₂ O) ⁺ .

[0242]

Example 12(13): 3-[2-[(E,3R)-3-hydroxy-5-[3-(2-hydroxy-1-phenylpropan-2-yl)phenyl]pent-4-enoxy]phenyl] propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.65-2.68, 2.94-3.14, 4.12-4.22, 4.62, 6.28, 6.64, 6.86-6.91, 7.00-7.02, 7.15-7.28, 7.44.

[0243]

Examples 13(1) - (19)

The same prescribed procedures were carried out as in example 9 → example 10 → example 11, using the corresponding amine compounds instead of the 3-bromoaniline used in example 9. The following example compounds were thereby obtained.

[0244]

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

[0245]

[Formula 45]

[0246]

HPLC retention time (min): 0.94;

¹ H-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.

[0247]

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

HPLC retention time (min): 0.95;

¹ H-NMR (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.

[0248]

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

HPLC retention time (min): 0.96;

¹ H-NMR (CD ₃ OD): δ 1.93-1.98, 2.12, 2.45-2.49, 2.79-2.83, 3.98, 4.05, 4.41 , 6.09, 6.37, 6.69, 6.74, 6.80-6.83, 7.03-7.08, 7.34-7.38, 7.44, 7.63-7 ,66.

[0249]

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

HPLC retention time (min): 0.94;

¹ H-NMR (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.

[0250]

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

HPLC retention time (min): 0.94;

¹ H-NMR (CD ₃ OD): δ 2.03-2.09, 2.55-2.59, 2.89-2.93, 4.09, 4.16, 4.53, 6.36 , 6.63, 6.86, 6.92, 7.06, 7.15-7.19, 7.30-7.37, 7.45-7.49, 7.57, 7.75-7 .77.

[0251]

Example 13(6): 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.94;

¹ H-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.

[0252]

Example 13(7): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.96;

¹ H-NMR (CD ₃ OD): δ 1.92-1.98, 2.44-2.48, 2.78-2.82, 3.98, 4.06, 4.42, 6.17 , 6.39, 6.68, 6.70-6.82, 7.03-7.08, 7.37-7.41, 7.47, 7.68-7.71.

[0253]

Example 13(8): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-fluorophenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.92;

¹ H-NMR (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.

[0254]

Example 13(9): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.95;

¹ H-NMR (CD ₃ OD): δ 1.94-2.00, 2.43-2.47, 2.78-2.82, 3.99, 4.06, 4.45, 6.08 , 6.74, 6.79-6.85, 7.03-7.10, 7.32-7.43, 7.50, 7.58-7.60.

[0255]

Example 13(10) 3-[2-[(E,3R)-5-[5-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.99;

¹ H-NMR (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.

[0256]

Example 13(11): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-5-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.99;

¹ H-NMR (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.

[0257]

Example 13(12): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)-4-(trifluoromethyl)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.97;

¹ H-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.

[0258]

Example 13(13): 3-[2-[(E,3R)-5-[6-(benzenesulfonamido)pyridin-2-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.85;

¹ H-NMR (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.

[0259]

Example 13(14): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-6-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (CD ₃ OD): δ 2.11-2.16, 2.59-2.63, 2.82-2.86, 2.94-2.98, 3.94-3.98 , 4.14, 4.22, 4.60, 6.34, 6.66, 6.87, 6.96, 7.05-7.09, 7.16-7.21, 7.48-7 .52, 7.63, 7.66, 7.78-7.81.

[0260]

Example 13(15): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-2,3-dihydroindol-4-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-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.

[0261]

Example 13(16): 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-1,3-dihydroisoindol-5-yl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (CD ₃ OD): δ 2.06-2.10, 2.55-2.59, 2.89-2.93, 4.10, 4.17, 4.54, 4.60 , 6.31, 6.60, 6.85, 6.92, 7.13-7.18, 7.28-7.30, 7.58-7.68, 7.90-7.93.

[0262]

Example 13(17): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-7-yl]-3-hydroxypent-4-enoxy] phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (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.

[0263]

Example 13(18): 3-[2-[(E,3R)-5-[1-(benzenesulfonyl)-3,4-dihydro-2H-quinolin-5-yl]-3-hydroxypent-4-enoxy] phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (CD ₃ OD): δ 1.50-1.57, 2.01-2.15, 2.19-2.37, 2.53-2.57, 2.88-2.92 , 3.75-3.78, 4.07, 4.16, 4.56, 6.12, 6.67, 6.84, 6.90, 7.13-7.21, 7.32, 7 .45-7.49, 7.56-7.65.

[0264]

Example 13(19): 3-[2-[(E,3R)-5-[2-(benzenesulfonyl)-3,4-dihydro-1H-isoquinolin-7-yl]-3-hydroxypent-4-enoxy] phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (CD ₃ OD): δ 2.07-2.12, 2.57-2.61, 2.87-2.95, 3.36-3.39, 4.11, 4.18 , 4.25, 4.55, 6.29, 6.57, 6.85, 6.93, 7.05, 7.14-7.19, 7.23, 7.59-7.70, 7 .87-7.89.

[0265]

Example 14: N-(3-bromophenyl)-N-(oxetan-2-ylmethyl)benzenesulfonamide

Oxetan-2-ylmethanol (132 mg), triphenylphosphine (394 mg) and diethyl azodicarboxylate (40% toluene solution, 0.68 ml) were added to a solution of the compound obtained in Example 9 (313 mg) in THF (2 ml), and the resulting solution 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). The title compound (381 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.34 (hexane:ethyl acetate=2:1).

[0266]

Example 15: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 10 → Example 11 were carried out, using instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 10, the compound obtained in Example 14. The title compound was thereby obtained having the physical values properties shown below.

HPLC retention time (min): 0.95;

¹ H-NMR (CD ₃ OD): δ 2.06-2.10, 2.48-2.69, 2.91-2.95, 3.80, 4.00, 4.10, 4.18 , 4.47-4.64, 4.83, 6.21, 6.55, 6.87, 6.94-6.96, 7.03, 7.17-7.21, 7.27, 7 ,38, 7.50-7.54, 7.60-7.65.

[0267]

Examples 16 (1) - (8):

The same prescribed procedures as in Example 14 → Example 10 → Example 11 were carried out, using the corresponding alcohol compounds instead of the oxetan-2-ylmethanol used in Example 14, and using the corresponding halide compounds instead of N-(3-bromophenyl)benzenesulfonamide, used in Example 10. The following compounds of the Examples were thereby obtained.

[0268]

Example 16(1): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxetan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.94;

¹ H-NMR (CD ₃ OD): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.04, 3.95, 4.10, 4.18 , 4.36-4.40, 4.55, 4.63-4.67, 6.22, 6.55, 6.85-6.97, 7.16-7.21, 7.29, 7 ,40, 7.52-7.56, 7.62-7.67.

[0269]

Example 16(2): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (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.

[0270]

Example 16(3): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxolan-3-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.97;

¹ H-NMR (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.

[0271]

Example 16(4):

3-[2-[(E,3R)-5-[3-[benzenesulfonyl(oxan-2-ylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.10;

¹ H-NMR (CD ₃ OD): δ 1.26, 1.39-1.55, 1.68, 1.82, 2.06-2.11, 2.57-2.61, 2.92 -2.95, 3.23-3.30, 3.51, 3.70, 3.87, 4.10, 4.18, 4.55, 6.20, 6.56, 6.87, 6 .93-6.96, 7.02, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.63.

[0272]

Example 16(5): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(propan-2-yl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.31 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 1.04, 1.98-2.21, 2.67, 2.89-3.01, 4.10-4.24, 4.55-4.66, 6.22, 6.59, 6.85-6.92, 7.07, 7.16-7.28, 7.38-7.57, 7.76.

[0273]

Example 16(6): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.34 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 0.91, 1.57, 2.08-2.15, 2.67, 2.97, 3.30, 4.10-4.24, 4.62, 6.20, 6.57, 6.83-6.92, 7.08, 7.16-7.25, 7.31, 7.40-7.47, 7.51-7.60.

[0274]

Example 16(7): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(cyclopropylmethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.79 (ethyl acetate);

¹ H-NMR (CDCl ₃ ): δ 0.09-0.13, 0.38-0.43, 0.80-0.90, 2.09-2.18, 2.67, 2.97, 3.42, 4.11-4.23, 4.63, 6.22, 6.58, 6.86-6.93, 7.14-7.26, 7.33, 7.44, 7, 55, 7.63.

[0275]

Example 16(8): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2-phenylethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.74 (ethyl acetate);

¹ H-NMR (CDCl ₃ ): δ 2.07-2.21, 2.64-2.71, 2.74-2.81, 2.94-3.01, 3.72-3.80, 4.11-4.24, 4.63, 6.22, 6.59, 6.81-6.93, 7.09-7.26, 7.31-7.45, 7.51-7, 60.

[0276]

Example 17: N-(3-bromophenyl)-N-(2-oxopropyl)benzenesulfonamide

Sodium hydride (60% in mineral oil, 141 mg) was added to a solution of the compound obtained in Example 9 (1.00 g) in DMF (6 ml) under ice-cooling, and the resulting solution was stirred at room temperature. After 30 minutes, chloroacetone (0.52 ml) was added to the solution, and then stirred at room temperature for 4 hours. Water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over magnesium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20 → 50:50). The title compound (1.10 g) was thereby obtained having the physical properties shown below.

TLC: Rf 0.42 (hexane:ethyl acetate=2:1).

[0277]

Example 18: N-(3-bromophenyl)-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide

Methylmagnesium bromide (0.95 M solution in THF, 1.0 ml) was added to a solution of the compound obtained in Example 17 (313 mg) in THF (3 ml) under ice-cooling, and the resulting solution was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20 → 50:50). The title compound (50 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.58 (hexane:ethyl acetate=1:1).

[0278]

Example 19: 3-[2-[(E,3R)-5-[3-[benzenesulfonyl-(2-hydroxy-2-methylpropyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 10 → Example 11 were carried out, using instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 10, the compound obtained in Example 18. The title compound having the physical values properties shown below.

HPLC retention time (min): 0.93;

¹ H-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, 7.17-7.21, 7.25, 7.35, 7.46-7 .54, 7.60.

[0279]

Examples 20 (1) - (4)

The same prescribed procedures were followed as in Example 17 → Example 10 → Example 11, using the appropriate halide compounds in place of the chloroacetone used in Example 17, and using the appropriate halide compounds in place of the N-(3-bromophenyl)benzenesulfonamide used in Example 10 Thus, the following example compounds were obtained.

[0280]

Example 20(1): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(methyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.99;

¹ H-NMR (CDCl ₃ ): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.20, 4.10, 4.19, 4.55, 6.24, 6.57, 6.87, 6.93-7.00, 7.08, 7.17-7.20, 7.27, 7.36, 7.50-7.56, 7, 63.

[0281]

Example 20(2): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(ethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.01;

¹ H-NMR (CDCl ₃ ): δ 1.07, 2.06-2.11, 2.57-2.61, 2.92-2.96, 3.66, 4.11, 4.19, 4.55, 6.22, 6.57, 6.87, 6.92-6.96, 7.01, 7.16-7.21, 7.29, 7.39, 7.50-7, 54, 7.59-7.65.

[0282]

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

HPLC retention time (min): 1.07;

¹ H-NMR (CDCl ₃ ): δ 2.04-2.09, 2.57-2.61, 2.91-2.95, 4.08, 4.16, 4.52, 4.80, 6.14, 6.48, 6.85-6.89, 6.93-6.96, 7.14-7.28, 7.54-7.58, 7.63-7.69.

[0283]

Example 20(4): 3-[2-[(E,3R)-5-[3-[benzenesulfonyl(2,2,2-trifluoroethyl)amino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propane acid

TLC: Rf 0.49 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 2.08-2.17, 2.62-2.70, 2.94-3.00, 4.11-4.26, 4.62, 6.21, 6.57, 6.83-6.93, 7.10, 7.17-7.25, 7.36, 7.47, 7.57-7.63.

[0284]

Example 21: (R)-1-(3-bromophenyl)-2-phenylethan-1-ol

(R)-Methyloxazaborolidine (1.0 M solution in toluene, 3.6 ml) and borane dimethyl sulfide (2.0 M solution in THF, 3.6 ml) were added to the solution of 1-(3-bromophenyl)-2- phenylethanone (CAS registration number: 40396-53-0) (2.00 g) in THF (70 ml) at -20°C, and the resulting solution was stirred at the same temperature for 1 hour. Methanol (1 ml) at -20°C, and the resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 → 2:1). The title compound (1.91 g, 96% ee) was thereby obtained having the physical properties shown below. The compound thus obtained was analyzed by SFC (column used: Daicel Corporation, CHIRALPAK-IA (10 mm × 250 mm), mobile phase: CO ₂ :acetonitrile:methanol=90:9:1, flow rate: 30 ml/min; pressure: 100 bar (10 MPa), wavelength: 220 nm, column temperature: 35°C). As a result, the retention time was 5.6 minutes.

HPLC retention time (min): 1.08.

[0285]

Example 22: isopropyl-3-(2-(((R, E)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pent-4-ene-1- yl)oxy)phenyl)propanoate

The same prescribed procedure as in Example 10 was carried out, using instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 10, the compound obtained in Example 21. The title compound was thereby obtained having the physical property values shown below.

HPLC retention time (min): 1.21.

[0286]

Example 23: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 22. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.95;

¹ H-NMR (CD ₃ OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56 , 4.84, 6.28, 6.62, 6.86, 6.94, 7.10-7.31.

[0287]

Example 24: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in Example 21 → Example 10 → Example 11, using (S)-methyloxazaborolidine instead of the (R)-methyloxazaborolidine used in Example 21, and using the corresponding halide compound instead of N-(3-bromophenyl) benzenesulfonamide used in Example 10. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.97;

¹ H-NMR (CD ₃ OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56 , 4.84, 6.27, 6.61, 6.86, 6.94, 7.10-7.31.

[0288]

Example 25: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2R)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 21 → Example 10 → Example 11 were carried out using 2-(3-bromophenyl)-1-phenylethanone (CAS registration number: 27798-44-3) instead of 1-(3-bromophenyl) -2-phenylethanone used in Example 21 and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.99;

¹ H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.64-2.68, 2.94-3.05, 4.10-4.21, 4.59-4.64, 4.92, 6.27, 6.61, 6.86-6.91, 7.05-7.24, 7.27-7.37.

[0289]

Example 26: 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2S)-2-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedure as in Example 25 was carried out, using (S)-methyloxazaborolidine instead of (R)-methyloxazaborolidine used in Example 25, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10 The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.98;

¹ H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.63-2.67, 2.94-3.05, 4.10-4.22, 4.59-4.64, 4.91, 6.27, 6.61, 6.86-6.91, 7.06-7.08, 7.14-7.24, 7.28-7.38.

[0290]

Example 27: 1-(3-bromophenyl)-3-phenylpropan-1-ol

A solution of 3-bromobenzaldehyde (500 mg) in THF (13.5 ml) was cooled to 0°C, phenylmagnesium chloride (1.0 M solution in THF, 3.5 ml) was added to the solution and the resulting reaction mixture was stirred at 0°C in for 30 minutes. The reaction mixture was poured into a saturated ammonium chloride solution, and the resulting solution was extracted with methyl tert-butyl ether. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 2:1). The title compound (610 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.85, 1.98-2.15, 2.65-2.80, 4.65-4.69, 7.18-7.31, 7.39- 7.42, 7.51.

[0291]

Example 28: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-3-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedure as in Example 10 → Example 11 was carried out, using instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 10, the compound obtained in Example 27. The title compound having the physical values properties shown below.

HPLC retention time (min): 1.00;

¹ H-NMR (CD ₃ OD): δ 1.82-2.03, 2.36-2.40, 2.47-2.63, 2.81-2.85, 3.96-4.09 , 4.46-4.51, 6.22, 6.54, 6.69-6.79, 6.98-7.29.

[0292]

Example 29: 1-(3-bromophenyl)-2-methyl-2-phenylpropan-1-ol

Potassium hydroxide (179 mg), 18-crown-6-ether (4 mg) and methyl iodide (0.29 ml) were added to a solution of 1-(3-bromophenyl)-2-phenyl-ethanone (CAS Registration No: 40396-53 -0) (220 mg) in toluene (0.4 ml), and the resulting reaction mixture was stirred at 70°C for 4 hours. Water was added to the reaction mixture, and the resulting solution 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 resulting residue in methanol (1.5 ml), and the resulting reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and then 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). The title compound (129 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.15 (corrected).

[0293]

Example 30: 3-[2-[(E,3R)-3-hydroxy-5-[3-(1-hydroxy-2-methyl-2-phenylpropyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 10 → Example 11 were carried out, using instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 10, the compound obtained in Example 29. The title compound having the physical values of properties shown below.

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 2.08-2.13, 2.64-2.68, 2.94-2.97, 4.08-4.21, 4.59, 4.75, 6.15, 6.56, 6.86-6.91, 6.97-7.00, 7.09, 7.15-7.25, 7.30-7.38.

