Compounds, angiotensin II type 1 receptor antagonists, and pharmaceutical compositions

Abstract

Provided is a compound represented by formula (1) or a pharmaceutically acceptable salt thereof (in formula (1), Ar is formula (Ar1) or (Ar2), and in these formulas, R1 and R2 each independently denote an alkyl, a haloalkyl, or a halogen, each R3 independently denotes an alkyl, a haloalkyl, a halogen, an alkoxy, or a haloalkoxy, and m is an integer of 0-3).

Description

Technical Field

[0001] The present invention relates to a compound, an angiotensin II type 1 receptor antagonist, and a pharmaceutical composition.

Background Art

[0002] As receptors for angiotensin II, there are angiotensin II type 1 receptor (AT1 receptor) and angiotensin II type 2 receptor (AT2 receptor), and various diseases related to (mediated by) the AT1 receptor have been reported.

[0003] Examples of AT1 receptor-related diseases include hypertension (Patent Document 1), heart diseases (such as cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, dilated cardiomyopathy, myocarditis, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, and myocardial infarction) (Non-Patent Documents 1 and 2), progression of heart failure after myocardial infarction (Non-Patent Document 3), kidney diseases (such as nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, and organ damage including radiation nephropathy) (Non-Patent Documents 4 and 5), vascular hypertrophy, occlusion, and organ damage after intervention (such as percutaneous coronary angioplasty, stent placement, coronary endoscopy, intravascular ultrasound, and coronary thrombolysis therapy) (Non-Patent Document 6), eye diseases (such as glaucoma and ocular hypertension) (Non-Patent Documents 7 and 8), neurodegenerative diseases (such as Alzheimer's disease) (Non-Patent Document 9), central nervous system disorders (such as disorders such as cerebral hemorrhage and cerebral infarction, and their sequelae and complications) (Non-Patent Document 10), dementia (such as vascular dementia) (Non-Patent Document 11), liver diseases (such as non-alcoholic fatty liver disease) (Non-Patent Documents 12 and 13), eosinophilic esophagitis (Non-Patent Document 14), bone diseases (such as osteoarthritis deformans) (Non-Patent Document 15), skin diseases (such as epidermolysis bullosa) (Non-Patent Document 16), systemic diseases (such as Marfan syndrome) (Non-Patent Document 17), and cancer (Non-Patent Document 18) have been reported.

Prior Art Documents

Patent Documents

[0004] [License 1] International Publication No. 2005 / 80384 [Non-licensed literature]

[0005] [Non-licensed Document 1] Vascular Health and Risk Management 2008,4,67. [Non-licensed Document 2] Annals of Palliative Medicine 2021,10,8684. [Non-licensed Document 3] The Lancet, 2002, 360, 752. [Non-licensed Document 4] The New England Journal of Medicine2001,345,861. [Non-licensed Document 5] Blood Pressure 2019, 28, 358. [Non-licensed Document 6] BMC Cardiovascular Disorders 2017,17,278. [Non-licensed Document 7] Experimental Eye Research 2005,80,629. [Non-licensed Document 8] Journal of Cardiovascular Pharmacology 2000,36,169. [Non-licensed Document 9] Journal of Clinical Investigation 2007,117,3393. [Non-licensed Document 10] International Journal of Molecular Sciences 2012,13,7739. [Non-licensed Document 11] Hypertension Research 2009,32, 738. [Non-licensed Document 12] Oncotarget 2018,9,24155. [Non-Patent Document 13] Physiological Reports 2016,4,e13016. [Non-Patent Document 14] Expert Review of Clinical Immunology 2020,16,421. [Non-Patent Document 15] Journal of Orthopedic Translation 2021,29,30. [Non-Patent Document 16] Dermatologic Therapy 2020,e14279. [Non-Patent Document 17] European Heart Journal 2020,41,4181. [Non-Patent Document 18] Biochemical Pharmacology 2018,151,96. [Overview of the project] [Problems that the invention aims to solve]

[0006] The present invention aims to provide a compound having AT1 receptor antagonistic activity, or an AT1 receptor antagonist or pharmaceutical composition containing said compound. [Means for solving the problem]

[0007] As a result of diligent research by the inventors, we discovered that a compound having a predetermined structure has AT1 receptor antagonistic activity, and thus completed the present invention.

[0008] The present invention includes the following embodiments. [1] Formula (1): [ka] [In the formula, Ar is given by the following formula (Ar1) or (Ar2): [ka] (In the formula, R 1 and R 2 Each of these is independently an alkyl, haloalkyl, or halogen. R 3 Each of these is independently an alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy, (m is an integer between 0 and 3) is A compound represented by or a pharmaceutically acceptable salt thereof. [2] The compound described in [1] or a pharmaceutically acceptable salt thereof, wherein Ar is of formula (Ar1). [3] R 1 and R 2 The compounds described in [1] or [2], or pharmaceutically acceptable salts thereof, each independently being alkyl. [4] The following compounds: [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of [1]. [5] An angiotensin II type 1 receptor antagonist comprising any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof. [6] A pharmaceutical composition comprising any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof. [7] A pharmaceutical composition according to [6] for the prevention or treatment of hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, occlusion after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorders, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer. [8] The pharmaceutical composition according to [6] or [7], which is an injection, a patch, or an eye drop. [9] The following formula (2):

Chemical formula

[10] The following formula (3):

Chemical formula

Chemical formula

[11] The following formula (4):

Chemical formula

[0009] The present invention also includes the following embodiments. [A1] A method for inhibiting angiotensin II type 1 receptors, comprising administering an effective amount of any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof to a patient in need thereof. [A2] A method for preventing or treating a disease, comprising administering an effective amount of any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof to a patient in need thereof. [A3] The method according to [A2], wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, occlusion after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

[0010] [B1] A compound described in any of [1] to [4] or a pharmaceutically acceptable salt thereof, for use in inhibiting angiotensin II type 1 receptors. [B2] A compound described in any of [1] to [4] or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease. [B3] The compound described in [B2] or a pharmaceutically acceptable salt thereof, wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, occlusion after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

[0011] [C1] Use of any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof for inhibiting the angiotensin II type 1 receptor. [C2] Use of any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof for the prevention or treatment of a disease. [C3] The use described in [C2], wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, occlusion after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

[0012] [D1] Use of any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof in the manufacture of an angiotensin II type 1 receptor antagonist. [D2] Use of any of the compounds described in [1] to [4] or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of a disease. [D3] The use described in [D2], wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, occlusion after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide a compound having AT1 receptor antagonistic activity, or an AT1 receptor antagonist or pharmaceutical composition containing the said compound. [Modes for carrying out the invention]

[0014] The embodiments of the present invention will be described in detail below, but the present invention is not limited to these, and various modifications are possible without departing from the spirit of the invention.

