Arylsulfonamide compound and its anti-influenza use

Abstract

The present invention relates to an aryl sulfonamide compound and its anti-influenza use, belonging to the technical field of biomedicine. The present invention provides a series of aryl sulfonamide compounds represented by the general formula I. Experimental verification shows that the aryl sulfonamide compounds have excellent antiviral activity. The toxicity of the compounds is evaluated by cytopathic effect assay. The compounds provided by the present invention have ideal safety and good development prospects.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular, relates to an arylsulfonamide compound and its anti-influenza use. Background Art

[0002] Seasonal influenza, caused by influenza viruses, is a major public health problem. Influenza viruses belong to the family Orthomyxoviridae, a negative-stranded, single-stranded RNA virus. Based on differences in the antigenic determinants of their nucleoprotein (NP) and matrix protein (MP), influenza viruses are classified into four types: A (A), B (B), C (C), and D (D). Influenza A viruses have a wide host range, infecting humans, pigs, dogs, poultry, and wild birds. They have high morbidity and mortality rates and are prone to causing large-scale outbreaks.

[0003] Currently, the two main strategies for combating influenza viruses are vaccination and drug treatment. While influenza vaccination offers excellent preventive effects, mutations in the influenza virus can reduce the vaccine's effectiveness. Currently, clinically used anti-influenza drugs primarily include the M2 ion channel inhibitors amantadine and rimantadine; the neuraminidase inhibitors oseltamivir and zanamivir; the hemagglutinin inhibitor arbidol; and the newly marketed caps-dependent endonuclease inhibitor Xofluza. However, with the long-term use of anti-influenza drugs, viral resistance is becoming increasingly serious. Therefore, there is an urgent need to develop novel anti-influenza drugs for clinical treatment. Summary of the Invention

[0004] One of the objects of the present invention is to provide a group of arylsulfonamide compounds, their pharmaceutically acceptable salts and isomers.

[0005] Another object of the present invention is to provide a method for synthesizing the arylsulfonamide compounds.

[0006] Another object of the present invention is to provide a composition containing the arylsulfonamide compound, its pharmaceutically acceptable salt and isomers.

[0007] Another object of the present invention is to provide a pharmaceutical composition or pharmaceutical preparation containing the arylsulfonamide compound, its pharmaceutically acceptable salt and isomer compound as an active ingredient, and the use of the pharmaceutical composition in treating or preventing influenza disease.

[0008] Definition of terms

[0009] The terminology used in this description of the present invention is intended only to describe specific embodiments and is not intended to limit the invention. The nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and biology described herein are well known and commonly used in the art. Unless otherwise noted, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0010] As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a," "an," "the," and "its" are intended to refer to both the singular and the plural, unless the context clearly dictates otherwise. For example, a compound includes one or more than one compound.

[0011] As used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items.

[0012] As used herein, the term "disease" or "disorder" refers to any change in the state of the body or some organ that interrupts or interferes with the performance of its functions and / or causes symptoms.

[0013] As used herein, the term "treating" is intended to alleviate or eliminate the targeted disease state or condition. If a subject receives a therapeutic amount of a compound, or a pharmaceutically acceptable salt, isomer, or pharmaceutical composition thereof, as described herein, and the subject exhibits an observable and / or detectable reduction or improvement in one or more signs and symptoms, the subject is successfully "treated." It should also be understood that treatment of the disease state or condition includes not only complete treatment, but also less than complete treatment while achieving some biologically or medically relevant outcome.

[0014] As used herein, the term "subject" may refer to a patient or other animal that receives the composition of the present invention to treat, prevent, alleviate and / or alleviate the disease or condition described in the present invention, and in the present invention, particularly refers to humans and mammals.

[0015] Technical Topic 1

[0016] The present invention provides arylsulfonamide compounds having a structure shown in Formula I, and pharmaceutically acceptable salts and isomers thereof:

[0017]

[0018] wherein ring A is selected from

[0019] X is selected from -CH2-, -O-, -S-, -SO-, -SO2-, -NR 3 —;

[0020] R1 is composed of one or more independent R 4 Substituted or unsubstituted phenyl, composed of one or more independent R 4 a substituted or unsubstituted 5-membered or 6-membered heteroaryl group;

[0021] R 2 is composed of one or more independent R 5 Substituted or unsubstituted phenyl, composed of one or more independent R 5 a substituted or unsubstituted 5-membered or 6-membered heteroaryl group;

[0022] R 3 Selected from H, C1-C6 chain or branched alkyl;

[0023] R 4 Selected from halogen, NO2, CN, OH, C1-C6 straight chain or branched hydrocarbon group, C1-C6 straight chain or branched hydrocarbon group, C1-C6 straight chain or branched hydrocarbon group substituted with 1-3 halogens, C1-C6 straight chain or branched hydrocarbon group substituted with 1-3 halogens;

[0024] R 5 Selected from halogen, OH, NO2, C1-C6 straight chain or branched hydrocarbon group, C1-C6 straight chain or branched hydrocarbon group, C1-C6 straight chain or branched hydrocarbon group substituted with 1-3 halogens, C1-C6 straight chain or branched hydrocarbon group substituted with 1-3 halogens, C2-C5 carboxylate group, one or more independent R 6 Substituted or unsubstituted 1-2 oxo or no oxo 3-7 membered cycloalkyl, composed of one or more independent R 6 Substituted or unsubstituted 1-2 oxo or no oxo 3-7 membered heterocycloalkyl, composed of one or more independent R 6 Substituted or unsubstituted phenyl, composed of one or more independent R 6 a substituted or unsubstituted 5- to 6-membered heteroaryl group.

[0025] R 6 Selected from halogen, C1-C6 straight chain or branched hydrocarbon group, C1-C6 straight chain or branched hydrocarbon group oxy group, -NR x R y 、—(CH2) n NR x R y ;

[0026] R x Selected from H, C1-C6 straight or branched alkyl;

[0027] R y Selected from H, C1-C6 straight or branched alkyl, C2-C5 carboxylate;

[0028] n is selected from 1, 2, 3, 4 or 5.

[0029] In some cases, the 5-membered or 6-membered heteroaryl is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; and the 3-7-membered heteroalkyl is selected from oxiranyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, pyranyl or tetrahydropyranyl.

[0030] In some cases, the C1-C6 straight chain or branched hydrocarbon group includes a C1-C6 straight chain or branched alkyl group, a C2-C6 straight chain or branched alkene group, and a C2-C6 straight chain or branched alkynyl group; the C1-C6 straight chain or branched alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, C5 branched alkyl group, hexyl, and C6 branched alkyl group; the C2-C6 straight chain or branched alkene group is selected from vinyl, propenyl, allyl, butenyl, pentenyl, and hexenyl; the C2-C6 straight chain or branched alkynyl group is selected from ethynyl, propynyl, propargyl, butynyl, pentynyl, and hexynyl.

[0031] In some cases, the C1-C6 straight chain or branched hydrocarbonoxy group includes a C1-C6 straight chain or branched alkoxy group, a C2-C6 straight chain or branched alkeneoxy group, and a C2-C6 straight chain or branched alkyneoxy group; the C1-C6 straight chain or branched alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, C5 branched alkoxy, hexyloxy, and C6 branched alkoxy group; the C2-C6 straight chain or branched alkeneoxy group is selected from ethyleneoxy, propyleneoxy, allyloxy, butenyloxy, pentenyloxy, and hexenyloxy group; the C2-C6 straight chain or branched alkyneoxy group is selected from ethynyloxy, propynyloxy, propargyloxy, butynyloxy, pentynyloxy, and hexynyloxy group.

[0032] The C2-C5 carboxylate group is selected from: ―C(O)OCH3, ―C(O)OC2H5, ―C(O)OC3H7, ―C(O)OC4H9, ―CH2C(O)OCH3, ―CH2C(O)OC2H5, ―CH2C(O)OC3H7, ―(CH2)2C(O)OCH3, ―(CH2)2C(O)OC2H5, ―(CH2)3C(O)OCH3, ―(CH2)3C(O)OC2H5, ―(CH2)4C(O)OCH3.

[0033] In some preferred embodiments, R 1 Selected from one or more independent R 4 Substituted or unsubstituted groups include: phenyl, thiazolyl, pyridyl.

[0034] R 2Selected from one or more independent R 5 Substituted or unsubstituted groups include: phenyl, pyridyl, pyrrolyl, triazolyl, and furyl.

[0035] R 4 Selected from halogen, NO2, CN, OH, CF3, OCF3, C1-C6 straight chain or branched hydrocarbon group, C1-C6 straight chain or branched hydrocarbon group, C1-C6 straight chain or branched hydrocarbon group substituted with 1-3 halogens, C1-C6 straight chain or branched hydrocarbon group substituted with 1-3 halogens.

[0036] The R 5 Selected from halogen, OH, NO2, CF3, OCF3, C1-C6 straight chain or branched alkyl, C1-C6 straight chain or branched alkyloxy, C2-C5 carboxylate, one or more independent R 6 Substituted or unsubstituted structures include piperazine, piperidine, tetrahydropyrrole, morpholine, thiomorpholine, thiomorpholine dioxide, thiomorpholine monoxide, 2-piperazinone, 2-piperidone, 2-tetrahydropyrrolidone, 3-morpholinone, 3-thiomorpholinone, 1,2-dioxide thiomorpholin-3-one, triazolyl, phenyl, pyrazolyl, and imidazolyl.

[0037] In some preferred embodiments of the present invention, the formula I is selected from the following structures:

[0038]

[0039]

[0040]

[0041]

[0042] As used herein, "halo" or "halogen" may be fluorine, chlorine, bromine or iodine, and is preferably F, Cl, Br.

[0043] As used herein, the term "hydrocarbyl" used alone or in combination includes alkyl, alkenyl, and alkynyl. The term "Cm-n" (m and n are each integers) refers to a straight or branched chain group containing x to y carbon atoms. The term "C1-6 straight or branched chain alkyl" used alone or in combination in the present invention refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms. The C1-6 alkyl of the present invention is preferably a C1-6 alkyl, more preferably a C1-5 alkyl, and more preferably a C1-4 alkyl. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 (preferably 2 to 4) carbon atoms having one or more carbon-carbon triple bonds. Examples of preferred alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-diynyl. "Alkenyl" refers to a straight or branched hydrocarbon group containing 2 to 6 (preferably 2 to 4) carbon atoms having one or more carbon-carbon double bonds. Examples of preferred alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, and 1-butenyl.

[0044] As used herein, the “1-3 halogen-substituted C1-C6 straight or branched hydrocarbon group” substituents are preferably 1, 2 or 3 substituents selected from F, Cl, Br, preferably CF3.