[0294]

Example 31: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanamide

Triethylamine (0.021 ml) and isobutyl chloroformate (0.016 ml) were added to a solution of the compound obtained in Example 11 (50 mg) in THF (1 ml) under ice-cooling, and the reaction mixture was stirred at 0°C for 10 minutes. Ammonia (0.5 M solution in 1,4-dioxane, 0.4 ml) was added to the solution at 0°C and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 → 0:1). The title compound (38 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.88;

¹ H-NMR (CDCl ₃ ): δ 2.09-2.21, 2.54-2.63, 3.01, 4.13-4.23, 4.59, 5.70, 6.36, 6.54, 6.87-6.94, 7.00-7.22, 7.40-7.53, 7.79-7.82, 7.93.

[0295]

Examples 32 (1) - (3)

The same prescribed procedure was carried out as in example 31, using the corresponding amine compounds instead of the ammonia used in example 31. The following example compounds were thereby obtained.

[0296]

Example 32(1): N-[3-[(E,3R)-3-hydroxy-5-[2-(3-morpholin-4-yl-3-oxopropyl)phenoxy]pent-1-enyl]phenyl] benzenesulfonamide

HPLC retention time (min): 0.94;

¹ H-NMR (CDCl ₃ ): δ 2.09-2.19, 2.60-2.65, 2.92-2.99, 3.41, 3.50-3.70, 4.09- 4.23, 4.57, 6.30, 6.52, 6.85-6.91, 7.02-7.20, 7.40-7.56, 7.78-7.81.

[0297]

Example 32(2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N,N-dimethylpropanamide

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 2.09-2.19, 2.60-2.65, 2.86-3.03, 4.09-4.22, 4.55, 6.33, 6.51, 6.84-6.91, 6.98-7.00, 7.12-7.20, 7.23-7.26, 7.40-7.52, 7.78-7, 83, 7.98.

[0298]

Example 32(3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-N-methylpropanamide

HPLC retention time (min): 0.90;

¹ H-NMR (CDCl ₃ ): δ 2.07-2.19, 2.41-2.53, 2.82, 2.93-2.97, 4.10-4.22, 4.60, 5.58, 6.31, 6.54, 6.86-6.90, 7.02-7.20, 7.40-7.54, 7.78.

[0299]

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

[0300]

[Formula 46]

[0301]

5% palladium on carbon (200 mg) was added to a solution of the compound obtained in Example 11 (1.1 g) in methanol (10 ml), and the resulting solution was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered, then 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). The title compound (1.05 g) was thereby obtained having the physical properties shown below.

TLC: Rf 0.30 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85- 7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.

[0302]

Example 34: 3-[2-[(3S)-5-[3-(benzylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid

The same prescribed procedure as in Example 33 was carried out using the compound obtained in Example 12(6) instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamide)phenyl]-3- hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33. The following compounds of the example were thereby obtained.

HPLC retention time (min): 0.81;

¹ H-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.

[0303]

Example 35: Isopropyl 3-(2-(((S)-3-hydroxy-5-(3-((R)-1-hydroxy-2-phenylethyl)phenyl)pentyl)oxy)phenyl)propanoate

p-Toluenesulfonylhydrazide (2.66 g) and sodium acetate (1.17 g) were added to a solution of the compound obtained in Example 22 (782 mg) in THF (10 ml) at room temperature, and the resulting solution was stirred at 80°C for 19 hours. The reaction solution was cooled to room temperature, then water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 → 1:1). The title compound (515 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.22.

[0304]

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

[0305]

[Formula 47]

[0306]

The same prescribed procedure as in Example 11 was carried out using the compound obtained in Example 35 instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl] -3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.99;

¹ H-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.

[0307]

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

[0308]

[Formula 48]

[0309]

The same prescribed procedures as in Example 21 → Example 10 → Example 35 → Example 11 were carried out using (S)-methyloxazaborolidine instead of the (R)-methyloxazaborolidine used in Example 21 and using the corresponding halide compound instead of N-(3 -bromophenyl)benzenesulfonamide used in Example 10. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.99;

¹ H-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.

[0310]

Example 38: Isopropyl 3-(2-((3R)-3-hydroxy-3-(2-(3-(phenylsulfonamide)phenyl)cyclopropyl)propoxy)phenyl)propanoate

A solution of the compound obtained in Example 10 (50 mg) in dichloromethane (2 ml) was cooled to 0°C, then diethylzinc (1 M solution in hexane, 0.5 ml) was added to the solution, then diiodomethane (128 mg) was added. the reaction mixture was stirred at 0°C for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the solution at 0°C, and the resulting solution was stirred at room temperature for 5 minutes. The reaction mixture was poured into water, the resulting solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 2:1). The title compound (15 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.10.

[0311]

Example 39: 3-[2-[(3R)-3-[2-[3-(benzenesulfonamido)phenyl]cyclopropyl]-3-hydroxypropoxy]phenyl]propanoic acid

The same prescribed procedure as in Example 11 was carried out using the compound obtained in Example 38 instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl] -3-hydroxypent-4-enoxy]phenyl]propanoate used in Example 11. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.92;

¹ H-NMR (CD ₃ OD): δ 0.85-0.92, 1.03-1.08, 1.72-1.75, 2.03-2.09, 2.57, 2.91 , 4.06-4.15, 6.68-6.69, 6.73-6.75, 6.84-6.89, 7.06, 7.14-7.20, 7.44-7 ,57, 7.72-7.74.

[0312]

Example 40: 5-((3-nitrobenzyl)sulfonyl)-1-phenyl-1H-tetrazole

5-[(3-nitrobenzyl)thio]-1-phenyl-1H-tetrazole solution [J. Org. Chem. (2001), 80, pp.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 aqueous solution hydrogen peroxide (35%, 26 ml) was added dropwise to the resulting solution over 10 minutes. The resulting reaction mixture was stirred at 0°C for 2 hours and then at room temperature for 2.5 hours. The reaction solution was again cooled to 0°C, and then an aqueous solution of sodium thiosulfate (1 M, 150 ml). The resulting solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine, then dried over sodium sulfate and further concentrated under reduced pressure. The oily product thus obtained was suspended in a mixed solvent of hexane and ethyl acetate, and the blue solid was filtered off. The solid material was dissolved in dichloromethane to obtain a solid material, and the solid material was filtered and the filtrate was concentrated under reduced pressure. The title compound (7.71 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 5.12, 7.46-7.64, 7.82, 8.27, 8.35.

[0313]

Example 41: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-ol

DMAP (0.73 g) and imidazole (6.08 g) were added to a solution of (R)-4-[(4-methoxybenzyl)oxy]butane-1,2-diol (CAS Registration No: 213978-61-1) (13.5 g) in DMF (300 ml), and the resulting reaction mixture was stirred at 0°C for 5 minutes. Chloro-tert-butyldimethylsilane (8.93 g) was added to the solution, and the resulting solution was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution to dilute the reaction solution, and the organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The title compound (18.1 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.02, 0.83, 1.65-1.71, 2.73, 3.62-3.41, 3.74, 3.74-3.76, 4.39, 6.82, 7.18-7.21.

[0314]

Example 42: (R)-1-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)butan-2-ylbenzoate

A solution of the compound obtained 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) then added to the solution. Benzyl chloride (2.5 ml) was added to the resulting reaction solution, and the solution was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was poured into ethyl acetate, the organic layer was then washed with 1 M hydrochloric acid and saturated aqueous sodium hydrogen carbonate, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 7:3). The title compound (6.31 g) was thereby obtained 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, 3.76, 3.79, 4.40, 5.27-5.30, 6.81, 7.21, 7.42, 7.53-7.56, 8.01.

[0315]

Example 43: (R)-1-hydroxy-4-((4-methoxybenzyl)oxy)butan-2-ylbenzoate

A solution of the compound obtained in Example 42 (6.31 g) in THF (170 ml) was cooled to 0°C, acetic acid (3.6 ml) and tetrabutylammonium fluoride (1.0 M solution in THF, 21 .2 ml), and the resulting solution was stirred at room temperature overnight. The resulting residue was poured into ethyl acetate, the organic layer was washed with saturated aqueous ammonia and saturated aqueous sodium hydrogen carbonate, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:1). The title compound (4.10 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 2.06-2.09, 2.57, 3.54-3.65, 3.78, 3.80-3.86, 4.41-4.46, 5.27-5.30, 6.84, 7.23, 7.43, 7.56, 8.02.

[0316]

Example 44: (R)-4-((4-methoxybenzyl)oxy)-1-oxobutan-2-ylbenzoate

Pyridinium dichromate (10.6 g) and molecular sieve (trade name) (21.7 g) were suspended in dichloromethane (30 ml), and a solution of the compound obtained in Example 43 (3.1 g) in dichloromethane (100 ml) added dropwise to the resulting solution. The resulting solution was stirred at room temperature for 2.5 hours and then diluted with diethyl ether, and the resulting solution was filtered. The filtrate was concentrated under reduced pressure. The title compound was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 2.27-2.40, 3.57-3.70, 3.76, 4.43, 5.40, 6.82, 7.15-7.24, 7.45, 7.60, 8.03, 9.64.

[0317]

Example 45: (R, E)-5-((4-methoxybenzyl)oxy)-1-(3-nitrophenyl)pent-1-en-3-ylbenzoate

A solution of the compound obtained in Example 40 (3.56 g) in THF (70 ml) was cooled to -70°C, and potassium hexamethyldisilazide (0.5 M solution in toluene, 22.5 ml) was added to the solution. The resulting reaction solution was stirred at -70°C for 30 minutes, then a solution of the compound obtained in Example 44 (3.09 g) in THF (20 ml) was added dropwise to the reaction solution over 5 minutes, and the reaction solution then stirred at room temperature overnight. Ethyl acetate was added to the reaction solution to dilute the reaction solution, the organic layer was washed with saturated saline, then dried over sodium sulfate and further concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:1) . The title compound (2.23 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 2.11-2.24, 3.60, 3.75, 6.81, 7.22, 7.43-7.47, 7.56-7.63, 8.04-8.09, 8.21.

[0318]

Example 46: (R, E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-ylbenzoate or (c,E)-5-hydroxy-1-(3-nitrophenyl)pent-1 -en-3-yl benzoate

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (2.26 g) was added to a solution of the compound obtained in Example 45 (2.23 g) in dichloromethane (100 ml) and phosphate buffer (pH 7, 100 ml) at room temperature, and the resulting solution was stirred vigorously at room temperature for 3.5 hours. The reaction mixture was poured into ethyl acetate and the organic layer was then washed with brine, then dried over sodium sulfate and further 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 of the title compounds (1.25 g). The resulting mixture was subjected to optical separation using SFC (column used: Daicel Corporation, CHIRALPAK-IA (20 mm × 250 mm), mobile phase: CO ₂ :methanol=90:10, flow rate: 100 ml/min; pressure: 120 bar (12 MPa), wavelength: 254 nm, column temperature: 35°C). The optically active substances obtained under optical separation conditions were analyzed by SFC (column used: Daicel Corporation, CHIRALPAK-IA (10 mm × 250 mm), mobile phase: CO ₂ : methanol = 75: 22.5: 2.5, flow rate: 30 ml/min, pressure: 100 bar (10 MPa), wavelength: 220 nm, column temperature: 35°C). As a result, the retention times for (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-yl benzoate and (c,E)-5-hydroxy-1-(3-nitrophenyl) )pent-1-en-3-yl benzoate were 5.4 min and 8.5 min, respectively.

¹ H-NMR (CDCl ₃ ): δ 2.04, 2.10-2.14, 3.77-3.82, 5.92-5.95, 6.47, 6.79, 7.46- 7.51, 7.60, 7.68, 8.08-8.12, 8.26.

[0319]

Example 47: Methyl 2-(2-hydroxyphenyl)-2-methylpropanoate

Lithium diisopropylamide (2.0 M solution in THF, 18 ml) was added to a solution of methyl 2-(2-hydroxyphenyl) acetate (CAS registration number: 22446-37-3) (1.5 g) in THF (120 ml) at -78°C, the resulting solution 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 resulting solution was stirred at room temperature for 30 minutes. Water (40 ml) and acetic acid (1 ml) were added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue (1.8 g) was dissolved in THF (150 ml), then lithium diisopropylamide (2.0 M solution in THF, 10 ml) was added to the solution at -78°C, and the resulting solution 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 resulting solution was stirred at room temperature for 30 minutes. Water (40 ml) and acetic acid (1 ml) were added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=7:1). The title compound (538 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (DMSO-d6): δ 1.42, 3.51, 6.70-6.83, 7.05, 7.19, 9.49.

[0320]

Example 48: Methyl 1-(2-hydroxybenzyl)cyclopropane-1-carboxylate

Sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 75 ml) was added to a solution of cyclopropylcarbonitrile (CAS registration number: 5500-21-0) (3.35 g) in THF (50 ml) at room temperature, and the resulting solution was 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 resulting solution was stirred for 3 hours under reflux. The solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the resulting solution 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 (petroleum ether:ethyl acetate=10:1) to obtain the crude product (6.00 g) of the nitrile compound. Conc. sulfuric acid (20 ml) was added to a solution of the crude product (4.50 g) of the nitrile compound in methanol (50 ml) at room temperature, and the resulting solution was stirred for 5 hours at reflux. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Ice-cooled water was added to the resulting residue, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the crude product (3.20 g) of the ester compound. Boron tribromide (1.0 M solution in dichloromethane, 18.2 ml) was added dropwise to a solution of the crude product (2.00 g) of the ester compound in dichloromethane (30 ml) at -10°C, and the resulting solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (mobile phase A (0.1% aqueous trifluoroacetic acid (hereinafter abbreviated as "TFA")):mobile phase B (0 .1% TFA/acetonitrile)=95:5 → 5:95). The title compound (550 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.11, 1.39, 2.90, 3.67, 6.87, 6.99, 7.18, 8.45.

[0321]

Example 49: Methyl 4-(2-hydroxyphenyl)-2,2-dimethylbutanoate

A solution of lithium diisopropylamide (2.0 M solution in THF, 22.5 ml) was added to a solution of methyl 4-(2-hydroxyphenyl)butanoate (CAS registration number: 93108-07-7) (3.00 g) in THF ( 150 ml) -78°C, and the resulting solution 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 resulting solution was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the resulting solution 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 preparative high-performance liquid chromatography (mobile phase A (0.1% aqueous TFA):mobile phase B (0.1% TFA/acetonitrile)=95:5 → 5:95). The title compound (538 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (DMSO-d6): δ 1.17, 1.67-1.73, 2.38-2.43, 3.59, 6.66-6.76, 6.95-7.00 , 9.19.

[0322]

Example 50: Methyl 1-(2-methoxyphenethyl)cyclopropane-1-carboxylate

Zinc (18.2 g) was added to a solution of bis(cyclopentadienyl) titanium (IV) dichloride (CAS registration number: 1271-19-8) (34.6 g) in THF (200 ml) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. Solution of methyl 2-(1-acetoxymethyl)-2-propenoate (CAS registration number: 30982-08-2) (11.0 g) and 1-(chloromethyl)-2-methoxybenzene (CAS registration number: 7035-02-1) (10.9 g) in THF (200 ml) was added to the reaction solution at room temperature, and the resulting solution was stirred at the same temperature overnight. Water was added to the reaction solution, and the resulting solution was 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 the crude product (13.0 g) of the ester compound. Palladium(II) acetate and diazomethane (0.5 M solution in diethyl ether, 32.6 ml) were added to a solution of the crude ester product (3.00 g) in diethyl ether (100 ml) under ice cooling, and the resulting the solution was stirred at room temperature for 4 hours. Acetic acid (4 ml) and water were added to the reaction solution, and the resulting solution was extracted with diethyl ether. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The title compound (3.00 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (DMSO-d6): δ 0.70, 1.21, 1.76-1.88, 2.76-2.87, 3.70, 3.83, 6.80-6.96 , 7.11-7.32.

[0323]

Example 51: Methyl 1-(2-hydroxyphenethyl)cyclopropane-1-carboxylate

Boron tribromide (1.0 M solution in dichloromethane, 38.4 ml) was added dropwise to a solution of the compound obtained in Example 50 (3.00 g) in dichloromethane (100 ml) at -78°C, and the resulting solution was stirred at the same temperature for 5 hours. Methanol (30 ml) and water were added to the reaction solution, and the resulting solution was extracted with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (mobile phase A (0.5% aqueous ammonium bicarbonate): mobile phase B (acetonitrile)=80:20 → 25:75). The title compound (515 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (DMSO-d6): δ 0.73, 1.06, 1.67-1.79, 2.58-2.70, 3.58, 6.63-6.80, 6.95 -7.01, 9.17.

[0324]

Example 52: Ethyl (E)-3-(2-(benzyloxy)-5-fluorophenyl)acrylate

A solution prepared by suspending sodium hydride (60% in mineral oil, 1.80 g) in DMF (30 ml) was cooled to 0°C. Triethylphosphonoacetate (10.0 g) was added to the solution, and the resulting solution was stirred at 0°C for 30 min, and 2-benzyloxy-5-fluorobenzaldehyde solution (CAS Registration No.: 312314-37-7) was added dropwise to the solution ) (8.70 g) in DMF (10 ml), and the resulting solution was stirred at 0°C for 1 hour. The mixed reaction solution was poured into ice water, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The title compound (13.2 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.33, 4.24, 5.13, 6.47, 6.85-7.00, 7.21-7.41, 7.99-8.05.

