Compounds, endothelin a receptor antagonists and pharmaceutical compositions

Abstract

The subject of this invention is to provide compounds having ETA receptor antagonistic effects, and the aforementioned subject can be solved by compounds represented by the following formula (1) [where the variable part is as described in the specification] or their pharmaceutically permissible salts.

Description

Technical Field

[0001] This invention relates to compounds, endothelin A receptor antagonists, and pharmaceutical compositions. Background Technology

[0002] Endothelin (ET) is a peptide derived from vascular endothelial cells that has vasoconstrictive effects. Endothelin receptors include endothelin A (ETA) and endothelin B (ETB) receptors. ETA receptors are involved in vasoconstriction, central sympathetic nerve activation, and the promotion of aldosterone secretion. ETB receptors are involved in vasodilation and endothelin clearance.

[0003] ETA receptors have been reported to be associated with various diseases. For example, associations have been reported with pulmonary hypertension (e.g., Non-Patent Literature 1 and 2), focal segmental glomerulosclerosis (e.g., Non-Patent Literature 3), IgA nephropathy (e.g., Non-Patent Literature 4), chronic kidney disease (including diabetic nephropathy) (e.g., Non-Patent Literature 5 and 6), kidney injury associated with sickle cell anemia (e.g., Non-Patent Literature 7), acute kidney injury (e.g., Non-Patent Literature 8), hypertension (e.g., Non-Alcoholic Steatohepatitis (NASH)) (e.g., Non-Patent Literature 10–12), cancer (e.g., Non-Patent Literature 13), pain associated with endometriosis (e.g., Non-Patent Literature 14 and 15), complications associated with scleroderma (e.g., Non-Patent Literature 16 and 17), cerebral vasospasm (e.g., Non-Patent Literature 18), and hypertrophic cardiomyopathy (e.g., Non-Patent Literature 19) and ETA receptors.

[0004] Various compounds with ETA receptor antagonistic activity have been reported (e.g., Patent Documents 1-11). In particular, sitaxentan, which has ETA receptor antagonistic activity, is known to selectively inhibit ETA receptors with ETB receptors as a control. It has been reported to show significant efficacy in clinical trials of pulmonary hypertension associated with connective tissue diseases (Non-Patent Document 20), without increasing blood endothelin concentration (Non-Patent Document 21) or causing peripheral edema (Non-Patent Document 22).

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: U.S. Patent No. 5,514,696

[0008] Patent Document 2: U.S. Patent No. 5,612,359

[0009] Patent Document 3: International Publication No. 1996 / 40681

[0010] Patent Document 4: International Publication No. 1996 / 31492

[0011] Patent Document 5: International Publication No. 1998 / 49162

[0012] Patent Document 6: International Publication No. 1998 / 13366

[0013] Patent Document 7: International Publication No. 1998 / 33780

[0014] Patent Document 8: International Publication No. 1998 / 33781

[0015] Patent Document 9: International Publication No. 2001 / 49685

[0016] Patent Document 10: International Publication No. 2004 / 35057

[0017] Patent Document 11: International Publication No. 2013 / 115162

[0018] Non-patent literature 1: The New England Journal of Medicine, 2002, 346, pp 896-903.

[0019] Non-patent literature 2: International Heart Journal, 2020, 61, pp 799-805.

[0020] Non-patent literature 3: Journal of the American Society of Nephrology, 2018, 29, pp. 2745-2754.

[0021] Non-patent literature 4: Nephron, 1996, 72, pp 454-460.

[0022] Non-patent literature 5: The Lancet, 2019, 393, pp 1937-1947.

[0023] Non-patent literature 6: Hypertension, 2011, 57, pp 772-779.

[0024] Non-patent literature 7: Journal of the American Society of Nephrology, 2017, 28, pp. 2443-2458.

[0025] Non-patent literature 8: Transplantation, 2001, 71, pp 211-216.

[0026] Non-patent literature 9: Hypertension, 2008, 52, pp 452-459.

[0027] Non-patent literature 10: Drug Research, 2015, 65, pp 272-280.

[0028] Non-patent literature 11: World Journal of Hepatology, 2016, 8, pp 933-941.

[0029] Non-patent literature 12: Digestive Diseases and Sciences, 2007, 52, pp. 2622-2628.

[0030] Non-patent literature 13: Nature reviews cancer, 2013, 13, pp 637-651.

[0031] Non-patent literature 14: European Journal of Pain, 2018, 22, pp 501-510.

[0032] Non-patent literature 15: Fertility and Sterility, 1994, 61, pp 1083-1087.

[0033] Non-patent literature 16: Inflammation & Allergy-Drug Targets, 2011, 10, pp 19-26.

[0034] Non-patent literature 17: Annals of the Rheumatic Diseases, 2011, 70, pp32-38.

[0035] Non-patent literature 18: Molecular medicine reports, 2018, 18, pp5229-5236.

[0036] Non-patent literature 19: Journal of the American Heart Association, 2014, 3, e001263.

[0037] Non-patent literature 20: European Heart Journal, 2008, 29, pp 1936-1948.

[0038] Non-patent literature 21: Pharmacological Reviews, 2016, 68, pp. 357-418.

[0039] Non-patent literature 22: Annual Review of Pharmacology and Toxicology, 2007, 47, pp731-759. Summary of the Invention

[0040] The problem that the invention aims to solve

[0041] The purpose of this invention is to provide compounds having ETA receptor antagonistic effects, or ETA receptor antagonists or pharmaceutical compositions comprising the aforementioned compounds.

[0042] Methods for solving problems

[0043] The inventors of this application conducted in-depth research and discovered that compounds with a defined structure have ETA receptor antagonistic effects, thus completing this invention.

[0044] The present invention includes the following embodiments. [1]

[0046] The compound represented by the following formula (1) or its pharmaceutically permissible salt.

[0047] [Chemical Formula 1]

[0048]

[0049] [In the formula,

[0050] R 1 and R 2 Each is independently hydrogen or alkyl.

[0051] R 3 and R 4 Each is independently hydrogen or alkyl, or

[0052] R 3 With R 4 Together they form oxygen groups.

[0053] R 5 ~R 7 Each is independently hydrogen, alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy.

[0054] R 8 Each is independently an alkyl, haloalkyl, or halogen.

[0055] n is an integer between 0 and 3.

[0056] Ar can be either (Ar1) or (Ar2) as follows:

[0057] [Chemical Formula 2]

[0058]

[0059] (in the formula,

[0060] X and Y represent nitrogen and oxygen, or oxygen and nitrogen, respectively.

[0061] R 9 and R 10 Each is independently hydrogen, alkyl, haloalkyl, or halogen.

[0062] R 11 Each is independently an alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy group, where m is an integer from 0 to 3. [2]

[0064] The compound as described in [1] or a pharmaceutically permissible salt thereof, wherein R 1 and R 2 It is hydrogen. [3]

[0066] Compounds as described in [1] or [2] or pharmaceutically permissible salts thereof, wherein R 5 and R 7 For hydrogen, R 6 It is an alkyl group. [4]

[0068] The compound or a pharmaceutically permissible salt thereof as described in any one of [1] to [3], wherein n is 0. [5]

[0070] The compound or its pharmaceutically permissible salt as described in any one of [1] to [4], wherein Ar is of formula (Ar1). [6]

[0072] The compound or a pharmaceutically permissible salt thereof as described in any one of [1] to [5], wherein R 9 and R 10 It is an alkyl group. [7]

[0074] The compound or its pharmaceutically permissible salt as described in any one of [1] to [6], wherein X and Y are nitrogen and oxygen, respectively. [8]

[0076] The compound or its pharmaceutically permissible salt as described in any one of [1] to [6], wherein X and Y are oxygen and nitrogen, respectively. [9]

[0078] The compound or a pharmaceutically permissible salt thereof as described in any one of [1] to [4], wherein Ar is of the formula (Ar2).

[10]

[0080] The compound or a pharmaceutically permissible salt thereof as described in any one of [1] to [4] and [9], wherein R 11 Each is independently an alkyl or alkoxy group.

[11]

[0082] The compound or a pharmaceutically permissible salt thereof as described in any one of [1] to [4], [9] and

[10] , wherein m is 2.

[12]

[0084] The compounds described in [1] or their pharmaceutically permissible salts are selected from the group consisting of the following compounds.

[0085] [Chemical Formula 3-1]

[0086]

[0087] [Chemical Formula 3-2]

[0088]

[13]

[0090] Endothelin A receptor antagonists comprising any one of the compounds described in [1] to

[12] or a pharmaceutically permissible salt thereof.

[14]

[0092] As described in

[13] , endothelin A receptor antagonists selectively inhibit endothelin A receptors with endothelin B receptors as a control.

[15]

[0094] A pharmaceutical composition comprising any one of the compounds described in [1] to

[12] or a pharmaceutically permissible salt thereof.

[16]

[0096] The pharmaceutical composition described in

[15] is used for the prevention or treatment of diseases selected from the group consisting of pulmonary hypertension, nephropathy, hypertension, hepatitis, cancer, pain, complications associated with autoimmune diseases, heart failure, and vasospasm.

[0097] In addition, the present invention also includes the following embodiments.

[0098] [A1]

[0099] A method for inhibiting endothelin A receptors, the method comprising administering to a patient in need an effective amount of any one of [1] to

[12] a compound or a pharmaceutically permissible salt thereof.

[0100] [A2]

[0101] The method described in [A1] involves selectively inhibiting endothelin A receptors, with endothelin B receptors as a control.

[0102] [A3]

[0103] A method for preventing or treating a disease, the method comprising administering to a patient in need an effective amount of any one of [1] to

[12] a compound or a pharmaceutically permissible salt thereof.

[0104] [A4]

[0105] As described in [A3], the aforementioned diseases are selected from the group consisting of pulmonary hypertension, nephropathy, hypertension, hepatitis, cancer, pain, complications associated with autoimmune diseases, heart failure, and vasospasm.

[0106] [B1]

[0107] The compound or a pharmaceutically permissible salt thereof, as described in any one of [1] to

[12] , is used to inhibit endothelin A receptors.

[0108] [B2]

[0109] The compound described in [B1] or its pharmaceutically permissible salt selectively inhibits the endothelin A receptor in contrast to the endothelin B receptor.

[0110] [B3]

[0111] The compound or its pharmaceutically permissible salt as described in any one of [1] to

[12] is used for the prevention or treatment of disease.

[0112] [B4]

[0113] The compound as described in [B3] or its pharmaceutically permissible salt, wherein the aforementioned diseases are selected from the group consisting of pulmonary hypertension, nephropathy, hypertension, hepatitis, cancer, pain, complications associated with autoimmune diseases, heart failure, and vasospasm.

[0114] [C1]

[0115] Use of any compound or pharmaceutically permissible salt thereof, as described in any one of [1] to

[12] , for the inhibition of endothelin A receptors.

[0116] [C2]

[0117] As described in [C1], wherein endothelin A receptor is selectively inhibited, with endothelin B receptor as a control.

[0118] [C3]

[0119] The use of any compound or a pharmaceutically permissible salt thereof, as described in any one of [1] to

[12] , for the prevention or treatment of disease.