[0045] As used herein, "pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of the target compound and exhibit minimal undesirable toxicological effects. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound of the present invention with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable bases include salts prepared from inorganic bases and organic bases, and the salts of the inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Salts of the organic non-toxic bases include salts of primary, secondary, and tertiary amines, including substituted amines and cyclic amines. For example: N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, and the like, including salts formed with sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0046] As used herein, "isomers" refers to the ability of compounds of the present invention to exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, single diastereomers, geometric isomers, and the like, when the compounds of Formula I contain one or more asymmetric centers and / or double bonds. These compounds may be represented by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom, or by the symbols "Z" or "E," depending on the arrangement of substituents around the carbon-carbon double bond, or the substituents around the carbon-carbon double bond may be referred to as "cis" or "trans." The compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended to be included within the scope of the present invention, even if only one tautomeric structure is depicted, such as keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like.

[0047] Technical Topic 2

[0048] The present invention also provides a method for synthesizing the compound represented by Formula I. Although the compound of the present invention can be prepared by the following method, the conditions of the method, such as the reactants, solvents, acids, bases, amounts of the compounds used, reaction temperature, reaction time, etc., are not limited to the following description. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known to those skilled in the art. Such combinations can be readily performed by those skilled in the art to which the present invention relates.

[0049]

[0050] Technical Theme 3

[0051] The present invention provides a pharmaceutical composition comprising a compound represented by Formula I, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0052] As used herein, a "pharmaceutical composition" comprises a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt or isomer thereof, and one or more pharmaceutically acceptable carriers, in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, elixirs, decoctions, lozenges, mixtures, suppositories, injections, inhalants, or sprays. The pharmaceutical composition preferably contains 0.1% to 99.5% by weight of the arylsulfonamide compound of the present invention or a pharmaceutically acceptable salt thereof as the active ingredient, and more preferably contains 0.5% to 99.5% by weight of the active ingredient.

[0053] As used herein, "pharmaceutically acceptable carriers or excipients" include: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used in more than one function and in alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example, when used for oral administration, oral preparations such as tablets, capsules, granules and pills can be prepared, containing fillers (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium; gum arabic; dextran; silicate derivatives such as magnesium aluminum metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (e.g., gelatin, polyvinyl pyrrolidone and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose, polyvinyl pyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.), flavoring agents (e.g., commonly used sweeteners, acidulants and spices, etc.). When used parenterally, the drug can be prepared as an injection, including sterile powder for injection and solvent for injection. The carrier or excipient used includes sterile water, Ringer's solution, and isotonic sodium chloride solution. Suitable additives such as antioxidants, buffers, and antibacterial agents may also be added depending on the properties of the drug. When used for rectal administration, the drug can be prepared as a suppository, etc. When used for pulmonary administration, the drug can be prepared as an inhaler or spray, etc. There are many resources available to those skilled in the art that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books such as "Remington's Pharmaceutical Compendium," "Chinese Pharmaceutical Annals," and "Pharmaceutics."

[0054] The present invention can be administered by any suitable method known in the art, for example, orally, intravenously, intraperitoneally, intramuscularly, topically, transdermally, ocularly, nasally, inhaled, subcutaneously, intramuscularly, buccally, sublingually, orally, orally, or by rectal administration. The compound as described above can be administered in any amount of 1 μg to 2000 mg / kg of subject body weight, for example, 1 μg to 1000 mg / kg body weight / day, 50 μg to 1000 mg / kg body weight / day, 100 μg to 1000 mg / kg body weight / day, 1 to 500 mg / kg body weight / day, 2 to 200 mg / kg body weight / day, or 5 to 100 mg / kg body weight / day. In some embodiments of the present invention, the compound as described above can be administered 4 times a day, 3 times a day, 2 times a day, once a day, once every two days, once a week, or at other intervals, and the dosing regimen as described above can be repeated weekly or monthly as appropriate. In the present invention, the dosage of the compound can be adjusted according to factors such as the severity of the patient's or subject's condition, age, weight, gender, administration method, and treatment course.

[0055] The compounds of the present invention can be used alone or in combination with one or more other active ingredients for the treatment, prevention, suppression or improvement of a disease or condition, wherein the combined use of the drugs is safer or more effective than the use of any one drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention in the manner and amount commonly used therefor. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing the other drugs and the compounds of the present invention in a unit dosage form is preferred, particularly in combination with a pharmaceutically acceptable carrier. However, combination therapy can also include administering the compounds of the present invention and one or more other drugs on different overlapping schedules. It can also be expected that, when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower doses than when each is used alone. Therefore, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention also include those compositions containing one or more other active ingredients.

[0056] Technical Theme 4

[0057] The present invention also provides the use of the benzenesulfonamide compound shown in I, its pharmaceutically acceptable salt or isomer in the preparation of a drug for treating or preventing influenza virus infection.

[0058] In some embodiments of the present invention, the influenza viruses include influenza A, influenza B, influenza C, and influenza D.

[0059] In some embodiments of the invention, influenza A includes H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7.

[0060] Advantageous Effects of the Invention

[0061] The benzenesulfonamide compounds provided by the present invention have been verified by experiments to have excellent antiviral activity. The toxicity of the compounds was evaluated by cytopathic effect assay. The compounds provided by the present invention have ideal safety and good development prospects. DETAILED DESCRIPTION

[0062] The present invention is described below in conjunction with specific examples. These examples are not intended to limit the scope of the present invention, but rather to provide guidance for those skilled in the art to prepare and use the compounds, compositions, and methods of the present invention. Where specific conditions are not specified in the examples, conventional conditions or manufacturer's recommended conditions were used. Reagents or instruments used, for which the manufacturer is not specified, are commercially available conventional products.

[0063] The chemical names of the compounds described in this application follow the principles of IUPAC nomenclature.

[0064] The preparation method of this embodiment is as follows:

[0065] Route 1

[0066]

[0067] Route 2

[0068]

[0069] Example 1

[0070]

[0071] (S)-2-Phenylmorpholine (100 mg, 0.61 mmol), 2-chlorobenzenesulfonyl chloride (143 mg, 0.67 mmol) and triethylamine (124 mg, 1.22 mmol) were dissolved in dichloromethane and stirred at room temperature for 4 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target compound I-1 as a white solid (178 mg, yield 86%). 1H NMR(500MHz, CDCl3)δ8.05(dd,J=7.9,1.7Hz,1H),7.57-7.47(m,2H),7.43-7.37(m,1H),7.37-7.28(m,5H),4.55(dd,J=10.4,2.7Hz,1H) ,4.08(dd,J=11.7,3.4Hz,1H),3.88-3.78(m,2H),3.74(d,J=12.6Hz,1H),3.09-3.00(m,1H),2.82-2.75(m,1H); MS-ESI(m / z):338(M+H) + .

[0072] Example 2

[0073]

[0074] Referring to the method in Example 1, 2-bromobenzenesulfonyl chloride was used as a raw material to replace 2-chlorobenzenesulfonyl chloride to prepare the target compound I-2. NMR(500MHz, CDCl3)δ8.09(dd,J=7.7,1.9Hz,1H),7.77(d,J=7.9Hz,1H),7.48-7.38(m,2H),7.37-7.27(m,5H),4.56(dd,J=10.5,2.7Hz,1H), 4.08(dd,J=11.8,3.2Hz,1H),3.87-3.78(m,2H),3.72(d,J=13.4Hz,1H),3.12-3.04(m,1H),2.87-2.79(m,1H); MS-ESI(m / z):382,384(M+H)+.

[0075] Example 3

[0076]

[0077] Referring to the method in Example 1, the target compound I-3 was prepared by using an equal molar amount of 2-fluorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.88-7.78(m,1H),7.64-7.53(m,1H),7.42-7.17(m,7H),4.58(dd,J=10.4,2.8Hz,1H),4.10(dd,J=1 1.6,3.4Hz,1H),3.92-3.80(m,2H),3.75(d,J=12.2Hz,1H),2.90-2.78(m,1H),2.62-2.51(m,1H); MS-ESI(m / z):322(M+H) +.

[0078] Example 4

[0079]

[0080] Referring to the method in Example 1, the target compound I-4 was prepared by using an equal molar amount of 2-nitrobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.97(d,J=7.6Hz,1H),7.75-7.65(m,2H),7.63(d,J=6.3Hz,1H),7.40-7.28(m,5H),4.57(dd,J=10.5,2.7Hz,1H), 4.11(dd,J=11.7,3.4Hz,1H),3.89-3.77(m,2H),3.73(d,J=12.5Hz,1H),3.12-3.01(m,1H),2.85-2.75(m,1H); MS-ESI(m / z):349(M+H) + .

[0081] Example 5

[0082]

[0083] Referring to the method in Example 1, the target compound I-5 was prepared by using an equal molar amount of 2-methoxybenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR(500MHz, CDCl3) δ7.88(d,J=7.7Hz,1H),7.52(t,J=8.0Hz,1H),7.37-7.27(m,5H),7.06-6.98(m,2H),4.55(dd,J=10.4,2.8Hz,1 H),4.07(dd,J=11.7,3.4Hz,1H),3.90(s,3H),3.88-3.70(m,3H),2.99-2.88(m,1H),2.65(t,J=11.4Hz,1H); MS-ESI(m / z):334(M+H) + .

[0084] Example 6

[0085]

[0086] Referring to the method in Example 1, the target compound I-6 was prepared by using an equal molar amount of 3-chlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1H NMR(500MHz, CDCl3)δ7.73(s,1H),7.64-7.55(m,2H),7.48(t,J=7.9Hz,1H),7.39-7.28(m,5H),4.60(dd,J=10.3,2.7Hz,1H),4.10(dd,J=12.1,3 .3Hz,1H),3.90-3.82(m,1H),3.78(d,J=11.6Hz,1H),3.67(d,J=11.5Hz,1H),2.62-2.54(m,1H),2.31(t,J=10.9Hz,1H); MS-ESI(m / z):338(M+H) + .

[0087] Example 7

[0088]

[0089] Referring to the method in Example 1, the target compound I-7 was prepared by using an equal molar amount of p-chlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.67(d,J=8.0Hz,2H),7.51(d,J=7.9Hz,2H),7.38-7.27(m,5H),4.60(d,J=10.3Hz,1H),4.09(d,J=11.8Hz,1H),3. 85(t,J=11.6Hz,1H),3.76(d,J=11.6Hz,1H),3.64(d,J=11.6Hz,1H),2.58-2.47(m,1H),2.27(t,J=10.9Hz,1H); MS-ESI(m / z):338(M+H) + .

[0090] Example 8

[0091]

[0092] Referring to the method in Example 1, the target compound I-8 was prepared by using an equal molar amount of p-fluorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1H NMR (500MHz, CDCl3) δ7.81-7.70(m,2H),7.40-7.27(m,5H),7.21(t,J=8.3Hz,2H),4.60(d,J=10.2Hz,1H),4.09(d,J=11.7Hz,1H),3.8 6(t,J=10.9Hz,1H),3.77(d,J=11.7Hz,1H),3.64(d,J=11.5Hz,1H),2.58-2.47(m,1H),2.26(t,J=11.0Hz,1H); MS-ESI(m / z):322(M+H) + .