[0325]

Example 53: Ethyl 3-(5-fluoro-2-hydroxyphenyl)propanoate

Palladium on carbon (1.95 g) was added to a solution of the compound obtained in Example 52 (11.0 g) in ethanol (18 ml), and the resulting solution was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 → 2:1). The title compound (5.8 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.24, 2.71, 2.86, 4.15, 6.77-6.83, 7.23.

[0326]

Example 54: (R, E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-nitrophenyl)pent-1-ene -3-yl benzoate

Diisopropyl azodicarboxylate (hereinafter abbreviated as “DIAD”) (0.1 ml) was added to a solution of (R,E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-ylbenzoate (110 mg) obtained in example 46, methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate (CAS registration number: 6236-69-7) (90 mg) and triphenylphosphine (130 mg) in THF (1 ml), and the resulting solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:2). The title compound (200 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 2.43-2.55, 3.78, 4.24, 5.94-5.98, 6.46-6.53, 6.82, 6.90, 6.96, 7.29-7.33, 7.44-7.51, 7.57-7.60, 7.68, 8.00, 8.07-8.10, 8.23-8, 24.

[0327]

Example 55: (R, E)-1-(3-aminophenyl)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)pent-1-ene -3-yl benzoate

Tin(IV) chloride (310 mg) was added to a solution of the compound obtained in Example 54 (160 mg) in ethanol (7 ml), and the resulting solution was stirred at 70°C for 3.5 hours. The reaction solution was cooled to room temperature temperature, then poured into ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:2). The title compound (120 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 2.39-2.52, 3.66, 3.79, 4.20, 5.90, 6.28, 6.53, 6.57-6.59, 6.68, 6.73, 6.79, 6.89, 6.94, 7.09, 7.28-7.32, 7.42-7.47, 7.49-7.50, 7, 54-7.58, 8.01, 8.05-8.07.

[0328]

Example 56: (R, E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)-1-(3-(phenylsulfonamide)phenyl)pent- 1-en-3-ylbenzoate

A solution of the compound obtained in Example 55 (60 mg) and pyridine (0.016 ml) in dichloromethane (1 ml) was cooled to 0°C, then phenylsulfonyl chloride (0.018 ml) was added to the resulting solution and the resulting solution was stirred overnight, heating the solution to room temperature. 1 M hydrochloric acid and saturated brine were added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:1). The title compound (62 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 2.41-2.45, 3.87, 4.18-4.22, 5.84-5.88, 6.30-6.34, 6.51, 6.64, 6.89, 6.99, 7.05-7.19, 7.30-7.34, 7.38-7.50, 7.50-7.52, 7.56-7, 59, 7.74-7.77, 8.04-8.07.

[0329]

Example 57: (E)-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]prop-2-enoic acid

A 1M aqueous solution of lithium hydroxide (0.5 ml) was added to a solution of the compound obtained in Example 56 (62 mg) in THF (1.5 ml) and methanol (0.5 ml), and the resulting solution was stirred at room temperature for 7 hours. 1 M hydrochloric acid and saturated brine were added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=10:0 → 9:1). The title compound (29 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.89;

¹ H-NMR (DMSO-d6): δ 1.91-2.04, 4.10-4.22, 4.36, 5.12, 6.21-6.25, 6.44, 6.55 , 6.93-6.99, 7.08-7.11, 7.16, 7.36-7.40, 7.52-7.55, 7.58-7.61, 7.66-7 .68, 7.75-7.77, 7.85, 10.27, 12.31.

[0330]

Example 58: N-[3-[(E,3R)-5-[2-(2-cyanoethyl)phenoxy]-3-hydroxypent-1-enyl]phenyl]benzenesulfonamide

The same prescribed procedures as in Example 54 → Example 55 → Example 56 were carried out, using the corresponding phenolic compound instead of the methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.99;

¹ H-NMR (CDCl ₃ ): δ 2.07-2.19, 2.60-2.65, 2.89-3.00, 4.10-4.23, 4.58, 6.24, 6.44, 6.56, 6.89-6.95, 7.10-7.27, 7.42-7.46, 7.52-7.56, 7.75-7.78.

[0331]

Example 59: Methyl 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1-carboxylate

The same prescribed procedures as in Example 54 → Example 55 → Example 56 were carried out, using instead of the methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, the phenolic compound obtained in Example 51. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 0.71, 1.22, 1.79-1.83, 2.07-2.15, 2.44, 2.77-2.81, 3.65, 4.10-4.23, 6.24, 6.44, 6.55, 6.83-6.94, 7.08-7.20, 7.41-7.45, 7.51-7, 55, 7.75-7.77.

[0332]

Example 60: Methyl 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoate

The same prescribed procedures as in Example 54 → Example 55 → Example 56 were carried out, using instead of the methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54, the phenolic compound obtained in Example 49. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.53, 1.56, 2.33-2.45, 3.63, 4.10-4.19, 5.95, 6.46, 6.71- 6.91, 7.17-7.24, 7.45-7.52, 7.57-7.68.

[0333]

Examples 61 (1) - (8)

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out, using the corresponding phenolics instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54 connections. The following example compounds were thereby obtained.

[0334]

Example 61(1): (E)-3-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]prop-2-enoic acid

HPLC retention time (min): 0.85;

¹ H-NMR (DMSO-d6): δ 1.84-1.92, 4.06-4.17, 4.32-4.33, 5.07, 5.60-6.00, 6.10 , 6.21, 6.37, 6.44, 6.94-6.97, 7.09-7.11, 7.16, 7.48-7.63, 7.75, 10.27, 12 ,15.

[0335]

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

HPLC retention time (min): 0.86;

¹ H-NMR (DMSO-d6): δ 1.80-1.84, 1.87-1.96, 2.48, 2.74, 3.95-4.01, 4.01-4.08 , 4.28-4.34, 5.04, 6.21, 6.43, 6.82-6.94, 6.93-6.96, 7.08-7.13, 7.17, 7 .51-7.56, 7.57-7.59, 7.75-7.78, 10.27, 12.04.

[0336]

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

HPLC retention time (min): 0.89;

¹ H-NMR (DMSO-d6): δ 1.83-1.98, 4.06-4.17, 4.31-4.35, 5.06, 6.20-6.25, 6.44 , 6.54, 6.94-6.99, 7.09-7.11, 7.17, 7.23-7.26, 7.31, 7.52-7.61, 7.75-7 .77, 10.27, 12.35.

[0337]

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

HPLC retention time (min): 0.89;

¹ H-NMR (DMSO-d6): δ 1.81-1.95, 2.51, 2.78, 4.31, 5.05, 6.21, 6.43, 6.73-6.79 , 6.93-6.96, 7.09-7.10, 7.14-7.18, 7.52-7.55, 7.58-7.61, 7.75-7.78, 10 ,25, 12,10.

[0338]

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

HPLC retention time (min): 0.93;

¹ H-NMR (DMSO-d6): δ 1.44, 1.81-1.97, 3.99-4.10, 4.30-4.35, 5.05, 6.21, 6.44 , 6.79-6.82, 6.84-6.85, 6.88-6.90, 6.93-6.96, 7.08-7.10, 7.16, 7.23, 7 .51-7.55, 7.57-7.61, 7.75-7.78, 10.25, 12.30.

[0339]

Example 61(6):

2-[4-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid

HPLC retention time (min): 0.92;

¹ H-NMR (DMSO-d6): δ 1.44, 1.83-1.93, 3.99-4.08, 4.29-4.33, 5.04, 6.21, 6.42 , 6.86-6.88, 6.93-6.95, 7.07-7.09, 7.16, 7.23-7.25, 7.51-7.55, 7.57-7 .60, 7.75-7.77, 10.25, 12.30.

[0340]

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

[0341]

[Formula 49]

[0342]

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 1.92-2.00, 2.12, 2.28-2.42, 2.68-2.71, 4.07-4.20, 4.63, 6.85-6.96, 7.08-7.19, 7.40-7.59, 7.59-7.63, 7.75-7.77.

[0343]

Example 61(8): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylpropanoic acid

HPLC retention time (min): 0.95

¹ H-NMR (CDCl ₃ ): δ 1.21, 2.05-2.15, 2.96, 4.07-4.15, 4.60, 6.23, 6.53, 6.85- 7.00, 7.07-7.20, 7.40-7.63, 7.76-7.78.

[0344]

Example 62: 2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2-methylpropanoic acid

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out, using a phenolic compound instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54 , obtained in Example 47. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 1.63-1.65, 2.09-2.14, 4.13-4.21, 4.58, 6.28, 6.52, 6.82- 6.84, 7.00-7.06, 7.15-7.19, 7.40-7.62, 7.76-7.78.

[0345]

Example 63: 1-[[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]methyl]cyclopropane-1-carboxylic acid

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out, using the compound obtained in Example 48. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.96;

¹ H-NMR (CDCl ₃ ): δ 1.38-1.40, 2.11-2.16, 4.13-4.18, 4.58, 6.28, 6.54, 6.85- 7.20, 7.38-7.52, 7.74-7.76.

[0346]

Example 64: 4-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]-2,2-dimethylbutanoic acid

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out, using the compound obtained in Example 49. The title compound was thereby obtained having the physical property values shown below.

HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 1.28, 1.74-1.91, 2.08-2.17, 2.61, 4.01-4.16, 4.62, 6.22, 6.51, 6.81-7.17, 7.39-7.43, 7.48-7.53, 7.75-7.78.

[0347]

Example 65: 1-[2-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]ethyl]cyclopropane-1-carboxylic acid

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out, using a phenolic compound instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54 , obtained in Example 51. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 0.66-0.76, 1.19-1.30, 1.64-1.72, 1.79-1.88, 2.08-2.14, 2.75-2.89, 4.10-4.21, 4.65, 6.28, 6.55, 6.83-6.90, 6.96-7.00, 7.07-7, 18, 7.35-7.39, 7.46-7.52, 7.73-7.76.

[0348]

Examples 66 (1) - (3)

The same prescribed procedures as in Example 1 → Example 54 → Example 55 → Example 56 → Example 57 were carried out, using the corresponding lactone compounds instead of the 3,4-dihydrocoumarin used in Example 1. The following example compounds were thereby obtained.

[0349]

Example 66(1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-bromophenyl]propanoic acid

HPLC retention time (min): 0.99;

¹ H-NMR (CD ₃ OD): δ 2.06-2.10, 2.56-2.60, 2.88-2.92, 4.07-4.19, 4.51, 6.23 , 6.53, 6.86-6.88, 6.97-7.00, 7.11-7.19, 7.29-7.32, 7.46-7.50, 7.54-7 .58, 7.76-7.78.

[0350]

Example 66(2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-methylphenyl]propanoic acid

HPLC retention time (min): 0.98;

¹ H-NMR (CD ₃ OD): δ 1.92-1.96, 2.13, 2.42-2.46, 2.75-2.79, 3.63-4.03, 4.41 , 6.11, 6.42, 6.69, 6.84-6.89, 6.99-7.06, 7.34-7.46, 7.64-7.66.

[0351]

Example 66(3): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-4-methylphenyl]propanoic acid

HPLC retention time (min): 0.97;

¹ H-NMR (CD ₃ OD): δ 1.92-1.97, 2.18, 2.41-2.45, 2.74-2.78, 3.93-4.06, 4.42 , 6.11, 6.41, 6.56, 6.64, 6.86-6.92, 7.00-7.07, 7.33-7.46, 7.64-7.66.

[0352]

Example 67: 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-5-fluorophenyl]propanoic acid

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out, using a phenolic compound instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54 , obtained in Example 53. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.94;

¹ H-NMR (CDCl ₃ ): δ 2.09-2.15, 2.67-2.71, 2.93-2.97, 4.10-4.15, 4.59, 6.27, 6.54, 6.77-6.80, 6.84-6.90, 6.95-7.00, 7.08-7.10, 7.16, 7.40-7.44, 7, 50-7.55, 7.76-7.78.

[0353]

Examples 68 (1) - (2)

The same prescribed procedures as in Example 52 → Example 53 → Example 54 → Example 55 → Example 56 → Example 57 were carried out using the appropriate aldehyde compounds instead of the 2-benzyloxy-5-fluorobenzaldehyde used in Example 52 and using the corresponding phenolic compounds instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. The following example compounds were thereby obtained.

[0354]

Example 68(1): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-6-fluorophenyl]propanoic acid

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 2.09-2.15, 2.61-2.65, 2.97-3.01, 4.10-4.17, 4.60, 6.26, 6.54, 6.65-6.70, 6.97-7.00, 7.05-7.18, 7.41-7.44, 7.50-7.54, 7.76-7, 79.

[0355]

Example 68(2): 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]-3-fluorophenyl]propanoic acid

HPLC retention time (min): 0.94;

¹ H-NMR (CDCl ₃ ): δ 2.09-2.15, 2.69-2.73, 3.01-3.05, 4.22-4.24, 4.67, 6.30, 6.58, 6.95-7.01, 7.10-7.20, 7.42-7.45, 7.51-7.54, 7.77-7.79.

[0356]

Example 69: 3-[2-[(E,3S)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 57 were carried out using the compound obtained in Example 1 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate, used in Example 54, and using (S, E)-5-hydroxy-1-(3-nitrophenyl)pent-1-en-3-ylbenzoate obtained in Example 54 instead of (R, E)-5-hydroxy- 1-(3-nitrophenyl)pent-1-en-3-yl benzoate used in Example 54. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.93;

¹ H-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.

[0357]

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

[0358]

[Formula 50]

[0359]

The same prescribed procedure as in Example 33 was carried out using the compound obtained in Example 69. The title compound was thereby obtained having the physical property values shown below.

HPLC retention time (min): 0.93;

¹ H-NMR (CD ₃ OD): δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85 -7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.

[0360]

Example 71: Isopropyl-(R,E)-3-(2-((5-(3-aminophenyl)-3-((trimethylsilyl)oxy)pent-4-en-1-yl)oxy)phenyl)propanoate

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 2 M aqueous solution of tripotassium phosphate (5.7 ml) were added to a solution of the compound obtained in Example 8 (1.00 g) in THF (10 ml), and the resulting solution was stirred at 70°C for 19 hours. The reaction solution was cooled to room temperature, then water was added to the solution, and the resulting solution 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 → 2:1). The title compound (515 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.82.

[0361]

Example 72: isopropyl-(R,E)-3-(2-((5-(3-((4-fluorophenyl)sulfonamide)phenyl)-3-hydroxypent-4-en-1-yl)oxy)phenyl) propanoate

Pyridine (0.018 ml), DMAP (2.7 mg) and 4-fluorobenzenesulfonyl chloride (CAS registration number: 349-88-2) (25.6 mg) were added to a solution of the compound obtained in Example 71 (50 mg) in THF (1 ml) at room temperature, and the resulting solution was stirred at the same temperature for 16 hours. TBAF (1.0 M solution in THF, 0.27 ml) was added to the reaction solution at room temperature, and the resulting solution was stirred at that at the same temperature for 1 hour. Water was added to the reaction solution, and the resulting solution 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 preparative high-performance liquid chromatography (mobile phase A (0.1% aqueous TFA) : mobile phase B (0.1% TFA/acetonitrile) = 90:0 → 10:90). The title compound (515 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.11.

[0362]

Example 73: 3-[2-[(E,3R)-5-[3-[(4-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 72. The title compound having the physical properties shown below was thereby obtained.

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, 4.10, 4.18, 4.55, 6.26 , 6.55, 6.86, 6.93, 6.99, 7.13-7.25, 7.79-7.82.

[0363]

Examples 74 (1) - (21)

The same prescribed procedures were carried out as in Example 72 → Example 11, using the corresponding sulfonyl compounds instead of the 4-fluorobenzenesulfonyl chloride used in Example 72. The following example compounds were thereby obtained.

[0364]

Example 74(1):3-[2-[(E,3R)-5-[3-[(4-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.98;

¹ H-NMR (CD ₃ OD): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26 , 6.55, 6.86, 6.93, 6.99, 7.13-7.21, 7.48-7.51, 7.71-7.75.

[0365]

Example 74(2):

3-[2-[(E,3R)-3-hydroxy-5-[3-[(4-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.96;

¹ H-NMR (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.

[0366]

Example 74(3): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[4-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.01;

¹ H-NMR (CD ₃ OD): δ 2.06-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.27 , 6.55, 6.86, 6.93, 6.99, 7.15-7.22, 7.80-7.83, 7.93-7.95.

[0367]

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

HPLC retention time (min): 1.08;

¹ H-NMR (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.

[0368]

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

HPLC retention time (min): 0.96;

MS (ESI, positive): 482 (M+HH ₂ O) ⁺ .

[0369]

Example 74(6): 3-[2-[(E,3R)-5-[3-[(3-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.00;

MS (ESI, positive): 498 (M+HH ₂ O) ⁺ .

[0370]

Example 74(7): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(3-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.97;

MS (ESI, positive): 478 (M+HH ₂ O) ⁺ .

[0371]

Example 74(8): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[3-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.00;

MS (ESI, positive): 532 (M+HH ₂ O) ⁺ .

[0372]

Example 74(9): 3-[2-[(E,3R)-5-[3-[(2-fluorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.94;

MS (ESI, positive): 482 (M+HH ₂ O) ⁺ .