[0120] [C4]

[0121] The use as described in [C3], wherein the aforementioned diseases are selected from the group consisting of pulmonary hypertension, nephropathy, hypertension, hepatitis, cancer, pain, complications associated with autoimmune diseases, heart failure, and vasospasm.

[0122] [D1]

[0123] Use of any compound or pharmaceutically permissible salt thereof, as described in any one of [1] to

[12] , in the manufacture of endothelin A receptor antagonists.

[0124] [D2]

[0125] As described in [D1], the aforementioned endothelin A receptor antagonist selectively inhibits endothelin A receptors, with endothelin B receptors as a control.

[0126] [D3]

[0127] Use of any compound or pharmaceutically permissible salt thereof, as described in any one of [1] to

[12] , in the manufacture of a pharmaceutical composition for the prevention or treatment of a disease.

[0128] [D4]

[0129] As described in [D3], the aforementioned diseases are selected from the group consisting of pulmonary hypertension, nephropathy, hypertension, hepatitis, cancer, pain, complications associated with autoimmune diseases, heart failure, and vasospasm.

[0130] Invention Effects

[0131] According to the present invention, compounds having ETA receptor antagonistic effects, or ETA receptor antagonists or pharmaceutical compositions comprising the aforementioned compounds, may be provided. Detailed Implementation

[0132] The embodiments of the present invention will be described in detail below, but the present invention is not limited thereto and various modifications can be made without departing from its spirit.

[0133] <Compound>

[0134] One embodiment of the present invention relates to a compound represented by the following formula (1) or a pharmaceutically permissible salt thereof.

[0135] [Chemical Formula 4]

[0136]

[0137] [In the formula,

[0138] R 1 and R 2 Each is independently hydrogen or alkyl.

[0139] R 3 and R 4 Each is independently hydrogen or alkyl, or

[0140] R 3 With R 4 Together they form oxygen groups.

[0141] R 5 ~R 7 Each is independently hydrogen, alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy.

[0142] R 8 Each is independently an alkyl, haloalkyl, or halogen.

[0143] n is an integer between 0 and 3.

[0144] Ar can be either (Ar1) or (Ar2) as follows:

[0145] [Chemical Formula 5]

[0146]

[0147] (in the formula,

[0148] X and Y represent nitrogen and oxygen, or oxygen and nitrogen, respectively.

[0149] R 9 and R 10 Each is independently hydrogen, alkyl, haloalkyl, or halogen.

[0150] R 11 Each is independently an alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy group, where m is an integer from 0 to 3.

[0151] In this specification, alkyl groups (including alkyl groups in haloalkyl groups; the same applies hereinafter) can be straight-chain, branched, or cyclic.

[0152] In this specification, the alkyl moiety in alkoxy (including alkoxy groups in haloalkoxy groups; the same applies hereinafter) can be linear, branched, or cyclic.

[0153] In this specification, alkyl and alkoxy groups may be substituted or unsubstituted. Examples of substituents, besides halogens, include hydroxyl, alkoxy, amino, carboxyl, and carbonyl groups.

[0154] In equation (1), R 1 and R 2 Each is independently hydrogen or alkyl, preferably hydrogen.

[0155] R 1 and R 2 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0156] In equation (1), R 3 and R 4 Each is independently hydrogen or alkyl, or R 3 With R 4 Both are oxo groups (=O), preferably R. 3 and R 4 Each is independently hydrogen or alkyl.

[0157] R 3 and R 4 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0158] In equation (1), R 5 It is hydrogen, alkyl, haloalkyl, halogen, alkoxy or haloalkoxy, preferably hydrogen.

[0159] R 5 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0160] R 5 The alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and even more preferably a methoxy group.

[0161] R 5 The halogen, and the halogen in the alkyl and alkoxy groups, are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine or chlorine.

[0162] In equation (1), R 6 It is hydrogen, alkyl, haloalkyl, halogen, alkoxy or haloalkoxy, preferably alkyl.

[0163] R 6 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0164] R6 The alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and even more preferably a methoxy group.

[0165] R 6 The halogen, and the halogen in the alkyl and alkoxy groups, are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine or chlorine.

[0166] In equation (1), R 7 It is hydrogen, alkyl, haloalkyl, halogen, alkoxy or haloalkoxy, preferably hydrogen.

[0167] R 7 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0168] R 7 The alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and even more preferably a methoxy group.

[0169] R 7 The halogen, and the halogen in the alkyl and alkoxy groups, are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine or chlorine.

[0170] In equation (1), R 8 Each is independently an alkyl, haloalkyl, or halogen, preferably an alkyl or halogen.

[0171] R 8 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0172] R 8 The halogen and the halogen in the halogen and the halogenated alkyl group are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine or chlorine.

[0173] In formula (1), n ​​is an integer from 0 to 3, preferably 0 or 1, and more preferably 0.

[0174] In equation (1), Ar is either (Ar1) or (Ar2) as described above.

[0175] In formula (Ar1), X and Y are nitrogen and oxygen, or oxygen and nitrogen, respectively.

[0176] In equation (Ar1), R 9 It is hydrogen, alkyl, haloalkyl or halogen, preferably alkyl.

[0177] R 9 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0178] R 9 The halogen and the halogen in the halogen and the halogenated alkyl group are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine or chlorine.

[0179] In equation (Ar1), R 10 It is hydrogen, alkyl, haloalkyl or halogen, preferably alkyl.

[0180] R 10 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0181] R 10 The halogen and the halogen in the halogen and the halogenated alkyl group are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine or chlorine.

[0182] In equation (Ar2), R 11 Each of them is independently alkyl, haloalkyl, halogen, alkoxy or haloalkoxy, preferably alkyl or alkoxy, more preferably alkyl and alkoxy.

[0183] R 11 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group.

[0184] R 11 The alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and even more preferably a methoxy group.

[0185] R 11 The halogen, and the halogen in the alkyl and alkoxy groups, are preferably fluorine, chlorine, bromine or iodine, more preferably fluorine or chlorine.

[0186] In formula (Ar2), m is an integer from 0 to 3, preferably 2.

[0187] The compound represented by formula (1) is not particularly limited, but is preferably the following compound.

[0188] [Chemical Formula 6-1]

[0189]

[0190] [Chemical Formula 6-2]

[0191]

[0192] The pharmaceutically permissible salts of the compounds represented by formula (1) are not particularly limited as long as they can be used in medicine. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and hydrobromide can be included; organic acid salts such as fumarate, maleate, malate, tartrate, succinate, citrate, methanesulfonate, p-toluenesulfonate, acetate, lactate, and palmitate can be included; alkali metal salts; and alkaline earth metal salts.

[0193] The compound represented by formula (1) or its pharmaceutically permissible salt may also form solvates such as hydrates. In this specification, solvates are included in the compound represented by formula (1) or its pharmaceutically permissible salt.

[0194] In the presence of stereoisomers (e.g., enantiomers and diastereomers) of the compound represented by formula (1) or its pharmaceutically permissible salt, the individual stereoisomers and mixtures thereof (e.g., racemates) are included in the compound represented by formula (1) or its pharmaceutically permissible salt.

[0195] The form of the compound represented by formula (1) or its pharmaceutically permissible salt is not particularly limited. The compound represented by formula (1) or its pharmaceutically permissible salt may be in crystalline or amorphous form. If the compound represented by formula (1) or its pharmaceutically permissible salt has a polymorphic form, the compound represented by formula (1) or its pharmaceutically permissible salt may be in any crystalline form.

[0196] Endothelin A receptor antagonists

[0197] One embodiment of the present invention relates to an ETA receptor antagonist comprising a compound represented by formula (1) or a pharmaceutically permissible salt thereof. Among endothelin receptors, ETA receptors and ETB receptors are known. Inhibition of ETB receptors can sometimes lead to problems such as elevated blood endothelin levels and peripheral edema. The ETA receptor antagonist of this embodiment preferably selectively inhibits endothelin A receptors using endothelin B receptors as a control.

[0198] Specifically, the ETB receptor inhibitory concentration (IC50) 50 ) / ETA receptor inhibitory concentration (IC50) 50 The concentration of ETB receptor inhibitory concentration (IC50) is preferably 2,000 or more, more preferably 4,000 or more, further preferably 6,000 or more, even more preferably 8,000 or more, and particularly preferably 10,000 or more. 50 ) / ETA receptor inhibitory concentration (IC50) 50There is no particular upper limit to the concentration of ETB receptor and ETA receptor, which can be set to 100,000, 80,000, 60,000, 40,000, etc. The ETB receptor inhibitory concentration and ETA receptor inhibitory concentration can be determined using the methods described in the examples.

[0199] The ETA receptor inhibitory concentration (IC50) of the ETA receptor antagonist in this embodiment 50 The concentration of ETA receptor inhibitory concentration (IC50) is preferably 10 nM or less, more preferably 8.0 nM or less, even more preferably 6.0 nM or less, even more preferably 4.0 nM or less, and particularly preferably 2.0 nM or less. 50 The lower limit is not specifically limited; for example, it can be set to 0.005nM, 0.01nM, 0.05nM, etc.

[0200] The ETB receptor inhibitory concentration (IC50) of the ETA receptor antagonist in this embodiment 50 The concentration of ETB receptor inhibitory concentration (IC50) is preferably 1,000 nM or more, more preferably 2,000 nM or more, further preferably 3,000 nM or more, even more preferably 4,000 nM or more, and particularly preferably 5,000 nM or more. 50 There is no specific upper limit for ), for example, it can be set to 10,000nM, 15,000nM, 20,000nM, etc.

[0201] By using the ETA receptor antagonist of this embodiment, it is possible to treat and / or prevent ETA receptor-related (mediated) diseases.

[0202] <Pharmaceutical Compositions>

[0203] One embodiment of the present invention relates to a pharmaceutical composition comprising a compound represented by formula (1) or a pharmaceutically permissible salt thereof.

[0204] Examples of diseases that can be targeted by the pharmaceutical composition of this embodiment include pulmonary hypertension, kidney disease, hypertension, hepatitis, cancer, pain, complications associated with autoimmune diseases, heart failure, and vasospasm.

[0205] Examples of kidney diseases include focal segmental glomerulosclerosis, IgA nephropathy, chronic kidney disease (including diabetic nephropathy), and kidney damage associated with sickle cell anemia.

[0206] Examples of hepatitis include, for instance, non-alcoholic steatohepatitis (NASH) and alcoholic hepatitis.

[0207] Examples of cancers include prostate cancer, squamous cell carcinoma, non-small cell lung cancer, and melanoma.

[0208] Examples of pain include, for instance, pain associated with endometriosis, chronic pain, neuropathic pain, cancer pain, and inflammatory pain.

[0209] As complications associated with autoimmune diseases, examples include complications associated with scleroderma and vasculitis.

[0210] As a type of heart failure, examples include right heart failure, left heart failure, heart failure associated with hypertrophic cardiomyopathy, heart failure associated with dilated cardiomyopathy, diastolic dysfunction heart failure, and systolic dysfunction heart failure.

[0211] Examples of vasospasm include cerebral vasospasm and vasospasm-related angina.

[0212] The pharmaceutical composition of this embodiment can be administered orally or non-orally. Examples of dosage forms for oral administration include tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions. Examples of dosage forms for non-oral administration include injections, infusions, drops, eye drops, and suppositories.