[0093] Example 9

[0094]

[0095] Referring to the method in Example 1, the target compound I-9 was prepared by using an equal molar amount of p-phenylbenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.80(d,J=8.2Hz,2H),7.73(d,J=8.4Hz,2H),7.60(d,J=7. 2Hz,2H),7.49(t,J=7.5Hz,2H),7.43(t,J=7.3Hz,1H),7.38-7.28(m,5H),4.63(d d,J=10.3,2.7Hz,1H),4.10(dd,J=11.4,3.3Hz,1H),3.94-3.78(m,2H),3.69(d,J =11.4Hz,1H),2.64-2.54(m,1H),2.33(t,J=10.9Hz,1H); MS-ESI(m / z):380(M+H) + .

[0096] Example 10

[0097]

[0098] Referring to the method in Example 1, the target compound I-10 was prepared by using an equal molar amount of p-cyclohexylbenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1H NMR (500MHz, CDCl3) δ7.64 (dd, J=8.2, 2.7Hz, 2H), 7.40-7.28 (m, 7H), 4.61 (d, J= 10.4Hz,1H),4.08(d,J=11.4Hz,1H),3.91-3.83(m,1H),3.79(d,J=11.6Hz,1H), 3.64(d,J=11.6Hz,1H),2.64-2.50(m,2H),2.35-2.24(m,1H),1.88(s,4H),1.77 (d,J=13.1Hz,1H),1.49-1.34(m,4H),1.33-1.21(m,1H); MS-ESI(m / z):386(M+H) + .

[0099] Example 11

[0100]

[0101] Referring to the method in Example 1, the target compound I-11 was prepared by using an equal molar amount of p-methoxybenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.67(d,J=8.5Hz,2H),7.38-7.27(m,5H),6.99(d,J=8.4Hz,2H),4.60(dd,J=10.3,2.7Hz,1H),4.07(dd,J=11.7,3.5Hz ,1H),3.90-3.81(m,4H),3.75(d,J=11.6Hz,1H),3.62(d,J=11.5Hz,1H),2.55-2.45(m,1H),2.25(t,J=10.9Hz,1H); MS-ESI(m / z):334(M+H) + .

[0102] Example 12

[0103]

[0104] Referring to the method in Example 1, the target compound I-12 was prepared by using an equal molar amount of methyl p-sulfonylchlorobenzoate instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1H NMR (500MHz, CDCl3) δ8.19(d,J=8.5Hz,2H),7.81(d,J=8.5Hz,2H),7.38-7.27(m,5H),4.59(dd,J=10.3,2.7Hz,1H),4.08(dd,J=11. 7,2.1Hz,1H),3.96(s,3H),3.89-3.75(m,2H),3.67(d,J=11.7Hz,1H),2.59-2.49(m,1H),2.33-2.20(m,1H); MS-ESI(m / z):362(M+H) + .

[0105] Example 13

[0106]

[0107] Referring to the method in Example 1, 2-chlorobenzenesulfonyl chloride was replaced with an equal molar amount of methyl 3-(4-(chlorosulfonyl)phenyl)propionate as a raw material to prepare the target compound I-13. NMR (500MHz, CDCl3) δ7.65 (d, J = 6.6 Hz, 2H), 7.41-7.27 (m, 7H), 4.60 (d, J = 10. 3Hz,1H),4.08(d,J=11.7Hz,1H),3.85(t,J=11.6Hz,1H),3.77(d,J=11.7Hz,1H ),3.67(s,3H),3.64(d,J=11.5Hz,1H),3.03(t,J=7.7Hz,2H),2.66(t,J=7.7H z,2H),2.53(t,J=11.5Hz,1H),2.26(t,J=11.5Hz,1H); MS-ESI(m / z):390(M+H) + .

[0108] Example 14

[0109]

[0110] Referring to the method in Example 1, an equal molar amount of 2-chloro-4-nitrobenzenesulfonyl chloride was used instead of 2-chlorobenzenesulfonyl chloride as a raw material to prepare the target compound I-14. 1H NMR(500MHz, CDCl3)δ8.39(d,J=2.2Hz,1H),8.28-8.19(m,2H),7.39-7.29(m,5H),4.55(dd,J=10.4,2.7Hz,1H) ,4.11(dd,J=11.5,3.2Hz,1H),3.91-3.74(m,3H),3.15-3.07(m,1H),2.89-2.81(m,1H); MS-ESI(m / z):383(M+H) + .

[0111] Example 15

[0112]

[0113] Referring to the method in Example 1, an equal molar amount of 2,3-dichlorobenzenesulfonyl chloride was used instead of 2-chlorobenzenesulfonyl chloride as a raw material to prepare the target compound I-15. 1 H NMR (500MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.42-7.28(m,6H),4.54(dd,J=10.4,2.7Hz,1H),4.09(dd, J=11.7,3.2Hz,1H),3.87-3.77(m,2H),3.72(d,J=13.1Hz,1H),3.10-2.99(m,1H),2.82-2.73(m,1H); MS-ESI(m / z):372(M+H) + .

[0114] Example 16

[0115]

[0116] Referring to the method in Example 1, an equal molar amount of 2,4-dichlorobenzenesulfonyl chloride was used instead of 2-chlorobenzenesulfonyl chloride as a raw material to prepare the target compound I-16. 1 H NMR (500MHz, CDCl3) δ7.60(d,J=8.8Hz,3H),7.41-7.28(m,5H),4.60(d,J=10.3Hz,1H),4.12(d,J=8.4Hz,1H),3.92-3.82(m,1H),3 .78(d,J=11.5Hz,1H),3.67(d,J=11.5Hz,1H),2.70-2.57(td,J=11.6,3.5Hz,1H),2.36(t,J=10.9Hz,1H); MS-ESI(m / z):372(M+H) + .

[0117] Example 17

[0118]

[0119] Referring to the method in Example 1, an equal molar amount of 2-chloro-4-fluorobenzenesulfonyl chloride was used to replace 2-chlorobenzenesulfonyl chloride as a raw material to prepare the target compound I-17. 1 H NMR (500MHz, CDCl3) δ8.06-7.99(m,1H),7.35-7.20(m,6H),7.10-7.01(m,1H),4.51(dd,J=10.4,2.8Hz,1H),4.05(dd,J=11. 8,3.3Hz,1H),3.82-3.72(m,2H),3.68(d,J=12.5Hz,1H),3.04-2.94(m,1H),2.74(t,J=11.5Hz,1H); MS-ESI(m / z):356(M+H) + .

[0120] Example 18

[0121]

[0122] Referring to the method in Example 1, the target compound 18 was prepared by using an equal molar amount of 2-chloro-4-bromobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.89(d,J=8.5Hz,1H),7.71(d,J=2.0Hz,1H),7.53(dd,J=8.4,2.0Hz,1H),7.41-7.28(m,5H),4.54(dd,J=10.4,2.8Hz,1H ),4.09(dd,J=11.4,3.0Hz,1H),3.88-3.77(m,2H),3.72(d,J=12.4Hz,1H),3.10-2.97(m,1H),2.83-2.72(m,1H); MS-ESI(m / z):415,417(M+H) + .

[0123] Example 19

[0124]

[0125] Referring to the method in Example 1, the target compound I-19 was prepared by using an equal molar amount of 2,5-dichlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1H NMR (500MHz, CDCl3) δ8.04(s,1H),7.47(s,2H),7.39-7.28(d,J=7.4Hz,5H),4.55(d,J=10.4Hz,1H),4.09 (d,J=11.4Hz,1H),3.89-3.71(m,3H),3.12-3.03(m,1H),2.83(t,J=11.5Hz,1H); MS-ESI(m / z):372(M+H) + .

[0126] Example 20

[0127]

[0128] Referring to the method in Example 1, the target compound I-20 was prepared by using an equal molar amount of 2,6-dichlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1 H NMR(500MHz, CDCl3) δ7.47(d,J=8.0Hz,2H),7.40-7.28(m,6H),4.56(dd,J=10.5,2.7Hz,1H),4.12-4.06(m ,1H),4.00-3.94(m,1H),3.87-3.78(m,2H),3.20-3.11(m,1H),2.97-2.87(m,1H); MS-ESI(m / z):372(M+H) + .

[0129] Example 21

[0130]

[0131] Referring to the method in Example 1, the target compound I-21 was prepared by using an equal molar amount of 3,4-dichlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1 H NMR (500MHz, CDCl3) δ7.83 (s, 1H), 7.66-7.53 (m, 2H), 7.41-7.29 (m, 5H), 4.60 (d, J = 9.8Hz, 1H), 4.11 (d, J = 10.9Hz, 1H), 3.92 -3.82(m,1H),3.77(d,J=10.8Hz,1H),3.66(d,J=11.6Hz,1H),2.64-2.54(m,1H),2.36-2.27(m,1H); MS-ESI(m / z):372(M+H) + .

[0132] Example 22

[0133]

[0134] Referring to the method in Example 1, the target compound I-22 was prepared using an equal molar amount of 3,5-dichlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1 H NMR (500MHz, CDCl3) δ7.60(d,J=8.8Hz,3H),7.41-7.28(m,5H),4.60(d,J=10.3Hz,1H),4.12(d,J=8.4Hz,1H),3.92-3.82(m,1H),3 .78(d,J=11.5Hz,1H),3.67(d,J=11.5Hz,1H),2.70-2.57(td,J=11.6,3.5Hz,1H),2.36(t,J=10.9Hz,1H); MS-ESI(m / z):372(M+H) + .

[0135] Example 23

[0136]

[0137] Referring to the method in Example 1, the target compound I-23 was prepared by using an equal molar amount of 2-fluoro-4-chlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.75(t,J=8.0Hz,1H),7.37-7.27(m,5H),7.24(t,J=7.4Hz,2H),4.56(d,J=10.3Hz,1H),4.08(d,J=11.8H z,1H),3.82(t,J=10.5Hz,2H),3.71(d,J=12.2Hz,1H),2.82(t,J=11.9Hz,1H),2.54(t,J=11.4Hz,1H); MS-ESI(m / z):356(M+H) + .

[0138] Example 24

[0139]

[0140] Referring to the method in Example 1, the target compound I-24 was prepared by using an equal molar amount of 2,4-difluorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1H NMR (500MHz, CDCl3) δ7.85(q,J=7.6Hz,1H),7.41-7.27(m,5H),7.06-6.92(m,2H),4.58(d,J=10.3Hz,1H),4.10(d,J=11.7Hz ,1H),3.84(t,J=11.5Hz,2H),3.73(d,J=12.1Hz,1H),2.83(t,J=11.7Hz,1H),2.55(t,J=11.2Hz,1H); MS-ESI(m / z):340(M+H) + .