[0373]

Example 74(10): 3-[2-[(E,3R)-5-[3-[(2-chlorophenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.97;

MS (ESI, positive): 498 (M+HH ₂ O) ⁺ .

[0374]

Example 74(11): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-methylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.97;

MS (ESI, positive): 478 (M+HH ₂ O) ⁺ .

[0375]

Example 74(12): 3-[2-[(E,3R)-3-hydroxy-5-[3-[[2-(trifluoromethyl)phenyl]sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.99;

MS (ESI, positive): 532 (M+HH ₂ O) ⁺ .

[0376]

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

[0377]

[Formula 51]

[0378]

HPLC retention time (min): 0.93;

¹ H-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.

[0379]

Example 74(14): 3-[2-[(E,3R)-3-hydroxy-5-[3-(oxan-4-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.48 (ethyl acetate);

¹ H-NMR (CDCl ₃ ): δ 1.88-2.00, 2.15-2.20, 2.63-2.74, 2.90-3.02, 3.22-3.35, 4.04, 4.17, 6.38, 6.60, 6.88, 7.13-7.28.

[0380]

Example 74(15): 3-[2-[(E,3R)-5-[3-(benzylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.55 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 2.13-2.18, 2.67, 2.96, 4.13-4.22, 4.34, 4.64, 6.35, 6.61, 6.89, 6.96, 7.06, 7.13-7.36.

[0381]

Example 74(16): 3-[2-[(E,3R)-3-hydroxy-5-[3-(pyridin-2-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.36 (ethyl acetate);

¹ H-NMR (CDCl ₃ ): δ 2.06-2.23, 2.72, 3.02, 4.16, 4.60, 6.31, 6.52, 6.86-6.93, 7.01, 7.10-7.22, 7.46, 7.85, 7.97, 8.41, 8.65.

[0382]

Example 74(17): 3-[2-[(E,3R)-5-[3-(1-benzofuran-3-ylsulfonylamino)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.98;

¹ H-NMR (CDCl ₃ ): δ 2.08-2.13, 2.69, 2.96, 4.11, 4.55-4.62, 6.21, 6.52, 684-6, 92, 6.99-7.03, 7.09-7.19, 7.30-7.40, 7.50, 7.70, 8.05.

[0383]

Example 74(18): 3-[2-[(E,3R)-5-[3-[(4-butoxyphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

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

¹ H-NMR (CDCl ₃ ): δ 0.95, 1.40-1.50, 1.68-1.79, 2.10-2.14, 2.68, 2.96, 3.93, 4.10-4.19, 4.60, 6.26, 6.52, 6.81-6.91, 6.97-7.09, 7.12-7.24, 7.68.

[0384]

Example 74(19): 3-[2-[(E,3R)-3-hydroxy-5-[3-(thiophen-3-ylsulfonylamino)phenyl]pent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.68, 2.96, 4.09-4.20, 4.62, 6.27, 6.54, 6.84- 6.92, 7.00-7.23, 7.27-7.32, 7.86.

[0385]

Example 74(20): 3-[2-[(E,3R)-3-hydroxy-5-[3-[(2-propylphenyl)sulfonylamino]phenyl]pent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.38 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 1.00, 1.64-1.74, 2.10-2.15, 2.70, 2.93-3.01, 4.10-4.19, 4.60, 6.26, 6.53, 6.85-6.92, 7.02-7.06, 7.10-7.24, 7.33, 7.45, 7.95.

[0386]

Example 74(21): 3-[2-[(E,3R)-5-[3-[(3-butylphenyl)sulfonylamino]phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

TLC: Rf 0.38 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 0.86, 1.18-1.28, 1.42-1.53, 2.08-2.14, 2.57, 2.69, 2.97, 4.10-4.21, 4.61, 6.25, 6.53, 6.84-6.92, 6.98, 7.04-7.21, 7.29-7.32, 7, 55-7.60.

[0387]

Example 75: 3-[2-[(3S)-5-[3-(cyclopentylsulfonylamino)phenyl]-3-hydroxypentoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in Example 33, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid , used in example 33, the compound obtained in example 74(13). The following example compound was thereby obtained.

HPLC retention time (min): 0.93;

¹ H-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.

[0388]

Example 76: Methyl-(R,E)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate

Trimethylsilyldiazomethane (2.0 M solution in hexane, 2.6 ml) was added to a solution of the compound obtained in Example 11 (500 mg) in methanol (10 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 30 min. . Acetic acid was added to the reaction solution under ice-cooling, and the resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 → 1:1). The title compound (495 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.03.

[0389]

Example 77: Methyl 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopent-4-enoxy]phenyl]propanoate

Manganese dioxide (868 mg) was added to a solution of the compound obtained in Example 76 (495 mg) in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 20 hours. The reaction solution was filtered through Celite (commercial name), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 → 1:1). The title compound (439 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.10.

¹ H-NMR (CDCl ₃ ): δ 2.59-2.63, 2.88-2.92, 3.08-3.11, 3.68, 4.31-4.34, 6.80, 6.85-6.92, 7.12, 7.18-7.34, 7.42-7.56, 7.77-7.80.

[0390]

Example 78: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3-oxopent-4-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in Example 77, using instead of methyl-(R,E)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamide)phenyl)pent-4-ene- 1-yl)oxy)phenyl)propanoate used in Example 77, the compound obtained in Example 11. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.97;

¹ H-NMR (CD ₃ OD): δ 2.44-2.48, 2.81-2.85, 3.22, 3.25,4.33-4.37, 6.82, 6.86 , 6.97, 7.14-7.21, 7.29, 7.33-7.39, 7.48-7.52, 7.56-7.63, 7.79-7.81.

[0391]

Example 79: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-3-oxopentoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in Example 33, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33, the compound obtained in Example 78. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.97;

¹ H-NMR (CD ₃ OD): δ 2.47-2.51, 2.80-2.85, 2.88-2.91, 4.21-4.24, 6.85-6.95 , 7.09-7.21, 7.44-7.48, 7.54, 7.74-7.76.

[0392]

Example 80: 3-[2-[5-[3-(1-Hydroxy-2-phenylethyl)phenyl]-3-oxopentoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in example 78 → example 79, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl ]propanoic acid used in Example 78, the compound obtained in Example 12(9). The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.00;

¹ H-NMR (CD ₃ OD): δ 2.48-2.52, 2.80-2.96, 3.03-3.08, 4.25, 4.82, 6.85-6.94 , 7.08-7.22.

[0393]

Example 81: Isopropyl 3-(2-(pent-4-yn-1-yl oxy)phenyl)propanoate

Cesium carbonate (9.39 g) was added to a solution of the compound obtained in Example 1 (3.00 g) in N,N-dimethylacetamide (25 ml) at room temperature, and the resulting solution was stirred at the same temperature for 15 minutes . 5-Chloro-1-pentine (CAS Registration No.: 14267-92-6) (1.63 g) was added to the reaction solution at room temperature, and the resulting solution was stirred at 60°C for 3 hours. Water was added to the reaction solution and the resulting solution was 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 (hexane:ethyl acetate=1:0 → 5:1). The title compound (2.40 g) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.13.

[0394]

Example 82: isopropyl-(E)-3-(2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pent-4-en-1-yl )hydroxy)phenyl)propanoate

4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added to a solution of the compound obtained in Example 81 (1.00 g), in heptane (2 ml) at room temperature, and the resulting solution was stirred at 100°C for 4 hours. The reaction solution was cooled to room temperature and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 → 4:1). The title compound (503 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.38.

[0395]

Example 83: Isopropyl-(E)-3-(2-((5-(3-(phenylsulfonamide)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate

The compound obtained 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 2 M aqueous solution of tripotassium phosphate (0.67 ml) were added to a solution of the compound obtained in Example 82 (180 mg) in THF (3 ml), and the resulting solution was stirred at 60 °C for 1 hour. The reaction solution was cooled to room temperature, then water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1 → 2:1). The title compound (113 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.24.

[0396]

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

[0397]

[Formula 52]

[0398]

A 1 M aqueous solution of lithium hydroxide (0.5 ml) was added to a solution of the compound obtained in Example 83 (146 mg) in THF (0.5 ml) and methanol (0.1 ml), and the resulting solution was stirred at 50° C for 8 hours. 1 M hydrochloric acid was added to the solution to make the solution acidic, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The title compound (105 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.10

¹ H-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.

[0399]

Example 85: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 83 → Example 84 were carried out, using 1-(4-bromophenyl)-2-phenylethan-1-ol (registration number) instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83 CAS: 20498-64-0). The following example compound was thereby obtained.

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.97-2.03, 2.41-2.45, 2.67-2.71, 2.96-3.03, 4.04, 4.86- 4.90, 6.23-6.30, 6.44, 6.83-6.89, 7.16-7.34.

[0400]

Example 86: 3-[2-[(E)-5-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 83 → Example 84 were carried out, using instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 83, the compound obtained in Example 21. The title compound was thereby obtained having the physical values properties shown below.

HPLC retention time (min): 1.20;

¹ H-NMR (CDCl ₃ ): δ 2.00, 2.43, 2.64-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.44, 6.83-6.89, 7.15-7.39.

[0401]

Example 87: 3-[2-[(E)-5-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in Example 21 → Example 83 → Example 84, using (S)-methyloxazaborolidine instead of the (R)-methyloxazaborolidine used in Example 21, and using the corresponding halide compound instead of N-(3-bromophenyl) benzenesulfonamide used in Example 83. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.20;

¹ H-NMR (CDCl ₃ ): δ 2.00, 2.44, 2.66-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.45, 6.83-8.89, 7.15-7.40.

[0402]

Examples 87 (1) - (10)

The same prescribed procedures were carried out as in example 9 → example 83 → example 84, using the corresponding amine compounds instead of the 3-bromoaniline used in example 9. The title compounds were thereby obtained having the physical properties shown below.

[0403]

Example 87(1): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2-(trifluoromethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.08;

¹ H-NMR (CDCl ₃ ): δ 1.92-1.99, 2.36-2.42, 2.64-2.68, 2.93-2.97, 3.99, 5.98, 6.02, 6.58-6.65, 6.81, 6.88, 7.00, 7.15-7.20, 7.39-7.45, 7.51-7.56, 7, 65, 7.70-7.73.

[0404]

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

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.97-2.04, 2.43-2.49, 2.74-2.78, 3.00-3.04, 4.04, 6.25- 6.32, 6.66, 6.85, 6.91, 7.10-7.25, 7.44-7.48, 7.53-7.58, 7.84-7.87.

[0405]

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

HPLC retention time (min): 1.11;

¹ H-NMR (CDCl ₃ ): δ 1.96-2.02, 2.41-2.46, 2.72-2.76, 2.97-3.01, 4.03, 6.31- 6.40, 6.84, 6.90, 7.15-7.25, 7.43-7.48, 7.52-7.57, 7.79-7.82.

[0406]

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

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.98-2.05, 2.45-2.50, 2.68-2.72, 2.97-3.01, 4.04, 6.36- 6.47, 6.80-6.91, 7.15-7.22, 7.37-7.44, 7.51-7.55, 7.74-7.79.

[0407]

Example 87(5): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2-cyanophenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.01;

¹ H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.44-2.49, 2.64-2.68, 2.93-2.97, 4.01, 6.44, 6.60, 6.82, 6.88, 7.15-7.20, 7.31-7.32, 7.42-7.50, 7.52-7.60, 7.82-7, 85.

[0408]

Example 87(6): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-cyanophenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (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.

[0409]

Example 87(7): 3-[2-[(E)-5-[3-(benzenesulfonamido)-2,4-dichlorophenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.07;

¹ H-NMR (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.

[0410]

Example 87(8): 3-[2-[(E)-5-[3-(benzenesulfonamido)-4-methylsulfonylphenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.98-2.05, 2.46-2.50, 2.67-2.50, 2.77, 2.96-3.00, 4.03, 6.40-6.42, 6.84, 6.90, 7.16-7.22, 7.47-7.52, 7.58, 7.64, 7.71, 7.91-7, 94.

[0411]

Example 87(9): 3-[2-[(E)-5-[3-(benzenesulfonamido)-5-methylsulfonylphenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 0.99;

¹ H-NMR (CDCl ₃ ): δ 1.97-2.03, 2.44-2.49, 2.72-2.76, 2.97-3.03, 4.04, 6.36, 6.41-6.48, 6.84, 6.90, 7.15-7.22, 7.40, 7.45-7.49, 7.54-7.58, 7.77, 7, 82-7.84.

[0412]

Example 87(10): 3-[2-[(E)-5-[3-(benzenesulfonamidomethyl)phenyl]pent-4-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.96-2.02, 2.39-2.44, 2.66-2.70, 2.93-2.97, 4.03, 4.12, 5.33, 6.24, 6.36, 6.83-6.90, 6.96-6.99, 7.14-7.21, 7.47-7.52, 7.54-7, 59, 7.84-7.88.

[0413]

Examples 88 (1) - (2)

The same prescribed procedures as in Example 83 → Example 35 → Example 84 were carried out, using the corresponding halide compounds instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 83. The title compounds were thereby obtained having the physical properties shown below.

[0414]

Example 88(1): 3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid

TLC: Rf 0.61 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 1.47-1.55, 1.67-1.74, 1.79-1.85, 2.58, 2.65, 2.88, 2.97- 3.07, 3.96, 4.89, 6.79-6.88, 7.09-7.33.

[0415]

Example 88(2): 3-[2-[5-[4-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid

HPLC retention time (min): 1.1;

¹ H-NMR (CDCl ₃ ): δ 1.47-1.80, 2.48-2.56, 2.64-2.69, 2.82-2.88, 3.02-3.06, 3.95, 4.89-4.93, 6.79-6.87, 7.11-7.34.

[0416]

Example 89: (R)-3-[2-[5-[3-(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid or (S)-3-[2-[5-[3 -(1-hydroxy-2-phenylethyl)phenyl]pentoxy]phenyl]propanoic acid

The compound obtained in Example 88 (1) was subjected to optical separation using SFC (column used: Daicel Corporation, CHIRALPAK-IF (10 mm × 250 mm), mobile phase: CO ₂ :acetonitrile:methanol=75:22.5: 2.5, flow rate: 30 ml/min, pressure: 100 bar (10 MPa), wavelength: 220 nm, column temperature: 35°C). The optically active substances of Example 88(1) obtained under optical separation conditions were analyzed by SFC (column used: Daicel Corporation, CHIRALPAK-IF (10 mm × 250 mm), mobile phase: CO ₂ :acetonitrile:methanol=75:22 ,5:2.5, flow rate: 30 ml/min, pressure: 100 bar (10 MPa), wavelength: 220 nm, column temperature: 35°C). As a result, the retention times for the first peak and the second peak were 14.9 min and 19.1 min, respectively.

[0417]

Example 90: 4-bromo-N-methoxy-N-methylthiazole-2-carboxamide

N,O-dimethylhydroxylamine hydrochloride (609 mg), diisopropylethylamine (2.5 ml) and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (2.4 g) were added to a solution of 4-bromothiazole-2-carboxylic acid (1, 0 g) in dichloromethane (9.6 ml), and the resulting solution 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). The title compound (1.0 g) was thereby obtained having the physical properties shown below.

TLC: Rf 0.3 (hexane:ethyl acetate=2:1).

[0418]

Example 91: 1-(4-bromothiazol-2-yl)-2-phenylethan-1-one

Benzylmagnesium bromide (0.1 M solution in diethyl ether, 40 ml) was added to a solution of the compound obtained in Example 90 (300 mg) in diethyl ether (1 ml) at 0°C, and the resulting solution was stirred at room temperature under for 1 hour. A saturated ammonium chloride solution was added to the reaction mixture, and the resulting solution was 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 (hexane:ethyl acetate=8:1). The title compound (181 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.7 (hexane:ethyl acetate=4:1).

[0419]

Example 92: 3-[2-[(E)-5-[2-(1-hydroxy-2-phenylethyl)-1,3-thiazol-4-yl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures as in Example 21 → Example 83 → Example 84 were carried out using the compound obtained in Example 91 instead of the 1-(3-bromophenyl)-2-phenylethanone used in Example 21 using (RS)- methyloxazaborolidine instead of (R)-methyloxazaborolidine used in Example 21, and using the corresponding halide compound instead of N-(3-bromophenyl)benzenesulfonamide used in Example 83. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.98;

¹ H-NMR (DMSO-d6): δ 1.92-2.00, 2.41-2.48, 2.80-2.84, 2.85-2.90, 3.10-3.15 , 4.01-4.06, 4.80-4.85, 5.83, 6.60-6.72, 6.85, 6.95, 7.14-7.18, 7.21-7 ,25.

[0420]

Example 93: 3-[2-[(E)-5-[4-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in Example 90 → Example 91 → Example 21 (in which (RS)-methyloxazaborolidine was used instead of (R)-methyloxazaborolidine) → Example 83 → Example 84 using 2-bromothiazole-4-carboxylic acid instead of the 4-bromothiazole-2-carboxylic acid used in Example 90, and using the corresponding halide compound instead of the N-(3-bromophenyl)benzenesulfonamide used in Example 83. The title compound was thereby obtained having the physical properties shown below .

HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 1.98-2.05, 2.41-2.47, 2.66-2.70, 2.96-3.00, 3.08, 3.34, 4.03, 5.18, 6.42-6.46, 6.58, 6.62, 6.83-6.89, 6.93, 7.16-7.25, 7.27-7, 34.

