A 4-quinazolinone derivative containing a benzene sulfonamide piperazinone and a preparation method and application thereof

Abstract

The application provides a 4-quinazolinone derivative containing a benzene sulfonamide piperazine ketone and a preparation method and application thereof. The derivative has the structure shown in the following general formula I. The application further relates to a preparation method of a compound containing the structure of formula I and application of the compound as an HIV-1 / HIV-2 capsid protein regulator in preparation of an anti-AIDS drug.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis and pharmaceutical application technology, specifically relating to a 4-quinazolinone derivative containing benzylsulfonamide piperazine ketone, its preparation method, and its use as an anti-HIV drug. Background Technology

[0002] AIDS (Acquired Immune Deficiency Syndrome) is a chronic infectious disease caused by the Human Immunodeficiency Virus (HIV). HIV is an RNA retrovirus with two subtypes, HIV-1 and HIV-2, with HIV-1 being the predominantly circulating pathogen. HIV-2 is mainly prevalent in West Africa, but with globalization and increasingly frequent people-to-people exchanges, the risk of HIV-2 infection is constantly increasing. Cases of HIV-2 infection have been found in countries and regions such as the United States, Europe, South Africa, India, and China, which should be given sufficient attention. Currently, anti-HIV drugs remain an effective weapon in the fight against AIDS. More than 30 chemical entities targeting key stages of the HIV-1 life cycle have been approved for marketing for combination therapy. However, drug resistance caused by rapid HIV mutations has become the biggest challenge facing existing anti-AIDS drugs, forcing researchers to develop anti-AIDS drugs with new targets, new mechanisms, and new structures.

[0003] The HIV-1 capsid protein is a structural protein essential for the formation of morphologically mature, infectious viral particles, encapsulating nucleic acids and enzymes crucial for viral infection. It plays a key role in both the early (uncoating, reverse transcription, nucleus entry, etc.) and late (assembly, maturation) stages of viral replication, and is a novel target for anti-AIDS drug research.

[0004] Our research group, using Pfizer's PF74 as a lead compound, discovered a novel benzylamide-piperazinone HIV capsid protein modulator through structural modification, with 11L as a representative compound. However, its antiviral activity still needs improvement. Based on the crystal structure characteristics of the 11L-HIV-1 capsid protein binding site complex, this invention, through rational drug design, chemical synthesis, and bioactivity evaluation, discovered a novel 4-quinazolinone derivative containing benzylamide-piperazinone as an HIV capsid protein modulator, which is expected to improve the problems of low efficacy, poor drug-like properties, and drug resistance of existing HIV capsid protein modulators.

[0005] Summary of the Invention

[0006] This invention provides a 4-quinazolinone derivative containing benzylsulfonamide piperazine ketone and its preparation method. This invention also provides the activity screening results of the above compound against HIV-1 / 2 and its pharmaceutical applications.

[0007] The technical solution of the present invention is as follows:

[0008] 1. 4-Quinazolone derivatives containing benzenesulfonamide piperazine ketone

[0009] 4-Quinazolinone derivatives containing benzylsulfonamide piperazine, or pharmaceutically acceptable salts thereof, having the structure shown in general formula I:

[0010]

[0011] in,

[0012] R1 is a hydrogen atom, a halogen atom, or a C1-C4 alkyl-substituted sulfonyl group; the halogen atom is selected from fluorine, chlorine, bromine, and iodine atoms; R2 is a hydrogen atom or a halogen atom; the halogen atom is selected from fluorine, chlorine, bromine, and iodine atoms; R3 is a methoxy group or a sulfonyl group substituted with various six-membered heterocycles; the six-membered heterocycle is selected from piperazine rings, morpholine rings, thiomorpholine rings, and 1,1-thiomorpholine dioxide rings; R4 is a nitro group or an amino group.

[0013] According to a preferred embodiment of the present invention, a 4-quinazolinone derivative containing benzylsulfonamide piperazine is characterized in that R1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a methanesulfonyl group; R2 is a hydrogen atom or a fluorine atom; R3 is a methoxy group, a 4-sulfonylmorpholine, or a 4-sulfonyl-1,1-thiomorpholine; and R4 is a nitro group or an amino group.

[0014] According to a further preferred embodiment of the present invention, the 4-quinazolinone derivative containing benzenesulfonamide piperazine is a compound having one of the following structures:

[0015]

[0016] The term "pharmaceutically acceptable salt" as used in this invention refers to a salt of a compound that, within the scope of reliable pharmaceutical evaluation, is suitable for contact with tissues of humans or lower animals without undue toxicity, irritation, or allergic reactions, possesses a reasonably reasonable benefit-risk ratio, is typically water- or oil-soluble or dispersible, and is effectively used for its intended purpose. This includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are suitable for the intended use and chemically compatible with the compound of formula I. For a list of suitable salts, see SM Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19.

[0017] 2. Preparation method of 4-quinazolinone derivatives containing benzenesulfonamide piperazine ketone

[0018] The present invention also provides a method for preparing the aforementioned 4-quinazolinone derivative containing benzenesulfonamide piperazine, the synthetic steps of which are as follows:

[0019] Synthesis of key intermediate 4: p-Nitrobenzenesulfonyl chloride 1 reacts with piperazine-2-one in dichloromethane as a solvent under the action of triethylamine to obtain intermediate 2; then intermediate 2 undergoes a nucleophilic substitution reaction with methyl bromoacetate in tetrahydrofuran as a solvent under the action of sodium hydride to obtain intermediate 3; finally, intermediate 3 undergoes an ester hydrolysis reaction in tetrahydrofuran and water as solvents under the action of lithium hydroxide to obtain intermediate 4;

[0020] The synthesis route is as follows:

[0021]

[0022] Reagents and conditions: (i) piperazine-2-one, triethylamine, dichloromethane, 0℃ → room temperature; (ii) methyl bromoacetate, sodium hydride, tetrahydrofuran, 0℃ → room temperature; (iii) lithium hydroxide, tetrahydrofuran:water = 1:1, room temperature.

[0023] Synthesis of target compounds 11a1-11e1, 11a2-11e2 and 12a1-12c1, 12e1, 12a2-12c2, 12e2: Starting with the correspondingly substituted 2-nitrobenzoyl chloride 5a-5e, acylation reaction was carried out with p-methoxyaniline in dichloromethane under the action of triethylamine to give intermediate 6a-6e; then, 6a-6e was hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to give intermediate 7a-7e; subsequently, 7a-7e reacted with N-Boc-L-phenylalanine and N-Boc-L-3,5-difluorophenylalanine in dichloromethane to generate intermediates 8a1-8e1 and 8a2-8e2. Then, 8a1-8e1 and 8a2-8e2 were reacted in N,O-bis(trimethylammonium chloride) in dichloromethane under acetonitrile as the reaction solvent. The intermediates 9a1-9e1 and 9a2-9e2 were obtained by a cyclization reaction under the action of silyl acetamide, N,N-diisopropylethylamine and 4-dimethylaminopyridine. 9a1-9e1 and 9a2-9e2 were then de-Boc-grouped in dichloromethane under the action of trifluoroacetic acid to obtain intermediates 10a1-10e1 and 10a2-10e2. Then, 10a1-10e1 and 10a2-10e2 were reacted with intermediate 4 in dichloromethane to obtain the target compounds 11a1-11e1 and 11a2-11e2. Finally, 11a1-11e1 and 11a2-11e2 were hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to obtain the target compounds 12a1-12c1, 12e1 and 12a2-12c2, 12e2.

[0024] The synthesis route is as follows:

[0025]

[0026] Reagents and conditions: (i) p-methoxyaniline, triethylamine, dichloromethane, 0℃ → room temperature; (ii) hydrogen, 10% palladium on carbon, dichloromethane, room temperature; (iii) N-Boc-L-phenylalanine or N-Boc-L-3,5-difluorophenylalanine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, 0℃ → room temperature; (iv) (v) N,O-bis(trimethylsilylacetamide), N,N-diisopropylethylamine, 4-dimethylaminopyridine, acetonitrile, 80 °C, reflux; (vi) trifluoroacetic acid, dichloromethane, room temperature; (vi) intermediate 4,2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, 0 °C → room temperature; (vii) hydrogen, 10% palladium on carbon, dichloromethane, room temperature.

[0027] Synthesis of target compounds 20a1-20b1, 20a2-20b2 and 21a1-21b1, 21a2-21b2: Starting from p-nitrobenzenesulfonyl chloride 1, acylation reaction was carried out with morpholine and 1,1-thiomorpholine dioxide in dichloromethane under the action of triethylamine to give intermediates 13a-13b; then, 13a-13b was hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to give intermediate 14a-14b. Subsequently, 14a-14b reacted with 2-nitrobenzyl chloride in dichloromethane to give intermediate 15a-15b. 15a-15b was then hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to give intermediate 16a-16b. Following this, 16a-16b underwent an amide condensation reaction with N-Boc-L-phenylalanine and N-Boc-L-3,5-difluorophenylalanine in dichloromethane to give intermediates 17a1-17b1 and... Next, 17a1-17b1 and 17a2-17b2 undergo a cyclization reaction in acetonitrile as the reaction solvent, with the aid of N,O-bis(trimethylsilylacetamide), N,N-diisopropylethylamine, and 4-dimethylaminopyridine, to give intermediates 18a1-18b1 and 18a2-18b2. Intermediates 18a1-18b1 and 18a2-18b2 are then deactivated using dichloromethane as the reaction solvent in the presence of trifluoroacetic acid to obtain intermediate 18a1-18b1. 19a1-19b1 and 19a2-19b2 were then reacted with intermediate 4 in dichloromethane to give target compounds 20a1-20b1 and 20a2-20b2; finally, 20a1-20b1 and 20a2-20b2 were subjected to hydrogenation reduction reaction in dichloromethane under 10% palladium on carbon catalysis to give target compounds 21a1-21b1 and 21a2-21b2.