[0141] Example 25

[0142]

[0143] Referring to the method in Example 1, the target compound I-25 was prepared by using an equal molar amount of 2-fluoro-5-chlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ7.81(dd,J=5.8,2.7Hz,1H),7.56-7.50(m,1H),7.39-7.29(m,5H),7.18(t,J=9.0Hz,1H),4.58(dd,J=10.4,2.7Hz,1H),4 .11(dd,J=11.9,3.3Hz,1H),3.89-3.80(m,2H),3.75(d,J=12.2Hz,1H),2.88(t,J=11.9Hz,1H),2.60(t,J=11.3Hz,1H); MS-ESI(m / z):356(M+H) + .

[0144] Example 26

[0145]

[0146] Referring to the method in Example 1, the target compound I-26 was prepared by using an equal molar amount of 2,5-difluorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1H NMR (500MHz, CDCl3) δ7.58-7.51(m,1H),7.39-7.23(m,6H),7.23-7.16(m,1H),4.58(d,J=10.3Hz,1H),4.11(d,J=11.7Hz,1 H),3.84(t,J=13.4Hz,2H),3.75(d,J=12.3Hz,1H),2.88(t,J=11.9Hz,1H),2.60(t,J=11.3Hz,1H); MS-ESI(m / z):340(M+H) + .

[0147] Example 27

[0148]

[0149] Referring to the method in Example 1, the target compound I-27 was prepared by using an equal molar amount of 2,5-dibromobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ8.22(d,J=2.3Hz,1H),7.61(d,J=8.4Hz,1H),7.52(dd,J=8.5,2.3Hz,1H),7.40-7.28(m,5H),4.56(dd,J=10.5,2.6Hz,1H), 4.09(dd,J=11.7,3.1Hz,1H),3.89-3.78(m,2H),3.72(d,J=12.8Hz,1H) ,3.16-3.07(m,1H),2.92-2.84(m,1H); MS-ESI(m / z):459,461,463(M+H) + .

[0150] Example 28

[0151]

[0152] Referring to the method in Example 1, an equal molar amount of 2-nitro-4-chlorobenzenesulfonyl chloride was used to replace 2-chlorobenzenesulfonyl chloride as a raw material to prepare the target compound I-28. 1H NMR (500MHz, CDCl3) δ7.90(d,J=8.4Hz,1H),7.64(d,J=11.0Hz,2H),7.42-7.28(m,5H),4.56(d,J=10.4Hz,1H),4.12(d,J=11.9 Hz,1H),3.81(t,J=13.3Hz,2H),3.71(d,J=12.6Hz,1H),3.07(t,J=12.2Hz,1H),2.80(t,J=11.5Hz,1H); MS-ESI(m / z):383(M+H) + .

[0153] Example 29

[0154]

[0155] Referring to the method in Example 1, the target compound I-29 was prepared by using an equal molar amount of 2,4-dimethoxybenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1 H NMR (500MHz, CDCl3) δ7.80(d,J=8.4Hz,1H),7.36-7.27(m,5H),6.53-6.48(m,2H),4.55(dd,J=10.4,2.7Hz,1H),4.06(dd,J=11.6,2.0Hz ,1H),3.86(s,3H),3.85(s,3H),3.83-3.77(m,2H),3.71(d,J=12.6Hz,1H),2.92-2.84(m,1H),2.62-2.55(m,1H); MS-ESI(m / z):364(M+H) + .

[0156] Example 30

[0157]

[0158] Referring to the method in Example 1, the target compound I-30 was prepared by using an equal molar amount of 2,4-dimethylbenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1H NMR(500MHz, CDCl3) δ7.75(d,J=8.0Hz,1H),7.39-7.28(m,5H),7.16-7.09(m,2H),4.54(d,J=10.4Hz,1H),4.08(d,J=11.7Hz,1H),3.85-3.77 (m,1H),3.70(d,J=12.1Hz,1H),3.58(d,J=12.1Hz,1H),2.90-2.81(m,1H),2.67-2.56(d,J=13.9Hz,4H),2.37(s,3H); MS-ESI(m / z):332(M+H) + .

[0159] Example 31

[0160]

[0161] Referring to the method in Example 1, the target compound I-31 was prepared by using an equal molar amount of 2,4,5-trichlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1 H NMR (500MHz, CDCl3) δ8.13(s,1H),7.64(s,1H),7.39-7.29(m,5H),4.55(dd,J=10.4,2.7Hz,1H),4.10(dd,J=11.6,3.2 Hz,1H),3.87-3.77(m,2H),3.74(d,J=12.9Hz,1H),3.12-3.03(m,1H),2.86-2.79(m,1H); MS-ESI(m / z):405,407(M+H) + .

[0162] Example 32

[0163]

[0164] Referring to the method in Example 1, the target compound I-32 was prepared by using an equal molar amount of 2,4,6-trichlorobenzenesulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as a raw material. 1 H NMR(500MHz, CDCl3)δ7.49(s,2H),7.40-7.28(m,5H),4.55(dd,J=10.5,2.7Hz,1H),4.10(dd,J=11.5,3.3Hz,1H ),3.94(d,J=12.8Hz,1H),3.86-3.76(m,2H),3.20-3.10(m,1H),2.97-2.86(m,1H); MS-ESI(m / z):405,407(M+H) + .

[0165] Example 33

[0166]

[0167] Referring to the method in Example 1, the target compound I-33 was prepared by using an equal molar amount of 2,6-dichloropyridine-3-sulfonyl chloride instead of 2-chlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ8.29(d,J=8.2Hz,1H),7.40(d,J=8.2Hz,1H),7.38-7.29(m,5H),4.55(dd,J=10.4,2.7Hz,1H),4.11(dd, J=11.7,3.2Hz,1H),3.86-3.78(m,2H),3.75(d,J=12.8Hz,1H),3.17-3.08(m,1H),2.89-2.82(m,1H); MS-ESI(m / z):373(M+H) + .

[0168] Example 34

[0169]

[0170] Compound I-17 (20 mg, 0.05 mmol) and tetrahydropyrrole (4.3 mg, 0.06 mmol) were dissolved in dimethyl sulfoxide, heated to 120 ° C for 2 h, and the reaction was monitored by TLC. After the reaction was complete, heating was stopped, and the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and separated and purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target compound II-1. 1 H NMR(500MHz, CDCl3)δ7.78(d,J=8.9Hz,1H),7.36-7.27(m,5H),6.57(d,J=2.5Hz, 1H), 6.38 (dd, J=9.0, 2.5Hz, 1H), 4.54 (dd, J=10.4, 2.7Hz, 1H), 4.05 (dd, J=11.6, 2.3Hz,1H),3.84-3.74(m,2H),3.67(d,J=13.5Hz,1H),3.32(t,J=6.5Hz,4H),2.9 8-2.90(m,1H),2.72-2.65(m,1H),2.04(t,J=6.5Hz,4H); MS-ESI(m / z):407(M+H) + .

[0171] Example 35

[0172]

[0173] Referring to the method in Example 34, the target compound II-2 was prepared by using an equimolar amount of piperidine instead of tetrahydropyrrole as the raw material. 1 H NMR (500MHz, CDCl3) δ7.79 (d, J = 9.0 Hz, 1H), 7.38-7.28 (m, 5H), 6.89 (d, J = 2.6 Hz,1H),6.71(dd,J=9.1,2.6Hz,1H),4.55(dd,J=10.5,2.7Hz,1H),4.06(dd,J =11.6,3.2Hz,1H),3.85-3.76(m,2H),3.68(d,J=12.3Hz,1H),3.34(s,4H),3. 01-2.92(m,1H),2.71(t,J=11.4Hz,1H),1.67(s,6H); MS-ESI(m / z):421(M+H) + .

[0174] Example 36

[0175]

[0176] Referring to the method in Example II-3, an equal molar amount of morpholine was used instead of tetrahydropyrrole as the raw material to prepare the target compound II-3. 1 H NMR(500MHz, CDCl3)δ7.82(d,J=9.1Hz,1H),7.38-7.27(m,5H),6.90(d,J=2.6Hz, 1H),6.73(dd,J=9.1,2.6Hz,1H),4.54(dd,J=10.4,2.7Hz,1H),4.06(dd,J=11.6,3 .2Hz,1H),3.85-3.74(m,2H),3.68(d,J=12.9Hz,1H),3.37(t,J=5.1Hz,4H),3.01- 2.91(m,1H),2.75-2.66(m,1H),2.57(s,4H),2.37(s,3H); MS-ESI(m / z):436(M+H) + .

[0177] Example 37

[0178]

[0179] Referring to the method in Example 34, the target compound II-4 was prepared by using an equal molar amount of thiomorpholine instead of tetrahydropyrrole as the raw material. 1H NMR(500MHz, CDCl3) δ7.80(d,J=9.0Hz,1H),7.37-7.26(m,5H),6.83(d,J=2.6Hz,1H),6.66(dd,J=9.1,2.7Hz,1H),4.54(dd,J=10.5,2.7Hz, 1H),4.09-4.02(m,1H),3.84-3.71(m,7H),3.67(d,J=12.6Hz,1H),2.97(td,J=12.0,3.3Hz,1H),2.75-2.61(m,5H).MS-ESI(m / z):439(M+H) + .

[0180] Example 38

[0181]

[0182] Referring to the method in Example 34, an equal molar amount of thiomorpholine dioxide was used instead of tetrahydropyrrole as the raw material, and 2 equivalents of potassium carbonate were added and heated to 120°C to react to prepare the target compound II-5. 1 H NMR(500MHz, CDCl3)δ7.90(d,J=8.9Hz,1H),7.39-7.28(m,5H),6.94(d,J=2.6Hz, 1H), 6.77 (dd, J=9.0, 2.7Hz, 1H), 4.56 (dd, J=10.4, 2.7Hz, 1H), 4.08 (dd, J=11.5, 3.1Hz,1H),3.97(t,J=5.0Hz,4H),3.86-3.76(m,2H),3.70(d,J=12.3Hz,1H),3.1 0(t,J=5.0Hz,4H),3.04-2.96(m,1H),2.79-2.68(m,1H); MS-ESI(m / z):471(M+H) + .

[0183] Example 39

[0184]

[0185] Referring to the method in Example 38, the target compound II-6 was prepared by using an equal molar amount of 2-piperidone instead of thiomorpholine dioxide as the raw material. 1H NMR (500MHz, CDCl3) δ8.01(d,J=8.7Hz,1H),7.54(s,1H),7.38-7.27(m,6H),4.55(d,J=10.5Hz,1H),4.08(d,J=11.8Hz,1H),3.88-3.76 (m,2H),3.75-3.63(m,3H),3.10-3.00(m,1H),2.80(t,J=11.4Hz,1H),2.59(t,J=6.4Hz,2H),2.04-1.88(m,4H); MS-ESI(m / z):435(M+H) + .

