Benzenesulfonamide compound as well as preparation method and application thereof

Abstract

The invention discloses a benzenesulfonamide compound as shown in a general formula (I) and a preparation method and application thereof. The series of compounds provided by the invention can be used as lead compounds of sodium ion channel inhibitors, and are expected to be used for preparing medicines for treating arrhythmia, including premature beat, acute and recurrent atrial fibrillation, heart failure, supraventricular tachyarrhythmia (PVC), ventricular premature contraction (PVC), ventricular tachycardia (VT) or ventricular fibrillation (VF).

Description

Technical Field

[0001] This invention discloses a benzenesulfonamide compound of general formula (I), its preparation method, pharmaceutical compositions containing the compound, and its use as a therapeutic agent, particularly its use as a NaV1.5 inhibitor and its use in the preparation of medicaments for treating arrhythmia-related diseases. Background Technology

[0002] Cardiac arrhythmia is a common cardiovascular disease that can occur in people of all ages. In recent years, with changes in people's lifestyles, such as long hours of work stress, poor dietary habits, and lack of exercise, the incidence of arrhythmia has been rising. In addition, people with other heart diseases, hypertension, diabetes, and other chronic diseases are also more prone to arrhythmia. Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice.

[0003] Atrial fibrillation (AF) is the loss of regular, orderly atrial electrical activity, replaced by rapid, unwanted fibrillation waves, representing a serious disorder of atrial electrical activity. It typically manifests as an irregular and rapid heart rhythm. During an AF episode, the atrial excitation frequency reaches 300–600 beats per minute, and the heart rate can reach 100–160 beats per minute, resulting in the atria losing their effective contractile function. AF can lead to atrial thrombosis, which in turn can cause thromboembolic events, such as ischemic stroke. 20%–30% of ischemic strokes are caused by AF, and the mortality and disability rates of ischemic stroke patients caused by AF are higher than those caused by non-AF-related ischemic strokes. In addition, AF can cause common clinical symptoms such as palpitations, fatigue, chest tightness, cognitive impairment, and decreased exercise tolerance, thus reducing patients' quality of life. These complications of AF place a heavy burden on the social healthcare system.

[0004] Currently, there are three main drug treatment options for atrial fibrillation:

[0005] (1) Rhythm control: Using medication to restore and maintain sinus rhythm (SR) is the ideal treatment option. Only by restoring sinus rhythm can atrial fibrillation be completely cured. However, existing medications have very poor cardioversion effects on persistent atrial fibrillation and have certain side effects. For newly diagnosed atrial fibrillation, since the rate of spontaneous sinus reversion within 48 hours is very high (about 60% within 24 hours), observation can be performed first, or propafenone or flecainide can be administered orally once. For atrial fibrillation that has lasted for more than 48 hours but less than 7 days, intravenous cardioversion drugs such as flecainide, dofetilide, propafenone, ibutilide, and amiodarone can be used, with a success rate of up to 50%. For atrial fibrillation episodes lasting more than one week (persistent atrial fibrillation), the effectiveness of drug cardioversion is greatly reduced. Commonly used and proven effective drugs include amiodarone, ibutilide, and dofetilide.

[0006] (2) Ventricular rate control: Regulating ventricular rate to prevent tachycardia. For atrial fibrillation patients who cannot restore sinus rhythm, medication can be used to control ventricular rate, ensuring basic cardiac function and reducing cardiac dysfunction caused by atrial fibrillation. Commonly used medications include beta-blockers, calcium channel antagonists, and digitalis. Among them, beta-blockers are the most effective and commonly used drugs for controlling ventricular rate. Calcium channel antagonists such as verapamil and diltiazem can also be effectively used for ventricular rate control in atrial fibrillation, especially for controlling ventricular rate during exercise, where they are superior to digoxin. The effect of using them in combination with digoxin is also better than using them alone. Digitalis is generally used in emergency situations to control ventricular rate in atrial fibrillation. Currently, it is mostly used clinically for controlling ventricular rate in patients with left heart failure.

[0007] (3) Anticoagulation therapy: It is a necessary means to prevent thrombosis and stroke in patients with atrial fibrillation. Anticoagulation therapy can prevent thrombosis and reduce the risk of stroke, but it cannot eliminate atrial fibrillation or improve the clinical symptoms of patients with atrial fibrillation, such as palpitations, fatigue, and heart failure.

[0008] Rhythm control is one of the two main treatment measures for improving symptoms in patients with atrial fibrillation (AF) and is also an important goal of AF treatment. In recent years, with the accumulation of evidence-based medicine, clinicians have placed greater emphasis on reducing adverse cardiovascular outcomes through rhythm control. Professor A. John Camm of St. George's University, London, also pointed out in an article published in JACC that for patients with AF that has not yet developed long-term, especially newly diagnosed AF and symptomatic patients, increasing evidence supports early rhythm control. Early rhythm control can effectively reduce irreversible atrial remodeling, prevent AF-related heart failure, stroke, and death in high-risk patients, and delay disease progression; therefore, this strategy should be adopted more widely. Therefore, from a clinical perspective, rhythm control drugs are indispensable in the management of AF, whether for acute cardioversion or long-term maintenance therapy after cardioversion. However, currently used antiarrhythmic drugs all have certain problems: for example, propafenone is only suitable for atrial fibrillation patients with no or only mild structural heart disease; while amiodarone, although it can be used for patients with structural heart disease, has thyroid toxicity and pulmonary toxicity, and also has tissue accumulation, resulting in many side effects with long-term use, and is generally not used for acute cardioversion of atrial fibrillation due to its slow onset of action; ibutilide has a moderate effect on atrial fibrillation conversion and a short duration of action (about 4 hours), although it can be used for patients with moderate structural heart disease other than heart failure, the incidence of lethal torsades de pointes (TdP) is as high as 4%. Therefore, there is an urgent clinical need for new antiarrhythmic drugs that can balance safety and efficacy to better meet the treatment needs of atrial fibrillation patients.

[0009] Sucinyl sulfate, developed by researchers at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, is a compound with potent antiarrhythmic activity. It was developed by using natural plant derivatives with antiarrhythmic effects as lead compounds, undergoing structural modification, and then screening them. Studies have found that sucinyl sulfate is a dose-dependent combination blocker of sodium, L-calcium, Ikr potassium, and Ito potassium channels. Unlike simple Ikr potassium channel blockers, sucinyl sulfate exhibits a very low risk of inducing torsades de pointes (TDPT), thus its safety profile is superior to currently available clinical drugs. Sucinyl sulfate demonstrated good efficacy and safety in Phase I and II clinical trials, showing significant efficacy against premature ventricular contractions (PVCs) without serious adverse reactions. Notably, no TDPT risk was observed in the clinical trials, and Phase III clinical trials are currently underway. Simultaneously, a Phase I clinical trial for atrial fibrillation is being conducted in injectable form. Summary of the Invention

[0010] Purpose of the invention: Based on the clinical research results of suxinidine sulfate on arrhythmia, atrial fibrillation and other related diseases, this invention develops a series of benzylsulfonamide compounds with sodium ion channel blocking activity, thereby expanding the types of drugs used to treat arrhythmia.

[0011] Based on the structure of suxinidine sulfate, this application obtains a series of novel benzylsulfonamide compounds through structural modification. These compounds can be used as lead compounds for sodium ion channel inhibitors and in the preparation of drugs for treating arrhythmias, including premature beats, acute and recurrent atrial fibrillation, heart failure, supraventricular tachyarrhythmias (PVC), premature ventricular contractions (PVC), ventricular tachycardia (VT), or ventricular fibrillation (VF).

[0012] Specifically, this application proposes compounds represented by general formula (I) or pharmaceutically acceptable salts, hydrates, and / or solvates thereof.

[0013]

[0014] in:

[0015] R 1 and R 2 Independently hydrogen-based, halogenated, methyl group with 1-3 fluorine-substituted groups, methoxy group with 1-3 fluorine-substituted groups, C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkoxy, C 1-6 alkylamine group, C 1-6 Alkylthio, C 3-7Cycloalkyl, N,N-dimethylamino, methoxy, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, where R is C 1-6 Alkyl groups;

[0016] When R 2 In R 1 Adjacent rings can close to form quinary or hexacyclic heterocycles. In some embodiments, when R... 2 In R 1 When adjacent, they can close to form pentagonal or hexacyclic heterocycles containing 1 to 3 N, O, and S atoms;

[0017] R 3 It can be hydrogen or methyl;

[0018] L represents a methylene or carbonyl group;

[0019] R 4 and R 5 Independently hydrogen, C 1-4 Alkyl, C 3-4 Cycloalkyl or 1-2 fluorinated substituted ethyl groups;

[0020] R 4 and R 5 They can close together to form 4-6 membered aliphatic heterocycles;

[0021] R 4 Or R 5 Can be used with R 6 Ring closure forms 4-7 membered aliphatic heterocycles containing 1-2 nitrogen atoms;

[0022] R 6 It can be hydrogen or methyl;

[0023] n is 0 or 1;

[0024] m is 1 or 2.

[0025] Preferably, R 1 It can be hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxyl, methoxy, hydroxymethyl, amino, N,N-dimethylamino, carbamoyl, acetyl, methyl with 1 to 3 fluorine substitutions, or methoxy with 1 to 3 fluorine substitutions.

[0026] R 2 It can be hydrogen, fluorine, chlorine, methyl, or ethyl;

[0027] When R 2 In R 1 When in the adjacent position, it can close the ring to form a five- or six-membered heterocycle containing 1 to 2 oxygen atoms and / or nitrogen atoms.