[0028] The synthesis route is as follows:

[0029]

[0030] Reagents and conditions: (i) Morpholine or 1,1-thiomorpholine, triethylamine, dichloromethane, 0℃ → room temperature; (ii) Hydrogen, 10% palladium on carbon, dichloromethane, room temperature; (iii) 2-nitrobenzoyl chloride, triethylamine, dichloromethane, 0℃ → room temperature; (iv) Hydrogen, 10% palladium on carbon, dichloromethane, room temperature; (v) N-Boc-L-phenylalanine or N-Boc-L-3,5-difluorophenylalanine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate Ester, N,N-diisopropylethylamine, dichloromethane, 0℃ → room temperature; (vi) N,O-bistrimethylsilylacetamide, N,N-diisopropylethylamine, 4-dimethylaminopyridine, acetonitrile, 80℃, reflux; (vii) trifluoroacetic acid, dichloromethane, room temperature; (viii) intermediate 4,2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, 0℃ → room temperature; (ix) hydrogen, 10% palladium on carbon, dichloromethane, room temperature.

[0031] The room temperature described in this invention is 20-30℃.

[0032] 3. Applications of 4-quinazolinone derivatives containing benzenesulfonamide piperazine ketone

[0033] This invention discloses the screening results of the anti-HIV-1 / 2 activity of 4-quinazolinone derivatives containing benzylamide piperazine ketone and their first application in the preparation of HIV-1 / 2 drugs. Experiments demonstrate that the 4-quinazolinone derivatives containing benzylamide piperazine ketone of this invention can be used as HIV-1 / 2 capsid protein regulators in the preparation of anti-AIDS drugs. Anti-HIV-1 / 2 activity and cytotoxicity experiments of the target compounds are also presented.

[0034] A 4-quinazolinone derivative containing benzylsulfamylpiperazinone synthesized according to the above method was tested for anti-HIV-1 / 2 activity and toxicity at the cellular level. Its anti-HIV-1 and HIV-2 activity and toxicity data are listed in Table 1, with the capsid protein regulators PF74 and 11L reported in the literature as positive controls.

[0035] The 26 newly synthesized 4-quinazolinone derivatives containing benzylsulfonamide piperazine exhibit significant anti-HIV activity. Most compounds showed anti-HIV-1 activity at sub-micromolar to low-micromolar levels, with 5 compounds exhibiting anti-HIV-1 activity exceeding that of lead 11L, and 12 compounds exceeding that of PF74. Compounds 12a2 and 21a2 are the most potent HIV-1 capsid protein regulators in this series, EC50. 50 The value is 0.11 μM, which is 11 L (EC). 50 =0.28μM) is 2.5 times that of PF74 (EC) 50=0.80 μM) 7.3 times that of [previous concentration]. It is noteworthy that this series of compounds also exhibits outstanding anti-HIV-2 activity, EC [value missing]. 50 The values ​​ranged from 0.08 to 1.97 μM, with compound 12c2 (EC) being one of them. 50 =0.08μM) and 21a2 (EC 50 =0.08μM) anti-HIV-2 activity and 11L (EC) 50 =0.03μM) is equivalent to PF74 (EC) 50 =3.78 μM) is 47 times that of the 4-quinazolinone derivative containing benzenesulfonamide piperazine ketone synthesized in this invention. Therefore, the 4-quinazolinone derivative containing benzenesulfonamide piperazine ketone synthesized in this invention is worthy of further research.

[0036] The 4-quinazolinone derivative containing benzylsulfonamide piperazine of the present invention is a novel HIV capsid protein regulator that can be used to prepare anti-HIV-1 / 2 drugs.

[0037] An anti-HIV-1 / 2 pharmaceutical composition comprising the present invention a 4-quinazolinone derivative containing benzylamide piperazine ketone and one or more pharmaceutically acceptable carriers or excipients.

[0038] This invention discloses a 4-quinazolinone derivative containing benzylsulfonamide piperazine, its preparation method, the results of its anti-HIV activity screening, and its first application as a preparation of anti-HIV-1 / 2 drugs. Detailed Implementation

[0039] The following examples help to understand the present invention, but do not limit the scope of the invention. All percentages are mass percentages.

[0040] Example 1: Preparation of compounds 11a1-11e1 and 11a2-11e2

[0041] Intermediate 4 (1.2 eq.) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.5 eq.) were dissolved in dichloromethane (30 mL), and the mixture was placed in an ice bath for 30 minutes. Intermediates 10a1-10e1 and 10a2-10e2 (1.0 eq.) and N,N-diisopropylethylamine (2.0 eq.) were then added. After removing the ice bath, the mixture was allowed to react at room temperature for 5 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was extracted with 1N HCl (20 mL) and ethyl acetate (3 × 20 mL). The organic phase was washed with saturated sodium bicarbonate solution (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the target compounds 11a1-11e1 and 11a2-11e2.

[0042] 11a1 is a white solid, yield: 65%, melting point: 213-214℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=7.6Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.17–8.11(m,1H,Ph-H),8.07(d,J=8.8Hz,2H,Ph -H),7.94–7.86(m,1H,Ph-H),7.74(d,J=8.1Hz,1H,Ph-H),7.57(t,J=7.3Hz,1H,Ph-H),7.30(dd,J=7.8,3.6Hz,1H,Ph-H),7.25–7 .07(m,6H,Ph-H),6.90–6.82(m,2H,Ph-H),4.63(td,J=9.1,4.5Hz,1H,CH),3.97–3.88(m,2H,CH2),3.85(s,3H,OCH3),3.70–3.5 9(m,2H,CH2),3.31–3.24(m,2H,CH2),3.24–3.17(m,2H,CH2),3.14(dd,J=13.7,4.3Hz,1H,CH),2.79(dd,J=13.8,9.5Hz,1H,CH). 13 C NMR (100MHz, DMSO-d6) δ167.63(C=O),163.46(C=O),161.88(C=O),160.09,157.69,150.76,147.36,141.03,137.96,135.28,130.55,130.33,12 9.67,129.32,129.02,128.64,127.52,127.35,127.00,126.96,125.29 ,121.22,115.15,56.02,53.46,48.69,48.48,46.93,43.07,38.76.HRMS m / zC 35 H 32 N6O8S[M+H] + 697.2080, 697.2075 [M+H] + .

[0043] 11b1 is a white solid with a yield of 58% and a melting point of 209-210℃. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=7.5Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.23–8.16(m,1H,Ph-H),8.07(d,J=8 .8Hz,2H,Ph-H),7.44(t,J=8.3Hz,2H,Ph-H),7.34–7.28(m,1H,Ph-H),7.24–7.20(m,1H,Ph-H),7.20–7.09(m,5H,Ph- H),6.90–6.82(m,2H,Ph-H),4.67–4.57(m,1H,CH),3.97–3.88(m,2H,CH2),3.85(s,3H,OCH3),3.69–3.59(m,2H,CH2 ),3.28(dt,J=10.2,5.4Hz,2H,CH2),3.24–3.17(m,2H,CH2),3.17–3.09(m,1H,CH),2.79(dd,J=13.8,9.6Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.74(C=O),166.40(d, 1 J CF =252.3Hz),163.46(C=O),161.20(C=O),160.15,159.36,150.75,149.51(d, 3 J CF =13.4Hz),140.92,137.85,130.52,130.28,129.68,129.30,128.76,128.67,127.01,125.30,118.29,118.28,116.11(d, 2 J CF =23.5Hz), 115.17, 112.38 (d, 2 J CF =21.6Hz),56.01,53.61,48.69,48.45,46.95,43.06,38.57.HRMS m / z C 35 H 31 FN6O8S[M+H] + 715.1981, 715.1981 [M+H] + .

[0044] 11c1 is a white solid with a yield of 52%. Melting point: 194-195℃. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ8.71(d,J=7.5Hz,1H,NH),8.43(d,J=8.9Hz,2H,Ph-H),8.13(d,J=8.5Hz,1H,Ph-H),8.07(d,J=8.9H z,2H,Ph-H),7.72(d,J=2.0Hz,1H,Ph-H),7.61(dd,J=8.5,2.0Hz,1H,Ph-H),7.35–7.28(m,1H,Ph-H),7.24–7.07(m,6H,Ph- H),6.90–6.82(m,2H,Ph-H),4.61(td,J=9.2,4.5Hz,1H,CH),3.98–3.88(m,2H,CH2),3.85(s,3H,OCH3),3.65(d,J=2.2Hz,2 H,CH2),3.31–3.25(m,2H,CH2),3.25–3.16(m,2H,CH2),3.13(dd,J=13.8,4.3Hz,1H,CH),2.78(dd,J=13.8,9.5Hz,1H,CH). 13 C NMR (100MHz, DMSO-d6) δ167.75(C=O),163.47(C=O),161.32(C=O),160.17,159.41,150.75,148.47,140.96,139.87,137.83,130.49,130.24,12 9.68,129.31,129.18,128.71,128.68,127.82,127.01,126.39,125.30 ,120.09,115.18,56.02,53.62,48.69,48.46,46.99,43.06,38.56.HRMS m / z C 35 H 31 ClN6O8S[M+H] + 731.1685, 731.1686 [M+H] + .

