Benzenesulfonamide compound as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicines, and relates to a benzenesulfonamide compound as well as a preparation method and application thereof. 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 the pharmaceutical field and relates to a benzenesulfonamide compound, its preparation method and application, specifically to a benzenesulfonamide compound of general formula (I), its preparation method, a pharmaceutical composition 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 lifestyle, such as prolonged work stress, poor dietary habits, and lack of exercise, the incidence of arrhythmia has been rising. Furthermore, people with other heart diseases, hypertension, diabetes, and other chronic conditions are also more prone to arrhythmias. Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. As of 2010, it was estimated that there were approximately 33.5 million people with atrial fibrillation worldwide.

[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] 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

[0005] The technical problem to be solved by the present invention is to address the shortcomings of the prior art. Based on the clinical research results of suxinidine sulfate in arrhythmia, atrial fibrillation and other related diseases, the present invention develops a series of benzyl sulfonamide compounds with sodium ion channel blocking activity from the structure of suxinidine sulfate itself, thereby expanding the types of drugs used to treat arrhythmia.

[0006] 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).

[0007] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0008] This invention discloses a compound of general formula (I) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof.

[0009]

[0010] in:

[0011] R 1 It is hydrogen, halogen, methyl group with 1 to 3 fluorine substitutions, methoxy group with 1 to 3 fluorine substitutions, 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, C1-6 Alkylthio, C 3-7 Cycloalkyl, N,N-dimethylamino, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl, carboxyl or amino C 1-4 Alkyl group, R is C 1-6 Alkyl groups;

[0012] R 2 Halogen, methyl group with 1-3 fluorine substitutions, methoxy group with 1-3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, where R is C 1-6 Alkyl groups;

[0013] Z is an integer in the range of 0 to 4;

[0014] Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 These can be combined to form substituted or unsubstituted five- or six-membered heterocycles; wherein the substitutions are selected from those formed by C. 1-4 Alkyl substitution;

[0015] R 3 It can be hydrogen or methyl;

[0016] R 4 and R 5 Independently hydrogen, C 1-4 Alkyl, C 3-4 Cycloalkyl or 1-2 fluorinated substituted ethyl groups;

[0017] Or, R 4 and R 5 These combine to form 4-6 membered aliphatic heterocycles;

[0018] Or, R 4 Or R 5 With R 3 These combine to form 4- to 7-membered aliphatic heterocycles containing 1 to 2 nitrogen atoms;

[0019] n is 0 or 1;

[0020] m is 1 or 2.

[0021] In some embodiments, preferably

[0022] 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-substituted groups, methoxy or aminomethyl with 1 to 3 fluorine-substituted groups;

[0023] R 2 It can be fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, or amino.

[0024] Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 They combine to form substituted or unsubstituted five- or six-membered heterocycles containing 1 to 2 oxygen atoms and / or nitrogen atoms; wherein the substitution is selected from those substituted with methyl groups.

[0025] In some embodiments, more preferably

[0026] R 1 It can be hydrogen, fluorine, chlorine, ethyl, cyclopropyl, methoxy, amino, or aminomethyl;

[0027] R 2 It can be fluorine, chlorine, ethyl, methoxy, hydroxy, or amino.

[0028] Z is an integer in the range of 0 to 2;

[0029] Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 They combine to form substituted or unsubstituted five- or six-membered heterocycles containing 1 to 2 oxygen atoms and / or nitrogen atoms; wherein the substitution is selected from those substituted with methyl groups.

[0030] In some embodiments, preferably, R 3 R 4 and R 5 Composition of fragments Selected from any one of the following groups:

[0031]

[0032] In some embodiments, and more preferably, R 3 R 4 and R 5 Composition of fragments Selected from any one of the following groups:

[0033]

[0034] In some embodiments, and more preferably, the compound represented by general formula (I) is selected from any of the following compounds: N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-2,3-difluorobenzenesulfonamide,

[0035] 5-Chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-2-fluorobenzenesulfonamide,

[0036] 4-Chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-2-fluorobenzenesulfonamide,

[0037] 2-Chloro-N-{3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}-3-fluorobenzenesulfonamide,

[0038] N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl}-2,6-difluorobenzenesulfonamide,

[0039] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2,3-difluorobenzenesulfonamide,

[0040] N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl}-3,4-difluorobenzenesulfonamide

[0041] N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl}-5-fluoro-2-methoxybenzenesulfonamide

[0042] 2-Chloro-N-{5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}-3-fluorobenzenesulfonamide,

[0043] 2-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3-fluorobenzenesulfonamide,

[0044] 5-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2-fluorobenzenesulfonamide,

[0045] N-{3,3-difluoro-5-[2-(1-methyltetrahydro-1H-pyrrolo-2-yl)ethyl]-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl}-2,3-difluorobenzenesulfonamide,

[0046] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2,3,4-trifluorobenzenesulfonamide,

[0047] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide,

[0048] 4-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2-fluorobenzenesulfonamide,

[0049] N-({3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide,

[0050] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)benzenesulfonamide,

[0051] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3,4,5-trifluorobenzenesulfonamide,

[0052] N-[(5-{2-[bis(2-fluoroethyl)amino]ethyl}-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl)methyl]-3,4-difluorobenzenesulfonamide,

[0053] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1-benzofuran-6-sulfonamide,

[0054] 4-Cyclopropyl-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)benzenesulfonamide,

[0055] N-({5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide,

[0056] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-4-fluorobenzenesulfonamide,

[0057] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1H-indazole-6-sulfonamide

[0058] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1-methylindole-5-sulfonamide

[0059] Alternatively, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-4-methoxybenzenesulfonamide.

[0060] The structural formulas of the compounds represented by the general formula (I) above are shown in Table 1:

[0061] Table 1

[0062]

[0063]

[0064]

[0065]

[0066] In some embodiments, the salt is in the form of any one of inorganic acid salts, organic acid salts, and organic base salts.

[0067] In some embodiments, preferably, 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.

[0068] Furthermore, the present invention discloses a method for preparing the compound represented by the above general formula (I), characterized in that it is selected from one of the following synthetic routes:

[0069] Synthesis Route 1:

[0070]

[0071] in,

[0072] X is selected from Cl or Br;

[0073] R 1 It is hydrogen, halogen, methyl group with 1 to 3 fluorine substitutions, methoxy group with 1 to 3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl, carboxyl or amino C 1-4 Alkyl group, R is C 1-6 Alkyl groups;

[0074] R 2 Halogen, methyl group with 1-3 fluorine substitutions, methoxy group with 1-3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, where R is C 1-6 Alkyl groups;

[0075] Z is an integer in the range of 0 to 4;

[0076] Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 These can be combined to form substituted or unsubstituted five- or six-membered heterocycles; wherein the substitutions are selected from those formed by C. 1-4 Alkyl substitution;

[0077] R 3 It can be hydrogen or methyl;

[0078] n is 0 or 1;

[0079] m is 1 or 2;

[0080] R 4 It is hydrogen; R 5 C 3-4 cycloalkyl;

[0081] or,

[0082] R 5 It is hydrogen; R 4 C 3-4 cycloalkyl;

[0083] Synthesis Route 2:

[0084]

[0085] in,

[0086] X is selected from Cl or Br;

[0087] R 1 It is hydrogen, halogen, methyl group with 1 to 3 fluorine substitutions, methoxy group with 1 to 3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl, carboxyl or amino C 1-4Alkyl group, R is C 1-6 Alkyl groups;

[0088] R 2 Halogen, methyl group with 1-3 fluorine substitutions, methoxy group with 1-3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, where R is C 1-6 Alkyl groups;

[0089] Z is an integer in the range of 0 to 4;

[0090] Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 These can be combined to form substituted or unsubstituted five- or six-membered heterocycles; wherein the substitutions are selected from those formed by C. 1-4 Alkyl substitution;

[0091] R 3 It can be hydrogen or methyl;

[0092] n is 0 or 1;

[0093] m is 1 or 2;

[0094] R 4 C 1-4 alkyl;

[0095] R 5 It is hydrogen;

[0096] Synthesis Route 3:

[0097]

[0098] in,

[0099] X is selected from Cl or Br;

[0100] R 1 It is hydrogen, halogen, methyl group with 1 to 3 fluorine substitutions, methoxy group with 1 to 3 fluorine substitutions, C 1-4 Alkyl, C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkyl, fluorine-substituted C 1-4 Alkoxy, C1-6 alkylamine group, C 1-6 Alkylthio, C 3-7 Cycloalkyl, N,N-dimethylamino, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl, carboxyl or amino C 1-4 Alkyl group, R is C 1-6 Alkyl groups;