[0015] <Compound> One embodiment of the present invention is given by the following formula (1): [ka] [In the formula, Ar is given by the following formula (Ar1) or (Ar2): [ka] (In the formula, R 1 and R 2 Each of these is independently an alkyl, haloalkyl, or halogen. R 3 Each of these is independently an alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy, (m is an integer between 0 and 3) is This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0016] The compound according to this embodiment, or a pharmaceutically acceptable salt thereof, has AT1 receptor antagonistic activity.

[0017] In this specification, alkyl groups (including alkyl groups in haloalkyl groups) may be linear or branched. In this specification, the alkyl portion of an alkoxy (including alkoxy in haloalkoxy) may be linear or branched.

[0018] In formula (1), Ar is either formula (Ar1) or formula (Ar2), and preferably formula (Ar1).

[0019] In equation (1), R 1 is an alkyl, haloalkyl, or halogen, preferably alkyl or halogen, and more preferably alkyl.

[0020] R 1 The alkyl group (including the alkyl group in haloalkyl groups) is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably an alkyl group having 1 or 2 carbon atoms, and particularly preferably a methyl group. R 1 The halogen and the halo in haloalkyl are preferably fluorine, chlorine, bromine, or iodine, and more preferably chlorine.

[0021] In equation (1), R 2 is an alkyl, haloalkyl, or halogen, preferably alkyl or halogen, and more preferably alkyl.

[0022] R 2 The alkyl group (including the alkyl group in haloalkyl groups) is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably an alkyl group having 1 or 2 carbon atoms, and particularly preferably a methyl group. R 2 The halogen and the halo in haloalkyl are preferably fluorine, chlorine, bromine, or iodine, and more preferably chlorine.

[0023] In equation (1), R 3Each of these elements is independently an alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy, preferably an alkyl or alkoxy.

[0024] R 3 The alkyl group (including the alkyl group in haloalkyl groups) is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably an alkyl group having 1 or 2 carbon atoms, and particularly preferably a methyl group. R 3 The halogen, and the halo in haloalkyl and haloalkoxy, are preferably fluorine, chlorine, bromine, or iodine, and more preferably chlorine. R 3 The alkoxy (including the alkoxy in haloalkoxy) is preferably an alkoxy having 1 to 6 carbon atoms, more preferably an alkoxy having 1 to 3 carbon atoms, even more preferably an alkoxy having 1 or 2 carbon atoms, and particularly preferably a methoxy.

[0025] In equation (1), m is an integer between 0 and 3, preferably 1 or 2, and more preferably 2.

[0026] The compound represented by formula (1) is not particularly limited, but is preferably one of the following compounds. [ka]

[0027] The pharmaceutically acceptable salts of the compound represented by formula (1) are not particularly limited as long as they are usable as medicines, but examples include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, and hydrobromide; organic salts such as fumarate, maleate, malate, tartrate, succinate, citrate, methanesulfonate, p-toluenesulfonate, acetate, lactate, and palmitate; inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, and ammonium salt; and organic base salts such as diethylamine salt, diethanolamine salt, meglumine salt, and N,N'-dibenzylethylenediamine salt.

[0028] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof may form solvates such as hydrates. In this specification, solvates are defined as the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0029] If a compound represented by formula (1) or a pharmaceutically acceptable salt thereof has stereoisomers (e.g., enantiomers and diastereomers), then each stereoisomer and mixture thereof (e.g., racemates) shall be considered to be encompassed by the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0030] <Angiotensin II type 1 receptor antagonist> One embodiment of the present invention relates to an AT1 receptor antagonist comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. The AT1 receptor antagonist of this embodiment can selectively inhibit the AT1 receptor, preferably with endothelin A receptor (ETA receptor) as a control. By selectively inhibiting the AT1 receptor, the risk of side effects (e.g., teratogenicity) caused by inhibition of the ETA receptor can be reduced.

[0031] Specifically, the ETA receptor inhibitory concentration (IC) 50 ) / AT1 receptor inhibitory concentration (IC 50The ETA receptor inhibitory concentration (IC) is preferably 100 or more, more preferably 200 or more, even more preferably 500 or more, and particularly preferably 1,000 or more. 50 ) / AT1 receptor inhibitory concentration (IC 50 The upper limit of ) is not particularly limited, but may be, for example, 10,000, 8,000, 6,000, 4,000, etc. The ETA receptor inhibitory concentration and the AT1 receptor inhibitory concentration can be measured by the method described in the examples.

[0032] The AT1 receptor inhibitory concentration (IC) of the AT1 receptor antagonist of this embodiment 50 The AT1 receptor inhibitory concentration (IC) is preferably 1.0 nM or less, more preferably 0.5 nM or less, even more preferably 0.2 nM or less, and particularly preferably 0.1 nM or less. 50 The lower limit of ) is not particularly limited, but may be, for example, 0.0025 nM, 0.005 nM, 0.01 nM, 0.02 nM, etc.