[0045] 11d1 is a white solid, yield: 55%. Melting point: 160-161℃. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ8.71(d,J=7.5Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.06(dd,J=11.1,8.7Hz,3H,Ph-H),7.88 (d,J=1.7Hz,1H,Ph-H),7.74(dd,J=8.5,1.8Hz,1H,Ph-H),7.30(dd,J=9.0,2.3Hz,1H,Ph-H),7.22–7.07(m,6H,Ph-H),6. 89–6.82(m,2H,Ph-H),4.61(td,J=9.2,4.5Hz,1H,CH),3.97–3.87(m,2H,CH2),3.85(s,3H,OCH3),3.65(d,J=1.9Hz,2H, CH2),3.32–3.25(m,2H,CH2),3.25–3.16(m,2H,CH2),3.12(dd,J=13.8,4.2Hz,1H,CH),2.78(dd,J=13.8,9.5Hz,1H,CH). 13 C NMR (100MHz, DMSO-d6) δ167.75(C=O),163.47(C=O),161.46(C=O),160.17,159.35,150.75,148.52,140.96,137.83,130.58,130.48,130.23,12 9.68,129.49,129.31,129.16,128.82,128.71,128.68,127.02,125.30 ,120.37,115.18,56.02,53.61,48.69,48.45,47.00,43.06,38.57.HRMS m / z C 35 H 31 BrN6O8S[M+H] + 775.1180, [M+H+2] + 777.1160,775.1179,[M+H] + 777.1165[M+H+2] + .

[0046] 11e1 is a white solid with a yield of 62% and a melting point of 185-186℃. Spectroscopic data: 1HNMR (400MHz, DMSO-d6) δ8.72(d,J=7.6Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.36(d,J=8.3Hz,1H,Ph-H),8.17(d, J=1.4Hz,1H,Ph-H),8.11–8.03(m,3H,Ph-H),7.38–7.30(m,1H,Ph-H),7.28–7.09(m,6H,Ph-H),6.93–6.81(m,2H,Ph- H),4.65(td,J=9.2,4.4Hz,1H,CH),3.98–3.89(m,2H,CH2),3.86(s,3H,OCH3),3.65(s,2H,CH2),3.39(s,3H,SO2CH3) ,3.31–3.25(m,2H,CH2),3.20(q,J=8.9,6.8Hz,2H,CH2),3.17–3.10(m,1H,CH),2.80(dd,J=13.9,9.6Hz,1H,CH).13C NMR (100MHz, DMSO-d6) δ167.76(C=O),163.47(C=O),161.22(C=O),160.26,159.82,150.75,147.40,146.64,140.92,137.76,130.44,130.1 9,129.68,129.29,129.01,128.71,128.58,126.12,125.30,124.60,115.25,56.04,53.54,48.69,48.44,46.97,43.62,43.05,38.66.HRMS m / z C 36 H 34 N6O 10 S2[M+H] + 775.1851, 775.1851 [M+H] + .

[0047] 11a2 is a white solid, yield: 46%, melting point: 198-200℃. Spectroscopic data: 1H NMR(400MHz,DMSO-d6)δ8.75(d,J=7.8Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.18–8.12(m,1H,Ph-H),8.07(d,J=8.8Hz,2H,Ph-H),7.94–7.87(m,1H,Ph-H),7.73(d,J=8.0Hz,1H,Ph-H),7.58(t,J=7.8Hz,1H,Ph-H),7.44(dd,J=9.0,2.4Hz,1H,Ph-H),7.31(dd,J=9.0,2.4Hz,1H,Ph-H),7.21–7.12(m,2H,Ph-H),7.02(ddd,J=11.5,5.7,2.1Hz,1H,Ph-H),6.51(d,J=6.4Hz,2H,Ph-H),4.66–4.57(m,1H,CH),3.96–3.88(m,2H,CH2),3.85(s,3H,OCH3),3.71–3.58(m,2H,CH2),3.33–3.26(m,2H,CH2),3.26–3.17(m,2H,CH2),3.14(dd,J=13.9,3.4Hz,1H,CH),2.83(dd,J=13.9,10.0Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.73(C=O),163.47(C=O),162.48(dd, 1 J CF =246.0, 3 J CF =13.5Hz),161.89(C=O),160.19,157.02,150.75,147.22,142.56(t, 3 J CF =9.1Hz)140.86,135.34,130.59,130.43,129.68,128.98,127.66,127.37,127.02,125.31,121.29,115.33,115.17,112.38(dd, 2 J CF =24.9Hz, 4 J CF =5.5Hz),102.60(t, 2 J CF =25.8Hz).56.00,53.10,48.67,48.51,47.04,43.06,38.01.HRMS m / zC 35 H30 F2N6O8S[M+H] + 733.1881, 733.1884 [M+H] + .

[0048] 11b2 is a white solid with a yield of 51%. Melting point: 195-196℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=7.7Hz,1H,NH),8.43(d,J=8.9Hz,2H,Ph-H),8.21(dd,J=9.6,6.2Hz,1H,Ph-H),8.12–8.04( m,2H,Ph-H),7.45(ddd,J=8.4,6.3,2.5Hz,3H,Ph-H),7.32(dd,J=9.0,2.5Hz,1H,Ph-H),7.23–7.12(m,2H,Ph-H),7.02(tt,J=9 .4,2.2Hz,1H,Ph-H),6.57–6.47(m,2H,Ph-H),4.69–4.56(m,1H,CH),3.96–3.88(m,2H,CH2),3.85(s,3H,OCH3),3.71–3.59(m ,2H,CH2),3.33–3.26(m,2H,CH2),3.27–3.17(m,2H,CH2),3.14(dd,J=13.9,3.4Hz,1H,CH),2.83(dd,J=13.9,10.0Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.80(C=O),166.39(d, 1 J CF =252.0Hz),163.49(C=O),162.56(dd, 1 J CF =245.6, 3 J CF =13.0Hz),161.20(C=O),160.27,158.61,150.75,149.38(d, 3 J CF =13.1Hz), 142.45(t, 3 J CF =9.4Hz),140.93,130.54,130.39,130.34,130.23,129.67,128.74,125.29,118.39,118.38,116.20(d, 2 J CF=23.7Hz),115.36,115.20,112.39(dd, 2 J CF =24.8, 4 J CF =6.7Hz), 102.63(t, 2 J CF =25.0Hz),56.01,53.21,48.68,48.52,43.07,38.71.HRMS m / z C 35 H 29 F3N6O8S[M+H] + 751.1792, 751.1790 [M+H] + .

[0049] 11c2 is a white solid, yield: 49%, melting point: 212-214℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=7.7Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.14(d,J=8.5Hz,1H,Ph-H),8.07(d,J=8.8Hz,2H,Ph-H),7 .72(d,J=1.9Hz,1H,Ph-H),7.62(dd,J=8.5,2.0Hz,1H,Ph-H),7.47–7.41(m,1H,Ph-H),7.31(dd,J=7.8,3.5Hz,1H,Ph-H),7.21–7.11(m,2 H,Ph-H),7.02(t,J=9.4Hz,1H,Ph-H),6.51(d,J=6.5Hz,2H,Ph-H),4.65–4.55(m,1H,CH),3.90(d,J=4.5Hz,2H,CH2),3.85(s,3H,OCH3),3 .71–3.59(m,2H,CH2),3.32–3.26(m,2H,CH2),3.26–3.17(m,2H,CH2),3.13(dd,J=13.9,3.3Hz,1H,CH),2.82(dd,J=13.9,9.9Hz,1H,CH). 13 CNMR(100MHz,DMSO-d6)δ167.82(C=O),163.49(C=O),162.43(d, 1 J CF =246.0, 3 J CF =13.6Hz),161.33(C=O),160.28,158.67,150.76,148.34,142.44(t,3 J CF =9.2Hz),140.94,139.87,130.51,130.36,129.67,129.19,128.69,127.92,126.42,125.30,120.20,115.38,115.21,112.40(d, 2 J CF =25.0, 4 J CF =6.3Hz), 102.64(t, 2 J CF =25.8Hz),56.02,53.23,48.68,48.52,47.09,43.08,37.84.HRMS m / z C 35 H 29 ClF2N6O8S[M+H] + 767.1497,767.1494[M+H] + .

