CN102285967A - 2-arylmethylmercapto-6-(tetrahydroquinoline-1-methyl)-4-pyrimidone derivatives, and preparation method and use thereof - Google Patents

Abstract

The invention discloses 2-[(substitutedphenylamino)carbonylmethylmercapto]-6-(2,6-dichlorobenzyl)-3H-pyrimidine-4-one derivatives. The general structural formula of the derivatives is shown below. In the general structural formula, R1 may be H, methyl or ethyl; R2 may be 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, benzyl bromide, 4-methyl benzyl chloride, 4-chlorobenzyl chloride, 4-nitrobenzyl chloride, p-cyanobenzyl chloride, alpha-chloro-4-methoxytoluene or 4-fluorobenzyl chloride. The invention also relates to the preparation method of the compounds and the use of the compounds as human immunodeficiency virus (HIV) inhibitors.

Description

2-arylmethylthio-6-(tetrahydroquinoline-1-methyl)-4-pyrimidinone derivatives and their preparation methods and applications

technical field

The invention relates to a derivative and a preparation method thereof, in particular to 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl] The invention relates to 3H-pyrimidin-4-one derivatives and their preparation method and application, which belong to the technical field of organic compound synthesis and medical application. the

Background technique

AIDS (AIDS) is an infectious disease caused by human immunodeficiency virus (HIV), which seriously affects human life and health. HIV is a retrovirus, and the important role of reverse transcriptase in the viral life cycle makes it an important target for antiviral therapy. There are two classes of reverse transcriptase inhibitors: nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have attracted much attention due to their high efficiency, low toxicity, and high selectivity. However, due to the spread of drug-resistant strains, such drugs rapidly lose their clinical efficacy. Therefore, the research and development of novel, efficient, low-toxicity, and broad-spectrum anti-drug-resistant NNRTIs is one of the important directions of anti-HIV drug research. the

According to the current literature reports, there are more than 50 types of NNRTIs, among which dihydro-alkylthio-benzyl-oxopyrimidines (DABOs) derivatives are a typical one. DABO derivatives can improve the flexibility of the molecular conformation and the adaptability of the position in the target, which is beneficial to the improvement of the activity of the compound. We summarized previous research results on DABOs and found that 2-thio DABO analogues have significantly improved anti-HIV-1RT activity, and have become a class of NNRTIs with development prospects. So far, with the S-DABOs pyrimidine parent ring as the basic skeleton, a series of structural modifications have been made to its C _2- , C _3- , C _4- , C _5- , and C _6- , and many highly active S-DABOs derivatives, and its structure-activity relationship (SAR) study.

Therefore, using the S-DABOs pyrimidine mother ring as the basic skeleton and using the effective information of the structure-activity relationship of the lead compound to modify the structure of its 6-position side chain is of great significance for the discovery of broad-spectrum and highly effective anti-HIV drugs. the

Contents of the invention

The present invention aims to provide 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-ones Derivatives and preparation methods thereof, the present invention also provides the use of the above compounds. the

Technical scheme of the present invention is as follows:

1.5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives

5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives of the present invention , the general structural formula I is as follows:

in,

R ₁ is: H, methyl or ethyl;

_R2 is: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano -2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitro Benzyl chloride, p-cyanobenzyl chloride, p-methoxybenzyl chloride or p-fluorobenzyl chloride.

Preferably, the above-mentioned general formula I compound is one of the following:

2. The synthetic route of 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives as follows:

Reagents: (i) K ₂ CO ₃ , toluene, reflux for 24h, 90°C; (ii) 15% NaOH, 15h; (iii) MgCl ₂ , Et ₃ N, CH ₃ CN, R ₁ CH(CO ₂ Et)( CO ₂ K), N, N-carbonyldiimidazole, stirred overnight at room temperature and then refluxed for 2 hours; (iv) thiourea, EtONa, refluxed for 6-12 hours; (v) substituted benzyl halides and substituted α-halogenated acetophenones , potassium carbonate (K ₂ CO ₃ ), N,N-dimethylformamide (DMF), room temperature for 12 hours.

