Type 2 ryanodine receptor inhibitor

Abstract

The purpose of the present invention is to provide a type 2 ryanodine receptor (RyR2) activity inhibitor having an excellent effect of inhibiting RyR2 activity.　An RyR2 activity inhibitor comprising a compound represented by formula (α1), a salt thereof or a solvate of the same. [In formula (α1); rings Q1 and Q2 independently represent a monocyclic heterocycle, a fused ring of a monocyclic carbon ring with a benzene ring, or a benzene ring; R1 and R2 independently represent an optionally substituted hydrocarbon group having 1-8 carbon atoms, an optionally substituted alkoxy group having 1-8 carbon atoms, an optionally substituted alkoxycarbonyl group having 2-8 carbon atoms, an optionally substituted alkanoyl group having 2-8 carbon atoms, an optionally substituted alkanoyloxy group having 2-8 carbon atoms, a hydroxy group, a cyano group or a halogen atom; R3 represents a hydrogen atom or an optionally substituted hydrocarbon group having 1-8 carbon atoms; R4 represents a divalent hydrocarbon group having 1-8 carbon atoms; X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; and n and m independently represent an integer of 0-5.　When n is an integer of 2-5, then n R1's may be either the same or different and two R1's may together form a ring. When m is an integer of 2-5, then m R2's may be either the same or different and two R2's may together form a ring.]

Description

[Technical Field]

[0001] The present invention relates to a type 2 ryanodine receptor activity inhibitor, and more particularly to a type 2 ryanodine receptor activity inhibitor, a medicine, a tetrazole compound, and the like. [Background technology]

[0002] Ryanodine receptors (RyRs) mediate the release of calcium ions (Ca) from the sarcoplasmic reticulum (SR), an essential step for muscle contraction. 2+ ) responsible for the release of Ca 2+ RyRs are Ca release channels. 2+ Stimulated by Ca 2+ releases Ca into the cytosol 2+ Inducible Ca 2+ free, CICR). This acts as a positive feedback mechanism, allowing the small amount of Ca present in the cytosol near the channel to be released. 2+ However, more Ca is released from the SR. 2+ causes liberation. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2019 / 082940 [Non-patent literature]

[0004] [Non-Patent Document 1] J.Electrocardiol.48(5),874-878(2015) [Non-patent document 2] Biochim Biophys Acta Mol Cell Res.1865:1687-1697,2018 [Non-patent document 3] Acta Neuropathol.134:749-767,2017 [Non-patent document 4] J Clin Invest.118:2230-2245,2008 [Non-patent document 5] Circ J.84(2),226-234,2019 [Non-patent document 6] Heart, Lung and Circulation.2019 Dec 6. [Non-Patent Document 7] Hum Mutat.,37,1231-1241,2016 Summary of the Invention [Problem to be solved by the invention]

[0005] Furthermore, RyRs are broadly classified into RyR1 (type 1 ryanodine receptor), which is mainly expressed in skeletal muscle, RyR2 (type 2 ryanodine receptor), which is mainly expressed in cardiac muscle, and RyR3 (type 3 ryanodine receptor), which is mainly expressed in the brain. Research by the present inventors has revealed that certain quinoline-3-carboxylic acid derivatives have the effect of inhibiting the activity of RyR1 (Patent Document 1), but they have not yet discovered an RyR2 activity inhibitor. Genetic mutations in RyR2 abnormally enhance CICR activity, causing diseases such as catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, and mental retardation. Furthermore, even in the case of wild-type RyR2, abnormal enhancement of RyR2 due to excessive phosphorylation or the like can cause chronic heart failure, Alzheimer's disease, and the like (e.g., Non-Patent Documents 1 to 6, etc.). Therefore, there is a need for the development of an RyR2 activity inhibitor that has an excellent inhibitory effect on RyR2 activity. Therefore, an object of the present invention is to provide an RyR2 activity inhibitor having an excellent effect of inhibiting RyR2 activity. [Means for solving the problem]

[0006] We have developed fluorescent endoplasmic reticulum Ca 2+ Cultured cells expressing the indicator and disease-mutated RyR, and fluorescent endoplasmic reticulum Ca 2+Cultured cells expressing the indicator and wild-type RyR were cultured, and the endoplasmic reticulum Ca concentration was measured in the presence of the test substance. 2+ Measure the concentration of Ca in the endoplasmic reticulum of both cultured cells. 2+ We found that by comparing the concentrations, it is possible to screen for CICR activity inhibitors, i.e., preventive or therapeutic drugs for diseases associated with abnormally increased ryanodine receptor activity (Non-Patent Document 7), and previously filed a patent application (Japanese Patent Application No. 2016-113147). Then, after screening various compounds using this screening method and further investigation, the inventors discovered that certain compounds have excellent RyR2 activity inhibitory effects and are useful as preventive or therapeutic agents for diseases associated with abnormally increased RyR2 activity, thereby completing the present invention.

[0007] That is, the present invention provides the following: <1> ~ <12> This provides: <1> A type 2 ryanodine receptor activity inhibitor (hereinafter also referred to as the type 2 ryanodine receptor activity inhibitor of the present invention or the RyR2 activity inhibitor of the present invention) containing a compound represented by the following formula (α1) or a salt thereof, or a solvate thereof (hereinafter these may be collectively referred to as "compound (α1)").

[0008] [ka]

[0009] [In formula (α1), Ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring; R 1 and R 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms, X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; n and m each independently represent an integer of 0 to 5; However, when n is an integer between 2 and 5, n R 1 may be the same or different, and two R 1 may be joined together to form a ring. When m is an integer of 2 to 5, m R 2 may be the same or different, and two R 2 may be joined together to form a ring.

[0010] <2> Ring Q 1 and Ring Q 2 are each independently a fused ring of a 4- to 8-membered oxygen-containing monocyclic heterocycle and a benzene ring, or a benzene ring; <1> The type 2 ryanodine receptor activity inhibitor according to claim 1. <3> R 1 and R 2 are each independently a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; <1> or <2> The type 2 ryanodine receptor activity inhibitor according to claim 1. <4> R 4 is an alkanediyl group having 1 to 8 carbon atoms or an alkenediyl group having 2 to 8 carbon atoms, <1> ~ <3> The ryanodine receptor type 2 activity inhibitor according to any one of the preceding claims.

[0011] <5> R 3is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms; <1> ~ <4> The ryanodine receptor type 2 activity inhibitor according to any one of the preceding claims. <6> R 3 is a methyl group, <1> ~ <5> The ryanodine receptor type 2 activity inhibitor according to any one of the preceding claims. <7> n is an integer from 1 to 5; <1> ~ <6> The ryanodine receptor type 2 activity inhibitor according to any one of the preceding claims. <8> m is an integer from 1 to 5; <1> ~ <7> The ryanodine receptor type 2 activity inhibitor according to any one of the preceding claims.

[0012] <9> A pharmaceutical for preventing or treating a disease associated with abnormally increased type 2 ryanodine receptor activity, comprising a compound represented by the above formula (α1) or a salt thereof, or a solvate thereof (hereinafter also referred to as the pharmaceutical of the present invention). <10> The disease associated with abnormally increased type 2 ryanodine receptor activity is a disease selected from catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, mental retardation, chronic heart failure, and Alzheimer's disease. <9> The pharmaceutical composition according to any one of the preceding claims.

[0013] <11> A compound represented by the following formula (α2) or a salt thereof, or a solvate thereof (hereinafter, these may be collectively referred to as "compound (α2)").

[0014] [ka]

[0015] [In formula (α2), Ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring; R 1 and R 2each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms, X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; n and m each independently represent an integer of 1 to 5; However, when n is an integer between 2 and 5, n R 1 may be the same or different, and two R 1 may be joined together to form a ring. When m is an integer of 2 to 5, m R 2 may be the same or different, and two R 2 may be joined together to form a ring.

[0016] <12> Compounds represented by any one of the following formulae (α3) to (α12), or salts thereof, or solvates thereof (hereinafter, these may be collectively referred to as "compounds (α3) to (α12)").

[0017] [ka]

[0018] [ka]

[0019] [ka]

[0020] [ka]

[0021] <13> Use of a compound represented by the above formula (α1) or a salt thereof, or a solvate of the compound or the salt for the manufacture of an inhibitor of type 2 ryanodine receptor activity. <14> Use of a compound represented by the above formula (α1) or a salt thereof, or a solvate of the compound or salt for the manufacture of a medicament for the prevention or treatment of a disease associated with abnormally increased type 2 ryanodine receptor activity. <15> A compound represented by the above formula (α1), a salt thereof, or a solvate of the compound or the salt for use in inhibiting type 2 ryanodine receptor activity. <16> A compound represented by the above formula (α1), a salt thereof, or a solvate of the compound or the salt for use in the prevention or treatment of a disease associated with abnormally increased type 2 ryanodine receptor activity.

[0022] <17> Use of a compound represented by the above formula (α1) or a salt thereof, or a solvate of the compound or the salt for inhibiting type 2 ryanodine receptor activity. <18> Use of a compound represented by the above formula (α1) or a salt thereof, or a solvate of the compound or salt for preventing or treating a disease associated with abnormally increased type 2 ryanodine receptor activity. <19> A method for inhibiting type 2 ryanodine receptor activity, comprising the step of administering a compound represented by the above formula (α1) or a salt thereof, or a solvate of the compound or the salt. <20> A method for preventing or treating a disease associated with abnormally increased type 2 ryanodine receptor activity, comprising the step of administering a compound represented by the above formula (α1) or a salt thereof, or a solvate of the compound or the salt. [Effects of the Invention]

[0023] The compound represented by formula (α1) or a salt thereof, or a solvate thereof has an excellent effect of inhibiting RyR2 activity, and is useful as a preventive or therapeutic drug for diseases associated with abnormally increased RyR2 activity. Furthermore, the compounds (α2) to (α12) of the present invention are novel compounds that have excellent effects of inhibiting RyR2 activity. [Brief explanation of the drawings]

[0024] [Figure 1] Electrocardiograms of RyR2 mutant mice before and after administration of compound 57. [Figure 2] FIG. 1 shows the effect of compound 57 on arrhythmia occurrence in RyR2 mutant mice under normal conditions. DETAILED DESCRIPTION OF THE INVENTION

[0025] The type 2 ryanodine receptor activity inhibitor and medicament of the present invention contain a compound represented by the following formula (α1), or a salt thereof, or a solvate thereof. It has not been known until now that the compound represented by formula (α1), or a salt thereof, or a solvate thereof has an inhibitory effect on RyR2 activity, or that it is useful as a prophylactic or therapeutic agent for diseases associated with abnormally increased RyR2 activity. In this specification, "prevention or treatment" of a disease includes use for both the prevention and treatment of a disease, in addition to the prevention or treatment of a disease.

[0026] [ka]

[0027] [In formula (α1), Ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring; R 1 and R 2each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms, X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; n and m each independently represent an integer of 0 to 5; However, when n is an integer between 2 and 5, n R 1 may be the same or different, and two R 1 may be joined together to form a ring. When m is an integer of 2 to 5, m R 2 may be the same or different, and two R 2 may be joined together to form a ring.

[0028] First, each symbol in the formulas (α1) and (α2) will be explained. In the formulae (α1) and (α2), Y represents a methine group or a nitrogen atom, and is preferably a nitrogen atom from the viewpoint of the effect of inhibiting RyR2 activity.

[0029] In formulas (α1) and (α2), ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring. The monocyclic heterocycle is preferably a 4- to 8-membered monocyclic heterocycle, more preferably a 5- to 7-membered monocyclic heterocycle, and particularly preferably a 5- to 6-membered monocyclic heterocycle. Examples of the monocyclic heterocycle include monocyclic heterocycles containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and are preferably oxygen-containing monocyclic heterocycles, more preferably 4- to 8-membered oxygen-containing monocyclic heterocycles. Examples of the monocyclic heterocycle include an oxetane ring, a dioxolane ring, a dioxane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydrothiophene ring, a tetrahydrothiopyran ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, etc. Among these, an oxetane ring, a dioxolane ring, and a dioxane ring are preferred. Specific examples of the fused ring of a monocyclic heterocycle and a benzene ring include a 7-oxabicyclo[4.2.0]octa-1(6),2,4-triene ring, a 1,3-benzodioxole ring, and a 1,4-benzodioxane ring.

[0030] The monocyclic carbocyclic ring is preferably a 4- to 8-membered monocyclic carbocyclic ring, more preferably a 5- to 7-membered monocyclic carbocyclic ring. Specific examples of the fused ring of a monocyclic carbocyclic ring and a benzene ring include an indane ring and a tetralin ring.

[0031] Also, Kan Q 1 When ring Q is a condensed ring of a monocyclic heterocycle or a monocyclic carbocycle and a benzene ring, the bonding site between Y and the adjacent carbon atom in formula (α1) or (α2) is not particularly limited, and may be a monocyclic heterocycle or a monocyclic carbocycle contained in the condensed ring, or a benzene ring, but a benzene ring contained in the condensed ring is preferred. 2 is a condensed ring of a monocyclic heterocycle or a monocyclic carbocycle and a benzene ring, R 3 The bonding site between the nitrogen atom and the adjacent nitrogen atom is not particularly limited, and may be a monocyclic heterocyclic ring or a monocyclic carbocyclic ring contained in the fused ring, or a benzene ring, but is preferably a benzene ring contained in the fused ring.

[0032] Ring Q 1 , ring Q 2From the viewpoint of the effect of inhibiting RyR2 activity, the ring is preferably a fused ring of a monocyclic heterocycle and a benzene ring, or a benzene ring, and more preferably a fused ring of a 4- to 8-membered oxygen-containing monocyclic heterocycle and a benzene ring. Among these, Tamaki Q 1 From the viewpoint of the RyR2 activity inhibitory effect, a benzene ring is particularly preferred as ring Q. 2 As the ring, a 1,3-benzodioxole ring and a benzene ring are particularly preferred from the viewpoint of the effect of inhibiting RyR2 activity.

[0033] In formulas (α1) and (α2), R 1 and R 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom. In addition, in formulas (α1) and (α2), R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms.

[0034] R 1 , R 2 and R 3 The "hydrocarbon group" represented by the formula (I) is a concept that encompasses aliphatic hydrocarbon groups, alicyclic hydrocarbon groups and aromatic hydrocarbon groups, with aliphatic hydrocarbon groups being preferred. The aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated. Examples of the aliphatic hydrocarbon group include alkyl groups, alkenyl groups, and alkynyl groups. Among these, from the viewpoint of the RyR2 activity inhibitory effect, alkyl groups and alkenyl groups are preferred, and alkyl groups are more preferred. From the viewpoint of the RyR2 activity inhibitory effect, the number of carbon atoms in the alkyl group is preferably 1 to 8, more preferably 1 to 4, even more preferably 1 to 3, and particularly preferably 1. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group. Of these, from the viewpoint of the RyR2 activity inhibitory effect, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are preferred, and a methyl group is particularly preferred. The number of carbon atoms in the alkenyl group or alkynyl group is preferably 2 to 8, more preferably 2 to 4, and particularly preferably 2 to 3. Examples of the alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, and 1-hexenyl. Examples of the alkynyl group include ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 3-pentynyl, and 1-hexynyl. Also, R 1 , R 2 and R 3 The "hydrocarbon group" represented by the formula (I) may or may not have a substituent. Examples of the substituent include halogen atoms such as fluorine, chlorine, bromine, and iodine atoms, hydroxyl groups, and cyano groups. The substitution position and number of substituents are optional, and when two or more substituents are present, the substituents may be the same or different. From the viewpoint of the RyR2 activity inhibitory effect, the substituted hydrocarbon group is preferably a haloalkyl group such as a trifluoromethyl group, a pentafluoroethyl group, or a 2,2,2-trifluoroethyl group.

[0035] R 1 and R 2 From the viewpoint of the RyR2 activity inhibitory effect, the number of carbon atoms in the "alkoxy group" represented by the formula (I) is preferably 1 to 6, more preferably 1 to 3, and particularly preferably 1. The alkoxy group may be linear or branched. Examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, and a hexyloxy group. Also, R 1 and R 2 The "alkoxy group" represented by the following formula may or may not have a substituent. Examples of the substituent include the same ones that the hydrocarbon group described above may have. The substitution position and the number of substituents are optional, and when there are two or more substituents, the substituents may be the same or different. As the alkoxy group having a substituent, from the viewpoint of the RyR2 activity inhibitory effect, a haloalkoxy group such as a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a pentafluoroethoxy group, or a 2,2,2-trifluoroethoxy group is preferred.

[0036] R 1 and R 2 From the viewpoint of the RyR2 activity inhibitory effect, the number of carbon atoms in the alkoxycarbonyl group, alkanoyl group, and alkanoyloxy group represented by the formula (I) is preferably 2 to 6, and more preferably 2 to 4. The alkoxycarbonyl group, alkanoyl group, and alkanoyloxy group may be linear or branched. Among the alkoxycarbonyl group, alkanoyl group, and alkanoyloxy group, the alkoxycarbonyl group is preferred from the viewpoint of the RyR2 activity inhibitory effect. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group, an n-butoxycarbonyl group, and a tert-butoxycarbonyl group. Examples of the alkanoyl group include an acetyl group and a propionyl group. Examples of the alkanoyloxy group include an acetoxy group and a propanoyloxy group. The alkoxycarbonyl group, alkanoyl group, and alkanoyloxy group may have the same substituents as those of the hydrocarbon group. The substitution position and the number of the substituents are optional, and when two or more substituents are present, the substituents may be the same or different.

[0037] R 1 and R2 Examples of the halogen atom represented by the formula (I) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a fluorine atom is preferred.

[0038] R 1 , R 2 From the viewpoint of the effect of inhibiting RyR2 activity, the alkyl group is preferably a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; more preferably a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group, or a halogen atom; even more preferably a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group, or a halogen atom; even more preferably a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms or a halogen atom, with a halogen atom being particularly preferred. In addition, R 1 The substitution position of ring Q 1 However, from the viewpoint of the inhibitory effect on RyR2 activity, 1 is a benzene ring and n is an integer of 1 to 5, R 1 is preferably substituted at least at position 3. From the viewpoint of the RyR2 activity inhibitory effect, the combination of n and the substitution position is preferably n=1 and R 1 is substituted at the 3-position, n=2 or 3 and R 1 is preferably substituted at the 3-position and at a position selected from the 4-position and the 5-position. 2 The substitution position of ring Q 2 However, from the viewpoint of the inhibitory effect on RyR2 activity, 2 is a benzene ring and m is an integer of 1 to 5, R 2is preferably substituted at least at position 4. From the viewpoint of the inhibitory effect on RyR2 activity, the combination of m and the substitution position is preferably m=1 and R 2 is substituted at the 4th position, m=2 and R 2 is preferably substituted at the 3- and 4-positions.

[0039] R 3 From the viewpoint of the effect of inhibiting RyR2 activity, the alkyl group is preferably a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, more preferably a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, even more preferably a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, still more preferably a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group.

[0040] In formulas (α1) and (α2), R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms. R 4 The divalent hydrocarbon group represented by the formula (I) encompasses divalent aliphatic hydrocarbon groups, divalent alicyclic hydrocarbon groups, and divalent aromatic hydrocarbon groups, with divalent aliphatic hydrocarbon groups being preferred. The divalent aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated. Examples of the divalent aliphatic hydrocarbon group include an alkanediyl group, an alkenediyl group, and an alkynediyl group. Among these, from the viewpoint of the RyR2 activity inhibitory effect, an alkanediyl group and an alkenediyl group are preferred, and an alkanediyl group is more preferred. The number of carbon atoms in the alkanediyl group is preferably 1 to 8, more preferably 1 to 4, even more preferably 1 to 3, and particularly preferably 1, from the viewpoint of the effect of inhibiting RyR2 activity. Examples of alkanediyl groups include methane-1,1-diyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-1,4-diyl, pentane-1,4-diyl, pentane-1,5-diyl, hexane-1,2-diyl, hexane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, and octane-1,8-diyl. Among these, methane-1,1-diyl is preferred from the viewpoint of RyR2 activity inhibitory effect. The number of carbon atoms in the alkenediyl group or alkynediyl group is preferably 2 to 8, more preferably 2 to 4, and particularly preferably 2 to 3. Examples of the alkenediyl group include an ethylene-1,1-diyl group and an ethylene-1,2-diyl group. Examples of the alkynediyl group include an acetylene-1,2-diyl group.

[0041] In formula (α1), n and m each independently represent an integer of 0 to 5. From the viewpoint of the effect of inhibiting RyR2 activity, an integer of 1 to 5 is preferred, an integer of 1 to 3 is more preferred, and an integer of 1 to 2 is particularly preferred. Similarly, n and m in formula (α2) are preferably integers of 1 to 3, and more preferably integers of 1 to 2, from the viewpoint of the inhibitory effect on RyR2 activity.

[0042] Compounds (α1) to (α12) also include salts of the compounds represented by formulas (α1) to (α12), and examples of such salts include alkali metal salts such as sodium salts and potassium salts; salts with metals of Group 2 elements such as calcium salts and magnesium salts; salts with metals of Group 13 elements such as aluminum salts; ammonium salts; and organic amine salts such as phenethylamine salts. In compounds (α1) to (α12), examples of solvates include hydrates and alcoholates. The compounds (α1) to (α12) may have crystalline polymorphism, and may be in a single crystalline form or a mixture of multiple crystalline forms, or may be in an amorphous form.

[0043] Among the compounds (α1), compounds (α2) and compounds (α3) to (α12) are novel compounds. Compound (α2) is a compound among the compounds (α1) in which n and m are integers of 1 to 5. Furthermore, the compound represented by formula (α3) is compound 39 in the Examples described later, the compound represented by formula (α4) is compound 44 in the Examples described later, the compound represented by formula (α5) is compound 61 in the Examples described later, the compound represented by formula (α6) is compound 66 in the Examples described later, the compound represented by formula (α7) is compound 40 in the Examples described later, the compound represented by formula (α8) is compound 38 in the Examples described later, the compound represented by formula (α9) is compound 59 in the Examples described later, the compound represented by formula (α10) is compound 47 in the Examples described later, the compound represented by formula (α11) is compound 37 in the Examples described later, and the compound represented by formula (α12) is compound 41 in the Examples described later.

[0044] Next, a method for producing compound (α1) will be described. Compound (α1) can be produced by appropriately combining known methods described in, for example, NT Pokhodylo, RD Savka, VS Matiichuk, and ND Obushak, "A Study of Alkylation Regioselectivity of 5-Substituted Tetrazoles with C Chloroacetamides," Russian Journal of General Chemistry, 80, 836-841 (2010), using a nitrile compound (CP1) or a bromocarboxylic acid (CP6) as a starting material. As shown in the following synthesis route, for example, in the compound (α1), Y in the formula (α1) is a nitrogen atom, X is an oxygen atom, and R 3When producing a compound in which is a hydrogen atom, in <Step SA1-1>, the nitrile compound (CP1) is reacted with sodium azide in the presence of an amine salt to obtain the tetrazole derivative (CP2), and in <Step SA1-2>, the aniline derivative (CP3) is amidated with a bromocarboxylic acid chloride using a base or the like to obtain the amide derivative (CP4), and in <Step SA2>, the tetrazole derivative (CP2) is reacted with the amide derivative (CP4) in the presence of a strong base or the like.

[0045] [ka]

[0046] In addition, in the compound (α1), Y in the formula (α1) is a methine group, X is an oxygen atom, and R 3 In the case of producing a compound in which R is a hydrogen atom, in <Step SB1> bromocarboxylic acid (CP6) is reacted with sodium azide in water, and in <Step SB2> the obtained azidocarboxylic acid (CP7) is converted into an acid chloride with oxalyl chloride. Then, the acid chloride is amidated with aniline derivative (CP8) using a base or the like to obtain azide-containing amide derivative (CP9), and in <Step SB3> the azide-containing amide derivative (CP9) is reacted with ethynyl compound (CP10) in the presence of a metal catalyst such as copper sulfate pentahydrate and sodium ascorbate.

[0047] [ka]

[0048] Furthermore, the compounds (CP5) and (CP11) obtained above can be reacted with an iodohydrocarbon in the presence of a base such as cesium carbonate to obtain the compound represented by R 3 In addition, by reacting compound (CP5) or compound (CP11), or a compound obtained by reacting these with an iodohydrocarbon, with a sulfurizing agent such as Lawesson's reagent, a compound in which X in formula (α1) is a sulfur atom can be obtained.

[0049] Furthermore, the compound represented by formula (α1) or a salt thereof, or a solvate thereof that can be produced as described above has an excellent effect of inhibiting RyR2 activity, and is useful as a preventive or therapeutic agent for diseases associated with abnormally increased RyR2 activity. Diseases associated with abnormally increased RyR2 activity may be caused by RyR2 mutations (specifically, hyperactive mutations) or by abnormally increased wild-type RyR2 activity, and examples include arrhythmia, heart failure, cardiomyopathy, neurological disorders, and Alzheimer's disease. Specific examples of diseases caused by RyR2 hyperactive mutations include catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, and mental retardation. Specific examples of diseases associated with abnormally increased wild-type RyR2 activity include chronic heart failure accompanied by sympathetic nervous tension in wild-type RyR2 and Alzheimer's disease. Compound (α1) of the present invention is particularly useful as a preventive or therapeutic agent for diseases selected from catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, mental retardation, chronic heart failure, and Alzheimer's disease.

[0050] Therefore, compound (α1) of the present invention can be an RyR2 activity inhibitor or a medicament for preventing or treating diseases associated with abnormally increased RyR2 activity, and can be used for the prevention or treatment of diseases associated with the inhibition of RyR2 activity or abnormally increased RyR2 activity, and can also be used to manufacture an RyR2 activity inhibitor or a medicament for the prevention or treatment of diseases associated with abnormally increased RyR2 activity. Note that the above "use" can be administration or ingestion to humans or non-human animals.

[0051] The RyR2 activity inhibitor and pharmaceutical agent of the present invention may be administered parenterally, such as by injection, rectal administration, or topical administration, or orally. Furthermore, compound (α1) of the present invention may be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition. Known pharmaceutically acceptable carriers, such as excipients, binders, buffers, thickeners, stabilizers, emulsifiers, dispersants, suspending agents, and preservatives, can be used, and the pharmaceutical composition can be formulated by a conventional method.

[0052] Examples of formulations for oral administration include tablets (including sugar-coated tablets, film-coated tablets, etc.), pills, granules, powders, capsules (including soft capsules, etc.), syrups, emulsions, suspensions, etc. Oral preparations can be prepared by known methods using additives commonly used in the pharmaceutical field, such as excipients such as lactose, mannitol, and anhydrous calcium hydrogen phosphate; binders such as hydroxypropyl cellulose, methyl cellulose, and polyvinylpyrrolidone; disintegrants such as starch and carboxymethyl cellulose; and lubricants such as magnesium stearate and talc.

[0053] On the other hand, examples of parenteral preparations include injections, rectal preparations, and topical preparations, among which injections are preferred.

[0054] Injectable preparations include, for example, sterile solutions or suspensions of the compound (α1) of the present invention. For example, they can be prepared by dissolving or suspending the compound (α1) of the present invention in Japanese Pharmacopoeia water for injection. The injectable preparations may contain, as necessary, isotonicity agents such as sodium chloride; buffers such as sodium dihydrogen phosphate and sodium monohydrogen phosphate; solubilizers, etc. Furthermore, injectable preparations can also be prepared as ready-to-use dissolution types (powder-filled, freeze-dried), in which case they can be prepared by a conventional method by adding excipients such as mannitol and lactose.

[0055] Examples of rectal administration preparations include suppositories. Suppositories can be produced, for example, by dissolving or suspending the compound (α1) of the present invention in a base such as cocoa butter or macrogol, and then pouring the solution into a mold. Alternatively, a liquid or cream can be placed in an injection container to prepare a rectal administration preparation.

[0056] Dosage forms of topical administration preparations include, for example, liquids, eye drops, creams, ointments, gel preparations, sprays, powders, and the like. A liquid formulation can be prepared by adding the compound (α1) of the present invention to water, and adding a stabilizer, solubilizer, thickener, dispersant, suspending agent, etc. as needed. Eye drops can be prepared, for example, by adding a preservative in addition to the compound (α1) of the present invention, a buffer, a pH adjuster, and an isotonic agent. Creams and ointments can be produced, for example, by using the compound (α1) of the present invention together with an aqueous or oily base (e.g., water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.), macrogol, etc.). Gel preparations can be produced, for example, using compound (α1) of the present invention together with gelatin, pectin, carrageenan, agar, tragacanth, alginate, cellulose ether (methylcellulose, sodium carboxymethylcellulose, etc.), pectin derivatives, polyacrylate, polymethacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc. The spray can be produced by dissolving or suspending the compound (α1) of the present invention in water or the like, and then pouring the solution into a spray container. When preparing powders, the compound (α1) of the present invention can be used as it is, but it may also be prepared by mixing it with a suitable excipient.

[0057] The dosage or intake of the RyR2 activity inhibitor or pharmaceutical of the present invention is determined taking into consideration the target disease or symptom, and the age, body weight, sex, etc. of the subject. In the case of oral administration, the compound (α1) of the present invention is usually 0.01 to 100 mg, preferably 0.01 to 30 mg, and more preferably 0.1 to 10 mg per day for an adult (body weight approximately 60 kg), and this is administered or ingested in a single dose or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose for an adult is usually 0.03 to 3000 μg, preferably 0.03 to 300 μg, and more preferably 0.03 to 30 μg per kg body weight of the compound (α1) of the present invention, and this is administered once or in divided doses per day. [Example]

[0058] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. 1 1 H NMR spectra were measured using a Bruker AVANCE 400 or AVANCE 500 spectrometer.

[0059] (Synthesis Example 1: Synthesis of Compound 1) Compound 1 was synthesized according to the following synthetic route.

[0060] [ka]

[0061] (1-1) Synthesis of tetrazole derivatives In a 300 mL eggplant-shaped flask, benzonitrile (3 mmol) was dissolved in 80 mL of toluene, and sodium azide (586 mg, 9 mmol) and triethylamine hydrochloride (1.24 g, 9 mmol) were added thereto and stirred at 100 °C for 24 hours. After returning the reaction solution to room temperature, it was added to concentrated hydrochloric acid / ice, and the resulting precipitate was collected by suction filtration. The solid was washed with water to obtain the tetrazole derivative as a white solid (yield: 90%).

[0062] (1-2) Synthesis of amide derivatives In a 100 mL eggplant-shaped flask, bromoacetyl chloride (4.72 g, 13.4 mmol) was dissolved in dichloromethane and stirred at 0°C. Aniline (10.7 mmol) and triethylamine (14.4 mmol) dissolved in dichloromethane were added dropwise, and the mixture was stirred for an additional 1 hour. The reaction solution was returned to room temperature, and the precipitated solid was filtered by suction. The resulting solution was then separated into water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the amide derivative as a brown solid (yield: 78%).

[0063] (1-3) Synthesis of Compound 1 In a 50 mL eggplant-shaped flask, the tetrazole derivative (2.5 mmol) and potassium hydroxide obtained above were dissolved in 20 mL of ethanol, to which the amide derivative (2.5 mmol) obtained above was added, and the mixture was heated under reflux for 16 hours. After the reaction solution was returned to room temperature, 50 mL of water was added, and the precipitated solid was collected by suction filtration. Compound 1 was obtained as colorless needle-like crystals by recrystallization from ethanol (yield: 60%). The obtained compound 1 1 The 1 H NMR spectrum is shown below.

[0064] compound 1 1 H NMR (500 MHz, DMSO-d6): δ = 10.63 (br s, 1H), 8.08 (dd, J = 7.8, 2.1 Hz, 2 H), 7.59-7.56 (m, 5 H), 7.34 (t, J = 7.4 Hz, 2 H), 7.10 (t, J = 7.4 Hz, 1 H), 5.76 (s, 2 H).

[0065] (Synthesis Examples 2 to 12: Synthesis of Compounds 2 to 12) Compounds 2 to 12 were synthesized in the same manner as in Synthesis Example 1, except that the aniline used in the synthesis of the amide derivatives was changed to a substituted aniline shown in Tables 1 and 2.

[0066] [Table 1]

[0067] [Table 2]

[0068] The obtained compounds 2 to 12 1 The 1 H NMR spectrum is shown below.

[0069] compound 2 1H NMR (500 MHz, DMSO-d6): δ = 9.95 (br s, 1H), 8.08 (dd, J = 8.1, 1.5 Hz, 2 H), 7.59-7.53(m, 3 H), 7.42 (d, J = 7.0 Hz, 1 H), 7.23 (d, J = 7.2 Hz, 1 H), 7.17 (t, J = 7.2 Hz, 1 H), 7.17 (td, J = 7.4, 1.3 Hz, 1 H), 5.80 (s, 2 H), 2.25 (s, 3 H).

[0070] Compound 3 1 H NMR (500 MHz, DMSO-d6): δ = 10.55 (br s, 1H), 8.08 (dd, J = 8.0, 2.0 Hz, 2 H), 7.59-7.53 (m, 3 H), 7.42 (s, 1H), 7.36 (d, J = 8.2 Hz, 2 H), 7.21 (t, J = 7.8 Hz, 3 H), 6.92 (d, J = 7.5 Hz, 3 H), 5.74 (s, 2 H), 2.27 (s, 3 H).

[0071] Compound 4 1 H NMR (500 MHz, DMSO-d6): δ = 10.54 (br s, 1H), 8.08 (dd, J = 8.0, 2.0 Hz, 2 H), 7.59-7.54 (m, 3 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.14 (d, J = 7.3 Hz, 2 H), 5.73 (s, 2 H), 2.25 (s, 3 H).

[0072] Compound 5 1H NMR (500 MHz, DMSO-d6): δ = 9.92 (br s, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 2 H), 7.92(d, J = 8.0 Hz, 1 H), 7.59-7.53 (m, 3 H), 7.13-7.08 (m, 2 H), 6.90 (td, J = 7.9, 1.7 Hz, 1 H), 5.86 (s, 2 H), 3.88 (s, 3 H).

[0073] Compound 6 1 H NMR (500 MHz, DMSO-d6): δ = 10.62 (br s, 1H), 8.08 (dd, J = 8.0, 1.9 Hz, 2 H), 7.59-7.55 (m, 3 H), 7.27 (t, J = 2.2 Hz, 1 H), 7.24 (t, J = 8.2 Hz, 1 H), 7.10 (dd, J = 8.0, 1.1 Hz, 1 H), 6.68 (dd, J = 7.9, 1.9 Hz, 1 H), 5.75 (s, 2 H), 3.71 (s, 3 H).

[0074] Compound 7 1 H NMR (500 MHz, DMSO-d6): δ = 10.49 (br s, 1H), 8.08 (dd, J = 8.0, 1.9 Hz, 2 H), 7.58-7.54 (m, 3 H), 7.49 (d, J = 9.1 Hz, 2 H), 6.91 (d, J = 9.1 Hz, 1 H), 5.71 (s, 2 H), 3.72 (s, 3 H).

[0075] Compound 8 1H NMR (500 MHz, DMSO-d6): δ = 0.85 (br s, 1H), 8.08 (dd, J = 7.9, 1.9 Hz, 2 H), 7.86 (dd, J = 7.8, 1.0 Hz, 1 H), 7.73-7.67 (m, 2 H), 7.59-7.55 (m, 3 H), 7.39 (td, J = 7.2 Hz, 2 H), 5.87 (s, 2 H).

[0076] Compound 9 1 H NMR (500 MHz, DMSO-d6): δ = 10.99 (br s, 1H), 8.09-8.06 (m, 2 H), 8.04-8.03 (m, 1 H), 7.82-7.80 (m, 1 H), 7.59-7.55 (m, 5 H), 5.81 (s, 2H).

[0077] Compound 10 1 H NMR (500 MHz, DMSO-d6): δ = 11.13 (br s, 1H), 8.09-8.06 (m, 2 H), 7.82 (d, J = 9.1 Hz, 2 H), 7.77 (d, J = 8.8 Hz, 2 H), 7.59-7.55 (m, 3 H), 5.83 (s, 2 H).

[0078] Compound 11 1 H NMR (500 MHz, MeOD): δ = 8.13 (dd, J = 7.7, 1.9 Hz, 2 H), 7.59 (dd, J = 7.0, 2.0 Hz, 2 H), 7.53-7.50 (m, 3 H), 7.07 (t, J = 8.8 Hz, 2 H), 5.66 (s, 2 H) ; 13C NMR (125 MHz, MeOD) δ 163.5(d, J = 166 Hz), 158.3 (d, J = 239 Hz), 134.7, 130.7, 129.3, 126.8, 126.4, 121.2, 121.1, 115.6, 115.5, 55.3.

[0079] compound 12 1 H NMR (500 MHz, DMSO-d6): δ = 11.11 (br s, 1H), 8.08 (d, J = 7.8 Hz, 2 H), 7.72 (d, J = 8.7 Hz, 2 H), 7.58-7.55 (m, 3 H), 7.35 (d, J = 8.7 Hz, 2 H), 5.81 (s, 2 H), 3.82 (s, 3 H), 3.71 (s, 3 H); 13 C NMR (125 MHz, DMSO-d6) δ 164.2, 163.2, 144.0, 137.5, 130.7, 129.3, 126.8, 126.4, 121.8, 121.1, 120.8, 119.0, 55.3.

[0080] (Synthesis Examples 13 to 15: Synthesis of Compounds 13 to 15) Compounds 13 to 15 were synthesized in the same manner as in Synthesis Example 1, except that the benzonitrile used in the synthesis of the tetrazole derivative was changed to a substituted benzonitrile shown in Table 3.

[0081] [Table 3]

[0082] The obtained compounds 13 to 15 1 The 1 H NMR spectrum is shown below.

[0083] compound 13 1H NMR (400 MHz, DMSO-d6): δ = 10.61 (br s, 1H), 7.83 (dd, J = 7.9, 1.8 Hz, 1 H), 7.58 (d, J = 8.5 Hz, 2 H), 7.52 (dt, J = 8.1, 1.8 Hz, 1 H), 7.34 (t, J = 7.9 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 1 H), 7.12 (tt, J =7.5, 1.4 Hz, 2 H), 5.73 (s, 2 H), 3.84 (s, 3H),

[0084] compound 14 1 H NMR (400 MHz, DMSO-d6): δ = 10.66 (br s, 1H), 7.66 (d, J = 7.7 Hz, 1 H), 7.59-7.56 (m, 3 H), 7.48 (t, J = 8.1 Hz, 1 H), 7.34 (t, J = 8.3 Hz, 2 H), 7.13- 7.08 (m, 2 H), 5.76 (s, 2 H), 3.84 (s, 3 H),

[0085] compound 15 1 H NMR (400 MHz, DMSO-d6): δ = 10.66 (br s, 1H), 8.01 (d, J = 8.9 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.34 (t, J = 7.9 Hz, 2 H), 7.13-7.08 (m, 3 H), 5.72 (s, 2 H), 3.82 (s, 3 H)

[0086] (Synthesis Examples 16 to 34: Synthesis of Compounds 16 to 34) Compounds 16 to 34 were synthesized in the same manner as in Synthesis Example 1, except that the benzonitrile used in the synthesis of the tetrazole derivatives was changed to a substituted benzonitrile shown in Tables 4 to 7, and the aniline used in the synthesis of the amide derivatives was changed to a substituted aniline shown in Tables 4 to 7.

[0087] [Table 4]

[0088] [Table 5]

[0089] [Table 6]

[0090] [Table 7]

[0091] The obtained compounds 16 to 34 1 The 1 H NMR spectrum is shown below.

[0092] compound 16 1 H NMR (500 MHz, DMSO-d6): δ = 10.50 (br s, 1H), 7.65 (dt, J = 7.5, 1.1 Hz, 1 H), 7.56-7.55 (m, 1H), 7.50-7.46 (m, 3 H), 7.11 (ddd, J = 8.4, 1.5, 0.9, Hz, 1 H), 6.90 (d, J = 9.1 Hz, 2 H), 5.69 (s, 2 H), 3.82(s, 3H), 3.70(s, 3 H).

[0093] compound 17 1H NMR (500 MHz, DMSO-d6): δ = 10.70 (br s, 1H), 7.65 (dt, J = 7.8, 1.1 Hz, 1 H), 7.59-7.55 (m, 2 H), 7.48 (t, J = 8.0 Hz, 2 H), 7.17 (t, J = 9.0 Hz, 2 H), 7.11 (ddd, J = 8.4, 2.7, 0.9 Hz, 1 H), 5.73 (s, 2 H), 3.82 (s, 3H).

[0094] Compound 18 1 H NMR (500 MHz, DMSO-d6): δ = 10.50 (br s, 1H), 7.93 (dt, J = 8.1, 1.3 Hz, 1 H), 7.82 (ddd, J = 9.7, 2.6, 1.5 Hz, 1 H), 7.63 (dd, J = 10.1, 4.0 Hz, 2 H), 7.49 (d, J = 9.1 Hz, 2 H), 7.41 (ddd, J = 8.8, 2.8, 0.9 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 2 H), 5.73 (s, 2 H), 3.72(s, 3H).

[0095] Compound 19 1 H NMR (500 MHz, DMSO-d6): δ = 10.69 (br s, 1H), 7.93 (dt, J = 8.1, 1.0 Hz, 1 H), 7.82 (ddd, J = 9.8, 2.6, 1.5 Hz, 1 H), 7.66-7.58 (m, 2 H), 7.41 (ddd, J = 9.1, 1.7, 0.9 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 2 H), 5.77 (s, 2 H).

[0096] Compound 20 1H NMR (500 MHz, DMSO-d6): δ = 10.61 (br s, 1H), 8.12 (t, J = 8.8 Hz, 2 H), 7.51 (d, J = 9.0 Hz, 2 H), 7.41 (t, J = 8.8 Hz, 2 H), 6.90 (d, J = 9.0 Hz, 2 H), 5.73 (s, 2 H), 3.71 (s, 3 H)

[0097] Compound 21 1 H NMR (500 MHz, DMSO-d6): δ = 10.92 (br s, 1H), 8.13 (t, J = 8.2 Hz, 2 H), 7.70 (d, J = 9.1 Hz, 2 H), 7.42 (t, J = 8.9 Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 5.79 (s, 2 H), 3.31 (s, 3 H)

[0098] Compound 22 1 H NMR (400 MHz, DMSO-d6): δ = 10.49 (s, 1H), 7.66 (dt, J = 7.6, 1.0 Hz, 1 H), 7.57 (dd, J = 2.6, 1.5 Hz, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.28 (d, J = 2.4 Hz, 1 H), 7.12 (ddd, J = 8.3, 2.7, 0.9, 1 H), 7.06 (dd, J = 8.7, 2.4, 1 H), 6.91 (d, J = 8.7, 1 H), 5.71 (s, 2 H), 3.84 (s, 3 H), 3.71 (s, 3 H), 3.70 (s, 3 H).

[0099] Compound 23 11H NMR (400 MHz, DMSO-d6): δ = 10.65 (s, 1 H), 7.66 (dt, J = 7.8, 1.1 Hz, 1 H), 7.57 (dd, J = 2.5, 1.5 Hz, 1 H), 7.52 (dd, J = 13.5, 2.5, 1 H), 7.49 (t, J = 7.9 Hz, 1 H), 7.27 (ddd, J = 9.9, 2.5, 1.4, 1 H), 7.15 (t, J = 9.5, 1 H), 7.12 (ddd, J = 8.3, 2.6, 0.9, 1 H), 5.73 (s, 2 H), 3.84 (s, 3 H), 3.80 (s, 3 H).

[0100] Compound 24 1 1H NMR (500 MHz, DMSO-d6): δ = 10.54 (s, 1 H), 7.66 (dt, J = 7.6, 1.3 Hz, 1 H), 7.56 (dd, J = 2.5, 1.5 Hz, 1 H), 7.48 (t, J = 8.1 Hz, - 1 H),

[0101] Compound 25 1 1H NMR (400 MHz, DMSO-d6): δ = 10.65 (s, 1 H), 7.65 (dd, J = 8.3, 2.0 Hz, 1 H), 7.63-7.57 (m, 2 H), 7.55 (d, J = 2.0 Hz, 1 H), 7.18 (t, J = 8.9, 2 H), 7.13 (d, J = 8.5 Hz, 1 H), 5.71 (s, 2 H), 3.84 (s, 3 H), 3.82 (s, 3 H).

[0102] Compound 26 1 H NMR (400 MHz, DMSO-d6): δ = 10.68 (s, 1 H), 7.75 (dd, J = 7.9, 1.9 Hz, 1 H), 7.67 (ddd, J = 8.4, 4.4, 2.0, 1 H), 7.62-7.58 (m, 2 H), 7.42 (dd, J = 11.4, 8.4, 1 H), 7.18 (t, J = 8.9, 2 H), 5.75 (s, 2 H), 3.94 (s, 3 H).

[0103] Compound 27 1 H NMR (400 MHz, DMSO-d6): δ = 10.69 (s, 1 H), 7.77-7.70 (m, 2 H), 7.62-7.56 (m, 2 H), 7.50 (tt, J = 9.3, 2.3, 1 H), 7.18 (t, J = 8.8, 2 H), 5.78 (s, 2 H).

[0104] Compound 28 1 H NMR (500 MHz, DMSO-d6): δ = 10.48 (br s, 1H), 8.01 (d, J = 8.6 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H), 7.11 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 5.67 (s, 2 H), 3.82 (s, 3 H), 3.71 (s, 3 H); 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 162.4, 161.0, 155.7, 131.3, 127.9, 120.9, 119.2, 114.7, 114.0, 55.3, 55.2.

[0105] Compound 29 11H NMR (500 MHz, DMSO-d6): δ = 10.69 (broad singlet, 1H), 8.23 (doublet, J = 8.1 Hz, 2 H), 8.14 (doublet, J = 8.1 Hz, 2 H), 7.61 - 7.50 (multiplet, 4 H), 7.18 (triplet, J = 8.8 Hz, 2 H), 5.77 (singlet, 2 H), 3.89 (singlet, 3 H); 13 13C NMR (125 MHz, DMSO-d6) δ 163.2, 162.8, 158.4 (doublet, J = 239 Hz), 149.8, 134.5, 131.1, 128.5, 125.9, 121.8, 121.2, 121.2, 115.7, 115.5, 55.4.

[0106] Compound 30 1 1H NMR (500 MHz, DMSO-d6): δ = 10.49 (broad singlet, 1H), 8.20 (doublet, J = 8.4 Hz, 2 H), 7.57 (doublet, J = 8.1 Hz, 2 H), 7.49 (doublet, J = 8.8 Hz, 2 H), 6.91 (doublet, J = 8.7 Hz, 2 H), 5.73 (singlet, 2 H), 3.72 (singlet, 3 H)

[0107] Compound 31 1 1H NMR (500 MHz, DMSO-d6): δ = 10.84 (broad singlet, 1H), 8.20 (doublet, J = 8.5 Hz, 2 H), 7.69 (doublet, J = 8.8 Hz, 2 H), 7.57 (doublet, J = 8.2 Hz, 2 H), 7.36 (doublet, J = 8.5 Hz, 3 H), 5.80 (singlet, 2 H); 13 13C NMR (125 MHz, DMSO-d6) δ 163.2, 163.1, 149.8, 144.1, 137.3, 128.5, 125.9, 122.0, 121.9, 121.8, 121.1, 121.0, 120.8, 119.1, 119.0, 55.4.

[0108] Compound 32 1 H NMR (500 MHz, DMSO-d6): δ = 10.50 (br s, 1H), 8.23 (d, J = 8.2 Hz, 2 H), 8.14 (d, J = 8.1 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 5.75 (s, 2 H), 3.72 (s, 3 H)

[0109] Compound 33 1 H NMR (500 MHz, DMSO-d6): δ = 10.70 (br s, 1H), 8.23 (d, J = 8.1 Hz, 2 H), 8.14 (d, J = 8.1 Hz, 2 H), 7.60 (dd, J = 8.1, 3.1 Hz, 2 H), 7.18 (t, J = 8.6 Hz, 2 H), 5.79 (s, 2 H), 3.89 (s, 3 H)

[0110] Compound 34 1 H NMR (500 MHz, DMSO-d6): δ =10.86 (br s, 1H), 8.23 (d, J = 8.0 Hz, 2 H), 8.14 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 8.7 Hz, 2 H), 7.36 (d, J = 8.5 Hz, 2 H), 5.81 (s, 2 H), 3.89 (s, 3 H); 13 C NMR (125 MHz, DMSO-d6) δ 165.6, 163.4, 163.1, 144.1, 137.3, 131.3, 130.9, 130.2, 126.7, 121.8, 121.1, 120.8, 120.1, 55.5, 52.4.

[0111] (Synthesis Example 35: Synthesis of Compound 35) The following synthetic route is used and compound 35 is synthesized.

[0112] [ka]

[0113] In a 50 mL eggplant-shaped flask, compound 1 (0.64 mmol) obtained in Synthesis Example 1 was dissolved in 15 mL of anhydrous DMF, and cesium carbonate (343 mg, 0.97 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Methyl iodide (1.4 mmol) was then added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and the resulting residue was separated into water and ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was then purified by silica gel column chromatography. The resulting solid was recrystallized from a mixed solvent of n-hexane and chloroform to give compound 35 as colorless prism-like crystals (yield: 73%). The obtained compound 35 1 The 1 H NMR spectrum is shown below.

[0114] compound 35 1 HNMR(500 MHz, CDCl3): δ = 8.14 (dd, J = 9.5, 2.5 Hz,2 H), 7.53(t, J = 9.0 Hz, 2 H),7.49-7.45 (m, 2 H), 7.36 (d, J = 9.0 Hz, 2 H), 5.23 (s, 2H), 4.98 (d, J = 6.2 Hz, 1H), 3.36 (s, 3H)

[0115] (Synthesis Examples 36 to 57: Synthesis of Compounds 36 to 57) Compounds 36 to 57 were synthesized in the same manner as in Synthesis Example 35, except that compound 1 was changed to compounds 2 to 10, 13 to 19, and 22 to 27. The obtained compounds 36 to 57 1 The 1 H NMR spectrum is shown below.

[0116] compound 36 1HNMR(500 MHz, CDCl3): δ = 8.16-8.14 (m, 2 H), 7.50-7.46 (m, 3 H), 7.42-7.34 (m, 3 H), 7.30 (d, J = 7.3 Hz, 1 H), 5.21 (d, J = 6.3 Hz, 1H), 4.98 (d, J = 6.2 Hz, 1H), 3.30 (s, 3H), 2.41 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 165.3, 163.9, 140.1, 135.7, 132.1, 130.3, 129.6, 128.8, 128.2, 128.0, 127.3, 127.0, 53.9, 36.5, 17.4.

[0117] Compound 37 1 HNMR(500 MHz, CDCl3): δ = 8.16-8.14 (m, 2 H), 7.50-7.46 (m, 3 H), 7.40 (t, J = 8.1 Hz, 1 H), 7.26 (d, J = 8.7 Hz, 1 H), 7.16-7.155 (m, 2 H), 5.25 (s, 2H), 3.35 (s, 3H), 2.43 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 165.3, 163.7, 141.6, 140.8, 130.3, 130.2, 129.8, 128.8, 127.8, 127.3, 127.0, 124.2, 54.2, 37.82, 21.3.

[0118] Compound 38 1 HNMR(500 MHz, CDCl3): δ = 8.16-8.13 (m, 2 H), 7.50-7.46 (m, 3 H), 7.32 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 9.2 Hz, 2 H), 5.23 (s, 2H), 3.34 (s, 3H), 2.42 (s, 3H); 1313C NMR (125 MHz, CDCl3) δ 165.3, 163.8, 139.2, 139.0, 131.0, 130.3, 128.8, 127.3, 127.0, 126.9, 54.11, 37.86, 21.11.

[0119] Compound 39 1 1H NMR(500 MHz, CDCl3): δ = 8.16 - 8.14 (m, 2 H), 7.50 - 7.45 (m, 3 H), 7.43 (ddd, J = 9.2, 7.6, 1.6 Hz, 1 H), 7.32 (dd, J = 8.2, 1.6 Hz, 1 H), 7.09 - 7.05(m, 2 H), 5.24 (d, J = 16.1 Hz, 1 H), 5.16 (d, J = 16.2 Hz, 1 H), 3.95 (s, 3H), 3.27 (s, 3 H); 13 13C NMR (125 MHz, CDCl3) δ 165.3, 164.5, 155.0, 130.6, 130.2, 129.9, 129.0, 128.8, 127.4, 127.0, 121.7, 55.8, 53.9, 36.8.

[0120] Compound 40 1 1H NMR(500 MHz, CDCl3): δ = 8.16 - 8.14 (m, 2 H), 7.50 - 7.46 (m, 3 H), 7.43 (t, J = 8.1 Hz, 1 H), 6.99 (dd, J = 8.4, 2.0 Hz, 1 H), 6.95 (ddd, J = 7.8, 1.9, 0.8 Hz, 1 H), 6.88 (t, J = 2.2 Hz, 1 H), 5.28 (s, 2 H), 3.87 (s, 3H), 3.35 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 165.3, 163.7, 161.1, 142.8, 131.2, 130.3, 128.8, 127.3, 127.0, 119.3, 114.5, 113.1, 55.6, 54.1, 37.8.

[0121] Compound 41 1 HNMR(500 MHz, CDCl3): δ = 8.16-8.13 (m, 2 H), 7.50-7.46 (m, 3 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.01 (d, J = 8.9 Hz, 2 H), 5.23 (s, 2 H), 3.85 (s, 3H), 3.33 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 165.3, 164.0, 159.8, 134.2, 130.3, 128.8, 128.4, 127.3, 127.0, 115.5, 55.6, 54.1, 38.0.

[0122] Compound 42 1 HNMR(500 MHz, CDCl3): δ = 8.15-8.13 (m, 2 H), 7.85 (dd, J = 7.7, 1.1 Hz, 1 H), 7.76 (dt, J = 7.8, 1.3 Hz, 1 H), 7.59(t, J = 7.7 Hz, 1 H), 7.52-7.47(m, 4 H), 5.25 (d, J = 2.0 Hz, 2 H), 3.43 (s, 3 H); 13 C NMR (125 MHz, CDCl3) δ 165.5, 163.2, 144.1, 135.0, 134.6, 130.4, 129.8, 129.3, 128.8, 127.0, 126.9, 115.2, 112.7, 53.8, 37.7.

[0123] Compound 43 1HNMR(500 MHz, CDCl3): δ = 7.92(s,3H), 7.52-7.42(m,5H), 7.05(s,1H), 5.03(s,2H), 3.16(s,3H); 13 C NMR (125 MHz, CDCl3) δ 165.5, 163.4, 142.6, 132.6, 132.0131.6, 130.9, 130.5, 128.9, 127.0, 126.9, 117.1, 114.9, 54.0. 38.1.

[0124] Environment44 1 HNMR(500 MHz, CDCl3): δ = 8.13 (dd, J = 7.7, 2.0 Hz, 2 H), 7.82 (d, J = 8.1 Hz, 2 H), 7.52-7.49(m, 5 H), 5.29 (s, 2 H), 3.40 (s, 3 H); 13 C NMR (125 MHz, CDCl3) δ 165.5, 163.3, 145.7, 134.3, 130.5, 128.9, 128.1, 127.0, 126.9, 117.5, 54.0, 37.9.

[0125] Environment45 1 HNMR(500 MHz, CDCl3): δ = 8.08 (dd, J = 6.9, 2.1 Hz, 1 H), 7.53 (t, J = 7.9 Hz, 2 H), 7.45 (dt, J = 7.9, 1.6 Hz, 2 H), 7.38 (dd, J = 7.2, 1.4 Hz, 2H), 7.09–7.04(m,2H), 5.27(s,2H), 3.93(s,3H), 3.36(s,3H); 13 C NMR (125 MHz, CDCl3) δ 163.7, 163.3, 157.4, 141.7, 131.5, 130.9, 130.4, 129.0, 127.3, 120.7, 116.4, 111.8, 56.0, 54.1. 37.8.

[0126] Compound 46 1 HNMR(500 MHz, CDCl3): δ = 7.74 (d, J = 7.6 Hz, 1 H), 7.69 (t, J = 1.5 Hz, 1 H), 7.54 (t, J = 7.2 Hz, 2 H), 7.48 (t, J = 7.3 Hz, 1 H), 7.40-7.36 (m, 3 H), 7.02 (dd, J = 8.1, 2.8, 1.1 Hz, 1 H), 5.24 (s, 2 H), 3.89 (s, 3 H), 3.37 (s, 3 H); 13 C NMR (125 MHz, CDCl3) δ 165.3, 163.7, 159.9, 141.7, 130.5, 129.9, 129.1, 128.5, 127.3, 119.4, 116.9, 111.5, 55.4, 54.1, 37.9.

[0127] Compound 47 1 HNMR(500 MHz, CDCl3): δ = 8.08 (d, J = 9.0 Hz, 2 H), 7.53 (t, J = 7.9 Hz, 2 H), 7.46 (tt, J = 7.4, 1.5 Hz, 1 H), 7.36 (dd, J = 7.2, 1.3 Hz, 2 H), 6.99 (d, J = 8.1 Hz, 2 H), 5.22 (s, 2 H), 3.87 (s, 3 H), 3.37 (s, 3 H); 13 C NMR (125 MHz, CDCl3) δ 165.2, 163.8, 161.2, 141.7, 130.5, 129.1, 128.5, 127.3, 119.9, 114.2, 55.3, 54.0, 37.9.

[0128] Compound 48 1HNMR(500 MHz, CDCl3): δ = 7.74 (dt, J = 7.7, 1.2 Hz, 1 H), 7.69 (dd, J = 2.5, 1.5 Hz, 1 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.28 (d, J = 8.9 Hz, 2 H), 7.03 - 7.00 (m, 3 H), 5.23 (s, 2 H), 3.89 (s, 3 H), 3.86 (s, 3 H), 3.33(s, 3 H); 13 C NMR (125 MHz, CDCl3) δ 165.2, 164.0, 159.9, 159.8, 134.2, 129.9, 128.5, 128.4, 119.4, 116.9, 115.6, 111.5, 55.6, 55.4, 54.2, 38.0.

[0129] Compound 49 1 HNMR(500 MHz, CDCl3): δ = 7.74 (dt, J = 7.7, 1.2 Hz, 2 H), 7.69 (dd, J = 2.5, 1.5 Hz, 2 H), 7.41 - 7.35 (m, 3 H), 7.22 (t, J = 8.7 Hz, 1 H), 7.02 (ddd, J = 8.3, 2.6, 1.0 Hz, 2 H), 5.22 (s, 2 H), 3.89 (s, 3 H), 3.45 (s, 3 H); 13 C NMR (125 MHz, CDCl3) δ 165.3, 163.7,162.4 (d, J = 249 Hz), 159.9, 137.6, 129.9, 129.3, 129.2, 128.4, 119.4, 117.7, 117.5, 116.9, 111.5, 55.4, 54.1, 38.1.

[0130] Compound 50 1HNMR (500 MHz, CDCl3): δ = 7.74 (dt, J = 7.9, 1.2 Hz, 1 H), 7.85 (ddd, J = 9.6, 2.6, 1.1 Hz, 2 H), 7.46 (td, J = 8.1, 5.8 Hz, 1 H), 7.28 (d, J = 9.7 Hz, 1 H), 7.16 (ddd, J = 7.5, 2.7, 0.9 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 2 H), 5.23 (s, 2 H), 3.86 (s, 3 H), 3.33 (s, 3 H) ; 13 C NMR (125 MHz, CDCl3) δ 164.4, 163.9, 163.1(d, J = 298 Hz), 159.8, 134.2, 130.5(d, J = 8.8 Hz), 129.3(d, J = 7.5 Hz), 128.44, 122.6(d, J = 2.5 Hz), 117.2(d, J = 21.3 Hz), 115.6, 114.0(d, J = 23.8 Hz), 55.6, 54.2, 38.0.

[0131] compound51 1 HNMR(500 MHz, CDCl3): δ = 7.95 (dt, J = 7.8, 1.1 Hz, 1 H), 7.85 (ddd, J = 9.5, 2.4, 0.9 Hz, 1 H), 7.46 (td, J = 8.1, 5.8 Hz, 1 H), 7.38-7.35(m, 2 H), 7.23 (t, J = 8.5 Hz, 1 H), 7.17 (ddd, J = 8.5, 2.6, 0.9 Hz, 1 H), 5.23 (s, 2 H), 3.35 (s, 3 H) ; 1313C NMR (125 MHz, CDCl3) δ 164.4, 164.0 (d, J = 123 Hz), 163.8 (d, J = 38 Hz), 161.8 (d, J = 61 Hz), 137.6 (d, J = 4 Hz), 130.5 (d, J = 8 Hz), 129.3 (d, J = 9 Hz), 128.44, 122.6 (d, J = 4 Hz), 117.6 (d, J = 23 Hz), 117.3 (d, J = 20 Hz), 115.6, 114.0 (d, J = 25 Hz), 54.1, 38.1.

[0132] Compound 52 1 1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 7.6, Hz, 1 H), 7.68 (s, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.01 (dd, J = 8.1, 1.9 Hz, 1 H), 6.95 - 6.91 (m, 2 H), 6.84 (d, J = 1.4, 1 H), 5.27 (s, 2 H), 3.93 (s, 3 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 3.34 (s, 3 H).

[0133] Compound 53 1 1H NMR (500 MHz, CDCl3): δ = 7.66 (dt, J = 7.6, 1.0 Hz, 1 H), 7.68 (dd, J = 2.5, 1.5 Hz, 1 H), 7.39 (t, J = 8.0, 1 H), 7.13 (dd, J = 11.4, 2.5 Hz, 1 H), 7.11 (dd, J = 8.5, 2.4, 1 H), 7.07 (t, J = 8.6, 1 H), 7.03 (ddd, J = 7.5, 2.7, 0.9, 1 H), 5.25 (s, 2 H), 3.94 (s, 3 H), 3.89 (s, 3 H), 3.32 (s, 3 H).

[0134] Compound 54 1 1H NMR (500 MHz, CDCl3): δ = 7.62 (dt, J = 8.0, 2.0 Hz, 1 H), 7.53 (dd, J = 2.5, 2.0 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.21 (d, J = 2.0, 1 H), 7.11 (ddd, J = 8.5, 2.5, 0.9, 1 H), 7.05 (dd, J = 8.0, 2.0, 1 H), 7.01 (d, J = 8.0, 1 H), 6.09 (s, 2 H), 5.46 (s, 2 H), 3.83 (s, 3 H), 3.16 (s, 3 H).

[0135] Compound 55 1 1H NMR (500 MHz, CDCl3): δ = 7.74 (dt, J = 8.4, 1.2 Hz, 1 H), 7.65 (s, 1 H), 7.38 - 7.33 (m, 2 H), 7.24 - 7.19 (m, 2 H), 6.96 (d, J = 8.3 Hz, 1 H), 5.21 (s, 2 H), 3.97 (s, 3 H), 3.95 (s, 3 H), 3.34 (s, 3 H).

[0136] Compound 56 1 1H NMR (500 MHz, CDCl3): δ = 7.77 (dd, J = 8.1, 1.9 Hz, 1 H), 7.70 (ddd, J = 8.4, 4.4, 2.0, 1 H), 7.39 - 7.34 (m, 2 H), 7.23 (t, J = 6.9, 2 H), 7.18 (dd, J = 10.9, 8.4, 1 H), 5.22 (s, 2 H), 3.98 (s, 3 H), 3.35 (s, 3 H).

[0137] Compound 57 1H NMR (500 MHz, CDCl3): δ = 7.72-7.66 (m, 2 H), 7.40-7.35 (m, 2 H), 7.24 (t, J = 8.7, 2 H), 6.92 (tt, J = 8.8, 2.4, 1 H), 5.23 (s, 2 H), 3.35 (s, 3 H).

[0138] (Synthesis Example 58: Synthesis of Compound 58) Compound 58 was synthesized in the same manner as in Synthesis Example 35, except that methyl iodide was changed to ethyl iodide. The obtained compound 58 1 The 1 H NMR spectrum is shown below.

[0139] compound 58 1 HNMR(500 MHz, CDCl3): δ = 8.15-8.13 (m,2 H), 7.53 (dd, J = 9.0, 2.0 Hz, 2 H), 7.50-7.45 (m, 4 H), 7.33 (dd, J = 9.0, 1.5 Hz, 2 H), 5.17 (s, 2 H), 3.83 (q, J = 7.2 Hz, 2 H), 1.17 (t, J = 7.2 Hz 3 H).

[0140] (Synthesis Examples 59 to 65: Synthesis of Compounds 59 to 65) Compounds 59 to 65 were synthesized in the same manner as in Synthesis Example 35, except that compound 1 was changed to compounds 7, 11, 12, 28, 29, 31, and 34, and methyl iodide was changed to ethyl iodide. The obtained compounds 59 to 65 1 The 1 H NMR spectrum is shown below.

[0141] compound 59 1HNMR(400 MHz, CDCl3): δ = 8.15-8.13 (m, 2 H), 7.50-7.46 (m, 3 H), 7.24 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 9.1 Hz, 2 H), 5.18(s, 2H), 3.85(s, 3H), 3.79 (q, J = 7.2 Hz, 2 H), 1.16 (t, J = 7.2 Hz, 3 H).

[0142] Compound 60 1 HNMR(400 MHz, CDCl3): δ = 8.16-8.13 (m, 2 H), 7.50-7.47 (m, 3 H), 7.35-7.32 (m, 2 H), 7.23 (t, J = 8.8 Hz, 2 H), 5.17(s, 2H), 3.81 (q, J = 7.2 Hz, 2 H), 1.17 (t, J = 7.2 Hz, 3 H).

[0143] Compound 61 1 HNMR(400 MHz, CDCl3): δ = 8.15-8.13 (m, 2 H), 7.50-7.46 (m, 3 H), 7.39 (s, 4 H), 5.19(s, 2H), 3.82 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H).

[0144] Compound 62 1 HNMR(400 MHz, CDCl3): δ = 8.07 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.00 (t, J = 8.0, 4 H), 5.16(s, 2H), 3.87(s, 3H), 3.85(s, 3H), 3.78 (q, J = 7.2 Hz, 2 H), 1.17 (t, J = 7.2 Hz, 3 H).

[0145] Compound 63 1HNMR(400 MHz, CDCl3): δ = 8.18 (d, J = 8.9 Hz, 2H), 7.35-7.32(m, 4 H), 7.24 (t, J = 8.0, 2 H), 5.17(s, 2H), 3.80(q, J = 7.2 Hz, 2 H), 1.17(t, J = 7.2 Hz, 3 H).

[0146] compound 64 1 HNMR(400 MHz, CDCl3): δ = 8.19 (d, J = 8.8 Hz, 2H), 7.40(s, 4 H), 7.33 (d, J = 8.1 Hz, 4H), 5.17(s, 2H), 3.81(q, J = 7.2 Hz, 2 H), 1.17 (t, J = 7.2 Hz, 3 H).

[0147] compound 65 1 HNMR(400 MHz, CDCl3): δ = 8.22 (d, J = 8.5 Hz, 2 H), 8.16 (d, J = 8.3 Hz, 2 H), 7.40 (s, 4H), 5.20(s, 2H), 3.96 (s, 3 H), 3.82(q, J = 7.1 Hz, 2 H), 1.18(t, J = 7.2 Hz, 3 H).

[0148] (Synthesis Example 66: Synthesis of Compound 66) Compound 66 was synthesized in the same manner as in Synthesis Example 35, except that methyl iodide was changed to n-propyl iodide. The obtained compound 66 1 The 1 H NMR spectrum is shown below.

[0149] compound 66 1HNMR(500 MHz, CDCl3): δ = 8.03 (dd, J = 7.8, 1.4 Hz, 2 H), 7.58-7.52 (m, 7 H), 7.48-7.44 (m, 1 H), 5.34 (s, 2 H), 3.65 (t, J = 7.4 Hz, 2 H), 1.43 (sext, J = 7.4 Hz, 2 H), 0.83 (t, J = 7.4 Hz 3 H).

[0150] (Synthesis Example 67: Synthesis of Compound 67) In a 50 mL eggplant-shaped flask, compound 48 (1.0 mmol) was dissolved in 10 mL of THF, and Lawesson's reagent (0.55 mmol) was added. After stirring at 80 °C for 4 hours, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. The resulting solid was recrystallized from a mixed solvent of n-hexane and chloroform to give compound 67 as colorless prisms (yield: 99%).

[0151] (Synthesis Examples 68 to 70: Synthesis of Compounds 68 to 70) Compounds 68 to 70 were synthesized in the same manner as in Synthesis Example 67, except that compound 48 was changed to compounds 49 to 51.

[0152] Compounds 67 to 70 obtained in Synthesis Examples 67 to 70 1 The 1 H NMR spectrum is shown below.

[0153] compound 67 11H NMR (500 MHz, CDCl3): δ = 7.74 (dt, J = 7.7, 1.2 Hz, 1 H), 7.69 (dd, J = 2.4, 1.5 Hz, 1 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.24 (d, J = 9.0 Hz, 2 H), 7.02 (ddd, J = 6.7, 2.6, 0.9 Hz, 1 H), 7.00 (d, J = 8.9 Hz, 2 H), 5.46 (s, 2 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.76 (s, 3 H); 13 13C NMR (125 MHz, CDCl3) δ 193.2, 164.0, 160.0, 159.9, 136.8, 129.2, 128.5, 126.6, 119.4, 116.9, 115.6, 111.5, 60.8, 55.6, 55.4, 46.3.

[0154] Compound 68 1 1H NMR (500 MHz, CDCl3): δ = 7.74 (dt, J = 7.6, 1.1 Hz, 1 H), 7.69 (dd, J = 2.5, 1.0 Hz, 1 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.34 - 7.31 (m, 2 H), 7.22 (t, J = 7.1 Hz, 2 H), 7.03 (ddd, J = 8.3, 2.7, 0.9 Hz, 1 H), 5.46 (s, 2 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.76 (s, 3 H); 13 13C NMR (125 MHz, CDCl3) δ 193.1, 165.1, 162.5 (d, J = 251 Hz), 159.9, 140.1, 130.0, 128.4, 127.6, 127.5, 119.4, 117.7, 117.6, 116.9, 111.6, 60.8, 55.4, 46.3.

[0155] Compound 69 11H NMR (500 MHz, CDCl3): δ = 7.95 (dt, J = 8.0, 1.2 Hz, 1 H), 7.85 (ddd, J = 9.6, 2.6, 1.1 Hz, 1 H), 7.46 (dt, J = 8.0, 5.7 Hz, 1 H), 7.25 (d, J = 8.9 Hz, 2 H), 7.17 (ddd, J = 8.4, 2.6, 0.9 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 2 H), 5.46 (s, 2 H), 3.85 (s, 3 H), 3.76 (s, 3 H); 13 13C NMR (125 MHz, CDCl3) δ 193.1, 164.2, 163.9, 160.0, 136.7, 130.5, 129.3, 126.6, 122.7, 117.2, 115.6, 114.0, 60.8, 55.6, 46.3.

[0156] Compound 70 1 1H NMR (500 MHz, CDCl3): δ = 7.95 (dt, J = 7.9, 1.2 Hz, 1 H), 7.85 (ddd, J = 9.5, 2.6, 1.1 Hz, 1 H), 7.47 (td, J = 8.1, 5.8 Hz, 1 H), 7.36 - 7.32 (m, 2 H), 7.23 (t, J = 8.0 Hz, 1 H), 7.17 (ddd, J = 8.4, 2.6, 1.0 Hz, 1 H), 5.46 (s, 2 H), 3.77 (s, 3 H); 13 13C NMR (125 MHz, CDCl3) δ 193.0, 164.2, 163.7, 161.7, 140.0, 130.6, 129.2, 127.5, 122.7, 117.7, 117.3, 114.0, 60.7, 46.3.

[0157] (Synthesis Examples 71 - 72 Synthesis of Compounds 71 - 72) Compounds 71 - 72 were synthesized according to the following synthetic route (R 2 = -H or 4 - OMe).

[0158] [ka]

[0159] (1) Synthesis of azidoacetic acid In a 50 mL eggplant-shaped flask, sodium azide (1.58 g, 2.43 mmol) was dissolved in 15 mL of water and stirred at 0°C. Bromoacetic acid (2.2 g, 16.2 mmol) dissolved in 10 mL of water was slowly added dropwise thereto, and the mixture was stirred at room temperature for 24 hours. The mixture was again cooled to 0°C, and 2N hydrochloric acid was added in small portions until the pH reached 2. The reaction solution was extracted with diethyl ether, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.96 g of azidoacetic acid as a colorless liquid (yield: 99%).

[0160] (2) Synthesis of azide derivatives In a 20 mL eggplant-shaped flask, the azidoacetic acid (200 mg, 1.98 mmol) obtained in (1) above was dissolved in 5 mL of dichloromethane, and one drop of DMF was added thereto, followed by stirring at 0°C. Oxalyl chloride (326 mg, 2.57 mmol) dissolved in dichloromethane was added dropwise thereto, and the mixture was stirred at 0°C to room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the resulting liquid was dissolved in 4 mL of dichloromethane and stirred at 0°C. Aniline (Synthesis Example 71) or 4-methoxyaniline (Synthesis Example 72) (2.18 mmol) and triethylamine (400 mg, 3.95 mmol) dissolved in dichloromethane were added dropwise thereto, followed by stirring at 0°C to room temperature. After 15 hours, water was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then partitioned between water and ethyl acetate. The organic layer was washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the azide derivative as a pale yellow solid (yield: 72-73%).

[0161] (3) Synthesis of compounds 71-72 In a 30 mL eggplant-shaped flask, the azide derivative (0.73 mmol) obtained in (2) above and ethynylbenzene (82 mg, 0.80 mol) were dissolved in 4 mL of DMF. Copper sulfate pentahydrate (9 mg, 0.037 mmol) and sodium ascorbate (14.4 mg, 0.073 mmol) were added, followed by 1 mL of water. After stirring at 60 °C for 20 h, the mixture was separated into water and ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate. After drying over sodium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography. The resulting solid was recrystallized from a mixed solvent of n-hexane and ethyl acetate to give compounds 71 and 72 as colorless needles (yields: 44–73%). The obtained compounds 71 to 72 1 The 1 H NMR spectrum is shown below.

[0162] compound 71 1 H NMR (500 MHz, acetone-d6): δ = 9.64 (br s, 1 H), 8.43 (s, 1 H), 7.93 (dd, J = 8.5, 1.0 Hz, 2 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 3 H), 7.11 (tt, J = 7.5, 1.0 Hz, 1 H), 5.42 (s, 2 H); 13 C NMR (126 MHz, CDCl3) δ 164.9, 148.0, 139.5, 132.4, 129.8, 129.7, 128.7, 126.3, 125.0, 123.2, 120.3, 53.6.

[0163] compound 72 1H NMR (500 MHz, DMSO-d6): δ = 10.38 (s, 1 H), 8.59 (s, 1 H), 7.93 (dd, J = 8.3, 1.3 Hz, 2 H), 7.50 (d, J = 9.1 Hz, 2 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.34 (tt, J = 7.5, 1.0 Hz, 1 H), 6.91 (d, J = 9.1 Hz, 2 H), 5.43 (s, 2 H), 3.72 (s, 3 H); 13 C NMR (126 MHz, CDCl3) δ 163.6, 155.6, 146.2, 131.5, 128.9, 127.9, 125.1, 123.0, 120.8, 114.0, 55.2, 52.3.

[0164] (Synthesis Examples 73 to 74: Synthesis of Compounds 73 to 74) In a 20 mL recovery flask, compound 71 (Synthesis Example 73) or compound 72 (Synthesis Example 74) (0.14 mmol) was dissolved in 2.5 mL of anhydrous DMF, and cesium carbonate (75 mg, 0.23 mmol) was added and stirred at room temperature for 10 minutes. Subsequently, methyl iodide (excess amount) was added, and the mixture was stirred at 60°C for 4 hours. The solvent was evaporated under reduced pressure, and the resulting residue was separated into water and dichloromethane. The organic layer was dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography. The resulting solid was recrystallized from a mixed solvent of n-hexane and chloroform to give compounds 73 and 74 as pale yellow needle crystals (yield: 73%).

[0165] (Synthesis Example 75: Synthesis of Compound 75) Compound 75 was synthesized in the same manner as in Synthesis Example 74, except that methyl iodide was changed to ethyl iodide.

[0166] Compounds 73 to 75 obtained in Synthesis Examples 73 to 75 1 The 1 H NMR spectrum is shown below.

[0167] compound 73 11H NMR (500 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.93 (dd, J = 8.5, 1.0 Hz, 2 H), 7.52 (t, J = 8.5 Hz, 2 H), 7.44 (t, J = 7.2 Hz, 2 H), 7.46 (tt, J = 7.5, 1.0 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.34 - 7.32 (m, 3 H), 4.97 (s, 2 H), 3.35 (s, 3 H); 13 13C NMR (126 MHz, CDCl3) δ 165.1, 148.1, 142.1, 130.9, 130.7, 129.3, 129.0, 128.3, 127.5, 126.0, 121.6, 51.5, 38.0.

[0168] Compound 74 1 1H NMR (500 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.83 (dd, J = 8.6, 1.2 Hz, 2 H), 7.41 (t, J = 7.4 Hz, 2 H), 7.32 (tt, J = 7.4, 1.8 Hz, 1 H), 7.22 (d, J = 8.9 Hz, 2 H), 7.00 (d, J = 8.9 Hz, 2 H), 4.96 (s, 2 H), 3.85 (s, 3 H), 3.31 (s, 3 H); 13 13C NMR (126 MHz, CDCl3) δ 165.4, 160.0, 148.0, 134.6, 130.9, 129.0, 128.6, 128.3, 121.6, 115.8, 55.8, 51.4, 38.2.

[0169] Compound 75 1H NMR (500 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.83 (dd, J = 8.6, 1.2 Hz, 2 H), 7.41 (t, J = 7.4 Hz, 2 H), 7.32 (tt, J = 7.4, 1.8 Hz, 1 H), 7.19 (d, J = 8.9 Hz, 2 H), 7.00 (d, J = 8.9 Hz, 2 H), 4.91 (s, 2 H), 3.86 (s, 3 H), 3.77 (q, J = 7.2 Hz, 2 H), 1.15 (t, J = 7.2 Hz, 2 H); 13 C NMR (126 MHz, CDCl3) δ 164.9, 160.1, 148.0, 132.8, 130.9, 129.7, 129.0, 128.2, 126.0, 121.7, 115.7, 55.8, 51.7, 45.0, 13.0.

[0170] In the compounds 1 to 75 obtained in Synthesis Examples 1 to 75, the symbols in the formula (α1) are as shown in Tables 8 to 12 below.

[0171] [Table 8]

[0172] [Table 9]

[0173] [Table 10]

[0174] [Table 11]

[0175] [Table 12]

[0176] [Test Example 1] According to the following procedure, the EC 2 inhibitory effect of each compound shown in Table 13 on type 2 ryanodine receptor activity was determined. 50 The values were measured.

[0177] (1) Construction of expression plasmid RyR2 cDNA was cloned from mouse myocardium by PCR and inserted into a hygromycin-resistant expression vector (pcDNA5 / FRT / TO) for Flp-In T-REX, which is tetracycline-inducible (Tet-On) and induces RyR expression in the presence of doxycycline. Furthermore, R-CEPIA1er, described in Nat. Commun., 2014, 5:4153, was inserted into the neomycin-resistant expression vector pCMV / myc / ER, which constitutively expresses R-CEPIA1er.

[0178] (2) Preparation of HEK293 cells HEK293 cells were prepared using Flp-In T-REX 293 cells, which are compatible with the Tet-On inducible system. These cells were cultured at 37°C in a CO2 incubator.

[0179] (3) Transfection of R-CEPIA1er and disease-mutated RyR genes into HEK293 cells A stable expression line was established by introducing the disease mutant RyR gene into Flp-In T-REX 293 cells by lipofection and culturing the cells in a medium supplemented with hygromycin for 10-14 days. An R-CEPIA1er expression vector was then introduced into the disease mutant RyR stable expression line by lipofection and culturing the cells in a medium supplemented with G418, resulting in the establishment of a stable expression line co-expressing the disease mutant RyR gene and R-CEPIA1er.

[0180] (4) Transfection of R-CEPIA1er and wild-type RyR genes into HEK293 cells The wild-type RyR gene was introduced into Flp-In T-REX 293 cells by lipofection and cultured in hygromycin-supplemented medium for 10–14 days to establish a stable expression line. The R-CEPIA1er expression vector was then introduced into this RyR stable expression line by lipofection and cultured in G418-supplemented medium to establish a stable expression line dually expressing the wild-type RyR gene and R-CEPIA1er.

[0181] (5) Fluorescent intraendoplasmic reticulum Ca 2+ Concentration measurement Cultured cells expressing disease-mutated RyR and R-CEPIA1er, and cultured cells expressing wild-type RyR and R-CEPIA1er, were cultured in plastic dishes at 37°C for 24 hours, and then the medium was changed to one containing doxycycline and cultured for another 24 hours. Fluorescence measurements were performed using a FlexStation. R-CEPIA1er was excited at 560 nm, and fluorescence at 610 nm was obtained. Fluorescence was acquired every 10 seconds for 300 seconds, and each compound shown in Table 13 was added 60 seconds after the start of the measurement to measure the fluorescence intracellular Ca. 2+ The concentration was measured.

[0182] (6) Evaluation of the inhibitory effect on type 2 ryanodine receptor activity The inhibitory effect of each compound shown in Table 13 on type 2 ryanodine receptor activity was measured using the above method at a final concentration of 10 -9 ~10 -4 From the measurement results, a dose-dependent curve was calculated using the least squares method, which was approximated to the Hill equation, and the EC 50 The values were calculated and the results are shown in Table 13. Compounds 48 to 53, 55 to 58, and 67 to 70 were tested for their effects on RyR1 using the RyR1 R2163C disease mutation, but no RyR1 activity inhibitory effect was confirmed.Compounds 48 to 51, 56, 57, and 67 to 70 were tested for their effects on RyR3, but no RyR3 activity inhibitory effect was confirmed.

[0183] [Table 13]

[0184] [Test Example 2] (1) Generation of RyR2 mutant mice At the RIKEN BRC, male mice treated with N-ethyl-N-nitrosourea (ENU) were mated with normal wild-type females to generate first-generation offspring (G1). These G1 mice were subjected to systematic phenotyping and analyzed for cardiac phenotypes, revealing mice carrying the RyR2 I4093V mutation (RyR2 c.12277A>G (NM_023868.2), p.I4093V (NP_076357.2)). These mice were backcrossed with normal wild-type mice for eight or more generations to obtain mice thought to carry only the RyR2 I4093V mutation. (2) Preparation of Compound 57-containing solution Compound 57 shown in Table 10 was dissolved in physiological saline (0.9% NaCl aqueous solution) to give a 0.03-0.1 mg / mL solution, thereby preparing a solution containing Compound 57. (3) Electrocardiogram measurement and drug administration in RyR2 mutant mice The mutant mice (4-5 months old) were anesthetized with 2% isoflurane and then maintained at 1% isoflurane. Electrocardiograms were continuously monitored with electrocardiogram electrodes attached to the limbs. After 10 minutes of monitoring before drug administration, Compound 57 was intraperitoneally injected at 0.3 mg / kg or 1 mg / kg, and electrocardiograms were recorded for another 15 minutes. The results of intraperitoneal injection of 0.3 mg / kg are shown in Figure 1. As shown in Figure 1, before administration of Compound 57, bidirectional ventricular tachycardia occurred periodically, but after intraperitoneal administration of 0.3 mg / kg of Compound 57, the ECG returned to normal. (4) Results and Discussion After administration of Compound 57, the time during which consecutive bigeminy, triplegia, or ventricular tachycardia occurred within 5-15 minutes was counted as arrhythmia for each individual, and the percentage of time during which arrhythmia occurred was calculated. The results are shown in Figure 2. The results shown in Figure 2 show that administration of Compound 57 at 0.3 mg / kg or 1 mg / kg reduced the likelihood of arrhythmia.

Claims

1. A type 2 ryanodine receptor activity inhibitor comprising a compound represented by the following formula (α1), a salt thereof, or a solvate thereof: 【Chemical 1】 [In formula (α1), Ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring; R 1 and R 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; R 3 indicates a methyl group, R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms, X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; n and m each independently represent an integer of 0 to 5; However, when n is an integer of 2 to 5, n R 1 may be the same or different, and two R 1 may be joined together to form a ring. When m is an integer of 2 to 5, m R 2 may be the same or different, and two R 2 may be joined together to form a ring.

2. Ring Q 1 and Ring Q 2 and each independently represent a fused ring of a 4- to 8-membered oxygen-containing monocyclic heterocycle and a benzene ring, or a benzene ring.

3. R 1 and R 2 are each independently a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom.

4. R 4 The type 2 ryanodine receptor activity inhibitor according to any one of claims 1 to 3, wherein is an alkanediyl group having 1 to 8 carbon atoms or an alkenediyl group having 2 to 8 carbon atoms.

5. The type 2 ryanodine receptor activity inhibitor according to any one of claims 1 to 4, wherein n is an integer of 1 to 5.

6. The type 2 ryanodine receptor activity inhibitor according to any one of claims 1 to 4, wherein m is an integer of 1 to 5.

7. A pharmaceutical for preventing or treating a disease associated with abnormally increased type 2 ryanodine receptor activity, comprising a compound represented by the following formula (α1) or a salt thereof, or a solvate thereof: 【Chemistry 2】 [In formula (α1), Ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring; R 1 and R 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; R 3 indicates a methyl group, R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms, X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; n and m each independently represent an integer of 0 to 5; However, when n is an integer of 2 to 5, n R 1 may be the same or different, and two R 1 may be joined together to form a ring. When m is an integer of 2 to 5, m R 2 may be the same or different, and two R 2 may be joined together to form a ring.

8. The pharmaceutical composition according to claim 7, wherein the disease associated with abnormally increased type 2 ryanodine receptor activity is a disease selected from catecholamine-induced polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, mental retardation, chronic heart failure, and Alzheimer's disease.

9. A compound represented by any one of the following formulas (α3) to (α12), a salt thereof, or a solvate thereof: 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】

10. Use of a compound represented by the following formula (α1), or a salt thereof, or a solvate of the compound or the salt, for the manufacture of an inhibitor of type 2 ryanodine receptor activity: 【Chemistry 7】 [In formula (α1), Ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring; R 1 and R 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; R 3 indicates a methyl group, R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms, X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; n and m each independently represent an integer of 0 to 5; However, when n is an integer of 2 to 5, n R 1 may be the same or different, and two R 1 may be joined together to form a ring. When m is an integer of 2 to 5, m R 2 may be the same or different, and two R 2 may be joined together to form a ring.

11. Use of a compound represented by the following formula (α1), or a salt thereof, or a solvate of either, for the manufacture of a medicament for the prevention or treatment of a disease associated with abnormally increased type 2 ryanodine receptor activity: 【Chemistry 8】 [In formula (α1), Ring Q 1 and Ring Q 2 each independently represents a fused ring of a monocyclic heterocycle or a monocyclic carbocycle with a benzene ring, or a benzene ring; R 1 and R 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; R 3 indicates a methyl group, R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms, X represents an oxygen atom or a sulfur atom; Y represents a methine group or a nitrogen atom; n and m each independently represent an integer of 0 to 5; However, when n is an integer of 2 to 5, n R 1 may be the same or different, and two R 1 may be joined together to form a ring. When m is an integer of 2 to 5, m R 2 may be the same or different, and two R 2 may be joined together to form a ring.

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