[0050] 11d2 is a white solid with a yield of 53% and a melting point >240℃. Spectroscopic data: 1 HNMR(400MHz,DMSO-d6)δ8.72(d,J=7.6Hz,1H,NH),8.43(d,J=8.7Hz,2H,Ph-H),8.15–8.01(m,3H,Ph-H),7.93–7.84(m,1H,P h-H),7.80–7.71(m,1H,Ph-H),7.49–7.39(m,1H,Ph-H),7.37–7.27(m,1H,Ph-H),7.15(t,J=6.6Hz,2H,Ph-H),7.02(t,J=9.3H z,1H,Ph-H),6.51(d,J=6.6Hz,2H,Ph-H),4.66–4.54(m,1H,NH),3.90(d,J=3.1Hz,2H,CH2),3.85(s,3H,OCH3),3.71–3.58(m, 2H,CH2),3.32–3.26(m,2H,CH2),3.23(dd,J=12.2,5.8Hz,2H,CH2),3.17–3.08(m,1H,CH),2.81(dd,J=13.7,10.0Hz,1H,CH). 13 C NMR (100MHz, DMSO-d6) δ167.82(C=O), 163.48(C=O), 162.49(dd, 1 J CF =245.9, 3 JCF =13.4Hz),161.47(C=O),160.28,158.61,150.76,148.39,142.44(t, 3 J CF =8.8Hz),140.95,130.68,130.50,130.34,129.67,129.52,129.16,128.81,128.69,125.30,120.48,115.38,115.21,112.40(d, 2 J CF =24.4, 4 J CF =5.5Hz), 102.64(t, 2 J CF =25.8Hz),56.02,53.23,48.68,48.52,47.10,43.08,37.85.HRMS m / z C 35 H 29 BrF₂N₆O₈S[M+H] + 811.0992, [M+2+H] + 813.0971, 811.0991 [M+H] + 813.0978[M+2+H] + .

[0051] 11e2 is a white solid, yield: 66%. Melting point: 198-199℃. Spectroscopic data: 1H NMR(400MHz,DMSO-d6)δ8.71(d,J=7.7Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.37(d,J=8.3Hz,1H,Ph-H),8.17(d,J=1.4Hz,1H,Ph-H),8.12–8.03(m,3H,Ph-H),7.51–7.42(m,1H,Ph-H),7.34(dd,J=8.0,3.4Hz,1H,Ph-H),7.25–7.13(m,2H,Ph-H),7.08–6.98(m,1H,Ph-H),6.52(d,J=6.5Hz,2H,Ph-H),4.73–4.59(m,1H,CH),3.94(d,J=16.9Hz,2H,CH2),3.86(s,3H,OCH3),3.71–3.59(m,2H,CH2),3.38(s,3H,SO2CH3),3.29(dd,J=8.8,3.7Hz,2H,CH2),3.23(dq,J=12.5,6.7,5.7Hz,2H,CH2),3.15(dd,J=14.0,3.3Hz,1H,CH),2.84(dd,J=14.2,10.2Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.83(C=O),163.51(C=O),162.50(dd, 1 J CF =245.9, 3 J CF =13.5Hz),161.25(C=O),160.37,159.04,150.75,147.28,146.61,142.35(t, 3 J CF =9.5Hz),140.86,130.46,130.29,129.67,129.02,128.55,126.14,125.31,124.73,115.44,115.29,112.38(dd, 2 J CF =24.8, 4 J CF =6.6Hz),102.67(t, 2 J CF =25.4Hz),56.03,53.16,48.67,48.50,47.08,43.62,43.05,37.92.HRMS m / z C 36 H 32 F2N6O 10S2[M+H] + 811.1662, 811.1664 [M+H] + .

[0052] Example 2: Preparation of compounds 12a1-12c1, 12e1, 12a2-12c2 and 12e2

[0053] The target compounds 11a1-c1, 11e1, 11a2-11c2, and 11e2 (150 mg) were dissolved in dichloromethane (10 mL), and then 10% palladium on carbon (10% w / w, 15 mg) was added. The mixture was purged three times with hydrogen gas and stirred overnight at room temperature under hydrogen balloon protection. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the solvent was evaporated under reduced pressure. The crude product was purified by recrystallization (ethyl acetate) or preparative thin-layer chromatography (methanol:dichloromethane = 1:30) to obtain the target compounds 12a1-12c1, 12e1, 12a2-12c2, and 12e2.

[0054] 12a1 is a white solid with a yield of 68% and a melting point of 201-202℃. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)δ8.72(d,J=7.6Hz,1H,NH),8.18–8.11(m,1H,Ph-H),7.94–7.86(m,1H,Ph-H),7.73(d,J=8.1Hz,1H,Ph-H),7.57(t,J=7.5Hz, 1H,Ph-H),7.40(d,J=8.7Hz,2H,Ph-H),7.32(dd,J=8.5,2.5Hz,1H,Ph-H),7.22(dd,J=8.5,2.5Hz,1H,Ph-H),7.19–7.14(m,3H,Ph-H),7.14–7.08(m, 2H,Ph-H),6.92–6.82(m,2H,Ph-H),6.67(d,J=8.7Hz,2H,Ph-H),6.18(s,2H,NH2),4.64(td,J=9.3,4.4Hz,1H,CH),3.89(s,2H,CH2),3.85(s,3H,OCH 3),3.45–3.36(m,2H,CH2),3.17(ddd,J=14.2,7.4,3.5Hz,2H,CH2),3.13–3.02(m,2H,CH2),3.02–2.94(m,1H,CH),2.80(dd,J=13.8,9.6Hz,1H,CH). 13C NMR(100MHz,DMSO-d6)δ167.73(C=O),164.00(C=O),161.89(C=O),160.09 ,157.78,154.17,147.36,137.97,135.30,130.56,130.40,130.30,129.3 2,129.03,128.64,127.52,127.34,127.01,126.97,121.23,118.58,115. 17,115.14,113.32,56.01,53.46,49.30,48.45,46.94,43.33,38.69.HRMS m / z C 35 H 34 N6O6S[M+H] + 667.2333, 667.2335 [M+H] + .

[0055] 12b1 is a white solid with a yield of 35% and a melting point of 188-189℃. Spectroscopic data: 1 H NMR(400MHz, DMSO-d6)δ8.71(d,J=7.6Hz,1H,NH),8.26–8.16(m,1H,Ph-H),7.45(d,J=9.1Hz,2H,Ph-H),7.43–7.37(m, 2H,Ph-H),7.33(dd,J=8.6,2.5Hz,1H,Ph-H),7.25–7.07(m,6H,Ph-H),6.94–6.82(m,2H,Ph-H),6.67(d,J=8.7Hz,2H,P h-H),6.17(s,2H,NH2),4.63(td,J=9.4,4.4Hz,1H,CH),3.89(s,2H,CH2),3.85(s,3H,OCH3),3.46–3.34(m,2H,CH2),3 .18(ddd,J=19.9,7.9,4.3Hz,2H,CH2),3.13–3.03(m,2H,CH2),3.03–2.94(m,1H,CH),2.80(dd,J=13.8,9.6Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.83(C=O),166.40(d, 1 J CF =251.9Hz),164.05(C=O),161.23(C=O),160.16,159.38,154.16,149.51(d, 3 J CF=13.2Hz),140.92,137.84,130.50,130.29,129.30,128.76,128.66,127.02,118.56,118.29,116.11(d, 2 J CF =23.8Hz),115.20,115.17,113.34,112.39(d, 2 J CF =21.5Hz),56.01,53.60,49.28,48.44,46.96,43.32,38.53.HRMS m / z C 35 H 33 FN6O6S[M+H] + 685.2239, 685.2237 [M+H] + .

[0056] 12C1 is a white solid, yield: 33%, melting point: >240℃. Spectroscopic data: 1 HNMR (400MHz, DMSO-d6) δ8.63 (d, J=7.5Hz, 1H, NH), 8.06 (d, J=8.5Hz, 1H, Ph-H), 7.65 (d, J=1.9Hz, 1H, Ph-H), 7.54 (dd, J=8.5, 2.0Hz,1H,Ph-H),7.33(d,J=8.7Hz,2H,Ph-H),7.25(dd,J=8.6,2.5Hz,1H,Ph-H),7.19–6.99(m,6H,Ph-H),6.86–6.74(m,2H,Ph -H),6.60(d,J=8.7Hz,2H,Ph-H),6.10(s,2H,NH2),4.62–4.50(m,1H,CH),3.82(s,2H,CH2),3.77(s,3H,OCH3),3.31(d,J=7.6H z,2H,CH2),3.16–3.05(m,2H,CH2),3.00(dt,J=17.2,4.3Hz,2H,CH2),2.95–2.87(m,1H,CH),2.72(dd,J=13.7,9.5Hz,1H,CH). 13C NMR(100MHz,DMSO-d6)δ167.84(C=O),164.01(C=O),161.34(C=O),160.17 ,159.48,154.18,148.48,139.87,137.84,130.48,130.32,130.29,129.3 1,129.19,128.71,128.67,127.82,127.02,126.38,120.09,118.52,115. 21,115.18,113.31,56.02,53.62,49.29,48.42,46.97,43.32,38.48.HRMS m / z C 35 H 33 ClN6O6S[M+H] + 701.1944, 701.1943 [M+H] + .

[0057] 12e1 is a white solid, yield: 30%, melting point: 193-194℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=7.6Hz,1H,NH),8.36(d,J=8.3Hz,1H,Ph-H),8.20–8.15(m,1H,Ph-H),8.05(dd,J=8.3,1.5Hz,1H,P h-H),7.40(d,J=8.6Hz,2H,Ph-H),7.35(dd,J=8.6,2.4Hz,1H,Ph-H),7.22(dd,J=8.5,2.4Hz,1H,Ph-H),7.20–7.08(m,5H,Ph-H),6.91 –6.82(m,2H,Ph-H),6.67(d,J=8.7Hz,2H,Ph-H),6.16(s,2H,NH2),4.66(td,J=9.2,4.4Hz,1H,CH),3.90(s,2H,CH2),3.85(s,3H,OCH 3),3.38(s,5H,SO2CH3,CH2),3.24–3.14(m,2H,CH2),3.14–3.04(m,2H,CH2),3.04–2.96(m,1H,CH),2.81(dd,J=13.8,9.6Hz,1H,CH). 13C NMR(100MHz,DMSO-d6)δ167.86(C=O),164.01(C=O),161.23(C=O),160.26 ,159.89,154.18,147.41,146.65,137.78,130.42,130.31,129.29,129.0 0,128.70,128.59,127.06,126.12,124.61,124.59,118.50,115.28,115. 24,113.31,56.03,53.55,49.30,48.41,46.98,43.63,43.30,38.58.HRMS m / z C 36 H 36 N6O8S2[M+H] + 745.2109, 745.2104 [M+H] + .