[0213] The pharmaceutical composition of this embodiment may include, as needed, excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, flavoring agents, stabilizers, thickeners, etc.

[0214] 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 physician can determine the appropriate dosage.

[0215] <Methods for manufacturing compounds>

[0216] The compound represented by formula (1) or its pharmaceutically permissible salt can be synthesized appropriately using known methods. As an example of a synthetic method, synthetic routes A to C are given below.

[0217] [Chemical Formula 7]

[0218] <Synthesis Path A>

[0219]

[0220] [Chemical Formula 8]

[0221] <Synthesis Path B>

[0222]

[0223] [Chemical Formula 9]

[0224] <Synthesis Path C>

[0225]

[0226] In synthesis pathways A through C, R 1 ~R 8 As mentioned above, Z, n, and Ar, are also related to Z. 1 and Z 2 It is a halogen, and Pro is a protecting group.

[0227] In synthetic route A, compound (1) is reacted with, for example, sodium hydride to obtain compound (2) (step 1). Compound (2) is then reacted with a halogen (e.g., iodine) to obtain compound (3) (step 2).

[0228] In synthetic route B, compound (4) is protected with an amino protecting group (e.g., methoxymethyl) to obtain compound (5) (step 3). Compound (5) is reacted with triisopropylsilylacetylene to obtain compound (6) (step 4). Compound (6) is reacted with, for example, tetrabutylammonium fluoride to obtain compound (7) (step 5).

[0229] In synthetic route C, compound (3) is reacted with compound (7) to obtain compound (8) (step 6). Compound (8) is then deprotected to obtain compound (9) (step 7).

[0230] When the compound represented by formula (1) or its pharmaceutically permissible salt exists in stereoisomers, the isomers can be separated using known methods. Examples of known methods include chromatography, enzymatic methods, and crystallization.

[0231] Example

[0232] The present invention will be described in more detail below using examples and comparative examples, but the technical scope of the present invention is not limited thereto.

[0233] [Manufacturing Example 1-1]

[0234] 6-Bromo-5-methylisobenzofuran-1(3H)-one

[0235] [Chemical Formula 10]

[0236]

[0237] To a mixture of 3-bromo-4-methylbenzoic acid (1.5 g, 7.01 mmol) and 1,1-dibromomethane (20 mL), dipotassium hydrogen phosphate (3.6 g, 21.0 mmol) and palladium(II) acetate (157 mg, 0.70 mmol) were added at room temperature, and the reaction mixture was stirred at 140 °C for 48 hours. The reaction mixture was then allowed to cool to room temperature and filtered through diatomaceous earth while washing with ethyl acetate. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was pulverized and washed with ethanol to give the title compound (1.3 g).

[0238] 1H NMR (400MHz, CDCl3): δ8.09(s,1H),7.37(s,1H),5.23(s,2H),2.53(s,3H).

[0239] [Manufacturing Examples 1-2]

[0240] 6-Bromo-1,1,5-Trimethyl-1,3-Dihydroisobenzofuran

[0241] [Chemical Formula 11]

[0242]

[0243] At -15 °C, methylmagnesium iodide (3.0 M diethyl ether solution, 4.5 mL, 13.5 mmol) was added to a mixture of 6-bromo-5-methylisobenzofuran-1(3H)-one (1.00 g, 4.41 mmol) and tetrahydrofuran (10 mL), and the mixture was stirred at the same temperature for 2 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (615 mg).

[0244] 1H NMR (400MHz, CDCl3): δ7.45 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 4.77 (d, J = 5.2 Hz, 2H), 2.37 (d, J = 5.2 Hz, 3H), 1.68 (d, J = 5.2 Hz, 6H).

[0245] [Manufacturing Examples 1-3]

[0246] 2-Chloro-N-(4,5-dimethylisoxazol-3-yl)pyridine-3-sulfonamide

[0247] [Chemical Formula 12]

[0248]

[0249] 4-Dimethylaminopyridine (109 mg, 0.892 mmol) and 2-chloropyridine-3-sulfonyl chloride (2.84 g, 13.4 mmol) were slowly added to a mixture of 4,5-dimethylisoxazol-3-amine (1.0 g, 8.92 mmol) and pyridine (20.0 mL) at 0 °C, and the reaction mixture was stirred at 50 °C for 16 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to give the title compound (1.50 g) in crude form. This compound was used in subsequent reactions without further purification.

[0250] ESI-MS: m / z 288.0 [M+1]+

[0251] [Manufacturing Examples 1-4]

[0252] 2-Chloro-N-(4,5-dimethylisoxazo-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0253] [Chemical Formula 13]

[0254]

[0255] 60% sodium hydride (695 mg, 17.4 mmol) was slowly added to a mixture of 2-chloro-N-(4,5-dimethylisoxazol-3-yl)pyridine-3-sulfonamide (1.80 g, 6.26 mmol) and DMF (30.0 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 min. Chloromethyl ether (1.06 mL, 13.9 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 3 h. Ice-cold water was added to the reaction mixture, 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.20 g).

[0256] ESI-MS: m / z 332.07 [M+1]+

[0257] [Manufacturing Examples 1-5]

[0258] N-(4,5-Dimethylisoxazo-3-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide

[0259] [Chemical Formula 14]

[0260]

[0261] Under an argon atmosphere, a mixture of 2-chloro-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (400 mg, 1.21 mmol), triethylamine (0.50 mL, 3.62 mmol), triisopropylsilylacetylene (440 mg, 2.41 mmol), and THF (5.00 mL) was added to bis(triphenylphosphine)palladium(II) chloride (84.6 mg, 0.121 mmol) and copper(I) iodide (11.5 mg, 0.0362 mmol), and the reaction mixture was stirred at 55 °C for 6 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.150 g).

[0262] 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H,J=4.8Hz),8.21(d,1H,J=8Hz),7.63-7.6 0(m,1H),5.16(s,2H),3.34(s,3H),2.32(s,3H),1.85(s,3H),1.14(bs,21H).

[0263] [Manufacturing Examples 1-6]

[0264] N-(4,5-Dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide

[0265] [Chemical Formula 15]

[0266]

[0267] Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.942 mL, 12.9 mmol) was slowly added to a mixture of N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide (150 mg, 4.3 mmol) and THF (3.00 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.060 g).

[0268] ESI-MS: m / z 322.19 [M+1]+

[0269] [Manufacturing Examples 1-7]

[0270] N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0271] [Chemical Formula 16]

[0272]

[0273] Under an argon atmosphere, a mixture of N-(4,5-dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (0.4 g, 1.25 mmol) and N,N-dimethylformamide (5 mL) was added to a mixture of 6-bromo-1,1,5-trimethyl-1,3-dihydroisobenzofuran (0.36 g, 1.49 mmol), copper(II) sulfate (7.8 mg, 0.04 mmol), triethylamine (1.04 mL, 7.48 mmol), sodium ascorbate (24 mg, 0.12 mmol), and tetrakis(triphenylphosphine)palladium(O) (28 mg, 0.02 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high performance liquid chromatography (Kinetex F5, (250×50mm) 5μm, 0.1% trifluoroacetic acid aqueous solution / acetonitrile-methanol (1:1) mixture) to obtain the title compound (615mg).

[0274] ESI-MS: m / z 482.29 [M+1]+

[0275] [Example 1]

[0276] N-(4,5-dimethylisoxazol-3-yl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0277] [Chemical Formula 17]

[0278]

[0279] To a mixture of N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide (90 mg, 0.18 mmol) and methanol (5 mL), 6 mol / L hydrochloric acid (1 mL) was added at 0 °C, and the reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Omega Ps C18 (250 × 21.2 mm) 5 μm, 0.1% trifluoroacetic acid aqueous solution / acetonitrile-methanol (1:1) mixture) to give the title compound (30 mg).

[0280] ESI-MS: m / z 438.24 [M+1]+

[0281] 1H NMR (400MHz, DMSO-d6): δ11.06(s,1H),8.83(d,J=4.8Hz,2H),8.35(d,J=8Hz,1H),7.66-7.63(m, 1H),7.48(s,1H),7.24(s,1H),4.96(s,2H),2.46(s,3H),2.07(s,3H),1.81(s,3H),1.43(s,6H).

[0282] [Manufacturing Example 2-1]

[0283] (E)-N'-(2-hydroxy-5-methylbenzyl)acetylhydrazine

[0284] [Chemical Formula 18]

[0285]

[0286] Acetylhydrazine (5.44 g, 73.5 mmol) was slowly added to a mixture of 2-hydroxy-5-methylbenzaldehyde (10 g, 73.5 mmol) and ethanol (50 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 16 hours. The solvent was removed from the reaction mixture under reduced pressure by distillation, and the residue was washed with hexane to give the title compound (10 g) in crude form. This compound was used in subsequent reactions without further purification.

[0287] [Manufacturing Example 2-2]

[0288] 2-Acetyl-5-methylbenzaldehyde

[0289] [Chemical Formula 19]

[0290]

[0291] Lead acetate (IV) (15.1 g, 34.4 mmol) was added to a mixture of (E)-N'-(2-hydroxy-5-methylbenzylmethyl)acetylhydrazine (6 g, 31.3 mmol) and tetrahydrofuran (90 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through diatomaceous earth while being washed with ethyl acetate. The filtrate was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.3 g).

[0292] ESI-MS: m / z 163.1 [M+1]+

[0293] [Manufacturing Examples 2-3]

[0294] 1-(2-(hydroxymethyl)-4-methylphenyl)ethane-1-ol

[0295] [Chemical Formula 20]

[0296]

[0297] Sodium borohydride (2.9 g, 77.2 mmol) was added to a mixture of 2-acetyl-5-methylbenzaldehyde (2.5 g, 15.4 mmol), tetrahydrofuran (10 mL), and ethanol (30 mL) at 0 °C, and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was brought to room temperature, and ice-cold water was added. Extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.8 g).

[0298] 1H NMR (400MHz, CDCl3): δ7.38-7.35(m,1H),7.16(d,J=2.4Hz,2H),5.19-5.14(m,1H),4.81(t, J=8Hz,1H),4.63(d,J=12Hz,2H),2.68(s,2H),2.35(d,J=4.8Hz,3H),2.45(d,J=5.2Hz,2H).

[0299] [Manufacturing Examples 2-4]

[0300] 1,5-Dimethyl-1,3-dihydroisobenzofuran

[0301] [Chemical Formula 21]

[0302]

[0303] 60% sodium hydride (1.07 g, 11.2 mmol) was slowly added to a mixture of 1-(2-(hydroxymethyl)-4-methylphenyl)ethane-1-ol (1.6 g, 9.64 mmol) and tetrahydrofuran (16 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 min. Trimethyl phosphate (3.5 g, 24.1 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 16 h. Water was added to the reaction mixture, 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.0 g).

[0304] 1H NMR (400MHz, CDCl3): δ7.12-7.06 (m, 3H), 5.31 (d, J = 6.4Hz, 1H), 5.14-5.01 (m, 2H), 2.39 (s, 3H), 1.50 (d, J = 6.4Hz, 3H).