[0101] R 2 Halogen, methyl group with 1-3 fluorine substitutions, methoxy group with 1-3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, where R is C 1-6 Alkyl groups;

[0102] Z is an integer in the range of 0 to 4;

[0103] Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 These can be combined to form substituted or unsubstituted five- or six-membered heterocycles; wherein the substitutions are selected from those formed by C. 1-4 Alkyl substitution;

[0104] R 3 It can be hydrogen or methyl;

[0105] n is 0 or 1;

[0106] m is 1 or 2;

[0107] R 4 It is hydrogen;

[0108] R 5 C 1-4 alkyl;

[0109] or,

[0110] Synthesis Route 4:

[0111]

[0112] in,

[0113] X is selected from Cl or Br;

[0114] R 1 It is hydrogen, halogen, methyl group with 1 to 3 fluorine substitutions, methoxy group with 1 to 3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl, carboxyl or amino C 1-4 Alkyl group, R is C 1-6 Alkyl groups;

[0115] R 2 Halogen, methyl group with 1-3 fluorine substitutions, methoxy group with 1-3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, where R is C 1-6 Alkyl groups;

[0116] Z is an integer in the range of 0 to 4;

[0117] Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 These can be combined to form substituted or unsubstituted five- or six-membered heterocycles; wherein the substitutions are selected from those formed by C. 1-4 Alkyl substitution;

[0118] R 3 It can be hydrogen or methyl;

[0119] R 4 and R 5 Independently for C 1-4 Alkyl groups or ethyl groups substituted with 1 to 2 fluorine atoms;

[0120] Or, R 4 and R5 These combine to form 4-6 membered aliphatic heterocycles;

[0121] Or, R 4 Or R 5 With R 3 These combine to form 4- to 7-membered aliphatic heterocycles containing 1 to 2 nitrogen atoms;

[0122] n is 0 or 1;

[0123] m is 1 or 2.

[0124] Furthermore, the present invention discloses a pharmaceutical composition comprising a compound represented by the above general formula (I) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0125] The use of the compound represented by the above general formula (I) or its pharmaceutically acceptable salts, hydrates and / or solvates, or the above pharmaceutical compositions in the preparation of a drug that inhibits voltage-gated sodium ion channels, is also within the scope of protection of this invention.

[0126] The use of the compounds represented by the above general formula (I) or their pharmaceutically acceptable salts, hydrates and / or solvates, or the above pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of arrhythmias, is also within the scope of protection of this invention.

[0127] In some embodiments, the arrhythmia is any one or a combination of premature beats, atrial fibrillation, atrial flutter, atrial tachycardia, and paroxysmal supraventricular tachycardia.

[0128] Beneficial effects:

[0129] Starting from the structure of suxinidine sulfate, this application developed a series of benzylsulfonamide 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

[0131] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0132] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms.-6 The unit (ppm) is given. NMR measurements were performed using a BRUKER AVANCE 300 or BRUKER AVANCE AV-500 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an Agilent 1260-6110 LC-MS / MS system.

[0133] All chemical structural formulas in this invention were drawn using the software InDraw and KingDraw.

[0134] Example 1:

[0135] N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-2,3-difluorobenzenesulfonamide

[0136]

[0137]

[0138] Step A: Synthesis of 3-chloro-2,2-difluoropropane-1-ol

[0139]

[0140] Under nitrogen atmosphere, 50 mL of carbon tetrachloride solution containing 11.3 g (114 mmol) of 2-chloro-1,1-difluoroethylene was added to a reaction flask, followed by 200 mL of methanol, 1.1 g (6.3 mmol) of tert-butyl peroxypentanoate, 0.13 g (0.64 mmol) of dodecyl mercaptan, and 4.9 g (14.3 mmol) of nano-basic zinc carbonate. The mixture was first heated to 110 °C and reacted for 6 h, then heated to 130 °C and reacted for 2 h. After the reaction was complete, the mixture was distilled under reduced pressure to give 11.6 g of 3-chloro-2,2-difluoropropane-1-ol, with a yield of 78%. MS (ESI) m / z 130.0 [M+H] + .

[0141] Step B: Synthesis of 3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyridine

[0142]

[0143] Potassium carbonate (17.25 g, 125 mmol) was added to 100 mL of anhydrous DMF (N,N-dimethylformamide), followed by the addition of 2-chloro-4-nitroaniline (8.63 g, 50 mmol). The mixture was stirred at room temperature for 1 h until completely dissolved. Under ice bath conditions, a DMF solution (20 mL) containing 3-chloro-2,2-difluoropropane-1-ol (6.53 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 the reaction mixture cooled, some solvent was distilled off under reduced pressure. 300-500 mL of ice water was slowly added under 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 vacuum dried to obtain a relatively pure intermediate product, a yellow powder, 3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazole, 7.82 g, yield 67.8%. 1 H NMR(500MHz,DMSO-d6)δ7.76(dd,J=8.5,2.2Hz,1H),7.71(d,J=2.1Hz,1H),6.49(d,J=8.5Hz ,1H),5.53–5.47(m,1H),4.24(t,J=13.0Hz,2H),3.40–3.31(m,2H).MS(ESI)m / z231.1[M+H] + .

[0144] Step C: Synthesis of 5-(2-chloroethyl)-3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyridine

[0145]

[0146] At 0 °C, 3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazole (5 g, 21.7 mmol) and NaH (2.6 g, 65 mmol, in 60% oil solution) were added to anhydrous DMF (50 mL), followed by the addition of 1,2-dichloroethane (2.15 g, 21.7 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 the reaction was complete, the reaction solution was cooled to room temperature and diluted with water (100 mL). The product was extracted into ethyl acetate (2 × 60 mL). The combined ethyl acetate layers were washed with brine (60 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude substance was purified by column chromatography (volume ratio 3:97 (2M NH3 in MeOH):CH2Cl2) to give the title compound 5-(2-chloroethyl)-3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazine, 5.01 g, 79%, as a yellow solid. MS (ESI) m / z 293.1 [M+H]+ .

[0147] Step D: Synthesis of 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-amine

[0148]

[0149] 5-(2-chloroethyl)-3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazole (5 g, 17 mmol) was added to 40 mL of solvent (EtOH:H2O = 3:1), and ammonium chloride (1.36 g, 25.5 mmol) and iron powder (2.38 g, 42.5 mmol) were added under stirring at room temperature. The mixture was then heated to 90 °C and refluxed 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 and dried under vacuum to obtain a relatively pure intermediate product, which was a yellow powder, 4.06 g of 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-amine, with a yield of 91%. This intermediate can be used directly in the next reaction without further purification.

[0150] Step E: Synthesis of N-[5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl]-2,3-difluorobenzenesulfonamide

[0151]

[0152] 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-amine (234 mg, 0.84 mmol) was added to anhydrous tetrahydrofuran (10 mL) and stirred at room temperature for half an hour. Then, triethylamine (128 mg, 1.26 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Finally, a solution of 2,3-difluorobenzenesulfonyl chloride (178.6 mg, 0.84 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise. The reaction was allowed to proceed for 12 hours at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. 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 title compound, N-[5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazaphen-8-yl]-2,3-difluorobenzenesulfonamide, was purified by column chromatography (206 mg, 56.1%). MS (ESI) m / z 439.1 [M+H] + .

[0153] Step F: Synthesis of N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl}-2,3-difluorobenzenesulfonamide

[0154]

[0155] Under nitrogen atmosphere, N-[5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl]-2,3-difluorobenzenesulfonamide (200 mg, 0.46 mmol), cyclopropylamine (132 mg, 2.4 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 obtain a yellow oily substance, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to a white solid N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl}-2,3-difluorobenzenesulfonamide (denoted as compound I-1), 99.2 mg, yield 47%. The NMR and mass spectrometry data of compound I-1 are as follows: 1H NMR(500MHz,Chloroform-d)δ7.68–7.62(m,1H),7.39–7.31(m,1H),7.31–7.23(m,1H),6.5 6(d,J=8.9Hz,1H),6.27(d,J=2.1Hz,1H),6.11(dd,J=9.0,2.1Hz,1H),6.02(s,1H),4.24(t ,J=12.9Hz,2H),3.95(t,J=4.9Hz,2H),3.65(t,J=12.8Hz,2H),2.81–2.75(m,2H),2.34–2. 26(m,1H),2.14–2.08(m,1H),0.46–0.38(m,2H),0.31–0.23(m,2H).MS(ESI)m / z460.1[M+H] + .