[0033] ETA receptor inhibitory concentration (IC) of the AT1 receptor antagonist in this embodiment 50 The ETA receptor inhibitory concentration (IC) is preferably 10 nM or higher, more preferably 20 nM or higher, even more preferably 50 nM or higher, and particularly preferably 100 nM or higher. 50 The upper limit of ) is not particularly limited, but may be, for example, 1,000 nM, 800 nM, 600 nM, 400 nM, etc.

[0034] By using the AT1 receptor antagonist of this embodiment, diseases related to (mediated by) the AT1 receptor can be treated and / or prevented. Examples of such diseases include those listed in the <Pharmaceutical Composition> section below.

[0035] The target population for the AT1 receptor antagonist of this embodiment and the pharmaceutical composition described later is preferably mammals, more preferably humans, monkeys, cats, pigs, horses, cattle, mice, rats, guinea pigs, dogs, and rabbits, and even more preferably humans.

[0036] <Pharmaceutical composition> One embodiment of the present invention relates to a pharmaceutical composition comprising a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0037] Examples of diseases that the pharmaceutical composition of this embodiment is intended to prevent or treat include the following: Hypertension; Cardiac diseases (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, diastolic dysfunction, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmias, tachycardia, and myocardial infarction); Progression of heart failure after myocardial infarction; Kidney diseases (e.g., organ damage including nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, and radiation-induced nephropathy); Vascular thickening, occlusion, and organ damage following interventions (e.g., percutaneous coronary intervention, stent placement, coronary endoscopy, intravascular ultrasound, and coronary thrombolysis); Eye diseases (e.g., glaucoma and ocular hypertension); Neurodegenerative diseases (e.g., Alzheimer's disease); Central nervous system disorders (for example, disorders such as cerebral hemorrhage and cerebral infarction, as well as their sequelae and complications); Dementia (for example, vascular dementia); Liver diseases (e.g., non-alcoholic fatty liver disease); Eosinophilic esophagitis; Bone diseases (e.g., osteoarthritis of the knee); Skin diseases (e.g., epidermolysis bullosa); Systemic diseases (e.g., Marfan syndrome); and cancer.

[0038] The pharmaceutical composition of this embodiment can be administered orally or parenterally. Examples of oral dosage forms include tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions. Examples of parenteral dosage forms include injections, infusions, drips, eye drops, patches, and suppositories. While not particularly limited, the pharmaceutical composition of this embodiment is preferably an injection. By being an injection, it can be suitably used for diseases requiring high urgency. Examples of diseases requiring high urgency include acute hypertension accompanied by organ damage such as cerebral hemorrhage and myocardial infarction.

[0039] When the pharmaceutical composition of this embodiment is prepared as an injectable preparation, the injectable preparation may contain a second active ingredient in addition to the compound represented by formula (1) or a pharmaceutically acceptable salt thereof. Examples of the second active ingredient include compounds other than the compound represented by formula (1) or a pharmaceutically acceptable salt thereof that have AT1 receptor antagonistic activity, specifically losartan, valsartan, candesartan, telmisartan, olmesartan, irbesartan, azilsartan, and the like.

[0040] The pharmaceutical composition of this embodiment may optionally contain excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, fragrances, flavoring agents, stabilizers, viscosity modifiers, etc.

[0041] The dosage of the pharmaceutical composition in this embodiment varies depending on the patient's condition, weight, type of compound, type of disease, route of administration, etc., and the appropriate amount can be determined by a physician.

[0042] <Intermediate compounds> One embodiment of the present invention relates to an intermediate compound that can be used in the synthesis of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. Examples of intermediate compounds include compounds represented by the following formulas (2) to (4) or salts thereof.

[0043] The salts of the compounds represented by formulas (2) to (4) are not particularly limited, and examples include those exemplified as pharmaceutically acceptable salts of the compound represented by formula (1).

[0044] Compounds represented by formulas (2) to (4) or salts thereof may form solvates such as hydrates. In this specification, solvates are defined as compounds represented by formulas (2) to (4) or salts thereof.

[0045] (Intermediate compound 1) One embodiment of the present invention is given by the following formula (2): [ka] [In the formula, R 4 This refers to a leaving group, boronic acid (-B(OH)2), boronic acid ester, or -BF3M 1 And, M 1 It is an alkali metal. This relates to a compound represented by or a salt thereof.

[0046] R 4 Examples of the leaving group include halogens (e.g., fluorine, chlorine, bromine, or iodine), methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy.

[0047] R 4 Boronic acid esters include, for example, -B(OR 4A ) can be expressed as 2. 4A Examples include alkyl groups (for example, alkyl groups with 1 to 6 carbon atoms, or alkyl groups with 1 to 3 carbon atoms). Also, -B(OR 4A )2 of 2 4AThese may, together with oxygen and boron to which they are directly or indirectly bonded, form a 5-membered or 6-membered heterocycle. The heterocycle may have substituents. Examples of substituents on the heterocycle include alkyl (e.g., alkyl with 1 to 3 carbon atoms), cycloalkyl (e.g., cycloalkyl with 5 or 6 carbon atoms), or aryl (e.g., phenyl). -B(OR 4A )2 For example, the following structure: [ka] Groups having the above characteristics are examples.

[0048] M 1 Examples of alkyl metals include lithium, sodium, or potassium.

[0049] (Intermediate compound 2) One embodiment of the present invention is given by the following formula (3): [ka] [In the formula, Ar is given by the following formula (Ar1) or (Ar2): [ka] (In the formula, R 1 and R 2 Each of these is independently an alkyl, haloalkyl, or halogen. R 3 Each of these is independently an alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy, (m is an integer between 0 and 3) And, R 5 is a leaving group, or -OR 5A And, R 5A is hydrogen, or a protecting group, R 6 [is hydrogen, or a protecting group] This relates to a compound represented by or a salt thereof.

[0050] In formula (3), the preferred form of Ar is as described in the <Compound> section above.

[0051] R 5 Examples of the leaving group include halogens (e.g., fluorine, chlorine, bromine, or iodine), methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy.