[0058] 12a2 is a white solid, yield: 45%, melting point: 185-186℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=7.8Hz,1H,NH),8.14(d,J=7.8Hz,1H,Ph-H),7.90(t,J=7.6Hz,1H,Ph-H),7.72(d,J=8.1Hz,1H,Ph-H),7.58(t,J= 7.5Hz,1H,Ph-H),7.47–7.42(m,1H,Ph-H),7.40(d,J=8.6Hz,2H,Ph-H),7.37–7.30(m,1H,Ph-H),7.22–7.12(m,2H,Ph-H),7.02(t,J=9.4Hz,1H,Ph- H),6.67(d,J=8.7Hz,2H,Ph-H),6.50(d,J=6.6Hz,2H,Ph-H),6.19(s,2H,NH2),4.68–4.58(m,1H,CH),3.89(s,2H,CH2),3.85(s,3H,OCH3),3.46–3. 36(m,2H,CH2),3.23(ddd,J=10.9,6.7,4.1Hz,1H,CH),3.14(dt,J=16.6,3.8Hz,2H,CH2),3.09–2.96(m,2H,CH2),2.85(dd,J=13.8,10.1Hz,1H,CH). 13 C NMR (100MHz, DMSO-d6) δ167.81(C=O), 164.02(C=O), 162.48(dd, 1 JCF =246.1, 3 J CF =13.3Hz),161.88(C=O),160.20,157.09,154.18,147.23,142.60(t, 3 J CF =9.3Hz),135.33,130.59,130.51,130.30,128.99,127.64,127.35,127.02,121.31,118.49,115.32,115.20,113.31,112.39(dd, 2 J CF =24.2, 4 J CF =5.8Hz), 102.63(t, 2 J CF =25.9Hz),56.00,53.12,49.29,48.47,47.04,43.32,37.95.HRMSm / z C 35 H 32 F2N6O6S[M+H] + 703.2145, 703.2147 [M+H] + .

[0059] 12b2 is a white solid with a yield of 36% and a melting point of 192-193℃. Spectroscopic data: 1H NMR(400MHz,DMSO-d6)δ8.73(d,J=7.7Hz,1H,NH),8.21(dd,J=9.6,6.2Hz,1H,Ph-H),7.49–7.42(m,3H,Ph-H),7.40(d,J=8.7Hz,2H,Ph-H),7.37–7.31(m,1H,Ph-H),7.24–7.12(m,2H,Ph-H),7.03(dt,J=11.4,5.7Hz,1H,Ph-H),6.67(d,J=8.7Hz,2H,Ph-H),6.51(d,J=6.5Hz,2H,Ph-H),6.17(s,2H,NH2),4.68–4.58(m,1H,CH),3.89(s,2H,CH2),3.85(s,3H,OCH3),3.48–3.37(m,2H,CH2),3.21(ddt,J=20.7,11.3,4.9Hz,2H,CH2),3.15–3.06(m,2H,CH2),3.02(ddd,J=11.3,6.7,3.9Hz,1H,CH),2.85(dd,J=13.9,10.0Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.89(C=O),166.39(d, 1 J CF =251.8Hz),164.04(C=O),162.56(dd, 1 J CF =245.7, 3 J CF =13.4Hz),161.21(C=O),160.27,158.68,154.17,149.39(d, 3 J CF =13.2Hz).142.49(t, 3 J CF =9.2Hz),130.52,130.48,130.34,130.29,130.23,128.75,118.53,118.41,118.39,116.19(d, 2 J CF =23.5Hz),115.36,115.23,113.32,112.38(dd, 2 J CF =25.0, 4 J CF =6.4Hz),102.63(t, 2 J CF=26.0Hz),56.01,53.25,49.28,48.46,47.06,43.32,38.71.HRMS m / zC 35 H 31 F3N6O6S[M+H] + 721.2051,721.2056[M+H] + .

[0060] 12C2 is a white solid, yield: 40%, melting point: 196-197℃. Spectroscopic data: 1 H NMR(400MHz, DMSO-d6)δ8.70(d,J=7.8Hz,1H,NH),8.14(d,J=7.6Hz,1H,Ph-H),7.96–7.85(m,1H,Ph-H),7.71(d,J=8.1Hz,1H,Ph-H), 7.58(t,J=7.5Hz,1H,Ph-H),7.47–7.37(m,3H,Ph-H),7.36–7.30(m,1H,Ph-H),7.15(d,J=8.9Hz,2H,Ph-H),7.01(t,J=9.4Hz,1H,Ph-H ),6.67(d,J=8.7Hz,2H,Ph-H),6.50(d,J=6.5Hz,2H,Ph-H),6.17(s,2H,NH2),4.70–4.58(m,1H,CH),3.88(s,2H,CH2),3.85(s,3H,OC H3),3.47–3.36(m,2H,CH2),3.26–3.14(m,2H,CH2),3.14–3.05(m,2H,CH2),3.05–2.96(m,1H,CH),2.85(dd,J=13.8,10.0Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.90(C=O),163.94(C=O),162.43(d, 1 J CF =246.0, 3 J CF =13.4Hz),161.34(C=O),160.29,158.72,156.44,148.35,142.47(t, 3 J CF =9.3Hz),139.88,130.50,130.43,129.70,129.19,128.69,127.92,126.42,122.34,120.20,115.37,115.24,112.39(d, 2 JCF =24.3, 4 J CF =6.6Hz), 111.84, 102.63(t, 2 J CF =26.7Hz),56.02,53.26,49.20,48.49,47.11,43.30,37.77.HRMS m / z C 35 H 31 ClF2N6O6S[M+H] + 737.1755, 737.1751 [M+H] + .

[0061] 12e₂ is a white solid, yield: 29%, melting point: 193-194℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=7.7Hz,1H,NH),8.38(d,J=8.3Hz,1H,Ph-H),8.16(d,J=1.5Hz,1H,Ph-H),8.06(dd,J=8.3,1.6Hz,1H,Ph-H),7. 46(dd,J=8.9,2.4Hz,1H,Ph-H),7.44–7.33(m,3H,Ph-H),7.24–7.14(m,2H,Ph-H),7.03(td,J=9.4,2.1Hz,1H,Ph-H),6.67(d,J=8.7Hz,2H,Ph-H) ,6.51(d,J=6.5Hz,2H,Ph-H),6.17(s,2H,NH2),4.72–4.61(m,1H,CH),3.91(s,2H,CH2),3.85(s,3H,OCH3),3.43(d,J=16.2Hz,2H,CH2),3.38(s, 3H,SO2CH3),3.20(dq,J=14.7,5.5,4.1Hz,2H,CH2),3.15–3.06(m,2H,CH2),3.03(dd,J=11.7,4.5Hz,1H,CH),2.85(dd,J=14.0,10.1Hz,1H,CH). 13 C NMR (100MHz, DMSO-d6) δ167.93(C=O), 164.06(C=O), 162.58(dd, 1 J CF =246.3Hz, 3 J CF=13.6Hz),161.24(C=O),160.38,159.12,154.17,147.30,146.65,142.41(t,J=9.6Hz),140.85,130 .45,130.30,129.30,129.01,128.57,126.12,124.75,118.52,115.44,115.31,113.32,112.38(dd, 2 J CF =24.8Hz, 4 J CF =6.2Hz), 102.67(t, 2 J CF =25.4Hz),56.03,53.20,49.29,48.45,47.08,43.65,43.31,37.83.HRMS m / zC 36 H 34 F2N6O8S2[M+H] + 781.1920, 781.1923 [M+H] + .

[0062] Example 3: Preparation of compounds 20a1-20b1 and 20a2-20b2

[0063] Intermediate 4 (1.2 eq.) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.5 eq.) were dissolved in dichloromethane (30 mL), and the mixture was placed in an ice bath for 30 minutes. Intermediates 19a1-19b1 and 19a2-19b2 (1.0 eq.) and N,N-diisopropylethylamine (2.0 eq.) were then added. After removing the ice bath, the mixture was allowed to react at room temperature for 5 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was extracted with 1N HCl (20 mL) and ethyl acetate (3 × 20 mL). The organic phase was washed with saturated sodium bicarbonate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the target compounds 20a1-20b1 and 20a2-20b2.

[0064] 20a1 is a white solid, yield: 56%. Melting point: 211-212℃. Spectroscopic data: 1H NMR(400MHz, DMSO-d6)δ8.79(d,J=7.8Hz,1H,NH),8.43(d,J=8.9Hz,2H,Ph-H),8.19–8.12(m,1H,Ph-H),8.07(d,J=8.9Hz,2H,Ph-H),8.0 2–7.90(m,3H,Ph-H),7.78(d,J=8.0Hz,1H,Ph-H),7.75–7.66(m,2H,Ph-H),7.66–7.58(m,1H,Ph-H),7.25–7.11(m,3H,Ph-H),6.87(d,J=6 .7Hz,2H,Ph-H),4.54(td,J=8.8,4.9Hz,1H,CH),3.97–3.80(m,2H,CH2),3.69(t,J=4.3Hz,4H,CH2×2),3.63(d,J=4.3Hz,2H,CH2),3.32–3 .24(m,2H,CH2),3.21(dd,J=11.7,8.6Hz,2H,CH2),3.18–3.11(m,1H,CH),2.97(t,J=7.3Hz,4H,CH2×2),2.84(dd,J=13.9,9.3Hz,1H,CH). 13 CNMR(100MHz,DMSO-d6)δ167.74(C=O),163.47(C=O),161.58(C=O),156.07, 150.78,147.23,141.00,140.83,137.87,135.78,135.62,130.86,130.84,1 29.72,129.66,129.35,129.21,128.73,127.90,127.55,127.07,126.99,12 5.30,121.11,65.83,53.31,48.70,48.48,47.02,46.45,43.07,38.43.HRMS m / z C 38 H 37 N7O 10 S2[M+H] + 816.2116,816.2118[M+H] + .

[0065] 20b1 is a white solid with a yield of 67% and a melting point of 219-220℃. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ8.77(d,J=7.7Hz,1H,NH),8.44(d,J=8.8Hz,2H,Ph-H),8.18–8.13(m,1H,Ph-H),8.08(d,J=8.8Hz,2H,Ph-H),8.05–7.98( m,2H,Ph-H),7.98–7.91(m,1H,Ph-H),7.79(d,J=8.1Hz,1H,Ph-H),7.73–7.68(m,1H,Ph-H),7.65–7.58(m,2H,Ph-H),7.19(dt,J=15.0,7.0Hz,3H, Ph-H),6.88(d,J=7.0Hz,2H,Ph-H),4.54(td,J=8.4,5.4Hz,1H,CH),3.98–3.78(m,2H,CH2),3.67(d,J=16.6Hz,2H,CH2),3.58(s,4H,CH2×2),3.42 –3.37(m,2H,CH2),3.34–3.30(m,4H,CH2×2),3.25(td,J=9.6,5.6Hz,2H,CH2),3.18(dd,J=12.0,5.6Hz,1H,CH),2.85(dd,J=13.9,9.1Hz,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.64(C=O),163.49(C=O),161.57(C=O),156.04, 150.78,147.21,141.10,140.75,137.76,137.70,135.65,131.14,131.03,1 29.71,129.25,129.16,128.88,128.80,127.93,127.56,127.06,126.98,12 5.33,121.07,53.22,50.93,48.70,48.42,46.98,45.49,43.06,38.54.HRMS m / zC 38 H 37 N7O 11 S3[M+H] + 864.1786, 864.1782 [M+H] + .

[0066] 20a2 is a white solid, yield: 48%, melting point: 209-210℃. Spectroscopic data: 1H NMR(400MHz,DMSO-d6)δ8.68(d,J=8.1Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.19–8.13(m,1H,Ph-H),8.07(d,J=8.8Hz,2H,Ph-H),7.95(dt,J=8.2,4.2Hz,2H,Ph-H),7.88(dd,J=8.3,2.0Hz,1H,Ph-H),7.83–7.75(m,2H,Ph-H),7.70–7.58(m,2H,Ph-H),7.08–6.96(m,1H,Ph-H),6.68(d,J=6.4Hz,2H,Ph-H),4.56(td,J=8.5,5.1Hz,1H,CH),3.95–3.74(m,2H,CH2),3.74–3.57(m,6H,CH2×3),3.31–3.28(m,1H,CH),3.28–3.24(m,2H,CH2),3.21(dd,J=11.5,5.3Hz,2H,CH2),2.96(dt,J=12.0,4.6Hz,4H,CH2×2),2.92–2.87(m,1H,CH). 13 C NMR(100MHz,DMSO-d6)δ167.44(C=O),163.47(C=O),162.50(dd, 1 J CF =245.9, 3 J CF =13.2Hz),161.62(C=O),155.14,150.79,147.05,142.46(t, 3 J CF =9.3Hz),140.86,140.71,135.99,135.65,131.07,130.49,129.73,129.52,129.38,128.06,127.61,126.97,125.31,121.20,112.56(dd, 2 J CF =24.6, 4 J CF =6.6Hz),102.59(t, 2 J CF =25.4Hz),65.82,52.43,48.68,48.54,47.13,46.31,43.07,38.02.HRMS m / z C 38 H 35 F2N7O 10 S2[M+H]+ 852.1928, 852.1925 [M+H] + .

[0067] 20b2 is a white solid with a yield of 58% and a melting point of 215-216℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=8.1Hz,1H,NH),8.43(d,J=8.8Hz,2H,Ph-H),8.15(d,J=7.9Hz,1H,Ph-H),8.12–8.0 1(m,3H,Ph-H),8.00–7.89(m,2H,Ph-H),7.84–7.74(m,2H,Ph-H),7.68–7.59(m,2H,Ph-H),7.01(dt,J=11.5,5.7Hz,1 H,Ph-H),6.67(d,J=6.4Hz,2H,Ph-H),4.56(td,J=8.5,5.2Hz,1H,CH),3.94–3.71(m,2H,CH2),3.70–3.59(m,2H,CH2) ,3.56(s,4H,CH2×2),3.40–3.32(m,2H,CH2),3.31–3.24(m,6H,CH2×3),3.22–3.17(m,1H,CH),2.98–2.88(m,1H,CH). 13 C NMR (100MHz, DMSO-d6) δ167.35(C=O), 163.51(C=O), 162.48(dd, 1 J CF =246.0, 3 J CF =13.3Hz),161.62(C=O),155.01,150.80,147.00,142.42(t, 2 J CF =9.3Hz),140.98,140.66,137.78,135.68,131.37,130.73,129.71,129.00,128.94,128.09,127.63,126.96,125.34,121.17,112.62(dd, 2 J CF =24.6, 4 J CF =6.4Hz), 102.60(t, 2 J CF=25.5Hz),52.40,50.93,48.67,48.44,47.04,45.34,43.05,37.97.HRMS m / z C 38 H 35 F2N7O 11 S3[M+H] + 900.1597, 900.1600 [M+H] + .

[0068] Example 4: Preparation of compounds 21a1-21b1 and 21a2-21b2

[0069] The target compounds 20a1-20b1 and 20a2-20b2 (150 mg) were dissolved in dichloromethane (10 mL), and then 10% palladium on carbon (10% w / w, 15 mg) was added. The mixture was purged with hydrogen three times and stirred overnight at room temperature under hydrogen balloon protection. After the reaction was completed, diatomaceous earth was added and filtered. The solvent was evaporated under reduced pressure. The crude product was purified by recrystallization (ethyl acetate) or preparative thin-layer chromatography (methanol:dichloromethane = 1:30) to obtain the target compounds 21a1-21b1 and 21a2-21b2.

[0070] 21a1 is a white solid, yield: 35%, melting point: 202-203℃. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)δ8.78(d,J=7.7Hz,1H,NH),8.23–8.12(m,1H,Ph-H),8.02–7.90(m,3H,Ph-H),7.78(d,J=8.1Hz,1H,Ph-H),7.76–7.71(m,1 H,Ph-H),7.71–7.66(m,1H,Ph-H),7.62(t,J=7.5Hz,1H,Ph-H),7.41(d,J=8.7Hz,2H,Ph-H),7.17(dq,J=14.2,6.9Hz,3H,Ph-H),6.87(d,J=6.8Hz, 2H,Ph-H),6.67(d,J=8.7Hz,2H,Ph-H),6.19(s,2H,NH2),4.55(td,J=8.7,5.0Hz,1H,CH),3.97–3.81(m,2H,CH2),3.69(t,J=4.3Hz,4H,CH2×2),3. 47–3.36(m,2H,CH2),3.21(tt,J=9.2,4.2Hz,2H,CH2),3.16–3.04(m,2H,CH2),2.97(t,J=8.4Hz,5H,CH2×2,CH),2.85(dd,J=13.9,9.4Hz,1H,CH). 13C NMR(100MHz,DMSO-d6)δ167.83(C=O),164.04(C=O),161.60(C=O),156.15, 154.19,147.25,141.00,137.88,135.76,135.63,130.91,130.85,130.31,1 29.73,129.33,129.20,128.73,127.89,127.54,127.08,126.99,121.11,11 8.46,113.33,65.83,53.32,49.31,48.49,47.05,46.47,43.32,38.37.HRMS m / zC 38 H 39 N7O8S2[M+H] + 786.2374, 786.2372 [M+H] + .

[0071] 21b1 is a white solid with a yield of 37% and a melting point of 206-208℃. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=7.7Hz,1H,NH),8.15(d,J=7.1Hz,1H,Ph-H),8.02(d,J=8.6Hz,2H,Ph-H),7.97–7.89(m,1H,Ph-H),7.77(d,J=8.1Hz,1 H,Ph-H),7.75–7.69(m,1H,Ph-H),7.66–7.56(m,2H,Ph-H),7.40(d,J=8.7H z,2H,Ph-H),7.17(dq,J=14.2,7.0Hz,3H,Ph-H),6.86(d,J=7.0Hz,2H,Ph-H) ,6.66(d,J=8.7Hz,2H,Ph-H),6.17(s,2H,NH2),4.53(td,J=8.5,5.4Hz,1H, CH),3.93–3.79(m,2H,CH2),3.58(s,4H,CH2×2),3.47–3.36(m,2H,CH2),3.3 5(s,4H,CH2×2),3.21(tt,J=10.8,4.7Hz,2H,CH2),3.10(ddd,J=16.5,9.6,5 .2Hz,2H,CH2),2.95(dq,J=11.3,5.3,4.0Hz,1H,CH),2.90–2.81(m,1H,CH). 13C NMR (100MHz, DMSO-d6) δ167.80(C=O),164.13(C=O),161.61(C=O),156.11,154.16,147.20,141.08,137.70,137.67,135.70,131.19,131.04,1 30.32,129.22,128.81,127.94,127.55,127.10,126.98,121.02,118.3 9,113.35,53.26,50.91,49.27,48.49,47.05,45.51,43.29,38.48.HRMS m / zC 38 H 39 N7O9S3[M+H] + 834.2044, 834.2047 [M+H] + .

[0072] 21a2 is a white solid, yield: 38%, melting point: 198-199℃. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)δ8.68(d,J=8.1Hz,1H,NH),8.22–8.12(m,1H,Ph-H),8.01–7.86(m,3H,Ph-H),7.85–7.75 (m,2H,Ph-H),7.70–7.58(m,2H,Ph-H),7.40(d,J=8.7Hz,2H,Ph-H),7.02(t,J=9.4Hz,1H,Ph-H),6.77–6.61(m, 4H,Ph-H),6.19(s,2H,NH),4.56(td,J=8.5,5.1Hz,1H,CH),3.94–3.74(m,2H,CH2),3.64(t,J=4.4Hz,4H,CH2×2 ),3.44(d,J=16.1Hz,2H,CH2),3.32–3.20(m,2H,CH2),3.20–3.06(m,2H,CH2),3.05–2.84(m,6H,CH2×2,CH×2). 13 C NMR (100MHz, DMSO-d6) δ167.53(C=O), 164.07(C=O), 162.51(dd, 1 J CF =246.1, 3 J CF =13.4Hz),161.63(C=O),155.20,154.20,147.06,142.48(t, 3 J CF=9.3Hz),140.87,136.04,135.64,131.13,130.48,130.32,129.57,129.34,128.04,127.61,126.97,121.21,118.42,113.33,112.56(dd, 2 J CF =24.7, 4 J CF =6.8Hz), 102.60(t, 2 J CF =25.5Hz),65.83,52.45,49.30,48.57,47.18,46.31,43.32,37.96.HRMS m / z C 38 H 37 F2N7O8S2[M+H] + 822.2186, 822.2186 [M+H] + .

[0073] 21b2 is a white solid with a yield of 32% and a melting point of 186-187℃. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)δ8.65(d,J=8.0Hz,1H,NH),8.22–8.12(m,1H,Ph-H),8.05(dd,J=8.3,2.0Hz,1H,Ph-H),7.99(dd,J=8.3,2.0Hz,1H,Ph-H),7.97–7 .90(m,1H,Ph-H),7.78(d,J=8.1Hz,2H,Ph-H),7.72(dd,J=5.7,3.2Hz,1H,Ph -H),7.70–7.57(m,2H,Ph-H),7.40(d,J=8.7Hz,2H,Ph-H),7.08–6.95(m,1H, Ph-H),6.66(d,J=8.7Hz,3H,Ph-H),6.17(s,2H,NH2),4.56(td,J=8.5,5.1H z,1H,CH),3.90–3.73(m,2H,CH2),3.57(s,4H,CH2×2),3.48–3.35(m,2H,CH2 ),3.30(d,J=5.2Hz,4H,CH2×2),3.23(dd,J=12.2,5.5Hz,2H,CH2),3.13(ddd ,J=11.5,7.9,4.7Hz,2H,CH2),3.04–2.95(m,1H,CH),2.95–2.88(m,1H,CH). 13C NMR (100MHz, DMSO-d6) δ167.53(C=O), 164.15(C=O), 162.48(dd, 1 J CF =246.1, 3 J CF =13.4Hz),161.64(C=O),155.12,154.17,147.01,142.41(t, 3 J CF =9.2Hz),140.98,137.84,135.70,132.02,131.42,130.75,130.32,129.05,128.08,127.62,126.97,121.15,118.39,113.35,112.59(dd, 2 J CF =24.8, 4 J CF =6.5Hz).102.61(t, 2 J CF =25.9Hz),52.48,50.95,49.25,48.56,47.16,45.35,43.28,37.90.HRMS m / z C 38 H 37 F2N7O9S3[M+H] + 870.1856, 870.1852 [M+H] + .

[0074] Example 5. In vitro anti-HIV activity assay of the target compound (MT-4 cells)

[0075] Terminology Explanation: MT-4 cells: human acute lymphoblastic leukemia cells; MTT assay: MTT stands for 3,4,5-dimethylthiazolium-2)-2,5-diphenyltetrazolium bromide, trade name: thiazolium blue; DMSO: dimethyl sulfoxide.

[0076] Test Principles

[0077] Because HIV-infected MT-4 cells undergo cytopathic effects within a certain period (5-7 days), an appropriate concentration of the test compound solution was added to an HIV-infected MT-4 cell suspension. After a period of culture (5-7 days), MT-4 cell viability was determined using the MTT assay to obtain the drug concentration (EC50) that protects 50% of cells from cytopathic effects. 50 This allows us to determine the anti-HIV activity of the target compound. Simultaneously, we can determine the concentration (CC) at which the target compound induces cytopathic effects in 50% of uninfected HIV-positive cells. 50), calculate the selectivity index (SI = CC) 50 / EC 50 ).

[0078] The principle of MTT assay: MTT binds to succinate dehydrogenase in living cells but does not react with dead cells. Currently, the MTT assay is a rapid enzyme analysis method for reflecting cell viability.

[0079] Test materials and methods

[0080] (1) HIV-1(III) B HIV-2 (ROD) strain: provided by the Institute of Microbiology and Immunology, Rega Institute, University of Leuven, Belgium;

[0081] (2) MT-4 cells: provided by the Institute of Microbiology and Immunology, Rega Institute, University of Leuven, Belgium;

[0082] (3) MTT: Purchased from Sigma, Inc., USA;

[0083] (4) Sample preparation: Dissolve the sample in DMSO to prepare an appropriate concentration before use, and dilute it 5 times with double-distilled water, with 5 dilutions in total;

[0084] (5) Positive controls: 11L, PF74;

[0085] (6) Test method: After dilution, the sample was added to the suspension of HIV-infected MT-4 cells. After a period of time, cell viability was determined by the MTT assay. The absorbance (A) value was recorded at 590 nm using an ELISA reader, and the EC50 was calculated. 50 CC 50 And SI;

[0086] (7) MTT staining method: After adding the sample and culturing for a period of time, add 20 μL of MTT solution (5 mg / mL) to each well and continue culturing for several hours. Discard the staining solution and add 150 μL of LDMSO to each well. Mix thoroughly and record the absorbance at 590 nm in an ELISA reader.

[0087] The specific steps are as follows: Dissolve the compound in DMSO or water, then dilute with phosphate buffer, adding 3×10... 5MT-4 cells were pre-incubated with 100 μL of different concentrations of compound solutions at 37°C for 1 hour. Then, 100 μL of an appropriate concentration of virus diluent was added to this mixture, and the cells were incubated at 37°C for 1 hour. After three washes, the cells were resuspended in culture media containing or without the compound. The cells were then incubated for another 7 days at 37°C in a 5% CO2 environment, and the original culture medium was replenished with either compound-containing or compound-free media on the third day post-infection. Each culture condition was repeated twice. The cytopathic effect of the virus was monitored daily using a reverse optical microscope. Generally, the virus diluents used in this experiment often resulted in cytopathic effects on the fifth day post-infection. The drug inhibitory concentration was defined as the concentration at which the drug produced 50% inhibition of the virus-induced cytopathic effect without direct cytotoxicity to the cells (EC50). 50 It is worth emphasizing that when a compound has poor water solubility and requires DMSO to dissolve, the volumetric concentration of DMSO relative to water is generally less than 10% (the final concentration of DMSO in MT-4 cell culture medium is less than 2%). Because DMSO can affect the antiviral activity of the tested compound, antiviral activity control experiments with the same concentration of DMSO solution should be performed in parallel. Furthermore, the final concentration of DMSO (1 / 1000) is far lower than the concentration required to affect HIV replication in MT-4 cells.

[0088] In vitro anti-HIV-1(III) activity of the target compound B The activity screening data for HIV-2 (ROD) were provided by the Institute of Microbiology and Immunology, Rega Institute, University of Leuven, Belgium. All activity data were obtained through at least three independent, parallel experiments, and the results are shown in Table 1.

[0089] Table 1. Anti-HIV-1 / 2 activity, toxicity, and selectivity index of the target compound (4-quinazolinone derivative containing benzylamide piperazine) (MT-4 cells)

[0090]

[0091]

[0092]

[0093] a EC 50 The concentration of compounds that protect 50% of HIV-1-infected cells from cytopathic effects; b CC 50 The concentration of a compound that causes 50% of uninfected HIV-1 cells to become diseased; c SI: Selectivity coefficient, CC 50 / EC 50The ratio; 11L, PF74: reported HIV-1 capsid protein regulators, used as positive controls.

[0094] Experimental Conclusions and Analysis: As shown in Table 1, the 26 newly synthesized 4-quinazolinone derivatives containing benzenesulfonamide piperazine exhibited significant anti-HIV activity. Most compounds showed anti-HIV-1 activity at sub-micromolar to low-micromolar levels, with 5 compounds exhibiting anti-HIV-1 activity exceeding that of lead 11L, and 12 compounds exhibiting anti-HIV-1 activity exceeding that of PF74. Among them, compounds 12a2 and 21a2 are the most effective HIV-1 capsid protein regulators in this series, EC... 50 The value is 0.11 μM, which is 11 L (EC). 50 =0.28μM) is 2.5 times that of PF74 (EC) 50 =0.80 μM) 7.3 times that of [previous concentration]. It is noteworthy that this series of compounds also exhibits outstanding anti-HIV-2 activity, EC [value missing]. 50 The values ​​ranged from 0.08 to 1.97 μM, with compound 12c2 (EC) being one of them. 50 =0.08μM) and 21a2 (EC 50 =0.08μM) anti-HIV-2 activity and 11L (EC) 50 =0.03μM) is equivalent to PF74 (EC) 50 =3.78 μM) is 47 times that of the 4-quinazolinone derivative containing benzenesulfonamide piperazine ketone synthesized in this invention. Therefore, the 4-quinazolinone derivative containing benzenesulfonamide piperazine ketone synthesized in this invention is worthy of further research.

Claims

1. A 4-quinazolinone derivative containing benzylsulfonamide piperazine, or a pharmaceutically acceptable salt thereof, having the structure shown in general formula I: in, R1 is a hydrogen atom, a halogen atom, or a C1-C4 alkyl-substituted sulfonyl group; the halogen atom is selected from fluorine, chlorine, bromine, and iodine atoms; R2 is a hydrogen atom or a halogen atom; the halogen atom is selected from fluorine, chlorine, bromine, and iodine atoms; R3 is a methoxy group or a sulfonyl group substituted with various six-membered heterocycles; the six-membered heterocycle is selected from piperazine rings, morpholine rings, thiomorpholine rings, and 1,1-thiomorpholine dioxide rings; R4 is a nitro group or an amino group.

2. The 4-quinazolinone derivative containing benzenesulfonamide piperazine as described in claim 1, characterized in that, R1 is a hydrogen atom, fluorine atom, chlorine atom, bromine atom, or methanesulfonyl group; R2 is a hydrogen atom or fluorine atom; R3 is a methoxy group, 4-sulfonylmorpholine, or 4-sulfonyl-1,1-thiomorpholine; R4 is a nitro group or amino group.

3. The 4-quinazolinone derivative containing benzenesulfonamide piperazine as described in claim 1 or 2, characterized in that, It is one of the compounds having the following structures: 。 4. The method for preparing the 4-quinazolinone derivative containing benzenesulfonamide piperazine ketone as described in claim 3, characterized in that, The synthesis steps are as follows: Synthesis of key intermediate 4: p-Nitrobenzenesulfonyl chloride 1 reacts with piperazine-2-one in dichloromethane as a solvent under the action of triethylamine to obtain intermediate 2; then intermediate 2 undergoes a nucleophilic substitution reaction with methyl bromoacetate in tetrahydrofuran as a solvent under the action of sodium hydride to obtain intermediate 3; finally, intermediate 3 undergoes an ester hydrolysis reaction in tetrahydrofuran and water as solvents under the action of lithium hydroxide to obtain intermediate 4; The synthesis route is as follows: Reagents and conditions: (i) piperazine-2-one, triethylamine, dichloromethane, 0℃ → room temperature; (ii) methyl bromoacetate, sodium hydride, tetrahydrofuran, 0℃ → room temperature; (iii) lithium hydroxide, tetrahydrofuran:water = 1:1, room temperature; Synthesis of target compounds 11a1-11e1, 11a2-11e2 and 12a1-12c1, 12e1, 12a2-12c2, 12e2: Starting with the correspondingly substituted 2-nitrobenzoyl chloride 5a-5e, acylation reaction was carried out with p-methoxyaniline in dichloromethane under the action of triethylamine to give intermediate 6a-6e; then, 6a-6e was hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to give intermediate 7a-7e; subsequently, 7a-7e reacted with N-Boc-L-phenylalanine or N-Boc-L-3,5-difluorophenylalanine in dichloromethane to generate intermediates 8a1-8e1 and 8a2-8e2, which were then reacted in N, using acetonitrile as the reaction solvent. O-bis(trimethylsilylacetamide), N, The intermediates 9a1-9e1 and 9a2-9e2 were obtained by cyclization reaction of N-diisopropylethylamine and 4-dimethylaminopyridine. 9a1-9e1 and 9a2-9e2 were then de-Boc-grouped in dichloromethane under the action of trifluoroacetic acid to obtain intermediates 10a1-10e1 and 10a2-10e2. 10a1-10e1 and 10a2-10e2 were then subjected to an amide condensation reaction with intermediate 4 in dichloromethane to obtain the target compounds 11a1-11e1 and 11a2-11e2. Finally, 11a1-11e1 and 11a2-11e2 were subjected to hydrogenation reduction reaction in dichloromethane under 10% palladium on carbon catalysis to obtain the target compounds 12a1-12c1, 12e1 and 12a2-12c2, 12e2. The synthesis route is as follows: Reagents and conditions: (i) p-Methoxyaniline, triethylamine, dichloromethane, 0℃ → room temperature; (ii) Hydrogen, 10% palladium on carbon, dichloromethane, room temperature; (iii) N-Boc-L-phenylalanine or N-Boc-L-3,5-difluorophenylalanine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, 0℃ → room temperature; (iv) N,O-bis(trimethylsilylacetamide), N,N-diisopropylethylamine, 4-dimethylaminopyridine, acetonitrile, 80℃, reflux; (v) Trifluoroacetic acid, dichloromethane, room temperature; (vi) Intermediate 4,2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N, N-Diisopropylethylamine, dichloromethane, 0°C → room temperature; (vii) Hydrogen, 10% palladium on carbon, dichloromethane, room temperature; Synthesis of target compounds 20a1-20b1, 20a2-20b2 and 21a1-21b1, 21a2-21b2: Starting from p-nitrobenzenesulfonyl chloride 1, acylation reaction was carried out with morpholine and 1,1-thiomorpholine dioxide in dichloromethane under the action of triethylamine to give intermediates 13a-13b; then, 13a-13b was hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to give intermediate 14a-14b. Subsequently, 14a-14b undergoes an acylation reaction with 2-nitrobenzoyl chloride in dichloromethane to yield intermediate 15a-15b. 15a-15b is then hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to yield intermediate 16a-16b. Following this, 16a-16b undergoes an amide condensation reaction with N-Boc-L-phenylalanine or N-Boc-L-3,5-difluorophenylalanine in dichloromethane to yield intermediates 17a1-17b1 and 17a2-17b2. Next, 17a1-17b1 and 17a2-17b2 are reacted in acetonitrile as a solvent in N,O-bis(trimethylsilylacetamide) and N, The intermediates 18a1-18b1 and 18a2-18b2 undergo a cyclization reaction with N-diisopropylethylamine and 4-dimethylaminopyridine. Intermediates 18a1-18b1 and 18a2-18b2 are then deactivated with trifluoroacetic acid in dichloromethane to obtain intermediates 19a1-19b1 and 19a2-19b2. These intermediates then undergo an amide condensation reaction with intermediate 4 in dichloromethane to yield the target compounds 20a1-20b1 and 20a2-20b2. Finally, 20a1-20b1 and 20a2-20b2 are hydrogenated and reduced in dichloromethane under 10% palladium on carbon catalysis to yield the target compounds 21a1-21b1 and 21a2-21b2. The synthesis route is as follows: Reagents and conditions: (i) Morpholine or 1,1-thiomorpholine dioxide, triethylamine, dichloromethane, 0℃ → room temperature; (ii) Hydrogen, 10% palladium on carbon, dichloromethane, room temperature; (iii) 2-nitrobenzyl chloride, triethylamine, dichloromethane, 0℃ → room temperature; (iv) Hydrogen, 10% palladium on carbon, dichloromethane, room temperature; (v) N-Boc-L-phenylalanine or N-Boc-L-3,5-difluorophenylalanine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, 0℃ → room temperature; (vi) N,O-bis(trimethylsilylacetamide), N,N-diisopropylethylamine, 4-dimethylaminopyridine, acetonitrile, 80℃, reflux; (vii) Trifluoroacetic acid, dichloromethane, room temperature; (viii) Intermediate 4,2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, 0°C → room temperature; (ix) Hydrogen, 10% palladium on carbon, dichloromethane, room temperature.

5. The use of the 4-quinazolinone derivative containing benzylsulfonamide piperazine as described in any one of claims 1-3 in the preparation of drugs for the treatment and prevention of AIDS.

6. An anti-HIV drug composition, characterized in that, It comprises a 4-quinazolinone derivative containing benzylsulfonamide piperazine as described in any one of claims 1-3, or a variety of pharmaceutically acceptable carriers or excipients.

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