[0421]

Example 94: 3-[2-[5-[5-(1-hydroxy-2-phenylethyl)-1,3-thiazol-2-yl]pentoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 35, using instead of isopropyl-3-(2-(((R, E)-3-hydroxy-5-(3-((R)-1-hydroxy-2- phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate used in Example 35, the compound obtained in Example 93. The following compound of Example was thereby obtained.

HPLC retention time (min): 0.96;

¹ H-NMR (CDCl ₃ ): δ 1.56-1.64, 1.80-1.90, 2.57-2.61, 2.94, 3.05, 3.09-3.11, 3.96, 5.14, 6.80, 6.86, 7.14-7.25, 7.29-7.33, 7.46.

[0422]

Example 95: 3-[2-[5-[2-(1-Hydroxy-2-phenylethyl)-1,3-thiazol-5-yl]pentoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 35, using instead of isopropyl-3-(2-(((R, E)-3-hydroxy-5-(3-((R)-1-hydroxy-2- phenylethyl)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate used in Example 35, the compound obtained in Example 92. The following compound of Example was thereby obtained.

HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 1.51-1.59, 1.68-1.85, 2.57-2.61, 2.84, 2.90, 3.09, 3.27, 3.97, 5.14, 6.81, 6.86, 7.13-7.25, 7.28-7.32, 7.39.

[0423]

Example 95(1): 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]-N-methylsulfonylpropanamide

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 obtained in Example 84 (100 mg) in DMF (1 ml ), and the resulting solution was stirred at room temperature for 23 hours. 1 M hydrochloric acid was added to the reaction mixture and the resulting solution 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 → 0:1). The title compound (80.7 mg) was thereby obtained having the physical properties shown below. HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 1.97-2.04, 2.37-2.42, 2.64-2.67, 2.96-2.99, 3.19, 4.05, 6.22, 6.33, 6.73, 6.85-6.92, 7.06-7.08, 7.13-7.17, 7.21, 7.41-7.45, 7, 50-7.54, 7.76-7.78.

[0424]

Example 95(2): 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanamide

The same prescribed procedure was carried out as in example 31, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 31, the compound obtained in Example 84. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.98;

¹ H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.40-2.45, 2.60-2.64, 3.03-3.07, 4.04, 5.55, 5.82, 6.29, 6.34-6.41, 6.86, 6.89-6.95, 7.03-7.06, 7.11-7.22, 7.41-7, 44, 7.49-7.53, 7.82-7.85, 8.25.

[0425]

Example 95(3): N-[3-[(E)-5-[2-(2-cyanoethyl)phenoxy]pent-1-enyl]phenyl]benzenesulfonamide

Pyridine (0.052 ml) and trifluoroacetic anhydride (67.8 mg) were added to a solution of the compound obtained in Example 95(2) (100 mg) in THF (1 ml) under ice-cooling, and the resulting solution was stirred at the same temperature for 1 hour. Methanol and 1 M sodium hydroxide aqueous solution were added to the reaction solution, and the resulting solution was stirred at room temperature for 1 hour. The reaction solution was poured into water, and the resulting solution 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=4:1 → 1:1). The title compound (91.0 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.37-2.42, 2.61-2.65, 2.95-2.99, 4.03, 6.20, 6.34, 6.49, 6.84-6.94, 7.05-7.25, 7.41-7.46, 7.51-7.55, 7.75-7.78.

[0426]

Example 95(4): N-[3-[(E)-5-[2-[2-(1H-tetrazol-5-yl)ethyl]phenoxy]pent-1-enyl]phenyl]benzenesulfonamide

Trimethylsilyl azide (44.0 mg) and dibutyltin oxide (24.0 mg) were added to a solution of the compound obtained in Example 95(3) (43.0 mg) in toluene (0.5 ml), and the resulting solution was stirred at 100° C overnight. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate:methanol=50:50:3 → 0:100:3). The title compound (15.0 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.99;

¹ H-NMR (CDCl ₃ ): δ 1.92-1.99, 2.34-2.39, 3.11-3.15, 3.30-3.34, 4.02, 6.20, 6.30, 6.83-6.90, 7.30-7.22, 7.39-7.43, 7.49-7.53, 7.76-7.78.

[0427]

Example 95(5): Isobutyl-(E)-(3-(5-(2-(3-amino-3-oxopropyl)phenoxy)pent-1-en-1-yl)phenyl)(phenylsulfonyl)carbamate

Triethylamine (0.20 ml) and isobutyl chloroformate (110 mg) were added to a solution of the compound obtained in Example 84 (100 mg) in THF (1 ml) under ice-cooling, and the reaction mixture was stirred at room temperature for 10 minutes. Ammonia (28% aqueous solution, 0.5 ml) was added to the reaction solution under ice-cooling, and the resulting solution was stirred at room temperature for 30 minutes. The reaction solution was poured into water, and the resulting solution 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=1:1 → 0:1). The title compound (120 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.11.

[0428]

Example 95(6): N-[3-[(E)-5-[2-[2-(1H-1,2,4-triazol-5-yl)ethyl]phenoxy]pent-1-enyl]phenyl ]benzenesulfonamide

N,N-dimethylformamide dimethyl acetal (0.5 ml) was added to a solution of the compound obtained in Example 95(5) (120 mg) in DMF (0.2 ml), and the resulting solution was stirred at 100°C for 4 hours. Reaction the solution was concentrated under reduced pressure, then acetic acid (1 ml) and hydrazine monohydrate (0.1 ml) were added to the solution, and the resulting solution was stirred at 100°C for 3 hours. The solution was cooled to room temperature, then saturated an aqueous sodium bicarbonate solution, and the resulting solution 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=1:1 → 0:1). A 2 M sodium hydroxide aqueous solution (0.2 ml) was added to a solution of the resulting residue (48 mg) in methanol (1 ml), and the resulting solution was stirred at room temperature overnight. The reaction mixture was neutralized with 1 M aqueous sodium dihydrogen phosphate and the resulting solution 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:methanol=50:50:3 → 0:100:3). The title compound (24.0 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.90;

¹ H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.38-2.43, 3.08-3.18, 4.04, 6.22, 6.32, 6.84- 6.89, 6.94-6.97, 7.02, 7.07-7.21, 7.39-7.43, 7.49-7.53, 7.67, 7.75-7, 77, 8.04.

[0429]

Example 96: Isopropyl-(E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamide)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate

The same prescribed procedures were carried out as in Example 2 → Example 3 → Example 4 → Example 5 → Example 7 → Example 8 → Example 10, using instead of 2-(2-bromoethyl)-1,3-dioxane used in Example 2, 2-(3-bromopropyl)-1,3-dioxane. The title compound was thereby obtained having the physical properties shown below.

TLC: Rf 0.43 (hexane:ethyl acetate=1:1).

[0430]

Example 97: 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 96. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.96;

¹ H-NMR (CDCl ₃ ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7, 54, 7.66, 7.78-7.81.

[0431]

Example 98: isopropyl-(R,E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate or isopropyl- (S, E)-3-(2-((4-hydroxy-6-(3-(phenylsulfonamido)phenyl)hex-5-en-1-yl)oxy)phenyl)propanoate

The compound obtained in Example 96 was subjected to optical separation using SFC (column used: Daicel Corporation, CHIRALPAK-IC (20 mm × 250 mm), mobile phase: CO ₂ :methanol=85:15, flow rate: 100 ml/min ; pressure: 120 bar (12 MPa), wavelength: 220 nm, column temperature: 35°C). The optically active substances of Example 96 obtained under optical separation conditions were analyzed by SFC (column used: Daicel Corporation, CHIRALPAK-IC (10 mm × 250 mm), mobile phase: CO ₂ :methanol=85:15, flow rate: 30 ml/min; pressure: 120 bar (12 MPa), wavelength: 220 nm, column temperature: 35°C). As a result, the retention times for the first peak and the second peak were 13.6 min and 15.8 min, respectively.

[0432]

Example 99: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid or (S)-3-[2- [(E)-6-[3-(benzenesulfonamide)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- Enoxy]phenyl]propanoate used in Example 11, the optically active substance corresponding to the first peak that was obtained in Example 98. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 0.96;

¹ H-NMR (CDCl ₃ ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7, 54, 7.66, 7.78-7.81.

[0433]

Example 100: (R)-3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid or (S)-3-[2- [(E)-6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhex-5-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- Enoxy]phenyl]propanoate used in Example 11, the optically active substance corresponding to the second peak that was obtained in Example 98. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 0.96;

¹ H-NMR (CDCl ₃ ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40-7.45, 7.49-7, 54, 7.66, 7.78-7.81.

[0434]

Example 101: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in Example 33, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33, the compound obtained in Example 97. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 0.96;

¹ H-NMR (CDCl ₃ ): δ 1.58-1.67, 1.72-2.00, 2.65-2.09, 2.93-3.07, 3.59-3.65, 3.95-4.05, 6.82-6.93, 6.98-7.01, 7.12-7.22, 7.40-7.45, 7.50-7.54, 7, 77-7.80.

[0435]

Example 102: (R)-3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid or (S)-3-[2-[6-[3-(benzenesulfonamido) )phenyl]-4-hydroxyhexoxy]phenyl]propanoic acid

The compound obtained in Example 101 was subjected to optical separation using SFC (column used: Daicel Corporation, CHIRALPAK-IB (20 mm × 250 mm), mobile phase: CO ₂ :acetonitrile:methanol=80:18:2, flow rate: 100 ml/min; pressure: 120 bar (12 MPa), wavelength: 220 nm, column temperature: 35°C). The optically active substances of Example 101 obtained under optical separation conditions were analyzed by SFC (column used: Daicel Corporation, CHIRALPAK-IB (20 mm × 250 mm), mobile phase: CO ₂ :acetonitrile:methanol=80:18:2, flow rate: 100 ml/min; pressure: 120 bar (12 MPa), wavelength: 220 nm, column temperature: 35°C). As a result, the retention times for the first peak and the second peak were 9.6 min and 12.3 min, respectively.

[0436]

Example 103: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-oxohexoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in example 78 → example 79, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl ]propanoic acid used in Example 78, the compound obtained in Example 97. The title compound having the physical property values shown below was thereby obtained.

TLC: Rf 0.45 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 2.01-2.10, 2.61-2.75, 2.83, 2.96, 3.96, 6.78-6.82, 6.86- 6.91, 6.96, 7.10, 7.14-7.21, 7.42, 7.51, 7.68-7.84.

[0437]

Examples 104 (1) - (2)

The same prescribed procedures as in Example 81 → Example 82 → Example 83 → Example 84 were carried out, using the corresponding phenolic compounds instead of the isopropyl-3-(2-hydroxyphenyl)propanoate used in Example 81. The following example compounds were thereby obtained.

[0438]

Example 104 (1): 2-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]acetic acid

HPLC retention time (min): 1.01;

¹ H-NMR (CDCl ₃ ): δ 1.89-1.96, 2.33-2.38, 3.67, 4.01, 6.14, 6.29, 6.68, 6.85- 6.94, 7.00-7.28, 7.39-7.43, 7.48-7.52, 7.74-7.77.

[0439]

Example 104(2): 4-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]butanoic acid

HPLC retention time (min): 1.07;

¹ H-NMR (CDCl ₃ ): δ 1.93-2.00, 2.37-2.43, 2.70, 4.00, 6.21, 6.33, 6.82-6.92, 7.04-7.19, 7.40-7.44, 7.49-7.53, 7.75-7.78.

[0440]

Examples 105 (1) - (3)

The same prescribed procedures as in Example 81 → Example 82 → Example 83 → Example 84 were carried out, using the appropriate halide compounds instead of the 5-chloro-1-pentine used in Example 81. The following example compounds were thereby obtained.

[0441]

Example 105(1): 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]but-3-enoxy]phenyl]propanoic acid

HPLC retention time (min): 1.01;

¹ H-NMR (CD ₃ OD): δ 2.52-2.56, 2.67-2.71, 2.88-2.92, 4.10-4.13, 6.31, 6.46 , 6.86, 6.93-6.98, 7.09-7.20, 7.44-7.49, 7.52-7.57, 7.75-7.78.

[0442]

Example 105(2): 3-[2-[(E)-6-[3-(benzenesulfonamido)phenyl]hex-5-enoxy]phenyl]propanoic acid

TLC: Rf 0.44 (hexane:ethyl acetate=1:1);

¹ H-NMR (CDCl ₃ ): δ 1.65-1.76, 1.77-1.88, 2.25-2.31, 2.69-2.75, 2.99-3.05, 3.99, 6.18, 6.33, 6.83, 6.89, 6.95-7.00, 7.10-7.21, 7.44, 7.53, 7.67, 7, 81.

[0443]

Example 105(3): 3-[2-[(E)-7-[3-(benzenesulfonamido)phenyl]hept-6-enoxy]phenyl]propanoic acid

TLC: Rf 0.44 (hexane:ethyl acetate=1:1);

¹ H-NMR (CDCl ₃ ): δ 1.61-1.73, 1.77-1.88, 2.27, 2.76-2.82, 3.02-3.07, 4.01, 6.29-6.33, 6.83-6.93, 7.08-7.23, 7.45, 7.53, 7.84, 8.75.

[0444]

Example 106: Methyl 3-(2-((4-hydroxy-5-(3-(phenylsulfonamido)phenyl)pentyl)oxy)phenyl)propanoate

The compound obtained in Example 84 (200 mg) was dissolved in ethyl acetate (1 ml). Methanol (1 mL) and trimethylsilyldiazomethane (2 M hexane solution, 0.3 mL) were added to the reaction solution, and the resulting solution 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 (2 ml) and m-chloroperoxybenzoic acid (171 mg) were added to the solution, and the resulting solution was stirred at room temperature for 5 hours. Saturated aqueous sodium thiosulfate was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The residue was dissolved in methanol (2 ml), then 5% palladium on carbon (20 mg) was added to the solution, and the resulting solution was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, 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). The title compound (53 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.31 (hexane:ethyl acetate=1:1).

[0445]

Example 107: 3-[2-[5-[3-(benzenesulfonamido)phenyl]-4-hydroxypentoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 106. The title compound having the physical property values shown below was thereby obtained.

TLC: Rf 0.60 (ethyl acetate);

¹ H-NMR (CDCl ₃ ): δ 1.50-1.68, 1.68-1.74, 1.77-2.00, 2.61-2.70, 2.72-2.79, 2.92-2.99, 3.87, 3.95-4.05, 6.82-7.03, 7.15-7.21, 7.38-7.45, 7.48-7, 53, 7.77.

[0446]

Example 108: Ethyl 3-(2-(4-oxobutyl)phenyl)propanoate

Sodium bicarbonate (0.56 g) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (CAS registration number: 87413-09-0) (1.13 d) added to a solution of ethyl 3-[2-(4-hydroxybutyl)phenyl]propanoate (CAS registration number: 864677-94-1) (0.56 g) in dichloromethane (9 ml) at 0°C, and the resulting the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and the resulting solution was then extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). The title compound (0.34 g) was thereby obtained having the physical properties shown below.

TLC: Rf 0.30 (hexane:ethyl acetate=4:1).

[0447]

Example 109: 3-[2-[(E)-6-[3-(benzenesulfonamide)phenyl]-4-hydroxyhex-5-enyl]phenyl]propanoic acid

The same prescribed procedures were carried out as in Example 4 → Example 5 → Example 7 → Example 8 → Example 10 → Example 11, using isopropyl 3-(2-(3-oxopropoxy)phenyl)propanoate used in Example 4 instead , the compound obtained in Example 108. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 1.60-1.79, 2.66-2.72, 2.97-3.01, 4.30-4.35, 6.16, 6.49, 6.98-7.07, 7.13-7.17, 7.40-7.53, 7.77-7.79.

[0448]

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

[0449]

[Formula 53]

[0450]

The compound obtained in Example 109 was subjected to optical separation using SFC (column used: Daicel Corporation, CHIRALPAK-IC (20 mm × 250 mm), mobile phase: CO ₂ :methanol=85:15, flow rate: 100 ml/min ; pressure: 120 bar (12 MPa), wavelength: 220 nm, column temperature: 35°C). The optically active substances of Example 109 obtained under optical separation conditions were analyzed by SFC (column used: Daicel Corporation, CHIRALPAK-IC (10 mm × 250 mm), mobile phase: CO ₂ :methanol=85:15, flow rate: 30 ml/min; pressure: 100 bar (10 MPa), wavelength: 220 nm, column temperature: 35°C). As a result, the retention times for the first peak and the second peak were 12.4 min and 14.4 min, respectively.

[0451]

Example 111: 3-[2-[6-[3-(benzenesulfonamido)phenyl]-4-hydroxyhexyl]phenyl]propanoic acid

The same prescribed procedure was carried out as in Example 33, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33, the compound obtained in Example 109. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 0.95;

¹ H-NMR (CD ₃ OD): δ 1.37-1.61, 2.39-2.58, 2.84, 6.79-6.81, 6.98-7.08, 7.30 -7.42, 7.61-7.63.

[0452]

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

[0453]

[Formula 54]

[0454]

The same prescribed procedures were carried out as in example 78 → example 79, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl ]propanoic acid used in Example 78, the compound obtained in Example 109. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 1.00;

¹ H-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, 7.43-7.48, 7.54, 7.74-7.76.