[0052] R 5A The protecting group is not particularly limited as long as it is a protecting group for a hydroxyl group, but examples include methoxymethyl (MOM), tert-butyldimethylsilyl (TBS), benzyl (Bn), benzoyl (Bz), acetyl (Ac), trimethylsilyl (TMS), or triethylsilyl (TES).

[0053] R 6 The protecting group is not particularly limited as long as it is an amino group protecting group, but examples include methoxymethyl (MOM), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl group (Fmoc), or allyloxycarbonyl group (Alloc).

[0054] (Intermediate compound 3) One embodiment of the present invention is given by the following formula (4): [ka] [In the formula, R 7 This refers to boronic acid (-B(OH)2), boronic acid ester, or -BF3M 2 And, M 2 It is an alkali metal, R 8 is -OR 8A And, R 8A [is hydrogen, or a protecting group] This relates to a compound represented by or a salt thereof.

[0055] R 7 Boronic acid esters include, for example, -B(OR 7A ) can be expressed as 2. 7A Examples include alkyl groups (for example, alkyl groups with 1 to 6 carbon atoms, or alkyl groups with 1 to 3 carbon atoms). Also, -B(OR 7A )2 of 2 7A These may, together with oxygen and boron to which they are directly or indirectly bonded, form a 5-membered or 6-membered heterocycle. The heterocycle may have substituents. Examples of substituents on the heterocycle include alkyl (e.g., alkyl with 1 to 3 carbon atoms), cycloalkyl (e.g., cycloalkyl with 5 or 6 carbon atoms), or aryl (e.g., phenyl). -B(OR 7A )2 For example, the following structure: [ka] Groups having the above characteristics are examples.

[0056] M 2 Examples of alkyl metals include lithium, sodium, or potassium.

[0057] R 8A The protecting group is not particularly limited as long as it is a protecting group for a hydroxyl group, but examples include methoxymethyl (MOM), tert-butyldimethylsilyl (TBS), benzyl (Bn), benzoyl (Bz), acetyl (Ac), trimethylsilyl (TMS), or triethylsilyl (TES).

[0058] <Method for producing compounds> Compounds represented by formula (1) or pharmaceutically acceptable salts thereof can be synthesized using known methods as appropriate. One example of a synthesis method is scheme A shown below. [ka]

[0059] In scheme A, Ar is as described above, and L 1 ~L 3 is a leaving group, and Pro is a protecting group.

[0060] In Scheme A, compound (A2) is reacted with a metal hydride (e.g., sodium hydride), and then reacted with compound (A1) to obtain compound (A3) (Step A1). The amino group of compound (A4) is protected with a protecting group (e.g., methoxymethyl group) to obtain compound (A5) (Step A2). Compound (A3) and compound (A5) are reacted to obtain compound (A6) (Step A3), and compound (A6) is deprotected to obtain compound (A7) (Step A4).

[0061] The method for synthesizing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is not limited to scheme A above, and a person skilled in the art can appropriately set an appropriate synthesis route and reaction conditions depending on the structure of the final compound. [Examples]

[0062] The present invention will be described in more detail below using examples, but the technical scope of the present invention is not limited thereto.

[0063] [Manufacturing Example 1-1] 7-Bromo-1,3-dihydroisobenzofuran-4-amine hydrochloride [ka] A mixture of tert-butyl(7-bromo-1,3-dihydroisobenzofuran-4-yl)carbamate (4.90 g, 15.6 mmol) and dichloromethane (50.0 mL) was slowly added with a solution of hydrogen chloride·1,4-dioxane (4 mol / L, 15.0 mL) at 0°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was removed under reduced pressure, and the residue was washed with diethyl ether to obtain the labeled compound (2.90 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.05 (bs, 2H), 4.89 (bs, 2H).

[0064] [Manufacturing Example 1-2] 4,7-Dibromo-1,3-Dihydroisobenzofuran [ka] Under an argon atmosphere, a mixture of 7-bromo-1,3-dihydroisobenzofuran-4-amine hydrochloride (2.90 g, 11.64 mmol) and acetonitrile (40.0 mL) was slowly added at 0°C to a mixture of copper(II) bromide (3.03 g, 13.5 mmol), tert-butyl nitrite (1.54 g, 14.9 mmol), and acetonitrile (20.0 mL). The mixture was stirred at 80°C for 6 hours. The reaction mixture was allowed to cool to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (1.70 g). 1H NMR (400 MHz, DMSO-d6) δ 7,45 (bs, 1H), 5.09 (s, 4H).

[0065] [Manufacturing Examples 1-3] 7-Bromo-1,3-dihydroisobenzofuran-4-carbaldehyde [ka] Under an argon atmosphere, a mixture of 4,7-dibromo-1,3-dihydroisobenzofuran (1.70 g, 6.12 mmol) and diethyl ether (20.0 mL) was slowly mixed with n-butyllithium (2.3 M hexane solution, 5.65 mL, 7.34 mmol) at -78°C and stirred at the same temperature for 1 hour. N,N-dimethylformamide (0.95 mL, 12.2 mmol) was slowly added to the reaction mixture and stirred at -78°C for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (0.80 g). 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.87-7.79 (m, 2H), 5.37 (s, 2H), 5.01 (s, 2H).

[0066] [Manufacturing Examples 1-4] (7-Bromo-1,3-dihydroisobenzofuran-4-yl)methanol [ka] A mixture of 7-bromo-1,3-dihydroisobenzofuran-4-carbaldehyde (800 mg, 3.52 mmol) and methanol (10 mL) was mixed with sodium borohydride (379 mg, 10.6 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (0.75 g). 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.26 (t, J = 5.6 Hz, 1H), 5.14 (s, 2H), 4.96 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H).