[0156] Example 2:

[0157] 5-Chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-2-fluorobenzenesulfonamide

[0158]

[0159] Using 5-chloro-2-fluorobenzenesulfonyl chloride and the key intermediate 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-amine as starting materials, 5-chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-yl}-2-fluorobenzenesulfonamide (denoted as compound I-2) was prepared according to the synthesis method of Example 1. The NMR and mass spectrometry data of compound I-2 are as follows:

[0160] 1H NMR(500MHz,DMSO-d6)δ10.20(s,1H),8.02(dd,J=3.3,2.1Hz,1H),7.73–7.67(m,1H),7 .22–7.14(m,1H),6.60(d,J=8.9Hz,1H),6.36(d,J=2.1Hz,1H),6.23(dd,J=8.8,2.1Hz, 1H),4.38–4.32(m,1H),4.27(t,J=13.0Hz,2H),3.89(t,J=5.0Hz,2H),3.61(t,J=12.8H z,2H),2.85–2.79(m,2H),2.36–2.28(m,1H),0.55–0.16(m,4H).MS(ESI)m / z476.1[M+H] + .

[0161] Example 3:

[0162] 4-Chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-2-fluorobenzenesulfonamide

[0163]

[0164] Using 4-chloro-2-fluorobenzenesulfonyl chloride and the key intermediate 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-amine as starting materials, 4-chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-yl}-2-fluorobenzenesulfonamide (denoted as compound I-3) was prepared according to the synthesis method of Example 1. The NMR and mass spectrometry data of compound I-3 are as follows:

[0165] 1H NMR(500MHz,Chloroform-d)δ7.65(dd,J=12.2,2.1Hz,1H),7.57(dd,J=9.0,4.7Hz,1H),7 .38(dd,J=9.1,2.1Hz,1H),6.59(d,J=8.6Hz,1H),6.30(s,1H),6.26–6.19(m,2H),4.27(t, J=13.0Hz,2H),3.89(t,J=5.0Hz,2H),3.69(t,J=12.8Hz,2H),3.14–3.08(m,1H),2.84–2.7 8(m,2H),2.36–2.28(m,1H),0.52–0.36(m,2H),0.33–0.18(m,2H).MS(ESI)m / z476.1[M+H] + .

[0166] Example 4:

[0167] 2-Chloro-N-{3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}-3-fluorobenzenesulfonamide

[0168]

[0169]

[0170] Step A: Synthesis of tert-butyl (2-(3,3-difluoro-8-nitro-3,4-dihydrobenzo[b][1,4]oxaz-5(2H)-yl)ethyl)(methyl)carbamate

[0171]

[0172] At 0 °C, 3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazole (6 g, 26 mmol) and NaH (3.12 g, 78 mmol, in 60% oil solution) were added to anhydrous DMF (50 mL), followed by the addition of (2-chloroethyl)(methyl)carbamate tert-butyl ester (5.03 g, 26 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 (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 over Na₂SO₄. The solvent was evaporated to obtain an oily compound. The oily compound was dissolved in 30 mL of LCM. Under nitrogen atmosphere, triethylamine (7.9 g, 78 mmol), DMAP (0.64 g, 5.2 mmol), and di-tert-butyl dicarbonate (8.5 g, 39 mmol) were added dropwise. The reaction was carried out at room temperature for 24 h, followed by rotary evaporation under reduced pressure. The crude substance was purified by column chromatography (3:97 (2 M NH3 in MeOH): CH2Cl2) to give the title compound (2-(3,3-difluoro-8-nitro-3,4-dihydrobenzo[b][1,4]oxaz-5(2H)-yl)ethyl)(methyl)carbamate, 6.3 g, 64%. MS (ESI) m / z 388.1 [M+H] + .

[0173] Step B: Synthesis of tert-butyl (2-(8-amino-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaz-5(2H)-yl)ethyl)(methyl)carbamate

[0174]

[0175] (2-(3,3-difluoro-8-nitro-3,4-dihydrobenzo[b][1,4]oxaz-5(2H)-yl)ethyl)(methyl)carbamate tert-butyl ester (500 mg, 1.29 mmol) was added to 8 mL of solvent (EtOH:H2O = 3:1), and ammonium chloride (69 mg, 1.29 mmol) and iron powder (180 mg, 3.3 mmol) were added under stirring at room temperature. The mixture was then heated to 90 °C and refluxed 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 and dried under vacuum to obtain a relatively pure intermediate product (2-(8-amino-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaza-5(2H)-yl)ethyl)(methyl)carbamate, 409 mg as a yellow powder, with a yield of 89%. This intermediate can be used directly in the next reaction without further purification.

[0176] Step C: Synthesis of tert-butyl(2-(8-((2-chloro-3-fluorophenyl)sulfonamido)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxazono-5(2H)-yl)ethyl)(methyl)carbamate

[0177]

[0178] (400 mg, 1.12 mmol) of tert-butyl (2-(8-amino-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaza-5(2H)-yl)ethyl)(methyl)carbamate was added to anhydrous tetrahydrofuran (10 mL) solvent. After stirring at room temperature for half an hour, triethylamine (170 mg, 1.68 mmol) was added, and after stirring at room temperature for 5 minutes, a tetrahydrofuran (3 mL) solution of 2-chloro-3-fluorobenzenesulfonyl chloride (256.5 mg, 1.12 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 12 hours. The solvent was removed by vacuum distillation, 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 (10 mL * 4), and the organic layers were combined and dried over anhydrous magnesium sulfate. The target product, tert-butyl(2-(8-((2-chloro-3-fluorophenyl)sulfonamido)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxazono-5(2H)-yl)ethyl)(methyl)carbamate, was purified by column chromatography, 299.4 mg, yield 49.3%, as a white powder. MS (ESI) m / z 550.1 [M+H] + Step D: Synthesis of 2-chloro-N-{3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-8-yl}-3-fluorobenzenesulfonamide

[0179]

[0180] 280 mg (0.51 mmol) of tert-butyl(2-(8-((2-chloro-3-fluorophenyl)sulfonamido)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxazono-5(2H)-yl)ethyl)(methyl)carbamate was added to 10 mL of DCM. 2 mL of trifluoroacetic acid was added dropwise under nitrogen atmosphere. The reaction was allowed to proceed at room temperature for 2 h. TLC was used to monitor the reaction until completion. The reaction mixture was then transferred to a flask containing 10 mL of saturated NaHCO3 solution. DCM was then used to further precipitate the solution. Extracted with 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, resulting in the washing of a white solid. Filtering yielded 208 mg of a white solid, which was 2-chloro-N-{3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazeta-8-yl}-3-fluorobenzenesulfonamide (denoted as compound I-4), with a yield of 91%. The NMR and mass spectrometry data for compound I-4 are as follows:

[0181] 1 H NMR(500MHz,Chloroform-d)δ7.47(dd,J=8.3,1.3Hz,1H),7.39–7.31(m,1H),7.32–7. 24(m,1H),6.63(d,J=8.7Hz,1H),6.31(s,1H),6.26(d,J=2.2Hz,1H),6.19(dd,J=8.9,2 .2Hz,1H),4.23(t,J=13.0Hz,2H),3.88(t,J=4.7Hz,2H),3.81(d,J=4.9Hz,3H),3.67( t,J=12.9Hz,2H),3.55–3.47(m,1H),3.01–2.92(m,1H),2.76–2.68(m,1H).MS(ESI)m / z 450.1[M+H] + .

[0182] Example 5:

[0183] N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-2,6-difluorobenzenesulfonamide

[0184]

[0185] Using 2,6-difluorobenzenesulfonyl chloride and the key intermediate 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-amine as starting materials, N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-yl}-2,6-difluorobenzenesulfonamide (denoted as compound I-5) was prepared according to the synthesis method of Example 1. The NMR and mass spectrometry data of compound I-5 are as follows:

[0186] 1 H NMR(300MHz,Chloroform-d)δ7.75–7.61(m,1H),6.83–6.65(m,2H),6.58(d,J= 8.8Hz,1H),6.28–6.19(m,2H),6.14(dd,J=8.9,2.2Hz,1H),4.26(t,J=13.0Hz, 2H),3.97(t,J=5.0Hz,2H),3.67(t,J=12.9Hz,2H),2.78–2.68(m,2H),2.40–2. 26(m,1H),2.22–2.12(m,1H),0.52–0.34(m,2H),0.40–0.19(m,2H).MS(ESI)m / z 460.1 [M+H] + .