[0186] Example 40

[0187]

[0188] Referring to the method in Example 38, the target compound II-7 was prepared by using an equal molar amount of N-methylpiperazine instead of thiomorpholine dioxide as the raw material. 1 H NMR(500MHz, CDCl3)δ7.82(d,J=9.1Hz,1H),7.38-7.27(m,5H),6.90(d,J=2.6Hz, 1H),6.73(dd,J=9.1,2.6Hz,1H),4.54(dd,J=10.4,2.7Hz,1H),4.06(dd,J=11.6,3 .2Hz,1H),3.85-3.74(m,2H),3.68(d,J=12.9Hz,1H),3.37(t,J=5.1Hz,4H),3.01- 2.91(m,1H),2.75-2.66(m,1H),2.57(s,4H),2.37(s,3H); MS-ESI(m / z):436(M+H) + .

[0189] Example 41

[0190]

[0191] Referring to the method in Example 38, an equal molar amount of 4-methylpiperidine was used instead of thiomorpholine dioxide as the raw material to prepare the target compound II-8. 1H NMR (500MHz, CDCl3) δ7.78 (d, J = 9.1Hz, 1H), 7.41-7.27 (m, 5H), 6.88 (d, J = 2.6Hz, 1H), 6.71 (dd, J = 9. 2,2.7Hz,1H),4.55(dd,J=10.5,2.7Hz,1H),4.06(dd,J=11.7,3.3Hz,1H),3.89-3.74(m,4H),3.68(d ,J=12.4Hz,1H),3.02-2.92(m,1H),2.92-2.80(m,2H),2.79-2.62(dd,J=12.3,10.4Hz,1H),1.74(d, J=13.3Hz,2H),1.68-1.58(m,1H),1.35-1.16(m,2H),0.98(d,J=6.6Hz,3H); MS-ESI(m / z):435(M+H) + .

[0192] Example 42

[0193]

[0194] Referring to the method in Example 38, an equal molar amount of 4-Boc-aminopiperidine was used instead of thiomorpholine dioxide as the raw material to prepare the target compound II-9. 11 H NMR(500MHz, CDCl3)δ7.80(d,J=9.0Hz,1H),7.37-7.27(m,5H),6.91(d,J=2.6 Hz,1H),6.73(dd,J=9.1,2.6Hz,1H),4.54(dd,J=10.4,2.7Hz,1H),4.48(s,1H) ,4.06(dd,J=11.2,3.1Hz,1H),3.84-3.60(m,6H),3.05-2.92(m,3H),2.74-2. 66(m,1H),2.05(d,J=11.2Hz,2H),1.52-1.39(m,11H);MS-ESI(m / z):536(M+H) + .

[0195] Example 43

[0196]

[0197] Compound II-9 is de-Bocized to obtain compound II-10. 1H NMR(500MHz, CDCl3)δ7.78(d,J=9.1Hz,1H),7.41-7.22(m,5H),6.88(d,J=2.6Hz ,1H),6.71(dd,J=9.1,2.6Hz,1H),4.54(dd,J=10.5,2.8Hz,1H),4.05(dd,J=11. 6,3.2Hz,1H),3.89-3.71(m,4H),3.66(d,J=12.4Hz,1H),2.95(t,J=11.5Hz,4H) ,2.70(t,J=11.4Hz,1H),1.93(s,4H),1.51-1.34(m,2H); MS-ESI(m / z):436(M+H) + .

[0198] Example 44

[0199]

[0200] Referring to the method in Example 38, the target compound II-11 was prepared by using an equal molar amount of 4-Boc-aminomethylpiperidine instead of thiomorpholine dioxide as the raw material. 1 H NMR (500MHz, CDCl3) δ7.79 (d, J = 9.0 Hz, 1H), 7.36-7.27 (m, 5H), 6.90 (d, J = 2.6 Hz, 1H), 6.73 (dd, J = 9. 0,2.6Hz,1H),4.64(s,1H),4.54(dd,J=10.4,2.7Hz,1H),4.06(dd,J=11.3,3.1Hz,1H),3.88-3.75(m, 4H),3.67(d,J=12.3Hz,1H),3.05(t,J=6.5Hz,2H),3.00-2.93(m,1H),2.92-2.83(m,2H),2.75-2.66 (m,1H),1.81(d,J=11.9Hz,2H),1.72(s,1H),1.45(s,9H),1.35-1.21(m,2H); MS-ESI(m / z):550(M+H) + .

[0201] Example 45

[0202]

[0203] Compound II-11 is de-Boced to obtain compound II-12. 1H NMR (500MHz, CDCl3) δ7.78 (d, J = 9.0Hz, 1H), 7.38-7.27 (s, 5H), 6.87 (s, 1H) ,6.70(d,J=9.2Hz,1H),4.53(d,J=10.4Hz,1H),4.23(s,2H),4.05(d,J=11.6 Hz,1H),3.91-3.72(m,4H),3.66(d,J=12.3Hz,1H),3.02-2.81(m,3H),2.80 -2.66(m,3H),1.94-1.68(m,3H),1.41-1.13(m,2H); MS-ESI(m / z):450(M+H) + .

[0204] Example 46

[0205]

[0206] Referring to the method in Example 38, the target compound II-13 was prepared by using an equal molar amount of 3-Boc-aminotetrahydropyrrole instead of thiomorpholine dioxide as the raw material. 1 H NMR(500MHz, CDCl3)δ7.78(d,J=8.9Hz,1H),7.37-7.27(m,5H),6.57(s,1H),6.38(d,J=9.6Hz ,1H),4.71(s,1H),4.53(d,J=10.5Hz,1H),4.36(s,1H),4.05(d,J=11.5Hz,1H),3.85-3.73(m, 2H),3.70-3.58(m,2H),3.50-3.34(m,2H),3.20(d,J=6.7Hz,1H),2.94(t,J=12.0Hz,1H),2.68 (t,J=11.4Hz,1H),2.36-2.25(m,1H),2.06-1.93(m,1H),1.45(s,9H); MS-ESI(m / z):522(M+H) + .

[0207] Example 47

[0208]

[0209] Compound II-13 is de-Bocized to obtain compound II-14. 1H NMR(500MHz, CDCl3)δ7.77(d,J=8.9Hz,1H),7.39-7.28(m,5H),6.56(s,1H),6.37(d,J=9.0Hz ,1H),4.53(d,J=10.4Hz,1H),4.05(d,J=11.6Hz,1H),3.84-3.73(m,3H),3.66(d,J=12.2Hz,1H ),3.58-3.46(m,2H),3.41-3.33(m,1H),3.06(dd,J=10.0,4.4Hz,1H),2.99-2.88(m,1H),2.68 (t,J=11.5Hz,1H),2.28-2.17(m,1H),1.90-1.79(m,1H),1.63(s,2H); MS-ESI(m / z):422(M+H) + .

[0210] Example 48

[0211]

[0212] Referring to the method in Example 38, an equal molar amount of 3-Boc-aminomethyltetrahydropyrrole was used instead of thiomorpholine dioxide as the raw material to prepare the target compound II-15. 1 H NMR (500MHz, CDCl3) δ7.80 (d, J = 8.8 Hz, 1H), 7.42-7.32 (m, 5H), 6.59 (d, J = 3.0 Hz, 1H), 6.45 -6.33(m,1H),4.74(s,1H),4.57(d,J=10.1Hz,1H),4.09(d,J=8.8Hz,1H),3.91-3.7 5(m,2H),3.69(d,J=12.5Hz,1H),3.54-3.42(m,3H),3.35(t,J=8.2Hz,1H),3.27(s,1 H),3.24-3.15(m,1H),3.09(d,J=7.6Hz,1H),3.04-2.89(m,1H),2.71(t,J=11.5Hz, 1H),2.57(s,1H),2.18(s,1H),1.91-1.77(m,1H),1.48(s,11H).ESI(m / z):536(M+H) + .

[0213] Example 49

[0214]

[0215] Compound II-15 is de-Bocized to obtain compound II-16.1 H NMR(500MHz, CDCl3) δ7.79(d,J=8.9Hz,1H),7.43-7.32(m,5H),6.58(d,J=2.4Hz,1H),6.39(dd,J=9.0, 2.4Hz,1H),4.56(dd,J=10.5,2.7Hz,1H),4.25-4.03(m,4H),3.88-3.76(m,2H),3.68(d,J=12.1Hz,1H) ,3.58-3.51(m,1H),3.47-3.40(m,1H),3.38-3.32(m,1H),3.13(t,J=8.5,8.1Hz,1H),2.98-2.91(m,2H ),2.72(t,J=11.4Hz,1H),2.62-2.52(m,1H),2.31-2.19(m,1H),1.89-1.75(m,1H).ESI(m / z):436(M+H) + .

[0216] Example 50

[0217]

[0218] Referring to the method in Example 38, the target compound II-17 was prepared by using an equal molar amount of 1,2,4-triazole instead of thiomorpholine dioxide as the raw material. 1 H NMR (500MHz, CDCl3) δ8.66(s,1H),8.17(d,J=8.6Hz,1H),8.14(s,1H),7.97(d,J=2.2Hz,1H),7.72(dd,J=8.7,2.2Hz,1H),7.39-7.27(m,5H), 4.55(dd,J=10.5,2.7Hz,1H),4.10(dd,J=11.7,3.1Hz,1H),3.89-3.71(m,3H),3.12-3.02(m,1H),2.85-2.75(m,1H); MS-ESI(m / z):405(M+H) + .

[0219] Example 51

[0220]

[0221] Referring to the method in Example 38, the target compound II-18 was prepared by using an equal molar amount of 1,2,3-triazole instead of thiomorpholine dioxide as the raw material. 1H NMR (500MHz, CDCl3) δ8.21(d,J=8.6Hz,1H),8.06(d,J=10.4Hz,2H),7.90(s,1H),7.79(d,J=8.6Hz,1H),7.40-7.28(s,5H),4.56(d ,J=10.4Hz,1H),4.11(d,J=11.7Hz,1H),3.90-3.73(m,3H),3.09(t,J=12.1Hz,1H),2.83(t,J=11.6Hz,1H); MS-ESI(m / z):405(M+H) + .

[0222] Example 52

[0223]

[0224] Referring to the method in Example 38, the target compound II-19 was prepared by using an equal molar amount of pyrazole instead of thiomorpholine dioxide as the raw material. 1 H NMR (500MHz, CDCl3) δ8.21(d,J=8.6Hz,1H),8.06(d,J=10.4Hz,2H),7.90(s,1H),7.79(d,J=8.6Hz,1H),7.40-7.28(s,5H),4.56(d ,J=10.4Hz,1H),4.11(d,J=11.7Hz,1H),3.90-3.73(m,3H),3.09(t,J=12.1Hz,1H),2.83(t,J=11.6Hz,1H); MS-ESI(m / z):405(M+H) + .