[0067] [Manufacturing Examples 1-5] 4-Bromo-7-(chloromethyl)-1,3-dihydroisobenzofuran [ka] A mixture of (7-bromo-1,3-dihydroisobenzofuran-4-yl)methanol (750 mg, 3.27 mmol) and dichloromethane (15 mL) was slowly mixed with thionyl chloride (584 mg, 4.91 mmol) at 0°C and stirred at the same temperature for 30 minutes. A small amount of N,N-dimethylformamide was added to the reaction mixture and stirred at the same temperature for 2 hours. Ice-cold water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (0.63 g). 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 5.00 (s, 2H), 4.73 (s, 2H).

[0068] [Manufacturing Examples 1-6] 3-((7-bromo-1,3-dihydroisobenzofuran-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]nona-1-en-4-one [ka] 2-butyl-1,3-diazaspiro[4.4]nona-1-en-4-one (494 mg, 2.55 mmol) and DMF (10 mL) were slowly mixed with 50% sodium hydride (153 mg, 6.36 mmol) at 0°C and stirred at the same temperature for 30 minutes. A mixture of 4-bromo-7-(chloromethyl)-1,3-dihydroisobenzofuran (630 mg, 2.55 mmol) and DMF (5 mL) was slowly added to the reaction mixture and stirred at the same temperature for 2 hours. Ice-cold water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (0.90 g). ESI-MS: m / z 405.10 [M+1]+, 407.12 [M+3]+

[0069] [Manufacturing Examples 1-7] 2-Butyl-3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisobenzofuran-4-yl)methyl)-1,3-diazaspiro[4.4]nona-1-en-4-one [ka] Under an argon atmosphere, a mixture of 3-((7-bromo-1,3-dihydroisobenzofuran-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]nona-1-en-4-one (500 mg, 1.23 mmol), bis(pinacorato)diborone (471 mg, 1.85 mmol), potassium acetate (245 mg, 2.47 mmol), and 1,4-dioxane (10 mL) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (50.3 mg, 0.0617 mmol), and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (0.35 g). ESI-MS: m / z 453.26 [M+1]+.

[0070] [Manufacturing Examples 1-8] 2-Bromo-N-(4,5-dimethylisoxazole-3-yl)benzenesulfonamide [ka] To a mixture of 4,5-dimethylisoxazole-3-amine (500 mg, 4.46 mmol) and pyridine (10.0 mL), 4-dimethylaminopyridine (54.5 mg, 0.446 mmol) and 2-bromobenzenesulfonyl chloride (1.71 g, 6.69 mmol) were slowly added at 0°C, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was allowed to cool to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol / L hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the labeled compound (1.20 g) was obtained as the crude product. The obtained crude product was used in the next reaction without further purification. ESI-MS: m / z 330.91 [M+1]+, 332.93 [M+3]+

[0071] [Manufacturing Examples 1-9] 2-Bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)benzenesulfonamide [ka] Crude 2-bromo-N-(4,5-dimethylisoxazole-3-yl)benzenesulfonamide (1.20 g, 3.62 mmol) and DMF (20.0 mL) were mixed, to which 50% sodium hydride (217 mg, 4.53 mmol) was slowly added at 0°C and the mixture was stirred at the same temperature for 30 minutes. Chloromethyl methyl ether (583 mg, 7.25 mmol) was slowly added to the reaction mixture and the mixture was stirred at room temperature for 3 hours. Ice-cold water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (0.90 g). 1H NMR (400 MHz, CDCl3) δ 8.02-8.00 (m, 1H), 7.76-7.74 (m, 1H), 7.40-7.38 (m, 2H), 5.24 (s, 2H), 3.54 (s, 3H), 2.30 (s, 3H), 1.99 (s, 3H).

[0072] [Manufacturing Examples 1-10] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4,4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide [ka] Under an argon atmosphere, a mixture of 2-bromo-N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide (347 mg, 0.92 mmol), 2-butyl-3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisobenzofuran-4-yl)methyl)-1,3-diazaspiro[4,4]nona-1-en-4-one (350 mg, 0.77 mmol), 1,4-dioxane (5.0 mL), water (0.5 mL), and potassium carbonate (314 mg, 1.54 mmol) was prepared, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride was added. Dichloromethane adduct (63 mg, 0.07 mmol) was added, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (0.25 g). ESI-MS: m / z 621.31 [M+1]+

[0073] [Example 1] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4,4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4,5-dimethylisoxazole-3-yl)benzenesulfonamide [ka] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide (250 mg, 0.40 mmol) and methanol (3 mL) were mixed with 6 mol / L hydrochloric acid (1.5 mL) at 0°C, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was allowed to cool to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (55 mg). ESI-MS: m / z 577.30 [M+1]+ 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.06 (dd, J = 7.6, 1.6 Hz, 1H), 7.67-7.60 (m, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.99-4.97 (m, 2H), 4.73-4.67 (m, 3H), 4.50-4.47 (m, 1H), 2.34 (t, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.89-1.84 (m, 6H), 1.71-1.69 (m, 2H), 1.63 (s, 3H), 1.55-1.48 (m, 2H), 1.33-1.23 (m, 3H), 0.82 (t, J = 7.2 Hz, 3H).

[0074] [Manufacturing Example 1-11] 4-Bromo-7-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1,3-dihydroisobenzofuran [ka] (7-bromo-1,3-dihydroisobenzofuran-4-yl)methanol (3.0 g, 13.1 mmol) and dichloromethane (30 mL) were slowly mixed with 3,4-hydro-2H-pyran (2.1 g, 26.2 mmol) and a small amount of p-toluenesulfonic acid at 0°C, and the mixture was stirred at room temperature for 3 hours. Ice-cold water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (2.9 g). 1H NMR (400 MHz, DMSO): δ 7.38 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.27 (d, J = 1.6 Hz, 2H), 5.11 (t, J = 4.0 Hz, 2H), 4.69 (t, J = 8.0 Hz, 2H), 4.42 (d, J = 12.4Hz, 1H), 3.90 - 3.85 (m, 1H), 3.59 - 3.54 (m, 1H), 1.88 - 1.84 (m, 1H), 1.79 -1.73 (m, 1H), 1.68 -1.57 (m, 4H).