[0305] [Manufacturing Examples 2-5]

[0306] 6-Bromo-1,5-dimethyl-1,3-dihydroisobenzofuran

[0307] [Chemical Formula 22]

[0308]

[0309] N-bromosuccinimide (842 mg, 4.73 mmol) and trifluoromethane (700 mg, 4.73 mmol) were added to a mixture of 1,5-dimethyl-1,3-dihydroisobenzofuran (700 mg, 4.73 mmol) and dichloromethane (7 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.7 g).

[0310] 1H NMR (400MHz, CDCl3): δ7.32 (dd, J=8.4Hz, J=9.2Hz, 1H), 7.09 (d, J=8Hz, 1H), 5.29-5.24 (m ,1H),5.07-5.02(m,1H),4.95(t,J=7.6Hz,1H),2.41(d,J=8.4Hz,3H),1.49-1.46(m,3H).

[0311] [Manufacturing Examples 2-6]

[0312] 2-((3,6-dimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0313] [Chemical Formula 23]

[0314]

[0315] Under an argon atmosphere, a mixture of N-(4,5-dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (0.7 g, 2.18 mmol) and N,N-dimethylformamide (5 mL) was added to 6-bromo-1,5-dimethyl-1,3-dihydroisobenzofuran (0.54 g, 2.40 mmol), copper iodide (I) (83 mg, 0.436 mmol), triethylamine (0.6 mL, 4.36 mmol), and tetrakis(triphenylphosphine)palladium (O) (250 mg, 0.218 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high performance liquid chromatography (Luna C8 (250×50mm) 10μm, 0.1% formic acid aqueous solution / acetonitrile) to obtain the title compound (50mg).

[0316] ESI-MS: m / z 468.27 [M+1]+

[0317] [Example 2]

[0318] 2-((3,6-dimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)pyridine-3-sulfonamide

[0319] [Chemical Formula 24]

[0320]

[0321] To a mixture of 2-((3,6-dimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (50 mg, 0.107 mmol) and methanol (5 mL), 6 mol / L hydrochloric acid (1 mL) was added at 0 °C, and the reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Luna C8 (250 × 50 mm) 10 μm, 0.1% formic acid aqueous solution / acetonitrile) to give the title compound (22 mg).

[0322] ESI-MS: m / z 424.31 [M+1]+

[0323] 1H NMR (400MHz, DMSO-d6): δ11.06(s,1H),8.82(d,J=4Hz,1H),8.34(t,J=6.8Hz,1H),7.66-7.62(m,1H),7.47(d,J=5.2Hz,1H),7.27(d,J=5.2Hz,1H ),5.22(d,J=9.6Hz,1H),5.05-5.00(m,1H),4.95-4.90(m,1H),2.47(s, 3H), 2.09 (d, J = 4.8Hz, 3H), 1.81 (d, J = 4.8Hz, 3H), 1.42 (t, J = 5.2Hz, 3H).

[0324] [Manufacturing Example 3-1]

[0325] (4-Methyl-1,2-phenylene)diethanol

[0326] [Chemical Formula 25]

[0327]

[0328] Borane dimethyl sulfide (156 mL, 1.85 mol) was slowly added to a mixture of 5-methylisobenzofuran-1,3-dione (100 g, 617 mmol) and THF (1000 mL) at 0 °C, and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was brought to room temperature, methanol was added, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (40.0 g).

[0329] 1H NMR (400MHz, DMSO-d6) δ7.23 (d, 1H, J = 8.0Hz), 7.18 (br s, 1H), 7.02 (d, 1H, J = 7.6Hz), 5.02 (t, 1H, J = 5.6Hz), 4.98 (t, 1H, J = 5.2Hz), 4.49 (dd, 4H, J = 8.4, 14Hz), 2.27 (s, 3H).

[0330] [Manufacturing Example 3-2]

[0331] 5-Methyl-1,3-dihydroisobenzofuran

[0332] [Chemical Formula 26]

[0333]

[0334] 50% sodium hydride (15.8 g, 657 mmol) was slowly added to a mixture of (4-methyl-1,2-phenylene)diethanol (40.0 g, 263 mmol) and DMF (200 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 minutes. Trimethyl phosphate (92.0 g, 657 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 the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (20.50 g).

[0335] 1 H NMR (400MHz, CDCl3) δ7.12 (d, 1H, J = 7.6Hz), 7.08 (br s, 1H), 7.06 (d, 1H, J = 4.8Hz), 5.08 (s, 4H), 2.37 (s, 3H).

[0336] [Manufacturing Example 3-3]

[0337] 5-Iodo-6-methyl-1,3-dihydroisobenzofuran

[0338] [Chemical Formula 27]

[0339]

[0340] Silver sulfate (4.65 g, 14.9 mmol) and iodine (1.89 g, 14.9 mmol) were slowly added to a mixture of 5-methyl-1,3-dihydroisobenzofuran (1.00 g, 7.45 mmol), methanol (5.00 mL), and ethanol (5.00 mL) at 0 °C, and the mixture was stirred at the same temperature for 1 hour. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.60 g).

[0341] 1 H NMR (400MHz, CDCl3) δ7.68 (s, 1H), 7.11 (s, 1H), 5.03 (d, 4H, J = 5.2Hz), 2.44 (s, 3H).

[0342] [Manufacturing Examples 3-4]

[0343] N-(4,5-Dimethylisoxazol-3-yl)-N-(methoxymethyl)-2-((6-methyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0344] [Chemical Formula 28]

[0345]

[0346] Under an argon atmosphere, a mixture of N-(4,5-dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (2.50 g, 7.78 mmol), 5-iodo-6-methyl-1,3-dihydroisobenzofuran (2.23 g, 8.56 mmol), triethylamine (2.19 mL, 15.6 mmol), and toluene (30.0 mL) was added to bis(triphenylphosphine)palladium(II) chloride (899 mg, 0.778 mmol) and copper(I) iodide (148 mg, 0.778 mmol), and the reaction mixture was stirred at 65 °C for 6 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.60 g).

[0347] ESI-MS: m / z 454.27 [M+1]+

[0348] [Example 3]

[0349] N-(4,5-dimethylisoxazol-3-yl)-2-((6-methyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0350] [Chemical Formula 29]

[0351]

[0352] To a mixture of N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2-((6-methyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide (1.00 g, 2.21 mmol) and methanol (10.0 mL), 6 mol / L hydrochloric acid (5.0 mL) was added at room temperature, and the reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was removed by distillation under reduced pressure. Ethyl acetate was added to the residue, which was washed with water, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.110 g).

[0353] 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.82(dd,1H,J=4.8,1.6Hz),8.33(dd,1H,J=8.4,1.6Hz),7. 63-7.60(m,1H),7.50(bs,1H),7.29(bs,1H),5.00(s,4H),2.50(s,3H),2.10(s,3H),1.80(s,3H).

[0354] [Manufacturing Example 4-1]

[0355] N-(4,5-Dimethylisoxazol-3-yl)-N-(methoxymethyl)-2-((6-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0356] [Chemical Formula 30]

[0357]

[0358] Under an argon atmosphere, a mixture of N-(4,5-dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (0.4 g, 1.24 mmol) and N,N-dimethylformamide (5 mL) was added to a mixture of 6-bromo-5-methylisobenzofuran-1(3H)-one (0.366 g, 1.61 mmol), copper iodide (I) (47 mg, 0.24 mmol), triethylamine (0.35 mL, 2.48 mmol), and tetrakis(triphenylphosphine)palladium (O) (143 mg, 0.12 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high performance liquid chromatography (Luna C8 (250×50mm) 10μm, 0.1% formic acid aqueous solution / acetonitrile) to obtain the title compound (50mg).

[0359] ESI-MS: m / z 468.24 [M+1]+

[0360] [Example 4]

[0361] N-(4,5-dimethylisoxazol-3-yl)-2-((6-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0362] [Chemical Formula 31]

[0363]

[0364] To a mixture of N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)-2-((6-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide (50 mg, 0.10 mmol) and methanol (5 mL), 6 mol / L hydrochloric acid (1 mL) was added at 0 °C, and the reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Luna C18 (250 × 50 mm) 10 μm, 0.1% formic acid aqueous solution / acetonitrile) to give the title compound (12 mg).

[0365] ESI-MS: m / z 424.18 [M+1]+

[0366] 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.86(t,J=5.2Hz,1H),8.37(t,J=5.2Hz,1H),8.08(d,J=4.8Hz,1H),7.6 7(t,J=4.8Hz,2H), 5.45(d,J=5.2Hz,2H), 2.61(d,J=5.2Hz,3H), 2.11(d,J=5.2Hz,3H), 1.81(d,J=5.2Hz,3H).

[0367] [Manufacturing Example 5-1]

[0368] 2-((1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0369] [Chemical Formula 32]

[0370]

[0371] Under an argon atmosphere, a mixture of N-(4,5-dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (250 mg, 0.778 mmol) and toluene (10 mL) was added to a mixture of 5-bromo-1,3-dihydroisobenzofuran (170 mg, 0.856 mmol), copper iodide (I) (15 mg, 0.077 mmol), triethylamine (0.22 mL, 1.56 mmol), and tetrakis(triphenylphosphine)palladium (0) (90 mg, 0.077 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high performance liquid chromatography (Luna C18 (250×50mm) 10μm, 0.1% formic acid aqueous solution / acetonitrile) to obtain the title compound (50mg).

[0372] ESI-MS: m / z 440.27 [M+1]+

[0373] [Example 5]

[0374] 2-((1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)pyridine-3-sulfonamide

[0375] [Chemical Formula 33]

[0376]

[0377] 6 mol / L hydrochloric acid (1 mL) was added to a mixture of 2-((1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (100 mg, 0.227 mmol) and methanol (5 mL) at 0 °C, and the reaction mixture was stirred at 50 °C for 8 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Luna C18 (250 × 50 mm) 10 μm, 0.1% formic acid aqueous solution / acetonitrile) to give the title compound (16 mg).

[0378] ESI-MS: m / z 396.23 [M+1]+

[0379] 1H NMR (400MHz, DMSO-d6): δ11.10(s,1H),8.80(s,1H),8.34(t,J=6.4Hz,1H),7.63(t,J=13.2Hz,1H),7 .57-7.53(m,2H),7.44(t,J=6.4Hz,1H),5.05(d,J=8Hz,1H),3.33(s,3H),2.09(s,3H),1.80(s,3H).

[0380] [Manufacturing Example 6-1]

[0381] 5-Chloro-6-iodobenzofuran-1(3H)-one

[0382] [Chemical Formula 34]

[0383]

[0384] Under an argon atmosphere, palladium(II) acetate (80 mg, 0.35 mmol) was added to a mixture of 4-chloro-3-iodobenzoic acid (1.0 g, 3.5 mmol), 1,1-dibromomethane (15 mL), and dipotassium hydrogen phosphate (2.25 g, 10.6 mmol). The reaction mixture was stirred at 140 °C for 16 hours. The reaction mixture was allowed to cool to room temperature and filtered through diatomaceous earth while washing with ethyl acetate. The filtrate was washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.4 g).

[0385] 1H NMR (400MHz, DMSO-d6): δ8.35(s,1H),7.97(s,1H),5.34(s,2H).