[0187] Example 6:

[0188] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2,3-difluorobenzenesulfonamide

[0189]

[0190] Step A: Synthesis of 3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-nitrile

[0191]

[0192] Potassium carbonate (0.55 g, 4.1 mmol) was added to 10 mL of anhydrous DMF (N,N-dimethylformamide), followed by the addition of 4-amino-3-chlorobenzonitrile (250 mg, 1.64 mmol). The mixture was stirred at room temperature for 1 h until completely dissolved. Under ice bath conditions, a 2 mL solution of 3-chloro-2,2-difluoropropanol (213 mg, 1.64 mmol) in DMF 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 the reaction mixture cooled, some solvent was distilled off under reduced pressure. 30-50 mL of ice water was slowly added under 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, 3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazeta-8-onitrile, as a white powder, yielding 234.4 mg (68% yield).

[0193] 1 H NMR(500MHz,Chloroform-d)δ7.25(s,1H),6.86(dd,J=8.4,2.1Hz,1H),6.79(d,J=8.3Hz,1H), 4.24(t,J=13.0Hz,2H),3.60(tt,J=5.2,2.0Hz,1H),3.36(td,J=13.0,5.2Hz,2H).MS(ESI)m / z 211.0[M+H] + .

[0194] Step B: Synthesis of 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-nitrile

[0195]

[0196] At 0 °C, 230 mg (1.1 mmol) of 3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazetatron-8-onitrile and 0.13 g (3.3 mmol) of NaH (in 60% oil solution) were added to anhydrous DMF (10 mL), followed by the addition of 1,2-dichloroethane (118 mg, 1.2 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 × 30 mL). The combined ethyl acetate layers were washed with brine (50 mL) and then dried (using Na₂SO₄). The solvent was evaporated, and the crude substance was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to give the title compound 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-onitrile, 242.9 mg, 81%.

[0197] 1 H NMR(500MHz,Chloroform-d)δ7.17(s,1H),6.85(d,J=7.8Hz,1H),6.78(dd,J=7.8,2.1Hz,1H),4.24(t,J=13.0Hz,2H),3.72–3.60(m,6H).MS(ESI)m / z 273.1[M+H] + .

[0198] Step C: Synthesis of [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl]methylamine

[0199]

[0200] A 1.0 mol / L BH3·THF (10 mL) composite solution was added to a mixture of 230 mg (0.84 mmol) of 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-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 obtain the desired material [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl]methylamine, 234 mg, 100%, a yellow oil, which can be used in the next synthetic step without further separation. MS (ESI) m / z 277.1 [M+H] + .

[0201] Step D: Synthesis of N-{[5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl]methyl}-2,3-difluorobenzenesulfonamide

[0202]

[0203] [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine (200 mg, 0.72 mmol) was added to anhydrous tetrahydrofuran (10 mL) solvent. After stirring at room temperature for half an hour, triethylamine (110 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, a tetrahydrofuran (5 mL) solution of 2,3-difluorobenzenesulfonyl chloride (168 mg, 0.792 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 12 hours. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. 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 title compound N-{[5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl]methyl}-2,3-difluorobenzenesulfonamide, 208.7 mg, 64%, was obtained by column chromatography. MS (ESI) m / z 453.1 [M+H] + .

[0204] Step E: Synthesis of N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2,3-difluorobenzenesulfonamide

[0205]

[0206] Under nitrogen atmosphere, N-{[5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl]methyl}-2,3-difluorobenzenesulfonamide (200 mg, 0.44 mmol), cyclopropylamine (121 mg, 2.2 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 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 obtain a yellow oily substance, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to a white solid N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2,3-difluorobenzenesulfonamide (denoted as compound I-6), 110 mg, yield 52.8%. The NMR and mass spectrometry data of compound I-6 are as follows:

[0207] 1 H NMR(500MHz,Chloroform-d)δ7.70–7.64(m,1H),7.51–7.43(m,1H),7.41–7.33(m,1H),6.92 –6.86(m,1H),6.74(d,J=8.9Hz,1H),6.65–6.61(m,1H),5.92(t,1H),4.25(t,J=13.0Hz,2H) ,3.96(t,J=5.0Hz,2H),3.87(dt,J=7.2,0.9Hz,2H),3.68(t,J=12.8Hz,2H),2.76–2.70(m,2 H),2.38–2.30(m,1H),2.21–2.15(m,1H),0.50–0.36(m,2H),0.35–0.21(m,2H).MS(ESI)m / z 474.1[M+H] + .

[0208] Example 7:

[0209] N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-3,4-difluorobenzenesulfonamide

[0210]

[0211] Using 3,4-difluorobenzenesulfonyl chloride and the key intermediate 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-amine as starting materials, N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-yl}-3,4-difluorobenzenesulfonamide (denoted as compound I-7) was prepared according to the synthesis method of Example 1. The NMR and mass spectrometry data of compound I-7 are shown below:

[0212] 1 H NMR(500MHz,Chloroform-d)δ7.72–7.64(m,1H),7.52–7.46(m,1H),7.25(td,J=10.2,4.7H z,1H),6.49(d,J=8.7Hz,1H),6.32(s,1H),6.31(d,J=2.0Hz,1H),6.17(dd,J=8.8,2.1Hz,1 H),4.27(t,J=13.0Hz,2H),3.89(t,J=5.0Hz,2H),3.68(t,J=12.8Hz,2H),2.79–2.73(m,2H ),2.37–2.29(m,1H),2.17–2.11(m,1H),0.50–0.31(m,2H),0.34–0.17(m,2H).MS(ESI)m / z 460.1[M+H] + .

[0213] Example 8:

[0214] N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}-5-fluoro-2-methoxybenzenesulfonamide

[0215]

[0216] Using 5-fluoro-2-methoxybenzenesulfonyl chloride and the key intermediate 5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-amine as starting materials, N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-yl}-5-fluoro-2-methoxybenzenesulfonamide (denoted as compound I-8) was prepared according to the synthesis method of Example 1. The NMR and mass spectrometry data of compound I-8 are as follows:

[0217] 1 H NMR(300MHz,Chloroform-d)δ7.77(dd,J=12.1,2.2Hz,1H),7.51–7.39(m,1H),7.14(dd,J= 8.3,4.7Hz,1H),6.59(d,J=8.8Hz,1H),6.22(d,J=2.2Hz,1H),6.13(dd,J=8.8,2.2Hz,1H),6 .04(s,1H),4.26(t,J=13.0Hz,2H),4.03(s,3H),3.91(t,J=5.0Hz,2H),3.69(t,J=12.8Hz,2 H),2.82–2.72(m,2H),2.38–2.24(m,1H),2.15–2.05(m,1H),0.55–0.15(m,4H).MS(ESI)m / z 472.1[M+H] + .

[0218] Example 9:

[0219] 2-Chloro-N-{5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}-3-fluorobenzenesulfonamide

[0220]

[0221] Step A: Synthesis of 2-(3,3-difluoro-8-nitro-3,4-dihydrobenzo[b][1,4]oxazapyro-5(2H)-yl)-N,N-dimethylethane-1-amine

[0222]

[0223] A suspension of 3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazazole (250 mg, 1.09 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (118.1 mg, 1.09 mmol), and K₂CO₃ (0.38 g, 2.73 mmol) in anhydrous DMF (10 mL) was stirred overnight (18 h) at 100 °C. After the reaction was complete, the reactants were 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 (2M NH3 in MeOH):CH2Cl2) to give the title compound 2-(3,3-difluoro-8-nitro-3,4-dihydrobenzo[b][1,4]oxazono-5(2H)-yl)-N,N-dimethylethane-1-amine, 233.1 mg, 71%, as a yellow solid. MS (ESI) m / z 303.1 [M+H] + .

[0224] Step B: Synthesis of 5-(2-(dimethylamino)ethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-8-amine

[0225]

[0226] 2-(3,3-difluoro-8-nitro-3,4-dihydrobenzo[b][1,4]oxazono-5(2H)-yl)-N,N-dimethylethane-1-amine (220 mg, 0.73 mmol) was added to 8 mL of solvent (EtOH:H2O = 3:1), and ammonium chloride (41 mg, 0.73 mmol) and iron powder (103 mg, 1.8 mmol) were added under stirring at room temperature. The mixture was then heated to 90 °C and refluxed 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 and dried under vacuum to obtain a relatively pure intermediate product, 5-(2-(dimethylamino)ethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazazepone-8-amine, as a yellow powder, 136.6 mg, with a yield of 69%. This intermediate can be used directly in the next reaction without further purification.