[0075] [Manufacturing Examples 1-12] 4,4,5,5-Tetramethyl-2-(7-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1,3-dihydroisobenzofuran-4-yl)-1,3,2-dioxaborolane [ka] Under an argon atmosphere, a mixture of 4-bromo-7-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1,3-dihydroisobenzofuran (1.0 g, 3.19 mmol), bis(pinacolato)diborone (969 mg, 3.38 mmol), potassium acetate (937 mg, 9.57 mmol), and 1,4-dioxane (10 mL) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (130 mg, 0.159 mmol), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was allowed to cool to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (300 mg). 1H NMR (400 MHz, DMSO): δ 7.38 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.07- 5.02 (m, 4H), 4.64 (t, J = 8.0 Hz, 2H), 4.42 (d, J = 12.4Hz, 1H), 3.77 - 3.72 (m, 1H), 3.49 - 3.45 (m, 1H), 1.67 - 1.64 (m, 2H), 1.52 -1.56 (m, 4H), 1.28 (s, 12H).

[0076] [Manufacturing Examples 1-13] N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)-2-(7-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1,3-dihydroisobenzofuran-4-yl)benzenesulfonamide [ka] Under an argon atmosphere, a mixture of 4,4,5,5-tetramethyl-2-(7-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1,3-dihydroisobenzofuran-4-yl)-1,3,2-dioxaborolane (600 mg, 1.66 mmol), 2-bromo-N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide (749 mg, 1.99 mmol), 1,4-dioxane (7.0 mL), water (0.5 mL), and potassium carbonate (687 mg, 4.98 mmol) was mixed with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (135 mg, 0.166 mmol), and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was allowed to cool to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (400 mg). 1H NMR (400 MHz, DMSO): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.15 (s, 2H), 4.84 - 4.78 (m, 2H), 4.75 - 4.67 (m, 2H), 4.51 - 4.47 (m, 1H), 4.31 - 4.23 (m, 2H), 3.80 - 3.76 (m, 1H), 3.50 - 3.47 (m, 1H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H), 1.68 - 1.65 (m, 2H), 1.51 -1.48 (m, 4H).

[0077] [Manufacturing Examples 1-14] N-(4,5-dimethylisoxazol-3-yl)-2-(7-(hydroxymethyl)-1,3-dihydroisobenzofuran-4-yl)-N-(methoxymethyl)benzenesulfonamide [ka] A mixture of N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)-2-(7-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1,3-dihydroisobenzofuran-4-yl)benzenesulfonamide (500 mg, 0.946 mmol) and methanol (8.0 mL) was mixed with p-toluenesulfonic acid (35.2 mg, 0.189 mmol) at 0°C and stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (300 mg). 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.28 - 5.25 (m, 1H), 5.13 - 5.06 (m, 2H), 4.82- 4.72 (m, 2H), 4.53 - 4.51 (m, 2H), 4.33 - 4.23 (m, 2H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H).

[0078] [Manufacturing Examples 1-15] 2-(7-(bromomethyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide [ka] To a solution of N-(4,5-dimethylisoxazole-3-yl)-2-(7-(hydroxymethyl)-1,3-dihydroisobenzofuran-4-yl)-N-(methoxymethyl)benzenesulfonamide (300 mg, 0.675 mmol) and dichloromethane (7.0 mL), tetrabromomethane (290 mg, 0.877 mmol) was added at 0°C, and after 10 minutes, triphenylphosphine (176 mg, 0.675 mmol) was added at the same temperature. The reaction mixture was raised to room temperature and stirred for 2 hours. Ice-cold water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (250 mg). 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.41 - 7.39 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 5.19 - 5.14 (m, 2H), 4.81 - 4.74 (m, 4H), 4.33- 4.21 (m, 2H), 3.19 (s, 3H), 2.31 (s, 3H), 1.81 (s, 3H).

[0079] [Manufacturing Examples 1-16] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4,4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide [ka] To a solution of 2-butyl-1,3-diazaspiro[4.4]nona-1-en-4-one (108 mg, 0.473 mmol) in DMF (2.0 mL), 60% sodium hydride (31.5 mg, 0.788 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, a mixture of 2-(7-(bromomethyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4,5-dimethylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide (200 mg, 0.394 mmol) and DMF (1.0 mL) was slowly added, and the mixture was stirred at room temperature for 2 hours. Ice-cold water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (80 mg). 1H NMR (400 MHz, DMSO): 7.97 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 14.8 Hz, 1H), 7.58 (t, J = 15.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.02 (s, 2H), 4.80 - 4.69 (m, 4H), 4.30 - 4.21 (m, 2H), 3.18 (s, 3H), 2.30 (s, 4H), 1.85 - 1.80 (m, 9H), 1.70 - 1.68 (m, 2H), 1.53 - 1.49 (m, 2H), 1.31 - 1.23 (m, 3H), 0.84 - 0.81 (m, 3H).

[0080] [Manufacturing Example 2-1] 2-Bromo-N-(3-methoxy-5-methylpyrazine-2-yl)benzenesulfonamide [ka] To a mixture of 3-methoxy-5-methylpyrazine-2-amine (500 mg, 3.5 mmol) and pyridine (5.0 mL), 4-dimethylaminopyridine (128 mg, 1.05 mmol) and 2-bromobenzenesulfonyl chloride (1.1 g, 4.3 mmol) were added at room temperature, and the reaction mixture was stirred at 50°C for 12 hours. The reaction mixture was allowed to cool to room temperature, 2 mol / L hydrochloric acid (5.0 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the labeled compound (1.20 g) was obtained as crude. The obtained crude was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (1.0 g). 1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 0.8 Hz, 1H), 7.59-7.51 (m, 3H), 3.86 (s, 3H), 2.26 (s, 3H).

