A cyclobutane-pyridine sulfonamide compound

Abstract

The present invention discloses a cyclobutane-pyridine sulfonamide compound, the structure of which is shown in the general formula in the abstract figure; the present invention also discloses a method for preparing the cyclobutane-pyridine sulfonamide compound. The present invention also discloses the use of the cyclobutane-pyridine sulfonamide as a reversible and selective cholinesterase inhibitor drug, which can be specifically applied to drugs or pharmaceutical compositions for treating and preventing diseases related to aging, Alzheimer's disease and Parkinson's disease.

Description

Technical Field

[0001] The present invention relates to the field of new compounds, in particular to a cyclobutane-pyridine sulfonamide compound. Background Art

[0002] Sulfonyl drugs account for a large proportion of clinical therapeutic drugs. As of the end of 2019, the US FDA has approved more than 150 sulfonyl drugs, accounting for about 8% of all approved small molecule drugs. Therefore, introducing sulfonyl groups into small molecules is one of the important strategies for modifying the molecular structure of drugs.

[0003] Sulfonyl fluoride compounds have special electrophilic functions and can be used as targeted covalent inhibitors of lysine, threonine, serine, tyrosine, cysteine ​​and histidine with high selectivity. They have great prospects in the rational design and development of innovative covalently bonded drugs with sulfonyl fluoride groups.

[0004] Sulfonamides are considered to be one of the special structural fragments in pharmaceutical chemistry and agricultural chemistry. According to statistics, there are more than 150 sulfonamides on the market. VI ) compounds, especially sulfonyl or sulfonamide compounds, show a variety of pharmacological properties, and their derivatives have a high degree of structural diversity, which lays the foundation for the search for new therapeutic drugs. Combined with the cholinergic hypothesis, the application of sulfonamide nucleus as the core substituent of Alzheimer's agent in drug development was discovered.

[0005] The reaction of sulfonyl fluoride and fluorosulfate with N-nucleophiles has been developed for the synthesis of sulfonamides and sulfamates by catalytic methods. Sulfonyl fluoride can be converted into sulfonamide drugs for drug development.

[0006] Based on the above technical problems and background, a centralized database of sulfonamides at the picomolar level can be created by reacting sulfonyl fluoride with primary or secondary amines. Combined with the potential significance of amide core structure modification, a high-throughput screening platform for cholinesterase inhibitors will be established to accelerate the discovery of new anti-Alzheimer's drugs. How to prepare a new compound by the above technology is the problem to be solved in this application. Summary of the invention

[0007] The purpose of the present invention is to provide a cyclobutane-pyridine sulfonamide compound for developing a drug capable of resisting Alzheimer's disease.

[0008] The above technical objectives of the present invention are achieved through the following technical solutions:

[0009] A cyclobutane-pyridine sulfonamide compound, characterized in that the structure of the compound is as shown in Formula I:

[0010]

[0011] Wherein, R1 and R2 are selected from H, (C1-C4) alkyl, pyridyl, furyl, thienyl, benzyl, substituted phenyl, and each optionally contains one or more substituents selected from halo, cyano, nitro, (C1-C3) alkoxy or alkanethio; or NR1R2 is selected from 3-7 membered cyclic amines and heterocyclic amines containing N, O or S, and each optionally contains one or more substituents selected from halo, cyano, alkoxy or alkanethio.

[0012] Preferably, the structure of the compound is as shown in Formula II:

[0013]

[0014] Wherein, R1 and R2 are selected from H, (C1-C4) alkyl, pyridyl, furyl, thienyl, benzyl, substituted phenyl, and each optionally contains one or more substituents selected from halo, cyano, nitro, (C1-C3) alkoxy or alkanethio; or NR2R3 is selected from 3-7 membered cyclic amines and heterocyclic amines containing N, O or S, and each optionally contains one or more substituents selected from halo, cyano, alkoxy or alkanethio. R3 is selected from Cl and Br.

[0015] Preferably, the preparation method of cyclobutane-pyridine sulfonamide compounds is as follows:

[0016] The amine compound and cyclobutane-pyridine sulfonyl fluoride undergo a substitution reaction under alkaline conditions to obtain a cyclobutane-pyridine sulfonamide compound.