[0455]

Example 113: Isopropyl 3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate

Triethylamine (6 ml), bis(triphenylphosphine) palladium(II) dichloride (100 mg) and copper(I) iodide (50 mg) were added to a solution of the compound obtained in Example 81 (1.5 g) and the compound obtained in Example 9 (1.7 g) in DMF (6 ml), and the resulting solution was stirred at 60°C overnight. Water was added to the reaction solution, then the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over magnesium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 → 0:1). The title compound (1.57 g) was thereby obtained having the physical properties shown below.

TLC: Rf 0.39 (hexane:ethyl acetate=2:1).

[0456]

Example 114: 3-[2-[5-[3-(benzenesulfonamido)phenyl]pent-4-ynoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 113. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 1.00;

¹ H-NMR (CD ₃ OD): δ 2.06-2.12, 2.55-2.59, 2.64-2.67, 2.92-2.96, 4.13-4.16 , 6.87, 6.95, 7.03-7.07, 7.12-7.20, 7.45-7.50, 7.56, 7.74-7.77.

[0457]

Example 115: Isopropyl-(R)-3-(2-((5-(3-(phenylsulfonamido)phenyl)-3-((trimethylsilyl)oxy)pent-4-yn-1-yl)oxy)phenyl)propanoate

The same prescribed procedure as in Example 113 was carried out, using the compound obtained in Example 7 instead of the isopropyl-3-(2-(pent-4-yn-1-yl oxy)phenyl)propanoate used in Example 113. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.12.

[0458]

Example 116: Isopropyl-(R)-3-(2-((3-hydroxy-5-(3-(phenylsulfonamide)phenyl)pent-4-yn-1-yl)oxy)phenyl)propanoate

TBAF (1.0 M solution in THF, 0.48 ml) was added to a solution of the compound obtained in Example 115 (170 mg) in THF (1 ml) at room temperature, and the resulting solution 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). The title compound (82.8 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.12.

[0459]

Example 117: 3-[2-[(3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-ynoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 116. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.93;

¹ H-NMR (CD ₃ OD): δ 2.19-2.30, 2.57-2.60, 2.91-2.95, 4.16-4.26, 4.85, 6.88 , 6.96, 7.07-7.22, 7.46-7.51, 7.57, 7.75-7.77.

[0460]

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

[0461]

[Formula 55]

[0462]

The same prescribed procedure was carried out as in Example 33, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33, the compound obtained in Example 114. The title compound having the physical property values shown below was thereby obtained.

TLC: Rf 0.42 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 1.42-1.49, 1.58-1.65, 1.75-1.82, 2.55, 2.67, 2.95, 3.95, 6.80-6.97, 7.10-7.21, 7.27, 7.40, 7.49, 7.76.

[0463]

Example 119: Isopropyl-(Z)-3-(2-((5-(3-(phenylsulfonamido)phenyl)pent-4-en-1-yl)oxy)phenyl)propanoate

Lindlar catalyst (containing palladium at 5% by weight) (10.0 mg) and quinoline (12.8 mg) were added to a solution of the compound obtained in Example 113 (100 mg) in ethyl acetate (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 5 hours under a hydrogen atmosphere. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 → 1:1). The title compound (92.3 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.23.

[0464]

Example 120: 3-[2-[(Z)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 119. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 1.10;

¹ H-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.

[0465]

Example 121: 3-[2-[(Z,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in example 119 → example 11, using isopropyl-3-(2-((5-(3-(phenylsulfonamide)phenyl)pent-4-yn-1-yl)oxy)phenyl instead )propanoate used in Example 119, the compound obtained in Example 116. The title compound was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.92;

¹ H-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.

[0466]

Example 122: Ethyl (E)-3-(2-(3-(benzyloxy)-2-hydroxypropoxy)phenyl)acrylate

Benzyl glycidyl ether (6.57 g) was added to a solution of ethyl (E)-3-(2-hydroxyphenyl)prop-2-enoate (CAS registration number: 6236-62-0) (1.92 g) and diisopropylethylamine ( 0.69 ml) in hexamethylformoramide (20 ml), and the reaction mixture was stirred at 80°C for 19 hours. The reaction solution was cooled to room temperature, then poured into water and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). The title compound (2.66 g) was thereby obtained having the physical properties shown below.

TLC: Rf 0.33 (hexane:ethyl acetate=2:1).

[0467]

Example 123: Ethyl (E)-3-(2-(3-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)propoxy)phenyl)acrylate

Tert-butyldimethylsilyl chloride (330 mg) was added to a solution of the compound obtained in Example 122 (300 mg) and imidazole (200 mg) in DMF (3 ml) at 0°C, and the reaction mixture was stirred at room temperature for 5 days. The reaction mixture was poured into water, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). The title compound (380 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.41 (hexane:ethyl acetate=9:1).

[0468]

Example 124: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-hydroxypropoxy)phenyl)propanoate

A solution of the compound obtained in Example 123 (380 mg) and 5% palladium on carbon (50% humidified, 180 mg) in ethanol (8 ml) was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name) and the filtrate was concentrated. The title compound (290 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.34 (hexane:ethyl acetate=4:1).

[0469]

Example 125: Ethyl 3-(2-(2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)propanoate

1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (390 mg) was added to a solution of the compound obtained in Example 124 (290 mg) and sodium hydrogen carbonate (190 mg ) in methylene chloride (3 ml) at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and the resulting solution was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). The title compound (250 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.40 (hexane:ethyl acetate=4:1).

[0470]

Example 126: Ethyl (E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate

The same prescribed procedures as in Example 45 → Example 55 → Example 56 → Example 116 were carried out, using (R)-4-((4-methoxybenzyl)oxy)-1-oxobutan-2-ylbenzoate used in Example 45, the compound obtained in Example 125. The title compound having the physical property values shown below was thereby obtained.

TLC: Rf 0.43 (hexane:ethyl acetate=1:1).

[0471]

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

[0472]

[Formula 56]

[0473]

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 126. The title compound having the physical properties shown below was thereby obtained.

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79.

[0474]

Example 128: Ethyl (S, E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamido)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate or ethyl- (R, E)-3-(2-((2-hydroxy-4-(3-(phenylsulfonamide)phenyl)but-3-en-1-yl)oxy)phenyl)propanoate

The compound obtained in Example 126 was subjected to optical separation using SFC (column used: Daicel Corporation, CHIRALPAK-IB (20 mm × 250 mm), mobile phase: CO ₂ :2-propanol=83:17, flow rate: 100 ml /min; pressure: 120 bar (12 MPa), wavelength: 220 nm, column temperature: 35°C). The optically active substances of Example 126 obtained under optical separation conditions were analyzed by SFC (column used: Daicel Corporation, CHIRALPAK-IB (10 mm × 250 mm), mobile phase: CO ₂ :2-propanol=83:17, flow rate : 30 ml/min; pressure: 100 bar (10 MPa), wavelength: 220 nm, column temperature: 35°C). As a result, the retention times for the first peak and the second peak were 12.6 min and 14.6 min, respectively.

[0475]

Example 129: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- Enoxy]phenyl]propanoate used in Example 11, the optically active substance corresponding to the first peak that was obtained in Example 128. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79.

[0476]

Example 130: 3-[2-[(E)-4-[3-(benzenesulfonamido)phenyl]-2-hydroxybut-3-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- Enoxy]phenyl]propanoate used in Example 11, the optically active substance corresponding to the second peak that was obtained in Example 128. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76-7.79.

[0477]

Example 131: N-(3-bromophenyl)-N-(phenylsulfonyl)benzenesulfonamide

Triethylamine (1.6 ml), DMAP (177 mg) and benzenesulfonic anhydride (1.9 g) were added to a solution of 3-bromoaniline (500 mg) in dichloromethane (10 ml), and the resulting solution was stirred at room temperature for 18 h. Water was added to the reaction mixture, and the resulting solution was extracted with dichloromethane. 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=4:1). The title compound (950 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.30 (hexane:ethyl acetate=4:1).

[0478]

Example 132: N-(3-(4-hydroxybut-1-yn-1-yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide

Triethylamine (1.5 ml), 3-butyn-1-ol (220 mg), copper iodide (40 mg) and bis(triphenylphosphine palladium) dichloride (147 mg) were added to a solution of the compound obtained in Example 131 (949 mg) in DMF (4 ml), and the resulting solution was stirred at 80°C for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). The title compound (771 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.30 (hexane:ethyl acetate=2:1).

[0479]

Example 133: N-(3-(4-hydroxybutyl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide

A solution of the compound obtained in Example 132 (600 mg) and 20% palladium hydroxide on carbon (50% humidified, 150 mg) in methanol (5 ml) was stirred at room temperature for 9 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name) and the filtrate was concentrated. The title compound (575 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.00.

[0480]

Example 134: 3-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid

Methyl 3-(3-hydroxyphenyl)propanoate (22 mg), DIAD (82 mg) and triphenylphosphine (40 mg) were added to a solution of the compound obtained in Example 133 (45 mg) in THF (0.5 ml), and the resulting the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. 5 n. An aqueous solution of sodium hydroxide (0.4 ml) was added to a solution of the resulting residue in methanol (0.5 ml) and 1,2-dimethoxyethane (0.5 ml), and the resulting solution was stirred at 45°C for 19 hours. 2 M hydrochloric acid was added to the reaction mixture and the resulting solution 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=1:1). The title compound (14 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.97;

¹ H-NMR (CDCl ₃ ): δ 1.66-1.75, 2.61, 2.74, 2.94, 3.94, 6.71-6.73, 6.79-6.86, 6.91-7.00, 7.14, 7.21, 7.37-7.41, 7.47-7.52, 7.72-7.74.

[0481]

Examples 135 (1) - (6)

The same prescribed procedure as in Example 134 was carried out, using the corresponding phenolic compounds instead of the methyl 3-(3-hydroxyphenyl)propanoate used in Example 134. The following example compounds were thereby obtained.

[0482]

Example 135(1): 3-[4-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid

HPLC retention time (min): 0.96;

¹ H-NMR (CD ₃ OD): δ 1.64-1.74, 2.55-2.61, 2.86, 3.91, 6.80-6.84, 6.92-6.94 , 7.11-7.15, 7.42-7.46, 7.50-7.54, 7.73-7.76.

[0483]

Example 135(2): 4-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid

HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 1.77-1.83, 1.96-2.03, 2.48, 2.60, 2.71-2.75, 3.97, 6.82, 6.87-6.90, 7.05-7.07, 7.11-7.20, 7.39-7.43, 7.47-7.52, 7.78-7.81.

[0484]

Example 135(3): 4-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]butanoic acid

HPLC retention time (min): 0.99;

¹ H-NMR (CDCl ₃ ): δ 1.70-1.74, 1.95-2.02, 2.40, 2.59, 2.65, 3.93, 6.71-6.78, 6.86, 6.93-6.95, 7.12-7.21, 7.39-7.43, 7.48-7.52, 7.74-7.77.

[0485]

Example 135(4): 2-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]acetic acid

HPLC retention time (min): 0.94;

¹ H-NMR (CDCl ₃ ): δ 1.68-1.72, 2.57, 3.65, 3.96, 6.80-6.94, 7.13, 7.21-7.24, 7.37-7.42, 7.47-7.52, 7.74-7.77.

[0486]

Example 135(5): 2-[3-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]acetic acid

HPLC retention time (min): 0.95;

¹ H-NMR (CDCl ₃ ): δ 1.74-1.77, 2.57-2.60, 3.66, 3.98, 6.83-6.86, 6.91-6.96, 7.11, 7.19-7.26, 7.36-7.43, 7.48-7.52, 7.75-7.78.

[0487]

Example 135(6): 3-[2-[4-[3-(benzenesulfonamido)phenyl]butoxy]phenyl]propanoic acid

HPLC retention time (min): 0.99;

¹ H-NMR (CDCl ₃ ): δ 1.70-1.86, 2.61, 2.66-2.70, 2.97-3.01, 3.97, 6.82, 6.87- 6.91, 7.03-7.06, 7.12-7.21, 7.40-7.44, 7.48-7.53, 7.60, 7.78-7.81.

[0488]

Example 136: Isopropyl-(E)-3-(2-((5-(3-nitrophenyl)-3-oxopent-4-en-1-yl)oxy)phenyl)propanoate

The same prescribed procedures were carried out as in Example 10 → Example 77, using 3-bromonitrobenzene instead of N-(3-bromophenyl)benzenesulfonamide used in Example 10. The title compound was thereby obtained having the physical properties shown below.

TLC: Rf 0.43 (hexane:ethyl acetate=2:1).

[0489]

Example 137: Isopropyl-(E)-3-(2-((3,3-difluoro-5-(3-nitrophenyl)pent-4-en-1-yl)oxy)phenyl)propanoate

The compound obtained in Example 136 (205 mg) was dissolved in dichloromethane (0.4 ml), then bis(2-methoxyethyl)aminosulfur trifluoride (1.5 ml) was added to the solution, and the resulting solution was stirred at room temperature for 3 days. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over magnesium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 → ethyl acetate). The title compound (29 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.66 (hexane:ethyl acetate=2:1).

[0490]

Example 138: 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]-3,3-difluoropent-4-enoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in example 55 → example 56 → example 11, using instead of (R, E)-5-(2-((E)-3-methoxy-3-oxoprop-1-ene-1 -yl)phenoxy)-1-(3-nitrophenyl)pent-1-en-3-ylbenzoate used in Example 55, the compound obtained in Example 137. The title compound was thereby obtained having the physical property values shown below .

TLC: Rf 0.22 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 2.50-2.62, 2.72, 2.93, 4.20, 6.30, 6.80-6.95, 7.05, 7.12- 7.25, 7.43, 7.53, 7.78, 7.89.

[0491]

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

[0492]

[Formula 57]

[0493]

The same prescribed procedure was carried out as in Example 33, using instead of 3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid used in Example 33, the compound obtained in Example 138. The title compound having the physical properties shown below was thereby obtained.

TLC: Rf 0.20 (hexane:ethyl acetate=1:2);

¹ H-NMR (CDCl ₃ ): δ 2.14-2.47, 2.67-2.74, 2.76-2.84, 2.88-2.98, 4.13-4.21, 6.79-6.88, 6.89-7.07, 7.11-7.25, 7.42, 7.52, 7.79.

[0494]

Example 140: (S)-5-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)thio)-1-phenyl-1H-tetrazole

1-Phenyl-1H-tetrazole-5-thiol (CAS registration number: 86-93-1) (3.66 g), triphenylphosphine (5.38 g) and DIAD (1.10 g) were added to the 2-[ solution (S)-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, and the resulting the solution was 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). The title compound (4.14 g) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.97.

[0495]

Example 141: (S)-5-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)sulfonyl)-1-phenyl-1H-tetrazole

Ammonium molybdate tetrahydrate (1.57 g) and 30% wt. an aqueous solution of hydrogen peroxide (8.3 ml) was added to a solution of the compound obtained in Example 140 (4.14 g) in acetonitrile (15 ml) and ethanol (15 ml) under ice-cooling, and the resulting solution was stirred at room temperature under for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in 2,2-dimethoxypropane (8.3 ml), then p-toluenesulfonic acid monohydrate (129 mg) was added to the solution at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate , and the resulting solution was washed with saturated aqueous sodium bicarbonate and saturated saline. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1 → 2:1). The title compound (3.96 g) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.96.

[0496]

Example 142: (S, E)-N-(3-(4,5-dihydroxypent-1-en-1-yl)phenyl)benzenesulfonamide

Potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 15.3 ml) was added to a solution of the compound obtained in Example 141 (1.04 g) in 1,2-dimethoxyethane (15 ml) at -78° C, and the resulting solution 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 the resulting solution was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the resulting solution 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=10:1). The resulting residue was dissolved in methanol (3 ml), then 2 M hydrochloric acid (3 ml) was added to the solution at room temperature, and the resulting solution was stirred at 50°C for 30 minutes. The reaction solution was cooled with ice, then neutralized with 2 M aqueous sodium hydroxide and 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=1:0 → 9:1). The title compound (675 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.73.

[0497]

Example 143: (S, E)-1-hydroxy-5-(3-(phenylsulfonamide)phenyl)pent-4-en-2-ylbenzoate

Tert-butyldimethylchlorosilane (0.7 M solution in DMF, 2 ml) was added dropwise to a solution of the compound obtained in Example 142 (450 mg) and imidazole (131 mg) in DMF (5 ml) over 5 minutes under ice cooling , and the resulting solution was stirred at room temperature for 24 hours. The reaction solution was cooled with ice, then imidazole (131 mg) and tert-butyldimethylchlorosilane (213 mg) were added to the solution, and the resulting solution was stirred at room temperature for 5 hours. water was added to the solution and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 ml), and then pyridine (0.42 ml), benzoyl chloride (215 mg) and DMAP (15.7 mg) were added to the solution under ice-cooling, and the resulting solution was stirred at room temperature for 1 .5 hours. The reaction solution was cooled with ice, then benzoyl chloride (215 mg) was added to the solution, and the resulting solution was stirred at room temperature for 1.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1 → 2:1). The resulting residue was dissolved in THF (3 ml) and acetic acid (0.30 ml), then TBAF (1.0 M solution in THF, 1.6 ml) was added to the solution under ice-cooling, and the resulting solution was stirred at room temperature in for 12 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1 → 2:1). The title compound (292 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 0.97.