[0028] In some embodiments, R 4 R 5 and R 6 Composition of fragments Selected from:

[0029]

[0030] In some embodiments, this application discloses the following compounds:

[0031] N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide,

[0032] N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide,

[0033] N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0034] N-(4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide,

[0035] N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide,

[0036] N-((4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-2-fluoro-4-methoxybenzenesulfonamide,

[0037] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0038] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methylbenzenesulfonamide,

[0039] N-(4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0040] N-(4-(2-aminoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0041] N-(4-(2-aminopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0042] 4-Methoxy-N-(4-((1-methylpyrrolidone-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0043] 4-Methoxy-N-(4-(2-(1-methylpyrrolidone-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0044] N-(4-(2-(diethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0045] N-(4-(2-(bis(2-fluoroethyl)amino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0046] 4-Methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0047] N-(4-(2-(diisopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0048] N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0049] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0050] N-(4-(2-((2,2-difluoroethyl)amino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide,

[0051] 4-Methoxy-N-(4-(piperidin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0052] 4-Methoxy-N-(4-((1-methylpiperidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0053] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-hydroxybenzenesulfonamide,

[0054] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-fluorobenzenesulfonamide,

[0055] 4-Cyano-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0056] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-ethylbenzenesulfonamide,

[0057] 4-Chloro-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0058] 4-Cyclopropyl-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0059] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-2,3-dihydrobenzofuran-5-sulfonamide

[0060] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-(dimethylamino)benzenesulfonamide,

[0061] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxy-3-methylbenzenesulfonamide,

[0062] 4-(N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)aminosulfonyl)benzamide,

[0063] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzo[d][1,3]m-dioxacyclopentene-5-sulfonamide

[0064] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-fluoro-4-methoxybenzenesulfonamide,

[0065] N-(4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide,

[0066] 2-Fluoro-4-methoxy-N-(4-((1-methylpyrrolidone-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0067] 2-Fluoro-4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0068] N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide,

[0069] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide,

[0070] 4-Amino-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide,

[0071] N-((4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide,

[0072] Or N-((4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-2-fluoro-4-methoxybenzenesulfonamide.

[0073] Wherein, the salt form of the compound is any one of inorganic acid salt, inorganic base salt, organic acid salt, or organic base salt; the inorganic acid salt is any one of hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; the organic acid salt is any one of acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and ascorbate; and the organic base salt is any one of arginine, benzyl benzoate, choline, diethylamine, diolamine, glycine, lysine, meglumine, ethanolamine, and aminobutanetriol.

[0074] The present invention also provides a method for preparing compounds as described in general formula (I), the method comprising:

[0075] (1) Preparation of the compound shown in formula (II):

[0076]

[0077] (2) React compound (II) with compound (III) to obtain compound (I).

[0078]

[0079] Wherein, the substituent is as described in claim 1.

[0080] The compound obtained by formula (I) can further undergo a cyclization reaction, causing R to... 4 and R 5 Between, or R 4 and R 6 Between, or R 5 and R 6 The relationship between them.

[0081] This application further provides a pharmaceutical composition comprising the above-described compound or its pharmaceutically acceptable salt, hydrate, and / or solvate, and one or more pharmaceutically acceptable excipients, diluents, or carriers. The compounds of this invention can form hydrates or solvates. The compounds of this invention or pharmaceutical compositions containing the compounds of this invention can be in various pharmaceutical dosage forms and administered in unit doses. The pharmaceutical dosage form or administration dosage form can be a liquid dosage form, a solid dosage form, a topical preparation, a spray, etc. Liquid dosage forms can be true solutions, colloids, microparticles, emulsions, or vortexes. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, inclusion complexes, implants, patches, liniments, etc.

[0082] This application further proposes the use of the above-mentioned compound or its pharmaceutically acceptable salts, hydrates and / or solvates, or the pharmaceutical composition of claim 6, in the preparation of a medicament for inhibiting voltage-gated sodium ion channels.

[0083] The voltage-gated sodium channel mentioned above is the cardiac sodium channel NaV1.5.

[0084] Furthermore, this application proposes the use of the above-mentioned compounds or their pharmaceutically acceptable salts, hydrates and / or solvates, or the pharmaceutical composition of claim 6, in the preparation of a medicament for treating and / or preventing arrhythmias.

[0085] The arrhythmia mentioned herein is any one or a combination of several of the following: premature beats, atrial fibrillation, atrial flutter, atrial tachycardia, and paroxysmal supraventricular tachycardia.

[0086] Beneficial Effects: Starting from the structure of suxinidine sulfate, this application developed a series of benzenesulfonamide compounds with sodium ion channel blocking activity, thereby expanding the types of drugs available for treating arrhythmias. Results show that the provided series of compounds can be used as lead compounds for sodium ion channel inhibitors, and are expected to be used in the preparation of drugs for treating arrhythmias, including premature beats, acute and recurrent atrial fibrillation, heart failure, supraventricular tachyarrhythmias (PVC), premature ventricular contractions (PVC), ventricular tachycardia (VT), or ventricular fibrillation (VF). Detailed Implementation

[0087] The present invention will be further described in detail below with reference to specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0088] Example 1: Preparation of N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide.

[0089] (1) Synthesis of 2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one.

[0090]

[0091] Potassium carbonate (17.25 g, 125 mmol) was added to 100 mL of dried DMF (N,N-dimethylformamide), followed by 2-amino-5-nitrophenol (7.7 g, 50 mmol). The mixture was stirred at room temperature for 1 h until completely dissolved. Under ice bath conditions, a DMF solution of ethyl 2-bromo-2-methylpropionate (9.75 g, 50 mmol) was slowly added dropwise. After half an hour, the reaction mixture was slowly brought to room temperature and reacted at 90 °C for 12 h. After cooling, some solvent was evaporated under reduced pressure. 300-500 mL of ice water was slowly added with stirring, resulting in the precipitation of a solid. The mixture was stirred under ice bath conditions for half an hour, filtered, and the filter cake was dried under vacuum to obtain a relatively pure intermediate product, a brown powder, weighing 8.05 g (77.4% yield). This intermediate can be used directly in the next step without further purification.

[0092] (2) Synthesis of 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one

[0093]

[0094] At 0 °C, 2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one (8 g, 36 mmol) and NaH (4.32 g, 108 mmol, in 60% oil solution) were added to dry DMF (10 mL), followed by 2-chloro-N,N-dimethylethylamine hydrochloride (3.88 g, 36 mmol), and the mixture was stirred for 1 h. The reaction mixture was heated to 90 °C and reacted for another 1 h. After cooling to room temperature, the mixture was diluted with water (150 mL), and the product was extracted into ethyl acetate (2 × 75 mL). The combined ethyl acetate layers were washed with brine (100 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude compound was purified by column chromatography (3:97 (2 M NH3 in MeOH):CH2Cl2) to give the title compound (8.02 g, 76%) as a yellow solid.

[0095] 1 H NMR(500MHz,Chloroform-d)δ7.96(dd,J=8.0,2.1Hz,1H),7.80(d,J=2.2Hz,1H),7.44(d,J=8 .0Hz,1H),4.00(t,J=5.8Hz,2H),3.05(t,J=5.8Hz,2H),2.46(s,6H),1.51(s,6H).MS(ESI)m / z 294.1[M+H] +

[0096] (3) Synthesis of 7-amino-4-(2-(dimethylamino)ethyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazine-3(4H)-one

[0097]

[0098] 7.3 g (25 mmol) of 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazine-3(4H)-one was added to 100 mL of solvent (EtOH:H2O = 3:1). Ammonium chloride (1.35 g, 25 mmol) and iron powder (4.2 g, 75 mmol) were added under stirring at room temperature, and the mixture was refluxed at 90 °C for 1-2 h. After the reaction was completed by thin-layer chromatography, excess iron powder was filtered off while hot. After the reaction solution cooled, the solvent was evaporated under reduced pressure. The residual solid was adjusted to pH 10 with an aqueous solution of potassium carbonate, resulting in solid precipitation. The solid was filtered, and the filter cake was washed with cooling water and dried under vacuum to obtain a relatively pure intermediate product, a yellow powder, weighing 4.97 g (yield 75.6%). This intermediate can be used directly in the next reaction without further purification.

[0099] (4) Synthesis of N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide

[0100]

[0101] 3.95 g (15 mmol) of 7-amino-4-(2-(dimethylamino)ethyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazine-3(4H)-one was added to a dry tetrahydrofuran (50 mL) solvent. After stirring at room temperature for half an hour, triethylamine (2.3 g, 22.5 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, a tetrahydrofuran (15 mL) solution of 4-methoxybenzenesulfonyl chloride (3.1 g, 15 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 12 hours. The solvent was removed under reduced pressure, and the remaining solid was dissolved in water and the pH was adjusted to 3 with dilute hydrochloric acid. The solution was then extracted with ethyl acetate (50 mL * 4), and the organic layers were combined and dried over anhydrous magnesium sulfate. The target product was purified by column chromatography to obtain 3.69 g of the product (56.8% yield) as a white powder.

[0102] 1H NMR(500MHz,Chloroform-d)δ8.76(s,1H),7.61–7.55(m,2H),7.39(dd,J=8.9,2.1Hz,1H),7.30(d,J=8.8Hz,1H),7.08–7.02(m,2H) ,6.66(d,J=2.2Hz,1H),4.02(t,J=5.6Hz,2H),3.80(s,3H),3.06(t,J=5.7Hz,2H),2.46(s,6H),1.52(s,6H).MS(ESI)m / z434.2[M+H] +

[0103] Example 2 Preparation of N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide.

[0104] (1) Synthesis of 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile.