[0081] [Manufacturing Example 2-2] 2-Bromo-N-(3-methoxy-5-methylpyrazine-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] 2-Bromo-N-(3-methoxy-5-methylpyrazine-2-yl)benzenesulfonamide (500 mg, 1.39 mmol) and DMF (5.0 mL) were mixed with potassium carbonate (380 mg, 2.79 mmol) at 0°C and stirred at the same temperature for 30 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (350 mg, 2.08 mmol) was slowly added to the reaction mixture at 0°C and stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (500 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.09-8.07 (m, 1H), 7.99 (s, 1H), 7.87-7.85 (m, 1H), 7.57-7.54 (m,2H), 5.14 (s, 2H), 3.78 (s, 3H), 3.62-3.58(m, 2H), 2.42(s, 3H), 0.76-0.72(m, 2H), 0.065(s, 9H).

[0082] [Manufacturing Example 2-3] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(3-methoxy-5-methylpyrazine-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide [ka] Under an argon atmosphere, a mixture of 2-bromo-N-(3-methoxy-5-methylpyrazine-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (400 mg, 0.78 mmol), 2-butyl-3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisobenzofuran-4-yl)methyl)-1,3-diazaspiro[4,4]nona-1-en-4-one (445 mg, 0.98 mmol), 1,4-dioxane (4.5 mL), water (0.5 mL), and potassium carbonate (340 mg, 2.71 mmol) was prepared, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride was added. Dichloromethane adduct (67 mg, 0.09 mmol) was added, and the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (170 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, J = 7.6 Hz, 1H), 7.796(s, 1H), 7.69-7.58 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.11 (d, , J = 8 Hz, 1H), 6.91 (d, , J = 7.6 Hz, 1H), 4.99 (s, 2H), 4.74-4.67 (m, 6H), 3.76 (s, 3H), 3.45(t, J = 8 Hz, 2H), 2.42 (s, 3H), 2.28(t, J = 7.2 Hz, 2H), 1.86-183 (m, 6H), 1.69 (s, 2H), 1.49-1.47 (m, 2H), 1.28-1.23 (m, 4H), 0.81 (m, 3H), 0.095(s, 9H).

[0083] [Example 2] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(3-methoxy-5-methylpyrazine-2-yl)benzenesulfonamide [ka] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(3-methoxy-5-methylpyrazine-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (170 mg, 0.231 mmol) and methanol (2 mL) were mixed with 50% sulfuric acid (2.0 mL) at 0°C, and the reaction mixture was stirred at 0°C for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ice-cold water and saturated sodium bicarbonate solution to neutralize the pH, then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (38 mg). ESI-MS: m / z 604.67 [M+1]+1H NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 10.04 (s, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.60-7.52 (m, 3H), 7.26-6.90 (m, 2H), 6.78-6.78 (m, 1H), 4.96 (s, 1H), 4.77-4.68 (m, 2H), 4.58-4.44 (m, 2H), 3.82-3.79(m, 3H), 2.32-2.26 (m, 5H), 1.86 (s, 6H), 1.69 (s, 2H), 1.49-1.47 (m, 2H), 1.26-1.25 (m, 2H), 0.79 (s, 3H).

[0084] [Manufacturing Example 3-1] 2-Bromo-N-(4-chloro-5-methylisoxazole-3-yl)benzenesulfonamide [ka] To a mixture of 4-chloro-5-methylisoxazole-3-amine (1.0 g, 7.6 mmol) and pyridine (5.0 mL), 4-dimethylaminopyridine (91 mg, 0.75 mmol) and 2-bromobenzenesulfonyl chloride (2.3 g, 9.1 mmol) were added at room temperature, and the reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was allowed to cool to room temperature, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude compound was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (850 mg). 1H NMR (400 MHz, DMSO-d6): δ 11.68(s, 1H), 8.00 (dd, J = 2 Hz, 1H), 7.92 (dd, J = 1.6 Hz 1H), 7.63-7.59 (m, 2H), 3.34(s, 3H).

[0085] [Manufacturing Example 3-2] 2-Bromo-N-(4-chloro-5-methylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide [ka] 2-Bromo-N-(4-chloro-5-methylisoxazole-3-yl)benzenesulfonamide (850 mg, 2.42 mmol) and DMF (5.0 mL) were mixed, and 60% sodium hydride (194 mg, 4.87 mmol) was slowly added at 0°C, and the mixture was stirred at the same temperature for 30 minutes. Chloromethyl methyl ether (292 mg, 3.63 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (800 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.01(dd, J = 2 Hz, 1H), 7.92 (dd, J = 1.6 Hz, 1H), 7.63-7.59 (m, 2H), 5.19(s, 2H), 3.38(s, 3H), 2.42(s, 3H).

[0086] [Manufacturing Example 3-3] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4,4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4-chloro-5-methylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide [ka] Under an argon atmosphere, a mixture of 2-bromo-N-(4-chloro-5-methylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide (400 mg, 1.01 mmol), 2-butyl-3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisobenzofuran-4-yl)methyl)-1,3-diazaspiro[4.4]nona-1-en-4-one (549 mg, 1.21 mmol), 1,4-dioxane (4.5 mL), water (0.5 mL), and potassium carbonate (419 mg, 3.03 mmol) was prepared, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride was added. Dichloromethane adduct (82.5 mg, 0.10 mmol) was added, and the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (150 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J =8 Hz, 1H), 7.74 (t, J =7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8 Hz, 1H), 5.02 (s, 2H), 4.76-4.70 (m, 4H), 4.45-4.34 (m, 2H), 3.22 (s, 3H), 2.41 (s, 3H), 2.32-2.28 (m, 2H), 1.85-1.83 (m, 6H), 1.70-1.68 (m, 2H), 1.53-1.49 (m, 2H), 1.31-1.23 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H).