[0498]

Example 144: (S, E)-1-iodo-5-(3-(phenylsulfonamido)phenyl)pent-4-en-2-ylbenzoate

Imidazole (68.6 mg) and triphenylphosphine (106 mg) were added to a solution of the compound obtained in Example 143 (147 mg) in DMF (1 ml) at room temperature. Iodine (102 mg) was added to the reaction solution under ice-cooling, and the resulting solution was stirred at 50°C for 1.5 hours. The reaction solution was cooled with ice, then triphenylphosphine (26.0 mg) and iodine (25.0 mg) were added to the solution. mg), and the resulting solution 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). The title compound (121 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.20.

[0499]

Example 145: (S, E)-1-(2-(3-isopropoxy-3-oxopropyl)phenoxy)-5-(3-(phenylsulfonamide)phenyl)pent-4-en-2-ylbenzoate

Sodium hydride (60% in mineral oil, 13.1 mg) was added to a solution of the compound obtained in Example 1 (68.4 mg) in DMF (0.5 ml) under ice-cooling, and the resulting solution was stirred at room temperature under for 15 minutes. A solution of the compound obtained in Example 144 (60 mg) in DMF (0.5 ml) was added to the reaction solution at room temperature, and the resulting solution was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature and then purified chromatography on a silica gel column (hexane: ethyl acetate = 7:1 → 3:2). The title compound (12.1 mg) was thereby obtained having the physical properties shown below.

HPLC retention time (min): 1.29.

[0500]

Example 146: 3-[2-[(E,2S)-5-[3-(benzenesulfonamido)phenyl]-2-hydroxypent-4-enoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 57, using instead of (R, E)-5-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)- 1-(3-(phenylsulfonamide)phenyl)pent-1-en-3-ylbenzoate used in Example 57, the compound obtained in Example 145. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 0.95

¹ H-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.

[0501]

Example 147: 2-(3-nitrophenethoxy)acetic acid

A solution of 2-(3-nitrophenyl)ethanol (CAS registration number: 52022-77-2) (2.00 g) in DMF (4 ml) was cooled to 0°C, then sodium hydride (60% in mineral oil, 0. 7 g) was added to the solution, and the resulting solution was stirred at 0°C for 15 minutes. Isopropyl bromoacetate (2.6 g) was added dropwise to the solution, and the resulting solution was stirred at 0°C for 1 hour, and then at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 2:1). The ester compound (1.80 g) was thereby obtained. The ester compound was dissolved in methanol (15 ml), then sodium hydroxide (2N aqueous solution, 10 ml) was added to the solution, and the resulting solution was stirred at room temperature overnight. The reaction mixture was poured into 2 M hydrochloric acid, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The title compound (1.15 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 3.05-3.07, 3.84-3.87, 4.14, 7.48, 7.58-7.60, 8.09-8.14.

[0502]

Example 148: 2-(3-nitrophenethoxy)ethan-1-ol

A solution of the compound obtained in Example 147 (1.15 g) and 4-methylmorpholine (0.8 ml) in THF (10 ml) was cooled to 0°C, and then isobutyl chloroformate (0.8 ml) was added dropwise to the solution. . The resulting solution was stirred at room temperature for 30 minutes to obtain a white solid, and the white solid was filtered. The filtrate was cooled to 0°C, then sodium borohydride (1.15 g) was added to the filtrate, then the resulting solution was stirred at 0°C for 10 min, then a small amount of water was added to the solution, and the resulting solution was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:1). The title compound (1.15 g) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 1.82, 3.00-3.03, 3.56-3.58, 3.69-3.78, 7.47, 7.56-7.58, 8.07-8.13.

[0503]

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

[0504]

[Formula 58]

[0505]

The same prescribed procedures as in Example 54 → Example 55 → Example 56 → Example 11 were carried out using the compound obtained in Example 148 instead of (R, E)-5-hydroxy-1-(3-nitrophenyl)pent- 1-en-3-ylbenzoate used in Example 54 and using the compound obtained in Example 1 instead of methyl (E)-3-(2-hydroxyphenyl)prop-2-enoate used in Example 54. Thereby obtaining a compound specified in the title having the physical property values shown below.

HPLC retention time (min): 0.99;

¹ H-NMR (DMSO-d6): δ 2.70-2.80, 3.17-3.18, 3.56-3.60, 3.68-3.71, 4.05-4.08 , 6.84-6.96, 7.09-7.19, 7.50-7.60, 7.74-7.76.

[0506]

Example 150: tert-butyl-(S)-2-(3-(1-hydroxy-2-phenylethyl)phenyl)acetate

Bromo-(2-tert-butoxy-2-oxoethyl)zinc (0.5 M solution in THF, 9 ml) and bis(tri-tert-butylphosphine)palladium (76 mg) were added to the solution of (1S)-1-( 3-bromophenyl)-2-phenylethanol (412 mg) in THF (0.5 ml), and the resulting solution was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, then a saturated aqueous chloride solution was added to the reaction mixture ammonium, and the resulting solution 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=4:1). The title compound (296 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.40 (hexane:ethyl acetate=4:1).

[0507]

Example 151: tert-butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)acetate

3,4-Dihydro-2H-pyran (239 mg) and pyridinium 4-toluenesulfonate (71 mg) were added to a solution of the compound obtained in Example 150 (296 mg) in dichloromethane (2 ml), and the resulting solution was stirred at room temperature for 1.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting solution was extracted with dichloromethane. 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=4:1). The title compound (341 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.60 (hexane:ethyl acetate=4:1).

[0508]

Example 152: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)ethan-1-ol

Water (0.15 ml) and lithium borohydride (187 mg) were added to a solution of the compound obtained in Example 151 (341 mg) in THF (4 ml), and the resulting solution was stirred at 40°C for 16 hours. To the reaction mixture water was added and then 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=1:1). The title compound (236 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.50 (hexane:ethyl acetate=1:1).

[0509]

Example 153: tert-butyl 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenethoxy)acetate

Tert-butyl bromoacetate (424 mg) and sodium hydride (60% in mineral oil, 87 mg) were added to a solution of the compound obtained in Example 152 (236 mg) in DMF (2 ml), and the resulting solution was stirred at room temperature for 2 .5 hours. A saturated aqueous sodium chloride solution was added to the reaction mixture, and the resulting solution 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=4:1). The title compound (250 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.60 (hexane:ethyl acetate=4:1).

[0510]

Example 154: 2-(3-((1S)-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenethoxy)ethan-1-ol

Water (0.1 ml) and lithium borohydride (123 mg) were added to a solution of the compound obtained in Example 153 (250 mg) in THF (0.5 ml), and the resulting solution was stirred at 40°C for 2.5 hours Water was added to the reaction mixture, and the resulting solution 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=1:1). The title compound (107 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.30 (hexane:ethyl acetate=1:1).

[0511]

Example 155: Isopropyl (S)-3-(2-(2-(3-(1-hydroxy-2-phenylethyl)phenethoxy)ethoxy)phenyl)propanoate

The compound obtained in Example 1 (90 mg), triphenylphosphine (114 mg) and 1,1-(azodicarbonyl)dipiperidine (110 mg) were added to a solution of the compound obtained in Example 154 (107 mg) in dichloromethane (1 ml) , and the resulting solution 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 the ester compound (181 mg). Water (0.8 ml) and acetic acid (3.2 ml) were added to a solution of the ester compound (181 mg) in THF (0.6 ml), and the resulting solution was stirred at 50°C for 7 hours. To the reaction mixture saturated aqueous sodium bicarbonate was added and the resulting solution 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=4:1). The title compound (97 mg) was thereby obtained having the physical properties shown below.

TLC: Rf 0.20 (hexane:ethyl acetate=4:1).

[0512]

Example 156: 3-[2-[2-[2-[3-[(1S)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- enoxy]phenyl]propanoate used in Example 11, the compound obtained in Example 155. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 1.10;

¹ H-NMR (CDCl ₃ ): δ 2.59-2.63, 2.90-2.94, 3.00-3.03, 3.76-3.80, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 7.13-7.21, 7.22-7.32.

[0513]

Example 157: 3-[2-[2-[2-[3-[(1R)-1-hydroxy-2-phenylethyl]phenyl]ethoxy]ethoxy]phenyl]propanoic acid

The same prescribed procedures were carried out as in example 150 → example 151 → example 152 → example 153 → example 154 → example 155 → example 11, using instead of (1S)-1-(3-bromophenyl)-2-phenyl-ethanol used in Example 150, the compound obtained in Example 21. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 1.00;

¹ H-NMR (CDCl ₃ ): δ 2.58-2.62, 2.90-2.95, 2.99-3.06, 3.77-3.81, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 6.88, 7.13-7.21, 7.25-7.32.

[0514]

Example 158: tert-butyl(trans-4-(3-hydroxypropyl)cyclohexyl)carbamate

A solution of methyl trans-3-[4-(tert-butoxycarbonylamino)cyclohexyl]propanoate (500 mg) in THF (5 ml) was cooled to 0°C, then a solution of lithium borohydride (72.8 mg) in THF (1 ml) was added to the solution, and the resulting solution was stirred at room temperature for 15 minutes, then at 50°C for 3.5 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The title compound (429 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.95-1.28, 1.44, 1.53-1.60, 1.75-1.78, 1.98-2.01, 2.27- 2.31, 3.36, 3.62, 4.36.

[0515]

Example 159: tert-butyl(trans-4-(3-oxopropyl)cyclohexyl)carbamate

A solution of the compound obtained in Example 158 (429 mg) in dichloromethane (8.3 ml) was cooled to 0°C, then 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol- 3(1H)-one (848 mg), and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:1). The title compound (429 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.96-1.28, 1.44, 1.53-1.60, 1.62-1.75, 1.98-2.01, 2.42- 2.46, 3.36, 4.38.

[0516]

Example 160: Ethyl(E)-5-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)pent-2-enoate

A solution of ethyl diethylphosphonoacetate (747 mg) in THF (5 ml) was cooled to 0°C, then sodium hydride (60% in mineral oil, 145 mg) was added to the solution and the resulting solution was stirred at 0°C for 15 minutes. A solution of the compound obtained in Example 159 (429 mg) in THF (5 ml) was added to the reaction mixture, and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 1:1). The title compound (270 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17- 2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00.

[0517]

Example 161: Ethyl 5-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)pentanoate

Palladium on carbon (54 mg) was added to a solution of the compound obtained in Example 160 (270 mg) in ethanol (10 ml), and the resulting solution 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. The title compound (282 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17- 2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00.

[0518]

Example 162: tert-butyl(trans-4-(5-hydroxypentyl)cyclohexyl)carbamate

A solution of the compound obtained in Example 161 (282 mg) in THF (5 ml) was cooled to 0°C, lithium borohydride (36 mg) was added to the solution, and the resulting solution was stirred at 50°C for 3 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and further concentrated under reduced pressure. The title compound (270 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.92-1.32, 1.44, 1.53-1.60, 1.73-1.78, 1.98-2.01, 2.26- 2.31, 3.36, 3.64, 4.36.

[0519]

Example 163: 5-(trans-4-aminocyclohexyl)pentan-1-ol hydrochloride

Hydrogen chloride (4.0 M solution in dioxane, 6 ml) was added to the compound obtained in Example 162 (140 mg), and the reaction mixture was stirred at room temperature for 1.5 hours, and then concentrated. The title compound (180 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (DMSO-d6): δ 0.88-0.97, 1.15-1.42, 1.73-1.76, 1.90-1.93, 2.91, 3.36 -3.75, 7.86.

[0520]

Example 164: 5-(trans-4-(phenylsulfonamide)cyclohexyl)pentylbenzenesulfonate

A solution of the compound obtained in Example 163 (180 mg) in pyridine (2 ml) and dichloromethane (2 ml) was cooled to 0°C and then DMAP (5 mg) was added to the solution. Benzenesulfonyl chloride (0.14 ml) was added dropwise to the reaction solution, and the resulting solution was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The title compound (180 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.84-0.89, 1.07-1.83, 3.04-3.09, 3.98-4.27, 7.51-8.07.

[0521]

Example 165: Isopropyl 3-(2-((5-(trans-4-(phenylsulfonamide)cyclohexyl)pentyl)oxy)phenyl)propanoate

Cesium carbonate (377 mg) was added to a solution of the compound obtained in Example 164 (180 mg) in 1-methyl-2-pyrrolidone (2 ml), and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 → 2:1). The title compound (60 mg) was thereby obtained having the physical properties shown below.

¹ H-NMR (CDCl ₃ ): δ 0.83-0.92, 1.07-1.84, 2.53-2.57, 2.89-2.93, 3.04-3.12, 3.92-3.95, 4.26-4.27, 4.96-5.02, 6.79-6.86, 7.13-7.17, 7.48-7.59, 7, 87-7.89.

[0522]

Example 166: 3-[2-[5-[4-(benzenesulfonamide)cyclohexyl]pentoxy]phenyl]propanoic acid

The same prescribed procedure was carried out as in example 11, using instead of propan-2-yl-3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4- Enoxy]phenyl]propanoate used in Example 11, the ester compound obtained in Example 165. The title compound having the physical property values shown below was thereby obtained.

HPLC retention time (min): 1.20;

¹ H-NMR (CDCl ₃ ): δ 0.83-0.92, 1.07-1.83, 2.64-2.68, 2.92-2.96, 3.05-3.13, 3.93-3.96, 4.42-4.43, 6.80-6.88, 7.14-7.20, 7.48-7.59, 7.87-7.89.

[0523]

Examples of biological experiments will be described below. The effect of the compounds of the present invention was confirmed by these experimental methods.

[0524]

Biological Experiment Example 1: In Vitro Test Using Schwann Cells

(Test method)

(1) Preparation of rat Schwann cells

The dorsal root ganglion (hereafter abbreviated as “DRG”) was dissected from a 0–2 day old neonatal rat in a sterile box and collected in DMEM. After collection, the tube was centrifuged at 400 g at room temperature for 3 minutes, then the supernatant was removed and a 0.25% collagenase solution was added. The resulting solution was incubated at 37°C for 30 min to disperse and separate the excised DRG, and then centrifuged at room temperature at 400 g for 3 min, then the supernatant was removed, and then 0.25% Trypsin/EDTA and DNase I were added. After incubation at 37°C for 30 min, trypsin was inactivated with DMEM supplemented with 10% FBS (10% FBS-DMEM), and centrifugation was performed at room temperature at 400 g for 3 min. The supernatant was removed, then 10% FBS-DMEM was added to the residue to prepare a cell suspension, and then the cell suspension was passed through a filter (diameter: 70 μm). The number of cells in the cell suspension passing through the filter was counted to prepare a solution having a concentration of 2.0 × 10 ⁵ cells/ml, and the suspension was seeded into a poly-D-lysine-coated black clear-bottom 96-well plate in an amount of 100 μl/ well and then statically cultured in a CO ₂ incubator under conditions including 5% CO ₂ , 95% air and 37°C.

(2) Adding a connection

The culture medium in the cell culture plate was removed by suction using an aspirator, and then DMEM supplemented with 1% dialyzed FBS and 100 μmol/L dibutyryl cyclic AMP was added. A solution of the compound of the present invention dissolved in DMSO was then added and the resulting solution was statically cultured in a CO ₂ incubator under conditions comprising 5% CO ₂ , 95% air and a temperature of 37°C. The final concentration of the compound of the present invention in each well of the cell culture plate was adjusted to 0.1, 0.3, 1 or 3 μmol/L.

(3) Cell immunostaining

Three days after treatment with the compound, formaldehyde was added to each well of the cell culture plate and the cell culture plate was allowed to stand at room temperature for 30 minutes or longer. The supernatant was removed and then 0.3% Triton X-100 was added to each well and the cell culture plate was then allowed to stand at room temperature for 20 minutes or longer. The supernatant was removed, then a solution of 5 μg/ml anti-myelin-associated glycoprotein antibody (anti-MAG antibody) was added to each well, and the cell culture plate was then allowed to stand at room temperature for 60 minutes or longer or at 4°C ( permissible range: 1-9 °C) overnight. Each well was washed three times with 0.1% Triton X-100, then 10 μg/mL anti-mouse IgG solution with Alexa fluor 488 was added to each well, and the cell culture plate was then allowed to stand at room temperature for 60 min or longer. or at 4°C overnight. Each well was washed four times with 0.1% Triton X-100, and then 1 μg/ml Hoechst33342 solution was added to each well to stain the nuclei.

[0525]

(Evaluation method)

The MAG-positive area and the number of cell nuclei in the fluorescent image were determined. For each MAG-positive area and number of cell nuclei, the total sum of the values obtained in 5 fields of view per well was determined. These values were used as the value for the MAG positive area and the value for the number of cell nuclei, respectively, in each well. The value determined by dividing the value for the MAG-positive region in each well by the value of the number of cell nuclei per well (ie, MAG number/cell nuclei) was then calculated. The indicator of stimulation of Schwann cell differentiation was determined for each of the carriers in accordance with the following formula.