[0105]

[0106] Potassium carbonate (0.65 g, 4.65 mmol) was added to 10 mL of dried DMF (N,N-dimethylformamide), followed by the addition of 4-amino-3-hydroxybenzonitrile (250 mg, 1.86 mmol). The mixture was stirred at room temperature for 1 h until completely dissolved. Under ice bath conditions, a DMF solution of ethyl 2-bromo-2-methylpropionate (362 mg, 1.86 mmol) was slowly added dropwise. After half an hour, the reaction mixture was slowly brought to room temperature and reacted at 90 °C for 12 h. After cooling, some solvent was evaporated under reduced pressure. 30-50 mL of ice water was slowly added with stirring, resulting in the precipitation of a solid. The mixture was stirred under ice bath conditions for half an hour, filtered, and the filter cake was dried under vacuum to obtain a relatively pure intermediate product, a white powder of 267.1 mg, with a yield of 71%. This intermediate can be used directly in the next step without further purification.

[0107] (2) Synthesis of 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile.

[0108]

[0109] At 0 °C, 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-onitrile (260 mg, 1.29 mmol) and NaH (155 mg, 3.87 mmol, in 60% oil solution) were added to dry DMF (10 mL), followed by the addition of 2-chloro-N,N-dimethylethylamine hydrochloride (139 mg, 1.29 mmol), and the mixture was stirred for 1 h. The reaction mixture was then heated to 90 °C and reacted for another 1 h. After cooling to room temperature, the mixture was diluted with water (30 mL), and the product was extracted into ethyl acetate (2 × 25 mL). The combined ethyl acetate layers were washed with brine (30 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude compound was purified by column chromatography (3:97 (2 M NH₃ in MeOH):CH₂Cl₂) to give the title compound as a white solid (264 mg, 75%).

[0110] 1 H NMR(500MHz,Chloroform-d)δ7.44–7.35(m,2H),7.21(d,J=2.1Hz,1H),3.96(t,J=5.8Hz,2H),3.05(t,J=5.8Hz,2H),2.46(s,6H),1.52(s,6H).MS(ESI)m / z 274.1[M+H] +

[0111] (3) Synthesis of 7-(aminomethyl)-4-(2-(dimethylamino)ethyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazine-3(4H)-one.

[0112]

[0113] A 1.0 mol / L BH3·THF (10 mL) composite solution was added to a mixture of 260 mg (0.95 mmol) of 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-onitrile in THF (5 mL). The reaction mixture was heated at 70 °C for 6 hours. Subsequently, the mixture was cooled to room temperature and quenched with HCl (2 M, 10 mL) at 0 °C. The solvent was removed under reduced pressure. The residue was diluted with H2O and the pH was adjusted to approximately 9 using NaOH (2 M). The aqueous layer was extracted with DCM, and the combined organic layer was dried over anhydrous Na2SO4. The solvent was removed to give the desired material (271 mg, 100%), a yellow oil, which could be used in the next synthetic step without further separation.

[0114] MS(ESI) m / z 278.2 [M+H] +

[0115] (4) Synthesis of N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide.

[0116]

[0117] 7-(aminomethyl)-4-(2-(dimethylamino)ethyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazine-3(4H)-one (271 mg, 0.95 mmol) was added to a dry tetrahydrofuran (10 mL) solvent. After stirring at room temperature for half an hour, triethylamine (146 mg, 1.425 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, a tetrahydrofuran (5 mL) solution of 4-methoxybenzenesulfonyl chloride (196 mg, 0.95 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 12 hours. The solvent was removed under reduced pressure, and the remaining solid was dissolved in water and the pH was adjusted to 3 with dilute hydrochloric acid. The solution was then extracted with ethyl acetate (20 mL * 4), and the organic layers were combined and dried over anhydrous magnesium sulfate. The target product was purified by column chromatography to obtain 201 mg of the product (49.2% yield) as a white powder.

[0118] 1 H NMR(500MHz,Chloroform-d)δ7.76–7.68(m,2H),7.18(d,J=8.8Hz,1H),7.14–7.11(m,1H),7.08–7.01(m,2H),6.90–6.88(m,1H),6.0 6(t,J=7.3Hz,1H),4.24(dt,J=7.3,0.9Hz,2H),4.00(t,J=5.9Hz,2H),3.80(s,3H),3.05(t,J=5.9Hz,2H),2.46(s,6H),1.51(s,6H).

[0119] MS(ESI) m / z 448.0 [M+H] +

[0120] Example 3 Preparation of N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide.

[0121] (1) Synthesis of 2-(2,2-dimethyl-7-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N,N-dimethylethane-1-amine.

[0122] A suspension of 2,2-dimethyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (250 mg, 1.2 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (130 mg, 1.2 mmol), and K₂CO₃ (0.4 g, 3 mmol) in dry DMF (10 mL) was stirred overnight (18 h) at 100 °C. The reaction mixture was brought to room temperature, diluted with water (30 mL), and the product was extracted into ethyl acetate (2 × 35 mL). The combined ethyl acetate layers were washed with brine (50 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude substance was purified by column chromatography (3:97 (2 M NH₃ in MeOH):CH₂Cl₂) to give the title compound (271.3 mg, 81%) as a yellow solid.

[0123] (2) Synthesis of 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-amine.

[0124]

[0125] 2-(2,2-dimethyl-7-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N,N-dimethylethane-1-amine (270 mg, 0.97 mmol) was added to 8 mL of solvent (EtOH:H2O = 3:1). Ammonium chloride (54 mg, 0.97 mmol) and iron powder (140 mg, 2.5 mmol) were added under stirring at room temperature, and the mixture was refluxed at 90 °C for 1-2 h. After the reaction was completed by thin-layer chromatography, excess iron powder was filtered off while hot. After the reaction solution cooled, the solvent was evaporated under reduced pressure. The residual solid was adjusted to pH 10 with an aqueous solution of potassium carbonate, resulting in solid precipitation. The solid was filtered, and the filter cake was washed with cooling water and dried under vacuum to obtain a relatively pure intermediate product, 176 mg of a yellow powder, with a yield of 74%. This intermediate can be used directly in the next reaction without further purification.

[0126] (3) Synthesis of N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0127]

[0128] 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-amine (170 mg, 0.7 mmol) was added to a dry tetrahydrofuran (5 mL) solvent. After stirring at room temperature for half an hour, triethylamine (102 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, a tetrahydrofuran (2 mL) solution of 4-methoxybenzenesulfonyl chloride (145 mg, 0.7 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 12 hours. The solvent was removed under reduced pressure, and the remaining solid was dissolved in water and the pH was adjusted to 3 with dilute hydrochloric acid. The solution was then extracted with ethyl acetate (5 mL * 4), and the organic layers were combined and dried over anhydrous magnesium sulfate. The target product was purified by column chromatography to obtain 143 mg of the product (49% yield) as a white powder.

[0129] 1 H NMR(500MHz,Chloroform-d)δ8.85(s,1H),7.62–7.56(m,2H),7.22(dd,J=9.0,2.2Hz,1H),7.08–7.02(m,2H),6.88–6.8 1(m,2H),3.80(s,3H),3.63(s,2H),3.56(t,J=5.6Hz,2H),2.81(t,J=5.5Hz,2H),2.36(s,6H),1.38(s,6H).MS(ESI)m / z 420.1[M+H] +

[0130] Example 4 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-2-fluoro-4-methoxybenzenesulfonamide. (1) Synthesis of 4-(2-chloroethyl)-2,2-dimethyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine.

[0131]

[0132] At 0 °C, 2,2-dimethyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (250 mg, 1.2 mmol) and NaH (1.5 g, 36 mmol, 60% oil solution) were added to dry DMF (30 mL), followed by the addition of 1,2-dichloroethane (118 mg, 12 mmol), and the mixture was stirred for 1 h. The reaction mixture was then heated to 90 °C and reacted for another 1 h. After cooling to room temperature, the mixture was diluted with water (60 mL), and the product was extracted into ethyl acetate (2 × 60 mL). The combined ethyl acetate layers were washed with brine (100 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude compound was purified by column chromatography (3:97 (2 M NH₃ in MeOH):CH₂Cl₂) to give the title compound as a yellow solid (265 mg, 82%).

[0133] (2)N-(4-(2-chloroethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide

[0134]

[0135] N-(4-(2-chloroethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide was prepared from 4-methoxybenzenesulfonyl chloride according to the method in Example 1.

[0136] (3) Synthesis of N-(4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide.

[0137]

[0138] Under nitrogen atmosphere, N-(4-(2-chloroethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide (100 mg, 0.233 mmol), cyclopropylamine (66 mg, 1.2 mmol), and methanol (5 mL) were added to a sealed tube and heated in an oil bath at 80 °C. After 24 hours, the tube was cooled, and the reaction mixture was rotary evaporated under reduced pressure. 30 mL of saturated sodium bicarbonate aqueous solution was added, and the resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a yellow oil, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to a white solid of 41 mg, yield 39.4%. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.90–7.83(m,1H),7.25–7.19(m,1H),6.91–6.86(m,1H),6.89–

[0139] 6.84(m,2H),6.82(d,J=8.8Hz,1H),3.78(s,3H),3.62(s,2H),3.55(t,J=5.0Hz,2H),3.47–3.43( m,1H),2.85–2.79(m,2H),2.51–2.46(m,1H),1.39(s,6H),0.86–0.78(m,2H),0.60–0.52(m,2H).

[0140] MS(ESI) m / z 450.1 [M+H] +

[0141] Example 5 Preparation of N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide. (1) Synthesis of 2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile

[0142]

[0143] Potassium carbonate (0.65 g, 4.65 mmol) was added to 10 mL of dried DMF (N,N-dimethylformamide), followed by the addition of 4-amino-3-hydroxybenzonitrile (250 mg, 1.86 mmol). The mixture was stirred at room temperature for 1 h until completely dissolved. Under ice bath conditions, a DMF solution of 1,2-dibromo-2-methylpropane (401 mg, 1.86 mmol) was slowly added dropwise. After half an hour, the reaction mixture was slowly brought to room temperature and reacted at 90 °C for 12 h. After cooling, some solvent was distilled off under reduced pressure. 30-50 mL of ice water was slowly added with stirring, resulting in the precipitation of a solid. The mixture was stirred under ice bath conditions for half an hour, filtered, and the filter cake was dried under vacuum to obtain a relatively pure intermediate product, a white powder of 227.6 mg, with a yield of 64%. This intermediate can be used directly in the next step without further purification.