[0386] [Manufacturing Example 6-2]

[0387] 5-Chloro-6-iodo-1,3-dihydroisobenzofuran-1-ol

[0388] [Chemical Formula 35]

[0389]

[0390] Diisobutylaluminum hydride (20% toluene solution, 1.7 mL, 2.0 mmol) was added to a mixture of 5-chloro-6-iodoisobenzofuran-1(3H)-one (200 mg, 0.680 mmol) and dichloromethane (30 mL), and the mixture was stirred at -78 °C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was filtered through diatomaceous earth while washing with ethyl acetate. The filtrate was washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (70 mg).

[0391] 1H NMR (400MHz, DMSO-d6): δ7.89(s,1H),7.61(s,1H),6.89(d,J=7.6Hz,1H),6.75(dd,J=7 .6, 8.0Hz, 1H), 4.99 (d, J = 13.6Hz, 1H), 4.84 (d, J = 12.8Hz, 1H), 4.83 (d, J = 13.6Hz, 1H).

[0392] [Manufacturing Example 6-3]

[0393] 5-Chloro-6-iodo-1,3-dihydroisobenzofuran

[0394] [Chemical Formula 36]

[0395]

[0396] At room temperature, trifluoroacetic acid (0.11 mL, 1.5 mmol) and triethylsilane (0.4 mL, 2.6 mmol) were added to a mixture of 5-chloro-6-iodo-1,3-dihydroisobenzofuran-1-ol (300 mg, 1.01 mmol) and dichloromethane (26 mL), and the mixture was stirred at the same temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (200 mg).

[0397] 1H NMR (400MHz, DMSO-d6): δ7.90 (s, 1H), 7.56 (s, 1H), 4.94 (s, 4H).

[0398] [Manufacturing Example 6-4]

[0399] 2-((6-chloro-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0400] [Chemical Formula 37]

[0401]

[0402] Under an argon atmosphere, a mixture of N-(4,5-dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (120 mg, 0.373 mmol) and N,N-dimethylformamide (5 mL) was added to a solution of 5-chloro-6-iodo-1,3-dihydroisobenzofuran (126 mg, 0.448 mmol), copper iodide (I) (7.08 mg, 0.037 mmol), triethylamine (0.16 mL, 1.12 mmol), and tetrakis(triphenylphosphine)palladium (0) (43 mg, 0.037 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (95 mg).

[0403] ESI-MS: m / z 473.9 [M+1]+

[0404] [Example 6]

[0405] 2-((6-chloro-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)pyridine-3-sulfonamide

[0406] [Chemical Formula 38]

[0407]

[0408] At 0 °C, 1.2 mL of 50% sulfuric acid was added to a mixture of 2-((6-chloro-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (120 mg, 0.253 mmol), methanol (5 mL), and acetonitrile (1 mL). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was brought to room temperature, and a saturated aqueous sodium bicarbonate solution was added. Extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Kinetex penta C18 (250 × 50 mm) 5 μm, 0.1% trifluoroacetic acid aqueous solution / acetonitrile) to give the title compound (40 mg).

[0409] ESI-MS: m / z 430.01 [M+1]+

[0410] 1H NMR (400MHz, DMSO-d6): δ11.08(s,1H),8.84(d,J=4.0Hz,1H),8.34(d,J=8.4Hz,1H), 7.69-7.65(m,1H),7.64(s,1H),7.61(s,1H),4.14(s,4H),2.11(s,3H),1.79(s,3H).

[0411] [Manufacturing Example 7-1]

[0412] 2-(2-(hydroxymethyl)-4-methylphenyl)propane-2-ol

[0413] [Chemical Formula 39]

[0414]

[0415] To a mixture of 5-methylisobenzofuran-1(3H)-one (2.40 g, 16.2 mmol) and tetrahydrofuran (30 mL), methyl magnesium bromide (3.0 M ether solution, 16.2 mL, 48.6 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.30 g).

[0416] 1H NMR(400Hz,DMSO-d6)δ7.30(s,1H),7.19(d,J=8.0Hz,1H),6.95(d,J=8.0Hz,1H),5 .09(s,1H),4.98(t,J=5.6Hz,1H),4.75(d,J=5.6Hz,2H),2.25(s,3H),1.46(s,6H).

[0417] [Manufacturing Example 7-2]

[0418] 1,1,5-Trimethyl-1,3-dihydroisobenzofuran

[0419] [Chemical Formula 40]

[0420]

[0421] 50% sodium hydride (0.69 g, 14.4 mmol) was slowly added to a mixture of 2-(2-(hydroxymethyl)-4-methylphenyl)propane-2-ol (1.30 g, 7.22 mmol) and tetrahydrofuran (20 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. Trimethyl phosphate (2.01 g, 14.4 mmol) was slowly added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 4 hours. Ice-cold water was added to the reaction mixture, 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.60 g).

[0422] 1H NMR (400Hz, DMSO-d6) δ7.11 (d, J = 7.6Hz, 1H), 7.04 (t, J = 4.8Hz, 2H), 4.89 (s, 2H), 2.29 (s, 3H), 1.37 (s, 6H).

[0423] [Manufacturing Example 7-3]

[0424] 6-Iodo-1,1,5-trimethyl-1,3-dihydroisobenzofuran

[0425] [Chemical Formula 41]

[0426]

[0427] N-iodosuccinimide (1.60 g, 7.40 mmol) and trifluoromethane (1.10 g, 7.40 mmol) were slowly added to a mixture of 1,1,5-trimethyl-1,3-dihydroisobenzofuran (0.60 g, 3.7 mmol) and dichloromethane (10 mL) at 0 °C, and the mixture was stirred at the same temperature for 2 hours. A 10% aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.30 g).

[0428] 1H NMR (400Hz, DMSO-d6) δ7.71(s,1H),7.22(s,1H),4.86(s,2H),2.35(s,3H),1.38(s,6H).

[0429] [Manufacturing Example 7-4]

[0430] 2-Chloro-N-(4-Chloro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide

[0431] [Chemical Formula 42]

[0432]

[0433] 4-Dimethylaminopyridine (0.69 g, 5.66 mmol) and 2-chloropyridine-3-sulfonyl chloride (4.0 g, 18.8 mmol) were slowly added to a mixture of 4-chloro-5-methylisoxazol-3-amine (2.98 g, 22.6 mmol) and pyridine (50 mL) at 0 °C, and the reaction mixture was stirred at 55 °C for 16 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to give the title compound (1.90 g) in crude form. This compound was used in subsequent reactions without further purification.

[0434] ESI-MS: m / z 307.98 [M+1]+

[0435] [Manufacturing Example 7-5]

[0436] 2-Chloro-N-(4-Chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0437] [Chemical Formula 43]

[0438]

[0439] 50% sodium hydride (594 mg, 12.3 mmol) was slowly added to a mixture of 2-chloro-N-(4-chloro-5-methylisoxazol-3-yl)pyridine-3-sulfonamide (1.90 g, 6.98 mmol) and N,N-dimethylformamide (20.0 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 min. Chloromethyl ether (0.69 mL, 9.28 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 3 h. Ice-cold water was added to the reaction mixture, 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.0 g).

[0440] 1H NMR (400Hz, DMSO-d6) δ 8.71 (d, J = 4.4Hz, 1H), 8.39 (d, J = 8.0Hz, 1H), 7.66 (dd, J = 7.6Hz, 4.8Hz, 1H), 5.20 (s, 2H), 3.39 (s, 3H), 2.43 (s, 3H).

[0441] [Manufacturing Example 7-6]

[0442] N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide

[0443] [Chemical Formula 44]

[0444]

[0445] Under an argon atmosphere, a mixture of 2-chloro-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (1.20 g, 3.41 mmol), triethylamine (1.44 mL, 10.2 mmol), triisopropylsilylacetylene (1.24 g, 6.83 mmol), and tetrahydrofuran (15 mL) was added to bis(triphenylphosphine)palladium(II) chloride (239 mg, 0.34 mmol) and copper(I) iodide (20 mg, 0.10 mmol). The reaction mixture was stirred at 55 °C for 6 hours. The reaction mixture was brought to room temperature, and ice-cold water was added. Extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.70 g).

[0446] 1H NMR(400Hz, DMSO-d6)δ8.83(d,J=3.6Hz,1H),8.28(t,J=7.2Hz,1H),7.62-7.66( m, 1H), 5.19 (s, 2H), 3.33 (d, J = 6.0Hz, 3H), 2.43 (s, 3H), 1.10 (d, J = 3.6Hz, 21H).

[0447] [Manufacturing Example 7-7]

[0448] N-(4-chloro-5-methylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide

[0449] [Chemical Formula 45]

[0450]

[0451] Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 2.81 mL, 2.81 mmol) was slowly added to a mixture of N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide (0.70 g, 1.4 mmol) and tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 2 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.38 g).

[0452] ESI-MS: m / z 342.15 [M+1]+

[0453] [Manufacturing Examples 7-8]

[0454] N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0455] [Chemical Formula 46]

[0456]

[0457] Under an argon atmosphere, a mixture of N-(4-chloro-5-methylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (0.38 g, 1.11 mmol) and toluene (5 mL) was added to 6-iodo-1,1,5-trimethyl-1,3-dihydroisobenzofuran (0.32 g, 1.11 mmol), copper iodide (I) (6.35 mg, 0.03 mmol), triethylamine (0.46 mL, 3.34 mmol), and tetrakis(triphenylphosphine)palladium (0) (128 mg, 0.11 mmol). The reaction mixture was stirred at 65 °C for 6 hours. The reaction mixture was brought to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.25 g).

[0458] ESI-MS: m / z 502.10[M+1]+

[0459] [Example 7]

[0460] N-(4-chloro-5-methylisoxazol-3-yl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0461] [Chemical Formula 47]

[0462]

[0463] To a mixture of N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide (0.25 g, 0.49 mmol) and methanol (3 mL), 6 mol / L hydrochloric acid (3 mL) was added at 0 °C, and the reaction mixture was stirred at 60 °C for 16 hours. The solvent was removed from the reaction mixture under reduced pressure by distillation, and the residue was extracted with ethyl acetate by adding a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (35 mg).

[0464] ESI-MS: m / z 458.08 [M+1]+

[0465] 1H-NMR(400Hz,DMSO-d6)δ8.52(d,J=3.6Hz,1H),8.19(d,J=8.0,1H),7.46(s,1H),7.39( dd,J=8.0,4.8Hz,1H),7.18(s,1H),4.94(s,2H),2.54(s,3H),2.11(s,3H),1.42(s,6H).

[0466] [Manufacturing Example 8-1]

[0467] 2-Chloro-N-(3,4-dimethylisoxazol-5-yl)pyridine-3-sulfonamide

[0468] [Chemical Formula 48]

[0469]

[0470] 4-Dimethylaminopyridine (108 mg, 0.89 mmol) and 2-chloropyridine-3-sulfonyl chloride (2.8 g, 13.2 mmol) were slowly added to a mixture of 3,4-dimethylisoxazol-5-amine (1.0 g, 8.9 mmol) and pyridine (10 mL) at room temperature, and the reaction mixture was stirred at 50 °C for 16 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with 2N hydrochloric acid, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.0 g).