[0225] Example 53

[0226]

[0227] Referring to the method in Example 38, the target compound II-20 was prepared by using an equal molar amount of 3-methylpyrazole instead of thiomorpholine dioxide as the raw material. 1H NMR (500MHz, CDCl3) δ8.07 (d, J = 8.7Hz, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.62 (d,J=8.5Hz,1H),7.39-7.28(m,5H),6.32(s,1H),4.55(d,J=10.5Hz,1H),4 .09(d,J=11.6Hz,1H),3.88-3.77(m,2H),3.74(d,J=12.6Hz,1H),3.04(t,J =12.1Hz,1H),2.78(t,J=11.6Hz,1H),2.37(s,3H); MS-ESI(m / z):418(M+H) + .

[0228] Example 54

[0229]

[0230] Referring to the method in Example 38, the target compound II-21 was prepared by using an equal molar amount of 5-methyl-1H-pyrazole instead of thiomorpholine dioxide as the raw material. 1 H NMR (500MHz, CDCl3) δ8.13 (d, J = 8.6Hz, 1H), 7.78 (s, 1H), 7.62 (s, 1H), 7.53 (d,J=8.6Hz,1H),7.40–7.28(m,5H),6.26(s,1H),4.56(d,J=10.4Hz,1H),4 .10(d,J=11.8Hz,1H),3.90–3.79(m,2H),3.75(d,J=12.6Hz,1H),3.07(t,J =12.3Hz,1H),2.82(t,J=11.5Hz,1H),2.46(s,3H).MS-ESI(m / z):418(M+H) + .

[0231] Example 55

[0232]

[0233] Referring to the method in Example 38, an equal molar amount of 4-dimethylaminopiperidine was used instead of thiomorpholine dioxide as the raw material to prepare the target compound II-22. 1H NMR (500MHz, CDCl3) δ7.79 (d, J = 9.0Hz, 1H), 7.39 -7.25(m,6H),6.89(d,J=2.6Hz,1H),6.72(dd,J=9.1,2.6Hz,1H),4.55(dd, J=10.4,2.7Hz,1H),4.06(dd,J=11.6,2.1Hz,1H),3.92-3.77(m,4H),3.68( d,J=12.4Hz,1H),3.01-2.88(m,3H),2.69(dd,J=12.3,10.4Hz,1H),2.35-2 .28(m,8H),1.93(d,J=10.5Hz,2H),1.60-1.49(m,2H).ESI(m / z):464(M+H) + .

[0234] Example 56

[0235]

[0236] Referring to the method in Example 38, the target compound II-23 was prepared by using an equal molar amount of 3-dimethylaminopiperidine instead of thiomorpholine dioxide as the raw material. 1 H NMR (500MHz, CDCl3) δ7.79(d,J=9.1Hz,1H),7.37-7.28(m,5H),6.88(d,J=2.6Hz,1H),6.71(dd,J=9.1,2.6Hz,1 H),4.55(dd,J=10.4,2.7Hz,1H),4.07(dd,J=11.7,2.2Hz,1H),3.91(d,J=12.6Hz,1H),3.85-3.72(m,3H),3.68 (d,J=11.2Hz,1H),2.96(td,J=12.0,3.3Hz,1H),2.89-2.79(m,2H),2.70(t,J=11.4Hz,1H),2.43-2.32(m,7H), 2.03(d,J=14.2Hz,1H),1.86(dt,J=13.4,3.4Hz,1H),1.64-1.52(m,1H),1.51-1.41(m,1H).ESI(m / z):464(M+H) + .

[0237] Example 57

[0238]

[0239] Referring to the method in Example 38, an equal molar amount of 3-(dimethylamino)tetrahydropyrrole was used instead of thiomorpholine dioxide as the raw material to prepare the target compound II-24. 1 H NMR (500MHz, CDCl3) δ7.78(d,J=8.9Hz,1H),7.36-7.27(m,5H),6.56(d,J=2.5Hz,1H),6.38(dd,J=9.0,2 .5Hz,1H),4.54(dd,J=10.4,2.7Hz,1H),4.06(dd,J=11.6,2.0Hz,1H),3.85-3.75(m,2H),3.67(d,J=12.5 Hz,1H),3.56-3.45(m,2H),3.38-3.30(m,1H),3.18(t,J=8.8Hz,1H),2.94(td,J=12.0,3.3Hz,1H),2.90 -2.82(m,1H),2.72-2.65(m,1H),2.32(s,6H),2.29-2.21(m,1H),2.01-1.90(m,1H).ESI(m / z):450(M+H) + .

[0240] Example 58

[0241]

[0242] Referring to the method in Example 38, an equal molar amount of N,N-dimethyl-1-(piperidin-4-yl)methanamine was used instead of thiomorpholine dioxide as the raw material to prepare the target compound II-25. 1 H NMR(500MHz, CDCl3) δ7.78(d,J=9.0Hz,1H),7.37–7.27(m,5H),6.88(d,J=2.6Hz,1H),6.71(dd,J=9.1,2.6 Hz,1H),4.55(dd,J=10.4,2.7Hz,1H),4.06(dd,J=11.6,2.0Hz,1H),3.86–3.76(m,4H),3.68(d,J=12.4Hz, 1H),2.96(td,J=12.0,3.3Hz,1H),2.89(td,J=12.7,2.7Hz,2H),2.70(dd,J=12.3,10.4Hz,1H),2.22(s,6H ),2.15(d,J=7.2Hz,2H),1.86(d,J=12.1Hz,2H),1.76–1.65(m,1H),1.31–1.20(m,3H).ESI(m / z):478(M+H) + .

[0243] Example 59

[0244]

[0245] Referring to the method in Example 16, the target compound III-1 was prepared by using equimolar amounts of benzomorpholine instead of (S)-2-phenylmorpholine and 2,5-dichlorobenzenesulfonyl chloride instead of 2,4-dichlorobenzenesulfonyl chloride as raw materials. 1 H NMR(500MHz, CDCl3)δ8.16(d,J=2.4Hz,1H),7.51-7.43(m,2H),7.35(dd,J=8.3,1.7Hz,1H),7.06-7 .00(m,1H),6.91-6.81(m,2H),4.19(t,J=4.5Hz,2H),4.01(t,J=4.5Hz,2H).MS-ESI(m / z):344(M+H) + .

[0246] Example 60

[0247]

[0248] Referring to the method in Example 59, the target compound III-2 was prepared by using an equal molar amount of tetrahydroquinoline instead of benzomorpholine as the raw material. 1 H NMR(500MHz, CDCl3)δ8.13(d,J=2.4Hz,1H),7.48-7.38(m,2H),7.35(d,J=8.1Hz,1H),7.13-7.01 (m,3H),3.91(t,J=6.0Hz,2H),2.76(t,J=6.7Hz,2H),2.01-1.91(m,2H).MS-ESI(m / z):342(M+H) + .

[0249] Example 61

[0250]

[0251] Referring to the method in Example 59, the target compound III-3 was prepared by using an equal molar amount of 2,4-dichlorobenzenesulfonyl chloride instead of 2,5-dichlorobenzenesulfonyl chloride as the raw material. 1H NMR (500MHz, CDCl3) δ8.08(d,J=8.6Hz,1H),7.53(s,1H),7.41(d,J=8.5Hz,1H),7.34(d,J=8.3Hz,1H),7.02(t,J=7.7Hz ,1H),6.88(d,J=8.2Hz,1H),6.82(t,J=7.8Hz,1H),4.19(t,J=4.5Hz,2H),4.01(t,J=4.6Hz,2H).MS-ESI(m / z):344(M+H) + .

[0252] Example 62

[0253]

[0254] Referring to the method in Example 60, the target compound III-4 was prepared by using an equal molar amount of 2,4-dichlorobenzenesulfonyl chloride instead of 2,5-dichlorobenzenesulfonyl chloride as the raw material. 1 H NMR (500MHz, CDCl3) δ8.05 (d, J = 8.7Hz, 1H), 7.49 (s, 1H), 7.43-7.31 (m, 2H), 7.13-6.98 (m, 3H ),3.91(t,J=5.9Hz,2H),2.75(t,J=6.4Hz,2H),1.94(t,J=6.0Hz,2H).MS-ESI(m / z):342(M+H) + .

[0255] Example 63

[0256]

[0257] Referring to the method in Example 16, an equal molar amount of 2-phenylmercaptomorpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-1. 1 H NMR(500MHz, CDCl3)δ7.99(d,J=8.4Hz,1H),7.53(d,J=2.2Hz,1H),7.41-7.20(m,6H ),4.27-3.99(m,3H),3.25-3.04(m,3H),2.72-2.58(m,1H).MS-ESI(m / z):388(M+H) + .

[0258] Example 64

[0259]

[0260] Referring to the method in Example 16, the target compound IV-2 was prepared by using an equal molar amount of 2-phenylthiomorpholine dioxide instead of (S)-2-phenylmorpholine as the raw material. 1 H NMR (600MHz, CDCl3) δ8.02(d,J=8.5Hz,1H),7.58(d,J=2.0Hz,1H),7.48-7.36(m,6H),4.41-4.32(m,2H),4.22(dt,J=14.4, 3.2Hz,1H),3.84-3.77(m,1H),3.74-3.64(m,1H),3.48-3.39(m,1H),3.20(dt,J=14.1,2.5Hz,1H).MS-ESI(m / z):420(M+H) + .

[0261] Example 65

[0262]

[0263] Referring to the method in Example 16, an equal molar amount of 2-phenylthiomorpholine monoxide was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-3. 1 H NMR (500MHz, CDCl3) δ7.99 (d, J = 8.7Hz, 1H), 7.54 (s, 1H), 7.40-7.28 (m, 6H), 4.26 -4.02(m,3H),3.23-3.04(m,3H),2.64(d,J=10.8Hz,1H).MS-ESI(m / z):404(M+H) + .

[0264] Example 66

[0265]

[0266] Referring to the method in Example 16, an equal molar amount of 3-phenylpiperidine was used to replace (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-4. 1H NMR (600MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.53(d,J=2.1Hz,1H),7.35(dd,J=8.5,2.1Hz,1H),7.33-7.28(m,2H),7.27-7.22(m,1H),7.21-7.17( m,2H),3.96-3.90(m,2H),2.88-2.69(m,3H),2.06-2.00(m,1H),1.89-1. 83(m,1H),1.79-1.70(m,1H),1.63-1.54(m,1H).MS-ESI(m / z):370(M+H) + .

[0267] Example 67

[0268]

[0269] Referring to the method in Example 16, an equimolar amount of (R)-3-phenylpiperidine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-4-1. 1 H NMR (500MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.53(d,J=2.1Hz,1H),7.35(dd,J=8.5,2.1Hz,1H),7.33-7.28(m,2H),7.27–7.21(m,1H),7.21-7.16( m,2H),3.97-3.89(m,2H),2.88-2.69(m,3H),2.08-2.00(m,1H),1.90-1. 83(m,1H),1.80-1.69(m,1H),1.63-1.53(m,2H).MS-ESI(m / z):370(M+H) + .