[0144] (2) Synthesis of 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile.

[0145]

[0146] A suspension of 2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-onitrile (220 mg, 1.17 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (126 mg, 1.17 mmol), and K₂CO₃ (0.41 g, 2.93 mmol) in dry DMF (10 mL) was stirred overnight (18 h) at 100 °C. The reaction mixture was brought to room temperature, diluted with water (30 mL), and the product was extracted into ethyl acetate (2 × 25 mL). The combined ethyl acetate layers were washed with brine (30 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude substance was purified by column chromatography (3:97 (2 M NH₃ in MeOH):CH₂Cl₂) to give the title compound (221 mg, 73%) as a white solid.

[0147] (3) Synthesis of N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide.

[0148]

[0149] It was prepared using 2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile as a raw material, according to the method of Example 2.

[0150] 1 H NMR(500MHz,Chloroform-d)δ7.75–7.70(m,2H),7.09–7.01(m,3H),6.87(d,J=8.9Hz,1H),6.83(dt,J=1.8,0.9Hz,1H),6.06(t,J=7.3 Hz,1H),4.24(dt,J=7.3,0.9Hz,2H),3.80(s,3H),3.62(s,2H),3.55(t,J=5.4Hz,2H),2.80(t,J=5.4Hz,2H),2.36(s,6H),1.39(s,6H).

[0151] MS(ESI) m / z 434.1 [M+H] +

[0152] Example 6 Preparation of N-((4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-2-fluoro-4-methoxybenzenesulfonamide.

[0153] (1) Synthesis of 2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile.

[0154]

[0155] Potassium carbonate (0.65 g, 4.65 mmol) was added to 10 mL of dried DMF (N,N-dimethylformamide), followed by the addition of 4-amino-3-hydroxybenzonitrile (250 mg, 1.86 mmol). The mixture was stirred at room temperature for 1 h until completely dissolved. Under ice bath conditions, a DMF solution of 1,2-dibromo-2-methylpropane (401 mg, 1.86 mmol) was slowly added dropwise. After half an hour, the reaction mixture was slowly brought to room temperature and reacted at 90 °C for 12 h. After cooling, some solvent was distilled off under reduced pressure. 30-50 mL of ice water was slowly added with stirring, resulting in the precipitation of a solid. The mixture was stirred under ice bath conditions for half an hour, filtered, and the filter cake was dried under vacuum to obtain a relatively pure intermediate product, a white powder of 227.6 mg, with a yield of 64%. This intermediate can be used directly in the next step without further purification.

[0156] (2) Synthesis of 4-(2-chloroethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxynitrile.

[0157]

[0158] The title compound was prepared from 2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile as a starting material, according to the method of Example 4.

[0159] (3) Synthesis of N-((4-(2-chloroethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide.

[0160]

[0161] The title compound was prepared from 4-(2-chloroethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxynitrile according to the method of Example 2.

[0162] (4) Preparation of N-((4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-2-fluoro-4-methoxybenzenesulfonamide.

[0163]

[0164] The title compound was prepared from N-((4-(2-chloroethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)methyl)-4-methoxybenzenesulfonamide according to the method of Example 4.

[0165] 1 H NMR(500MHz,Chloroform-d)δ7.80(dd,J=9.3,4.6Hz,1H),7.08–7.05(m,1H),6.90–6.85 (m,3H),6.84–6.83(m,1H),6.34(t,J=7.3Hz,1H),4.27(dt,J=7.2,0.9Hz,2H),3.78(s,3 H),3.62(s,2H),3.55(t,J=5.0Hz,2H),3.45(dt,J=6.6,2.7Hz,1H),2.82(td,J=5.0,2.7 Hz,2H),2.49(dp,J=6.6,4.4Hz,1H),1.39(s,6H),0.85–0.78(m,2H),0.60–0.53(m,2H).

[0166] MS(ESI) m / z 464.2 [M+H] +

[0167] Example 7 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0168] (1) Synthesis of 4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazacyclohexane-7-amine.

[0169]

[0170] The title compound was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine and 1,2-dichloroethane as starting materials, following the synthetic method for 4-(2-chloroethyl)-2,2-dimethyl-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine described in Example 4.

[0171]

[0172] The title compound was prepared from 4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazacyclohexane-7-amine as a starting material, and benzenesulfonyl chloride and cyclopropaneamine as key intermediates, according to the method in Example 4.

[0173] 1 H NMR(500MHz,Chloroform-d)δ8.76(s,1H),7.95(tt,J=7.3,1.3Hz,1H),7.74–7.68(m,2 H),7.45–7.38(m,2H),7.21(dd,J=8.8,2.2Hz,1H),6.81(d,J=8.7Hz,1H),6.55(d,J=2. 1Hz,1H),4.25–4.19(m,2H),4.11(dt,J=6.6,2.7Hz,1H),3.56–3.48(m,4H),2.85(td,J =5.7,2.7Hz,2H),2.54–2.46(m,1H),0.87–0.79(m,2H),0.60–0.52(m,2H).MS(ESI)m / z 374.1[M+H] +

[0174] Example 8 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methylbenzenesulfonamide.

[0175] (1) Synthesis of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methylbenzenesulfonamide.

[0176]

[0177] The title compound was prepared using 4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazacyclohexane-7-amine as a starting material and p-methylbenzenesulfonyl chloride as a key intermediate, according to the method of Example 4.

[0178] 1 H NMR(500MHz,Chloroform-d)δ8.73(s,1H),7.72–7.66(m,2H),7.33(dq,J=8.6 ,0.9Hz,2H),7.22(dd,J=8.9,2.1Hz,1H),6.82(d,J=8.8Hz,1H),6.54(d,J=2. 2Hz,1H),4.24–4.18(m,2H),3.54–3.42(m,5H),2.82(td,J=5.5,2.7Hz,2H),2 .49(dp,J=6.6,4.4Hz,1H),2.39(s,3H),0.85–0.79(m,2H),0.60–0.53(m,2H).

[0179] MS(ESI) m / z 388.2 [M+H]+

[0180] Example 9 Preparation of N-(4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0181] (1) Synthesis of N,N-dimethyl-2-(7-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethane-1-amine

[0182]

[0183] A suspension of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (250 mg, 1.39 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (150.6 mg, 1.39 mmol), and K₂CO₃ (0.46 g, 3.48 mmol) in dry DMF (10 mL) was stirred overnight (18 h). The reaction mixture was brought to room temperature, diluted with water (30 mL), and the product was extracted into ethyl acetate (2 × 35 mL). The combined ethyl acetate layers were washed with brine (50 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude substance was purified by column chromatography (3:97 (2 M NH₃ in MeOH):CH₂Cl₂) to give the title compound (265.46 mg, 76%) as a yellow solid.

[0184] (2) Synthesis of N-(4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0185]

[0186] The title compound was prepared using N,N-dimethyl-2-(7-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethane-1-amine as a starting material and p-methoxybenzenesulfonyl chloride as a key intermediate, according to the method of Example 1.

[0187] 1H NMR(500MHz,Chloroform-d)δ8.83(s,1H),7.62–7.56(m,2H),7.21(dd,J=8.8,2.2Hz,1H),7.07–7.01(m,2H),6.81(d,J= 8.8Hz,1H),6.54(d,J=2.1Hz,1H),4.24–4.18(m,2H),3.80(s,3H),3.55–3.46(m,4H),2.79(t,J=6.0Hz,2H),2.36(s,6H).

[0188] MS(ESI) m / z 392.2 [M+H] +

[0189] Example 10 Preparation of N-(4-(2-aminoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0190] (1) Synthesis of 2-(7-bromo-2,3-dihydro-4H-benzo[B][1,4]oxazin-4-yl)ethylamine.

[0191]

[0192] At 0 °C, 7-bromo-3,4-dihydro-2H-1,4-benzoxazine (1 g, 4.67 mmol) and NaH (0.56 g, 14 mmol, in 60% oil solution) were added to dry DMF (10 mL), followed by 2-chloroethylamine hydrochloride (542 mg, 4.67 mmol), and the mixture was stirred for 1 h. The reaction mixture was heated to 90 °C and reacted for another 1 h. After cooling to room temperature, the mixture was diluted with water (30 mL), and the product was extracted into ethyl acetate (2 × 35 mL). The combined ethyl acetate layers were washed with brine (50 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude substance was purified by column chromatography (3:97 (2 M NH₃ in MeOH):CH₂Cl₂) to give the title compound (936.8 mg, 78%) as a gray solid.

[0193] (2) Synthesis of N-(4-(2-aminoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0194]

[0195] 2-(7-bromo-2,3-dihydro-4H-benzo[B][1,4]oxazin-4-yl)ethylamine (900 mg, 3.5 mmol) was added to CuI (0.67 g, 3.5 mmol), potassium carbonate (1.5 g, 10.5 mmol) was added to DCM (20 mL), and 4-methoxybenzenesulfonamide (0.72 g, 3.85 mmol) was added. The reaction was carried out at room temperature for 16 h. The reaction was monitored by TLC until completion. The mixture was filtered, rotary evaporated under reduced pressure, and column chromatography was performed to give 1.02 g of white solid, yield 80%.