[0471] ESI-MS: m / z 287.9 ​​[M+1]+

[0472] [Manufacturing Example 8-2]

[0473] 2-Chloro-N-(3,4-dimethylisoxazol-5-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0474] [Chemical Formula 49]

[0475]

[0476] 60% sodium hydride (334 mg, 13.9 mmol) was slowly added to a mixture of 2-chloro-N-(3,4-dimethylisoxazol-5-yl)pyridine-3-sulfonamide (2.0 g, 7.0 mmol) and N,N-dimethylformamide (10 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 minutes. Chloromethyl ether (0.83 g, 10.5 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Ice-cold water was added to the reaction mixture, 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.0 g).

[0477] ESI-MS: m / z 332.18 [M+1]+

[0478] [Manufacturing Example 8-3]

[0479] N-(3,4-Dimethylisoxazo-5-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide

[0480] [Chemical Formula 50]

[0481]

[0482] Under an argon atmosphere, a mixture of 2-chloro-N-(3,4-dimethylisoxazol-5-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (2.0 g, 6.0 mmol), triethylamine (1.8 g, 18 mmol), triisopropylsilylacetylene (1.65 g, 9.06 mmol), and N,N-dimethylformamide (10 mL) was added to bis(triphenylphosphine)palladium(II) chloride (150 mg, 0.604 mmol) and copper(I) iodide (114 mg, 0.604 mmol), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.5 g).

[0483] ESI-MS: m / z 478.1 [M+1]+

[0484] [Manufacturing Example 8-4]

[0485] N-(3,4-Dimethylisoxazol-5-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide

[0486] [Chemical Formula 51]

[0487]

[0488] Tetrabutylammonium fluoride (1 mol / L tetrabutylammonium fluoride solution, 3.1 mL, 3.1 mmol) was slowly added to a mixture of N-(3,4-dimethylisoxazol-5-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide (1.0 g, 2.1 mmol) and tetrahydrofuran (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (350 mg).

[0489] ESI-MS: m / z 322.0 [M+1]+

[0490] [Manufacturing Example 8-5]

[0491] N-(3,4-Dimethylisoxazol-5-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0492] [Chemical Formula 52]

[0493]

[0494] Under an argon atmosphere, a mixture of N-(3,4-dimethylisoxazol-5-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (300 mg, 0.93 mmol) and N,N-dimethylformamide (3 mL) was added to a mixture of 6-iodo-1,1,5-trimethyl-1,3-dihydroisobenzofuran (296 mg, 1.02 mmol), copper iodide (I) (17 mg, 0.09 mmol), triethylamine (282 mg, 2.79 mmol), and tetrakis(triphenylphosphine)palladium (O) (103 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (250 mg).

[0495] ESI-MS: m / z 482.39 [M+1]+

[0496] [Example 8]

[0497] N-(3,4-Dimethylisoxazol-5-yl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0498] [Chemical Formula 53]

[0499]

[0500] At 0 °C, 50% sulfuric acid (4 mL) was added to a mixture of N-(3,4-dimethylisoxazol-5-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide (200 mg, 0.415 mmol) and methanol (4 mL), and the reaction mixture was stirred at 50 °C for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was extracted with ethyl acetate by adding saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Luna C18 (250 × 50 mm) 10 μm, 0.1% formic acid aqueous solution / acetonitrile) to give the title compound (60 mg).

[0501] ESI-MS: m / z 438.31 [M+1]+

[0502] 1H NMR (400MHz, DMSO-d6): δ11.25(s,1H),8.79(s,1H),8.30(d,J=7.2Hz,1H),7.609(s,1H),7. 390(s,1H),7.224(s,1H),4.95(s,2H),2.46(s,3H),1.82(s,3H),1.66(s,3H),1.43(s,6H).

[0503] [Manufacturing Example 9-1]

[0504] 2-Chloro-N-(4-chloro-3-methylisoxazol-5-yl)pyridine-3-sulfonamide

[0505] [Chemical Formula 54]

[0506]

[0507] At 0 °C, 60% sodium hydride (909 mg, 22.7 mmol) and 2-chloropyridine-3-sulfonyl chloride (2.89 g, 13.6 mmol) were slowly added to a mixture of 4-chloro-3-methylisoxazol-5-amine (1.5 g, 11.4 mmol) and tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.5 g).

[0508] ESI-MS: m / z 307.9 [M+1]+

[0509] [Manufacturing Example 9-2]

[0510] 2-Chloro-N-(4-Chloro-3-methylisoxazol-5-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0511] [Chemical Formula 55]

[0512]

[0513] 60% sodium hydride (467 mg, 11.7 mmol) was slowly added to a mixture of 2-chloro-N-(4-chloro-3-methylisoxazol-5-yl)pyridine-3-sulfonamide (1.8 g, 5.8 mmol) and N,N-dimethylformamide (20 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 min. Chloromethyl ether (0.54 mL, 8.8 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. Ice-cold water was added to the reaction mixture, 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.3 g).

[0514] ESI-MS: m / z 352.27 [M+1]+

[0515] [Manufacturing Example 9-3]

[0516] N-(4-chloro-3-methylisoxazol-5-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide

[0517] [Chemical Formula 56]

[0518]

[0519] Under an argon atmosphere, a mixture of 2-chloro-N-(4-chloro-3-methylisoxazol-5-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (1.3 g, 3.7 mmol), triethylamine (1.46 mL, 11.1 mmol), triisopropylsilylacetylene (0.8 g, 4.4 mmol), and N,N-dimethylformamide (6.5 mL) was added to bis(triphenylphosphine)palladium(II) chloride (134 mg, 0.184 mmol) and copper(I) iodide (140 mg, 0.738 mmol), and the reaction mixture was stirred at 100 °C for 4 hours. The reaction mixture was allowed to cool to room temperature and filtered through diatomaceous earth while washing with ethyl acetate. The filtrate was washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (600 mg).

[0520] ESI-MS: m / z 498.51 [M+1]+

[0521] [Manufacturing Example 9-4]

[0522] N-(4-chloro-3-methylisoxazol-5-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide

[0523] [Chemical Formula 57]

[0524]

[0525] Tetrabutylammonium fluoride (1.2 mL, 1 mol / L tetrahydrofuran solution, 1.2 mmol) was slowly added to a mixture of N-(4-chloro-3-methylisoxazol-5-yl)-N-(methoxymethyl)-2-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide (600 mg, 1.20 mmol) and tetrahydrofuran (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (220 mg).

[0526] ESI-MS: m / z 342.0 [M+1]+

[0527] [Manufacturing Example 9-5]

[0528] N-(4-chloro-3-methylisoxazol-5-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0529] [Chemical Formula 58]

[0530]

[0531] Under an argon atmosphere, a mixture of N-(4-chloro-3-methylisoxazol-5-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (250 mg, 0.73 mmol) and N,N-dimethylformamide (5 mL) was added to a mixture of 6-iodo-1,1,5-trimethyl-1,3-dihydroisobenzofuran (232 mg, 0.81 mmol), copper iodide (I) (27 mg, 0.15 mmol), triethylamine (0.48 mL, 3.66 mmol), and tetrakis(triphenylphosphine)palladium (0) (84 mg, 0.073 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (200 mg).

[0532] ESI-MS: m / z 502.56 [M+1]+

[0533] [Example 9]

[0534] N-(4-chloro-3-methylisoxazol-5-yl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0535] [Chemical Formula 59]

[0536]

[0537] At 0 °C, 2 mL of 50% sulfuric acid was added to a mixture of N-(4-chloro-3-methylisoxazol-5-yl)-N-(methoxymethyl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide (200 mg, 0.39 mmol) and methanol (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was extracted with ethyl acetate by adding a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was recrystallized from diethyl ether to give the title compound (35 mg).

[0538] ESI-MS: m / z 458.36 [M+1]+

[0539] 1H NMR (400MHz, DMSO-d6): δ8.69(d,J=3.6Hz,1H),8.30(dd,J=8.0Hz,1.2Hz,1H),7.55-7.5 2(m,1H),7.49(s,1H),7.07(s,1H),4.94(s,2H),2.49(s,3H),1.89(s,3H),1.42(s,6H).

[0540] [Manufacturing Example 10-1]

[0541] 2-Chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide

[0542] [Chemical Formula 60]

[0543]

[0544] 4-Dimethylaminopyridine (17.5 mg, 0.143 mmol) and 2-chloropyridine-3-sulfonyl chloride (366 mg, 1.73 mmol) were slowly added to a mixture of 3-methoxy-5-methylpyrazine-2-amine (0.2 g, 1.4 mmol) and pyridine (5 mL) at room temperature, and the reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with 6N hydrochloric acid, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.16 g).

[0545] ESI-MS: m / z 315.0 [M+1]+

[0546] [Manufacturing Example 10-2]

[0547] 2-Chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide

[0548] [Chemical Formula 61]

[0549]

[0550] Potassium carbonate (44 mg, 0.32 mmol) was slowly added to a mixture of 2-chloro-N-(3-methoxy-5-methylpyrazine-2-yl)pyridine-3-sulfonamide (50 mg, 0.16 mmol) and N,N-dimethylformamide (2 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 min. 2-(trimethylsilyl)ethoxymethyl chloride (0.1 mL, 0.24 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (40 mg).

[0551] ESI-MS: m / z 445.0 [M+1]+

[0552] [Manufacturing Example 10-3]

[0553] N-(3-methoxy-5-methylpyrazin-2-yl)-2-((triisopropylsilyl)ethynyl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide

[0554] [Chemical Formula 62]

[0555]

[0556] Under an argon atmosphere, a mixture of 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide (0.4 g, 0.9 mmol), triethylamine (0.4 mL, 2.7 mmol), triisopropylsilylacetylene (0.3 mL, 1.3 mmol), and N,N-dimethylformamide (5 mL) was added to bis(triphenylphosphine)palladium(II) chloride (63 mg, 0.089 mmol) and copper(I) iodide (34.2 mg, 0.179 mmol). The reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was allowed to cool to room temperature and filtered through diatomaceous earth while washing with ethyl acetate. The filtrate was washed with water and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (160 mg).

[0557] ESI-MS: m / z 591.55 [M+1]+

[0558] [Manufacturing Example 10-4]

[0559] 2-Ethynyl-N-(3-methoxy-5-methylpyrazin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide

[0560] [Chemical Formula 63]

[0561]

[0562] Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.27 mL, 0.27 mmol) was slowly added to a mixture of N-(3-methoxy-5-methylpyrazin-2-yl)-2-((triisopropylsilyl)ethynyl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide (0.16 g, 0.27 mmol) and tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (80 mg).

[0563] ESI-MS: m / z 435.2 [M+1]+

[0564] [Manufacturing Example 10-5]

[0565] N-(3-methoxy-5-methylpyrazin-2-yl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide

[0566] [Chemical Formula 64]

[0567]

[0568] Under an argon atmosphere, a mixture of 2-ethynyl-N-(3-methoxy-5-methylpyrazin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide (200 mg, 0.460 mmol) and N,N-dimethylformamide (5 mL) was added to a mixture of 6-iodo-1,1,5-trimethyl-1,3-dihydroisobenzofuran (146 mg, 0.506 mmol), copper iodide (I) (9 mg, 0.046 mmol), triethylamine (0.2 mL, 1.38 mmol), and tetra(triphenylphosphine)palladium (0) (53 mg, 0.046 mmol). The reaction mixture was stirred at room temperature for 1 hour. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (170 mg).