[0270] Example 68

[0271]

[0272] Referring to the method in Example 16, an equal molar amount of (S)-3-phenylpiperidine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-4-2. 1H NMR (500MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.53(d,J=2.1Hz,1H),7.35(dd,J=8.5,2.1Hz,1H),7.33-7.28(m,2H),7.27-7.21(m,1H),7.21-7.16( m,2H),3.97-3.89(m,2H),2.88-2.69(m,3H),2.08-2.00(m,1H),1.90-1. 83(m,1H),1.80-1.70(m,1H),1.65-1.52(m,2H).MS-ESI(m / z):370(M+H) + .

[0273] Example 69

[0274]

[0275] Referring to the method in Example 16, an equal molar amount of 1-methyl-2-phenylpiperazine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-5. 1 H NMR (500MHz, CDCl3) δ7.95(d,J=8.5Hz,1H),7.53(d,J=2.1Hz,1H),7.37-7.27(m,6H),3.84(dd,J=12.3,2.6Hz,1H),3.66(dt,J=12.5,2. 8Hz,1H),3.15-3.03(m,2H),2.96(d,J=12.0Hz,1H),2.76(t,J=11.6Hz,1H),2.40(t,J=11.9Hz,1H),2.04(s,3H).MS-ESI(m / z):385(M+H) + .

[0276] Example 70

[0277]

[0278] Referring to the method in Example 16, an equal molar amount of 1-ethyl-2-phenylpiperazine was used to replace (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-6. 1H NMR(600MHz, CDCl3) δ7.94(d,J=8.5Hz,1H),7.53(d,J=2.0Hz,1H),7.36-7.27(m,6H),3.9 0-3.83(m,1H),3.68-3.61(m,1H),3.30(dd,J=10.6,3.3Hz,1H),3.10(dt,J=11.6,2.6Hz, 1H),3.04(td,J=12.0,2.9Hz,1H),2.71(dd,J=12.3,10.6Hz,1H),2.59-2.50(m,1H),2.35 (td,J=11.8,3.2Hz,1H),2.07-1.99(m,1H),0.91(t,J=7.1Hz,3H).MS-ESI(m / z):399(M+H) + .

[0279] Example 71

[0280]

[0281] Referring to the method in Example 16, an equal molar amount of 1-isopropyl-2-phenylpiperazine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound IV-7. 1 H NMR(600MHz, CDCl3)δ7.93(d,J=8.5Hz,1H),7.53(d,J=2.1Hz,1H),7.37-7.27(m,6H), 3.88(dd,J=11.7,2.5Hz,1H),3.62(dt,J=12.1,2.8Hz,1H),3.56(dd,J=10.4,3.2Hz,1 H),3.02-2.90(m,2H),2.87-2.78(m,1H),2.70(dd,J=12.1,10.3Hz,1H),2.49(td,J=1 1.5,2.9Hz,1H),0.97(d,J=6.9Hz,3H),0.76(d,J=6.6Hz,3H).MS-ESI(m / z):413(M+H) + .

[0282] Example 72

[0283]

[0284] Referring to the method in Example 16, an equal molar amount of 2-(4-bromophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the starting material to prepare the target compound V-1. 1H NMR (500MHz, CDCl3) δ7.97(d,J=8.5Hz,1H),7.55(d,J=2.1Hz,1H),7.48(d,J=8.4 Hz,2H),7.38(dd,J=8.5,2.1Hz,1H),7.21(d,J=8.1Hz,2H),4.51(dd,J=10.4,2.7H z,1H),4.07(dd,J=11.7,2.6Hz,1H),3.87-3.75(m,2H),3.70(d,J=12.7Hz,1H),3. 01(td,J=12.1,3.3Hz,1H),2.72(dd,J=12.6,10.4Hz,1H).MS-ESI(m / z):452(M+H) + .

[0285] Example 73

[0286]

[0287] Referring to the method in Example 16, an equal molar amount of 2-(4-fluorophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the starting material to prepare the target compound V-2. 1 H NMR(600MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.56(d,J=2.0Hz,1H),7.38(dd,J=8 .5,2.0Hz,1H),7.34-7.28(m,2H),7.08-7.00(m,2H),4.52(dd,J=10.5,2.7Hz,1 H),4.08(dd,J=11.7,2.2Hz,1H),3.85-3.77(m,2H),3.71(d,J=12.7Hz,1H),3.0 3(td,J=12.1,3.3Hz,1H),2.75(dd,J=12.6,10.5Hz,1H).MS-ESI(m / z):390(M+H) + .

[0288] Example 74

[0289]

[0290] Referring to the method in Example 16, the target compound V-3 was prepared by using an equal molar amount of 2-(4-trifluoromethylphenyl)morpholine instead of (S)-2-phenylmorpholine as the raw material. 1H NMR(500MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.62(d,J=8.1Hz,2H),7.56(d,J=2.1 Hz,1H),7.47(d,J=8.0Hz,2H),7.39(dd,J=8.5,2.1Hz,1H),4.62(dd,J=10.5,2.7H z,1H),4.11(dd,J=11.8,2.1Hz,1H),3.89-3.78(m,2H),3.72(d,J=12.7Hz,1H),3. 04(td,J=11.9,3.3Hz,1H),2.74(dd,J=12.6,10.4Hz,1H).MS-ESI(m / z):440(M+H) + .

[0291] Example 75

[0292]

[0293] Referring to the method in Example 16, an equal molar amount of 2-(4-chlorophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-4. 1 H NMR (600MHz, CDCl3) δ7.97(d,J=8.5Hz,1H),7.55(d,J=2.1Hz,1H),7.38(dd, J=8.5,2.1Hz,1H),7.35-7.30(m,2H),7.29-7.24(m,2H),4.52(dd,J=10.4,2 .7Hz,1H),4.10-4.05(m,1H),3.85-3.75(m,2H),3.73-3.67(m,1H),3.02(td ,J=12.1,3.3Hz,1H),2.73(dd,J=12.6,10.4Hz,1H).MS-ESI(m / z):408(M+H) + .

[0294] Implementation 76

[0295]

[0296] Referring to the method in Example 16, an equal molar amount of 2-(4-methoxyphenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-5. 1H NMR (500MHz, CDCl3) δ7.97(d,J=8.5Hz,1H),7.55(d,J=2.1Hz,1H),7.37(dd,J=8 .5,2.1Hz,1H),7.28-7.22(m,2H),6.91-6.84(m,2H),4.48(dd,J=10.5,2.7Hz,1 H),4.07(dd,J=11.7,2.1Hz,1H),3.83-3.75(m,5H),3.70(d,J=12.6Hz,1H),3.0 2(td,J=12.1,3.3Hz,1H),2.77(dd,J=12.5,10.5Hz,1H).MS-ESI(m / z):402(M+H) + .

[0297] Example 77

[0298]

[0299] Referring to the method in Example 16, an equal molar amount of 2-(4-methylphenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-6. 1 H NMR(500MHz, CDCl3) δ7.96(d,J=8.6Hz,1H),7.55(d,J=2.1Hz,1H),7.37(dd,J=8.5, 2.1Hz,1H),7.21(d,J=8.0Hz,2H),7.15(d,J=7.9Hz,2H),4.50(dd,J=10.5,2.7Hz,1H ),4.07(dd,J=11.7,2.0Hz,1H),3.83-3.75(m,2H),3.74-3.68(m,1H),3.02(td,J=1 2.1,3.3Hz,1H),2.76(dd,J=12.5,10.4Hz,1H),2.33(s,3H).MS-ESI(m / z):386(M+H) + .

[0300] Example 78

[0301]

[0302] Referring to the method in Example 16, an equal molar amount of 2-(2-fluorophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-7. 1H NMR (500MHz, CDCl3) δ8.00(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.44(td,J=7.5,1.8Hz,1H),7.38(d d,J=8.5,2.1Hz,1H),7.33-7.26(m,1H),7.15(td,J=7.6,1.2Hz,1H),7.08-7.01(m,1H),4.83(dd,J=10. 4,2.7Hz,1H),4.09(dd,J=11.7,2.1Hz,1H),3.89(dt,J=12.5,2.3Hz,1H),3.81(td,J=11.8,2.7Hz,1H), 3.75-3.68(m,1H),3.08(td,J=12.2,3.3Hz,1H),2.78(dd,J=12.5,10.4Hz,1H).MS-ESI(m / z):390(M+H) + .

[0303] Example 79

[0304]

[0305] Compound V-7 was split to obtain compound V-7-1, chromatographic column AS-H, 5μm*10mmI.D.*250mmL, mobile phase: n-hexane:isopropanol=95:5, flow rate 3.76mL / min. 1 H NMR (500MHz, CDCl3) δ8.00(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.44(t,J=7.4Hz,1H),7.38(dd,J =8.5,2.0Hz,1H),7.32-7.28(m,1H),7.15(t,J=7.5Hz,1H),7.04(t,J=9.5Hz,1H),4.83(dd,J=10.4,2 .6Hz,1H),4.09(dd,J=11.7,3.3Hz,1H),3.89(d,J=12.1Hz,1H),3.81(td,J=11.8,2.8Hz,1H),3.72(d ,J=12.7Hz,1H),3.08(td,J=12.2,3.3Hz,1H),2.78(dd,J=12.5,10.4Hz,1H).MS-ESI(m / z):390(M+H) + ;

[0306]

[0307] Example 80

[0308]

[0309] Compound V-7 was split to obtain compound V-7-2, chromatographic column AS-H, 5μm*10mmI.D.*250mmL, mobile phase: n-hexane:isopropanol = 95:5, flow rate 3.76mL / min. 1 H NMR (500MHz, CDCl3) δ8.00(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.44(t,J=7.2Hz,1H),7.39(dd ,J=8.5,2.1Hz,1H),7.33-7.27(m,1H),7.15(t,J=7.6Hz,1H),7.04(t,1H),4.83(dd,J=10.3,2.7Hz ,1H),4.09(dd,J=11.9,2.7Hz,1H),3.89(d,J=12.7Hz,1H),3.81(td,J=11.8,2.7Hz,1H),3.72(d,J =12.9Hz,1H),3.08(td,J=12.2,3.4Hz,1H),2.78(dd,J=12.5,10.4Hz,1H).MS-ESI(m / z):390(M+H) + ;

[0310] Example 81

[0311]

[0312] Referring to the method in Example 16, an equal molar amount of 2-(2-chlorophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-8. 1H NMR (500MHz, CDCl3) δ8.01(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.50(dd,J=7.6,1.9Hz,1H),7. 38(dd,J=8.5,2.1Hz,1H),7.34(dd,J=7.7,1.6Hz,1H),7.31-7.21(m,2H),4.88(dd,J=10.2,2.6Hz, 1H), 4.11 (dd, J=11.8, 2.2Hz, 1H), 3.98 (dt, J=12.5, 2.3Hz, 1H), 3.84 (td, J=11.8, 2.8Hz, 1H), 3.75 -3.69(m,1H),3.10(td,J=12.3,3.4Hz,1H),2.63(dd,J=12.5,10.2Hz,1H).MS-ESI(m / z):408(M+H) + .

[0313] Example 82

[0314]

[0315] Referring to the method in Example 16, an equal molar amount of 2-(3-fluorophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-9. 1 H NMR (500MHz, CDCl3) δ7.98 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.5, 2. 1Hz,1H),7.35-7.29(m,1H),7.12-7.05(m,2H),7.00(td,J=8.4,1.7Hz,1H),4.55(dd, J=10.4,2.7Hz,1H),4.09(dd,J=11.7,2.0Hz,1H),3.87-3.76(m,2H),3.75-3.69(m,1H ),3.03(td,J=12.1,3.3Hz,1H),2.74(dd,J=12.6,10.4Hz,1H).MS-ESI(m / z):390(M+H) + .

[0316] Example 83

[0317]

[0318] Compound V-9 was decomposed into compound V-9-1, chromatographic column AS-H, 5μm*10mmI.D.*250mmL, mobile phase: n-hexane:isopropanol=95:5, flow rate 3.76mL / min. 1 H NMR (500MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.56(d,J=2.0Hz,1H),7.39(d,J =8.4Hz,1H),7.35-7.28(m,1H),7.12-7.04(m,2H),7.00(t,J=7.7Hz,1H),4.5 5(d,J=10.2Hz,1H),4.09(d,J=11.6Hz,1H),3.87-3.77(m,2H),3.71(d,J=13 .0Hz,1H),3.02(t,J=12.0Hz,1H),2.78-2.70(m,1H).MS-ESI(m / z):390(M+H) + ;

[0319] Example 84

[0320]

[0321] Compound V-9 was split to obtain compound V-9-2, chromatographic column AS-H, 5μm*10mmI.D.*250mmL, mobile phase: n-hexane:isopropanol=95:5, flow rate 3.76mL / min. 1 H NMR (500MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.39(dd,J=8.5,2.1Hz ,1H),7.32(td,J=7.9,5.8Hz,1H),7.12-7.05(m,2H),7.00(td,J=8.4,2.0Hz,1H),4.55(d d,J=10.4,2.7Hz,1H),4.09(dd,J=12.0,2.3Hz,1H),3.87-3.77(m,2H),3.72(d,J=12.6Hz ,1H),3.03(td,J=12.1,3.3Hz,1H),2.74(dd,J=12.6,10.4Hz,1H).MS-ESI(m / z):390(M+H) + ;

[0322] Example 85

[0323]

[0324] Referring to the method in Example 16, an equal molar amount of 2-(2,4-difluorophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-10. 1 H NMR(500MHz, CDCl3)δ8.00(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.45-7.36(m,2H),6.8 8(td,J=8.1,2.3Hz,1H),6.84-6.77(m,1H),4.77(dd,J=10.4,2.7Hz,1H),4.08(dd,J=12.2 ,2.7Hz,1H),3.87(dt,J=12.5,2.3Hz,1H),3.79(td,J=11.8,2.7Hz,1H),3.70(d,J=12.7Hz ,1H),3.06(td,J=12.2,3.3Hz,1H),2.76(dd,J=12.5,10.4Hz,1H).MS-ESI(m / z):408(M+H) + .

[0325] Example 86

[0326]

[0327] Referring to the method in Example 16, an equal molar amount of 2-(3,4-difluorophenyl)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-11. 1 H NMR(500MHz, CDCl3) δ7.98(d,J=8.5Hz,1H),7.56(d,J=2.1Hz,1H),7.39(dd,J=8 .6,2.1Hz,1H),7.23-7.09(m,2H),7.08-7.01(m,1H),4.51(dd,J=10.5,2.7Hz,1 H),4.08(dd,J=11.7,2.1Hz,1H),3.87-3.75(m,2H),3.70(d,J=12.7Hz,1H),3.0 1(td,J=12.0,3.4Hz,1H),2.71(dd,J=12.6,10.4Hz,1H).MS-ESI(m / z):408(M+H) + .

[0328] Example 87

[0329]

[0330] Referring to the method in Example 16, the target compound V-12 was prepared by using an equal molar amount of 2-(thiazol-2-yl)morpholine instead of (S)-2-phenylmorpholine as the starting material. 1 H NMR (600MHz, CDCl3) δ8.03(d,J=8.5Hz,1H),7.75(d,J=3.2Hz,1H),7.55(d,J= 2.0Hz,1H),7.39(dd,J=8.5,2.0Hz,1H),7.34(d,J=3.2Hz,1H),4.87(dd,J=10. 1,2.9Hz,1H),4.20-4.09(m,2H),3.87(td,J=11.6,2.7Hz,1H),3.82-3.75(m, 1H),3.17-3.09(m,1H),2.98(dd,J=12.7,10.2Hz,1H).MS-ESI(m / z):379(M+H) + .

[0331] Example 88

[0332]

[0333] Referring to the method in Example 16, an equal molar amount of 2-(4-pyridine)morpholine was used instead of (S)-2-phenylmorpholine as the raw material to prepare the target compound V-13. 1 H NMR (500MHz, CDCl3) δ8.59(d,J=6.1Hz,2H),7.98(d,J=8.6Hz,1H),7.55(d,J=2.1Hz,1H), 7.39(dd,J=8.6,2.1Hz,1H),7.26(d,J=5.9Hz,2H),4.57(dd,J=10.4,2.7Hz,1H),4.14-4. 07(m,1H),3.88(dt,J=12.5,2.3Hz,1H),3.80(td,J=11.7,2.7Hz,1H),3.71(d,J=12.9Hz, 1H),3.03(td,J=12.2,3.3Hz,1H),2.73(dd,J=12.6,10.4Hz,1H).MS-ESI(m / z):373(M+H) + .

[0334] Biological Example 1 Determination of Anti-Influenza Efficacy by CPE Method

[0335] MDCK cells were grown at 2.5×10 4After 24 hours, the cells were washed with PBS and infected with 100 times the 50% tissue culture infective dose (TCID 50 ) virus solution (using MEM medium containing 1% double antibody and 1% NEAA) was used to infect MDCK cells, adsorbed for 2 hours, discarded the virus solution, and added virus maintenance solution containing different dilutions of compounds and positive control drugs (MEM medium supplemented with 2μg ml -1 TPCK-treated trypsin, 1% double antibody and 0.08% BSA). Continue incubating in a 37°C incubator for about 2 days. When the cytopathic effect (CPE) of the virus control group reaches 75%-100%, observe CPE under an inverted microscope. Calculate the 50% inhibitory concentration (IC) of the drug by the Reed & Muench method. 50 ).

[0336]

[0337] Where: A = drug concentration at which cumulative lesion rate < 50%, B = percentage at which cumulative lesion rate > 50%, C = cumulative inhibition rate

[0338] Percentage <50%, D = log dilution factor

[0339] The results are shown in Table 1.

[0340] Table 1. In vitro anti-influenza virus (IAV H1N1) activity of compounds

[0341]

[0342]

[0343] RBV, ribavirin

[0344] Table 2. Inhibitory activity of preferred compounds against different influenza virus strains

[0345]

[0346] RBV, ribavirin; OP, oseltamivir phosphate

[0347] Biological Example 3 Cytopathic Effect (CPE) Compound Toxicity Evaluation Experiment

[0348] MDCK cells were grown at 2.5×10 4 After 24 h of culture, the culture medium was discarded and the cells were added with 100 μL of maintenance solution (MEM medium supplemented with 2 μg ml-1 Compound solutions of varying concentrations (TPCK-treated trypsin, 1% double-stranded antibody, and 0.08% BSA) were prepared, with cell controls and blank controls set up. Cultures were continued. Two days after administration, drug toxicity to cells was assessed under an inverted microscope (CPE assay), and the median toxic concentration (CC) was calculated using the Reed-Muench method. 50 , the calculation formula is as follows:

[0349]

[0350] Where: A = drug concentration at which cumulative lesion rate is <50%, B = percentage at which cumulative lesion rate is >50%, C = percentage at which cumulative inhibition rate is <50%, D = log dilution factor

[0351] It has been verified that all compounds in the examples have good safety, and some of the results are shown in Table 4.

[0352] Table 3. Toxicity evaluation results of preferred compounds

[0353] Compd. <![CDATA[CC 50 (μM)]]> Ⅰ-16 >50 Ⅰ-18 >50 Ⅰ-28 >50 Ⅳ-4-2 >50 Ⅴ-7-2 >50 Ⅴ-8 38.49 Ⅴ-9-2 >50 OP >200 RBV >50

[0354] Biological Example 2 Pharmacokinetic Experiment

[0355] Following a single oral dose of the target compound in female Kunming mice, blood samples were collected at various time points. Plasma compound concentrations were determined by LC-MS / MS, and pharmacokinetic parameters were calculated to investigate compound exposure in mice. Nine Kunming mice were provided by Beijing Huafukang Biotechnology Co., Ltd., and the experiments were performed according to Table 4.

[0356] Table 4. Pharmacokinetic Dosing Regimen

[0357]

[0358] 0.15 mL of blood was collected from each mouse via orbital sampling and anticoagulated with sodium heparin at 5, 15, 30, 1, 2, 4, 6, 8, 12, and 24 hours after administration of the test substance. Blood samples were collected from nine mice per group. Blood samples were stored on ice and centrifuged within 30 minutes to separate plasma (5000 rpm, 10 minutes, 4°C). Blood samples were stored at –80°C until analysis.

[0359] The data acquisition and control system software was Analyst 1.5.1 (Applied Biosystems). The peak integration method for the chromatogram samples was automatic integration; the ratio of the sample peak area to the internal standard peak area was used as an indicator and regressed with the sample concentration. Regression method: linear regression with a weighting factor of 1 / X. 2Pharmacokinetic parameters were analyzed using WinNonlin Professional v6.3 (Pharsight, USA) using a non-compartmental model. max The area under the plasma concentration-time curve AUC is the maximum measured plasma concentration. (0→inf) Calculated by the trapezoidal method, T max The experimental data are expressed as "mean ± standard deviation" (n≥3). The results are shown in Table 5.

[0360] Table 5. Pharmacokinetic parameters of preferred compounds

[0361]

Claims

1. An arylsulfonamide compound, its pharmaceutically acceptable salt and isomer, characterized in that: The structure of the aryl sulfonamide compound is as follows:

2. A pharmaceutical composition comprising the arylsulfonamide compound, a pharmaceutically acceptable salt or an isomer thereof according to claim 1.

3. The pharmaceutical composition according to claim 2, characterized in that Contains one or more pharmaceutically acceptable carriers or excipients.

4. Use of a compound, a pharmaceutically acceptable salt and an isomer thereof in the preparation of a medicament for treating or preventing influenza virus infection, characterized in that: The structure of the compound is as shown in claim 1 or as follows: The influenza virus is H1N1 influenza A.

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