[0227] Step C: Synthesis of 2-chloro-N-{5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-8-yl}-3-fluorobenzenesulfonamide

[0228]

[0229] 5-(2-(dimethylamino)ethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazazepone-8-amine (130 mg, 0.48 mmol) was added to anhydrous tetrahydrofuran (5 mL) solvent. After stirring at room temperature for half an hour, triethylamine (97 mg, 0.96 mmol) was added, and after stirring at room temperature for 5 minutes, a tetrahydrofuran (2 mL) solution of 2-chloro-3-fluorobenzenesulfonyl chloride (132.8 mg, 0.58 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 12 hours. The solvent was removed by vacuum distillation, 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, 2-chloro-N-{5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazeta-8-yl}-3-fluorobenzenesulfonamide (denoted as compound I-9), was purified by column chromatography, 136 mg, yield 61%, as a white powder. The NMR and mass spectrometry data of compound I-9 are as follows: 1 H NMR (500MHz, DMSO-d6) δ10.23(s,1H),7.57–7.48(m,1H),7.48–7.38(m,2H),6.55(d,J=8.9Hz,1H),6.41(d,J=2.1Hz,1H),6.19(dd,J=8.9,2. 2Hz,1H),4.26(t,J=12.9Hz,2H),3.66(t,J=12.8Hz,2H),3.25(t,J=5.4Hz,2H),2.72(t,J=5.4Hz,2H),2.41(s,3H),2.34(s,3H).MS(ESI)m / z 464.1[M+H] + .

[0230] Example 10:

[0231] 2-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3-fluorobenzenesulfonamide

[0232]

[0233]

[0234] Using 2-chloro-3-fluorobenzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl]methylamine as starting materials, 2-chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl}methyl)-3-fluorobenzenesulfonamide (denoted as compound I-10) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-10 are as follows:

[0235] 1 H NMR(500MHz,Chloroform-d)δ7.56(dd,J=8.1,1.3Hz,1H),7.45–7.31(m,2H),6.91–6.85(m ,1H),6.71(d,J=8.9Hz,1H),6.65–6.61(m,1H),5.83(t,1H),4.26(t,J=12.9Hz,2H),3.92( d,J=7.1Hz,2H),3.89(t,J=5.0Hz,2H),3.67(t,J=12.9Hz,2H),2.79–2.73(m,2H),2.37–2. 29(m,1H),2.17–2.11(m,1H),0.47–0.36(m,2H),0.33–0.22(m,2H).MS(ESI)m / z490.1[M+H] + .

[0236] Example 11:

[0237] 5-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2-fluorobenzenesulfonamide

[0238]

[0239] Using 5-chloro-2-fluorobenzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl]methylamine as starting materials, 5-chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl}methyl)-2-fluorobenzenesulfonamide (denoted as compound I-11) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-11 are as follows:

[0240] 1H NMR(300MHz,Chloroform-d)δ7.96(dd,J=3.2,2.2Hz,1H),7.69–7.59(m,1H),7.18(dd,J=10 .1,7.2Hz,1H),7.00–6.90(m,1H),6.72(d,J=8.9Hz,1H),6.68–6.60(m,1H),5.79(t,1H),4. 25(t,J=13.0Hz,2H),4.02–3.89(m,4H),3.67(t,J=12.9Hz,2H),2.80–2.70(m,2H),2.40–2. 26(m,1H),2.21–2.11(m,1H),0.52–0.30(m,2H),0.36–0.18(m,2H).MS(ESI)m / z490.1[M+H] + .

[0241] Example 12:

[0242] N-{3,3-difluoro-5-[2-(1-methyltetrahydro-1H-pyrrolo-2-yl)ethyl]-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapheno-8-yl}-2,3-difluorobenzenesulfonamide

[0243]

[0244] Starting with N-(2-chloroethyl)-pyrrolidine hydrochloride, 3,3-difluoro-8-nitro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyrrolidine, and 2,3-difluorobenzenesulfonyl chloride, N-{3,3-difluoro-5-[2-(1-methyltetrahydro-1H-pyrrolo-2-yl)ethyl]-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyrrolidine-8-yl}-2,3-difluorobenzenesulfonamide (denoted as compound I-12) was prepared according to the synthesis method of Example 1. The NMR and mass spectrometry data of compound I-12 are as follows:

[0245] 1H NMR(500MHz,DMSO-d6)δ10.23(s,1H),7.69–7.63(m,1H),7.40–7.32(m,1H),7.32–7.24(m,1H),6.6 3(d,J=8.7Hz,1H),6.39(d,J=2.1Hz,1H),6.23(dd,J=8.8,2.1Hz,1H),4.27(t,J=13.0Hz,2H),3.71– 3.59(m,3H),3.40–3.27(m,2H),2.97–2.87(m,1H),2.23(d,J=1.5Hz,3H),2.18–2.07(m,1H),2.11–2 .01(m,1H),1.92–1.82(m,1H),1.76–1.66(m,1H),1.66–1.48(m,2H),1.49–1.40(m,1H).MS(ESI)m / z 488.1[M+H] + .

[0246] Example 13:

[0247] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2,3,4-trifluorobenzenesulfonamide

[0248]

[0249] Using 2,3,4-trifluorobenzene-1-sulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl}methyl)-2,3,4-trifluorobenzenesulfonamide (denoted as compound I-13) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-13 are as follows:

[0250] 1H NMR(500MHz,Chloroform-d)δ7.60–7.52(m,1H),7.05(td,J=10.0,4.8Hz,1H),6.98–6.92( m,1H),6.68(d,J=8.9Hz,1H),6.65–6.62(m,1H),5.83(t,1H),4.23(t,J=13.0Hz,2H),3.92( d,J=7.1Hz,2H),3.87(t,J=5.0Hz,2H),3.67(t,J=12.9Hz,2H),2.85–2.79(m,2H),2.37–2. 29(m,1H),2.19–2.13(m,1H),0.45–0.37(m,2H),0.33–0.21(m,2H).MS(ESI)m / z492.1[M+H] + .

[0251] Example 14:

[0252] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide

[0253]

[0254] Using 3,4-difluorobenzene-1-sulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl}methyl)-3,4-difluorobenzenesulfonamide (denoted as compound I-14) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-14 are as follows:

[0255] 1H NMR(300MHz,Chloroform-d)δ7.81–7.69(m,1H),7.60–7.46(m,1H),7.29(td,J=10.2, 4.7Hz,1H),6.98–6.88(m,1H),6.67(d,J=8.9Hz,1H),6.63–6.58(m,1H),5.79(t,1H),4 .20(t,J=12.9Hz,2H),3.96–3.85(m,4H),3.61(t,J=12.8Hz,2H),2.81–2.71(m,2H),2 .40–2.26(m,1H),2.22–2.12(m,1H),0.54–0.34(m,2H),0.36–0.18(m,2H).MS(ESI)m / z 474.1[M+H] + .

[0256] Example 15:

[0257] 4-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2-fluorobenzenesulfonamide

[0258]

[0259] Using 4-chloro-2-fluorobenzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine as starting materials, 4-chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl}methyl)-2-fluorobenzenesulfonamide (denoted as compound I-15) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-15 are as follows:

[0260] 1H NMR(500MHz,Chloroform-d)δ7.75(dd,J=9.0,4.8Hz,1H),7.62(dd,J=12.0,2.1Hz,1H),7. 36(dd,J=8.9,2.1Hz,1H),6.98–6.92(m,1H),6.72(d,J=8.8Hz,1H),6.66–6.62(m,1H),5.79 (t,1H),4.25(t,J=13.0Hz,2H),3.96–3.90(m,4H),3.67(t,J=12.9Hz,2H),2.80–2.74(m,2 H),2.36–2.28(m,1H),2.16–2.10(m,1H),0.47–0.36(m,2H),0.31–0.20(m,2H).MS(ESI)m / z 490.1[M+H] + .

[0261] Example 16:

[0262] N-({3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide

[0263]

[0264] Step A: Synthesis of tert-butyl (2-(8-cyano-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaza-5(2H)-yl)ethyl)(methyl)carbamate

[0265]

[0266] At 0 °C, 3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-onitrile (500 mg, 2.38 mmol) and NaH (285.6 mg, 7.14 mmol, in 60% oil solution) were added to anhydrous DMF (10 mL), followed by the addition of (2-chloroethyl)(methyl)carbamate tert-butyl ester (459 mg, 2.38 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 over Na₂SO₄. The solvent was evaporated to obtain an oily compound. The oily compound was dissolved in 10 mL of DCM. Under nitrogen atmosphere, triethylamine (722.5 mg, 7.14 mmol), DMAP (58.2 mg, 0.48 mmol), and di-tert-butyl dicarbonate (779 mg, 3.57 mmol) were added dropwise. The reaction was carried out at room temperature for 24 h. The mixture was then rotary evaporated under reduced pressure. The crude substance was purified by column chromatography (3:97 (2 MNH3 in MeOH): CH2Cl2) to obtain the title compound (2-(8-cyano-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaz-5(2H)-yl)ethyl)(methyl)carbamate, 513 mg, 57.3%. MS (ESI) m / z 368.1 [M+H] + .