[0087] [Example 3] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4,4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4-chloro-5-methylisoxazole-3-yl)benzenesulfonamide [ka] 2-(7-((2-butyl-4-oxo-1,3-diazaspiro[4.4]nona-1-en-3-yl)methyl)-1,3-dihydroisobenzofuran-4-yl)-N-(4-chloro-5-methylisoxazole-3-yl)-N-(methoxymethyl)benzenesulfonamide (150 mg, 0.23 mmol) and methanol (2 mL) were mixed with 50% sulfuric acid (2.0 mL) slowly at 0°C, and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with ice-cold water and saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the labeled compound (48 mg). ESI-MS: m / z 597.67 [M+1]+ 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 7.97 (t, J = 3.6 Hz, 1H), 7.39 (bs, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 8 Hz, 1H), 4.91 (s, 2H), 4.63 (s, 2H), 4.52 (s, 2H), 2.36-2.32 (m, 2H), 2.12 (s, 3H), 1.88-1.83 (m, 6H), 1.70-1.68 (m, 2H), 1.55-1.48 (m, 2H), 1.33-1.23 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H).

[0088] [Test Example 1: Angiotensin II type 1 receptor inhibitory effect] The inhibitory effect on angiotensin II type 1 receptors was investigated using the following method. CHO-K1-mt aequorin-Gα16 cells overexpressing human angiotensin II type 1 receptor (Accession Number NP_000676.1) were cultured in antibiotic-free medium for 18 hours, then treated with PBS-EDTA (5 mM EDTA), centrifuged (2 minutes, 405 × g, room temperature), and suspended in assay buffer (DMEM / HAM's F12 with HEPES + 0.1% BSA protease free). 1 x 10 6 Cells at a concentration of 5 μM / mL were incubated at room temperature for more than 4 hours in the presence of Coelenterazin h (Molecular Probes) to confirm the agonist reaction with Angiotensin II, and the Angiotensin II concentration corresponding to EC80 was determined. Next, 50 μL of Coelenterazin h-treated cell suspension (10,000 cells / well) and 50 μL of assay buffer containing the test substance (final concentration 0.5% DMSO) were added to a 96-well plate. After 15 minutes, 100 μL of Angiotensin II solution was added to achieve a final concentration of EC80, and receptor activity was measured by luminescence using FDSS6000 (Hamamatsu Photonics). The IC50 value was calculated using XLfit (IDBS).

[0089] If the IC50 value was 1.0 nM or less, or if it showed an inhibitory effect of 50% or more at 1.0 nM, it was classified as "A". If the IC50 value was greater than 100 nM, or if it showed an inhibitory effect of less than 50% at 100 nM, it was classified as "C". If it fell between "A" and "C", it was classified as "B". The results are shown in Table 1. [Table 1]

[0090] [Test Example 2: Endothelin A receptor inhibitory effect] The inhibitory effect on endothelin A receptors was investigated using the following method. CHO-K1-mt aequorin cells, overexpressing the human endothelin A receptor (Accession Number NP_001948.1), were cultured in antibiotic-free medium for 18 hours. They were then treated with PBS-EDTA (5 mM EDTA), centrifuged (2 minutes, 405 × g, room temperature), and suspended in assay buffer (DMEM / HAM's F12 with HEPES + 0.1% BSA protease free). 1 x 10 6 Cells at a concentration of 5 μM / mL were incubated at room temperature for 4 hours in the presence of 5 μM Coelenterazin h (Molecular Probes), and the agonist reaction with Endothelin was confirmed to determine the Endothelin concentration corresponding to EC80. Next, 50 μL of a cell suspension treated with Coelenterazin h at a concentration of 10,000 cells / well and 50 μL of assay buffer containing the test substance (final concentration 0.5% DMSO) were added to a 96-well plate. After 15 minutes, Endothelin was added to reach a final concentration of EC80, and receptor activity was measured by luminescence using FDSS6000 (Hamamatsu Photonics). The IC50 value was calculated using XLfit (IDBS).

[0091] If the IC50 value was 1.0 nM or less, or if it showed an inhibitory effect of 50% or more at 1.0 nM, it was classified as "A". If the IC50 value was greater than 100 nM, or if it showed an inhibitory effect of less than 50% at 100 nM, it was classified as "C". If it fell between "A" and "C", it was classified as "B". The results are shown in Table 2. [Table 2]

[0092] [Test Example 3: Inhibitory effect on angiotensin II-induced vasoconstrictive effect] Male Wistar rats aged 8-12 weeks were analgesic and under urethane anesthesia, and catheters were inserted into the trachea for airway management, the carotid artery for blood pressure measurement, and the femoral vein for angiotensin II (ATII) administration. After confirming that blood pressure and heart rate were stable, 1 mg / kg (15 mL / kg) of the test substance (compound from Example 1) prepared with a solvent (PBS) or solvent was administered intravenously over 10 minutes. Subsequently, ATII (300 ng / kg) was administered intravenously, and blood pressure was monitored until 10 minutes after administration. Each group consisted of n=3, and for analysis, the pre-value was set 2 minutes before ATII administration. The systolic and diastolic blood pressure were calculated for the 20 seconds immediately after ATII administration when the blood pressure was maximum, and the difference from the pre-value (delta value) was calculated. Student's t-test was used to compare the delta values ​​of the solvent administration group and the test substance administration group. [Table 3]

Claims

1. The following formula (1): 【Chemistry 1】 [In the formula, Ar is given by the following formula (Ar1) or (Ar2): 【Chemistry 2】 (In the formula, R 1 and R 2 Each of these is independently an alkyl, haloalkyl, or halogen. R 3 Each of these is independently an alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy, (m is an integer between 0 and 3) is] A compound represented by or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is formula (Ar1).

3. R 1 and R 2 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each is independently alkyl.

4. The following compounds: 【Transformation 3】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

5. An angiotensin II type 1 receptor antagonist comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6 for preventing or treating hypertension, heart disease, progression of heart failure after myocardial infarction, kidney disease, vascular thickening after intervention, occlusion after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorders, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

8. The pharmaceutical composition according to claim 6, which is an injection, a patch, or an eye drop.

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