[0017] The present invention also discloses a method for preparing the above-mentioned cyclobutane-pyridine sulfonamide compounds. Preferably, the preparation method is as follows:

[0018] The intermediate amine (1.2eq) and K2CO3 (1.5eq) were added to a solution of cyclobutane-pyridine sulfonyl fluoride compound (0.1mmol) in acetonitrile (3mL), and the suspended solution was stirred at room temperature for 8 hours. After the reaction was completed, the reaction solution was poured into water (15mL). After stirring for 10 minutes, the reaction solution was extracted with ethyl acetate (3×30mL), the ethyl acetate layers were combined, and washed twice with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate overnight and concentrated, and the concentrate was purified by an automatic chromatography system to obtain cyclobutane-pyridine sulfonamide compounds.

[0019] Preferably, the corresponding amine in step S1 is any one of the following amine compounds: N-benzylpiperazine, N-(2-fluoro)-benzylpiperazine, N-(3-fluoro)-benzylpiperazine, N-(4-fluoro)-benzylpiperazine, N-benzyl-4-aminomethylpiperidine, N-(2-fluoro)-benzyl-4-aminomethylpiperidine, N-(3-fluoro)-benzyl-4-aminomethylpiperidine, N-(4-fluoro)-benzyl-4-aminomethylpiperidine, o-fluorophenethylamine, p-fluorophenethylamine, morpholine, N-(2-aminoethyl)morpholine, 2-aminopyridine, 4-(aminomethyl)pyridine, 4-(2-amino ethyl)pyridine, 2-(2-aminoethyl)pyridine, n-propylamine, isopropylamine, cyclohexylamine, cyclopropylmethylamine, cyclopropylamine, cyclopentylamine, thiazolidine, pyrrole, indole, carbazole, N-methylpiperazine, N-hydroxyethylpiperazine, diphenylamine, dimethylamine, dihexylamine, piperidine, 4-benzylpiperidine, N-benzyl-4-aminopiperidine, N-benzyl-4-aminoethylpiperidine, diethylamine, methylethylamine, N-methylbenzylamine, N-methyl-3-fluorobenzylamine, N-methyl-3-chlorobenzylamine, N-methyl-3-bromobenzylamine, N-methyl-4-fluorobenzylamine, N-methyl-4-chlorobenzylamine, N-methyl-4-bromobenzylamine.

[0020] The above-mentioned cyclobutane-pyridine sulfonamide derivatives have a partial structural formula:

[0021]

[0022]

[0023] The present invention also discloses a pharmaceutical preparation with cyclobutane-pyridine sulfonamide compounds as active compounds, and the active compounds are added with excipients acceptable in pharmacy to prepare one or more dosage forms of tablets, capsules, lozenges, injections, suspensions, suppositories, and ointments.

[0024] Preferably, the auxiliary materials include excipients and carriers, the excipients include one or more combinations of calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol, and the carriers include one or more combinations of diluents, disintegrants, binders and lubricants.

[0025] Preferably, the dosage strength of the active compound in the pharmaceutical preparation is 10-100 mg.

[0026] Preferably, the dosage strength of the active compound in the pharmaceutical preparation is 20 mg.

[0027] The present invention also applies the above-mentioned pharmaceutical preparation to the preparation of anti-Alzheimer's disease drugs.

[0028] The beneficial effects of the present invention are:

[0029] 1. The preparation process is simple and easy to operate;

[0030] 2. It has good anti-cholinesterase activity, and shows good application prospects and potential in the treatment of Alzheimer's disease. DETAILED DESCRIPTION

[0031] The following is only a preferred embodiment of the present invention, and the protection scope is not limited to this embodiment. All technical solutions under the concept of the present invention should belong to the protection scope of the present invention.

[0032] Example 1

[0033] Preparation of (1R, 6R, 7R)-4-fluoro-N-(2-fluorophenylethyl)-2-methyl-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7-sulfonamide (as shown in structural formula 1):

[0034]

[0035] 2-Fluorophenylethylamine (1.2 eq) and K2CO3 (1.5 eq) were added to a solution of compound J13 (0.1 mmol) in acetonitrile (3 mL). The suspended reaction solution was stirred at room temperature for 8 hours. After the reaction was completed, the reaction mixture was poured into water (15 mL). After stirring for 10 minutes, the mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate layer was washed twice with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate overnight and concentrated; the residue was purified by an automated chromatography system to obtain the target product (1R, 6R, 7R)-4-fluoro-N-(2-fluorophenylethyl)-2-methyl-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7-sulfonamide.

[0036] Structural data characterization: 1 H NMR (500MHz, CDCl3) δ7.27(d,J=4.7Hz,1H),7.22(t,J=7.6Hz,1H),7.13(dt,J=9 .1,4.7Hz,1H),7.10–7.03(m,1H),5.82–5.75(m,1H),4.50(t,J=6.1Hz,1H),4.2 9–4.19(m,1H),3.67(t,J=7.4Hz,1H),3.52(dq,J=9.5,4.8,4.2Hz,1H),3.43(qd ,J=6.6,2.5Hz,2H),2.94–2.89(m,2H),2.89(d,J=2.7Hz,3H),2.78–2.50(m,2H).

[0037] Example 2 Preparation of (1R, 6R, 7R)-4-fluoro-N-(4-fluorophenylethyl)-2-methyl-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7-sulfonamide (as shown in structural formula 2):

[0038]

[0039] 4-Fluorophenylethylamine (1.2 eq) and K2CO3 (1.5 eq) were added to a solution of compound J13 (0.1 mmol) in acetonitrile (3 mL). The suspension was stirred at room temperature for 8 hours. After the reaction was completed, the reaction mixture was poured into water (15 mL). After stirring for 10 minutes, the mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate layer was washed twice with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate overnight and concentrated; the concentrate was purified by an automated chromatography system to obtain the target product (1R, 6R, 7R)-4-fluoro-N-(4-fluorophenylethyl)-2-methyl-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7-sulfonamide.

[0040] Structural data characterization: 1 H NMR (500MHz, CDCl3) δ7.16(dd,J=8.4,5.3Hz,2H),7.02(t,J=8.5Hz,2H),5.82(dd,J=10.1,4.6Hz,1H),4.40(t,J=6.1Hz,1H),4.23(q,J= 7.9Hz,1H),3.73–3.65(m,1H),3.59(dt,J=9.6,4.8Hz,1H),3.37(q,J=6.2Hz,2H),2.89(s,3H),2.84(t,J=6.7Hz,2H),2.77–2.56(m,2H).

[0041] Example 3 Preparation of (1R, 6R, 7R)-7-((4-benzylpiperidin-1-yl)sulfonyl)-4-fluoro-2-methyl-2-azabicyclo[4.2.0]oct-4-ene-3-one (as shown in structural formula 3):

[0042]

[0043] 4-Benzylpiperidine (1.5 eq) and K2CO3 (2.0 eq) were added to a solution of compound J13 (0.2 mmol) in acetonitrile (3 mL). The suspension was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (15 mL). After stirring for 10 minutes, the mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate layer was washed twice with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate overnight and concentrated; the concentrate was purified by an automated chromatography system to obtain the target product (1R, 6R, 7R)-7-((4-benzylpiperidin-1-yl)sulfonyl)-4-fluoro-2-methyl-2-azabicyclo[4.2.0]oct-4-ene-3-one.

[0044] Structural data characterization: 1 H NMR (600MHz, CDCl3) δ7.28(d,J=7.4Hz,2H),7.23–7.20(m,1H),7.12(d,J=7.3Hz,2H),5.87(d d,J=10.0,4.7Hz,1H),4.32–4.25(m,1H),3.77(dt,J=14.3,3.9Hz,3H),3.63(dt,J=10.1,5.0H z,1H),2.91(s,3H),2.81(dt,J=14.3,6.0Hz,1H),2.72(tdd,J=12.3,6.1,2.5Hz,2H),2.67–2 .60(m,1H),2.57(d,J=7.1Hz,2H),1.73(d,J=13.8Hz,4H),1.66(ddt,J=11.3,7.5,3.8Hz,1H). 13 C NMR (151MHz, CDCl3) δ157.21,149.40,129.23,128.54,126.40,110.79,56.85,52.06,46.76,46.54,42.87,37.65,35.48,32.18,32.15,32.08.

[0045] Example 4 Preparation of (1R, 6R, 7R)-N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-fluoro-2-methyl-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7-sulfonamide (as shown in Structural Formula 4):

[0046]

[0047] 2-(1-benzylpiperidin-4-yl)ethane-1-amine (1.2 eq) and K2CO3 (1.5 eq) were added to a solution of compound J13 (0.1 mmol) in acetonitrile (3 mL). The suspension was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (15 mL). After stirring for 10 minutes, the mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate layer was washed twice with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate overnight and concentrated; the concentrate was purified by an automated chromatography system to obtain the title product (1R, 6R, 7R)-N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-fluoro-2-methyl-3-oxo-2-azabicyclo[4.2.0]oct-4-ene-7-sulfonamide.

[0048] Structural data characterization: 1 H NMR (500MHz, CDCl3) δ7.35–7.31(m,4H),7.32–7.26(m,1H),5.92(dd,J=10.1,4.7Hz,1 H),4.48(s,1H),4.28(dt,J=9.7,7.2Hz,1H),3.79–3.72(m,1H),3.68(dt,J=10.0,5.0 Hz,1H),3.59(s,2H),3.48(s,1H),3.14(q,J=6.7Hz,2H),2.97(d,J=11.1Hz,2H),2.91 (s,3H),2.84–2.65(m,2H),1.67(d,J=9.1Hz,2H),1.50(q,J=7.1Hz,3H),1.42(s,1H).

[0049] Example 5 Preparation of (1R, 2aR, 8bR)-N-(2-(1-benzylpiperidin-4-yl)ethyl)-8-bromo-4-oxo-1,2,2a,3,4,8b-hexahydrocyclobutane[c]isoquinoline-1-sulfonamide (as shown in Structural Formula 5):

[0050]

[0051] To a solution of compound J4 (0.1 mmol) in acetonitrile (3 mL) were added 2-(1-benzylpiperidin-4-yl)ethane-1-amine (1.2 eq) and K2CO3 (1.5 eq). The suspension was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (15 mL). After stirring for 10 minutes, the mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate layers were washed twice with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate overnight and concentrated; the residue was purified by an automated chromatography system to obtain the target product (1R,2aR,8bR)-N-(2-(1-benzylpiperidin-4-yl)ethyl)-8-bromo-4-oxo-1,2,2a,3,4,8b-hexahydrocyclobutane[c]isoquinoline-1-sulfonamide.

[0052] Structural data characterization: 1 H NMR (600MHz, CDCl3) δ8.20 (dd, J=7.8, 1.3Hz, 1H), 7.74 (dd, J=8.0, 1.3Hz, 1H), 7.30 (d, J=5.8 Hz,5H),6.39–6.35(m,1H),4.55–4.46(m,2H),4.40(t,J=7.2Hz,1H),3.94(dt,J=8.8,6.7Hz,1 H),3.49(s,2H),3.16–2.95(m,2H),2.85(d,J=6.5Hz,2H),2.84–2.81(m,1H),2.48(ddd,J=12. 7,8.7,4.1Hz,1H),2.06–1.59(m,6H),1.54(ddt,J=15.2,10.1,2.7Hz,2H),1.39–1.33(m,1H). 13 C NMR(151MHz, CDCl3)δ162.95,137.37(2C),135.87,129.72,129.56,129.45(2C),128.56,128.35(2C),127.24, 123.06,77.37,77.16,76.95,63.42,59.94,53.59(2C),46.23,41.27,39.44,37.04,33.56(2C),32.94,31.97.

[0053] Example 6 Preparation of (1R, 2aR, 8bR)-N-(2-(1-benzylpiperidin-4-yl)ethyl)-8-chloro-4-oxo-1,2,2a,3,4,8b-hexahydrocyclobutane[c]isoquinoline-1-sulfonamide (as shown in Structural Formula 6):

[0054]

[0055] To a solution of compound J8 (0.1 mmol) in acetonitrile (3 mL) were added 2-(1-benzylpiperidin-4-yl)ethane-1-amine (1.2 eq) and K2CO3 (1.5 eq). The suspension was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (15 mL). After stirring for 10 minutes, the mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate layers were washed twice with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate overnight and concentrated; the concentrate was purified by an automated chromatography system to obtain the target product (1R,2aR,8bR)-N-(2-(1-benzylpiperidin-4-yl)ethyl)-8-chloro-4-oxo-1,2,2a,3,4,8b-hexahydrocyclobutane[c]isoquinoline-1-sulfonamide.