[0267] Step B: Synthesis of tert-butyl (2-(8-(aminomethyl)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaza-5(2H)-yl)ethyl)(methyl)carbamate

[0268]

[0269] A 1.0 mol / L BH3·THF (10 mL) composite solution was added to a mixture of (500 mg, 1.36 mmol) of tert-butyl (2-(8-cyano-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaza-5(2H)-yl)ethyl)(methyl)carbamate 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 obtain the desired material (2-(8-(aminomethyl)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaza-5(2H)-yl)ethyl)(methyl)carbamate tert-butyl ester, 504 mg, 100%, yellow oil, which can be used in the next synthetic step without further separation.

[0270] Step C: Synthesis of N-({3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide

[0271]

[0272] Using (2-(8-(aminomethyl)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxaza-5(2H)-yl)ethyl)(methyl)carbamate tert-butyl ester and 3,4-difluorobenzenesulfonyl chloride as raw materials, N-({3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxaza-8-yl}methyl)-3,4-difluorobenzenesulfonamide (denoted as compound I-16) was prepared according to the synthesis method of Example 4. The NMR and mass spectrometry data of compound I-16 are as follows:

[0273] 1H NMR(500MHz,DMSO-d6)δ8.61–8.53(m,1H),8.13(t,J=7.3Hz,1H),7.79–7.71(m ,1H),7.70–7.64(m,1H),7.41(td,J=10.2,4.7Hz,1H),6.93–6.87(m,1H),6.83 –6.79(m,1H),6.63(d,J=8.8Hz,1H),4.22(t,J=13.0Hz,2H),3.97–3.90(m,4H) ,3.63(t,J=12.8Hz,2H),2.79(d,J=4.9Hz,3H),2.65–2.59(m,2H).MS(ESI)m / z 448.1[M+H] + .

[0274] Example 17:

[0275] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)benzenesulfonamide

[0276]

[0277]

[0278] Using benzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl}methyl)benzenesulfonamide (denoted as compound I-17) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-17 are as follows:

[0279] 1 H NMR(300MHz, DMSO-d6)δ8.11(t,J=7.3Hz,1H),7.90–7.70(m,2H),7.66–7.45(m,3H),7.00–6.90(m,1H),6.83–6.75(m,1H),6.71(d,J=8.9Hz,1H), 4.28–4.10(m,3H),3.94–3.83(m,4H),3.59(t,J=12.8Hz,2H),2.75(td,2 H),2.39–2.25(m,1H),0.52–0.29(m,2H),0.35–0.18(m,2H).MS(ESI)m / z 438.1[M+H]+ .

[0280] Example 18:

[0281] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3,4,5-trifluorobenzenesulfonamide

[0282]

[0283] Using 3,4,5-trifluorobenzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl}methyl)-3,4,5-trifluorobenzenesulfonamide (denoted as compound I-18) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-18 are as follows:

[0284] 1 H NMR(500MHz,DMSO-d6)δ8.11(t,J=7.3Hz,1H),7.56–7.48(m,2H),6.96–6.90(m,1H),6. 87–6.83(m,1H),6.71(d,J=8.8Hz,1H),4.25(t,J=13.0Hz,2H),4.16–4.10(m,1H),3.96 (t,J=5.0Hz,2H),3.92(d,J=7.3Hz,2H),3.67(t,J=12.9Hz,2H),2.81(td,J=5.0,2.7Hz ,2H),2.36–2.28(m,1H),0.46–0.35(m,2H),0.33–0.21(m,2H).MS(ESI)m / z492.1[M+H] + .

[0285] Example 19:

[0286] N-[(5-{2-[bis(2-fluoroethyl)amino]ethyl}-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl)methyl]-3,4-difluorobenzenesulfonamide

[0287]

[0288] Starting with (2-chloroethyl)[bis(2-fluoroethyl)]amine, 3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-onitrile, and 3,4-difluorobenzenesulfonyl chloride, N-[(5-{2-[bis(2-fluoroethyl)amino]ethyl}-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl)methyl]-3,4-difluorobenzenesulfonamide (denoted as compound I-19) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-19 are as follows:

[0289] 1 H NMR(500MHz,DMSO-d6)δ8.14(t,J=7.3Hz,1H),7.83–7.73(m,2H),7.49–7.37(m,1 H),6.93–6.87(m,1H),6.85–6.81(m,1H),6.71(d,J=8.8Hz,1H),4.66(t,J=4.5Hz, 2H),4.56(t,J=4.5Hz,2H),4.27(t,J=13.0Hz,2H),3.93(d,J=7.2Hz,2H),3.66(t, J=12.8Hz,2H),3.25(t,J=5.1Hz,2H),2.60(q,2H),2.57–2.50(m,4H).MS(ESI)m / z 526.1[M+H] + .

[0290] Example 20:

[0291] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1-benzofuran-6-sulfonamide

[0292]

[0293] Using benzofuran-6-sulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl}methyl)-1-benzofuran-6-sulfonamide (denoted as compound I-20) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-20 are as follows:

[0294] 1H NMR(500MHz,Chloroform-d)δ8.12(d,J=2.0Hz,1H),7.87–7.81(m,1H),7.81–7.75(m,1H), 7.58(dd,1H),6.92–6.86(m,1H),6.78–6.74(m,1H),6.72(d,J=8.8Hz,1H),6.66–6.62(m,1 H),5.81(t,1H),4.25(t,J=13.0Hz,2H),3.94–3.87(m,4H),3.67(t,J=12.9Hz,2H),2.76(t d,J=5.0,2.7Hz,2H),2.36–2.28(m,1H),2.16–2.10(m,1H),0.48–0.20(m,4H).MS(ESI)m / z 478.1[M+H] + .

[0295] Example 21:

[0296] 4-Cyclopropyl-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)benzenesulfonamide

[0297]

[0298] Using 4-cyclopropylbenzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine as starting materials, 4-cyclopropyl-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl}methyl)benzenesulfonamide (denoted as compound I-21) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-20 are as follows:

[0299] 1H NMR(300MHz,Chloroform-d)δ7.90–7.72(m,2H),7.64–7.45(m,2H),6.96–6.86(m,1H),6.68(d,J= 8.9Hz,1H),6.64–6.57(m,1H),5.79(t,J=7.3Hz,1H),4.26(t,J=13.0Hz,2H),3.96–3.85(m,4H),3 .63(t,J=12.8Hz,2H),3.57–3.44(m,1H),2.76(td,J=5.0,2.7Hz,2H),2.39–2.25(m,1H),2.18–2. 08(m,1H),1.07–0.86(m,2H),0.78–0.54(m,2H),0.48–0.33(m,2H),0.36–0.19(m,2H).MS(ESI)m / z 478.1[M+H] + .

[0300] Example 22:

[0301] N-({5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide

[0302]

[0303] Step A: Synthesis of 5-(2-(dimethylamino)ethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-8-nitrile

[0304]

[0305] A suspension of 3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazetaphon-8-onitrile (230 mg, 1.09 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (117 mg, 1.09 mmol), and K₂CO₃ (0.38 g, 2.73 mmol) in anhydrous 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 compound was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to give the title compound 5-(2-(dimethylamino)ethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-onitrile, 230 mg, 75%, as a white solid. MS (ESI) m / z 282.1 [M+H] + .

[0306] Step B: Synthesis of 2-(8-(aminomethyl)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxazapyro-5(2H)-yl)-N,N-dimethylethane-1-amine

[0307]

[0308] A 1.0 mol / L BH3·THF (10 mL) composite solution was added to a mixture of 220 mg (0.78 mmol) of 5-(2-(dimethylamino)ethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-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 obtain the desired material 2-(8-(aminomethyl)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxazono-5(2H)-yl)-N,N-dimethylethane-1-amine, 226 mg, 100%, yellow oil, which can be used in the next synthesis step without further separation.