[0569] ESI-MS: m / z 595.4 [M+1]+

[0570] [Example 10]

[0571] N-(3-methoxy-5-methylpyrazin-2-yl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)pyridine-3-sulfonamide

[0572] [Chemical Formula 65]

[0573]

[0574] At 0 °C, 3 mL of 50% sulfuric acid was added to a mixture of N-(3-methoxy-5-methylpyrazin-2-yl)-2-((3,3,6-trimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyridine-3-sulfonamide (200 mg, 0.336 mmol) and methanol (5 mL). The reaction mixture was stirred at 60 °C for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was extracted with ethyl acetate by adding saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Luna C18 (250 × 50 mm) 10 μm, 0.1% formic acid aqueous solution / acetonitrile) to give the title compound (35 mg).

[0575] ESI-MS: m / z 465.35 [M+1]+

[0576] 1H NMR (400MHz, DMSO-d6): δ10.98 (s, 1H), 8.79 (d, J = 4.0Hz, 1H), 8.36 (dd, J = 1.6, 8.0Hz, 1H), 7.62 (dd, J = 4. 8,8.4Hz,1H)7.51(s,1H),7.22(s,1H),4.95(s,2H),3.80(s,3H),2.44(s,3H),2.22(s,3H),1.44(s,6H).

[0577] [Manufacturing Example 11-1]

[0578] (E)-N'-(2-hydroxy-4-methylbenzyl)acetylhydrazine

[0579] [Chemical Formula 66]

[0580]

[0581] Acetylhydrazine (1.64 g, 22.1 mmol) was added to a mixture of 2-hydroxy-4-methylbenzaldehyde (3.0 g, 22 mmol) and ethanol (40 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was washed with hexane to give the title compound (3.0 g) in crude form. This compound was used in subsequent reactions without further purification.

[0582] [Manufacturing Example 11-2]

[0583] 2-Acetyl-4-methylbenzaldehyde

[0584] [Chemical Formula 67]

[0585]

[0586] Lead acetate (IV) (11.7 g, 26.3 mmol) was added to a mixture of (E)-N'-(2-hydroxy-4-methylbenzylmethyl)acetylhydrazine (4.6 g, 24 mmol) and tetrahydrofuran (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through diatomaceous earth while being washed with ethyl acetate. The filtrate was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.0 g).

[0587] 1H NMR (400MHz, CDCl3): δ10.19 (d, J = 4Hz, 1H), 7.84-7.81 (m, 1H), 7.46 (t, J = 6.8Hz, 2H), 2.65 (d, J = 4Hz, 3H), 2.50 (d, J = 3.6Hz, 3H).

[0588] [Manufacturing Example 11-3]

[0589] 1-(2-(hydroxymethyl)-5-methylphenyl)ethane-1-ol

[0590] [Chemical Formula 68]

[0591]

[0592] Sodium borohydride (1.5 g, 40 mmol) was added to a mixture of 2-acetyl-4-methylbenzaldehyde (1.4 g, 8.0 mmol), tetrahydrofuran (3.8 mL), and ethanol (11.2 mL) at 0 °C, and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was brought to room temperature, and ice-cold water was added. Extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.85 g).

[0593] 1H NMR (400MHz, CDCl3): δ7.27(s,1H),7.20(d,J=7.6Hz,1H),6.83(d,J=7.2Hz,1 H), 5.01-4.91 (m, 3H), 4.53-4.46 (m, 2H), 2.27 (s, 3H), 1.28 (d, J = 6.4Hz, 3H).

[0594] [Manufacturing Example 11-4]

[0595] 1,6-Dimethyl-1,3-dihydroisobenzofuran

[0596] [Chemical Formula 69]

[0597]

[0598] 60% sodium hydride (0.52 g, 13.6 mmol) was slowly added to a mixture of 1-(2-(hydroxymethyl)-5-methylphenyl)ethane-1-ol (0.90 g, 5.4 mmol) and tetrahydrofuran (10 mL) at 0 °C, and the mixture was stirred at the same temperature for 30 min. Trimethyl phosphate (1.5 mL, 13.6 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 16 h. Water was added to the reaction mixture, 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 by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.6 g).

[0599] 1H NMR (400MHz, CDCl3): δ7.12-7.07(m,2H),6.98(d,J=5.2Hz,1H),5.31-5.28(m,1H),5.13-5.00(m,2H),2.39(d,J=5.2Hz,3H),1.52-1.48(m,3H).

[0600] [Manufacturing Example 11-5]

[0601] 5-Bromo-1,6-dimethyl-1,3-dihydroisobenzofuran

[0602] [Chemical Formula 70]

[0603]

[0604] N-bromosuccinimide (721 mg, 4.05 mmol) and trifluoromethane (1.8 g, 12.2 mmol) were added to a mixture of 1,6-dimethyl-1,3-dihydroisobenzofuran (600 mg, 4.05 mmol) and dichloromethane (10 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. Ice-cold water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.3 g).

[0605] 1H NMR (400MHz, CDCl3): δ7.51(d,J=5.2Hz,1H),7.26(d,J=5.2Hz,1H),5.17-5.12(m,1H) ,4.96(d,J=12.8Hz,1H),4.88-4.84(m,1H),2.35(d,J=5.2Hz,3H),1.37(t,J=6Hz,3H).

[0606] [Manufacturing Example 11-6]

[0607] 2-((1,6-dimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide

[0608] [Chemical Formula 71]

[0609]

[0610] Under an argon atmosphere, a mixture of N-(4,5-dimethylisoxazol-3-yl)-2-ethynyl-N-(methoxymethyl)pyridine-3-sulfonamide (0.40 g, 1.24 mmol) and N,N-dimethylformamide (5 mL) was added to a mixture of 5-bromo-1,6-dimethyl-1,3-dihydroisobenzofuran (0.337 g, 1.49 mmol), copper iodide (I) (47 mg, 0.249 mmol), triethylamine (0.36 mL, 2.49 mmol), and tetrakis(triphenylphosphine)palladium (0) (143 mg, 0.124 mmol). The reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was brought to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high performance liquid chromatography (Luna C18 (250×50mm) 10μm, 0.1% formic acid aqueous solution / acetonitrile) to obtain the title compound (25mg).

[0611] ESI-MS: m / z 468.23 [M+1]+

[0612] [Example 11]

[0613] 2-((1,6-dimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)pyridine-3-sulfonamide

[0614] [Chemical Formula 72]

[0615]

[0616] To a mixture of 2-((1,6-dimethyl-1,3-dihydroisobenzofuran-5-yl)ethynyl)-N-(4,5-dimethylisooxazol-3-yl)-N-(methoxymethyl)pyridine-3-sulfonamide (30 mg, 0.064 mmol) and methanol (5 mL), 6 mol / L hydrochloric acid (0.5 mL) was added at 0 °C, and the reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was brought to room temperature, ice-cold water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by high-performance liquid chromatography (Luna C18 (250 × 50 mm) 10 μm, 0.1% formic acid aqueous solution / acetonitrile) to give the title compound (5 mg).

[0617] ESI-MS: m / z 424.0 [M+1]+

[0618] 1H NMR (400MHz, DMSO-d6): δ11.02(s,1H),8.81(d,J=5.2Hz,1H),8.34(t,J=8H z,1H),7.63(t,J=4.4Hz,1H),7.48(d,J=5.6Hz,1H),7.26(d,J=5.6Hz,1H),5 .22(d,J=5.6Hz,1H),5.05-5.00(m,1H),4.92(t,J=6.4Hz,1H),2.48(d,J=8 .8Hz, 3H), 2.09 (d, J = 6.4Hz, 3H), 1.81 (d, J = 6.4Hz, 3H), 1.41 (t, J = 6Hz, 3H).

[0619] [Comparative Example 1]

[0620] As a comparative example 1, simethicone is expressed using the following formula.

[0621] [Chemical Formula 73]

[0622]

[0623] [Comparative Example 2]

[0624] As Comparative Example 2, a compound represented by the following formula was used. This compound is the compound described in Example 1 of International Publication No. 2013 / 115162.

[0625] [Chemical Formula 74]

[0626]

[0627] [Experimental Example 1-1: Endothelin A Receptor Inhibition]

[0628] The inhibitory effect of endothelin A receptor was investigated using the following methods.

[0629] CHO-K1-mtaquorin cells that were forcibly expressed with human endothelin A receptor (accession number NP_001948.1) were cultured in antibiotic-free medium for 18 hours, then treated with PBS-EDTA (5 mM EDTA), centrifuged (2 min, 405 × g, room temperature), and resuspended in detection buffer (DMEM / HAM's F12 containing HEPES + 0.1% BSA (protease-free)).

[0630] In the presence of 5 μM coelenterazine h (molecular probe), 1 × 10⁻⁶ mol / L was prepared at room temperature. 6 Cells were incubated at 1 cell / mL for 4 hours to confirm the agonistic response induced by endothelin and the endothelin concentration equivalent to EC80 was determined.

[0631] Next, 50 μL of a 10,000-cell / well coelenterate-treated cell suspension and 50 μL of detection buffer containing the test substance (final concentration of 0.5% DMSO) were added to a 96-well plate. After 15 minutes, endothelin was added at the final EC80 concentration. Receptor activity was measured by luminescence intensity using an FDSS6000 (Hamamatsu Photonics). The IC50 value was calculated using XLfit (IDBS).

[0632] Cases with IC50 values ​​below 1.0 nM, or showing greater than 50% inhibition at 1.0 nM, are denoted as "A". Cases with IC50 values ​​greater than 10 nM, or showing less than 50% inhibition at 10 nM, are denoted as "C". Cases between "A" and "C" are denoted as "B". The results are shown in Table 1-1.

[0633] [Table 1-1]

[0634] Table 1-1: ETA receptor inhibition

[0635] Example 1 A Example 2 A Example 3 A Example 4 A Example 5 B Example 6 B Example 7 A Example 8 A Example 9 A Example 10 A Example 11 B Comparative Example 1 B Comparative Example 2 A

[0636] [Experimental Examples 1-2: Inhibition of Endothelin B Receptors]

[0637] The inhibitory effect of endothelin B receptor was investigated using the following methods.

[0638] CHO-K1-mtaequorin cells that were forcibly expressed with human endothelin B receptor (accession number NP-000106.1) were cultured in antibiotic-free medium for 18 hours, then treated with PBS-EDTA (5 mM EDTA), centrifuged (2 min, 405 × g, room temperature), and resuspended in detection buffer (DMEM / HAM's F12 containing HEPES + 0.1% BSA (protease-free)).

[0639] In the presence of coelenterate h (molecular probe) at a final concentration of 5 μM, 1 × 10 6 Cells were incubated at 1 cell / mL for 4 hours to confirm the agonistic response induced by endothelin and the endothelin concentration equivalent to EC80 was determined.