[0056] Structural data characterization: 1 H NMR (600MHz, CDCl3) δ8.17(dd,J=7.8,1.3Hz,1H),7.57(dd,J=8.0,1.3Hz,1H),7.39(t,J=7.9Hz,1H),7. 31(d,J=5.5Hz,5H),6.24(d,J=2.9Hz,1H),4.57–4.50(m,1H),4.40(dt,J=12.7,6.3Hz,2H),3.89(dt,J= 8.9,6.0Hz,1H),3.50(s,2H),3.17–3.00(m,2H),2.87(t,J=3.9Hz,2H),2.85–2.83(m,1H),2.51(ddd,J= 13.3,9.0,4.9Hz,1H),1.93(d,J=12.2Hz,2H),1.68–1.66(m,6H),1.61–1.52(m,2H),1.39–1.36(m,1H). 13 C NMR(151MHz, CDCl3)δ162.79,134.30(2C),134.00,132.98,129.46(2C),129.32,129.27,128.36(2C),127.87, 127.26,77.37,77.16,76.95,63.43,59.63,53.60(2C),46.12,41.36,37.46,37.08,33.71(2C),32.96,32.05.

[0057] Example 7

[0058] The cyclobutane-pyridine sulfonamide compound prepared in the above example is used as the active compound. According to the conventional preparation method of pharmaceutical preparations, the above active compound is prepared into one or more dosage forms of tablets, capsules, lozenges, injections, suspensions, suppositories, and ointments. The preparation includes the active compound itself and pharmaceutically acceptable excipients, and the excipients are carriers or excipients.

[0059] Wherein, the dosage specification of the active compound in the above-mentioned pharmaceutical preparation is 10-100 mg.

[0060] Among them, the excipient is calcium carbonate, calcium phosphate, sugar, starch, cellulose derivative, gelatin, vegetable oil or polyethylene glycol; the carrier is a diluent, disintegrant, binder or lubricant.

[0061] Formulation Examples

[0062] Tablets each containing 10*100 mg of active ingredient can be prepared as follows:

[0063]

[0064]

[0065] Raw material pretreatment → weighing → sieving (lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose are sieved through 100 meshes respectively, and magnesium stearate is sieved through 40 meshes) → mixing (olanzapine, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose are pre-mixed, and then lactose is added and mixed) → wet granulation (20 meshes) → drying → whole granulation (20 meshes) → total mixing (detection of intermediate particle content) → tableting. The prescription and test results are shown in the table below.

[0066] Anticholinesterase activity verification experiment: In order to verify that the sulfonamide compounds disclosed in the present invention have anticholinesterase activity, the anti-Alzheimer's disease sulfonamide tablets prepared in the above examples were selected.

[0067] 1. Experimental principle: The experiment adopts the modified Ellman method, using eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE) and their corresponding substrates iodoacetylcholine iodide and thiobutyrylcholine iodide to simulate the in vivo reaction environment. 5,5'-ditiobis-2-nitrobenzoico (DTNB) combines with the enzyme-substrate complex to produce a yellow anion 5-thio-2-nitrobenzoic acid, and then the inhibitory activity of the compound on the enzyme is calculated by measuring the absorbance.

[0068] 2. The experimental steps are as follows:

[0069] (1) preparing the compound using phosphate buffer at pH 8.0;

[0070] (2) The 48-well plate was divided into four groups: positive control group (donepezil + AChE / BuChE + solvent + iodoacetylcholine iodide / thiobutyrylcholine iodide + DTNB), experimental group (compound + AChE / BuChE + solvent + iodoacetylcholine iodide / thiobutyrylcholine iodide + DTNB), blank control group (AChE / BuChE + solvent + iodoacetylcholine iodide / thiobutyrylcholine iodide + DTNB), and background group (solvent + DTNB);

[0071] (3) Add 100 μL of compound (0.05, 0.5, 5, 50, 100 μM) solution to a 48-well plate, and replace the blank control wells and background wells with solvent;

[0072] (4) Add 100 μL of AChE / BuChE (0.18 U / mL) solution to a 48-well plate, except for the background wells which were replaced with solvent, and incubate at 37°C, 100 rpm on a constant temperature shaker for 20 min;

[0073] (5) Add 100 μL of solvent to the 48-well plate;

[0074] (6) Add 100 μL of iodoacetylcholine iodide / thiobutyrylcholine iodide (0.35 mM / 0.5 mM) solution to a 48-well plate, except for the background wells which were replaced with solvent;

[0075] (7) Add 100 μL of DTNB (0.35 mM) solution to a 48-well plate and incubate in a constant temperature shaker at 37°C, 100 rpm, in the dark for 20 or 40 min;

[0076] (8) Use an ELISA reader to measure the absorbance at 410 nm and calculate the inhibition rate.

[0077] (10) The above experiments were repeated three times, and the results were analyzed using SPSS17.0 statistical analysis software to calculate IC 50 .

[0078] 3. Experimental results: The experimental results are shown in Table 1, Table 2 and Table 3:

[0079] Table 1. Statistical table of anticholinesterase data of corresponding numbered compounds in each example

[0080]

[0081]

[0082]

[0083] Table 2. IC of the above active compounds 50 value

[0084] Compound <![CDATA[AChE inhibition(IC 50 ,μM)]]> H8 0.094±0.003 H18 0.24±0.01 H21 10.76±0.14 H22 4.56±0.07 H23 1.30±0.19 H24 6.78±0.35 H25 5.38±0.47 H26 7.87±0.27 H28 0.38±0.13

[0085] Table 3. hAChE a Enzyme inhibitory activity

[0086]

[0087]

[0088] Note: Each IC 50 Values ​​are means (±SEM) of at least 3 independent experiments;

[0089] IC 50 The value unit is: μmol / L, "na" means no activity.

[0090] It can be seen from the above table that the cyclobutane-pyridine sulfonamide compounds provided in this example have good anticholinesterase activity and show good application prospects and potential in the treatment of Alzheimer's disease.

[0091] The specific embodiments described above further illustrate the technical problems, technical solutions and beneficial effects solved by the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A cyclobutane-pyridine sulfonamide compound, characterized in that: The structure of the compound is shown in Formula I: R1 and R2 are one of H, (C1‒C4) alkyl, and substituted phenyl, and R1 and R2 optionally contain one or more substituents, and the substituents include halogen; or NR1R2 is selected from 3‒7 membered cyclic amines and 3‒7 membered heterocyclic amines containing N, O or S, and R1 and R2 optionally contain one or more substituents, and the substituents are selected from halogen.

2. According to the method for preparing a cyclobutane-pyridine sulfonamide compound according to claim 1, the cyclobutane-pyridine sulfonamide intermediate amine I is subjected to a substitution reaction with a cyclobutane-pyridine sulfonyl fluoride raw material II under alkaline conditions to obtain a cyclobutane-pyridine sulfonamide compound, and the reaction process is as follows: 。 3. A cyclobutane-pyridine sulfonamide compound, characterized in that: The structure of the compound is shown in Formula II: R1 and R2 are one of H, (C1‒C4) alkyl, and substituted phenyl, and R1 and R2 both optionally contain one or more substituents selected from halo; or NR1R2 is selected from 3‒7 membered cyclic amines and 3‒7 membered heterocyclic amines containing N, O or S, and both optionally contain one or more substituents selected from halo, and R3 is selected from Cl and Br.

4. A method for preparing a cyclobutane-pyridine sulfonamide compound according to claim 3, wherein the cyclobutane-pyridine sulfonamide intermediate amine I is subjected to a substitution reaction with a cyclobutane-pyridine sulfonyl fluoride raw material II under alkaline conditions to obtain a cyclobutane-pyridine sulfonamide compound, and the reaction process is as follows: 。 5. The use of a cyclobutane-pyridine sulfonamide compound according to any one of claims 1 or 3, characterized in that: The cyclobutane-pyridine sulfonamide compounds are used as active compounds in the preparation of pharmaceutical preparations. After adding auxiliary materials, the active compounds are prepared into one or more dosage forms of tablets, capsules, lozenges, injections, suspensions, suppositories, and ointments.

6. The use of a cyclobutane-pyridine sulfonamide compound according to claim 5, characterized in that: The auxiliary materials include excipients and carriers, wherein the excipients are one or more combinations of calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol, and the carriers are one or more combinations of diluents, disintegrants, binders and lubricants.

7. The use of a cyclobutane-pyridine sulfonamide compound according to claim 6, characterized in that: The dosage specification of the active compound in the pharmaceutical preparation is 10-100 mg.

8. The use of a cyclobutane-pyridine sulfonamide compound according to claim 7, characterized in that: The pharmaceutical preparation is used for preparing anti-Alzheimer's disease drugs.

9. A cyclobutane-pyridine sulfonamide compound, characterized in that: The structure of the compound is shown below: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。

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