[0309] Step C: Synthesis of N-({5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-8-yl}methyl)-3,4-difluorobenzenesulfonamide

[0310]

[0311] 2-(8-(aminomethyl)-3,3-difluoro-3,4-dihydrobenzo[b][1,4]oxazono-5(2H)-yl)-N,N-dimethylethane-1-amine (220 mg, 0.77 mmol) was added to anhydrous tetrahydrofuran (10 mL) and stirred at room temperature for half an hour. Then, triethylamine (118.5 mg, 1.16 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Finally, a tetrahydrofuran (5 mL) solution of 3,4-difluorobenzenesulfonyl chloride (163 mg, 0.77 mmol) was slowly added dropwise. The reaction was allowed to proceed for 12 hours at room temperature. The solvent was removed by vacuum distillation, 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, N-({5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide (denoted as compound I-22), was purified by column chromatography, 151.6 mg, yield 44.6%, as a white powder. The NMR and mass spectrometry data of compound I-22 are as follows:

[0312] 1 H NMR(500MHz,DMSO-d6)δ8.14(t,J=7.3Hz,1H),7.82–7.74(m,2H),7.47–7.38 (m,1H),6.96–6.90(m,1H),6.83–6.79(m,1H),6.71(d,J=8.8Hz,1H),4.23(t ,J=13.0Hz,2H),3.93(dt,J=7.3,0.9Hz,2H),3.66(t,J=12.8Hz,2H),3.26(t ,J=5.4Hz,2H),2.75(t,J=5.4Hz,2H),2.39(s,3H),2.35(s,3H).MS(ESI)m / z 462.1[M+H] + .

[0313] Example 23:

[0314] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-4-fluorobenzenesulfonamide

[0315]

[0316] Using 4-fluorobenzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl}methyl)-4-fluorobenzenesulfonamide (denoted as compound I-23) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-23 are as follows:

[0317] 1 H NMR(500MHz,Chloroform-d)δ7.81–7.70(m,2H),7.24–7.14(m,2H),6.94–6.88(m,1H),6 .72(d,J=8.9Hz,1H),6.65–6.61(m,1H),5.81(t,1H),4.26(t,J=13.0Hz,2H),3.94(t,J= 5.0Hz,2H),3.89(d,J=7.3Hz,1H),3.68(t,J=12.8Hz,2H),2.77–2.71(m,2H),2.36–2.28 (m,1H),2.19–2.13(m,1H),0.49–0.36(m,2H),0.33–0.20(m,2H).MS(ESI)m / z456.1[M+H] + .

[0318] Example 24:

[0319] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1H-indazole-6-sulfonamide

[0320]

[0321]

[0322] Using 1H-indazole-6-sulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapine-8-yl}methyl)-1H-indazole-6-sulfonamide (denoted as compound I-24) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-24 are as follows:

[0323] 1 H NMR(500MHz,Chloroform-d)δ12.40(s,1H),8.28(d,J=2.1Hz,1H),8.14(d,J=2.0Hz,1H),8.10–8.04(m, 1H),7.91–7.85(m,1H),6.95–6.89(m,1H),6.70(d,J=8.8Hz,1H),6.64–6.60(m,1H),5.77(t,J=7.3Hz,1H ),4.24(t,J=13.0Hz,2H),3.95(t,J=5.0Hz,2H),3.91(dt,J=7.3,0.9Hz,2H),3.65(t,J=12.8Hz,2H),2. 81–2.75(m,2H),2.34–2.26(m,1H),2.14–2.08(m,1H),0.47–0.37(m,2H),0.32–0.22(m,2H).MS(ESI)m / z 478.1[M+H] + .

[0324] Example 25:

[0325] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1-methylindole-5-sulfonamide

[0326]

[0327] Using 1-methylindole-5-sulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazazepone-8-yl}methyl)-1-methylindole-5-sulfonamide (denoted as compound I-25) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-25 are as follows:

[0328] 1H NMR(300MHz,DMSO-d6)δ8.11(t,J=7.3Hz,1H),7.98–7.89(m,2H),7.85(dd,J=8.6,2.0Hz,1H),7.13(d, J=5.0Hz,1H),6.96–6.86(m,1H),6.85–6.77(m,1H),6.67(d,J=8.8Hz,1H),6.50–6.41(m,1H),4.26(t, J=13.0Hz,2H),4.18–4.08(m,1H),3.97(t,J=5.0Hz,2H),3.93(d,J=7.3Hz,2H),3.77(s,3H),3.67(t,J =12.8Hz,2H),2.86–2.76(m,2H),2.38–2.24(m,1H),0.54–0.35(m,2H),0.38–0.19(m,2H).MS(ESI)m / z 491.1[M+H] + .

[0329] Example 26:

[0330] N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-4-methoxybenzenesulfonamide

[0331]

[0332] Using 4-methoxybenzenesulfonyl chloride and the key intermediate [5-(2-chloroethyl)-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl]methylamine as starting materials, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazon-8-yl}methyl)-4-methoxybenzenesulfonamide (denoted as compound I-26) was prepared according to the synthesis method of Example 6. The NMR and mass spectrometry data of compound I-26 are shown below:

[0333] 1H NMR(500MHz,DMSO-d6)δ8.15(t,J=7.3Hz,1H),7.84–7.70(m,2H),7.17–7.04(m,2H),6.9 2–6.86(m,1H),6.86–6.82(m,1H),6.71(d,J=8.8Hz,1H),4.29–4.21(m,3H),3.98(t,J=5 .0Hz,2H),3.92(dt,J=7.3,0.8Hz,2H),3.87(s,3H),3.67(t,J=12.8Hz,2H),2.82–2.76( m,2H),2.36–2.28(m,1H),0.48–0.36(m,2H),0.34–0.22(m,2H).MS(ESI)m / z468.1[M+H] + .

[0334] Comparative Example 1:

[0335] N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-chlorobenzenesulfonamide

[0336]

[0337] Step A: Synthesis of 4-(2-chloroethyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0338]

[0339] At 0 °C, 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (5 g, 27.8 mmol) and NaH (3.4 g, 83.4 mmol, in 60% oil solution) were added to anhydrous DMF (30 mL), followed by the addition of 1,2-dichloroethane (2.75 g, 27.8 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 the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (200 mL), and the product was extracted into ethyl acetate (2 × 150 mL). The combined ethyl acetate layers were washed with saturated brine (200 mL) and then dried (Na₂SO₄). The solvent was evaporated, and the crude substance was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to give the title compound 4-(2-chloroethyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine, 5.46 g, 81%, as a yellow solid.

[0340] Step B: Synthesis of 4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-amine

[0341]

[0342] 4-(2-chloroethyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (250 mg, 1.03 mmol) was added to 20 mL of solvent (EtOH:H2O = 3:1). Ammonium chloride (82.9 mg, 1.55 mmol) and iron powder (144.5 mg, 2.58 mmol) were added under stirring at room temperature. The mixture was then 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, 4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-amine, 164.4 mg, yield 77.3%. This intermediate can be used directly in the next reaction without further purification.

[0343] Step C: Synthesis of 4-chloro-N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide

[0344]

[0345] 4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)amine (150 mg, 0.71 mmol) was added to anhydrous tetrahydrofuran (5 mL) solvent. After stirring at room temperature for half an hour, triethylamine (108 mg, 1.07 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, a tetrahydrofuran (2 mL) solution of 4-chlorobenzenesulfonyl chloride (149.8 mg, 0.71 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 sodium sulfate. The target product, 4-chloro-N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzenesulfonamide, 162 mg (59% yield), was obtained by column chromatography as a white powder.

[0346] Step D: Preparation of N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-chlorobenzenesulfonamide

[0347]

[0348] Under nitrogen atmosphere, 4-chloro-N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzenesulfonamide (150 mg, 0.387 mmol), cyclopropylamine (110.5 mg, 1.94 mmol), and methanol (10 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 oily substance, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to a white solid N-(4-(2-(cyclopropylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-chlorobenzenesulfonamide (denoted as reference compound 1), 68 mg, yield 43%. The NMR and mass spectrometry data of reference compound 1 are as follows:

[0349] 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).MS(ESI)m / z 408.1[M+H]+.

[0350] Comparative Example 2:

[0351] 2-Fluoro-4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)benzenesulfonamide

[0352]

[0353] Starting with (2-chloroethyl)(methyl)carbamate, 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine and 2-fluoro-4-methoxybenzenesulfonyl chloride, tert-butyl(2-(7-(((2-fluoro-4-methoxyphenyl)sulfonamido)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-yl)ethyl)(methyl)carbamate was prepared according to the method of Comparative Example 1.

[0354]

[0355] 150 mg (0.30 mmol) of tert-butyl(2-(7-((2-fluoro-4-methoxyphenyl)sulfonamido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)(methyl)carbamate was added to 10 mL of DCM. 2 mL of trifluoroacetic acid was added dropwise under nitrogen atmosphere. The reaction was carried out at room temperature for 2 h. TLC monitoring confirmed the completion of the reaction. The reaction mixture was then poured into a flask containing 10 mL of saturated NaHCO3 solution and subjected to DCM. Extracted (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, precipitating a white solid. Filtering yielded 108 mg of a white solid, 2-fluoro-4-methoxy-N-(4-(2-(methylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzenesulfonamide (designated as reference compound 2), with a yield of 91%. The NMR and mass spectrometry data for reference compound 2 are as follows: 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).MS(ESI)m / z 396.1[M+H]+.