[0640] Next, 50 μL of a 10,000-cell / well coelenterin-treated cell suspension and 50 μL of a detection buffer containing the test substance (final concentration of 0.5% DMSO) were added to a 96-well plate. After 15 minutes, endothelin was added to achieve the final concentration of EC80. Receptor activity was measured by luminescence using an FDSS6000 (Hamamatsu Photonics).

[0641] Cases with IC50 values ​​below 1000 nM, or showing greater than 50% inhibition at 1000 nM, are denoted as "A". Cases with IC50 values ​​greater than 5000 nM, or showing less than 50% inhibition at 5000 nM, are denoted as "C". Cases between "A" and "C" are denoted as "B". The results are shown in Table 1-2.

[0642] [Table 1-2]

[0643] Table 1-2: ETB receptor inhibition

[0644] Example 1 C Example 2 C Example 3 C Example 4 C Example 5 C Example 6 C Example 7 Inhibits 57% at 5000 nM Example 8 C Example 9 C Example 10 C Example 11 C Comparative Example 1 C Comparative Example 2 C

[0645] Regarding ETA selectivity, the case that satisfies any of the following is denoted as "++".

[0646] 1. The ratio of the IC50 value of ETB to the IC50 value of ETA is greater than 5000.

[0647] 2. It showed more than 50% ETA inhibition at 1.0 nM and less than 50% ETB inhibition at 5000 nM.

[0648] A "+" is used to represent the case where the IC50 value of ETB / IC50 value of ETA is greater than 1000 but less than 5000.

[0649] The results are shown in Table 1-3.

[0650] [Table 1-3]

[0651] Table 1-3: ETA Selectivity (ETB / ETA)

[0652] Example 1 ++ Example 2 ++ Example 3 ++ Example 4 ++ Example 8 ++ Example 9 ++ Example 10 ++ Comparative Example 1 ++ Comparative Example 2 ++

[0653] [Experimental Example 2: CYP2C9 Inhibition]

[0654] The inhibitory effect on CYP2C9 was evaluated using the following methods.

[0655] (1) Dissolve the pre-frozen liver microsomal fraction on ice and dilute with potassium phosphate buffer (PPB) to a final concentration of 0.5 mg / mL.

[0656] (2) Add the evaluation substrate (Diclofenac: Sigma-Aldrich D6899) ​​to a final concentration of 2.5 μM.

[0657] (3) Mix slowly and incubate at 37±1℃ for 5 minutes to prepare a reaction solution.

[0658] (4) Aliquot 801 μL of the reaction solution into tubes and add 0.9 μL of the evaluation compound serially diluted with DMSO to a final concentration of 9.1–20000 nM (1 / 3 dilution for 8 concentrations). In the negative control group, add 0.9 μL of DMSO, and in the positive control group, add 0.9 μL of sulfaphenazole (Sigma Aldrich S0758), adjusted to a final concentration of 1 μM with DMSO.

[0659] (5) After mixing, transfer 270 μL of each mixture to two other tubes and incubate them in a shaking water bath at 37±1℃ for 5 minutes.

[0660] (6) Add 30 μL of 10 mM NADPH to start the reaction and incubate at 37℃±1℃ for 10 minutes.

[0661] (7) Remove the tube from the shaking water bath, add 300 μL of reaction termination solution to terminate the reaction, mix, and centrifuge at 4 °C for 20 minutes at 1021 × g.

[0662] (8) The metabolic amount of the evaluation substrate was determined by LC-MS / MS, and the inhibition rate of each concentration of the evaluation compound was calculated accordingly.

[0663] (9) Calculate the IC50 value using GraphPad Prism5. A value below 1 μM is denoted as "++", a value between 1 μM and 10 μM is denoted as "+", and a value above 10 μM is denoted as "-". The results are shown in Table 2.

[0664] [Table 2]

[0665] Table 2

[0666] CYP2C9 inhibition Example 1 - Example 3 - Example 4 - Example 5 - Example 6 + Example 7 + Example 8 - Example 9 + Example 10 - Comparative Example 1 ++ Comparative Example 2 ++

[0667] [Experiment 3: Metabolic stability of human and mouse liver microsomes was tested]

[0668] The metabolic stability of human liver microsomes was evaluated using the following method.

[0669] 1. Materials

[0670] (1) Human liver microsomes: 20 mg / mL

[0671] (2) Test compound: 1.1 mM DMSO solution

[0672] (3) Potassium phosphate buffer: 66.7 mM (pH 7.4)

[0673] (4) NADPH solution: 10 mM in potassium phosphate buffer

[0674] (5) Quenching solution: 0.5% formic acid-acetonitrile solution with warfarin as an internal standard.

[0675] 2. Methods

[0676] 971.5 μL of potassium phosphate buffer and 27.5 μL of human liver microsomes were added to a propylene tube and allowed to suspend. 1 μL of the test compound was added, and 180 μL of the mixture was transferred to another tube. The mixture was pre-incubated at 37°C for 5 minutes, followed by the addition of 20 μL of NADPH solution (for a 30-minute incubation) or 20 μL of potassium phosphate buffer (for a 0-minute incubation). After incubation, 200 μL of quenching solution was added to terminate the reaction. The mixture was then centrifuged at 3220 × g for 20 minutes, and the concentration of the unaltered form of the test compound in the 200 μL supernatant was determined by LC-MS / MS. Based on the peak area of ​​the unaltered form, the 0-minute incubation time was set as 100%, and the percentage of unaltered form was calculated.

[0677] For metabolic stability in mouse liver microsomes, mouse liver microsomes were used instead of human liver microsomes, and the same method as described above was used for evaluation. The percentage of unchanged microsomes after 30 minutes is shown in Table 3.

[0678] [Table 3]

[0679] Table 3

[0680]

[0681] [Experimental Example 4: PAMPA (Parallel Artificial Membrane Permeability Model) Membrane Permeability Test]

[0682] The permeability of membranes using PAMPA was studied. The specific methods are described below.

[0683] (1) Add lecithin to dodecane liquid at a concentration of 2% (w / v) and dissolve it completely.

[0684] (2) Add 5 μL of lecithin / dodecane liquid to the donor plate. At this time, make sure the pipette tip is not in contact with the membrane.

[0685] (3) Immediately add 150 μL of the evaluation compound (10 μM) in donor solution (5% DMSO-PBS) to each well of the donor plate and add 300 μL of aqueous buffer to each well of the PTFE acceptor plate.

[0686] (4) The donor plate, filled with the donor solution containing the evaluation compound, was slowly placed on the acceptor plate to confirm that the lower surface of the membrane was in contact with the buffer solution in all pores.

[0687] (5) Cover the device and incubate it at room temperature for 16 hours.

[0688] (6) After incubation, 100 μL of solution was recovered from the upper and lower surfaces of the membrane of the acceptor plate and acetonitrile containing an equal amount of internal standard was added.

[0689] (7) The concentration of the evaluation compound is determined and the permeation rate is calculated.

[0690] The results are shown in Table 4. The membrane permeation rate is 1 × 10⁻⁶. -8 When the speed is below 1 × 10 cm / sec, it is recorded as "C"; when it is greater than 1 × 10 cm / sec, it is recorded as "C". - 8 cm / sec and 10×10 -8 When the speed is below 10 cm / sec, it is recorded as "B"; when it is above 10 × 10 cm / sec, it is recorded as "B". -8 When the speed is cm / sec, it is recorded as "A".

[0691] [Table 4]

[0692] Table 4

[0693] Membrane permeation rate Example 1 A Example 3 A Example 4 C Example 5 B Example 6 A Example 7 A Example 8 B Example 9 A Example 10 A

[0694] [Experiment 5: BigET-1 (Big Endothelin-1) Induced Blood Pressure Evaluation Test]

[0695] In male Wistar rats aged 8–20 weeks, under analgesic administration and urethane anesthesia, the trachea was intubated for airway maintenance, the carotid artery for blood pressure measurement, the femoral vein for BigET-1 administration, and the duodenum for test substance administration. After confirming stable blood pressure and heart rate, 30 mg / kg (5 mL / kg) of the solvent (0.5% methylcellulose 400 solution) or the test substance adjusted with the solvent was administered into the duodenum. One hour later, BigET-1 (20 μg / kg) was administered, and blood pressure was monitored until 60 minutes after BigET-1 administration. The study was conducted with n=6 groups. Analysis was performed by taking systolic and diastolic blood pressure measurements for 20 seconds every 5 minutes from 5 minutes before BigET-1 administration to 60 minutes after administration. The AUC (0-60min) was calculated using the difference (Δ value) between the values ​​taken 5 minutes before BigET-1 administration and the values ​​taken 60 minutes after administration. The Student's t-test was used to compare the AUCs of the solvent administration group and the test substance administration group.

[0696] [Table 5]

[0697] Table 5

[0698]

[0699] Mean ± SD, N = 6, #: p < 0.01 vs solvent group.

Claims

1. The compound represented by the following formula (1) or its pharmaceutically permissible salt, [Chemical Formula 1] In equation (1), R 1 and R 2 each independently is hydrogen or an alkyl group having 1 to 6 carbon atoms, R 3 and R 4 each independently is hydrogen or an alkyl group having 1 to 6 carbon atoms, or R 3 with R 4 is oxo, R 5 ~R 7 Each of the following is independently hydrogen, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a halogen, an alkoxy group having 1 to 6 carbon atoms, or a haloalkoxy group having 1 to 6 carbon atoms. R 8 Each is independently an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, or a halogen. n is an integer between 0 and 3. Ar can be either (Ar1) or (Ar2): [Chemical Formula 2] In the formula, X and Y represent nitrogen and oxygen, or oxygen and nitrogen, respectively. R 9 and R 10 Each is independently hydrogen, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, or a halogen. R 11 Each of these can be independently an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a halogen, an alkoxy group having 1 to 6 carbon atoms, or a haloalkoxy group having 1 to 6 carbon atoms. m is an integer between 0 and 3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R 1 and R 2 is hydrogen.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R 5 and R 7 For hydrogen, R 6 It is an alkyl group having 1 to 6 carbon atoms.

4. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein, n is 0.

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

6. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein, R 9 and R 10 is an alkyl group having 1 to 6 carbon atoms.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, X and Y represent nitrogen and oxygen, respectively.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, X and Y represent oxygen and nitrogen, respectively.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ar is the formula (Ar2).

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R 11 Each is independently an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, m is 2.

12. The compound of claim 1 or a pharmaceutically permissible salt thereof, selected from the group consisting of compounds, 。 13. An endothelin A receptor antagonist comprising any one of claims 1 to 12 or a pharmaceutically permissible salt thereof.

14. The endothelin A receptor antagonist of claim 13, wherein it selectively inhibits endothelin A receptors with endothelin B receptors as a control.

15. A pharmaceutical composition comprising any one of the compounds of claims 1 to 12 or a pharmaceutically permissible salt thereof.

16. The pharmaceutical composition of claim 15, for the prevention or treatment of diseases selected from the group consisting of pulmonary hypertension, kidney disease, hypertension, hepatitis, cancer, pain, complications of autoimmune diseases, heart failure, and vasospasm.

17. The following compounds or their pharmaceutically permissible salts, 。 18. The following compounds or their pharmaceutically permissible salts, 。 19. The following compounds or their pharmaceutically permissible salts, 。 20. The following compounds or their pharmaceutically permissible salts, 。

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