[0196] 1 H NMR(500MHz,Chloroform-d)δ8.84(s,1H),7.61–7.55(m,2H),7.22(dd,J=8.8,2.2Hz,1H),7.08–7.02(m,2H),6.81(d,J=8.8Hz,1H),6.54(d ,J=2.2Hz,1H),4.24–4.18(m,2H),3.80(s,3H),3.52–3.46(m,2H),3.35(t,J=5.1Hz,2H),2.90(tt,J=6.8,5.1Hz,2H),1.61(t,J=6.8Hz,2H).

[0197] MS(ESI) m / z 364.2 [M+H] +

[0198] Example 11 Preparation of N-(4-(2-aminopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide.

[0199] (1) Synthesis of 1-(7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazacyclohexane-4-yl)propyl-2-amine.

[0200]

[0201] 1-(7-bromo-3,4-dihydro-2H-1,4-benzoxazine and 1-chloropropane-2-amine hydrochloride were used as starting materials to prepare 1-(7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazacyclohexane-4-yl)prop-2-amine according to the method of Example 10.

[0202] (2) Synthesis of N-(4-(2-aminopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0203]

[0204] It was prepared using 1-(7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazacyclohexane-4-yl)prop-2-amine and p-methoxybenzenesulfonamide as raw materials, according to the method of Example 10.

[0205] 1 H NMR(500MHz,Chloroform-d)δ8.84(s,1H),7.58(d,J=9.3Hz,2H),7.22(dd,J= 8.8,2.2Hz,1H),7.08–7.04(m,2H),6.76(d,J=8.8Hz,1H),6.54(d,J=2.2Hz,1H ),4.22(dd,J=5.1,4.5Hz,2H),3.80(s,3H),3.55–3.43(m,3H),3.27(dd,J=12. 5,3.8Hz,1H),3.18–3.09(m,1H),1.92(d,J=6.1Hz,2H),1.13(d,J=5.7Hz,3H).

[0206] MS(ESI) m / z 378.2 [M+H] +

[0207] Example 12 Preparation of 4-methoxy-N-(4-(((1-methylpyrrolidone-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0208]

[0209] It was prepared according to the method of Example 1, using 2-(chloromethyl)-1-methyl-pyrrolidine hydrochloride and 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials.

[0210] 1H NMR(500MHz,Chloroform-d)δ8.86(s,1H),7.62–7.56(m,2H),7.22(dd,J=8.8,2.2Hz,1H),7.08–7.0 2(m,2H),6.74(d,J=8.7Hz,1H),6.54(d,J=2.2Hz,1H),4.27–4.17(m,2H),3.80(s,3H),3.66(dd,J=10 .8,4.6Hz,1H),3.60–3.46(m,2H),3.41(dd,J=10.8,4.6Hz,1H),2.97–2.84(m,1H),2.81–2.73(m,1H ),2.58–2.47(m,1H),2.33(d,J=1.4Hz,3H),2.05–1.92(m,1H),1.91–1.76(m,1H),1.78–1.66(m,2H).

[0211] MS(ESI) m / z 418.2 [M+H] +

[0212] Example 13 Preparation of 4-methoxy-N-(4-(2-(1-methylpyrrolidone-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0213]

[0214] It was prepared using N-(2-chloroethyl)-pyrrolidine hydrochloride and 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials, according to the method of Example 1.

[0215] 1 H NMR(500MHz,Chloroform-d)δ8.84(s,1H),7.60–7.56(m,2H),7.22(dd,J=8.9,2.1 Hz,1H),7.07–7.04(m,2H),6.82(d,J=8.8Hz,1H),6.31(d,J=2.1Hz,1H),4.24–4.1 9(m,2H),3.80(s,3H),3.49–3.38(m,3H),3.35–3.27(m,1H),2.92–2.83(m,2H),2. 23(d,J=1.4Hz,3H),2.08–2.00(m,2H),1.97–1.90(m,1H),1.85–1.75(m,2H),1.72–

[0216] 1.64(m,2H).

[0217] MS(ESI) m / z 432.2 [M+H] +

[0218] Example 14 Preparation of N-(4-(2-(diethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide.

[0219]

[0220] It was prepared according to the method of Example 1, using N,N-diethylchloroethylamine hydrochloride and 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials. 1 H NMR(500MHz,DMSO-d6)δ9.88(s,1H),7.65–7.60(m,2H),7.22(dd,J=8.8,2.2Hz,1H),7.08–7.03(m,2H),6.83(d,J=8.8Hz,1H),6.33(d,J=2.2Hz,1H ),4.19(t,J=5.0Hz,2H),3.78(s,3H),3.55–3.44(m,2H),3.38(t,J=5.2Hz ,2H),2.65(t,J=5.3Hz,2H),2.55(q,J=6.9Hz,4H),0.97(t,J=6.9Hz,6H).

[0221] MS(ESI) m / z 420.1 [M+H] +

[0222] Example 15 Preparation of N-(4-(2-(bis(2-fluoroethyl)amino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0223]

[0224] It was prepared according to the method of Example 1, using 2-chloro-N,N-bis(2-fluoroethyl)ethylamine and 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials. 1H NMR(500MHz,Chloroform-d)δ7.67–7.63(m,2H),7.10(dd,J=8.8,2.2Hz,1H),6.98–6.94(m,3H),6.82(d,J=2.2Hz,1 H),4.63(dt,J=48.1,4.5Hz,4H),4.28–4.17(m,2H),3.78(s,3H),3.48–3.36(m,4H),2.95–2.83(m,6H).MS(ESI)m / z 456.2[M+H]+

[0225] Example 16 Preparation of 4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0226] (1) Preparation of tert-butyl(2-(7-((4-methoxyphenyl)sulfonamido)-2,3-dihydro-4H-benzo[1,4]oxazine-4-yl)ethyl)methylcarbamate.

[0227]

[0228] Tert-butyl(2-(7-((4-methoxyphenyl)sulfonamido)-2,3-dihydro-4H-benzo[1,4]oxazine-4-yl)ethyl)methylcarbamate was prepared using (2-chloroethyl)(methyl)carbamate and 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials according to the method of Example 1.

[0229] (2) Synthesis of 4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0230]

[0231] 80 mg (0.17 mmol) of tert-butyl(2-(7-((4-methoxyphenyl)sulfonamido)-2,3-dihydro-4H-benzo[1,4]oxazin-4-yl)ethyl)methylcarbamate was added to 10 mL of DCM. 2 mL of trifluoroacetic acid was added dropwise under nitrogen. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction mixture was poured into a flask containing 10 mL of saturated NaHCO3 solution and extracted with DCM (10 mL * 3). The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a yellow oil. 10 mL of n-hexane was added and stirred for 5 h. A white solid was washed off and filtered to obtain 41 mg of white solid, which was 4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)benzenesulfonamide.

[0232] 1 H NMR(500MHz,Chloroform-d)δ7.61–7.54(m,2H),7.22(dd,J=8.8,2.2Hz,1H),7.08–7.03(m,2H),6.78(d,J=8.8Hz,1H),6.43(d,J=2.2Hz,1H),4 .23–4.18(m,2H),3.80(s,3H),3.54–3.48(m,2H),3.43(t,J=5.3Hz,2H) ,2.87(td,J=5.3,4.1Hz,2H),2.50(d,J=5.0Hz,3H),1.90–1.83(m,1H).

[0233] MS(ESI) m / z 378.1 [M+H] +

[0234] Example 17 Preparation of N-(4-(2-(diisopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide.

[0235]

[0236] It was prepared using diisopropylaminoethyl chloride hydrochloride and 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials, according to the method of Example 1. 1H NMR(500MHz,Chloroform-d)δ8.81(s,1H),7.81–7.76(m,2H),7.22(dd,J=8.8,2.2Hz,1H),7.05–7.00(m,2H),6.95(d,J=8.8Hz,1H),6.82(d,J =2.2Hz,1H),4.25–4.18(m,2H),3.78(s,3H),3.42(dt,J=20.5,5.0Hz,4 H),3.10–3.00(m,2H),2.85(t,J=5.0Hz,2H),1.08(s,6H),1.07(s,6H).

[0237] MS(ESI)m / z 448.2[M+H]+

[0238] Example 18 Preparation of N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0239] (1) Synthesis of N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0240]

[0241] N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide was prepared using 1,2-dichloroethane and 7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide as starting materials according to the method of Example 1.

[0242] (2) Synthesis of N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0243]

[0244] Under nitrogen atmosphere, N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide (100 mg, 0.261 mmol), tert-butylamine (95 mg, 1.3 mmol), and methanol (5 mL) were added to a sealed tube and heated in an oil bath at 80 °C. After 24 hours, the tube was cooled, and the reactants were rotary evaporated under reduced pressure. 30 mL of saturated sodium bicarbonate aqueous solution was added, and the resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a yellow oil, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to a white solid of 52.4 mg, yield 47.8%.

[0245] 1 H NMR(500MHz,DMSO-d6)δ9.89(s,1H),7.81–7.75(m,2H),7.22(dd,J=8.9,2.1Hz,1H),7.09–6.99(m,3H),6.89(d,J=2.2 Hz,1H),4.25–4.18(m,2H),3.76(s,3H),3.58(t,J=5.4Hz,1H),3.46–3.38(m,4H),2.91(q,J=5.3Hz,2H),1.12(s,9H).

[0246] MS(ESI)m / z 420.2[M+H]+

[0247] Example 19 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide.

[0248]

[0249] It was prepared using N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide and cyclopropane as starting materials, according to the method of Example 18.

[0250] 1H NMR(500MHz,Chloroform-d)δ8.83(s,1H),7.82–7.76(m,2H),7.21(dd,J=8.8,2.2Hz,1H), 7.05–7.00(m,2H),6.95(d,J=8.8Hz,1H),6.82(d,J=2.2Hz,1H),4.24–4.19(m,2H),3.78(s, 3H),3.69–3.63(m,1H),3.48–3.42(m,2H),3.37(t,J=5.5Hz,2H),2.79(td,J=5.5,2.7Hz,2 H), 2.59 (dp, J=6.6, 4.4Hz, 1H), 0.80 (dd, J=10.6, 4.5Hz, 2H), 0.55 (dd, J=10.6, 4.4Hz, 2H).

[0251] MS(ESI)m / z 404.2[M+H]+

[0252] Example 20 Preparation of N-(4-(2-((2,2-difluoroethyl)amino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide.

[0253]

[0254] It was prepared using N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide and 2,2-difluoroethylamine as starting materials, according to the method of Example 18.

[0255] 1 H NMR(500MHz,Chloroform-d)δ8.77(s,1H),7.72–7.66(m,2H),7.15(dd,J=8.7,2.1Hz,1H),7.08–7.03(m,2H),6.85(d,J=8.7Hz,1H),6.75(d,J=2.1Hz,1 H),6.23(tt,J=54.9,3.4Hz,1H),4.23–4.15(m,2H),3.78(s,3H),3.47–3.4 2(m,2H),3.39–3.29(m,3H),3.27–3.16(m,2H),2.99(td,J=5.6,3.7Hz,2H).

[0256] MS(ESI)m / z 428.2[M+H]+

[0257] Example 21 Preparation of 4-methoxy-N-(4-(piperidin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0258]

[0259] It was prepared using N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide as the starting material and tert-butyl 2-(chloromethyl)-1-piperidinecarboxylate as the key intermediate, according to the method of Example 16.

[0260] 1 H NMR(500MHz,Chloroform-d)δ8.84(s,1H),7.61–7.55(m,2H),7.22(dd,J=8.8,2.2Hz,1H) ,7.08–7.02(m,2H),6.76(d,J=8.8Hz,1H),6.54(d,J=2.2Hz,1H),4.27–4.17(m,2H),3.80( s,3H),3.65(dd,J=11.9,3.7Hz,1H),3.55–3.44(m,2H),3.40(dd,J=11.9,3.9Hz,1H),3.13 –3.05(m,1H),2.93–2.84(m,2H),2.73–2.64(m,1H),1.84–1.74(m,1H),1.69–1.40(m,5H).

[0261] MS(ESI)m / z 418.2[M+H]+

[0262] Example 22 Preparation of 4-methoxy-N-(4-(((1-methylpiperidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzenesulfonamide.

[0263]

[0264] It was prepared according to the method of Example 1, using 2-chloromethyl-1-methylpiperidine hydrochloride and 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as starting materials. 1H NMR(500MHz,Chloroform-d)δ7.58–7.53(m,2H),7.18(dd,J=8.6,2.2Hz,1H),7.03–6.98(m, 2H),6.91(d,J=8.6Hz,1H),6.28(d,J=2.3Hz,1H),4.25–4.19(m,2H),3.75(s,3H),3.66(dd,J =10.8,5.3Hz,1H),3.59–3.48(m,2H),3.41(dd,J=10.8,5.3Hz,1H),2.78–2.70(m,1H),2.66– 2.58(m,1H),2.45–2.38(m,1H),2.31(d,J=1.6Hz,3H),1.94–1.84(m,1H),1.69–1.41(m,5H).

[0265] MS(ESI)m / z 432.2[M+H]+

[0266] Example 23 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-hydroxybenzenesulfonamide.

[0267]

[0268] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide (100 mg, 0.25 mmol, Example 19) was added to DCM (10 mL) under nitrogen protection. BBr3 (125 mg, 0.5 mmol) in DCM (5 mL) was added dropwise and stirred for 2 h. The reaction was detected by TLC and the reaction was completed. 10 mL of saturated saline was added and extracted with DCM (10 x 3 mL). The organic phases were combined, and the mixture was purified by rotary evaporation under reduced pressure and column chromatography to obtain 91 mg of white solid.

[0269] 1H NMR(300MHz,DMSO-d6)δ10.06(s,1H),9.66(s,1H),7.64–7.56(m,2H),7.12(dd,J=8.6, 2.3Hz,1H),6.89(d,J=8.7Hz,1H),6.83–6.75(m,2H),6.53(d,J=2.4Hz,1H),4.96(dt,J =6.7,2.7Hz,1H),4.16–4.08(m,2H),3.58(dd,J=5.4,4.5Hz,2H),3.31(t,J=5.5Hz,2H) ,2.73(td,J=5.5,2.7Hz,2H),2.57–2.45(m,1H),0.89–0.79(m,2H),0.66–0.56(m,2H).

[0270] MS(ESI)m / z 390.2[M+H]+

[0271] Example 24 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-fluorobenzenesulfonamide.

[0272]

[0273] It was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-fluorobenzenesulfonyl chloride as the key intermediate, according to the method of Example 4. 1 H NMR(500MHz,Chloroform-d)δ7.96–7.88(m,2H),7.44–7.35(m,2H),7.31(dd,J=8.5,2.1Hz,1H),6.77(d,J=8.5Hz,1H),6.60(d,J=2.1Hz, 1H),4.49–4.43(m,1H),4.33–4.27(m,2H),3.58–3.49(m,4H),2.74–2 .69(m,2H),2.49–2.41(m,1H),0.83–0.76(m,2H),0.58–0.51(m,2H).

[0274] MS(ESI)m / z 392.1[M+H]+

[0275] Example 25 Preparation of 4-cyano-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0276]

[0277] It was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-4-cyanobenzenesulfonyl chloride as the key intermediate, according to the method of Example 4. 1 H NMR(500MHz,Chloroform-d)δ8.72(s,1H),8.02–7.96(m,2H),7.87–7.81(m,2H),7.31(dd,J=8.4,2.4Hz,1H) ,6.72(d,J=8.4Hz,1H),6.49(d,J=2.4Hz,1H),4.22–4.16(m,3H),3.57–3.51(m,4H),2.82–2.76(m,2H),2.61–

[0278] 2.54(m,1H),0.86–0.80(m,2H),0.63–0.56(m,2H).

[0279] MS(ESI)m / z 399.1[M+H]+

[0280] Example 26 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-ethylbenzenesulfonamide.

[0281]

[0282] It was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-4-ethylbenzenesulfonyl chloride as the key intermediate, according to the method of Example 4.

[0283] 1 H NMR(500MHz,Chloroform-d)δ8.79(s,1H),7.81–7.77(m,2H),7.42–7.31(m,3H),6.94 (d,J=8.5Hz,1H),6.61(d,J=2.3Hz,1H),4.55–4.50(m,1H),4.33–4.26(m,2H),3.70(t, J=5.5Hz,2H),3.63–3.55(m,2H),2.90(td,J=5.5,2.7Hz,2H),2.71–2.64(m,2H),2.51 –2.44(m,1H),1.22(t,J=7.2Hz,3H),0.88–0.79(m,2H),0.60–0.53(m,2H).MS(ESI)m / z 402.1[M+H]+

[0284] Example 27 Preparation of 4-chloro-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0285]

[0286] It was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-4-chlorobenzenesulfonyl chloride as the key intermediate, according to the method of Example 4. 1 H NMR(500MHz,Chloroform-d)δ7.73–7.68(m,2H),7.48–7.42(m,3H),6.95(d,J=8.6Hz,1H),6.71(d,J=2.1Hz,1H),4.33–4.29(m, 1H),4.19–4.15(m,2H),3.51–3.46(m,4H),2.85(td,J=5.5,2.6Hz,2H),2.55–2.48(m,1H),0.87–0.80(m,2H),0.61–0.55(m,2H).

[0287] MS(ESI)m / z 408.1[M+H]+

[0288] Example 28 Preparation of 4-cyclopropyl-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0289]

[0290] It was prepared according to the method of Example 4, using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-4-cyclopropylbenzene-1-sulfonyl chloride as the key intermediate.

[0291] 1 H NMR(500MHz,Chloroform-d)δ8.73(s,1H),7.84–7.77(m,2H),7.43–7.34(m,3H),6.93(d,J=8.5Hz,1H),6.65(d,J=2.1Hz,1H),4.30–4.21(m, 3H),3.55(q,J=5.1Hz,4H),2.87–2.83(m,2H),2.63–2.48(m,2H),1.88 –1.80(m,2H),1.64–1.57(m,2H),0.86–0.80(m,2H),0.64–0.55(m,2H).

[0292] MS(ESI)m / z 414.1[M+H]+

[0293] Example 29 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-2,3-dihydrobenzofuran-5-sulfonamide.

[0294]

[0295] It was prepared according to the method of Example 4, using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-2,3-dihydrobenzofuran-5-sulfonyl chloride as the key intermediate.

[0296] 1 H NMR(500MHz,Chloroform-d)δ8.63(s,1H),7.81(dt,J=2.1,1.0Hz,1H),7.72(dd,J=9.4,2.1Hz,1H ),7.34–7.28(m,1H),6.94(d,J=9.2Hz,1H),6.89(d,J=8.5Hz,1H),6.61(d,J=2.1Hz,1H),4.46(t, J=4.2Hz,2H),4.23–4.17(m,2H),4.16(dt,J=6.6,2.9Hz,1H),3.54–3.45(m,4H),3.14(td,J=4.1, 0.9Hz,2H),2.82(td,J=5.5,2.8Hz,2H),2.54–2.46(m,1H),0.86–0.78(m,2H),0.61–0.52(m,2H).

[0297] MS(ESI)m / z 416.1[M+H]+

[0298] Example 30 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-(dimethylamino)benzenesulfonamide.

[0299]

[0300] Using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-4-(dimethylamino)benzenesulfonyl chloride as the key intermediate, the following preparation was carried out according to the method of Example 4.

[0301] 1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),7.70–7.64(m,2H),7.31–7.26(m,1H),7.07–7.01(m,2H),6.85(d,J=8.4Hz,1H),6.56(d,J=2.4Hz,1H), 4.23–4.17(m,2H),4.12–4.08(m,1H),3.55–3.46(m,4H),2.92(s,6H),2. 85–2.79(m,2H),2.53–2.44(m,1H),0.86–0.78(m,2H),0.61–0.52(m,2H).

[0302] MS(ESI)m / z 417.1[M+H]+

[0303] Example 31 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxy-3-methylbenzenesulfonamide.

[0304]

[0305] It was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and p-4-methoxy-3-methylbenzenesulfonyl chloride as the key intermediate, according to the method of Example 4.

[0306] 1 H NMR(500MHz,Chloroform-d)δ7.74(d,J=2.1Hz,1H),7.66(dd,J=9.5,2.2Hz,1H),7.24 (dd,J=8.7,2.1Hz,1H),6.96(d,J=9.4Hz,1H),6.79(d,J=8.8Hz,1H),6.55(d,J=2.2Hz, 1H),4.28–4.22(m,2H),4.14–4.08(m,1H),3.82(s,3H),3.55–3.49(m,4H),2.86(td,J= 5.6,2.8Hz,2H),2.56–2.48(m,1H),2.22(s,3H),0.86–0.78(m,2H),0.60–0.52(m,2H).

[0307] MS(ESI)m / z 418.1[M+H]+

[0308] Example 32 Preparation of 4-(N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)aminosulfonyl)benzamide.

[0309]

[0310] At 0 °C, 4-cyano-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)benzenesulfonamide (100 mg, 0.25 mmol, Example 25) was added to 10 mL of methanol, sodium borohydride (19 mg, 0.5 mmol) was added, and the mixture was stirred for 2 h. The reaction was monitored by TLC until it was complete. Saturated sodium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and subjected to column chromatography to give 67 mg of a white compound.

[0311] 1 H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.11–8.05(m,2H),7.92–7.86(m,2H),7.2 4(dd,J=8.8,2.2Hz,1H),6.90(s,2H),6.84(d,J=8.7Hz,1H),6.34(d,J=2.3Hz,1 H),4.25–4.19(m,2H),4.02–3.96(m,1H),3.51–3.46(m,2H),3.36(t,J=5.5Hz,2 H),2.79–2.73(m,2H),2.54–2.46(m,1H),0.88–0.80(m,2H),0.66–0.57(m,2H).

[0312] MS(ESI)m / z 417.1[M+H]+

[0313] Example 33 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzo[d][1,3]m-dioxacyclopentene-5-sulfonamide.

[0314]

[0315] It was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and 1,3-benzodioxo-5-sulfonyl chloride as the key intermediate, according to the method of Example 4.

[0316] 1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.65(dd,J=9.4,2.1Hz,1H),7.34(d,J=2 .2Hz,1H),7.26(dd,J=8.6,2.4Hz,1H),7.05(d,J=9.3Hz,1H),6.88(d,J=8.6Hz,1H) ,6.57(d,J=2.4Hz,1H),5.93(s,2H),4.22–4.16(m,2H),3.54–3.46(m,4H),3.14–3. 08(m,1H),2.87–2.81(m,2H),2.51(dp,J=6.6,4.7Hz,1H),0.84–0.76(m,2H),0.59–

[0317] 0.51(m,2H).

[0318] MS(ESI)m / z 418.1[M+H]+

[0319] Example 34 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-fluoro-4-methoxybenzenesulfonamide.

[0320]

[0321] It was prepared according to the method of Example 4, using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and 3-fluoro-4-methoxybenzenesulfonyl chloride as the key intermediate.

[0322] 1 H NMR(500MHz,Chloroform-d)δ8.65(s,1H),7.70–7.63(m,2H),7.20(dd,J=8.9,2.1Hz,1H),7.10–7.02(m,1H),6.81(d,J=8.8Hz,1H),6.55(d,J=2.2Hz, 1H),4.23–4.17(m,2H),3.90(s,3H),3.54–3.45(m,4H),3.09–3.03(m,1H), 2.84–2.78(m,2H),2.56–2.48(m,1H),0.86–0.78(m,2H),0.60–0.52(m,2H).

[0323] MS(ESI)m / z 422.1[M+H]+

[0324] Example 35 Preparation of N-(4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-2-fluoro-4-methoxybenzenesulfonamide.

[0325]

[0326] It was prepared using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and 2-fluoro-4-methoxybenzenesulfonyl chloride as the key intermediate, according to the method of Example 1.

[0327] 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.90–7.83(m,1H),7.21(dd,J=8.7,2.3Hz,1H),6.91–6.85(m,2H),6.82(d,J= 8.7Hz,1H),6.56(d,J=2.2Hz,1H),4.23–4.17(m,2H),3.78(s,3H),3.55–3.47(m,4H),2.79(t,J=6.1Hz,2H),2.36(s,6H).

[0328] MS(ESI)m / z 410.1[M+H]+

[0329] Example 36 Preparation of 2-fluoro-4-methoxy-N-(4-(((1-methylpyrrolidone-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0330]

[0331] It was prepared according to the method of Example 12, using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and 2-fluoro-4-methoxybenzenesulfonyl chloride and 2-(chloromethyl)-1-methyl-pyrrolidine hydrochloride as key intermediates.

[0332] 1H NMR(500MHz,Chloroform-d)δ8.72(s,1H),7.90–7.83(m,1H),7.20(dd,J=8.7,2.3Hz,1H),6.92–6.8 6(m,2H),6.74(d,J=8.7Hz,1H),6.55(d,J=2.4Hz,1H),4.26–4.18(m,2H),3.78(s,3H),3.64(dd,J=10 .6,4.5Hz,1H),3.58–3.47(m,2H),3.40(dd,J=10.8,4.6Hz,1H),3.00–2.92(m,1H),2.79–2.71(m,1H ),2.56–2.48(m,1H),2.33(d,J=1.4Hz,3H),2.03–1.93(m,1H),1.87–1.77(m,1H),1.77–1.67(m,2H).

[0333] MS(ESI)m / z 436.2[M+H]+

[0334] Example 37 Preparation of 2-fluoro-4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0335]

[0336] It was prepared according to the method of Example 16, using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and 2-fluoro-4-methoxybenzenesulfonyl chloride and (2-chloroethyl)(methyl)carbamate tert-butyl ester as key intermediates.

[0337] 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.92–7.84(m,1H),7.22(dd,J=8.8,2.2Hz,1H),6.91–6.85(m,2H),6.82(d,J=8.9Hz,1H),6.54( d,J=2.2Hz,1H),4.25–4.19(m,2H),3.78(s,3H),3.53–3.46(m,4H),2.85(td,J=5.4,4.0Hz,2H),2.50(d,J=5.0Hz,3H),1.95–1.87(m,1H).

[0338] MS(ESI)m / z 396.1[M+H]+

[0339] Example 38 Preparation of N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-2-fluoro-4-methoxybenzenesulfonamide.

[0340]

[0341] It was prepared according to the method of Example 18, using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material and 2-fluoro-4-methoxybenzenesulfonyl chloride, 1,2-dichloroethane, and tert-butylamine as key intermediates.

[0342] 1 H NMR(500MHz,Chloroform-d)δ8.70(s,1H),7.90–7.83(m,1H),7.22(dd,J=8.8,2.2Hz,1H),6.92–6.86(m,2H),6.82(d,J=8.8Hz,1H), 6.54(d,J=2.2Hz,1H),4.24–4.18(m,2H),3.78(s,3H),3.56–3.46(m,4H),2.94(q,J=5.3Hz,2H),2.61(t,J=5.4Hz,1H),1.15(s,9H).

[0343] MS(ESI)m / z 438.2[M+H]+

[0344] Example 39 Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide.

[0345]

[0346] Using 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as the starting material, 2-fluoro-4-methoxybenzenesulfonyl chloride was prepared according to the method of Example 4.

[0347] 1H NMR (500MHz, DMSO-d6) δ10.09 (s, 1H), 7.82 (dd, J = 9.0, 4.7Hz, 1H), 7.22 (dd, J = 8. 8,2.2Hz,1H),6.99–6.86(m,3H),6.38(d,J=2.2Hz,1H),4.24–4.18(m,2H),3.98( dt,J=6.6,2.7Hz,1H),3.77(s,3H),3.51–3.46(m,2H),3.34(t,J=5.5Hz,2H),2.7 7(td,J=5.6,2.8Hz,2H),2.55–2.47(m,1H),0.88–0.80(m,2H),0.65–0.57(m,2H).

[0348] MS(ESI)m / z 422.1[M+H]+

[0349] Example 40 Preparation of 4-amino-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide.

[0350]

[0351] (1) Synthesis of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)-4-nitrobenzenesulfonamide.

[0352] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine and 4-nitrobenzenesulfonyl chloride were prepared using 7-nitro-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)-4-nitrobenzenesulfonamide as starting materials according to the method in Example 4.

[0353] (2) Synthesis of 4-amino-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide

[0354]

[0355] In 8 mL of solvent (EtOH:H2O = 3:1), N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-4-nitrobenzenesulfonamide (65 mg, 0.155 mmol) was added with stirring at room temperature. Ammonium chloride (10 mg, 0.185 mmol) and iron powder (26 mg, 0.465 mmol) were then added, and the mixture was refluxed at 90 °C for 1-2 h. After the reaction was detected by thin-layer chromatography, excess iron powder was filtered off while hot. After the reaction solution cooled, the solvent was evaporated under reduced pressure. The residual solid was adjusted to pH 10 with an aqueous solution of potassium carbonate, resulting in solid precipitation. The solid was filtered, and the filter cake was washed with cooling water, vacuum dried, and purified by column chromatography to obtain 42 mg of white powder, with a yield of 74%. 1 H NMR(300MHz,Chloroform-d)δ8.78(s,1H),7.50–7.40(m,2H),7.22(dd,J=8.7 ,2.1Hz,1H),6.82(d,J=8.8Hz,1H),6.58–6.44(m,3H),5.09(s,2H),4.27–4.1 7(m,2H),4.12–4.02(m,1H),3.56–3.45(m,4H),2.82(td,J=5.8,2.6Hz,2H),2 .56–2.41(m,1H),0.89–0.75(m,2H),0.56(dddd,J=8.8,7.9,4.8,0.9Hz,2H).

[0356] MS(ESI)m / z 389.2[M+H]+

[0357] Example 41 Preparation of N-((4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide.

[0358]

[0359] It was prepared using 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile as the starting material, according to the method of Example 2.

[0360] 1H NMR (300MHz, DMSO-d6) δ7.80–7.70(m,2H),7.19(t,J=7.3Hz,1H),7.13–7.03(m,3H),6.90(d,J=8.9Hz,1H),6.81(dt,J=1.7 ,0.8Hz,1H),4.30–4.18(m,4H),3.78(s,3H),3.55–3.45(m,2H),3.40(t,J=5.8Hz,2H),2.77(t,J=5.8Hz,2H),2.36(s,6H).

[0361] MS(ESI)m / z 406.2[M+H]+

[0362] Example 42 Preparation of N-((4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-2-fluoro-4-methoxybenzenesulfonamide.

[0363]

[0364] It was prepared using 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-nitrile as the starting material and 2-fluoro-4-methoxybenzenesulfonyl chloride as the key intermediate, according to the method in Example 6.

[0365] 1 H NMR(500MHz,Chloroform-d)δ7.80(dd,J=9.4,4.7Hz,1H),7.10–7.04(m,1H),6.91–6.83(m,3H),6.76–6.72(m,1H),6.34(t,J=7.3Hz,1H),4.27(dt,J=7 .2,0.9Hz,2H),4.24–4.18(m,2H),3.78(s,3H),3.54–3.42(m,5H),2.82(td, J=5.5,2.7Hz,2H),2.53–2.44(m,1H),0.86–0.77(m,2H),0.60–0.52(m,2H).

[0366] MS(ESI)m / z 436.2[M+H]+

[0367] Example 43: Detection of NaV1.5 channel inhibitory activity.

[0368] 1. Experimental Materials and Reagents

[0369]

[0370]

[0371] 2. Cell Culture

[0372] CHO hNav1.5 cell line was purchased from B'SYS GmbH. Cells were cultured in F12 (HAM) medium containing 10% FBS, 100 U / mL penicillin-streptomycin, 20 mM HEPES, and 700 μg / mL G418. Cells were cultured weekly using TrypLE. TM Express cells were passaged approximately three times and maintained at around 80% fusion.

[0373] 3 Experimental Procedures

[0374] 1.3.1 Preparation of working solution

[0375] (1) The compound was prepared by dissolving it in DMSO and the storage concentration was 10 mM.

[0376] (2) The test compound was serially diluted 3 times with DMSO.

[0377] (3) Before hNav1.5 assay, the compound (3 mM) was diluted 500-fold with extracellular fluid to prepare a working solution with a concentration of 6 μM. A 60 μM working solution was prepared by diluting the compound stock solution (10 mM) 166.67-fold. In hNav1.5 assay, 40 μL of the working solution was added to 40 μL of cell solution, thus preparing a working solution with twice the experimental concentration of the compound.

[0378] 1.3.2 Patch-clamp experiment

[0379] Recording was performed using a SyncroPatch 384i / 384 automated patch-clamp, with a hold potential set to -90 mV for 500 ms, a recording current of 20 kHz, and a filter of 10 kHz. Leakage current was measured at -120 mV. The sodium channel detection protocol consisted of an 8-s conditional voltage step to inactivation at V0.5, followed by a 2-ms hyperpolarization pulse to -120 mV, and then a 20-ms test pulse to -10 mV. The scan interval was set to 15 seconds. The maximum peak current magnitude was used to determine the hNav1.5 current amplitude. The current was recorded for 120 seconds to assess current stability. A baseline was first established for the cells using a blank control (DMSO). After the hNav1.5 current had stabilized for at least 5 minutes, an equal volume of 2× test solution was added to the liquid system to reach the final concentration. The hNav1.5 current was recorded for at least 5 minutes in the presence of each working concentration of the test compound to reach a steady state, followed by 5 scans. The hNav1.5 current suppression was detected in three independent wells at five different concentrations of the test sample. The current suppression data were fitted using Graphpad Prism 8.0 software, and the IC50 was calculated. The results are shown in the table below:

[0380]

[0381]

[0382]

[0383]

[0384]

[0385] This invention provides a concept and method for developing benzenesulfonamide compounds with sodium ion channel blocking activity. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, in: R 1 and R 2 Independently hydrogen-based, halogenated, methyl group with 1-3 fluorine-substituted groups, methoxy group with 1-3 fluorine-substituted groups, C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkoxy, C 1-6 alkylamine group, C 1-6 Alkylthio, C 3-7 Cycloalkyl, N,N-dimethylamino, methoxy, hydroxymethyl, hydroxyl, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, R is C 1-6 Alkyl groups; When R 2 In R 1 Adjacent positions can close loops to form quinary or hexacyclic heterocycles; R 3 It can be hydrogen or methyl; L represents a methylene or carbonyl group; R 4 and R 5 Independently hydrogen, C 1-4 Alkyl, C 3-4 Cycloalkyl or 1-2 fluorinated substituted ethyl groups; R 4 and R 5 They can close together to form 4-6 membered aliphatic heterocycles; R 4 Or R 5 Can be used with R 6 Ring closure forms 4-7 membered aliphatic heterocycles containing 1-2 nitrogen atoms; R 6 It can be hydrogen or methyl; n is 0 or 1; m is 1 or 2.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein, R 1 It can be hydrogen, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxyl, methoxy, hydroxymethyl, amino, N,N-dimethylamino, carbamoyl, acetyl, methyl with 1 to 3 fluorine substitutions, or methoxy with 1 to 3 fluorine substitutions. R 2 It can be hydrogen, fluorine, chlorine, methyl, or ethyl; When R 2 In R 1 When in the adjacent position, it can close the ring to form a five- or six-membered heterocycle containing 1 to 2 oxygen atoms and / or nitrogen atoms.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein, R 4 R 5 and R 6 Composition of fragments Selected from:

4. The compound of general formula (I) according to claims 1 to 3, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein the compound is: N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide, N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-4-methoxybenzenesulfonamide, N-(4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide N-(4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide, N-((4-(2-(dimethylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide, N-((4-(2-(cyclopropylamino)ethyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-2-fluoro-4-methoxybenzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methylbenzenesulfonamide, N-(4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, N-(4-(2-aminoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, N-(4-(2-aminopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, 4-Methoxy-N-(4-((1-methylpyrrolidone-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, 4-Methoxy-N-(4-(2-(1-methylpyrrolidone-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-(4-(2-(diethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, N-(4-(2-(bis(2-fluoroethyl)amino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, 4-Methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-(4-(2-(diisopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, N-(4-(2-((2,2-difluoroethyl)amino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide, 4-Methoxy-N-(4-(piperidin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, 4-Methoxy-N-(4-((1-methylpiperidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-hydroxybenzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-fluorobenzenesulfonamide, 4-Cyano-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-ethylbenzenesulfonamide, 4-Chloro-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, 4-Cyclopropyl-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-2,3-dihydrobenzofuran-5-sulfonamide N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-(dimethylamino)benzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxy-3-methylbenzenesulfonamide, 4-(N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)aminosulfonyl)benzamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzo[d][1,3]m-dioxacyclopentene-5-sulfonamide N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-fluoro-4-methoxybenzenesulfonamide, N-(4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide, 2-Fluoro-4-methoxy-N-(4-((1-methylpyrrolidone-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, 2-Fluoro-4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide, N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide, 4-Amino-N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide, N-((4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-4-methoxybenzenesulfonamide, Or N-((4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)methyl)-2-fluoro-4-methoxybenzenesulfonamide.

5. A compound of general formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, wherein, The salt is any one of inorganic acid salts, inorganic base salts, organic acid salts, or organic base salts. The inorganic acid salt is any one of hydrochloride, hydrobromide, sulfate, phosphate, and nitrate. The organic acid salt is any one of acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and ascorbate. The organic base salt is any one of arginine, benzyl benzoate, choline, diethylamine, diolamine, glycine, lysine, meglumine, ethanolamine, and aminobutanetriol.

6. A method for preparing a compound of general formula (I) as defined in claim 1, characterized in that, The method includes: (1) Preparation of the compound shown in formula (II): (2) React compound (II) with compound (III) to obtain compound (I). Wherein, the substituent is as described in claim 1. The compound obtained by formula (I) can further undergo a cyclization reaction, causing R to... 4 and R 5 Between, or R 4 and R 6 Between, or R 5 and R 6 The relationship between them.

7. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate and / or solvate thereof and one or more pharmaceutically acceptable excipients, diluents or carriers.

8. The use of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, or the pharmaceutical composition of claim 6, in the preparation of a medicament for inhibiting voltage-gated sodium ion channels.

9. The application according to claim 8, wherein the voltage-gated sodium channel is NaV1.

5.

10. The use of any one of the compounds of claims 1 to 4 or pharmaceutically acceptable salts, hydrates and / or solvates thereof, or the pharmaceutical composition of claim 6, in the preparation of a medicament for the treatment and / or prevention of arrhythmias.

11. The application according to claim 10, characterized in that, The arrhythmia mentioned is any one or a combination of several of the following: premature beats, atrial fibrillation, atrial flutter, atrial tachycardia, and paroxysmal supraventricular tachycardia.

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