[0526]

[Math Formula 1]

Schwann cell differentiation promotion rate for the carrier (%) = {(numeric MAG value of the compound of the invention/cell nuclei) - A}/(B - A) × 100

A: Numerical value of MAG/cell nuclei in untreated plate

B: numerical value of MAG/carrier cell nuclei

[0527]

(Results)

The Schwann cell differentiation promotion rate (% of vehicle) for vehicles in the case where each of the compounds of the present invention was added at a concentration of 0.3 μmol/L or 3 μmol/L is shown below. Based on these results, it was recognized that the compounds of the present invention have potent neuroprotective and/or neurorestorative activities.

[0528]

[Table 1]

Example No. % carrier Example No. % carrier 0.3 µmol/l 3 µmol/l 0.3 µmol/l 3 µmol/l 10 86.2 593.4 37 170.6 914.9 eleven 113.7 248.1 39 211.3 322.6 12(1) 120.0 274.5 74(13) 79.9 184.2 12(5) 146.7 234.5 74(15) 204.5 428.1 12(6) 143.5 435.1 74(16) 212.0 300.5 12(7) 110.8 379.4 74(17) 85.6 252.4 12(8) 157.9 458.8 74(19) 187.0 270.0 12(11) 202.8 505.4 75 181.0 244.4 13(15) 219.1 325.8 77 115.1 255.6 13(16) 169.9 376.9 84 161.9 445.3 13(19) 142.1 598.0 93 107.7 373.7 26 195.5 438.6 103 198.7 353.9 28 187.8 628.2 112 255.0 503.7 32(1) 408.0 1007.4 139 208.6 541.0 32(2) 340.3 787.5 149 159.6 644.6 36 125.7 732.1 166 103.7 464.6

[0529]

Biological Experiment Example 2: Test Using Streptozotocin-Induced Rat Model

To evaluate the therapeutic effect of each of the compounds of the present invention on diabetic peripheral neuropathy, an in vivo test was conducted using a streptozotocin model.

(Test method)

(1) Receiving the model

The model was obtained by intravenously injecting streptozotocin (hereinafter abbreviated as “STZ”) into a rat at a single dose of 55 mg/kg.

(2) Measuring nociceptive threshold

The rat was placed in a clear acrylic cage for measurements one or more times for 10 min or longer until STZ administration began. Thus, the rat was acclimatized to the measurement conditions. Eight von Frey threads, weighing 0.4 g, 0.6 g, 1 g, 2 g, 4 g, 6 g, 8 g, and 15 g, respectively, were applied vertically to the rat's hind paw from under a metal mesh floor. When a rapid avoidance or withdrawal response was observed, a positive response was determined to have occurred (i.e., “a response was observed”). Each of the compounds of the present invention was administered orally once a day from 14 to 28 days after administration of STZ, and the dose value of each compound was 0.03 mg/kg, 0.3 mg/kg, or 3 mg/kg. Nociceptive threshold was measured 2 hours after administration of each of the compounds of the present invention at the time points before administration of STZ, 14 days after administration of STZ (i.e., on the day of initiation of administration of each of the compounds of the present invention), 21 days after administration of STZ (t .i.e., 7 days after the start of administration of the compound), 28 days after the administration of STZ (i.e., 14 days after the start of administration of the compound), and 35 days after administration of STZ (i.e., 7 days after the cessation of administration connections).

[0530]

(Evaluation method)

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

[0531]

[Math Formula 2]

Nociceptive threshold improvement rate (%) = (nociceptive threshold on each of the number of days elapsed after STZ administration - B) / (A - B) × 100

A: Nociceptive threshold before STZ administration

B: Nociceptive threshold 14 days after STZ administration

[0532]

(Results)

The results of nociceptive thresholds and nociceptive threshold improvement scores obtained when each of the compounds of the present invention were administered at a dose of 0.3 mg/kg are shown in Figure 1 and Table 2, respectively. As for all compounds, a strong analgesic effect was observed in relation to peripheral neuropathy. With regard to the compound of Example 11, for example, an improvement in the nociceptive threshold was observed 7 days after the start of administration of the compound, and this effect continued even 7 days after the cessation of administration. Thus, a long-term analgesic effect was confirmed.

[0533]

[Table 2]

Example No. Nociceptive threshold improvement rate (%) After an initial single dose 7 days after the start of administration 14 days after the start of administration 7 days after discontinuation of administration eleven -14.6 ± 6.37 26.6 ± 9.30 27.1 ± 8.39 41.1 ± 13.71 12(1) 6.2 ± 5.72 17.4 ± 17.19 44.6 ± 11.54 9.1 ± 13.37 13(15) -15.4 ± 14.26 15.9 ± 7.17 8.5 ± 11.50 7.1 ± 9.51 13(16) -6.0 ± 3.87 25.8 ± 5.28 29.6 ± 8.19 -7.8 ± 14.90 36 3.6 ± 7.07 57.1 ± 13.78 64.2 ± 13.02 57.4 ± 10.74 37 -11.9 ± 10.78 61.3 ± 16.58 78.9 ± 9.85 58.7 ± 19.84 74(13) 2.6 ± 1.69 28.3 ± 7.44 57.3 ± 17.63 76.3 ± 13.41 84 5.7 ± 2.48 35.0 ± 16.24 49.9 ± 11.50 58.8 ± 12.51

[0534]

Biological Experiment Example 3: Reactive Metabolite Measurement Test

The complex of the reactive metabolite of each of the compounds of the present invention and quaternary ammonium glutathione (QA-GSH) was determined semi-quantitatively using LC/MS/MS (Soglia JR et al., Chem. Res. Toxicol. 19(3), 480-490, 2006) , and the amount of NADPH-dependent reactive metabolite was measured.

In 100 mM phosphate buffer (pH 7.4) (187.5 μl), 20 mg/ml human liver microsomes (Xenotech) were added in an amount of 12.5 μl (final concentration: 1 mg/ml), 10 mmol/l QA- GSH in an amount of 25 μl (final concentration: 1 mmol/l), and 0.5 mmol/l solution of each of the compounds of the present invention (DMSO:acetonitrile:water=5:38:57) in an amount of 5 μl (final concentration of the compound: 10 µmol/l). The resulting solution was preincubated in a water bath at 37°C for 3 min, and then 25 mmol/L NADPH was added to the solution in an amount of 20 μL (final concentration: 2 mmol/L) to initiate the reaction. After the reaction was carried out for 1 h, 500 μL of IS-containing acetonitrile was added to the reaction solution to terminate the reaction. The complex of the reactive metabolite and QA-GSH (i.e., QA-GS adduct) obtained in the completed reaction sample was analyzed by LC/MS/MS. Measurements were also carried out on the internal standard (IS) substance for the QA-GS adduct.

[0535]

The concentration of QA-GS adduct was calculated according to the following formula.

[0536]

[Math Formula 3]

QA-GS adduct concentration = (QA-GS adduct peak area)/(IS peak area) × (IS concentration)

[0537]

(Results)

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

[0538]

Biological Experiment Example 4: Hand-1EST Test

The reproductive and embryotoxicity of each of the compounds of the present invention was measured using POCA (registered trademark) Hand1-EST (DS Pharma Biomedical Co., Ltd.), using as indicators the number of living cells and differentiation efficiency in the process of differentiation from murine ES cell to cardiac muscle cells (Le Coz F et al., J. Toxicol., 40(2):251-61. 2015).

[0539]

A solution of 1000 mg/ml of each of the compounds of the present invention was prepared in DMSO. A DMSO solution of 1000 mg/ml of each of the compounds of the present invention was diluted with cardiomyocyte differentiation culture medium to obtain a 1000 μg/ml compound solution (final DMSO concentration: 0.1%). The solution was serially diluted three times with cardiomyocyte differentiation culture medium (final concentration of DMSO: 0.1%), confirming the presence or absence of precipitation by the naked eye, and the concentration at which no precipitation was observed was recorded as the maximum solubility.

[0540]

Thawed Hand1-ES cells (mouse ES cells each transfected with the promoter region for the cardiac differentiation marker gene Hand1 and the luciferase gene downstream of the promoter region using pGL4.17 as a vector) were suspended in undifferentiated culture medium , and the resulting solution was seeded into a gelatin-coated 60 mm dish and then cultured for 2-3 days. After culturing for 2-3 days, trypsin-treated Hand1-ES cells were subcultured at a concentration of 2 x ¹⁰⁶ cells/5 ml in a gelatin-coated 60 mm dish and then cultured overnight. Next, trypsin-treated Hand1-ES cells were suspended in culture medium to differentiate into cardiomyocytes, and the resulting solution was seeded into a round-bottom 96-well PrimeSurface (registered trademark) plate at a concentration of 750 cells/50 μl/well and then cultured for 2 h After 2 hours, 50 μl of cardiomyocyte differentiation culture medium containing each of the compounds of the present invention or the positive control substance 5-FU was added (final concentration of the compound of the present invention: 1000 μg/ml, 333 μg/ml, 111 μg/ml, 37). .0 µg/ml, 12.3 µg/ml, 4.12 µg/ml and 1.37 µg/ml; final concentration of 5-FU: 1 µg/ml, 0.333 µg/ml, 0.111 µg/ml, 0. 0370 µg/ml, 0.0123 µg/ml, 0.00412 µg/ml and 0.00137 µg/ml; final concentration of DMSO: 0.1%) for 5 days. After the compounds of the present invention or 5-FU were exposed to cells for 5 days, CellTiter-Fluor (registered trademark) (Promega) was added to determine the number of living cells and fluorescence was measured at an Ex excitation wavelength of 390 nm, and Em fluorescence wavelength of 505 nm using a SpectraMax M5e plate reader (Molecular Devices). Additionally, to determine differentiation efficiency, Steady-Glo (registered trademark) (Promega) was added and fluorescence was measured using a SpectraMax M5e plate reader. The maximum solubility, the concentration at which the number of living cells was inhibited by 50%, and the concentration at which the differentiation efficiency was inhibited by 50%, which were determined above, were entered into the special software POCA Hand1-EST Analysis Software to determine the teratogenic risk. The definition criteria were as follows: low risk: probability less than 0.52; high risk: probability of 0.52 or more (Nagahori et al., Toxicology Letters 259.44-51).

[0541]

(Results)

Among the compounds of the present invention, each of the compounds of Examples 84, 86 and 87 had a probability of less than 0.52, and accordingly, these compounds were found to have a low teratogenic risk.

[0542]

[Song examples]

Composition example 1

The components below were mixed together in the usual manner and the mixture was compressed into tablets. In this way, 10,000 tablets were obtained, each containing 10 mg of active ingredient per tablet.

3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid: 100 g

Potassium carboxymethylcellulose: 20 g

Magnesium stearate: 10 g

Microcrystalline cellulose: 870 g

[0543]

Composition example 2

The components below were mixed together in the usual manner, then the mixture was filtered through a dust filter, then the filtrate was packed into ampoules at a volume of 5 ml per ampoule, and the ampoules were thermally sterilized in an autoclave. In this way, 10,000 ampoules were obtained, each containing the active ingredient in an amount of 20 mg/ampoule.

3-[2-[(E,3R)-5-[3-(benzenesulfonamido)phenyl]-3-hydroxypent-4-enoxy]phenyl]propanoic acid: 200 g

Mannitol: 20 g

Distilled water: 50 l

INDUSTRIAL APPLICABILITY

[0544]

The compound of the present invention has strong neuroprotective and/or neurorestorative activity and can therefore be used for the prevention and/or treatment of diseases associated with neuropathies.

Claims (73)

1. The compound represented by the general formula (I) [Formula 1] Where: 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 [Formula 2] (where: ring 1 represents morpholine and n represents the integer 0); each of R ¹¹ , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ²⁰ independently represents (1) a C1-6 alkylene group, (2) a C2-6 alkenylene group, which may be substituted by 1-3 halogen atoms, wherein, when the alkylene group or alkenylene group is branched, two C1-2 alkyl groups branched from one carbon atom can together form a C3-5 saturated carbocyclic ring; R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁹ each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group; CycD is a triazole or tetrazole; R ² represents (1) a halogen atom, or (2) a C1-4 alkyl group, and p is an integer from 0 or 1; X represents (1) CH ₂ or (2) an oxygen atom; L ¹ represents (1) a linear C3-7 alkylene group, which may be substituted by 1-2 R ^L1a , or (4) (a linear C1-3 alkylene group)-O-(a linear C1-3 alkylene group); R ^L1a represents (1) a halogen atom, (2) a hydroxyl group, or (3) an oxo group, wherein: when at least two R ^L1a are present, the plurality of R ^L1a may be the same or different from each other; [Formula 3] represents a single bond, double bond or triple bond; R ³ represents (1) a hydrogen atom, (2) a halogen atom, or (4) a C1-2 alkyl group, and q represents an integer from 0 to 2, wherein: when [Formula 4] represents a single bond and q is 2, the set of R ³ may be the same or different from each other; and when at least one of R ³ is a methyl group, the methyl group can form cyclopropane in combination with a carbon atom in adjacent L ¹ ; CycA is (1) a C6 monocyclic carbocyclic ring or (2) a 5-10 membered monocyclic or bicyclic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom; R ⁴ represents (1) a halogen atom, (2) a hydroxyl group, (3) a C1-4 alkyl group, (4) a C1-4 haloalkyl group; (7) a cyano group or (8) a -SO ₂ -C1-2 alkyl group, and r is an integer from 0 to 3, wherein when r is 2 or more, the plurality of R ⁴ may be the same or different from each other; 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 -, or (7) -S(O) ₂ -; each of R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ and R ²⁰⁵ independently represents (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, wherein the alkyl group or haloalkyl group may be substituted by (1) a hydroxyl group, (3) a C3-6 monocyclic carbocyclic ring, or (4) a 3-6 membered monocyclic heterocyclic ring containing a heteroatom selected from oxygen; each of R ³¹ and R ³² independently represents (1) a bond or (2) a C1-3 alkylene group; CycB is (1) a C5-6 monocyclic ring or (2) a 5-10 membered monocyclic or bicyclic heterocyclic ring containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom; And R ⁵ represents (1) a halogen atom, (2) a C1-6 alkyl group, (5) a C1-6 haloalkyl group, or (8) a C1-6 alkoxy group, and t represents the integer 0 or 1, or a pharmaceutically acceptable salt thereof . 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, where in the general formula (I) the group is: [Formula 5] is (1) =CH-(linear C2-6 alkylene group which may be substituted by 1-2 R ^L1a )-, (2) -(linear C3-7 alkylene group which may be substituted by 1-2 R ^L1a ) -, or (3) -(linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-O-(linear C1-3 alkylene group, which may be substituted by 1-2 R ^L1a )-, (in (1)-(3) R ^L1a has the same meaning as stated in paragraph 1). 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ¹ is -R ¹¹ -COOR ¹² . 4. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-3, where L ² represents (1) -NR ²⁰² -S(O) ₂ - or (2) -CR ²⁰⁴ (OH)-CH ₂ -. 5. A compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-4, where CycA is a C6 monocyclic carbocyclic ring. 6. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-5, where CycB is a C5-6 monocyclic carbocyclic ring. 7. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-6, where the general formula (I) is the general formula (I-1) [Formula 6] where: R ^11-1 represents a C2-4 alkylene group; L ^1-1 represents a linear C3-4 alkylene group which may be substituted by 1-2 R ^L1a ; each of CycA ¹ is a C6 monocyclic carbocyclic ring; CycB ¹ is a C5-6 monocyclic carbocyclic ring; L ^2-1 is (1) -NH-S(O) ₂ - or (2) -CH(OH)-CH ₂ -; and other symbols have the same meaning as indicated in paragraph 1. 8. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-7, where X represents an oxygen atom. 9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound 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]-3,3-difluoropentoxy]phenyl]propanoic acid. 10. Pharmaceutical composition for the treatment and/or prevention of peripheral neuropathy and/or central neuropathy, containing an effective amount of a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof according to claim 1. 11. An agent for promoting Schwann cell differentiation, containing an effective amount of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1. 12. A prophylactic and/or therapeutic agent for peripheral neuropathy, containing an effective amount of a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof according to claim 1. 13. The agent according to claim 12, where the peripheral neuropathy is chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, periarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, compressive neuropathy, peripheral neuropathy associated with Charcot-Marie-Tooth disease, peripheral neuropathy , associated with an infectious disease, drug-induced peripheral neuropathy associated with the administration of an anticonvulsant, antimicrobial agent, chemotherapy drug or sedative, multifocal motor neuropathy or toxic peripheral neuropathy associated with ingestion of a heavy metal, organic solvent, toxic substance or alcohol. 14. The agent according to claim 13, wherein drug-induced peripheral neuropathy is peripheral neuropathy associated with the administration of a chemotherapy drug. 15. A prophylactic and/or therapeutic agent for central neuropathy, containing an effective amount of a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof according to claim 1. 16. The agent according to claim 15, where the central neuropathy is amyotrophic lateral sclerosis. 17. A method for the prevention and/or treatment of peripheral neuropathy and/or central neuropathy, comprising administering an effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 to a mammal. 18. Use of a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof according to claim 1, for the prevention and/or treatment of peripheral neuropathy and/or central neuropathy. 19. Use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a prophylactic and/or therapeutic agent for peripheral neuropathy and/or central neuropathy. 20. 3-[2-[(E)-5-[3-(benzenesulfonamido)phenyl]pent-4-enoxy]phenyl]propanoic acid or a pharmaceutically acceptable salt thereof: