Blood-brain barrier permeability regulator

Abstract

The purpose of the present invention is to provide a novel blood-brain barrier permeability regulator.　The present invention pertains to a blood-brain barrier permeability regulator containing a compound represented by formula (I) (Symbols in the formula (I) are as defined in the present specification.) or an isomer thereof, or a salt thereof. The present invention also pertains to a medicine for preventing and / or treating various brain diseases, severe infections, or sepsis by using the compound or an isomer thereof, or a salt thereof alone or in combination with a drug for preventing and / or treating a brain disease.

Description

Blood-brain barrier permeability regulator

[0001] The present invention relates to a compound or an isomer thereof, or a salt thereof for regulating blood-brain barrier permeability. The present invention also relates to a pharmaceutical composition for preventing and / or treating various brain diseases, which contains the compound or an isomer thereof, or a salt thereof as an active ingredient, either alone or in combination with a drug for preventing and / or treating the brain disease.

[0002] The blood-brain barrier (BBB) ​​is a mechanism that restricts the exchange of substances between the blood and the brain, playing an important role in protecting the brain from the invasion of foreign substances. However, the BBB also prevents the transfer of drugs from the blood to the brain, posing a major obstacle to the development of therapeutic drugs for brain diseases. The function of the BBB is achieved by the tight junctions formed between brain capillary endothelial cells, which differs significantly from the gaps between capillary endothelial cells in other organs, which allow the permeation of substances.

[0003] Claudin (CLDN) family molecules play an important role in the formation of tight junctions between epithelial cells and vascular endothelial cells. The CLDN family consists of 27 four-transmembrane proteins, each with two extracellular loops (the first and second extracellular loops from the N-terminus), and the interaction between these cells contributes to tight junction formation. The types (composition ratios) and amounts of CLDN family molecules expressed in each tissue vary, and these differences result in tissue-specific tight junctions and barrier function. In particular, CLDN5 is highly expressed in tight junctions between cerebrovascular endothelial cells, significantly affecting the function of the blood-brain barrier. In fact, it has been reported that CLDN5-deficient mice lose blood-brain barrier function and allow the permeation of substances with a molecular weight of 800 Da or less (Non-Patent Document 1). Furthermore, Non-Patent Document 2 describes that inhibition of CLDN5 function can be a useful drug delivery strategy for delivering small and medium-molecule drugs with a molecular weight of 800 Da or less into the brain, which accounts for 98% of all pharmaceuticals.

[0004] In addition, Non-Patent Document 3 reports that when traumatic brain injury occurs, inhibiting the expression of CLDN5 protein at the blood-brain barrier reversibly modifies the blood-brain barrier, reducing the amount of fluid accumulated in the brain, thereby reducing cerebral edema and improving brain function.

[0005] Based on the above findings, it has been reported that molecules that bind to CLDN5 and loosen adhesion between cerebrovascular endothelial cells (e.g., antibodies, peptides, small molecular weight compounds) or molecules that suppress CLDN5 expression can be used to loosen the blood-brain barrier and deliver drugs into the brain (Non-Patent Document 2). For example, the present inventors have reported that R9, an antibody that binds to the extracellular domain of CLDN5, specifically binds to CLDN5, a CLDN family molecule, and increases the permeability of cerebrovascular endothelial cells in an in vitro blood-brain barrier model (Non-Patent Document 4, Patent Document 1). The present inventors have also reported that administration of R9 loosens the blood-brain barrier of cynomolgus monkeys and strongly promotes the transfer of a low-molecular-weight tracer (sodium fluorescein (376 Da)) into the brain, but at the same time, induces side effects that are presumably due to the strong and sustained binding activity of R9 (Non-Patent Document 5).

[0006] Furthermore, Non-Patent Document 6 describes a peptide analog C5C2 derived from the sequence of the extracellular domain of CLDN5 as a CLDN5-binding molecule having a binding activity milder than that of an antibody, and describes that when C5C2 is administered to mice, the brain uptake of a small molecule tracer is promoted after 4 hours and the effect disappears after 12 hours. However, the use of such peptide analogs has the risk of opening the blood-brain barrier for several hours, and the high synthesis cost of peptide analogs has been a problem.

[0007] Furthermore, Non-Patent Document 7 reports that, through screening of low molecular weight compounds that suppress the expression of CLDN5, a compound represented by the following formula:

[0008]

[0009] It is described that M01, which is represented by the formula (I), has been identified and that it promotes the therapeutic effect on brain tumors, and that the mechanism of action of M01 is to bind to CLDN5 and suppress the expression of CLDN5 at the mRNA or protein level, which is different from the mechanism of action of CLDN5-binding antibodies and peptides, which bind directly to CLDN5 and control the blood-brain barrier by loosening the binding.

[0010] International Publication No. 2018 / 207638

[0011] Nitta T, et al. J Cell Biol 161, 653-660 (2003).Hashimoto Y, et al. Biol Pharm Bull 44, 1380-1390 (2021).Campbell M, et al. Nature Commun 3, 1-12 (2012).Hashimoto Y, et al. J Pharmacol Exp Ther 363, 275-283 (2017).Tachibana K, et al. J Control Release 336, 105-111 (2021).Dithmer S, et al. Ann NY Acad Sci. 1397, 169-184 (2017).Breitkreuz-Korff O, et al. J Control Release 338, 137-148 (2021).

[0012] Under these circumstances, the search for a compound that acts on CLDN5, can transiently and efficiently regulate the blood-brain barrier permeability of drugs, and has few side effects is an urgent issue. The present invention aims to provide a low-molecular-weight compound that binds to CLDN5 and directly loosens the adhesion between vascular endothelial cells for a short period of time without changing its expression, thereby transiently promoting the delivery of drugs into the brain and the movement of water from brain tissue fluid to circulating blood, or to provide a low-molecular-weight compound that binds to CLDN5 and directly strengthens the adhesion between vascular endothelial cells for a short period of time without changing its expression, thereby transiently suppressing the delivery of drugs or pathogens into the brain and the movement of water from brain tissue fluid to circulating blood, and also to provide a pharmaceutical composition for preventing and / or treating various brain diseases, psychiatric diseases, severe infections, sepsis, etc., by using the low-molecular-weight compound alone or in combination with a drug for preventing and / or treating brain diseases.

[0013] As a result of intensive research to solve the above problems, the present inventors have discovered a compound that binds to CLDN5 and transiently regulates adhesion between vascular endothelial cells, thereby suitable for regulating the intracerebral delivery of drugs for preventing and / or treating brain diseases and the movement of water from brain tissue fluid to circulating blood, and have completed the present invention. One embodiment of the present invention is, for example, as follows.

[0014] [1] Formula (I):

[0015]

[0016] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0017]

[0018] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0019]

[0020] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula:

[0021]

[0022] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0023]

[0024] (wherein each symbol has the same meaning as defined above.) or an isomer thereof (hereinafter also referred to as "compound (I) of the present invention" or "compound (I)"), or a blood-brain barrier permeability regulator containing a pharmaceutically acceptable salt thereof (hereinafter also referred to as "blood-brain barrier permeability regulator of the present invention"). [1'] Formula (I):

[0025]

[0026] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0027]

[0028] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0029]

[0030] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ represents a hydrocarbon ring group, provided that when X is a single bond, L is a group represented by the formula:

[0031]

[0032] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0033]

[0034] (wherein each symbol has the same meaning as defined above). ] or an isomer thereof, or a pharmaceutically acceptable salt thereof. [2] A is an optionally substituted 2-furyl group, and L is a divalent group represented by the formula:

[0035]

[0036] (wherein each symbol has the same meaning as defined above), and X is a single bond, an oxygen atom, or a divalent group represented by the formula:

[0037]

[0038] (wherein each symbol has the same meaning as defined above), and B is a divalent group represented by C ６－１８[2'] A is an optionally substituted 2-furyl group, and L is a group represented by the formula:

[0039]

[0040] (wherein each symbol has the same meaning as defined above), and X is a single bond, an oxygen atom, or a divalent group represented by the formula:

[0041]

[0042] (wherein each symbol has the same meaning as defined above), and B is an optionally substituted C ６－１８ [3] The blood-brain barrier permeability regulator according to the above [1'], wherein A is an optionally substituted 6-benzofuryl group, and L is a group represented by the formula:

[0043]

[0044] (wherein each symbol has the same meaning as defined above), X is a single bond, NH or an oxygen atom, and B is an optionally substituted phenyl group. [3'] A is an optionally substituted 6-benzofuryl group, and L is a group represented by the formula:

[0045]

[0046] (wherein each symbol has the same meaning as defined above), X is a single bond, NH or an oxygen atom, and B is an optionally substituted phenyl group. [4] The blood-brain barrier permeability regulator according to the above [1] or [1'], wherein A is an optionally substituted 7-quinolyl group, and L is a group represented by the formula:

[0047]

[0048] (wherein each symbol has the same meaning as defined above), X is a single bond, NH or an oxygen atom, and B is an optionally substituted phenyl group. [5] The blood-brain barrier permeability regulator according to the above [1] or [1'], wherein A is an optionally substituted 2-thienyl group, and L is a group represented by the formula:

[0049]

[0050] (wherein each symbol has the same meaning as defined above), X is NH, and B is an optionally substituted phenyl group. [6] The blood-brain barrier permeability regulator according to the above [1] or [1'], wherein X is a divalent group represented by the following formula:

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] [6'] A blood-brain barrier permeability regulator comprising any compound represented by the following formula:

[0057]

[0058]

[0059]

[0060] [6″] A blood-brain barrier permeability regulator comprising any compound represented by the following formula:

[0061]

[0062]

[0063]

[0064]

[0065]

[0066] [6'''] A blood-brain barrier permeability regulator comprising any compound represented by the following formula:

[0067]

[0068] or an isomer thereof, or a pharmaceutically acceptable salt thereof. [7] The blood-brain barrier permeability regulator according to any one of the above [1] to [6], [1'], [2'], [3'], and [6"], which is a blood-brain barrier permeation enhancer. [7'] The blood-brain barrier permeability regulator according to any one of the above [1] to [6], [1'], [2'], [3'], and [6'"], which is a blood-brain barrier permeation inhibitor. [8] The blood-brain barrier permeability regulator according to the above [7], which is administered in combination with a drug for preventing and / or treating a brain disease. [9] The blood-brain barrier permeability regulator according to the above [8], which is administered separately from a drug for preventing and / or treating a brain disease.

[10] The blood-brain barrier permeability regulator according to the above [8], which is administered simultaneously with or sequentially to a drug for preventing and / or treating a brain disease.

[11] The blood-brain barrier permeability regulator according to any one of [8] to

[10] above, wherein the brain disease is selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

[12] A pharmaceutical composition for treating cerebral edema, comprising the blood-brain barrier permeability regulator according to [7] above and a pharmaceutically acceptable carrier.

[13] A pharmaceutical composition for delivering a drug for preventing and / or treating a brain disease into the brain, comprising the blood-brain barrier permeability regulator according to [7] above and a drug for preventing and / or treating a brain disease. [13'] A pharmaceutical composition for preventing and / or treating a disease selected from the group consisting of psychiatric disorders, severe infections, sepsis, and cerebral edema, comprising the blood-brain barrier permeability regulator described in [7'] above.

[14] The pharmaceutical composition according to the above-mentioned

[13] , wherein the brain disease is selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

[15] A conjugate in which the blood-brain barrier permeability regulator according to the above-mentioned [7] is bound to a drug directly or via a linker.

[16] The conjugate according to the above-mentioned

[15] , wherein the drug is a drug for preventing and / or treating a brain disease selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

[17] A compound represented by the following formula:

[0069]

[0070]

[0071]

[0072]

[0073] [17'] A compound represented by the following formula:

[0074]

[0075]

[0076] [17″] A compound represented by the following formula:

[0077]

[0078]

[0079]

[0080]

[0081] [17'''] A compound represented by the following formula:

[0082]

[0083] or an isomer thereof, or a salt thereof.

[18] A pharmaceutical composition containing the compound described in

[17] or [17'] above, or an isomer thereof, or a salt thereof, and a pharmaceutically acceptable carrier. [18'] A pharmaceutical composition containing the compound described in [17''] above, or an isomer thereof, or a salt thereof, and a pharmaceutically acceptable carrier. [18''] A pharmaceutical composition containing the compound described in [17'''] above, or an isomer thereof, or a salt thereof, and a pharmaceutically acceptable carrier.

[19] The pharmaceutical composition described in

[18] above for treating cerebral edema.

[20] The pharmaceutical composition described in [18'] above for preventing and / or treating a brain disease, which is administered in combination with a drug for preventing and / or treating a brain disease.

[21] The pharmaceutical composition described in

[20] above, which is administered separately from a drug for preventing and / or treating a brain disease.

[22] The pharmaceutical composition described in

[20] above, which is administered simultaneously with or sequentially with a drug for preventing and / or treating a brain disease.

[23] The pharmaceutical composition according to the above [18'] for transporting a drug for preventing and / or treating a brain disease into the brain. [23'] The pharmaceutical composition according to the above [18''] for inhibiting the transport of a pathogenic substance into the brain.

[24] The pharmaceutical composition according to any of the above

[20] to

[23] , wherein the brain disease is selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome. [24'] The pharmaceutical composition according to the above [18''] for preventing and / or treating a disease selected from the group consisting of psychiatric disorders, severe infections, sepsis, and cerebral edema.

[25] A compound represented by formula (I):

[0084]

[0085] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0086]

[0087] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0088]

[0089] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula:

[0090]

[0091] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0092]

[0093] (wherein each symbol has the same meaning as defined above). ) or an isomer thereof, or a pharmaceutically acceptable salt thereof, is administered to the subject in a pharmaceutically effective amount. [25'] A method for treating cerebral edema in a subject, comprising administering to the subject a compound represented by formula (I):

[0094]

[0095] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0096]

[0097] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0098]

[0099] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ represents a hydrocarbon ring group, provided that when X is a single bond, L is a group represented by the formula:

[0100]

[0101] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0102]

[0103] (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof.

[26] A method for treating cerebral edema in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound represented by formula (I):

[0104]

[0105] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0106]

[0107] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0108]

[0109] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula:

[0110]

[0111] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0112]

[0113] (wherein each symbol has the same meaning as defined above.) A method for preventing and / or treating a brain disease, psychiatric disease, severe infection, or sepsis in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound represented by the formula (I): [26'] or an isomer thereof, or a pharmaceutically acceptable salt thereof, alone or together with a drug for preventing and / or treating the brain disease.

[0114]

[0115] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0116]

[0117] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0118]

[0119] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ represents a hydrocarbon ring group, provided that when X is a single bond, L is a group represented by the formula:

[0120]

[0121] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0122]

[0123] (wherein each symbol has the same meaning as defined above.) A method for preventing and / or treating a brain disease selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome, comprising administering to a subject a pharmaceutically effective amount of a compound represented by the formula:

[28] The method for preventing and / or treating a brain disease according to the above-mentioned

[26] or [26'], wherein the compound is administered to a subject simultaneously with or sequentially to a subject with a drug for preventing and / or treating the brain disease.

[29] The method for preventing and / or treating a brain disease according to any one of the above-mentioned

[26] to

[28] and [26'], wherein the drug for preventing and / or treating the brain disease is a prophylactic and / or therapeutic agent for a brain disease selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

[30] A compound of formula (I):

[0124]

[0125] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0126]

[0127] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0128]

[0129] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula:

[0130]

[0131] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0132]

[0133] (wherein each symbol has the same meaning as defined above). )] or an isomer thereof, or a pharmaceutically acceptable salt thereof, is administered to the subject in a pharmaceutically effective amount. [30'] A method for preventing and / or treating cerebral edema in a subject, comprising administering to the subject a compound represented by formula (I):

[0134]

[0135] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0136]

[0137] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0138]

[0139] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ represents a hydrocarbon ring group, provided that when X is a single bond, L is a group represented by the formula:

[0140]

[0141] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0142]

[0143] (wherein each symbol has the same meaning as defined above.) A method for preventing and / or treating cerebral edema in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound represented by formula (I):

[0144]

[0145] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0146]

[0147] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0148]

[0149] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula:

[0150]

[0151] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0152]

[0153] (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof. [31'] Use of a compound represented by formula (I):

[0154]

[0155] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0156]

[0157] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0158]

[0159] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ represents a hydrocarbon ring group, provided that when X is a single bond, L is a group represented by the formula:

[0160]

[0161] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0162]

[0163] (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof.

[32] Use of a compound represented by the following formula:

[0164]

[0165]

[0166]

[0167]

[0168]

[0169] [32'] Use of any compound represented by the following formula: or an isomer thereof, or a pharmaceutically acceptable salt thereof, for producing a blood-brain barrier permeation enhancer for transporting a drug for preventing and / or treating a brain disease into the brain.

[0170]

[0171]

[0172]

[33] The use according to the above

[31] or

[32] , wherein the brain disease is selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

[34] A compound of formula (I):

[0173]

[0174] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0175]

[0176] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0177]

[0178] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula:

[0179]

[0180] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0181]

[0182] (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof. [34'] A compound represented by formula (I):

[0183]

[0184] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0185]

[0186] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0187]

[0188] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ represents a hydrocarbon ring group, provided that when X is a single bond, L is a group represented by the formula:

[0189]

[0190] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0191]

[0192] (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof.

[35] A compound represented by the following formula:

[0193]

[0194]

[0195]

[0196]

[0197]

[0198] [35'] A compound represented by the following formula: or an isomer thereof, or a pharmaceutically acceptable salt thereof, for use in intracerebral delivery of a drug for preventing and / or treating a brain disease:

[0199]

[0200]

[0201]

[36] A compound represented by formula (I): or an isomer thereof, or a pharmaceutically acceptable salt thereof, for use as a drug for preventing and / or treating a brain disease and / or for regulating water permeability in brain tissue fluid at the blood-brain barrier.

[0202]

[0203] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula:

[0204]

[0205] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0206]

[0207] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula:

[0208]

[0209] (wherein each symbol has the same meaning as defined above), and L is -CH ２-, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0210]

[0211] (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof. [36'] A compound represented by formula (I): for use as a drug for preventing and / or treating a brain disease at the blood-brain barrier and / or for regulating water permeability in cerebral tissue fluid:

[0212]

[0213] [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group represented by the formula:

[0214]

[0215] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula:

[0216]

[0217] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ represents a hydrocarbon ring group, provided that when X is a single bond, L is a group represented by the formula:

[0218]

[0219] (wherein each symbol has the same meaning as defined above), and L is -CH ２-, X represents an oxygen atom, and when n is 1, L represents a group of the formula:

[0220]

[0221] (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof.

[37] A compound represented by the following formula:

[0222]

[0223]

[0224]

[0225]

[0226]

[0227] [37'] A compound represented by the following formula: or an isomer thereof, or a pharmaceutically acceptable salt thereof, for use as a drug for preventing and / or treating a brain disease and / or promoting water permeability in brain tissue fluid at the blood-brain barrier:

[0228]

[0229]

[0230]

[38] A method for screening a blood-brain barrier permeability regulator, comprising: (i) mixing a test compound with hCLDN5 proteoliposomes, adding an anti-hCLDN5 antibody and detection beads, and then irradiating with excitation light to detect and evaluate the proximity of the hCLDN5 proteoliposomes and the anti-hCLDN5 antibody by AlphaScreen; and (ii) mixing a test compound with hCLDN1 proteoliposomes, adding an anti-hCLDN1 antibody and detection beads, and then irradiating with excitation light to detect and evaluate the proximity of the hCLDN1 proteoliposomes and the anti-hCLDN1 antibody by AlphaScreen. (iii) A screening method comprising a step of selecting a compound that inhibits only the binding of hCLDN5 and anti-hCLDN5 antibody based on the evaluations (i) and (ii) above (hereinafter sometimes referred to as the "screening method of the present invention").

[0231] The compound (I) of the present invention, or a salt thereof, directly loosens or strengthens adhesion between vascular endothelial cells for a short period of time without reducing the expression of CLDN5, thereby transiently regulating the amount of water in cerebral tissue fluid, inhibiting the delivery of drugs to the brain for preventing and / or treating brain diseases, and preventing the entry of pathogenic substances into the brain. Furthermore, since compound (I) of the present invention or a salt thereof can be easily synthesized and provided at low cost, and has few side effects, a pharmaceutical comprising compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is useful for the prevention and / or treatment of brain diseases such as cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorders, REM sleep behavior disorder, traumatic brain injury, restless legs syndrome, and other psychiatric diseases, severe infectious diseases, sepsis, etc. Furthermore, the present invention can also provide a method for screening for a compound useful as a blood-brain barrier permeability regulator.

[0232] Figure 1 shows the test results for changes in the activity of inhibiting the binding of hCLDN5 to anti-hCLDN5 antibodies and changes in the activity of inhibiting the binding of hCLDN1 to anti-hCLDN1 antibodies with changes in the dose of compound (1). Figure 2 shows the results of the time-dependent changes in TEER when 0 to 100 μM of compound (1) was added to human dermal microvascular endothelial cells HDMEC and bEnd. 3. The horizontal axis shows the time after addition of compound (1), and the vertical axis shows the value obtained by dividing the TEER value measured at each time by the TEER value at the start of the test. Figure 3A-1 shows the results of the time-dependent changes in TEER when 50 μM of each test compound (compounds (2) to (33) and compounds (35) to (37)) was added to human dermal microvascular endothelial cells HDMEC. The horizontal axis indicates the time after the addition of the test compound, and the vertical axis indicates the value obtained by dividing the TEER value measured at each time by the TEER value at the start of the test. Here, the group to which only 0.25% DMSO solution was added served as the negative control, and the group to which compound (1) was added served as the positive control. Figure 3A-2 shows the results of the time-dependent change in TEER when 50 μM of each test compound (compounds (38) to (62)) was added to human dermal microvascular endothelial cells (HDMEC). The horizontal axis indicates the time after the addition of the test compound, and the vertical axis indicates the value obtained by dividing the TEER value measured at each time by the TEER value at the start of the test. Here, the group to which only 0.25% DMSO solution was added served as the negative control, and the group to which compound (1) was added served as the positive control. Figure 3B shows the results of the time-dependent change in TEER when 25 μM of each test compound was added to human dermal microvascular endothelial cells (HDMEC). The horizontal axis indicates the time after the addition of the test compound, and the vertical axis indicates the value obtained by dividing the TEER value measured at each time by the TEER value at the start of the test. Here, the group to which only 0.25% DMSO solution was added was the negative control group, and the group to which compound (1) was added was the positive control group. Figure 4 shows the permeability coefficient (Papp) of HDMEC 30 minutes after the addition of sodium fluorescein solution when compound (1) was added at each concentration (0 μM, 50 μM, and 100 μM). Figure 5 shows the localization of CLDN5 when HDMEC was treated with 50 μM compound (1). Figure 6 shows the protocol for the in vivo activity evaluation test of compound (I).Figure 7A shows stereomicroscopic photographs of brains excised from hCLDN5-KI mice one hour after administration of sodium fluorescein via the tail vein immediately after administration of compound (1), and a comparison of the amount of sodium fluorescein leakage one hour later in the presence or absence of compound (1). Figure 7B shows stereomicroscopic photographs of brains excised from hCLDN5-KI mice one hour after administration of sodium fluorescein via the tail vein, and a further hour after administration of compound (1), and a comparison of the amount of sodium fluorescein leakage one hour later in the presence or absence of compound (1). Figure 7C shows stereomicroscopic photographs of brains excised from hCLDN5-KI mice one hour after administration of FD-4 via the tail vein immediately after administration of compound (1), and a comparison of the amount of FD-4 leakage one hour later in the presence or absence of compound (1). Figure 7D shows stereomicroscopic photographs of brains excised from wild-type mice (C57BL / 6N) one hour after administration of compound (1) followed by tail vein administration of sodium fluorescein, and a comparison of the amount of sodium fluorescein leakage one hour after administration with and without compound (1). Figure 8 shows a comparison of the amount of sodium fluorescein leakage one hour after administration of test compounds (compounds (5), (16), and (19)) to wild-type mice one hour after administration of test compounds (compounds (5), (16), and (19)). Figure 9 shows fluorescent microscopic photographs of frozen sections of brains excised from wild-type mice after administration of DyLight (registered trademark) 594-labeled tomato lectin via the tail vein, followed by sequential administration of compound (1) and the middle molecular tracer Hoechst 33258 via the tail vein 5 minutes later. Figure 10 shows a comparison of the amount of sodium fluorescein leakage in each organ in the presence or absence of compound (1) in hCLDN5-KI mice one hour after administration of sodium fluorescein via the tail vein immediately after intravenous administration of compound (1). Figure 11A shows a comparison of the amount of methylscopolamine leakage in the brain in the presence or absence of compound (1) in wild-type (C57BL / 6) mice one hour after administration of methylscopolamine (MSco), which has low brain penetration, via the tail vein immediately after intravenous administration of compound (1).Figure 11B shows a comparison of vancomycin leakage into the brain 1 hour after intravenous administration of Compound (1) to wild-type (C57BL / 6) mice, in the presence or absence of Compound (1), after vancomycin, which has low brain penetration, was administered via the tail vein immediately after intravenous administration of Compound (1). Figure 12A shows an experimental protocol in which wild-type mice were subcutaneously administered methylscopolamine (MSco), and 30 minutes later, pilocarpine was administered intraperitoneally to induce epileptic seizures. Immediately after pilocarpine administration, methylscopolamine and Compound (1) were administered via the tail vein, and the survival time and seizure severity of the mice were evaluated. Figure 12B shows wild-type mice subcutaneously administered methylscopolamine (MSco), followed 30 minutes later by intraperitoneal administration of pilocarpine to induce epileptic seizures. Immediately after pilocarpine administration, the survival times of the mice were analyzed for each of the following groups: a control group, a group administered with compound (1) alone, a group administered with methylscopolamine alone, and a group administered with methylscopolamine and compound (1). Figure 12C shows the definition of the Racine Scale (modified). Figure 12D shows a comparison of the Racine Scale scores for the control group, a group administered with compound (1) alone, a group administered with methylscopolamine (MSco) alone, and a group administered with methylscopolamine and compound (1). FIG. 12E shows a comparison of the mean Racine scale scores (90 minutes) in each of the control group, the group administered with compound (1) alone, the group administered with methylscopolamine (MSco) alone, and the group administered with methylscopolamine and compound (1).

[0233] The definitions of the terms and symbols used in this specification are explained below. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs.

[0234] In this specification, a numerical range represented by "to" or "-" means a numerical range with the numbers before and after "to" or "-" as the lower or upper limit. In this specification, when a numerical range with the element symbol "C" and the numbers before and after "-" is attached to the name of an arbitrary group, it indicates an arbitrary group having an integer number of carbon atoms with the numbers before and after "-" as the lower or upper limit. For example, an alkyl group having 1 to 6 carbon atoms is represented by "C １－６The alkyl group is sometimes referred to as an alkyl group. ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ The same applies to other groups.

[0235] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0236] In this specification, "C １－６ The term "alkyl group" means a straight or branched chain alkyl group having 1 to 6 carbon atoms. １－６ Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl.

[0237] In this specification, "C １－４ Examples of the "alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

[0238] In this specification, "C １－６ The term "haloalkyl group" refers to the group defined above as "C １－６ It means a group in which one or more hydrogen atoms in an "alkyl group" are substituted with halogen. １－６Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0239] In this specification, "C １－４ Examples of the "haloalkyl group" include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and the like.

[0240] In this specification, "C １－６ The term "haloalkyl-carbonyl group" refers to the same group as defined above. １－６ "Haloalkyl group" means a group bonded to a carbonyl group. １－６ Examples of haloalkyl-carbonyl groups include fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, 2-chloroethylcarbonyl, 2-bromoethylcarbonyl, 2-iodoethylcarbonyl, 2-fluoroethylcarbonyl, 2,2-difluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, pentafluoroethylcarbonyl, 2,2,3,3-tetrafluoropropylcarbonyl, 3,3,3-trifluoropropylcarbonyl, 4,4,4-trifluorobutylcarbonyl, 5,5,5-trifluoropentylcarbonyl, and 6,6,6-trifluorohexylcarbonyl. １－４ A haloalkyl-carbonyl group is preferred.

[0241] In this specification, "C １－６ The "alkoxy group" is the same as the "C １－６"Alkyl group" means a group bonded to an oxygen atom. １－６ Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, and n-hexyloxy.

[0242] In this specification, "C １－４ Examples of the "alkoxy group" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy.

[0243] In this specification, "C １－６ The "alkoxy-carbonyl group" is the same as the "C １－６ "Alkoxy group" means a group bonded to a carbonyl group. １－６ Examples of the alkoxy-carbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, and n-hexyloxycarbonyl. １－４ Alkoxy-carbonyl groups are preferred.

[0244] In this specification, "C １－６ The term "alkylsulfanyl group" refers to the group defined above as "C １－６ "Alkyl group" means a group bonded to a sulfur atom. １－６ Examples of alkylsulfanyl groups include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl, 2-methylbutylsulfanyl, and n-hexylsulfanyl.

[0245] In this specification, "C １－６ The term "alkylsulfonyl group" refers to the same group as defined above in "C １－６ The alkyl group is a sulfonyl (-S(=O) ２-) group bonded to the sulfur atom of the C １－６ Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, and n-pentylsulfonyl.

[0246] In this specification, "C １－６ The term "alkylsulfonyloxy group" refers to the same group as defined above in "C １－６ "Alkylsulfonyl group" means a group bonded to an oxygen atom. １－６ Examples of alkylsulfonyloxy groups include methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, and n-pentylsulfonyloxy.

[0247] In this specification, "C １－６ The term "alkyl-carbonyl group" refers to the same as the above "C １－６ "Alkyl group" means a group bonded to a carbonyl group. １－６ Examples of the alkyl-carbonyl group include acetyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl. １－４ An alkyl-carbonyl group is preferred.

[0248] In this specification, "C １－６ The term "alkyl-carbonyloxy group" refers to the same group as defined above. １－６ "Alkyl-carbonyl group" means a group bonded to an oxygen atom. １－６ Examples of the alkyl-carbonyloxy group include acetyloxy, ethylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, pentylcarbonyloxy, and hexylcarbonyloxy.

[0249] In this specification, "C １－６ The "haloalkoxy group" is defined as the same as the "C １－６"Alkoxy group" means a group in which one or more hydrogen atoms are substituted with halogen. １－６ Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, and 6,6,6-trifluorohexyloxy.

[0250] In this specification, "C １－４ Examples of the "haloalkoxy group" include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, and 4,4,4-trifluorobutoxy.

[0251] In this specification, "C １－６ The term "haloalkoxy-carbonyl group" refers to the same group as defined above in "C １－６ "Haloalkoxy group" means a group bonded to a carbonyl group. １－６ Examples of haloalkoxy-carbonyl groups include fluoromethoxycarbonyl, difluoromethoxycarbonyl, trifluoromethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, 2-fluoroethoxycarbonyl, 2,2-difluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, pentafluoroethoxycarbonyl, 2,2,3,3-tetrafluoropropoxycarbonyl, 3,3,3-trifluoropropoxycarbonyl, 4,4,4-trifluorobutoxycarbonyl, 5,5,5-trifluoropentyloxycarbonyl, and 6,6,6-trifluorohexyloxycarbonyl.

[0252] In this specification, "C ３－１２ The term "cycloalkyl group" means a 3- to 12-membered monocyclic, polycyclic, or bridged monovalent saturated hydrocarbon ring group. ３－１２ Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and 2-norbornyl.

[0253] In this specification, "C ３－８ "Cycloalkyl group" means a 3- to 8-membered monocyclic monovalent saturated hydrocarbon ring group. ３－８ Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. ３－６ Cycloalkyl groups are preferred.

[0254] In this specification, "C ３－８ The "cycloalkyloxy group" is the same as the "C ３－８ "Cycloalkyl" means a group in which a "cycloalkyl group" is bonded to an oxygen atom. ３－８ Cycloalkyloxy groups include, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0255] In this specification, "C ２－６ The "alkynyl group" is a C ２－６ C means a linear or branched monovalent group having 2 to 6 carbon atoms formed by removing one hydrogen atom from any carbon atom of an alkyne. ２－６ Alkynyl groups include, for example, ethynyl, propargyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, and the like.

[0256] In this specification, "C ２－４ The "alkynyl group" includes, for example, ethynyl, propargyl, 3-butynyl, 2-butynyl, etc.

[0257] In the present specification, the term "aryl group" refers to a monocyclic or polycyclic (fused) monovalent hydrocarbon group exhibiting aromaticity. Examples of the aryl group include C aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, terphenylyl, phenanthryl, 2-anthryl, fluorenyl, and 1-pyrenyl. ６－１８ Among them, C ６－１６ An aryl group is preferred, and C ６－１０ An aryl group is more preferred, and a phenyl group is even more preferred.

[0258] In this specification, "C ６－１０ The term "aryloxy group" refers to the group defined above as "C ６－１０ "Aryl group" means a group bonded to an oxygen atom. ６－１８ Examples of the aryloxy group include phenyloxy, 1-naphthyloxy, and 2-naphthyloxy.

[0259] In this specification, "C ６－１０ The term "arylsulfanyl group" refers to the same group as defined above in "C ６－１０ "Aryl group" means a group bonded to a sulfur atom. ６－１０ Examples of arylsulfanyl groups include phenylsulfanyl, 1-naphthylsulfanyl, and 2-naphthylsulfanyl.

[0260] In this specification, "C ６－１０ The term "arylsulfonyl group" refers to the same group as defined above in "C ６－１０ The "aryl group" is a sulfonyl (-S(=O) ２ -) group bonded to the sulfur atom of the C ６－１０ Examples of the arylsulfonyl group include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0261] In this specification, "C ６－１０ The "arylsulfonyloxy group" is the same as the "C ６－１０ "Arylsulfonyl group" means a group bonded to an oxygen atom. ６－１０ Examples of the arylsulfonyloxy group include phenylsulfonyloxy, 1-naphthylsulfonyloxy, and 2-naphthylsulfonyloxy.

[0262] In this specification, "C ６－１０ The term "aryl-carbonyl group" refers to the same as the above "C ６－１０ "Aryl group" means a group bonded to a carbonyl group. ６－１０ Aryl-carbonyl groups include, for example, phenylcarbonyl (benzoyl), 1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like.

[0263] In this specification, "C ６－１０ The term "aryl-carbonyloxy group" refers to the same as the above "C ６－１０ "Aryl-carbonyl group" means a group bonded to an oxygen atom. ６－１０ Examples of the aryl-carbonyloxy group include phenylcarbonyloxy (benzoyloxy), 1-naphthylcarbonyloxy, and 2-naphthylcarbonyloxy.

[0264] In this specification, "C ７－１６ The "aralkyl group" refers to the C ６－１０ The aryl group is １－６ It means a group bonded to an alkyl group. ７－１６ Examples of the aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl, etc. Among these, the benzyl group is particularly preferred.

[0265] In this specification, "C ７－１６ The "aralkyloxy group" refers to the group ７－１６ An aralkyl group is a group bonded to an oxygen atom. ７－１６ Examples of the aralkyloxy group include benzyloxy, phenethyloxy, naphthylmethyloxy, biphenylylmethyloxy, etc. Among these, the benzyloxy group is particularly preferred.

[0266] In this specification, "C ７－１６ The "aralkyloxy-carbonyl group" refers to the C ７－１６ It means an aralkyloxy group bonded to a carbonyl group. ７－１６Examples of the aralkyloxy-carbonyl group include benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl, biphenylylmethyloxycarbonyl, etc. Among these, the benzyloxycarbonyl group is particularly preferred.

[0267] As used herein, the term "carbocyclyl group" refers to a monovalent, monocyclic, bicyclic, or tricyclic non-aromatic hydrocarbon ring group, and includes those having a partially unsaturated bond, a partially bridged structure, a partially spiro-bonded structure, and one, two, or more carbonyl structures. The term "carbocyclyl group" encompasses cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups. The term "carbocyclyl group" is preferably a "C ３－１８ carbocyclyl," and more preferably "C ３－６ "C carbocyclyl". ３－１８ Examples of "carbocyclyl groups" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, adamantyl, norbornyl, and the like.

[0268] In this specification, the term "hydrocarbon ring group" refers to all cyclic hydrocarbon groups consisting of aromatic hydrocarbon ring groups (the aforementioned "aryl group") and non-aromatic hydrocarbon groups (the aforementioned "carbocyclyl group").

[0269] As used herein, the term "heteroaryl group" refers to a monovalent, monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms.

[0270] As used herein, the term "5- or 6-membered heteroaryl group" refers to a monocyclic monovalent aromatic heterocyclic group consisting of 5 or 6 atoms, containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. Specific examples of the "5- or 6-membered heteroaryl group" include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl.

[0271] In the present specification, the term "5- to 10-membered heteroaryl group" refers to a monovalent monocyclic or bicyclic aromatic heterocyclic group consisting of 5 to 10 atoms, containing 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms. Specific examples of the "5- to 10-membered heteroaryl group" include, in addition to the specific examples of the "5- or 6-membered heteroaryl group", benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrid ... These include, but are not limited to, pyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

[0272] In the present specification, the term "nitrogen-containing heteroaryl group" refers to the above-mentioned heteroaryl group having at least one nitrogen atom as a ring-constituting atom.

[0273] As used herein, the term "heterocyclyl group" refers to a monovalent, monocyclic or bicyclic non-aromatic heterocyclic group composed of three or more atoms, including one, two, or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and includes saturated heterocyclyls, those having a partially unsaturated bond, those having a partially bridged structure, and those having a partially spiro-substituted heterocyclyl. The "heterocyclyl group" may form a condensed ring with an aryl or heteroaryl. For example, C ６－１０ A heterocyclyl group also includes a group fused with an aryl or a 5- or 6-membered heteroaryl. The heterocyclyl may contain one, two, or more carbonyls, thiocarbonyls, sulfinyls, or sulfonyls, and cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the heterocyclyl group. Here, the oxygen atom of a carbonyl, sulfinyl, or sulfonyl, and the sulfur atom of a thiocarbonyl are not included in the number of ring members (ring size) or the number of heteroatoms constituting the ring.

[0274] In the present specification, the term "3- to 14-membered heterocyclyl group" refers to a 3- to 14-membered monovalent group among the above-mentioned "heterocyclyl groups".

[0275] Preferable examples of the "heterocyclyl group" include aziridinyl, diazirinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuryl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, and tetrahydroisoxazolyl. 3- to 10-membered monocyclic heterocyclyl groups (preferably 3- to 6-membered monocyclic heterocyclyl groups) such as zolyl, piperidyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl;Tetrahydrotriazolopyridyl, tetrahydrotriazolopyrazinyl, tetrahydropyrazolopyrazinyl, dihydropyrazolopyrrolyl, dihydropyrazolopyrazinyl, tetrahydropyrazolopyridyl, tetrahydroimidazolopyridyl, dihydroimidazolopyridyl, dihydroimidazolopyrrolyl, tetrahydroimidazolopyrazinyl, dihydropyrimidopyrrolyl, dihydropyridopyrrolyl, tetrahydropyridopyridyl, tetrahydrooxazolopyrazinyl, tetrahydropyridopyridyl, tetrahydrotriazolodiazepinyl, octahydro-1,4-oxazinopyrazinyl, dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, dihydroisoquinolyl 8- to 14-membered fused heterocyclyl groups (fused polycyclic (preferably bicyclic) heterocyclyl groups) such as tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridyl, dihydrothiazolo[4,5-c]pyridyl, dihydrothiazolo[5,4-c]pyridyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, dihydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl;

[0276] In the present specification, the term "nitrogen-containing heterocyclyl group" refers to the above-mentioned heterocyclyl groups having at least one nitrogen atom as a ring-constituting atom. Among these, 3- to 6-membered nitrogen-containing heterocyclyl groups (e.g., diazirinyl) are preferred.

[0277] As used herein, the term "an amino group optionally substituted with a protecting group" refers to an amino group in which one or two hydrogen atoms of the amino group may be substituted with a "protecting group." The "protecting group" is not particularly limited, and examples of the amino protecting groups that can be used include those described in "Protective Groups in Organic Synthesis" by P.G. Wuts, 5th Edition, Wiley, 2014. Specific examples of the amino protecting group include protecting groups such as methyl, ethyl, benzyl, acetyl, trifluoroacetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, and benzyloxycarbonyl, as well as 3-(5-methylfuran-2-yl)acryloyl.

[0278] In this specification, "C １－６ Alkyl groups, and C ６－１０ The term "silyl group substituted with three substituents selected from the group consisting of aryl groups" refers to a silyl group substituted with three of the same or different "C １－６ alkyl group" or the "C ６－１０ C means a silyl group substituted with an "aryl group." １－６ Alkyl groups, and C ６－１０ Examples of the silyl group substituted with three substituents selected from the group consisting of aryl groups include trialkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, and tert-butyldimethylsilyl group (preferably, triC １－６ alkylsilyl group), tert-butyldiphenylsilyl group, triphenylsilyl group, etc.

[0279] In this specification, "C １－６ Alkyl groups, and C ６－１０ The term "silyloxy group substituted with three substituents selected from the group consisting of aryl groups" refers to the above-mentioned "C １－６ Alkyl groups, and C ６－１０The term "silyl group substituted by three substituents selected from the group consisting of aryl groups" means a group bonded to an oxygen atom, and specifically includes, for example, a trialkylsilyloxy group such as a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, or a tert-butyldimethylsilyloxy group (preferably, a triC １－６ alkylsilyloxy group), tert-butyldiphenylsilyloxy group, triphenylsilyloxy group, etc.

[0280] In this specification, the term "a pharmaceutically acceptable salt thereof" means a salt that can be used as a medicine. When Compound (I) of the present invention has an acidic group (e.g., a carboxy group) or a basic group (e.g., an amino group, a nitrogen-containing heteroaryl group, a nitrogen-containing heterocyclyl group, etc.), it can be converted into a basic salt or an acid salt by treating it with a base or an acid. The salt is preferably water-soluble.

[0281] Examples of the pharmaceutically acceptable "basic salt" of compound (I) of the present invention include alkali metal salts such as sodium salt, potassium salt, lithium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; ammonium salts such as ammonium salt, tetramethylammonium salt, etc.; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt, etc.; basic amino acid salts such as lysine salt, arginine salt, etc., and preferably alkali metal salts (particularly sodium salt or potassium salt) and basic amino acid salts.

[0282] Examples of the pharmaceutically acceptable "acid salt" of compound (I) of the present invention include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonates such as benzenesulfonate, p-toluenesulfonate, etc.; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; and the like, and preferably hydrohalides (particularly hydrochloride).

[0283] In the present specification, "salts thereof" refers to all salts including the above-mentioned "pharmaceutically acceptable salts thereof".

[0284] In this specification, "optionally substituted" in groups A and B in formula (I) means unsubstituted or substituted with one or more substituents. The number of substituents is not particularly limited as long as it is a substitutable number, but is usually 1 to 5, and preferably 1 to 3. When multiple substituents are present, the respective substituents may be the same or different. The substituents are not particularly limited, but examples thereof include groups selected from the following substituent group (a), substituent group (a'), substituent group (b), substituent group (b'), substituent group (c), and substituent group (c').

[0285] In this specification, the phrase "optionally substituted with a substituent (1 to 3 substituents, or 1 or 2 substituents) selected from substituent group (a) (or substituent group (a'), substituent group (b), substituent group (b'), substituent group (c), or substituent group (c'))" means that (1 to 3, or 1 or 2) hydrogen atoms of the group may each independently be substituted with (1 to 3, or 1 or 2) substituents selected from substituent group (a) below (or substituent group (a'), substituent group (b), substituent group (b'), substituent group (c), or substituent group (c')). As the substituent group, substituent group (a'), substituent group (b), substituent group (b'), substituent group (c), or substituent group (c') may be employed instead of substituent group (a).

[0286] (Substituent group (a)) Halogen atom; cyano group; nitro group; azido group; hydroxy group; carboxy group; formyl group; oxo group; amino group optionally substituted with a protecting group; (i) azido group, (ii) cyano group, (iii) nitro group, (iv) hydroxy group, (v) C １－６ an alkoxy group, (vi) C １－６ (vii) an amino group optionally substituted with a protecting group; (viii) a carboxy group; (ix) C ６－１０ (x) an aryl group, and (x) a 3- to 14-membered heterocyclyl group, optionally substituted by 1 to 3 substituents selected from the group consisting of １－６ alkyl group; １－６ haloalkyl group; (i) C １－６ an alkyl group, and (ii) C ６－１０ an aryl group; and a silyl group substituted with three substituents selected from the group consisting of C. ２－６ Alkynyl group; C １－６ Alkoxy group; C ３－８ a cycloalkyloxy group; １－６ alkylsulfanyl group; １－６ Alkylsulfonyl group; C １－６ haloalkylsulfonyl group; C ７－１６ Aralkyloxy group; C １－４ an alkylenedioxy group; １－６ haloalkoxy group; C １－６ Alkyl-carbonyl group; C １－６ Alkyl-carbonyloxy group; C １－６ an alkylsulfonyloxy group; １－６ haloalkylsulfonyloxy group; C １－６ Alkoxy-carbonyl group; C ７－１６ Aralkyloxy-carbonyl group; C １－６ haloalkyl-carbonyl group; C １－６Haloalkoxy-carbonyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ Aryl-carbonyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ (i) an aryl-carbonyloxy group; １－６ (ii) (a) a halogen atom; (b) a cyano group; (c) a nitro group; (d) an azido group; (e) C １－６ (f) an alkyl group; １－６ (g) a haloalkyl group; １－６ an alkoxy group, and (h) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ a carbamoyl group optionally substituted by 1 or 2 substituents selected from the group consisting of an aryl group; １－６ (ii) (a) a halogen atom; (b) a cyano group; (c) a nitro group; (d) an azido group; (e) C １－６ (f) an alkyl group; １－６ (g) a haloalkyl group; １－６ an alkoxy group, and (h) C １－６a sulfamoyl group optionally substituted by 1 or 2 substituents selected from the group consisting of a haloalkoxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted by a protecting group, and (vii) a C optionally substituted by an azido group. １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１６ Aryl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group which may be substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ Aryloxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ Arylsulfanyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C１－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１６ Arylsulfonyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１６ Arylsulfonyloxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ３－１８ Carbocyclyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ a 5- to 10-membered heteroaryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; and (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted by a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６an alkoxy group, and (x) C １－６ (i) a 3- to 14-membered heterocyclyl group optionally substituted by 1 to 3 substituents selected from the group consisting of haloalkoxy groups; １－６ an alkyl group, and (ii) C ６－１０ a silyl group substituted with three substituents selected from the group consisting of an aryl group; and (i) C １－６ an alkyl group, and (ii) C ６－１０ a silyloxy group substituted with three substituents selected from the group consisting of: an aryl group;

[0287] (Substituent group (a')) Halogen atom; cyano group; nitro group; azido group; hydroxy group; carboxy group; formyl group; oxo group; amino group optionally substituted with a protecting group; (i) azido group, (ii) cyano group, (iii) nitro group, (iv) hydroxy group, (v) C １－６ an alkoxy group, (vi) C １－６ (vii) an amino group optionally substituted with a protecting group; (viii) a carboxy group; (ix) C ６－１０ (x) an aryl group, and (x) a 3- to 14-membered heterocyclyl group, optionally substituted by 1 to 3 substituents selected from the group consisting of １－６ alkyl group; １－６ haloalkyl group; (i) C １－６ an alkyl group, and (ii) C ６－１０ an aryl group; and a silyl group substituted with three substituents selected from the group consisting of C. ２－６ Alkynyl group; C １－６ Alkoxy group; C ３－８ a cycloalkyloxy group; １－６ alkylsulfanyl group; １－６ Alkylsulfonyl group; C １－６ haloalkylsulfonyl group; C ７－１６ Aralkyloxy group; C １－４ an alkylenedioxy group; １－６ haloalkoxy group; C １－６ Alkyl-carbonyl group; C １－６Alkyl-carbonyloxy group; C １－６ an alkylsulfonyloxy group; １－６ haloalkylsulfonyloxy group; C １－６ Alkoxy-carbonyl group; C ７－１６ Aralkyloxy-carbonyl group; C １－６ haloalkyl-carbonyl group; C １－６ Haloalkoxy-carbonyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ Aryl-carbonyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ (i) an aryl-carbonyloxy group; １－６ (ii) (a) a halogen atom; (b) a cyano group; (c) a nitro group; (d) an azido group; (e) C １－６ (f) an alkyl group; １－６ (g) a haloalkyl group; １－６ an alkoxy group, and (h) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ a carbamoyl group optionally substituted by 1 or 2 substituents selected from the group consisting of an aryl group; １－６(ii) (a) a halogen atom; (b) a cyano group; (c) a nitro group; (d) an azido group; (e) C １－６ (f) an alkyl group; １－６ (g) a haloalkyl group; １－６ an alkoxy group, and (h) C １－６ a sulfamoyl group optionally substituted by 1 or 2 substituents selected from the group consisting of a haloalkoxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted by a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１６ Aryl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group which may be substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０ Aryloxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１０Arylsulfanyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１６ Arylsulfonyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ６－１６ Arylsulfonyloxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ３－１８ Carbocyclyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted with a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６a 5- to 10-membered heteroaryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; and (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) an amino group optionally substituted by a protecting group, (vii) C １－６ (viii) an alkyl group; １－６ (ix) a haloalkyl group; １－６ an alkoxy group, and (x) C １－６ (i) a 3- to 14-membered heterocyclyl group optionally substituted by 1 to 3 substituents selected from the group consisting of haloalkoxy groups; １－６ an alkyl group, and (ii) C ６－１０ a silyl group substituted with three substituents selected from the group consisting of an aryl group; and (i) C １－６ an alkyl group, and (ii) C ６－１０ a silyloxy group substituted with three substituents selected from the group consisting of: an aryl group;

[0288] (Substituent group (b)) Halogen atom; cyano group; nitro group; azide group; hydroxy group; (i) azide group, (ii) cyano group, (iii) nitro group, (iv) hydroxy group, (v) C １－４ an alkoxy group, (vi) C １－４ (vii) a phenyl group; and (viii) a 3- to 6-membered heterocyclyl group, optionally substituted by 1 to 3 substituents selected from the group consisting of: １－４ alkyl group; １－４ haloalkyl group; (i) C １－４ (ii) a silyl group substituted by three substituents selected from the group consisting of an alkyl group, and a phenyl group; ２－４ Alkynyl group; C １－４ Alkoxy group; methylenedioxy group; C １－４ haloalkoxy group; C １－４ Alkyl-carbonyl group; C １－４ Alkoxy-carbonyl group; C １－４ haloalkyl-carbonyl group; C１－４ haloalkoxy-carbonyl group; (i) C １－４ (ii) (a) a halogen atom; (b) a cyano group; (c) a nitro group; (d) an azido group; (e) C １－４ (f) an alkyl group; １－４ (g) a haloalkyl group; １－４ an alkoxy group, and (h) C １－４ a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; a carbamoyl group optionally substituted by 1 or 2 substituents selected from the group consisting of (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) a C group optionally substituted by an azido group １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ３－８ Cycloalkyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azide group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４a 5- to 10-membered heteroaryl group optionally substituted by 1 to 3 substituents selected from the group consisting of: a haloalkoxy group; and (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ a 3- to 6-membered nitrogen-containing heterocyclyl group optionally substituted by 1 to 3 substituents selected from the group consisting of haloalkoxy groups;

[0289] (Substituent group (b')) Halogen atom; cyano group; nitro group; azide group; hydroxy group; (i) azide group, (ii) cyano group, (iii) nitro group, (iv) hydroxy group, (v) C １－４ an alkoxy group, (vi) C １－４ (vii) a phenyl group; and (viii) a 3- to 6-membered heterocyclyl group, optionally substituted by 1 to 3 substituents selected from the group consisting of: １－４ alkyl group; １－４ haloalkyl group; (i) C １－４ (ii) a silyl group substituted by three substituents selected from the group consisting of an alkyl group, and a phenyl group; ２－４ Alkynyl group; C １－４ Alkoxy group; methylenedioxy group; C １－４ haloalkoxy group; C １－４ Alkyl-carbonyl group; C １－４ Alkoxy-carbonyl group; C １－４ haloalkyl-carbonyl group; C １－４ haloalkoxy-carbonyl group; (i) C １－４ (ii) (a) a halogen atom; (b) a cyano group; (c) a nitro group; (d) an azido group; (e) C １－４ (f) an alkyl group; １－４ (g) a haloalkyl group; １－４ an alkoxy group, and (h) C１－４ a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; a carbamoyl group optionally substituted by 1 or 2 substituents selected from the group consisting of (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ C optionally substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy groups ３－８ Cycloalkyl group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azide group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ a 5- to 10-membered heteroaryl group optionally substituted by 1 to 3 substituents selected from the group consisting of: a haloalkoxy group; and (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ a 3- to 6-membered nitrogen-containing heterocyclyl group optionally substituted by 1 to 3 substituents selected from the group consisting of haloalkoxy groups;

[0290] (Substituent group (c)) Halogen atom; Azido group; C optionally substituted with an azido group １－４ alkyl group; １－４ haloalkyl group; (i) C １－４ (ii) a silyl group substituted by three substituents selected from the group consisting of an alkyl group, and a phenyl group; ２－４ Alkynyl group; C １－４ Alkoxy group; methylenedioxy group; C １－４ Haloalkoxy group: (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) a C optionally substituted with an azido group １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ (i) a 5- or 6-membered heteroaryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; and １－４ an alkyl group, and (ii) C １－４ a 3- to 6-membered nitrogen-containing heterocyclyl group optionally substituted with a substituent selected from the group consisting of haloalkyl groups;

[0291] (Substituent group (c')) A halogen atom; An azide group; A C optionally substituted with an azide group １－４ alkyl group; １－４ haloalkyl group; (i) C １－４ (ii) a silyl group substituted by three substituents selected from the group consisting of an alkyl group, and a phenyl group; ２－４Alkynyl group; C １－４ Alkoxy group; methylenedioxy group; C １－４ Haloalkoxy group: (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azide group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; (i) a halogen atom, (ii) a cyano group, (iii) a nitro group, (iv) an azido group, (v) a hydroxy group, (vi) C １－４ (vii) an alkyl group; １－４ (viii) a haloalkyl group; １－４ an alkoxy group, and (ix) C １－４ (i) a 5- or 6-membered heteroaryl group optionally substituted by 1 to 3 substituents selected from the group consisting of a haloalkoxy group; and １－４ an alkyl group, and (ii) C １－４ a 3- to 6-membered nitrogen-containing heterocyclyl group optionally substituted with a substituent selected from the group consisting of haloalkyl groups;

[0292] Depending on the type and combination of substituents, compound (I) of the present invention may exist as geometric isomers such as cis isomer (Z isomer) or trans isomer (E isomer), tautomers, or, if an asymmetric carbon atom is present in the molecule, as multiple stereoisomers (i.e., diastereomers, enantiomers) based on the asymmetric carbon atom. The present invention encompasses any one of these isomers and a mixture containing multiple isomers in any ratio. Specifically, for example, compound (I) of the present invention is represented by the following formula:

[0293]

[0294] (wherein each symbol has the same meaning as defined above) or a mixture of both isomers in any ratio can be used. Compound (I) of the present invention is preferably the E-isomer.

[0295] As used herein, "prevention" includes preventing the onset of a disease, delaying the onset of a disease, and preventing the occurrence of a pathological condition. A "prophylactically effective amount" refers to a dose of an active ingredient sufficient to achieve the purpose of prevention.

[0296] As used herein, "treatment" includes curing a disease, improving the pathology of a disease (e.g., one or more symptoms), and inhibiting the progression of a disease (or its severity). A "therapeutically effective amount" refers to a dose of an active ingredient sufficient to achieve the therapeutic purpose. Therefore, "improvement" is a concept encompassed by "treatment."

[0297] As used herein, the term "pharmaceutically effective amount" encompasses the concepts of "prophylactically effective amount" and "therapeutically effective amount." In the present invention, the term "pharmaceutically effective amount" may also refer to an amount sufficient to regulate blood-brain barrier permeability (e.g., promote blood-brain barrier permeability) of a drug or the like for preventing and / or treating a brain disease.

[0298] As used herein, the term "subject" refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient is administered to prevent and / or treat (or improve) a disease or the pathology of a disease. The "subject" may be a human or a non-human animal, particularly a mammal (e.g., a human, a mouse, a rat, a guinea pig, a hamster, a rabbit, a cat, a dog, a cow, a sheep, a monkey, etc.).

[0299] As used herein, the term "blood-brain barrier permeability regulator" refers to a drug for regulating (promoting or inhibiting) the passage of a drug in circulating blood (e.g., a drug for preventing and / or treating a brain disease) between brain capillary endothelial cells, reaching brain intercellular fluid, and then migrating into the brain, and / or a drug for regulating (promoting or inhibiting) the migration of water, etc. from brain tissue fluid into circulating blood. In the present invention, the blood-brain barrier permeability of a drug or the like is regulated by allowing compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, to act on CLDN5, a protein important for the formation of tight junctions at the blood-brain barrier, thereby transiently loosening or strengthening the tight junctions between brain capillary endothelial cells. The level of blood-brain barrier permeability of compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, can be evaluated, for example, by transendothelial electrical resistance (TEER) measurements as described in Non-Patent Document 4 or the test examples described below.

[0300] As used herein, the term "blood-brain barrier permeation enhancer" refers to a drug among the above-mentioned "blood-brain barrier permeability regulators" that promotes the transfer of drugs for preventing and / or treating brain diseases into the brain and / or the transfer of water and the like from brain tissue fluid into the circulating blood by temporarily loosening the tight junctions between brain capillary endothelial cells.

[0301] As used herein, the term "blood-brain barrier permeability inhibitor" refers to a drug among the above-mentioned "blood-brain barrier permeability regulators" that inhibits the migration of drugs or pathogenic substances for preventing and / or treating brain diseases into the brain, and / or the migration of water and the like from brain tissue fluid into the circulating blood, by temporarily strengthening the tight junctions between brain capillary endothelial cells.

[0302] As used herein, the term "drug for preventing and / or treating a brain disease" refers to a drug other than compound (I) of the present invention or a salt thereof, and examples thereof include drugs similar to the "concomitant drugs" described below.

[0303] As used herein, the term "brain disease" is not particularly limited, but examples thereof include cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, restless legs syndrome, and the like.

[0304] As used herein, the term "mental disorder" includes, for example, depression, bipolar disorder, autism spectrum disorder, obsessive-compulsive disorder, developmental disorder, and the like.

[0305] As used herein, "severe infectious diseases" include, for example, novel coronavirus infection, influenza virus infection, sepsis, bacterial meningitis, viral encephalitis, and the like.

[0306] As used herein, the term "conjugate" refers to any compound (complex) formed by binding Compound (I) of the present invention or a salt thereof to a drug directly or indirectly via a linker. The binding mode is not particularly limited, and examples include covalent bonds, coordinate bonds, and ionic bonds. Alternatively, Compound (I) of the present invention or a salt thereof may be modified on the surface of a fine particle such as a liposome, and the drug may be contained within the fine particle. The binding of Compound (I) of the present invention or a salt thereof to a drug can be carried out according to or in accordance with a known method, depending on the binding mode.

[0307] The covalent bond can be achieved, for example, by reacting the functional groups of the compound (I) of the present invention or a salt thereof with the drug, or functional groups introduced as needed. Examples of the combination of functional groups include an amino group and a carboxy group, a carboxy group and a hydroxy group, a maleimide group and a sulfanyl group, a sulfanyl group and a sulfanyl group, a hydrazide group and a carbonyl group, a hydrazide group and a formyl group, an amino group and a formyl group, a sulfanyl group and a carboxy group, an amino group and a squaric acid derivative, a dienyl aldehyde and an amino group, a haloester and a sulfanyl group, an azide group and an alkynyl group, etc.

[0308] The drug is not particularly limited and can be appropriately selected depending on the purpose. Examples of drugs include physiologically active substances such as nucleic acids, polynucleotides, genes and their analogs, glycosaminoglycans and their derivatives, oligosaccharides, polysaccharides and their derivatives, proteins, and peptides; antineurotic agents, antiviral agents, anticancer agents, antibiotics, enzymes, antioxidants, anti-inflammatory agents, steroids, angiotensin converting enzyme inhibitors, vasodilators, smooth muscle cell proliferation and / or migration inhibitors, platelet aggregation inhibitors, anticoagulants, chemical mediator release inhibitors, immunosuppressants, lipid uptake inhibitors, hormones, angiotensin receptor antagonists, vascular endothelial cell proliferation or inhibitors, aldose reductase inhibitors, lipoxygenase inhibitors, immunostimulants, Maillard reaction inhibitors, amyloidosis inhibitors, nitric oxide synthase (NOS) inhibitors, advanced glycation end products (AGEs), and Examples of suitable drugs include inhibitors of neurological diseases (e.g., anti-amyloid β (Aβ) antibodies, anti-Tau antibodies, etc.), radical scavengers, etc. The conjugate of the present invention contains compound (I) of the present invention or a salt thereof as a partial structure, which allows it to more efficiently penetrate the blood-brain barrier. Therefore, among the above drugs, anti-neurological agents that can be used in the treatment and / or diagnosis of the central nervous system are preferred.

[0309] Specific examples of anti-nerve drugs include anti-anxiety drugs such as Constan, Sepazone, Selene, Serenax, Xanax, Depas, Balance, Melax, Rize, Rivotril, Lexotan, Wybax, Sedir, Grandaxin, and Erispan; antidepressants such as Anafranil, Tofranil, Tryptanol, Amoxan, Amprit, Prothiaden, Tesipur, Tetramid, Ludiomil, Desyrel, Reslin, Abilit, Dogmatil, Miradol, Ritalin, Depromel, Paxil, Luvox, and Toledomin; and antidepressants such as Amovan, Halcion, Evamil, Myslee, Rismy, Lendormin, Loramet, Silace, Doral, Benzalin, Eurodin, Rohypnol, Insmin, Somelin, Dalmate, and Fen. antiinsomniacs such as Noval and Isomital; tranquilizers such as Wintermin, Contomin, Neureptil, Hilnamin, PZC, Melleril, Impromen, Serenece, Orap, Cremin, Clofecton, Defecton, Forrit, Lodopin, and Atarax; manic-depressants such as Limas and Tegretol; antiepileptics such as ethotoin, phenytoin, acetylpheneturide, primidone, sulthiame, ethosuximide, clonazepam, carbamazepine, sodium valproate, and zonisamide; and therapeutic agents for Parkinson's disease such as levodopa, pergolide mesylate, amantazine hydrochloride, trihexyphenidyl hydrochloride, piroheptine hydrochloride, mazaticol hydrochloride, metixene hydrochloride, biperiden, profenamine, and droxidopa.

[0310] Although there is some overlap with the drugs exemplified above, the "drugs for preventing and / or treating brain diseases" (concomitant drugs) described below, i.e., drugs conventionally used in the treatment of brain diseases, can also be suitably used as drugs constituting the conjugate.

[0311] The linker is not particularly limited as long as it can be used as a conjugate between compound (I) of the present invention or a salt thereof and a drug, and can be appropriately selected depending on the purpose of use. Examples of the linker include those described in known literature (Pharmacol Rev 68:3-19, January 2016, Protein Cell DOI 10. 1007 / s13238-016-0323-0, etc.), and more specific examples include VC (valine-citrulline), MC (maleimidocaproyl), SMCC (succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate), SPP (N-succinimidyl Examples of such conjugates include 4-(2-pyridyldithio)pentanoic acid: N-succinimidyl 4-(2-pyridyldithio)pentanoate, SS (disulfide), SPDB (N-succimidyl 4-(2-pyridyldithio)butyrate): N-succinimidyl 4-(2-pyridyldithio)butyrate, SS / hydrazone, hydrazone, carbonate, etc. The conjugate can be produced from compound (I) of the present invention or a salt thereof and a drug, or from compound (I) of the present invention or a salt thereof, a linker, and a drug, by a method known per se or a method analogous thereto.

[0312] Herein, various Claudin proteins may be referred to as "XCLDNY" or "XCLDNY protein." X indicates the species of origin (h: human, c: cynomolgus monkey, m: mouse), and Y indicates the number of the Claudin protein. For example, human Claudin-5 protein is referred to as "hCLDN5" or "hCLDN5 protein."

[0313] Claudin-5 protein is an expression product of the Claudin-5 (sometimes referred to as CLDN5) gene and is the CLDN5 protein expressed in an organism. The species from which the CLDN5 protein is derived is not particularly limited, and includes animals, such as various mammals such as humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer.

[0314] The amino acid sequences of CLDN5 proteins derived from various biological species are known. Specifically, for example, human CLDN5 (hCLDN5) protein includes a protein consisting of the amino acid sequence shown in SEQ ID NO: 1, cynomolgus monkey CLDN5 (cCLDN5) protein includes a protein consisting of the amino acid sequence shown in SEQ ID NO: 2, and mouse CLDN5 (mCLDN5) protein includes a protein consisting of the amino acid sequence shown in SEQ ID NO: 3.

[0315] The CLDN5 protein may have amino acid mutations such as substitutions, deletions, additions, and insertions, as long as the original activity and the ability of CLDN5 proteins to interact with each other via their extracellular loops to form tight junctions are maintained. From the viewpoint of less impairment of activity, preferred mutations include substitutions, more preferably conservative substitutions.

[0316] Preferred specific examples of the CLDN5 protein include the proteins described in (a) below and the proteins described in (b) below: (a) a protein consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1, 2, and 3, and (b) a protein consisting of an amino acid sequence having 85% or more identity with the amino acid sequence shown in any one of SEQ ID NOs: 1, 2, and 3, and having the ability to form tight junctions. At least one protein selected from the group consisting of:

[0317] In the above (a) and (b), the amino acid sequences are preferably SEQ ID NOs: 1 and 2.

[0318] In the above (b), the identity is more preferably 90% or more, even more preferably 95% or more, and particularly preferably 98% or more.

[0319] An example of the protein described in (b) above is (b') a protein having inositol phosphate bond hydrolysis activity, which consists of an amino acid sequence in which one or more amino acids have been substituted, deleted, added, or inserted relative to the amino acid sequence shown in any of SEQ ID NOs: 1, 2, and 3. In (b') above, "multiple" means, for example, 2 to 20, preferably 2 to 10, more preferably 2 to 5, and particularly preferably 2 or 3.

[0320] The extracellular region of the CLDN5 protein is a region exposed to the outside of the cell when the CLDN5 protein is arranged in a cell membrane (endothelial cell membrane, preferably vascular endothelial cell membrane, more preferably brain capillary endothelial cell membrane) by transmembrane binding four times, and is not particularly limited thereto. The extracellular region of the CLDN5 protein consists of a first extracellular loop located on the N-terminus and a second extracellular loop located on the C-terminus. The extracellular region of each CLDN5 protein, as well as the first and second extracellular loops, are already known or can be easily determined using various transmembrane region prediction tools (e.g., SOSUI: http: / / harrier.nagahama-i-bio.ac.jp / sosui / , etc.).

[0321] Specific examples of the extracellular domain include, for example, in the hCLDN5 protein consisting of the amino acid sequence shown in SEQ ID NO: 1, the region from the N-terminus from the 28th amino acid (proline) to the 80th amino acid (alanine) (first extracellular loop), and the region from the N-terminus from the 147th amino acid (phenylalanine) to the 163rd amino acid (alanine) (second extracellular loop). Specific examples of the extracellular domain in other CLDN5 proteins include corresponding regions. Here, the "corresponding region" refers to, for example, a region that corresponds when the amino acid sequence of the hCLDN5 protein is compared with another CLDN5 amino acid sequence using a sequence analysis tool (FASTA, BLAST, etc.).

[0322] As used herein, the term "identity" of an amino acid sequence refers to the degree of correspondence between two or more comparable amino acid sequences. Therefore, the greater the correspondence between two amino acid sequences, the greater the identity or similarity between those sequences. The level of identity of amino acid sequences can be determined, for example, using the sequence analysis tool FASTA with default parameters. Alternatively, it can be determined using the BLAST algorithm by Karlin and Altschul (Karlin S, Altschul S F. "Methods for assessing the statistical significance of molecular sequence features by using general scoring schemes," Proc. Natl. Acad. Sci. USA. 87: 2264-2268 (1990); Karlin S, Altschul S F. "Applications and statistics for multiple high-scoring segments in molecular sequences," Proc. Natl. Acad. Sci. USA. 90: 5873-7 (1993)). A program called BLASTX based on this BLAST algorithm has been developed. Specific techniques for these analysis methods are known, and can be found on the National Center for Biotechnology Information (NCBI) website (http: / / www.ncbi.nlm.nih.gov / ). The "identity" of nucleotide sequences is also defined in the same manner as above.

[0323] As used herein, the term "conservative substitution" refers to the substitution of an amino acid residue with an amino acid residue having a similar side chain. For example, substitution between amino acid residues having basic side chains such as lysine, arginine, and histidine corresponds to a conservative substitution. Other examples of conservative substitutions include substitution between amino acid residues having acidic side chains such as aspartic acid and glutamic acid; amino acid residues having uncharged polar side chains such as glycine, asparagine, glutamine, serine, threonine, tyrosine, and cysteine; amino acid residues having nonpolar side chains such as alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan; amino acid residues having β-branched side chains such as threonine, valine, and isoleucine; and amino acid residues having aromatic side chains such as tyrosine, phenylalanine, tryptophan, and histidine.

[0324] [Compound of the Present Invention (Compound (I))] Hereinafter, each group in the above formula (I) of compound (I) will be explained.

[0325] A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted. A is preferably a 2-furyl group, a 6-benzofuryl group, a 2-thienyl group, or a 7-quinolyl group, each of which may be substituted with a substituent selected from the substituent group (a) (or the substituent group (a'), the substituent group (b), the substituent group (b'), the substituent group (c), or the substituent group (c')), and more preferably a 2-furyl group, a 2-thienyl group, or a 7-quinolyl group, each of which may be substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c), or the substituent group (c')).

[0326] L is a group of the formula:

[0327]

[0328] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊indicates the bonding position to the group X.) However, when L is -CH ２ -, X represents an oxygen atom.

[0329] L is preferably of the formula:

[0330]

[0331] (wherein the symbols have the same meanings as defined above), and more preferably, a divalent group represented by the formula:

[0332]

[0333] (wherein the symbols have the same meanings as defined above), and more preferably a divalent group represented by the formula:

[0334]

[0335] (wherein the symbols have the same meanings as defined above) is a divalent group represented by the formula:

[0336] X is a single bond, an oxygen atom, or a group of the formula:

[0337]

[0338] (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ and n is 0 or 1.

[0339] X is preferably a single bond, an oxygen atom, or a group of the formula:

[0340]

[0341] (each symbol in the formula has the same meaning as defined above), and more preferably a single bond or NH. However, when X is a single bond, L is a divalent group represented by the formula:

[0342]

[0343] (each symbol in the formula has the same meaning as defined above), and X is a divalent group represented by the formula:

[0344]

[0345] (wherein n is 1, and the other symbols are as defined above), L is a divalent group represented by the formula:

[0346]

[0347] (wherein each symbol has the same meaning as defined above).

[0348] B is optionally substituted, C ３－１８ It represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group.

[0349] B is preferably C, each of which may be substituted with a substituent selected from the substituent group (a) (or the substituent group (a'), the substituent group (b), the substituent group (b'), the substituent group (c), or the substituent group (c')). ６－１８ C is an aryl group, a dibenzofuryl group, or a dibenzothienyl group, and more preferably each of which may be substituted with a substituent selected from the substituent group (b), the substituent group (b'), the substituent group (c), or the substituent group (c'). ６－１６ An aryl group, a dibenzofuryl group, or a dibenzothienyl group, and more preferably a phenyl group, a biphenyl group, a terphenyl group, a fluorenyl group, an anthracenyl group, a phenanthryl group, a dibenzofuryl group, or a dibenzothienyl group, each of which may be substituted with a substituent selected from the substituent group (b), the substituent group (b'), the substituent group (c), or the substituent group (c').

[0350] Suitable compounds (I) include the following compounds: [Compound (IA)] A is an optionally substituted 2-furyl group;

[0351]

[0352] (wherein each symbol has the same meaning as defined above); X is a single bond, an oxygen atom, or a divalent group represented by the formula:

[0353]

[0354] (wherein each symbol has the same meaning as defined above); and B is a divalent group represented by C ６－１８ an aryl group, a dibenzofuryl group, or a dibenzothienyl group (provided that when X is a single bond, L is a group of the formula:

[0355]

[0356] (wherein each symbol has the same meaning as defined above), and X is a divalent group represented by the formula:

[0357]

[0358] (wherein n is 1, and the other symbols are as defined above), L is a divalent group represented by the formula:

[0359]

[0360] (wherein each symbol has the same meaning as defined above), Compound (I).

[0361] [Compound (IA')] A is an optionally substituted 2-furyl group; L is a compound of the formula:

[0362]

[0363] (wherein each symbol has the same meaning as defined above); X is a single bond, an oxygen atom, or a divalent group represented by the formula:

[0364]

[0365] (wherein each symbol has the same meaning as defined above); and B is an optionally substituted C ６－１８ and an aryl group (provided that when X is a single bond, L is a group of the formula:

[0366]

[0367] (wherein each symbol has the same meaning as defined above), and X is a divalent group represented by the formula:

[0368]

[0369] (wherein n is 1, and the other symbols are as defined above), L is a divalent group represented by the formula:

[0370]

[0371] (wherein each symbol has the same meaning as defined above), Compound (I).

[0372] [Compound (IB)] A compound represented by the formula:

[0373]

[0374] (each symbol in the formula has the same meaning as defined above); X is a single bond, NH, or an oxygen atom; and B is an optionally substituted phenyl group (provided that when X is a single bond, L is a divalent group represented by the formula:

[0375]

[0376] (wherein each symbol has the same meaning as defined above), Compound (I).

[0377] [Compound (IB')] A compound in which A is an optionally substituted 6-benzofuryl group; L is a compound of the formula:

[0378]

[0379] (each symbol in the formula has the same meaning as defined above); X is a single bond, NH, or an oxygen atom; and B is an optionally substituted phenyl group (provided that when X is a single bond, L is a divalent group represented by the formula:

[0380]

[0381] (wherein each symbol has the same meaning as defined above), Compound (I).

[0382] [Compound (IC)] A is an optionally substituted 7-quinolyl group; L is a compound of the formula:

[0383]

[0384] (each symbol in the formula has the same meaning as defined above); X is a single bond, NH, or an oxygen atom; and B is an optionally substituted phenyl group (provided that when X is a single bond, L is a divalent group represented by the formula:

[0385]

[0386] (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X is an oxygen atom.), Compound (I).

[0387] [Compound (ID)] A is an optionally substituted 2-thienyl group; L is a compound of the formula:

[0388]

[0389] (wherein each symbol has the same meaning as defined above), X is NH; and B is an optionally substituted phenyl group.

[0390] [Compound (IE)] A is a 2-furyl group, a 6-benzofuryl group, a 2-thienyl group or a 7-quinolyl group, each of which may be substituted with a substituent selected from the substituent group (a) (or the substituent group (a'), the substituent group (b), the substituent group (b'), the substituent group (c) or the substituent group (c')); L is a compound represented by the formula:

[0391]

[0392] (wherein the symbols have the same meanings as defined above), X is a single bond, an oxygen atom, or a divalent group represented by the formula:

[0393]

[0394] (each symbol in the formula has the same meaning as defined above); and B is a divalent group represented by the formula (I) (or the formula (I'), ... ６－１８an aryl group, a dibenzofuryl group, or a dibenzothienyl group (provided that when X is a single bond, L is a group of the formula:

[0395]

[0396] (wherein each symbol has the same meaning as defined above), and X is a divalent group represented by the formula:

[0397]

[0398] (wherein n is 1, and the other symbols are as defined above), L is a divalent group represented by the formula:

[0399]

[0400] (wherein each symbol has the same meaning as defined above), Compound (I).

[0401] [Compound (IE')] A is a 2-furyl group, a 6-benzofuryl group, a 2-thienyl group or a 7-quinolyl group, each of which may be substituted with a substituent selected from the substituent group (a') (or the substituent group (b') or the substituent group (c')); L is a compound represented by the formula:

[0402]

[0403] (wherein the symbols have the same meanings as defined above), X is a single bond, an oxygen atom, or a divalent group represented by the formula:

[0404]

[0405] (wherein each symbol has the same meaning as defined above); and B is a divalent group represented by C optionally substituted with a substituent selected from the substituent group (a') (or the substituent group (b') or the substituent group (c')). ６－１８ and an aryl group (provided that when X is a single bond, L is a group of the formula:

[0406]

[0407] (wherein each symbol has the same meaning as defined above), and X is a divalent group represented by the formula:

[0408]

[0409] (wherein n is 1, and the other symbols are as defined above), L is a divalent group represented by the formula:

[0410]

[0411] (wherein each symbol has the same meaning as defined above), Compound (I).

[0412] [Compound (IF)] A is a 2-furyl group, a 2-thienyl group or a 7-quinolyl group, each of which may be substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c) or the substituent group (c')); L is a compound represented by the formula:

[0413]

[0414] (wherein the symbols have the same meanings as defined above); X is a single bond or NH; and B is C optionally substituted with a substituent selected from the substituent group (b), the substituent group (b'), the substituent group (c), or the substituent group (c'). ６－１６ and an aryl group (provided that when X is a single bond, L is a group of the formula:

[0415]

[0416] (wherein each symbol has the same meaning as defined above), Compound (I).

[0417] [Compound (IF')] A is a 2-furyl group, a 2-thienyl group or a 7-quinolyl group, each of which may be substituted with a substituent selected from the aforementioned substituent group (b') (or the aforementioned substituent group (c')); L is a compound represented by the formula:

[0418]

[0419] (wherein the symbols have the same meanings as defined above); X is a single bond or NH; and B is C optionally substituted with a substituent selected from the substituent group (b') or the substituent group (c'). ６－１６ and an aryl group (provided that when X is a single bond, L is a group of the formula:

[0420]

[0421] (wherein each symbol has the same meaning as defined above), Compound (I).

[0422] [Compound (IG)] A is a 2-furyl group, a 6-benzofuryl group, a 2-thienyl group or a 7-quinolyl group, each of which may be substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c) or the substituent group (c')); L is a compound represented by the formula:

[0423]

[0424] (wherein the symbols have the same meanings as defined above); X is a single bond, NH or an oxygen atom; and B is a phenyl group, a biphenyl group, a terphenyl group, a fluorenyl group, an anthracenyl group, a phenanthryl group, a dibenzofuryl group or a dibenzothienyl group, each of which may be substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c) or the substituent group (c')) (provided that when X is a single bond, L is a divalent group represented by the formula:

[0425]

[0426] (wherein each symbol has the same meaning as defined above), Compound (I).

[0427] [Compound (IG')] A is a 2-furyl group, a 6-benzofuryl group, a 2-thienyl group or a 7-quinolyl group, each of which may be substituted with a substituent selected from the substituent group (b') (or the substituent group (c')); L is a compound represented by the formula:

[0428]

[0429] (wherein the symbols have the same meanings as defined above); X is a single bond, NH or an oxygen atom; and B is a phenyl group optionally substituted with a substituent selected from the substituent group (b') (or the substituent group (c')) (provided that when X is a single bond, L is a divalent group represented by the formula:

[0430]

[0431] (wherein each symbol has the same meaning as defined above), Compound (I).

[0432] [Compound (IH)] A is a 2-furyl group optionally substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c) or the substituent group (c')); L is a compound represented by the formula:

[0433]

[0434] (each symbol in the formula has the same meaning as defined above); X is a single bond or NH; and B is C optionally substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c), or the substituent group (c')). ６－１８ and an aryl group (provided that when X is a single bond, L is a group of the formula:

[0435]

[0436] (wherein each symbol has the same meaning as defined above), Compound (I).

[0437] [Compound (IH')] A is a 2-furyl group optionally substituted with a substituent selected from the aforementioned substituent group (b') (or the aforementioned substituent group (c')); L is a compound represented by the formula:

[0438]

[0439] (each symbol in the formula has the same meaning as defined above); X is a single bond or NH; and B is C optionally substituted with a substituent selected from the substituent group (b') (or the substituent group (c')). ６－１８ and an aryl group (provided that when X is a single bond, L is a group of the formula:

[0440]

[0441] (wherein each symbol has the same meaning as defined above), Compound (I).

[0442] [Compound (IJ)] A is a 7-quinolyl group optionally substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c) or the substituent group (c')); L is a compound represented by the formula:

[0443]

[0444] (each symbol in the formula has the same meaning as defined above); X is a single bond, NH or an oxygen atom; and B is a phenyl group optionally substituted with a substituent selected from the substituent group (b) (or the substituent group (b'), the substituent group (c) or the substituent group (c')) (provided that when X is a single bond, L is a divalent group represented by the formula:

[0445]

[0446] (wherein each symbol has the same meaning as defined above), and when X is an oxygen atom, L is -CH ２ -), Compound (I).

[0447] [Compound (IJ')] A is a 7-quinolyl group optionally substituted with a substituent selected from the aforementioned substituent group (b') (or the aforementioned substituent group (c')); L is a compound represented by the formula:

[0448]

[0449] (each symbol in the formula has the same meaning as defined above); X is a single bond, NH or an oxygen atom; and B is a phenyl group optionally substituted with a substituent selected from the substituent group (b') (or the substituent group (c')) (provided that when X is a single bond, L is a divalent group represented by the formula:

[0450]

[0451] (wherein each symbol has the same meaning as defined above), and when X is an oxygen atom, L is -CH ２ -), Compound (I).

[0452] Specific examples of suitable compound (I) include the below-described example compounds (compounds (1) to (62)) or their isomers, or salts thereof. Among them, compounds of the following formula:

[0453]

[0454]

[0455]

[0456]

[0457]

[0458] or an isomer thereof, or a salt thereof, exhibits a suitable permeability-regulating effect, and

[0459]

[0460]

[0461]

[0462]

[0463] or an isomer thereof, or a salt thereof.

[0464] In addition, among the compounds having a blood-brain barrier permeability regulating effect, compounds represented by the following formula:

[0465]

[0466]

[0467]

[0468]

[0469]

[0470] or an isomer thereof, or a pharmaceutically acceptable salt thereof exhibits a blood-brain barrier permeation promoting effect, transiently increasing the blood-brain barrier permeability of other drugs and the like.

[0471]

[0472] or an isomer thereof, or a pharmaceutically acceptable salt thereof exhibits a blood-brain barrier permeation inhibitory effect of transiently suppressing blood-brain barrier permeability.

[0473] The compound (I) of the present invention or a salt thereof may contain an isotope (e.g., ２ H. ３ H. １３ C. １４ C. １５ N. １８ F. ３２ P. ３５ S. １２３ I, １２５ I, １３１ The compound may be a compound labeled or substituted with an isotope (e.g., I), and a compound labeled or substituted with an isotope can be used as a tracer (PET tracer) used in, for example, Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.

[0474] The compound (I) of the present invention or a salt thereof may be in the form of a crystal, and may be in a single crystalline form or a mixture of multiple crystalline forms.

[0475] The compound (I) or a salt thereof of the present invention may also include its internal salts, adducts, and solvates thereof. These solvates are compounds in which solvent molecules are coordinated to the compound (I) or a salt thereof, and also include hydrates. Examples of the solvates include hydrates, ethanol solvates, and dimethyl sulfoxide solvates of the compound (I) or a salt thereof.

[0476] Compound (I) of the present invention may be a prodrug.

[0477] The prodrug of compound (I) of the present invention refers to a compound that is converted to compound (I) in vivo by a reaction catalyzed by an enzyme, gastric acid, or the like. Examples of the prodrug of compound (I) include, when compound (I) has an amino group, compounds in which the amino group has been acylated, alkylated, or phosphorylated (for example, compounds in which the amino group of compound (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when compound (I) has a hydroxy group, compounds in which the hydroxy group has been acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxy group of compound (I) has been acetylated, palmitoylated, propanoylated, or pivaloylated). When compound (I) has a carboxy group, examples thereof include compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, 1-{(ethoxycarbonyl)oxy}ethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl-esterified, or methylamidized). These compounds can be produced by methods known per se. Furthermore, the prodrug of compound (I) may be either a hydrate or a non-hydrate. Furthermore, the prodrug of compound (I) may be one that is converted into a compound represented by compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, Hirokawa Publishing, 1990.

[0478] [Method for Producing Compound (I)] Compound (I) of the present invention can be produced by various known production methods utilizing characteristics based on its basic skeleton or the type of substituent. Examples of known methods include those described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS," 2nd Edition, Academic Press, Inc., 1989, and "Comprehensive Organic Transformations," VCH Publishers Inc., 1989. Depending on the type of functional group, it may be effective from a production technology perspective to protect the functional group with an appropriate protecting group at the raw material or intermediate stage, or to replace the functional group with a group that can be easily converted to the functional group. Examples of such functional groups include amino groups, hydroxyl groups, and carboxy groups. Protecting groups for these groups include those described in "Protective Groups in Organic Synthesis (3rd Edition, 1999)" by T.W. Greene and P.G. Wuts. These protecting groups may be appropriately selected depending on the reaction conditions. According to such a method, after the reaction is carried out by introducing the substituent, the protecting group can be removed or converted into the desired group as necessary to obtain the desired compound.

[0479] Representative methods for producing compound (I) of the present invention are described below. However, the production methods are not limited to the methods described below. In addition, unless a specific production method is described, the starting compounds in each reaction can be easily obtained commercially and used, or can be produced according to a method known per se or a method similar thereto.

[0480] (Manufacturing method 1)

[0481]

[0482] (The symbols in the formula are as defined above.)

[0483] This reaction is a method known per se, for example, a method for producing compound (I-1) by directly condensing compound (i) with compound (ii).

[0484] The method of directly condensing compound (i) with compound (ii) is carried out in the presence of a condensing agent in a solvent that does not influence the reaction.

[0485] Examples of condensing agents include carbodiimide condensation reagents (e.g., dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide (EDC) and its hydrochloride salt (EDC·HCl)), phosphoric acid condensation reagents (e.g., diethyl cyanophosphate, diphenylphosphoryl azide), azolide condensation reagents (e.g., N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, etc.), 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc. Among these, EDC·HCl is preferred.

[0486] The amount of compound (ii) used is usually 1 to 5 moles, preferably 1 to 2 moles, relative to 1 mole of compound (i). The amount of condensing agent used is usually 1 to 5 moles, preferably 1 to 2 moles, relative to 1 mole of compound (i).

[0487] When the carbodiimide-based condensation reagent is used as the condensing agent, the reaction yield can be improved by using a condensation promoter (e.g., 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.) as needed. Furthermore, when the phosphoric acid-based condensation reagent is used as the condensing agent, the reaction yield can be improved by adding an organic base such as triethylamine or N,N-diisopropylethylamine as needed. Furthermore, when the azolide-based condensation reagent is used as the condensing agent, it is desirable to carry out the reaction in the presence of a base such as an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; or an alkali metal carbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or cesium carbonate.

[0488] The amount of the condensation promoter and / or base used is usually 1 to 5 moles, preferably 1 to 2 moles, per mole of compound (i).

[0489] This reaction is carried out in a solvent that does not affect the reaction. Examples of such solvents include ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and 1,4-dioxane; aromatic hydrocarbons such as toluene, benzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; alcohols such as methanol, ethanol, and 2-propanol; and nitriles such as acetonitrile. Two or more of these solvents may be mixed in an appropriate ratio. Among these, dichloromethane or N,N-dimethylformamide is preferred.

[0490] The reaction conditions such as reaction temperature and reaction time vary depending on the reagents used (condensing agent, condensation promoter, base, etc.), reaction solvent, etc., but are usually −30° C. to 150° C. and 30 minutes to 24 hours.

[0491] (Manufacturing method 2)

[0492]

[0493] (The symbols in the formula are as defined above.)

[0494] This reaction is carried out by reacting compound (iii) with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) or P ２ S ５ This is a process for producing compound (I-2) by reacting

[0495] Lawesson's reagent or P ２ S ５ The amount of is usually 0.5 to 3 moles, preferably 0.5 to 1.5 moles, relative to compound (iii).

[0496] This reaction is carried out in a solvent that does not affect the reaction. Examples of such solvents include ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and 1,4-dioxane; aromatic hydrocarbons such as toluene, benzene, and xylene; alcohols such as methanol and ethanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. Two or more of these solvents may be mixed in an appropriate ratio.

[0497] The reaction temperature is usually from -100°C to 200°C, preferably from 100°C to 150°C.

[0498] The reaction time is not particularly limited, but is usually 30 minutes to 48 hours, preferably 1 hour to 12 hours.

[0499] (Manufacturing method 3)

[0500]

[0501] (The symbols in the formula are as defined above.)

[0502] This reaction is a step for producing compound (I-3) by carrying out the Mitsunobu reaction between compound (iv) and compound (v) in a solvent that does not affect the reaction.

[0503] This reaction is carried out in a solvent that does not affect the reaction. Examples of such solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Among these, halogenated hydrocarbons or ethers are preferred, and dichloromethane or tetrahydrofuran is more preferred.

[0504] The reagent used in the Mitsunobu reaction is not particularly limited as long as it is a known reagent that can normally be used in the Mitsunobu reaction, but examples include combinations of azo compounds such as di-lower alkyl azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, etc.; azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide) and 1,1'-(azodicarbonyl)dipiperidine, etc., with phosphines such as triarylphosphines such as triphenylphosphine, etc.; tri-lower alkylphosphines such as tri-n-butylphosphine, etc. Of these, the combination of diisopropyl azodicarboxylate and triphenylphosphine is preferred.

[0505] The reaction temperature varies depending on the starting compounds or reagents, but is usually -50 to 100°C, preferably 0 to 60°C.

[0506] The reaction time varies depending on the reaction temperature, the starting compounds, the reaction reagents, and the types of solvent used, but is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0507] (Manufacturing method 4)

[0508]

[0509] (In the formula, X １ represents a leaving group (e.g., a halogen atom), and other symbols are as defined above.)

[0510] Step 1 is a step of producing compound (viii) by a cross-coupling reaction (Suzuki-Miyaura cross-coupling reaction) between compound (vi) and compound (vii) in the presence of a palladium catalyst and cesium fluoride (CsF) in a solvent that does not influence the reaction.

[0511] Compound (vii) can be produced by a method known per se (Hosoya T, Niwa, T, et al., J. Org. Chem. 86, 1622-1632 (2021)) or a method analogous thereto. The amount of compound (vii) used is usually 1 mol to 3 mol, preferably 1 mol to 2 mol, per mol of compound (vi).

[0512] Palladium salts include palladium(II) acetate, palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and bis(dibenzylideneacetone)palladium(0) (Pd ２ (dba) ３ ), tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride.diphenylphosphinoferrocene (PdCl ２ (dppf)), PdCl ２ (dppf) dichloromethane complex, palladium (0) on carbon, bis(triphenylphosphine)palladium dichloride, etc., and among these, palladium (II) chloride is preferred.

[0513] The ligands include 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (QPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2 -dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 3,6-dimethoxy-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (BrettPhos), tri-t-butylphosphine, tricyclohexylphosphine, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos), Phosphine ligands such as (S)-1-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (JoshiPhos); N-heterocyclic carbene (NHC) ligands (e.g., 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr), 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene (IPr), Examples of suitable imidazol-2-ylidene include 1,3-bis(2,6-diisopropylphenyl)imidazolidine-2-ylidene (IMes), 1,3-bis(2,6-diisopropylphenyl)imidazolidine-2-ylidene (SIPr), and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (SIMes), and among these, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos) is preferred.

[0514] Palladium catalysts include PdCl ２ (AmPhos) ２ (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)) is preferred.

[0515] The amount of the palladium catalyst used is usually 0.01 mol to 0.2 mol, preferably 0.02 mol to 0.05 mol, per 1 mol of compound (vi).

[0516] The amount of the ligand used is usually 0.01 to 0.2 moles, preferably 0.02 to 0.05 moles, per mole of compound (vi).

[0517] The amount of cesium fluoride used is usually 1 to 5 moles, preferably 1.2 to 3.5 moles, per mole of compound (vi).

[0518] This reaction is carried out in a solvent that does not affect the reaction. Examples of such solvents include ethers such as tetrahydrofuran and cyclopentyl methyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; and alcohols such as ethylene glycol and methanol. Two or more of these solvents may be mixed in an appropriate ratio. Among these, ethylene glycol is preferred.

[0519] The reaction temperature is, for example, 0°C to 100°C, preferably 70°C to 90°C.

[0520] The reaction time varies depending on the reaction temperature, the raw material compound, the palladium catalyst, the ligand, and / or the type of solvent used, but is usually 10 minutes to 48 hours, preferably 30 minutes to 30 hours.

[0521] Step 2 is a step of producing compound (I-4) by a cross-coupling reaction (Suzuki-Miyaura cross-coupling reaction) between compound (viii) and compound (ix) in the presence of a palladium catalyst and cesium fluoride (CsF) in a solvent that does not influence the reaction.

[0522] Compound (ix) may be a commercially available product (e.g., arylboronic acid compound manufactured by Tokyo Chemical Industry Co., Ltd. (https: / / www.tcichemicals.com / JP / ja / p / I0620)) and used as is, or may be produced by a method known per se or a method analogous thereto. The amount of compound (ix) used is usually 1 to 3 moles, and preferably 1.2 to 2 moles, per mole of compound (viii).

[0523] As the palladium catalyst, 2-(2-dicyclohexylphosphanylphenyl)-1-N,1-N,3-N,3-N-tetramethylbenzene-1,3-diamine; methanesulfonic acid; N-methyl-2-phenylalanine; or a palladium catalyst coordinated with a Buchwald ligand, such as palladium (CPhos Pd G4), can be suitably used.

[0524] The amount of the palladium catalyst used is usually 0.01 mol to 0.2 mol, preferably 0.02 mol to 0.05 mol, per 1 mol of compound (viii).

[0525] The amount of cesium fluoride used is usually 1 to 4 moles, preferably 1.2 to 2 moles, per mole of compound (viii).

[0526] This reaction is carried out in a solvent that does not affect the reaction. Examples of such solvents include ethers such as tetrahydrofuran and cyclopentyl methyl ether (CPME); aromatic hydrocarbons such as benzene, toluene, and xylene; and alcohols such as ethylene glycol and methanol. Two or more of these solvents may be mixed in an appropriate ratio. Among these, a mixed solvent of CPME and methanol is preferred.

[0527] The reaction temperature is, for example, 0°C to 100°C, preferably 70°C to 90°C.

[0528] The reaction time varies depending on the reaction temperature, the raw material compound, the palladium catalyst, the ligand, or the type of solvent used, but is usually 10 minutes to 48 hours, preferably 30 minutes to 30 hours.

[0529] (Manufacturing method 5)

[0530]

[0531] (In the formula, R １ and R ２ each independently represents a hydrogen atom or an alkyl group, or R １ and R ２ may be bonded together to form a cyclic boronic acid ester, such as a pinacol ester of a boronic acid, with the boron atom; X ２and X ３ each independently represents a leaving group (e.g., a halogen atom), and other symbols are as defined above.)

[0532] Step 1 is a step of producing compound (xi) by a cross-coupling reaction (Suzuki-Miyaura cross-coupling reaction) between compound (x) and compound (ix) in the presence of a palladium catalyst and a base in a solvent that does not influence the reaction.

[0533] Compound (x) can be produced by a method known per se or a method analogous thereto. Compound (ix) is a commercially available product, or can be produced by a method known per se [for example, the method described in "Advanced Organic Chemistry, 4th Ed." (Jerry March) or "Comprehensive Organic Transformations, 2nd Ed." (Richard C. Larock)] or a method analogous thereto. The amount of compound (ix) used is usually 1 to 3 moles, preferably 1 to 2 moles, per mole of compound (x).

[0534] Palladium catalysts include palladium(II) acetate, palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and bis(dibenzylideneacetone)palladium(0) (Pd ２ (dba) ３ ), tetrakis(triphenylphosphine)palladium(0), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl ２ (dppf)), PdCl ２ (dppf) dichloromethane complex, palladium on carbon (0), bis(triphenylphosphine)palladium dichloride, etc., among which PdCl ２Furthermore, if necessary, 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 3,6-dimethoxy-2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), Phosphine ligands such as ',6'-triisopropylbiphenyl (BrettPhos), tri-t-butylphosphine, tricyclohexylphosphine, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (AmPhos), (S)-1-[(RP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (JosiPhos), and ligands such as phenanthroline may be added. The amount of the palladium catalyst used is usually 0.01 mol to 1 mol, and preferably 0.05 mol to 0.1 mol, relative to 1 mol of compound (x). The amount of the ligand used is usually 0 mol to 1 mol, and preferably 0.01 mol to 0.2 mol, relative to 1 mol of compound (x).

[0535] Examples of the base include potassium acetate, tripotassium phosphate, trisodium phosphate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc., and among these, potassium acetate is preferred. The amount of the base used is usually 1 mol to 5 mol, preferably 2 mol to 4.5 mol, per mol of compound (x).

[0536] This reaction is carried out in a solvent that does not affect the reaction. Examples of such solvents include amides such as N,N-dimethylformamide and N-methylpyrrolidone; ethers such as tetrahydrofuran and 1,4-dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene and xylene; nitriles such as acetonitrile; water; and mixtures thereof. Of these, a mixed solvent of 1,4-dioxane and water is preferred.

[0537] The reaction temperature is, for example, 0°C to 120°C, preferably 90°C to 100°C.

[0538] The reaction time varies depending on the reaction temperature, the raw material compound, the palladium catalyst, the ligand, and / or the type of solvent used, but is usually 10 minutes to 48 hours, preferably 30 minutes to 12 hours.

[0539] Step 2 is a step of producing compound (I-5) by a cross-coupling reaction (Buchwald-Hartwig cross-coupling reaction) between compound (xi) and compound (xii) in the presence of a palladium catalyst, a ligand, and a base in a solvent that does not influence the reaction.

[0540] Compound (xii) may be a commercially available product, or may be prepared by a method known per se or a method analogous thereto. The amount of compound (xii) used is usually 1 to 3 moles, and preferably 1.2 to 2 moles, per mole of compound (xi).

[0541] Examples of the palladium catalyst include palladium(II) acetate, palladium(II) chloride, dichlorobis(tricyclohexylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and bis(dibenzylideneacetone)palladium(0) (Pd ２ (dba) ３ ), tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride.diphenylphosphinoferrocene (PdCl ２ (dppf)), PdCl ２ (dppf) dichloromethane complex, palladium on carbon (0), bis(triphenylphosphine)palladium dichloride, etc., among which palladium (II) acetate or Pd ２ (dba) ３ The amount of the palladium catalyst used is usually 0.01 mol to 0.2 mol, preferably 0.02 mol to 0.05 mol, relative to 1 mol of compound (xi).

[0542] Examples of the ligand include triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,1'-bis(di-t-butylphosphino)ferrocene (dtbpf), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropylphosphine, and 2-dicyclohexylphosphino-2',4',6'-triisopropylphosphine. Examples of suitable phosphine ligands include propyl-1,1'-biphenyl (XPhos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), (2-biphenylyl)di-tert-butylphosphine (JohnPhos), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), with BINAP being preferred. The amount of the ligand used is typically 0.01 mol to 0.5 mol, and preferably 0.02 mol to 0.1 mol, per 1 mol of compound (xi).

[0543] Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal bicarbonates such as potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; and metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide. Of these, sodium tert-butoxide is preferred. The amount of the base used is usually 1 mol to 4 mol, preferably 1.2 mol to 2 mol, per 1 mol of compound (xi).

[0544] This reaction is carried out in a solvent that does not affect the reaction. Examples of such solvents include ethers such as tetrahydrofuran and cyclopentyl methyl ether (CPME); aromatic hydrocarbons such as benzene, toluene, and xylene; and alcohols such as ethylene glycol and methanol. Of these, toluene is preferred.

[0545] The reaction temperature is, for example, 0°C to 100°C, preferably 70°C to 90°C.

[0546] The reaction time varies depending on the reaction temperature, the raw material compound, the palladium catalyst, the ligand, or the type of solvent used, but is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0547] The compound (I) of the present invention or a salt thereof produced by the above method can be isolated and purified by known methods, such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization, etc. The chemical structure of the compound (I) of the present invention or a salt thereof is １ H-NMR, １３ The compound can be identified using conventional instrumental analysis methods such as C-NMR, HPLC, and high-resolution liquid chromatography-mass spectrometry (LC-MS / MS).

[0548] [Medicine (Pharmaceutical Composition) of the Present Invention] The medicament of the present invention means a medicine (pharmaceutical composition) containing Compound (I) or a salt thereof (a pharmaceutically acceptable salt thereof) as an active ingredient. Specifically, it is a medicine for preventing and / or treating brain diseases by transiently regulating (preferably promoting) the blood-brain barrier permeability of a drug for preventing and / or treating brain diseases, or by regulating (promoting or inhibiting) the transfer of water and the like from brain tissue fluid to circulating blood.

[0549] The pharmaceutical of the present invention may be either a pharmaceutical consisting of compound (I) or a pharmaceutically acceptable salt thereof alone, or a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc. The pharmaceutical of the present invention can be administered in a pharmaceutically effective amount to a subject (e.g., a mammal such as a mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, or human).

[0550] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethylcellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), solubilizers (e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.), suspending agents (e.g., stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.), and the like. surfactants such as phosphorus; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonic agents (for example, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), buffers (for example, buffer solutions such as phosphates, acetates, carbonates, citrates, etc.), soothing agents (for example, benzyl alcohol, chol, etc.), preservatives (for example, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (for example, sulfites, ascorbic acid, etc.), coloring agents (for example, water-soluble food tar dyes (for example, food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2), water-insoluble lake dyes (for example, aluminum salts of the above-mentioned water-soluble food tar dyes), natural dyes (for example, β-carotene, chlorophyll, red iron oxide), etc.), flavoring agents, etc.

[0551] The medicament (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then processing the mixture according to a known method into oral preparations such as tablets, fine granules, granules, capsules, and dry syrups, or parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, and liposome preparations. Furthermore, if necessary, the medicament can also be prepared as a lyophilized preparation for preparation immediately before use. The preferred dosage form of the medicament of the present invention is a parenteral preparation, more preferably an injection.

[0552] Preparations for parenteral administration may be packaged in ampoules, vials, or syringes with needles. All preparations for parenteral administration should be sterile, as is known and practiced in the art.

[0553] Injectables may be designed for local and systemic administration. Compound (I) may be administered at once or divided into several smaller doses administered at intervals. It should be noted that the dosage of the medicament of the present invention may vary depending on the parenteral administration site, the age, weight, general health condition, sex, severity of the condition, type of disease, type of concomitant medication, etc. of the subject to be treated. Therefore, the dosage and content ranges described herein are intended to be representative and not to limit the scope or practice of the claimed formulations.

[0554] The content of compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the medicament (pharmaceutical composition) of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.0001% by weight to 90% by weight, preferably about 0.001% by weight to 50% by weight, and more preferably about 0.01% by weight to 20% by weight, based on 100% by weight of the total preparation.

[0555] The daily dose of Compound (I) of the present invention or a pharmaceutically acceptable salt thereof, when parenterally administered to an adult human patient (body weight: approximately 60 kg), is usually 0.001 mg to 1000 mg, preferably 0.01 mg to 100 mg, of Compound (I) as the active ingredient, and can be administered once or several times a day, regardless of whether it is before, after, or between meals. The administration period is not particularly limited.

[0556] Compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, directly loosens adhesion between vascular endothelial cells for a short period of time without reducing the expression of CLDN5, thereby transiently regulating the amount of water in cerebral tissue fluid and promoting the delivery of drugs for preventing and / or treating brain diseases into the brain. As a result, a pharmaceutical containing compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient is useful for the prevention and / or treatment of brain diseases such as cerebral edema, brain tumors, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorders, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

[0557] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof is preferably administered (concomitantly administered) in combination with a drug (concomitant drug) for preventing and / or treating a brain disease, as long as its efficacy is not impaired. The concomitant drug is not particularly limited, as long as it is one or more known drugs conventionally used in the treatment of a brain disease. Specific examples include drugs for preventing and / or treating a brain disease selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

[0558] Examples of drugs for treating cerebral edema include hypertonic solutions such as glycerol and mannitol; steroid drugs such as methylprednisone and dexamethasone; diuretics such as furosemide and acetazolamide; calcium channel blockers such as nimodipine and flunarizine; free radical scavengers such as iron ion chelators; aprotinin; barbiturates such as phenobarbital, amobarbital, and pentobarbital; naloxone, etc.

[0559] Examples of therapeutic agents for brain tumors include temozolomide, bevacizumab, carboplatin, cisplatin, etoposide, ifomide, rituximab, methotrexate, and texelpatuleb.

[0560] Examples of migraine treatment drugs include triptan preparations such as rizatriptan, naratriptan, eletriptan, sumatriptan, and zolmitriptan; ergotamine preparations such as ergotamine tartrate-anhydrous caffeine and dihydroergotamine mesylate; nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and acetaminophen; calcium antagonists such as lomerizine hydrochloride; and antiserotonin drugs such as dimethotiazine mesylate.

[0561] Examples of therapeutic agents for cerebral infarction include thrombolytic agents such as alteplase and urokinase; antiplatelet agents such as ozagrel sodium, aspirin and clopidogrel; anticoagulants such as heparin and argatroban; cerebroprotective agents such as edaravone; and anticerebral edema agents such as hypertonic glycerol.

[0562] Examples of drugs for treating Alzheimer's disease include donepezil, galantamine, rivastigmine, and memantine.

[0563] Examples of therapeutic agents for Parkinson's disease include levodopa, levodopa-carbidopa combination preparations, levodopa-benserazide combination preparations, and levodopa-carbidopa-entacapone combination preparations; dopamine agonists such as pramipexole, ropinirole, rotigotine, apomorphine, cabergoline, and bromocriptine; catechol-O-methyltransferase (COMT) inhibitors such as entacapone; monoamine oxidase B (MAO-B) inhibitors such as selegiline and safinamide methocil hydrochloride; levodopa action potentiators such as zonisamide; dopamine release promoters such as amantadine and oseltamivir; adenosine A2A receptor antagonists such as istradefylline; anticholinergics such as trihexyphenidyl; and noradrenaline precursors such as droxidopa.

[0564] Examples of antiepileptic drugs include acetazolamide, cannabidiol, carbamazepine, clobazam, clonazepam, divalproex, eslicarbazepine, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0565] Examples of antispasmodics include butylscopolamine, N-methylscopolamine, propantheline, timepidium, ptropium, tiquizium, mepenzolate, piperidolate, etc.

[0566] Examples of therapeutic agents for myasthenia gravis include steroid drugs such as prednisolone; oral immunosuppressants such as tacrolimus hydrate and cyclosporine; cholinesterase inhibitors such as ambenonium chloride; and immunoglobulin preparations.

[0567] Examples of therapeutic agents for Guillain-Barre syndrome include immunoglobulin preparations and low molecular weight heparin (LMWH).

[0568] Examples of therapeutic agents for chronic inflammatory demyelinating polyneuropathy (CIDP) include immunoglobulin preparations.

[0569] Examples of therapeutic agents for multiple sclerosis include corticosteroids such as prednisolone and methylprednisolone; immunomodulators such as interferon β1b, interferon β1a, glatiramer acetate, fingolimod, siponimod, ozanimod, teriflunomide, and dimethyl fumarate; immunoglobulin preparations; and molecularly targeted drugs such as alemtuzumab, rituximab, and cladribine.

[0570] Examples of therapeutic agents for encephalitis and meningitis include corticosteroids such as prednisolone, methylprednisolone, and dexamethasone; antiviral agents such as acyclovir and ganciclovir; fluoroquinolones; glycopeptide agents such as vancomycin; and immunoglobulin preparations.

[0571] Examples of therapeutic agents for sleep apnea syndrome include acetazolamide, modafinil, chlormadinone acetate, medroxyprogesterone acetate, theophylline, naloxone hydrochloride, doxapram hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, clonidine hydrochloride, paroxetine hydrochloride hydrate, metoprolol tartrate, and cilazapril.

[0572] Examples of therapeutic agents for narcolepsy include modafinil, armodafinil, solriamfetol, pitolisant, sodium gamma-hydroxybutyrate, clomipramine, imipramine, protriptyline, venlafaxine, fluoxetine, methylphenidate, methamphetamine, dextroamphetamine, etc.

[0573] Examples of therapeutic agents for schizophrenia include haloperidol, chlorpromazine, levomepromazine, sulpiride, perphenazine, bromperidol, propericiazine, risperidone, perospirone, paliperidone, blonanserin, olanzapine, asenapine, aripiprazole, and brexpiprazole.

[0574] Examples of drugs for treating mood disorders include minerals such as lithium; antiepileptic drugs such as valproic acid, lamotrigine, carbamazepine, oxcarbazepine, topiramate, riluzole, and gabapentin; and antipsychotic drugs such as risperidone, olanzapine, quetiapine, paliperidone, and ziprasidone.

[0575] Examples of therapeutic agents for REM sleep behavior disorder include clonazepam and paroxetine.

[0576] Examples of therapeutic agents for traumatic brain injury include pentobarbital, phenytoin, and fosphenytoin.

[0577] Examples of therapeutic agents for restless legs syndrome include pramipexole, gabapentin enacarbil, and rotigotine.

[0578] When a concomitant drug is used, the administration timing is not limited, and they may be administered to the subject simultaneously or at staggered times. Staggered administration may involve administering the medicament of the present invention first and the concomitant drug later, or the concomitant drug first and the medicament of the present invention later. The administration methods may be the same or different. Alternatively, compound (I) of the present invention or a pharmaceutically acceptable salt thereof and the concomitant drug may be administered in combination as a single formulation.

[0579] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The mixing ratio of compound (I) of the present invention or a pharmaceutically acceptable salt thereof to the concomitant drug can be appropriately selected depending on the subject of administration (the subject's age, body weight, general health condition, sex, severity of disease, etc.), administration route, type of disease, type of concomitant drug, etc.

[0580] The mass ratio of compound (I) of the present invention or a pharmaceutically acceptable salt thereof to a concomitant drug is not particularly limited.

[0581] Furthermore, concomitant drugs that complement and / or enhance the therapeutic effect of compound (I) of the present invention or a pharmaceutically acceptable salt thereof also include those that have not been discovered so far but will be discovered in the future, based on the above-mentioned mechanism.

[0582] Furthermore, in order to complement and / or enhance the therapeutic effect of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, it is also effective to use it in combination with supportive therapy or the like.

[0583] The medicament or pharmaceutical composition of the present invention may be provided in the form of a kit together with instructions for administration and the like. The drugs contained in the kit are supplied in a container made of a material that maintains the activity of the components of the medicament or pharmaceutical composition effectively for a long period of time, does not adsorb to the inside of the container, and does not alter the components. For example, a sealed glass ampoule may contain a buffer or the like sealed in the presence of a neutral, non-reactive gas such as nitrogen gas. The kit may also include instructions for use. The instructions for use of the kit may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and provided to the user.

[0584] [Screening method of the present invention] The blood-brain barrier permeability regulator of the present invention is required to act only on CLDN5, which plays a major role in the permeability of the blood-brain barrier, so it is necessary to select a candidate compound that specifically acts on CLDN5. Examples of screening methods for candidate compounds for the blood-brain barrier permeability regulator of the present invention include the following methods.

[0585] That is, the screening method for blood-brain barrier permeability regulators includes the steps of: (i) mixing a test compound with hCLDN5 proteoliposomes, adding an anti-hCLDN5 antibody (e.g., mouse IgG antibody clone M48) that recognizes the three-dimensional structure of CLDN5 (prepared according to the methods described in Non-Patent Document 4 and Patent Document 1) and detection beads, and then irradiating with excitation light to detect and evaluate the proximity of the hCLDN5 proteoliposomes and the anti-hCLDN5 antibody by AlphaScreen; and (ii) mixing a test compound with hCLDN1 proteoliposomes, adding an anti-hCLDN1 antibody (e.g., clone 3A2) (Fukasawa M, et al. J. Virol. 89, 4866-4879). (2015). ) and detection beads are added, followed by irradiating with excitation light to detect and evaluate the proximity of the hCLDN1 proteoliposome and the anti-hCLDN1 antibody by AlphaScreen; and (iii) selecting a compound that inhibits only the binding of hCLDN5 and the anti-hCLDN5 antibody based on the evaluations in (i) and (ii) above.

[0586] The principle of the above screening method is as follows. Specifically, the CLDN5 proteoliposome contains a biotinylated lipid and binds to streptavidin donor beads. Meanwhile, the anti-CLDN5 antibody binds to Protein G acceptor beads. The CLDN5 proteoliposome and the anti-CLDN5 antibody antigen-antibody complex are formed, and when the donor beads and acceptor beads are in close proximity, excitation light is irradiated onto the donor beads, producing singlet oxygen, which the acceptor beads receive and emit chemiluminescence. When a test compound that inhibits the binding of CLDN5 and anti-CLDN5 antibody is added to this assay system, the donor beads and acceptor beads cannot be brought into close proximity, resulting in quenching.

[0587] Candidate compounds selected by such screening methods can be evaluated for blood-brain barrier permeability by measuring transendothelial electrical resistance (TEER) using HDMEC or hCLDN5 protein-expressing MDCKII cells (MDCKII-hCLDN5) prepared according to the method described in Patent Document 1.

[0588] The present invention will be described in detail below based on examples and test examples, but the present invention is not limited to the examples and test examples and may be modified within the scope of the present invention.

[0589] % indicates mol / mol% for yield, and % by weight for other values ​​unless otherwise specified. Room temperature indicates a temperature of 15°C to 30°C unless otherwise specified. Other abbreviations used in the text have the following meanings. EDC·HCl: 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride Lawesson's reagent: 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide THF: tetrahydrofuran DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DPPA: diphenylphosphoryl azide DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DIAD: diisopropyl azodicarboxylate CPME: cyclopentyl methyl ether HOBt: 1-hydroxybenzotriazole CDCl ３ : deuterated chloroform PFA: paraformaldehyde BSA: bovine serum albumin MSco: methylscopolamine PdCl ２ (dppf): [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd ２ (dba) ３ : Bis(dibenzylideneacetone)palladium(0) rac-BINAP: rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0590] Nuclear magnetic resonance spectroscopy (NMR) was performed using a Bruker AVANCE 400. １ H-NMR was performed at 400 MHz, room temperature, and using CDCl as a deuterated solvent. ３ was measured using

[0591] Unless otherwise specified, the raw material compounds used in the following examples and test examples are known compounds, and were synthesized and identified according to known methods or methods equivalent thereto, or were commercially available products and used as they were. Furthermore, unless otherwise specified, the reagents and devices used in the following examples and test examples are commercially available.

[0592] Example 1: Synthesis of (E)-N-(4-isopropylphenyl)-3-(5-methylfuran-2-yl)acrylamide (compound (1))

[0593]

[0594] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (306 mg, 2.01 mmol) and HOBt.H ２ To a solution of 2H2O (459 mg, 3.00 mmol) in DMF (6.0 mL), DIPEA (523 μL, 3.00 mmol), 4-isopropylaniline (compound (ii-1)) (406 mg, 3.00 mmol), and EDC.HCl (575 mg, 3.00 mmol) were added, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate, water, and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (compound (1)) (404 mg, 1.50 mmol, 74.6%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.23 (d, 6H, J = 6.8 Hz), 2.33 (s, 3H), 2.88 (sept, 1H, J = 6.8 Hz), 6.06 (dd, 1H, J = 3.0, 1.2 Hz), 6.37 (d, 1H, J = 15.2 Hz), 6.46 (d, 1H, J = 3.0 Hz), 7.16-7.22 (AA'BB', 2H), 7.36 (brs, 1H), 7.44 (d, 1H, J = 15.2 Hz), 7.47-7.56 (AA'BB', 2H).

[0595] Example 2: Synthesis of (E)-3-(5-methylfuran-2-yl)-N-(pyren-1-yl)acrylamide (compound (2))

[0596]

[0597] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (304 mg, 2.00 mmol) and 1-aminopyrene (compound (ii-2)) (652 mg, 3.00 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (2)) (34.5 mg, 98.2 μmol, 4.92%) as a yellow solid. 1 H NMR (CDCl3, 500 MHz) δ 2.38 (s, 3H), 6.04-6.17 (brs, 1H), 6.46-6.76 (m, 2H),7.59 (d, 1H, J = 14.9 Hz), 7.82-8.23 (m, 9H), 8.55 (brs, 1H).

[0598] Example 3: Synthesis of (E)-3-(5-methylfuran-2-yl)-N-(pyren-4-yl)acrylamide (compound (3))

[0599]

[0600] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (305 mg, 2.00 mmol) and 4-aminopyrene (compound (ii-3)) (651 mg, 3.00 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (3)) (208 mg, 0.591 mmol, 29.5%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 6.04-6.15 (m, 1H), 6.49-6.72 (m, 2H), 7.60 (d, 1H, J = 14.8 Hz), 7.92-8.28 (m, 9H), 8.74 (brs, 1H).

[0601] Example 4: Synthesis of (E)-3-(5-methylfuran-2-yl)-N-(4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)acrylamide (compound (4))

[0602]

[0603] Using dichloromethane as a reaction solvent, in the absence of DIPEA and in the presence of DMAP instead of HOBt, (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (67.0 mg, 0.440 mmol) and 4-(3-(trifluoromethyl)-3H-diazirin-3-yl)aniline (compound (ii-4)) (80.3 mg, 0.399 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (4)) (106 mg, 0.317 mmol, 79.3%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 6.09 (dd, 1H, J = 3.2, 0.8 Hz), 6.34 (d, 1H, J = 14.8 Hz), 6.52 (d, 1H, J = 3.2 Hz), 7.14-7.19 (AA'BB', 2H), 7.31 (brs, 1H), 7.45 (d, 1H, J = 14.8 Hz), 7.62-7.67 (AA'BB', 2H).

[0604] Example 5: Synthesis of (E)-3-(furan-2-yl)-N-(4-isopropylphenyl)acrylamide (compound (5))

[0605]

[0606] (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (138 mg, 0.999 mmol) and 4-isopropylaniline (compound (ii-1)) (203 mg, 1.50 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (5)) (153 mg, 0.600 mmol, 60.1%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.24 (d, 6H, J = 6.8 Hz), 2.89 (sept, 1H, J = 6.8 Hz), 6.44 (d, 1H, J = 15.2 Hz), 6.47 (dd, 1H, J = 3.4, 1.8 Hz), 6.59 (d, 1H, J = 3.4 Hz), 7.17-7.24 (AA'BB', 2H), 7.44-7.56 (m, 4H).

[0607] Example 6: Synthesis of (E)-3-(5-bromofuran-2-yl)-N-(4-isopropylphenyl)acrylamide (compound (6))

[0608]

[0609] The title compound (compound (6)) (1.43 g, 4.28 mmol, 85.5%) was obtained as a pale yellow solid by treating the same manner as in Example 1 using (E)-3-(5-bromofuran-2-yl)acrylic acid (compound (i-3)) (1.09 g, 5.01 mmol) and 4-isopropylaniline (compound (ii-1)) (1.02 g, 7.51 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1 H NMR (CDCl3, 400 MHz) δ 1.17 (d, 6H, J = 6.8 Hz), 2.82 (sept, 1H, J = 6.8 Hz), 6.33 (d, 1H, J = 3.6 Hz), 6.37 (d, 1H, J = 14.8 Hz), 6.46 (d, 1H, J = 3.6 Hz), 7.11-7.15 (AA'BB', 2H), 7.17 (brs, 1H), 7.34 (d, 1H, J = 14.8 Hz), 7.40-7.47 (AA'BB', 2H).

[0610] Example 7: Synthesis of (E)-N-(4-(tert-butyl)phenyl)-3-(5-methylfuran-2-yl)acrylamide (compound (7))

[0611]

[0612] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (152 mg, 0.999 mmol) and 4-(tert-butyl)aniline (compound (ii-5)) (258 mg, 1.73 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (7)) (173 mg, 0.612 mmol, 61.2%) as a pale yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 2.35 (s, 3H), 6.08 (d, 1H, J = 3.2, 0.8 Hz), 6.36 (d, 1H, J = 15.2 Hz), 6.49 (d, 1H, J = 3.2 Hz), 7.19 (brs, 1H), 7.33-7.39 (AA'BB', 2H), 7.44 (d, 1H, J = 15.2 Hz), 7.48-7.58 (AA'BB', 2H).

[0613] Example 8: Synthesis of (E)-N-(4-bromophenyl)-3-(5-methylfuran-2-yl)acrylamide (compound (8))

[0614]

[0615] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (457 mg, 3.00 mmol) and 4-bromoaniline (compound (ii-6)) (774 mg, 4.50 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (8)) (799 mg, 2.61 mmol, 87.0%) as a pale yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 6.09 (dd, 1H, J = 3.2, 0.8 Hz), 6.34 (d, 1H, J = 15.2 Hz), 6.51 (d, 1H, J = 3.2 Hz), 7.21 (brs, 1H), 7.41-7.47 (m, 3H), 7.47-7.53 (AA'BB', 2H).

[0616] Example 9: Synthesis of (E)-N-(4-ethylphenyl)-3-(5-methylfuran-2-yl)acrylamide (compound (9))

[0617]

[0618] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (153 mg, 1.00 mmol) and 4-ethylaniline (compound (ii-7)) (187 μL, 1.50 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (9)) (220 mg, 0.862 mmol, 86.0%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.22 (t, 1H, J = 7.6 Hz), 2.34 (s, 3H), 2.62 (q, 1H, J = 7.6 Hz), 6.07 (d, 1H, J = 3.1 Hz), 6.36 (d, 1H, J = 15.1 Hz), 6.48 (d, 1H, J = 3.1 Hz), 7.13-7.19 (AA'BB', 2H), 7.21-7.28 (m, 1H), 7.44 (d, 1H, J = 15.1 Hz), 7.47-7.55 (AA'BB', 2H).

[0619] Example 10: Synthesis of (E)-N-(4-isopropylphenyl)benzofuran-6-carboxamide (compound (10))

[0620]

[0621] Benzofuran-6-carboxylic acid (648 mg, 4.00 mmol) and 4-isopropylaniline (compound (ii-1)) (811 mg, 6.00 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (10)) (1.01 g, 3.612 mmol, 90.6%) as a colorless solid. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H, J = 7.2 Hz), 2.91 (sept, 1H, J = 7.2 Hz), 6.84 (dd, 1H, J = 2.0, 0.8 Hz), 7.22-7.28 (AA'BB' 2H), 7.54-7.60 (AA'BB', 2H), 7.68 (d, 1H, J = 8.4 Hz), 7.73-7.78 (m, 2H), 7.84 (brs, 1H), 8.07 (s, 1H).

[0622] Example 11: Synthesis of 3-(furan-2-yl)-N-(4-isopropylphenyl)propanamide (compound (11))

[0623]

[0624] (E)-3-(furan-2-yl)propanoic acid (1.09 mg, 4.01 mmol) and 4-isopropylaniline (compound (ii-1)) (811 mg, 6.00 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (11)) (950 mg, 3.69 mmol, 92.0%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz) δ 1.22 (d, 1H, J = 7.2 Hz), 2.68 (t, 2H, J = 7.4 Hz), 2.87 (sept, 1H, J = 7.2 Hz), 3.07 (t, 2H, J = 7.4 Hz), 6.07 (d, 1H, J = 2.8 Hz), 6.29 (dd, 1H, J = 2.4, 2.4 Hz), 7.12-7.23 (m, 3H), 7.29-7.34 (m, 1H), 7.34-7.40 (AA'BB', 2H).

[0625] Example 12: Synthesis of 4-isopropylphenyl(E)-3-(5-methylfuran-2-yl)acrylic acid (compound (12))

[0626]

[0627] Dichloromethane was used as a reaction solvent, and in the presence of DMAP instead of HOBt, (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (375 mg, 2.48 mmol) and 4-isopropylphenol (851 mg, 6.25 mmol) were used, and the reaction was treated in the same manner as in Example 1 to give the title compound (compound (12)) (392 mg, 1.45 mmol, 58.4%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.25 (d, 6H, J = 6.8 Hz), 2.37 (s, 1H), 2.92 (sept, 1H, J = 6.8 Hz), 6.11 (dd, 1H, J = 3.6 Hz), 6.41 (d, 1H, J = 15.6 Hz), 6.58 (d, 1H, J = 3.6 Hz), 7.03-7.09 (AA'BB', 2H), 7.21-7.27 (AA'BB', 2H), 7.52 (d, 1H, J = 15.6 Hz).

[0628] Example 13: Synthesis of (E)-N-(4-isopropylphenyl)-3-(thiophen-2-yl)acrylamide (compound (13))

[0629]

[0630] (E)-3-(thiophen-2-yl)acrylic acid (compound (i-4)) (773 mg, 5.01 mmol) and 4-isopropylaniline (compound (ii-1)) (1.02 g, 7.50 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (13)) (1.21 g, 4.46 mmol, 89.0%) as a colorless solid. 1H NMR (CDCl3, 400 MHz) δ 1.24 (d, 6H, J = 6.8 Hz), 2.89 (sept, 6H, J = 6.8 Hz), 6.35 (d, 1H, J = 15.2 Hz), 7.05 (dd, 1H, J = 5.0, 3.8 Hz), 7.17-7.23 (AA'BB', 2H), 7.23-7.32 (m, 2H), 7.34 (d, 1H, J = 5.0 Hz), 7.47-7.56 (AA'BB', 2H), 7.86 (d, 1H, J = 15.2 Hz).

[0631] Example 14: Synthesis of N-(4-isopropylphenyl)quinoline-7-carboxamide (compound (14))

[0632]

[0633] Quinoline-7-carboxylic acid (597 mg, 4.00 mmol) and 4-isopropylaniline (compound (ii-1)) (811 mg, 6.03 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (14)) (520 mg, 1.79 mmol, 44.8%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H, J = 6.8 Hz), 2.92 (sept, 1H, J = 6.8 Hz), 7.23-7.29 (AA'BB', 2H), 7.50 (dd, 1H, J = 8.2, 4.2 Hz), 7.60-7.65 (AA'BB', 2H), 7.93 (d, 1H, J = 8.8 Hz), 8.11 (dd, 1H, J = 8.8, 1.6 Hz), 8.18-8.26 (m, 2H), 8.54 (m, 1H), 8.96-9.02 (m, 1H).

[0634] Example 15: Synthesis of (E)-N-(anthracen-2-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (15))

[0635]

[0636] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (76.1 mg, 5.04 mmol) and 2-aminoanthracene (compound (ii-8)) (147 mg, 7.61 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (15)) (83.6 mg, 0.259 mmol, 51.3%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 2.37 (s, 3H), 6.11 (d, 1H, J = 3.2 Hz), 6.44 (d, 1H, J = 14.8 Hz), 6.54 (d, 1H, J = 3.2 Hz), 7.40-7.48 (m, 4H), 7.52 (d, 1H, J = 14.8 Hz), 7.94-8.01 (m, 3H), 8.37 (s, 1H), 8.38 (s, 1H), 8.52 (brs, 1H).

[0637] Example 16: Synthesis of (E)-N-([1,1'-biphenyl]-4-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (16))

[0638]

[0639]

[0133] The title compound (compound (16)) (77.2 mg, 0.254 mmol, 85.0%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (65.0 mg, 0.300 mmol) and 4-aminobiphenyl (compound (ii-9)) (76.2 mg, 0.450 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1H NMR (CDCl3, 400 MHz) δ 2.39 (s, 3H), 6.12 (dd, 1H, J = 3.2, 0.8 Hz), 6.40 (d, 1H, J = 15.2 Hz), 6.54 (d, 1H, J = 3.2 Hz), 7.26-7.30 (m, 1H), 7.35 (t, 1H, J = 7.4 Hz), 7.43-7.53 (m, 3H), 7.58-7.63 (AA'BB', 4H), 6.53 (d, 1H, J = 3.2 Hz), 7.67-7.73 (m, 2H).

[0640] Example 17: Synthesis of (E)-N-([1,1':4',1''-terphenyl]-4-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (17))

[0641]

[0642] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (76.9 mg, 0.509 mmol) and 4-amino-p-terphenyl (compound (ii-10)) (185 mg, 0.753 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (17)) (46.0 mg, 0.121 mmol, 23.8%) as a pale yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 2.37 (s, 3H), 6.10 (d, 1H, J = 3.2 Hz), 6.39 (d, 1H, J = 15.2 Hz), 6.53 (d, 1H, J = 3.2 Hz), 7.27-7.31 (m, 1H), 7.33-7.39 (m, 1H), 7.43-7.51 (m, 3H), 7.60-7.73 (m, 10H).

[0643] Example 18: Synthesis of (E)-3-(5-methylfuran-2-yl)-N-(pyren-1-ylmethyl)acrylamide (compound (18))

[0644]

[0645] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (75.7 mg, 0.501 mmol) and 1-pyrenemethylamine hydrochloride (compound (ii-11)) (200 mg, 0.747 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (18)) (66.2 mg, 0.181 mmol, 36.2%) as a pale yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 2.27 (s, 3H), 5.26 (d, 1H, J = 5.6 Hz), 5.85-5.93 (m, 1H), 6.03 (dd, 1H, J = 3.2, 1.0 Hz), 6.20 (d, 1H, J = 15.2 Hz), 6.45 (d, 1H, J = 3.2 Hz), 7.43 (d, 1H, J = 15.2 Hz), 7.97-8.09 (m, 4H), 8.12-8.22 (m, 4H), 8.28 (d, 1H, J = 9.2 Hz).

[0646] Example 19: Synthesis of (E)-N-(9H-fluoren-2-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (19))

[0647]

[0648] In the absence of DIPEA, (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (77.4 mg, 0.512 mmol) and 9H-fluoren-2-amine (compound (ii-12)) (136 mg, 0.753 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (19)) (24.4 mg, 77.4 μmol, 15.1%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 2.36 (s, 3H), 3.91 (s, 1H), 6.09 (dd, 1H, J = 3.2, 1.2 Hz), 6.39 (d, 1H, J = 15.2 Hz), 6.52 (d, 1H, J = 3.2 Hz), 7.28 (dd, 1H, J = 7.2, 1.0 Hz), 7.31-7.39 (m, 2H), 7.39-7.45 (m, 1H), 7.47 (d, 1H, J = 15.2 Hz), 7.50-7.55 (m, 1H), 7.72 (d, 1H, J = 8.0 Hz), 7.74 (d, 1H, J = 7.2 Hz), 8.00 (brs, 1H).

[0649] Example 20: Synthesis of 4-isopropylphenyl(E)-3-(furan-2-yl)acrylic acid (compound (20))

[0650]

[0651] The title compound (compound (20)) (45.9 mg, 0.179 mmol, 35.3%) was obtained as a colorless solid by treating the compound (i-2) in the same manner as in Example 1 using (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (70.0 mg, 5.07 mmol) and 4-isopropylphenol (1.02 g, 0.625 mmol) in the presence of DMAP instead of HOBt, but without DIPEA, using dichloromethane as a reaction solvent. 1 H NMR (CDCl3, 500 MHz) δ 1.28 (d, 1H, J = 7.0 Hz), 2.95 (sept, 1H, J = 7.0 Hz), 6.53 (d, 1H, J = 15.5 Hz), 6.53 (dd, 1H, J = 3.5, 2.0 Hz), 6.71 (d, 1H, J = 3.5 Hz), 7.07-7.13 (AA'BB', 2H), 7.24-7.31 (AA'BB', 2H), 7.56 (d, 1H, J = 2.0 Hz), 7.62 (d, 1H, J = 15.4 Hz).

[0652] Example 21: Synthesis of (E)-N-(anthracen-2-yl)-3-(furan-2-yl)acrylamide (compound (21))

[0653]

[0654]

[0133] The title compound (compound (21)) (57.2 mg, 0.183 mmol, 60.7%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (41.5 mg, 0.300 mmol) and 2-aminoanthracene (compound (ii-8)) (87.1 mg, 0.451 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1 H NMR (CDCl3, 400 MHz) δ 6.52 (d, 1H, J = 15.1 Hz), 6.50 (dd, 1H, J = 3.3, 1.9 Hz), 6.65 (d, 1H, J = 3.3 Hz), 7.40-7.53 (m, 5H), 7.59 (d, 1H, J = 15.1 Hz), 7.95-8.02 (m, 3H), 8.37 (s, 1H), 8.39 (s, 1H), 8.53 (brs, 1H).

[0655] Example 22: Synthesis of (E)-N-([1,1'-biphenyl]-4-yl)-3-(furan-2-yl)acrylamide (compound (22))

[0656]

[0657]

[0133] The title compound (compound (22)) (65.8 mg, 0.227 mmol, 75.8%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (41.5 mg, 0.300 mmol) and 4-aminobiphenyl (compound (ii-9)) (76.1 mg, 0.450 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1H NMR (CDCl3, 400 MHz) δ 6.47 (d, 1H, J = 15.2 Hz), 6.49 (dd, 1H, J = 3.4, 1.8 Hz), 6.62 (d, 1H, J = 3.4 Hz), 7.29-7.37 (m, 2H), 7.40-7.49 (m, 3H), 7.55 (d, 1H, J = 15.2 Hz), 7.57-7.61 (m, 4H), 7.64-7.73 (m, 2H).

[0658] Example 23: Synthesis of (E)-N-([1,1':4',1''-terphenyl]-4-yl)-3-(furan-2-yl)acrylamide (compound (23))

[0659]

[0660]

[0133] The title compound (compound (23)) (35.5 mg, 97.1 µmol, 32.2%) was obtained as a pale yellow solid by treating the same procedure as in Example 1 using (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (41.7 mg, 0.302 mmol) and 4-amino-p-terphenyl (compound (ii-10)) (110 mg, 0.450 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1 H NMR (CDCl3, 400 MHz) δ 6.47 (d, 1H, J = 15.1 Hz), 6.49 (dd, 1H, J = 3.4, 1.8 Hz), 6.63 (d, 1H, J = 3.4 Hz), 7.31-7.38 (m, 2H), 7.43-7.49 (m, 3H), 7.55 (d, 1H, J = 15.1 Hz), 7.61-7.76 (m, 10H).

[0661] Example 24: Synthesis of (E)-N-(9H-fluoren-2-yl)-3-(furan-2-yl)acrylamide (compound (24))

[0662]

[0663]

[0133] Dichloromethane was used as a reaction solvent in the absence of DIPEA, and treatment was carried out in the same manner as in Example 1 using (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (41.5 mg, 0.300 mmol) and 9H-fluoren-2-amine (compound (ii-12)) (81.6 mg, 0.450 mmol) to give the title compound (compound (24)) (65.8 mg, 0.218 µmol, 72.6%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz) δ 3.91 (s, 2H), 6.42-6.51 (m, 2H), 6.62 (d, 1H, J = 3.3 Hz), 7.29 (dd, 1H, J = 7.4, 1.0 Hz), 7.32-7.40 (m, 2H), 7.41-7.50 (m, 2H), 7.53 (d, 1H, J = 7.4 Hz), 7.54 (d, 1H, J = 15.2 Hz), 7.69-7.78 (m, 2H), 8.01 (brs, 1H).

[0664] Example 25: Synthesis of (E)-3-(5-(azidomethyl)furan-2-yl)-N-(4-isopropylphenyl)acrylamide (compound (25))

[0665]

[0666] (1) Ethyl (E)-3-(5-(hydroxymethyl)furan-2-yl)acrylate (1.39 g, 6.28 mmol) and DPPA (1.80 mL, 8.37 mmol) were dissolved in toluene (21 mL) and cooled to 0°C. DBU (1.25 mL, 8.37 mmol) was added to this solution, and the mixture was warmed to room temperature and stirred for 21 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give ethyl (E)-3-(5-(azidomethyl)furan-2-yl)acrylate (1.35 g, 6.09 mmol, 97.0%) as a brown oil.

[0667] (2) Ethyl (E)-3-(5-(azidomethyl)furan-2-yl)acrylate (1.23 g, 5.54 mmol) and lithium hydroxide monohydrate (1.16 g, 27.6 mmol) were dissolved in methanol (55 mL) and water (28 mL), and the solution was heated to 55°C and stirred for 3 hours. After the reaction solution was cooled to room temperature, it was acidified with 1 M hydrochloric acid, extracted three times with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain (E)-3-(5-(azidomethyl)furan-2-yl)acrylic acid (compound (i-5)) (1.03 g, 5.34 mmol, 96.3%) as a light brown solid.

[0668] (3) In the absence of DIPEA, (E)-3-(5-(azidomethyl)furan-2-yl)acrylic acid (compound (i-5)) (196 mg, 1.02 mmol) and 4-isopropylaniline (compound (ii-1)) (214 μL, 1.50 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (25)) (288 mg, 0.929 mmol, 91.4%) as a light brown solid. 1 H NMR (CDCl3, 400 MHz) δ 1.22 (d, 6H, J = 6.8 Hz), 2.86 (sept, 1H, J = 6.8 Hz), 4.25 (s, 2H), 6.37 (d, 1H, J = 3.6 Hz), 6.45 (d, 1H, J = 3.6 Hz), 6.52 (d, 1H, J = 15.2 Hz), 7.13-7.20 (AA'BB', 2H), 7.45 (d, 1H, J = 15.2 Hz), 7.50-7.60 (AA'BB', 2H), 7.98 (brs, 1H).

[0669] Example 26: Synthesis of (E)-3-(5-(azidomethyl)furan-2-yl)-N-(4-azidophenyl)acrylamide (compound (26))

[0670]

[0671] (E)-3-(5-(azidomethyl)furan-2-yl)acrylic acid (compound (i-5)) (194 mg, 1.00 mmol) and 4-azidoaniline hydrochloride (compound (ii-13)) (257 g, 1.51 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (26)) (284 mg, 0.919 mmol, 91.6%) as a brown solid. 1 H NMR (CDCl3, 400 MHz) δ 4.29 (s, 2H), 6.40 (d, 1H, J = 3.2 Hz), 6.49 (d, 1H, J = 15.2 Hz), 6.51 (d, 1H, J = 3.2 Hz), 6.93-7.00 (AA'BB', 2H), 7.46 (d, 1H, J = 15.2 Hz), 7.58-7.67 (AA'BB', 2H), 7.97 (brs, 1H).

[0672] Example 27: Synthesis of N-(4-isopropylphenyl)benzofuran-6-carbothioamide (compound (27))

[0673]

[0674] A solution of compound (10) (83.9 mg, 0.300 mmol) and Lawesson's reagent (71.8 mg, 0.178 mmol) in toluene (2.4 mL) was heated at 110° C. and stirred for 7 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (compound (27)) (33.8 mg, 0.114 mmol, 38.1%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H, J = 6.8 Hz), 2.95 (sept, 1H, J = 6.8 Hz), 6.82 (s, 1H), 7.27-7.36 (AA'BB', 2H), 7.59-7.81 (m, 5H), 8.04-8.12 (m, 1H), 9.03 (brs, 1H).

[0675] Example 28: Synthesis of N-(4-isopropylphenyl)quinoline-7-carbothioamide (compound (28))

[0676]

[0677] Compound (14) (87.0 mg, 0.300 mmol) was treated in the same manner as in Example 27 to give the title compound (compound (28)) (14.8 mg, 48.3 μmol, 16.1%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.29 (d, 6H, J = 7.2 Hz), 2.96 (sept, 1H, J = 7.2 Hz), 7.30-7.37 (AA'BB', 2H), 7.47 (dd, 1H, J = 8.2, 4.2 Hz), 7.76-7.83 (AA'BB', 2H), 7.87 (d, 1H, J = 8.4 Hz), 8.19 (d, 1H, J = 8.2 Hz), 8.22 (dd, 1H, J = 8.4, 1.4 Hz), 8.35-8.40 (m, 1H), 8.96 (d, 6H, J = 4.2 Hz), 9.55 (brs, 1H).

[0678] Example 29: Synthesis of (E)-N-(4-isopropylphenyl)-3-(5-((trimethylsilyl)ethynyl)furan-2-yl)acrylamide (compound (29))

[0679]

[0680] To a solution of compound (6) (168 mg, 0.501 mmol) and trimethylsilylacetylene (73.7 mg, 0.750 μmol) in THF (438 μL), triethylamine (175 μL, 1.26 mmol), tetrakis(triphenylphosphine)palladium(0) (29.1 mg, 25.2 μmol), and copper(I) iodide (9.52 mg, 50.0 μmol) were added and stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (compound (29)) (61.4 mg, 0.175 mmol, 34.9%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz) δ 0.27 (s, 9H), 1.24 (d, 6H, J = 7.2 Hz), 2.89 (sept, 1H, J = 7.2 Hz), 6.52 (d, 1H, J = 15.2 Hz), 6.54 (d, 1H, J = 3.6 Hz), 6.65 (d, 1H, J = 3.6 Hz), 7.17-7.23 (m, 3H), 7.43 (d, 1H, J = 15.2 Hz), 7.47-7.54 (AA'BB', 2H).

[0681] Example 30: Synthesis of (E)-3-(5-ethynylfuran-2-yl)-N-(4-isopropylphenyl)acrylamide (compound (30))

[0682]

[0683] A methanol solution (1.0 mL) of compound (29) (34.5 mg, 98.1 μmol) and potassium carbonate (41.5 mg, 0.300 μmol) was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (compound (30)) (26.1 mg, 93.4 μmol, 95.2%) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 1.23 (d, 6H, J = 6.8 Hz), 2.88 (sept, 1H, J = 6.8 Hz), 3.49 (s, 1H), 6.529 (d, 1H, J = 14.8 Hz), 6.533 (d, 1H, J = 3.6 Hz), 6.69 (d, 1H, J = 3.6 Hz), 7.16-7.23 (AA'BB', 2H), 7.39 (brs, 1H), 7.44 (d, 1H, J = 14.8 Hz), 7.47-7.58 (AA'BB', 2H).

[0684] Example 31: Synthesis of 7-((4-isopropylphenoxy)methyl)quinoline (compound (31))

[0685]

[0686] To a solution of quinolin-3-ylmethanol (compound (iv-1)) (78.3 mg, 0.492 mmol), 4-isopropylphenol (compound (v-1)) (88.0 mg, 0.646 mmol), and triphenylphosphine (172 mg, 0.655 mmol) in THF (1.0 mL) was added DIAD (approximately 1.9 M toluene solution, 340 μL, 0.646 mmol) at 0°C, and the mixture was then warmed to room temperature and stirred for 22 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (compound (31)) (21.7 mg, 78.2 μmol, 15.9%) as a colorless solid. 1H NMR (CDCl3, 400 MHz) δ 1.22 (d, 6H, J = 6.8 Hz), 2.86 (sept, 1H, J = 6.8 Hz), 5.27 (s, 2H), 6.93-6.99 (AA'BB', 2H), 7.12-7.18 (AA'BB', 2H), 7.40 (dd, 1H, J = 8.4, 4.4 Hz), 7.64 (dd, 1H, J = 8.4, 1.6 Hz), 7.84 (d, 1H, J = 8.4 Hz), 8.14-8.18 (m, 2H), 8.92 (dd, 1H, J = 4.4, 1.6 Hz).

[0687] Example 32: Synthesis of (Z)-6-(1-fluoro-2-(4-isopropylphenyl)vinyl)benzofuran (compound (32))

[0688]

[0689] (1) 6-Bromobenzofuran (compound (vi-1)) (100 mg, 0.508 mmol), potassium (Z)-1-fluoro-2-tosyloxyethenyl(trifluoro)borate (compound (vii)) (243 mg, 0.753 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (17.5 mg, 25.0 μmol), and cesium fluoride (228 mg, 1.50 mmol) were dissolved in ethylene glycol (5.0 mL), and the solution was heated to 80° C. and stirred for 24 hours. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (Z)-2-(benzofuran-6-yl)-2-fluorovinyl 4-methylbenzenesulfonate (compound (viii-1)) (143 mg, 0.430 mmol, 84.7%) as a yellow solid.

[0690] (2) To a solution of (Z)-2-(benzofuran-6-yl)-2-fluorovinyl 4-methylbenzenesulfonate (compound (viii-1)) (66.5 mg, 0.200 mmol) obtained in (1) above and p-isopropylphenylboronic acid (compound (ix-1)) (49.2 mg, 0.300 mmol) in CPME / methanol (10:1, 2.2 mL) was added Pd CPhos G4 (4.2 mg, 5.12 μmol) and cesium fluoride (61.0 mg, 0.201 mmol), and the solution was heated to 80° C. and stirred for 18 hours. After cooling to room temperature, water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (compound (32)) (35.2 mg, 0.126 mmol, 63.0%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H, J = 6.8 Hz), 2.93 (sept, 1H, J = 6.8 Hz), 6.35 (d, 1H, J = 40.0 Hz), 6.79 (dd, 1H, J = 2.4, 0.8 Hz), 7.22-7.28 (AA'BB', 2H), 7.54 (dd, 1H, J = 8.2, 1.0 Hz), 7.57-7.62 (m, 3H), 7.67 (d, 1H, J = 2.4 Hz), 7.77-7.80 (m, 1H).

[0691] Example 33: Synthesis of (Z)-7-(1-fluoro-2-(4-isopropylphenyl)vinyl)quinoline (compound (33))

[0692]

[0693] By using 7-bromoquinoline (compound (vi-2)) (105 mg, 0.505 mmol) instead of 6-bromobenzofuran (compound (vi-1)) in Example 32, (Z)-2-fluoro-2-(quinolin-7-yl)vinyl 4-methylbenzenesulfonate (compound (viii-2)) (169 mg, 0.493 mmol, 97.8%) was obtained as a yellow-brown solid. The obtained (Z)-2-fluoro-2-(quinolin-7-yl)vinyl 4-methylbenzenesulfonate (compound (viii-2)) (34.2 mg, 99.6 μmol) was treated in the same manner as in (2) of Example 32 to give the title compound (compound (33)) (13.5 mg, 46.3 μmol, 46.5%) as a pale yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.28 (d, 6H, J = 6.8 Hz), 2.94 (sept, 1H, J = 6.8 Hz), 6.54 (d, 1H, J = 39.6 Hz), 7.26-7.31 (AA'BB', 2H), 7.43 (dd, 1H, J = 8.0, 4.2 Hz), 7.62-7.67 (AA'BB', 2H), 7.81 (dd, 1H, J = 8.8, 1.4 Hz), 7.85 (d, 1H, J = 8.8 Hz), 8.18 (d, 1H, J = 8.0 Hz), 8.40 (s, 1H), 8.95 (dd, 1H, J = 4.2, 1.4 Hz).

[0694] Example 34: Synthesis of (E)-3-(5-bromofuran-2-yl)-N-(3-isopropylphenyl)acrylamide (compound (34))

[0695]

[0696]

[0133] The title compound (compound (34)) (59.9 mg, 0.179 mmol, 35.9%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(5-bromofuran-2-yl)acrylic acid (compound (i-3)) (108 mg, 0.499 mmol) and 3-isopropylaniline (compound (ii-14)) (101 mg, 0.750 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1 H NMR (CDCl3, 400 MHz) δ 1.18 (d, 6H, J = 6.9 Hz), 2.83 (sept, 1H, J = 6.9 Hz), 6.33 (d, 1H, J = 3.4 Hz), 6.39 (d, 1H, J = 15.1 Hz), 6.45 (d, 1H, J = 3.4 Hz), 6.94 (d, 1H, J = 7.8 Hz), 7.19 (d, 1H, J = 15.1 Hz), 7.23-7.38 (m, 3H), 7.42 (brs, 1H).

[0697] Example 35: Synthesis of (E)-3-(5-phenylfuran-2-yl)-N-(3-isopropylphenyl)acrylamide (compound (35))

[0698]

[0699] (E)-3-(5-bromofuran-2-yl)-N-(3-isopropylphenyl)acrylamide (compound (34)) (101 mg, 0.303 mmol), phenylboronic acid (91.8 mg, 0.450 mmol), and potassium phosphate (159 mg, 0.750 mmol) were dissolved in DMF (1.5 mL) and water (0.38 mL). Tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 15.0 μmol) was added to this solution, and the solution was heated to 80°C and stirred for 14 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (compound (35)) (38.2 mg, 0.115 mmol, 38.0%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 1.29 (d, 6H, J = 7.2 Hz), 2.94 (sept, 1H, J = 7.2 Hz), 2.94 (sept, 1H, J = 7.2 Hz), 6.58 (d, 1H, J = 15.2 Hz), 6.70 (d, 1H, J = 3.6 Hz), 6.76 (d, 1H, J = 3.6 Hz), 7.03 (d, 1H, J = 7.6 Hz), 7.26-7.39 (m, 3H), 7.41-7.49 (m, 3H), 7.52-7.59 (m, 2H), 7.72-7.79 (m, 2H).

[0700] Example 36: Synthesis of (E)-3-(5-methylfuran-2-yl)-N-(9-oxo-9H-fluoren-2-yl)acrylamide (compound (36))

[0701]

[0702] The title compound (compound (36)) (38.0 mg, 0.115 mmol, 38.3%) was obtained as an orange solid by treating the same procedure as in Example 1 using (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (45.8 mg, 0.301 mmol) and 2-amino-9H-fluoren-9-one (87.2 mg, 0.447 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1 H NMR (DMSO-d6, 500 MHz): δ 10.41 (s, 1H), 8.04 (s, 1H), 7.77 (dd, 1H, J = 7.3, 1.5 Hz), 7.73 (dd, 1H, J = 7.3, 1.6 Hz), 7.70 (d, 1H, J = 7.5 Hz), 7.58 (dd, 1H, J = 7.3, 7.3 Hz), 7.57 (d, 1H, J = 7.5 Hz), 7.34 (d, 1H, J = 15.4 Hz), 7.31 (dd, 1H, J = 7.3, 7.3 Hz), 6.77 (d, 1H, J = 3.0 Hz), 6.53 (d, 1H, J = 15.4 Hz), 6.27 (d, 1H, J = 3.0 Hz), 2.35 (s, 3H).

[0703] Example 37: Synthesis of (E)-N-(dibenzofuran-3-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (37))

[0704]

[0705] The title compound (compound (37)) (42.1 mg, 0.133 mmol, 44.2%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (45.7 mg, 0.300 mmol) and 3-aminodibenzofuran (82.8 mg, 0.452 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1H NMR (CDCl3, 400 MHz): δ 8.18 (s, 1H), 7.89 (dd, 1H, J = 8.0, 0.4 Hz), 7.87 (d, 1H, J = 8.4 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.50 (d, 1H, J = 15.2 Hz), 7.45-7.39 (m, 2H), 7.37-7.28 (m, 2H), 6.53 (d, 1H, J = 3.2 Hz), 6.40 (d, 1H, J = 15.2 Hz), 6.10 (dd, 1H, J = 3.2, 1.2 Hz), 2.42 (s, 3H).

[0706] Example 38: Synthesis of (E)-N-(dibenzothiophen-3-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (38))

[0707]

[0708] The title compound (compound (38)) (34.7 mg, 0.104 mmol, 34.4%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (46.0 mg, 0.302 mmol) and 3-aminodibenzothiophene (89.7 mg, 0.450 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1 H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.11-8.05 (m, 2H), 7.85-7.80 (m, 1H), 7.49 (d, 1H, J = 15.0 Hz), 7.48-7.41 (m, 3H), 7.38 (s, 1H), 6.54 (d, 1H, J = 3.2 Hz), 6.40 (d, 1H, J = 15.0 Hz), 6.10 (dd, 1H, J = 3.2, 0.9 Hz), 2.37 (s, 3H).

[0709] Example 39: Synthesis of (E)-N-(phenanthren-2-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (39))

[0710]

[0711] Example 40: Synthesis of (E)-N-(9,9-dimethylfluoren-2-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (40))

[0712]

[0713] Example 41: Synthesis of (E)-N-(9,9-diphenylfluoren-2-yl)-3-(5-methylfuran-2-yl)acrylamide (compound (41))

[0714]

[0715] The title compound (compound (39), compound (40), or compound (41)) was obtained in the same manner as in Example 1 using (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)), 2-aminophenanthrene, 2-amino-9,9-dimethylfluorene, or 2-amino-9,9-diphenylfluorene in the absence of DIPEA, and using dichloromethane as a reaction solvent.

[0716] Example 42: Synthesis of (E)-N-(dibenzofuran-3-yl)-3-(furan-2-yl)acrylamide (compound (42))

[0717]

[0718] The title compound (compound (42)) (45.1 mg, 0.149 mmol, 48.9%) was obtained as a pale yellow solid by treating the same procedure as in Example 1 using (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (42.0 mg, 0.304 mmol) and 3-aminodibenzofuran (82.4 mg, 0.450 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1H NMR (CDCl3, 400 MHz): δ 8.19 (s, 1H), 7.92-7.86 (m, 2H), 7.57 (d, 1H, J = 15.2 Hz), 7.58-7.54 (m, 1H), 7.50-7.45 (m, 2H), 7.43 (ddd, 1H, J = 7.8, 7.8, 1.3 Hz), 7.36 (dd, 1H, J = 5.2, 1.8 Hz), 7.33 (ddd, 1H, J = 7.8, 7.8, 0.9 Hz), 6.64 (d, 1H, J = 3.4 Hz), 6.50 (dd, 1H, J = 3.4, 1.8 Hz), 6.48 (d, 1H, J = 15.2 Hz).

[0719] Example 43: Synthesis of (E)-N-(dibenzothiophen-3-yl)-3-(furan-2-yl)acrylamide (compound (43))

[0720]

[0721]

[0133] The title compound (compound (43)) (41.7 mg, 0.131 mmol, 43.5%) was obtained as a pale yellow solid in the same manner as in Example 1 using (E)-3-(furan-2-yl)acrylic acid (compound (i-2)) (41.5 mg, 0.300 mmol) and 3-aminodibenzothiophene (89.7 mg, 0.450 mmol) and dichloromethane as a reaction solvent in the absence of DIPEA. 1 H NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 8.12-8.05 (m, 2H), 7.85-7.79 (m, 1H), 7.57 (d, 1H, J = 15.1 Hz), 7.50-7.38 (m, 5H), 6.63 (d, 1H, J = 3.4 Hz), 6.49 (dd, 1H, J = 3.4, 1.8 Hz), 6.48 (d, 1H, J = 15.1 Hz).

[0722] Example 44: Synthesis of N-([1,1'-biphenyl]-4-yl)-4-(5-methylfuran-2-yl)pyridin-2-amine (compound (44))

[0723]

[0724] (1) A solution of (5-methylfuran-2-yl)boronic acid pinacol ester (compound (ix-1)) (2.08 g, 10.0 mmol) in 1,4-dioxane / water (5:1, 25 mL) was added with 4-bromopyridin-2-amine (compound (x-1)) (865 mg, 5.00 mmol), PdCl ２ (dppf) (366 mg, 0.500 mmol) and potassium acetate (1.47 g, 15.0 mmol) were added, and the mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite using dichloromethane. A saturated aqueous solution of sodium bicarbonate was added to the filtrate, and the mixture was extracted three times with dichloromethane. The mixture was then washed successively with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-(5-methylfuran-2-yl)pyridin-2-amine (compound (xi-1)) (530 mg, 3.04 mmol, 60.9%) as a light brown solid. 1 H NMR (CDCl3, 400 MHz) δ 7.97 (d, 1H, J = 5.7 Hz), 6.85 (dd, 1H, J = 5.7, 1.4 Hz), 6.74 (s, 1H), 6.70 (d, 1H, J = 3.3 Hz), 6.10 (dd, 1H, J = 3.3, 1.4 Hz), 4.82 (brs, 2H), 2.37 (s, 3H).

[0725] (2) 4-(5-methylfuran-2-yl)pyridin-2-amine (compound (xi-1)) (30.0 mg, 0.172 mmol), 4-bromobiphenyl (60.2 mg, 0.258 mmol), Pd ２ (dba) ３A solution of 4.19 mg, 4.58 μmol), rac-BINAP (5.55 mg, 8.91 μmol), and sodium tert-butoxide (24.5 mg, 0.255 mmol) in toluene (0.85 mL) was stirred at 80°C for 21 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (compound (44)) (19.2 mg, 58.8 μmol, 34.2%) as a light brown solid. 1 H NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H, J = 5.4 Hz), 7.63-7.56 (m, 4H), 7.48-7.40 (m, 4H), 7.35-7.30 (AA'BB'C, 1H), 7.12 (s, 1H), 6.96 (dd, 1H, J = 5.4, 1.4 Hz), 6.71 (d, 1H, J = 3.3 Hz), 6.60 (s, 1H), 6.10 (dd, 1H, J = 3.3, 1.0 Hz), 2.37 (s, 3H).

[0726] Example 45: Synthesis of 4-(5-methylfuran-2-yl)-N-([1,1':4',1''-terphenyl]-4-yl)pyridin-2-amine (compound (45))

[0727]

[0728] 4-(5-methylfuran-2-yl)pyridin-2-amine (compound (xi-1)) (52.3 mg, 0.300 mmol) and 4-bromo-p-terphenyl (139 mg, 0.450 mmol) were treated in a similar manner to (2) of Example 44 to give the title compound (compound (45)) (28.9 mg, 71.8 μmol, 23.9%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H, J = 5.4 Hz), 7.70-7.61 (m, 8H), 7.50-7.43 (m, 4H), 7.39-7.32 (AA'BB'C, 1H), 7.14 (s, 1H), 6.97 (dd, 1H, J = 5.4, 1.4 Hz), 6.76-6.70 (m, 2H), 6.10 (dd, 1H, J = 3.4, 1.0 Hz), 2.38 (s, 3H).

[0729] Example 46: Synthesis of N-(anthracen-2-yl)-4-(5-methylfuran-2-yl)pyridin-2-amine (compound (46))

[0730]

[0731] 4-(5-methylfuran-2-yl)pyridin-2-amine (compound (xi-1)) (52.3 mg, 0.300 mmol) and 2-bromoanthracene (117 mg, 0.455 mmol) were treated in a similar manner to (2) of Example 44 to give the title compound (compound (46)) (9.37 mg, 26.7 μmol, 8.91%) as a brown solid. 1 H NMR (CDCl3, 400 MHz): δ 8.36 (s, 1H), 8.32 (s, 1H), 8.24 (d, 1H, J = 5.6 Hz), 8.06 (s, 1H), 8.01-7.93 (m, 3H), 7.47-7.38 (m, 3H), 7.21 (s, 1H), 7.01 (dd, 1H, J = 5.6, 1.4 Hz), 6.78 (s, 1H), 6.73 (d, 1H, J = 3.2 Hz), 6.10 (dd, 1H, J = 3.2, 0.8 Hz), 2.37 (s, 3H).

[0732] Example 47: Synthesis of N-(fluoren-2-yl)-4-(5-methylfuran-2-yl)pyridin-2-amine (compound (47))

[0733]

[0734] 4-(5-methylfuran-2-yl)pyridin-2-amine (compound (xi-1)) (60.0 mg, 0.344 mmol) and 2-bromofluorene (128 mg, 0.522 mmol) were treated in a similar manner to (2) of Example 44 to give the title compound (compound (47)) (26.2 mg, 77.4 μmol, 22.5%) as a light brown solid. 1 H NMR (CDCl3, 400 MHz) δ 8.18 (d, 1H, J = 5.2 Hz), 7.75 (d, 1H, J = 8.2 Hz), 7.74 (d, 1H, J = 7.4 Hz), 7.63 (d, 1H, J = 1.4 Hz), 7.53 (d, 1H, J = 7.4 Hz), 7.40-7.30 (m, 2H), 7.30-7.24 (m, 1H), 7.09 (s, 1H), 6.95 (dd, 1H, J = 5.2, 1.4 Hz), 6.69 (d, 1H, J = 3.2 Hz), 6.62 (s, 1H), 6.09 (dd, 1H, J = 3.2, 1.0 Hz), 3.92 (s, 2H), 2.36 (s, 3H).

[0735] Example 48: Synthesis of N-(dibenzofuran-3-yl)-4-(5-methylfuran-2-yl)pyridin-2-amine (compound (48))

[0736]

[0737] 4-(5-methylfuran-2-yl)pyridin-2-amine (compound (xi-1)) (59.9 mg, 0.344 mmol) and 3-bromodibenzofuran (128 mg, 0.518 mmol) were treated in a similar manner to (2) of Example 44 to give the title compound (compound (48)) (44.0 mg, 0.129 mmol, 37.6%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.21 (d, 1H, J = 5.0 Hz), 7.89 (dd, 1H, J = 7.5, 1.4 Hz), 7.87 (d, 1H, J = 8.3 Hz), 7.82 (d, 1H, J = 1.8 Hz), 7.55 (d, 1H, J = 7.5 Hz), 7.40 (ddd, 1H, J = 7.5, 7.5, 1.4 Hz), 7.33 (ddd, 1H, J = 7.5, 7.5, 1.0 Hz), 7.24 (dd, 1H, J = 8.3, 1.8 Hz), 7.14 (s, 1H), 6.99 (d, 1H, J = 5.0 Hz), 6.73 (s, 1H), 6.72 (d, 1H, J = 3.3 Hz), 6.10 (dd, 1H, J = 3.3, 1.0 Hz), 2.37 (s, 3H).

[0738] Example 49: Synthesis of N-(dibenzothiophen-3-yl)-4-(5-methylfuran-2-yl)pyridin-2-amine (compound (49))

[0739]

[0740] 4-(5-methylfuran-2-yl)pyridin-2-amine (compound (xi-1)) (52.3 mg, 0.300 mmol) and 3-bromodibenzothiophene (119 mg, 0.452 mmol) were treated in a similar manner to (2) of Example 44 to give the title compound (compound (49)) (37.0 mg, 0.104 mmol, 34.6%) as a pale yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 8.21 (d, 1H, J = 5.4 Hz), 8.11-8.03 (m, 3H), 7.82 (dd, 1H, J = 7.0, 1.4 Hz), 7.47-7.36 (m, 3H), 7.11 (s, 1H), 6.99 (dd, 1H, J = 5.4, 1.4 Hz), 6.714 (d, 1H, J = 3.4 Hz), 6.710 (s, 1H), 6.10 (dd, 1H, J = 3.4, 1.0 Hz), 2.37 (s, 3H).

[0741] Example 50: Synthesis of N-([1,1'-biphenyl]-4-yl)-4-(furan-2-yl)pyridin-2-amine (compound (50))

[0742]

[0743] (1) Furan-2-ylboronic acid (compound (ix-2)) (811 mg, 7.25 mmol) and 4-bromopyridin-2-amine (compound (x-1)) (1.04 g, 6.01 mmol) were treated in a similar manner to (1) of Example 44 to give 4-(furan-2-yl)pyridin-2-amine (compound (xi-2)) (440 mg, 2.75 mmol, 45.7%) as a light brown solid. 1 H NMR (CDCl3, 400 MHz) δ 8.06 (dd, 1H, J = 5.4, 0.6 Hz), 7.51 (dd, 1H, J = 1.8, 0.6 Hz), 6.91 (dd, 1H, J = 5.4, 1.4 Hz), 6.81-6.77 (m, 2H), 6.50 (dd, 1H, J = 3.4, 1.8 Hz), 4.46 (brs, 2H).

[0744] (2) 4-(furan-2-yl)pyridin-2-amine (compound (xi-2)) (44.2 mg, 0.276 mmol) and 4-bromobiphenyl (compound (xii-1)) (98.1 mg, 0.421 mmol) were treated in a similar manner to (2) of Example 44 to give the title compound (compound (50)) (39.8 mg, 0.127 mmol, 46.2%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.22 (dd, 1H, J = 5.4, 0.5 Hz), 7.63-7.57 (m, 4H), 7.51 (dd, 1H, J = 1.8, 0.6 Hz), 7.47-7.40 (m, 4H), 7.36-7.30 (AA'BB'C, 1H), 7.18 (s, 1H), 7.01 (dd, 1H, J = 5.4, 1.4 Hz), 6.81 (dd, 1H, J = 3.5, 0.6 Hz), 6.69 (s, 1H), 6.50 (d, 1H, J = 3.5, 1.8 Hz).

[0745] Example 51: Synthesis of N-(anthracen-2-yl)-4-(furan-2-yl)pyridin-2-amine (compound (51))

[0746]

[0747] 4-(furan-2-yl)pyridin-2-amine (compound (xi-2)) (48.2 mg, 0.301 mmol) and 2-bromoanthracene (116 mg, 0.451 mmol) were treated in a similar manner to (2) of Example 50 to give the title compound (compound (51)) (28.0 mg, 83.2 μmol, 27.7%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz): δ 8.37 (s, 1H), 8.32 (s, 1H), 8.28 (dd, 1H, J = 5.2, 0.4 Hz), 8.06 (d, 1H, J = 2.0 Hz), 8.02-7.93 (m, 3H), 7.52 (dd, 1H, J = 1.8, 0.6 Hz), 7.48-7.38 (m, 3H), 7.28 (s, 1H), 7.06 (dd, 1H, J = 5.2, 1.2 Hz), 6.83 (dd, 1H, J = 3.4, 0.6 Hz), 6.78 (s, 1H), 6.51 (dd, 1H, J = 3.4, 1.8 Hz).

[0748] Example 52: Synthesis of N-(dibenzofuran-3-yl)-4-(furan-2-yl)pyridin-2-amine (compound (52))

[0749]

[0750] 4-(furan-2-yl)pyridin-2-amine (compound (xi-2)) (48.1 mg, 0.300 mmol) and 3-bromodibenzofuran (112 mg, 0.453 mmol) were treated in a similar manner to (2) of Example 50 to give the title compound (compound (52)) (32.3 mg, 99.0 μmol, 33.0%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz): δ 8.25 (d, 1H, J = 5.3 Hz), 7.89 (dd, 1H, J = 7.5, 1.0 Hz), 7.88 (d, 1H, J = 8.3 Hz), 7.82 (d, 1H, J = 1.8 Hz), 7.55 (d, 1H, J = 7.5 Hz), 7.52 (dd, 1H, J = 1.4, 0.6 Hz), 7.41 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz), 7.33 (ddd, 1H, J = 7.5, 7.5, 1.0 Hz), 7.25 (dd, 1H, J = 8.3, 2.0 Hz), 7.20 (s, 1H), 7.04 (dd, 1H, J = 5.3, 1.4 Hz), 6.82 (d, 1H, J = 3.5 Hz), 6.77 (s, 1H), 6.51 (dd, 1H, J = 3.5, 1.8 Hz).

[0751] Example 53: Synthesis of N-(dibenzothiophen-3-yl)-4-(furan-2-yl)pyridin-2-amine (compound (53))

[0752]

[0753] 4-(furan-2-yl)pyridin-2-amine (compound (xi-2)) (48.3 mg, 0.302 mmol) and 3-bromodibenzothiophene (119 mg, 0.452 mmol) were treated in a similar manner to (2) of Example 50 to give the title compound (compound (53)) (26.3 mg, 76.8 μmol, 25.5%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.25 (dd, 1H, J = 5.4, 0.6 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.08 (dd, 1H, J = 7.0, 0.6 Hz), 8.04 (d, 1H, J = 1.8 Hz), 7.82 (dd, 1H, J = 7.0, 1.5 Hz), 7.51 (d, 1H, J = 1.8, 0.6 Hz), 7.47-7.37 (m, 3H), 7.16 (s, 1H), 7.03 (dd, 1H, J = 5.4, 1.8 Hz), 6.81 (dd, 1H, J = 3.5, 0.6 Hz), 6.72 (s, 1H), 6.51 (dd, 1H, J = 3.5, 1.8 Hz).

[0754] Example 54: Synthesis of N-(fluoren-2-yl)-4-(furan-2-yl)pyridin-2-amine (compound (54))

[0755]

[0756] 4-(furan-2-yl)pyridin-2-amine (compound (xi-2)) (48.3 mg, 0.302 mmol) and 2-bromofluorene (110 mg, 0.449 mmol) were treated in a similar manner to (2) of Example 50 to give the title compound (compound (54)) (20.3 mg, 62.6 μmol, 20.8%) as a light brown solid. 1H NMR (CDCl3, 400 MHz) δ 8.21 (d, 1H, J = 5.3 Hz), 7.76 (d, 1H, J = 8.0 Hz), 7.74 (d, 1H, J = 7.4 Hz), 7.62 (s, 1H), 7.53 (d, 1H, J = 7.4 Hz), 7.50 (dd, 1H, J = 1.8, 0.5 Hz), 7.37 (dd, 1H, J = 7.4, 7.4 Hz), 7.34 (dd, 1H, J = 8.0, 1.9 Hz), 7.27 (ddd, 1H, J = 7.4, 7.4, 1.1 Hz), 7.14 (s, 1H), 6.99 (d, 1H, J = 5.3, 1.3 Hz), 6.80 (dd, 1H, J = 3.4, 0.5 Hz), 6.63 (s, 1H), 6.50 (dd, 1H, J = 3.4, 1.8 Hz), 3.92 (s, 2H).

[0757] Example 55: Synthesis of 6-((4-isopropylphenoxy)methyl)benzofuran (compound (55))

[0758]

[0759] Benzofuran-6-ylmethanol (78.2 mg, 0.528 mmol) and 4-isopropylphenol (compound (v-1)) (89.8 mg, 0.659 mmol) were used and treated in a similar manner to Example 31 to give the title compound (compound (55)) (9.8 mg, 37 μmol, 7.0%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz): δ 7.63 (d, 1H, J = 2.4 Hz), 7.60 (s, 1H), 7.59 (d, 1H, J = 7.6 Hz), 7.30 (dd, 1H, J = 7.6, 1.2 Hz), 7.17-7.12 (AA'BB', 2H), 6.95-6.91 (AA'BB', 2H), 6.76 (dd, 1H, J = 2.4, 1.2 Hz), 5.15 (s, 2H), 2.86 (sept, 1H, J = 6.8 Hz), 1.22 (d, 6H, J = 6.8 Hz).

[0760] Example 56: Synthesis of (E)-3-(5-methylfuran-2-yl)-N-(phenanthren-2-yl)acrylamide (compound (56))

[0761]

[0762] The title compound (compound (56)) (12.3 mg, 37.6 μmol, 12.5%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (45.6 mg, 0.300 mmol) and phenanthrene-2-amine (86.5 mg, 0.448 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1 H NMR (CDCl3, 400 MHz): δ 8.64 (d, 1H, J = 8.4 Hz), 8.62 (d, 1H, J = 7.6 Hz), 8.33 (s, 1H), 7.88 (dd, 1H, J = 7.6, 1.2 Hz), 7.76-7.70 (m, 3H), 7.65 (ddd, 1H, J = 7.6, 7.6, 1.6 Hz), 7.57 (ddd, 1H, J = 7.6, 7.6, 0.8 Hz), 7.52 (d, 1H, J = 15.2 Hz), 7.43 (s, 1H), 6.54 (d, 1H, J = 3.2 Hz), 6.43 (d, 1H, J = 15.2 Hz), 6.11 (dd, 1H, J = 3.2, 0.8 Hz), 2.37 (s, 3H).

[0763] Example 57: Synthesis of (E)-N-(3-isopropylphenyl)-3-(5-methylfuran-2-yl)acrylamide (compound (57))

[0764]

[0765] (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (153 mg, 1.01 mmol) and 3-isopropylaniline (compound (ii-14)) (203 mg, 1.50 mmol) were used and treated in the same manner as in Example 1 to give the title compound (compound (57)) (245 mg, 0.910 mmol, 90.5%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz) δ 7.53-7.37 (m, 2H), 7.45 (d, 1H, J = 15.2 Hz), 7.27 (s, 1H), 7.25 (d, 1H, J = 7.6, 7.6 Hz), 6.99 (d, 1H, J = 7.6 Hz), 6.49 (d, 1H, J = 3.2 Hz), 6.37 (d, 1H, J = 15.2 Hz), 6.08 (dd, 1H, J = 3.2, 0.8 Hz), 2.90 (sept, 1H, J = 7.2 Hz), 2.35 (s, 3H), 1.25 (d, 6H, J = 7.2 Hz).

[0766] Example 58: Synthesis of (2E,2E')-N,N'-(1,3-phenylene)bis(3-(5-methylfuran-2-yl)acrylamide) (compound (58))

[0767]

[0768] The title compound (compound (58)) (16.2 mg, 43.0 μmol, 14.4%) was obtained as a yellow solid by treating the same procedure as in Example 1 using (E)-3-(5-methylfuran-2-yl)acrylic acid (compound (i-1)) (137 mg, 0.900 mmol) and benzene-1,3-diamine (32.4 mg, 0.300 mmol) in the absence of DIPEA and using dichloromethane as a reaction solvent. 1H NMR (CDCl3, 400 MHz): δ 7.96 (s, 1H), 7.44 (d, 2H, J = 15.2 Hz), 7.43-7.36 (m, 3H), 7.29 (d, 2H, J = 8.0 Hz), 6.50 (d, 2H, J = 3.2 Hz), 6.34 (d, 2H, J = 15.2 Hz), 6.08 (dd, 2H, J = 3.2, 1.0 Hz), 2.35 (s, 6H).

[0769] Example 59: Synthesis of 3-hydroxy-N-(4-isopropylphenyl)benzamide (compound (59))

[0770]

[0771] In the absence of DIPEA, 3-hydroxybenzoic acid (71.9 mg, 0.521 mmol) and 4-isopropylaniline (compound (ii-1)) (101 mg, 0.747 mmol) were treated in the same manner as in Example 1 to give the title compound (compound (59)) (56.5 mg, 0.221 mmol, 42.5%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.53-7.48 (AA'BB', 2H), 7.32-7.27 (m, 2H), 7.25-7.20 (AA'BB', 2H), 7.05-7.00 (m, 1H), 2.89 (sept, 1H, J = 6.8 Hz), 1.24 (d, 6H, J = 6.8 Hz).

[0772] Example 60: Synthesis of 4-isopropylphenyl benzofuran-6-carboxylate (compound (60))

[0773]

[0774] The reaction was carried out in the same manner as in Example 1 using dichloromethane as a reaction solvent, benzofuran-6-carboxylic acid (81.1 mg, 0.500 mmol) and 4-isopropylphenol (84.9 mg, 0.623 mmol), in the presence of DMAP instead of HOBt, in the absence of DIPEA, to give the title compound (compound (60)) (78.3 mg, 0.279 mmol, 55.8%) as a colorless solid. 1 H NMR (CDCl3, 400 MHz): δ 8.36 (s, 1H), 8.10 (d, 1H, J = 8.4 Hz), 7.78 (d, 1H, J = 2.0 Hz), 7.68 (d, 1H, J = 8.4 Hz), 7.30-7.25 (AA'BB', 2H), 7.18-7.13 (AA'BB', 2H), 6.84 (dd, 1H, J = 2.0, 0.8 Hz), 2.94 (sept, 1H, J = 7.2 Hz), 1.27 (d, 6H, J = 7.2 Hz).

[0775] Example 61: Synthesis of (E)-N-(4-isopropylphenyl)-3-(5-phenylfuran-2-yl)acrylamide (compound (61))

[0776]

[0777] (E)-3-(5-bromofuran-2-yl)-N-(4-isopropylphenyl)acrylamide (compound (6)) (101 mg, 0.302 mmol) and phenylboronic acid pinacol ester (91.8 mg, 0.450 mmol) were used and treated in the same manner as in Example 35 to give the title compound (compound (61)) (82.0 mg, 0.247 mmol, 81.9%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.76-7.71 (AA'BB', 2H), 7.56-7.50 (m, 2H), 7.53 (d, 1H, J = 15.2 Hz), 7.45-7.39 (AA'BB'C, 2H), 7.35-7.29 (AA'BB'C, 1H), 7.29-7.25 (m, 1H), 7.24-7.19 (AA'BB', 2H), 6.74 (d, 1H, J = 3.2 Hz), 6.68 (d, 1H, J = 3.2 Hz), 6.53 (d, 1H, J = 15.2 Hz), 2.90 (sept, 1H, J = 6.8 Hz), 1.25 (d, 6H, J = 6.8 Hz).

[0778] Example 62: Synthesis of (E)-3-(5-(3-azido-5-(azidomethyl)phenyl)furan-2-yl)-N-(4-isopropylphenyl)-acrylamide (compound (62))

[0779]

[0780] (E)-3-(5-bromofuran-2-yl)-N-(4-isopropylphenyl)acrylamide (compound (6)) (100 mg, 0.299 mmol) and (3-azido-5-(azidomethyl)phenyl)boronic acid pinacol ester (109 mg, 0.363 mmol) were used and treated in the same manner as in Example 35 to give the title compound (compound (62)) (84.5 mg, 0.198 mmol, 66.1%) as a yellow solid. 1 H NMR (CDCl3, 400 MHz): δ 7.60-7.49 (m, 4H), 7.41 (s, 1H), 7.29 (s, 1H), 7.24-7.19 (AA'BB', 2H), 6.92 (s, 1H), 6.77 (d, 1H, J = 3.2 Hz), 6.69-6.63 (m, 1H), 6.58 (d, 1H, J = 15.2 Hz), 4.40 (s, 2H), 2.90 (sept, 1H, J = 6.8 Hz), 1.25 (d, 6H, J = 6.8 Hz).

[0781] Test Example 1: Screening method for compounds that bind to CLDN5 (1) Experimental method Using hCLDN5 proteoliposomes prepared using wheat cell-free synthesis technology and an anti-hCLDN5 antibody (mouse IgG antibody clone M48) that recognizes the three-dimensional structure of hCLDN5 (prepared according to the methods described in Non-Patent Document 4 and Patent Document 1), a screening system was constructed in which the test compound and hCLDN5 proteoliposomes were mixed, the anti-hCLDN5 antibody and detection beads were added, and then excitation light was irradiated to detect the proximity of the two using AlphaScreen. The hCLDN5 proteoliposomes contained biotinylated lipids and bound to streptavidin donor beads. Meanwhile, the anti-hCLDN5 antibody bound to Protein G acceptor beads. When the hCLDN5 proteoliposome and the anti-CLDN5 antibody antigen-antibody complex are formed, and the donor beads and the acceptor beads are in close proximity, excitation light is irradiated onto the donor beads to generate singlet oxygen, which the acceptor beads that receive it emit chemiluminescence. When a compound that inhibits the binding of hCLDN5 (SEQ ID NO: 1) and the anti-hCLDN5 antibody is added to this assay system, the donor beads and the acceptor beads cannot be brought into close proximity, resulting in quenching.

[0782] This assay system was used to screen for compounds that inhibit the binding of hCLDN5 and anti-hCLDN5 antibodies. Using the same method, a system was constructed using hCLDN1 proteoliposomes and anti-hCLDN1 antibodies (clone 3A2) (prepared according to the method described in Fukasawa M, et al. J. Virol. 89, 4866-4879 (2015)), and screening was performed in parallel.

[0783] (2) Test Results Among the compounds that inhibited the binding of hCLDN5 and anti-hCLDN5 antibodies in the screening of hCLDN5, compounds that did not inhibit the binding of hCLDN1 and anti-hCLDN1 antibodies in the screening of hCLDN1 (SEQ ID NO: 4) were selected. The obtained compounds were screened using hCLDN5 and hCLDN1 at multiple concentrations, and compounds that were confirmed to have dose-dependence and specificity in binding to hCLDN5 were selected as compound (I) of the present invention.

[0784] Figure 1 shows the test results for the dose dependency and specificity of the binding of compound (1) to hCLDN5. Figure 1 shows that compound (1) does not inhibit the binding of hCLDN1 to anti-hCLDN1 antibody, but inhibits the binding of hCLDN5 to anti-hCLDN5 antibody in a dose-dependent manner.

[0785] Test Example 2: Measurement of transendothelial electrical resistance (TEER) (1) Cell preparation HDMEC (Lonza) was cultured in EGM-2MV (Lonza, #CC-3202). bEnd. 3 (ATCC) was cultured in Dulbecco's modified Eagle's medium (DMEM; Nacalai Tesque, #08459-64) containing 10% fetal bovine serum (FBS). The cells were incubated at 37°C and 5% CO ２ The cells were cultured under the conditions.

[0786] (2) Experimental Method (2-1) Human dermal microvascular endothelial cells (HDMEC) (4.0 × 10 ４ cells) and bEnd. 3 (8.0 × 10 ４ HDMEC cells were seeded onto Falcon® cell culture inserts (pore size 0.4 μm; Corning). HDMECs were cultured for 3 days, and bEnd. 3 cells were cultured for 9 days. The medium on top of the cell culture insert containing these cells was replaced with a 0.25% DMSO solution containing 0 to 100 μM of compound (1), and transendothelial electrical resistance (TEER) was measured using a CellZScope (CellSeed). The change in relative TEER (TEER measured at each time point divided by the TEER value at the start of the test) over time following the addition of compound (1) was examined. The results are shown in Figure 2. The horizontal axis indicates the time after the addition of compound (1), and the vertical axis indicates the relative TEER.

[0787] (2-2) Using the same method as in (2-1) above, the change in relative TEER over time was examined for human dermal microvascular endothelial cells (HDMEC) upon addition of 50 μM or 25 μM of each test compound. The results are shown in Figure 3. In Figure 3, the group treated with 0.25% DMSO solution alone served as the negative control, and the group treated with compound (1) served as the positive control.

[0788] (3) Test Results As shown in Figure 2, it was confirmed that the addition of compound (1) stabilized the relative TEER at a low value in a dose-dependent manner for a short period of time. Furthermore, as shown in Figures 3A-1, 3A-2, and 3B, it was confirmed that at both concentrations of 50 μM (Figures 3A-1, 3A-2) and 25 μM (Figure 3B), each test compound stabilized at a low relative TEER compared to the negative control group (DMSO only), similar to the case when compound (1) was added. These results confirmed that compound (I) of the present invention, or a salt thereof, has the effect of directly loosening or strengthening adhesion between human dermal microvascular endothelial cells in a short period of time (regulatory effect).

[0789] Test Example 3: Substance permeation test (sodium fluorescein permeation test) (1) Experimental method Human dermal microvascular endothelial cells (HDMEC) (4.0 × 10 ４ Cells were seeded onto Falcon® cell culture inserts (pore size 0.4 μm; Corning). After 4 days, various concentrations of compound (1) (0 μM, 50 μM, and 100 μM, 0.25% DMSO solution) were added to the top of the inserts and cultured for 10 hours. The medium in the bottom of the inserts was replaced with phenol red-free DMEM medium, and sodium fluorescein solution was added to the top. After 30 minutes, the amount of sodium fluorescein that had migrated to the bottom of the inserts was measured using a SpectraMax5Me (Molecular Devices) (Ex / Em / cutoff = 485 nm / 525 nm / 515 nm), and the permeability coefficient (Papp) was calculated using the following formula:

[0790]

[0791] (2) Test Results As shown in FIG. 4, it was confirmed that the amount of sodium fluorescein permeated increased in a dose-dependent manner with compound (1).

[0792] Test Example 4: Fluorescent immunostaining (1) Experimental method HDMEC (1.0 × 10 ５Cells) were seeded onto a chamber slide (#154534PK; Thermo Fisher Scientific). After 4 days of culture, compound (1) was added to a final concentration of 50 μM. After 10 hours, the cells were treated with a 4% PFA / PBS solution for 15 minutes and a 1% BSA / PBS solution for 2 hours. The obtained cells were reacted with an anti-hCLDN5 rat IgG antibody (R9, 5 ng / μL) prepared according to the methods described in Non-Patent Document 4 and Patent Document 1 at 4 ° C overnight, and with AlexaFluor546-labeled anti-rat IgG (A11081; Invitrogen, 200-fold diluted) for 2 hours. The obtained cells were mounted in VECTORSHIELD Mounting Medium with DAPI (H-1200) and observed under a fluorescence microscope BZ-X700 (manufactured by KEYENCE).

[0793] (2) Test Results As shown in Figure 5, it was confirmed that compound (1) partially inhibits CLDN5 adhesion and increases the permeability of vascular endothelial cells (vascular endothelium).

[0794] Test Example 5: Evaluation of cerebrovascular permeability using mice (1) Experimental method (Figure 6) (1-1) Compound (1) (2.5 mg / kg body weight, PBS solution containing 10% DMSO) was administered via the tail vein to hCLDN5-KI mice prepared according to the method described in Non-Patent Document 4, or wild-type mice (C57BL / 6N). Immediately after administration or one hour later, sodium fluorescein (376 Da) or FITC-dextran (4 kDa) (FD-4) was administered via the tail vein at a dose of 10 mg / mouse. One hour later, the mice were perfused with PBS containing 2 mM EDTA. The excised brains were homogenized and incubated overnight at 4°C in 1 mL of PBS. The obtained samples were centrifuged (13,500 rpm × 5 min) to collect the supernatant, and the fluorescence intensity was measured using Spectra Max 5Me (Molecular Devices) ( Figure 7 ). In addition, the brain transfer amount of sodium fluorescein was measured 1 hour after administration of other example compounds (compound (5), compound (16), compound (19)) to wild-type mice.

[0795] (1-2) Wild-type mice were administered DyLight® 594-labeled tomato lectin (0.1 mg / mouse; Vector Laboratories, #DL-1177) via the tail vein. Five minutes later, compound (1) (2.5 mg / kg body weight; 10% DMSO / PBS) and Hoechst 33258 (molecular weight 533, 10 mg / mouse; Invitrogen, #H3569) were administered sequentially via the tail vein, followed by perfusion with 2 mM EDTA-PBS one minute later. Frozen sections were prepared from brains removed from the mice, mounted in glycerol, and observed under a BZ-X700 fluorescence microscope (KEYENCE).

[0796] (2) Test Results (2-1) The results of (1-1) above are shown in Figures 7 and 8. Figures 7A and 7D show that when sodium fluorescein (376 Da) was administered immediately after the administration of compound (1), sodium fluorescein permeated the cerebral blood vessels and was transferred to the brain after one hour. Figure 7C shows that when FD-4, which has a relatively large molecular weight, was administered immediately after the administration of compound (1), no transfer to the brain was confirmed. Furthermore, when sodium fluorescein was administered one hour after the administration of compound (1), no transfer to the brain was confirmed (Figure 7B). Furthermore, when other example compounds (compounds (5), (16), and (19)) were used as test compounds, high relative permeation amounts of sodium fluorescein were also shown after one hour (Figure 8).

[0797] (2-2) The results of (1-2) above are shown in Figure 9. As shown in Figure 9, it was confirmed that administration of compound (1) caused Hoechst 33258 to leak from blood vessels stained with tomato lectin and migrate into brain tissue.

[0798] From the above results, it was found that administration of compound (I) of the present invention, which exhibits the effect of increasing blood-brain barrier permeability (the effect of loosening the blood-brain barrier), or a pharmaceutically acceptable salt thereof, transiently loosens the blood-brain barrier, but this is a reversible effect that returns to its original state within a short period of time. On the other hand, it was confirmed that compound (FD-4), which has a relatively large molecular weight, cannot permeate even immediately after administration of compound (I). It was also confirmed that the permeability-enhancing effect can be adjusted by modifying the chemical structure of compound (I).

[0799] Test Example 6: Evaluation of vascular permeability in each organ using mice (1) Experimental method Compound (1) (2.5 mg / kg body weight, PBS solution containing 10% DMSO) was intravenously administered to hCLDN5-KI mice. Immediately after administration, sodium fluorescein (376 Da) was administered at a dose of 10 mg / mouse via the tail vein. After 1 hour, the mice were perfused with PBS containing 2 mM EDTA. The excised organs were homogenized and incubated overnight at 4°C in 1 mL of PBS. The obtained samples were centrifuged to collect the supernatant, and the fluorescence intensity was measured using a Spectra Max 5Me (Molecular devices).

[0800] (2) Test Results The results of (1) above are shown in Figure 10. Figure 10 shows that when sodium fluorescein (376 Da) was administered immediately after administration of compound (1), sodium fluorescein permeated cerebral blood vessels and was specifically transferred into the brain one hour later.

[0801] Test Example 7: Evaluation of cerebrovascular permeability in mice (1) Experimental method Compound (1) (2.5 mg / kg body weight, PBS solution containing 10% DMSO) was intravenously administered to wild-type (C57BL / 6) mice. Immediately after administration, methylscopolamine (MSco) (429 Da; 2 mg / kg body weight) or vancomycin (1.4 kDa; 100 mg / kg body weight), which has low brain penetration, was administered via the tail vein. After 1 hour, the mice were perfused with PBS containing 2 mM EDTA. The excised brains were homogenized and incubated overnight at 4°C in 1 mL of PBS. The obtained samples were centrifuged to collect the supernatant, and the fluorescence intensity was measured using a Spectra Max 5Me.

[0802] (2) Test Results The results of (1) above are shown in Figure 11A (methylscopolamine) and Figure 11B (vancomycin). Figures 11A and 11B confirm that administration of compound (1) significantly increased the amount of both methylscopolamine and vancomycin transported into the brain.

[0803] Test Example 8: Evaluation of the severity of drug-induced epilepsy (1) Experimental method (FIG. 12A) To prevent the peripheral effects of pilocarpine, wild-type mice were subcutaneously administered methylscopolamine (1 mg / kg body weight, saline). Thirty minutes later, pilocarpine (400 mg / kg body weight, saline) was administered intraperitoneally to induce epileptic seizures. Immediately after pilocarpine administration, PBS solution containing 10% DMSO alone, a solution of Compound (1) (2.5 mg / kg body weight) (PBS solution containing 10% DMSO) alone, a solution of methylscopolamine (2 mg / kg body weight) (PBS solution containing 10% DMSO) alone, or a solution of methylscopolamine (2 mg / kg body weight) and Compound (1) (2.5 mg / kg body weight) (PBS solution containing 10% DMSO) were administered via the tail vein. The survival time and seizure intensity of mice in each treatment group were analyzed. The attack intensity was analyzed using the modified Racine scale score, and the evaluation was performed by another experimenter who was unaware of the administration conditions.

[0804] (2) Test Results The results of (1) above are shown in Figures 12B to 12E. Figures 12B to 12E confirm that the combined use of methylscopolamine and compound (1) significantly suppressed the intensity of epileptic seizures.

[0805] Compound (I) of the present invention, or a salt thereof, directly loosens or strengthens adhesion between vascular endothelial cells for a short period of time without changing the expression of CLDN5, thereby transiently regulating the amount of water in cerebral tissue fluid, regulating the intracerebral delivery of drugs for preventing and / or treating brain diseases, and preventing the entry of pathogenic substances into the brain. Furthermore, since compound (I) of the present invention or a salt thereof can be easily synthesized, provided at low cost, and has few side effects, a pharmaceutical comprising compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is useful for the prevention and / or treatment of brain diseases such as cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorders, REM sleep behavior disorder, traumatic brain injury, restless legs syndrome, psychiatric diseases, severe infectious diseases, or sepsis. Furthermore, the present invention can also provide a method for screening for a compound useful as a blood-brain barrier permeability regulator.

[0806] This application is based on Japanese Patent Application No. 2024-082779 filed on May 21, 2024 in Japan, and Japanese Patent Application No. 2025-010830 filed on January 24, 2025, the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I): [In the formula, A represents a phenyl group, a 2-furyl group, a 2-benzofuryl group, a 6-benzofuryl group, a 2-thienyl group, a 2-pyridyl group, a 7-quinolyl group, or a 6-quinoxalinyl group, each of which may be substituted; L represents a group of the formula: (wherein the wavy line indicates the bonding site of the group represented by the above chemical formula; ＊ indicates the bonding position to group A; and ＊＊ represents a bonding position to the group X; X represents a single bond, an oxygen atom, or a divalent group represented by the formula: (wherein the wavy line indicates the binding site; ＊＊＊ indicates the bonding position with group B; R is a hydrogen atom, C １－６ Alkyl group, C ７－１６ Aralkyl group, or C ２－６ represents an alkynyl group; and n represents 0 or 1; and B represents a divalent group represented by the formula (I) ３－１８ and represents a hydrocarbon ring group, a dibenzofuryl group, or a dibenzothienyl group, provided that when X is a single bond, L is a group represented by the formula: (wherein each symbol has the same meaning as defined above), and L is -CH ２ -, X represents an oxygen atom, and when n is 1, L represents a group of the formula: (wherein each symbol has the same meaning as defined above.) or an isomer thereof, or a pharmaceutically acceptable salt thereof.

2. A is an optionally substituted 2-furyl group, and L is a group of the formula: (wherein each symbol has the same meaning as defined above), and X is a single bond, an oxygen atom, or a divalent group represented by the formula: (wherein each symbol has the same meaning as defined above), and B is a divalent group represented by C ６－１８ The blood-brain barrier permeability regulator according to claim 1 , wherein the aryl group is an aryl group, a dibenzofuryl group, or a dibenzothienyl group.

3. A is an optionally substituted 6-benzofuryl group, and L is a group of the formula: (wherein each symbol has the same meaning as defined above), X is a single bond, NH or an oxygen atom, and B is an optionally substituted phenyl group. The blood-brain barrier permeability regulator according to claim 1, 4. A is an optionally substituted 7-quinolyl group, and L is a group of the formula: (wherein each symbol has the same meaning as defined above), X is a single bond, NH or an oxygen atom, and B is an optionally substituted phenyl group. The blood-brain barrier permeability regulator according to claim 1, 5. A is an optionally substituted 2-thienyl group, and L is a group of the formula: (wherein each symbol has the same meaning as defined above), X is NH, and B is an optionally substituted phenyl group. The blood-brain barrier permeability regulator according to claim 1, 6. Below formula: or an isomer thereof, or a pharmaceutically acceptable salt thereof.

7. Below formula: or an isomer thereof, or a pharmaceutically acceptable salt thereof.

8. Below formula: or an isomer thereof, or a pharmaceutically acceptable salt thereof.

9. A blood-brain barrier permeability regulator according to any one of claims 1 to 7, which is a blood-brain barrier permeation enhancer.

10. The blood-brain barrier permeability regulator of claim 9, which is administered in combination with a drug for preventing and / or treating a brain disease.

11. The blood-brain barrier permeability regulator according to claim 10, which is administered separately from a drug for preventing and / or treating a brain disease.

12. The blood-brain barrier permeability regulator according to claim 10, which is administered simultaneously or sequentially with a drug for preventing and / or treating a brain disease.

13. The blood-brain barrier permeability regulator according to any one of claims 10 to 12, wherein the brain disease is selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

14. A pharmaceutical composition for treating cerebral edema, comprising the blood-brain barrier permeability regulator according to claim 9 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for transporting a drug for preventing and / or treating a brain disease into the brain, comprising the blood-brain barrier permeability regulator according to claim 9 and a drug for preventing and / or treating a brain disease.

16. The pharmaceutical composition of claim 15, wherein the brain disease is selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

17. A conjugate in which the blood-brain barrier permeability regulator according to claim 9 is bound to a drug directly or via a linker.

18. The conjugate of claim 17, wherein the drug is for preventing and / or treating a brain disease selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

19. Below formula: or an isomer thereof, or a salt thereof.

20. Below formula: or an isomer thereof, or a salt thereof.

21. Below formula: or an isomer thereof, or a salt thereof.

22. A pharmaceutical composition comprising the compound of claim 19 or an isomer thereof, or a salt thereof, and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising the compound according to claim 20 or an isomer thereof, or a salt thereof, and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising the compound according to claim 21 or an isomer thereof, or a salt thereof, and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition according to claim 22 for treating cerebral edema.

26. The pharmaceutical composition according to claim 23 for preventing and / or treating a brain disease, which is administered in combination with a drug for preventing and / or treating a brain disease.

27. The pharmaceutical composition according to claim 23, which is administered separately from a drug for preventing and / or treating a brain disease.

28. The pharmaceutical composition according to claim 23, which is administered simultaneously or sequentially with a drug for preventing and / or treating a brain disease.

29. A pharmaceutical composition according to any one of claims 23 and 26 to 28, for delivering a drug for preventing and / or treating a brain disease into the brain.

30. The pharmaceutical composition according to any one of claims 23 and 26 to 28, wherein the brain disease is selected from the group consisting of cerebral edema, brain tumor, migraine, cerebral infarction, Alzheimer's disease, Parkinson's disease, epilepsy, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multiple sclerosis, encephalitis / meningitis, sleep apnea syndrome, narcolepsy, schizophrenia, mood disorder, REM sleep behavior disorder, traumatic brain injury, and restless legs syndrome.

31. The pharmaceutical composition according to claim 24 for preventing and / or treating a disease selected from the group consisting of psychiatric disorders, severe infections, sepsis, and cerebral edema.

32. A screening method for blood-brain barrier permeability regulators, comprising: (i) a step of mixing a test compound with hCLDN5 proteoliposomes, adding an anti-human CLDN5 antibody and detection beads, and then irradiating with excitation light to detect and evaluate the proximity of the hCLDN5 proteoliposomes and the anti-human CLDN5 antibody by AlphaScreen; and (ii) a step of mixing a test compound with hCLDN1 proteoliposomes, adding an anti-hCLDN1 antibody and detection beads, and then irradiating with excitation light to detect and evaluate the proximity of the hCLDN1 proteoliposomes and the anti-human CLDN1 antibody by AlphaScreen. And (iii) a step of selecting a compound that inhibits only the binding of hCLDN5 to the anti-hCLDN5 antibody based on the evaluations in (i) and (ii).

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