[0356] Comparative Example 3:

[0357] 2-Fluoro-N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)-4-methoxybenzenesulfonamide

[0358]

[0359] N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide was prepared using 4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide as the starting material and 2-fluoro-4-methoxybenzenesulfonyl chloride as the key intermediate, following the synthesis method of Comparative Example 1.

[0360]

[0361] Under nitrogen atmosphere, N-(4-(2-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-fluoro-4-methoxybenzenesulfonamide (100 mg, 0.25 mmol), tert-butylamine (91.4 mg, 1.25 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 oily substance, which was purified by silica gel column chromatography (DCM:MeOH = 20:1) to a white solid, 2-fluoro-N-(4-(2-(tert-butylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-4-methoxybenzenesulfonamide (denoted as reference compound 3), 46 mg, yield 42%. The NMR and mass spectrometry data of reference compound 3 are as follows: 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).MS(ESI)m / z438.2[M+H]+.

[0362] Example 27: Detection of NaV1.5 channel inhibitory activity

[0363] 1. Experimental Materials and Reagents

[0364]

[0365]

[0366] 2. Cell Culture

[0367] 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.

[0368] 3 Experimental Procedures

[0369] 1.3.1 Preparation of working solution

[0370] (1) The compounds (the compounds prepared in Examples 1 to 26 and Comparative Examples 1 to 3, shuxindine sulfate, mexiletine, etc.) were dissolved in DMSO and stored at a concentration of 10 mM.

[0371] (2) The test compound was serially diluted 3 times with DMSO.

[0372] (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.

[0373] 1.3.2 Patch-clamp experiment

[0374] 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 Table 2 below:

[0375] Table 2

[0376]

[0377]

[0378] The structures of reference compound 1, reference compound 2, and reference compound 3 are as follows:

[0379]

[0380] Example 28: In vitro metabolic stability study

[0381] 1. Experimental reagents, consumables and instruments

[0382]

[0383] 2. Experimental Procedure

[0384] A phase-one oxidative metabolic reaction initiated by NADPH: The incubation system consisted of 100 μL of 0.1 M phosphate buffer (pH 7.2–7.4), 50 μL of 20 mM MgCl2 solution, 20 μL of 5 μM working solution of the test compound, 20 μL of 10 mM NADPH, and 10 μL of 4 mg / mL liver microsomes, with a final reaction volume of 200 μL. The working solution of the test compound and human liver microsomes were pre-incubated in a 37°C water bath for 5 min, followed by the addition of NADPH to initiate the reaction. Incubation times were 0 min, 2 min, 5 min, 15 min, 30 min, 45 min, 60 min, and 120 min. The organic solvent content in the entire system was ≤1%. A blank control group without the test compound was also incubated for 120 min. After incubation at 37℃, 800 μL of 100 ng / ml iced caffeine internal standard working solution was added, vortexed for 5 min, centrifuged at 15000 rpm for 10 min at 4℃, and 40 μL of supernatant was collected. 200 μL of 0.1% formic acid aqueous solution was added, vortexed for 5 min, and 1 μL was injected for analysis. The half-life was calculated. The test compounds were those prepared in Examples 1-4, Examples 6-7, Examples 9-10, and Comparative Examples 1-3. The experimental results are shown in Table 3 below.

[0385] Table 3

[0386]

[0387] This invention provides a benzenesulfonamide compound, its preparation method, and its application. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. 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 It is hydrogen, halogen, methyl group with 1 to 3 fluorine substitutions, methoxy group with 1 to 3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl, carboxyl or amino C 1-4 Alkyl group, R is C 1-6 Alkyl groups; R 2 Halogen, methyl group with 1-3 fluorine substitutions, methoxy group with 1-3 fluorine substitutions, 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, hydroxymethyl, hydroxy, amino, mercapto, -NHCOR, -NHSO2R, aldehyde, -NHCONH2, cyano, -NHCN, -CH(CN)2, acetyl or carboxyl, where R is C 1-6 Alkyl groups; Z is an integer in the range of 0 to 4; Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 These can be combined to form substituted or unsubstituted five- or six-membered heterocycles; wherein the substitutions are selected from those formed by C. 1-4 Alkyl substitution; R 3 It can be hydrogen or methyl; R 4 and R 5 Independently hydrogen, C 1-4 Alkyl, C 3-4 Cycloalkyl or 1-2 fluorinated substituted ethyl groups; Or, R 4 and R 5 These combine to form 4-6 membered aliphatic heterocycles; Or, R 4 Or R 5 With R 3 These combine to form 4- to 7-membered aliphatic heterocycles containing 1 to 2 nitrogen atoms; n is 0 or 1; m is 1 or 2.

2. The compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, hydrate, and / or solvate, characterized in that, 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-substituted groups, methoxy or aminomethyl with 1 to 3 fluorine-substituted groups; R 2 It can be fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, or amino. Or, when z is 1 and R 2 Located in R 1 When adjacent, R 1 and R 2 They combine to form substituted or unsubstituted five- or six-membered heterocycles containing 1 to 2 oxygen atoms and / or nitrogen atoms; wherein the substitution is selected from those substituted with methyl groups.

3. The compound of general formula (I) according to claim 1 or 2, or its pharmaceutically acceptable salt, hydrate, and / or solvate, characterized in that, R 3 R 4 and R 5 Composition of fragments Selected from any one of the following groups:

4. The compound of general formula (I) according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, hydrate, and / or solvate, characterized in that, The compound represented by general formula (I) is selected from any of the following compounds: N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapheno-8-yl}-2,3-difluorobenzenesulfonamide, 5-chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapheno-8-yl}-2-fluorobenzenesulfonamide, 4-chloro-N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapheno-8-yl}-2-fluorobenzenesulfonamide 2-Chloro-N-{3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-8-yl}-3-fluorobenzenesulfonamide, N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazaphen-8-yl}-2,6-difluorobenzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazaphen-8-yl}methyl)-2,3-difluorobenzenesulfonamide, N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazaphen-8-yl}-3,4-difluorobenzenesulfonamide, N-{5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazaphen-8-yl}-5-fluoro-2-methoxybenzenesulfonamide, 2-Chloro-N-{5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}-3-fluorobenzenesulfonamide, 2-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3-fluorobenzenesulfonamide, 5-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2-fluorobenzenesulfonamide, N-{3,3-difluoro-5-[2-(1-methyltetrahydro-1H-pyrrolo-2-yl)ethyl]-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazapyro-8-yl}-2,3-difluorobenzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2,3,4-trifluorobenzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide, 4-Chloro-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-2-fluorobenzenesulfonamide, N-({3,3-difluoro-5-[2-(methylamino)ethyl]-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)benzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-3,4,5-trifluorobenzenesulfonamide, N-[(5-{2-[bis(2-fluoroethyl)amino]ethyl}-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl)methyl]-3,4-difluorobenzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1-benzofuran-6-sulfonamide, 4-Cyclopropyl-N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)benzenesulfonamide, N-({5-[2-(dimethylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-8-yl}methyl)-3,4-difluorobenzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-4-fluorobenzenesulfonamide, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1H-indazole-6-sulfonamide N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-1-methylindole-5-sulfonamide Alternatively, N-({5-[2-(cyclopropylamino)ethyl]-3,3-difluoro-2,3,4,5-tetrahydrobenzo[2,1-b][1,4]oxazono-8-yl}methyl)-4-methoxybenzenesulfonamide.

5. The compound of general formula (I) according to any one of claims 1 to 4, or its pharmaceutically acceptable salt, hydrate, and / or solvate, characterized in that, The salt is in the form of any one of inorganic acid salts, organic acid salts, and organic base salts.

6. The compound of general formula (I) according to any one of claims 5, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, characterized in that, 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.

7. A pharmaceutical composition, characterized in that, It comprises a compound of general formula (I) as described in any one of claims 1 to 6, 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 general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for inhibiting voltage-gated sodium ion channels.

9. The use of the compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating and / or preventing arrhythmias.

10. The application according to claim 9, characterized in that, The arrhythmia mentioned is any one or a combination of premature beats, atrial fibrillation, atrial flutter, atrial tachycardia, and paroxysmal supraventricular tachycardia.

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