3. The preparation method of intermediate 1,2,3,4-tetrahydroquinoline-1-acetic acid

Put 30.37mmol of 1,2,3,4-tetrahydroquinoline and 60.78mmol of K ₂ CO ₃ in 80mL of toluene, add 29.94mmol of ethyl bromoacetate dropwise under stirring condition, react at 90°C for 24h, detect by TLC The reaction was carried out; after the reaction was completed, the reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure, and the remaining liquid was extracted three times with chloroform, and washed with brine; after drying over anhydrous magnesium sulfate, the oily crude product was obtained, and the volume ratio was 1:4 ethyl acetate Purified by ester-petroleum ether column chromatography, the pure product was obtained as a brown oil. Add directly to 1mol/L NaOH aqueous solution without purification and reflux for 12h, drop in 1mol/L HCl after cooling, a brown precipitate appears, filter and dry to obtain the crude product.

1,2,3,4-Tetrahydroquinoline-1-acetic acid (3), brown solid, yield 46.5%, mp: 45-46°C (dec). MS (ESI): m/z192.31 (M +1).

4. Preparation of β-ketoesters (4a-c)

Put 0.5 mol of substituted diethyl malonate in 800 mL of anhydrous acetonitrile, add 0.595 mol of anhydrous MgCl ₂ , 0.717 mol of Et ₃ N, and stir at room temperature for 2 hours; add 0.25 mol of 1, 2, 3 , 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N,N-carbonyldiimidazole were placed in 300mL acetonitrile for 15 minutes, and then the reaction mixture was poured into substituted diethyl malonate, anhydrous MgCl ₂ , Et ₃ N mixture; stirred at room temperature overnight, heated to reflux for 2h, followed by TLC until the reaction was complete; 150mL of 13% HCl was added dropwise in an ice-bath environment, stirred for 10min after dropping, and the organic layer was separated and evaporated to dryness , add 150ml ethyl acetate; wash the ethyl acetate mixture three times with NaHCO ₃ , 150ml each time, then wash three times with NaCl solution, 150ml each time, then dry with anhydrous MgSO ₄ , and distill under reduced pressure to obtain β-keto acid Crude esters (4a-c) were used in the next step without purification.

Ethyl 3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4a): yellow transparent oil, yield: 15.1%, MS (ESI): m/ z 262.30(M+1).. the

Ethyl 2-methyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4b): yellow transparent oil, yield: 12.1%, MS ( ESI): m/z 276.41 (M+1). the

Ethyl 2-ethyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4c): yellow transparent oil, yield: 10.7%, MS ( ESI): m/z 290.33 (M+1). the

5. Synthesis of 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one

In a dry reaction flask, add 0.3 mol of sodium in batches to 100 mL of absolute ethanol, wait for the sodium to dissolve and cool, add 0.225 mol of thiourea at one time, then add 0.15 mol of the crude product β-ketoester 4a-c, and dissolve the mixture Heat to reflux, TLC traces until the β-keto ester raw material point disappears, then stop heating, evaporate the solvent under reduced pressure after cooling, dissolve the residue in 100mL water, filter, adjust the pH to 4 with 1mol/L hydrochloric acid and glacial acetic acid, A white precipitate is produced; filter and wash the filter cake with glacial ethanol and glacial ether to obtain 5a-c white solids; they can be directly used in the next step without purification (about 90% or more of the pure product). the

6-(1,2,3,4-tetrahydroquinolinylmethyl)-2-mercapto-4(3H)pyrimidinone (5a): white solid, yield: 67.1%, mp: 238-240°C ( dec). ¹ H NMR (DMSO-d ₆ , ppm) δ: 12.41 (s, 1H, N ₃ H), 12.37 (s, 1H, N ₁ H), 6.35-6.95 (m, 4H, quinoline-H) , 5.41 (s, 1H, C ₅ -H), 4.19 (s, 2H, NCH ₂ ) 3.31-3.33 (m, 2H, quinoline-H ₂ ), 2.71-2.73 (m, 2H, quinoline-H ₄ ), 1.89-1.90 (m, 2H, quinoline- _H3 ); ESI-MS: m/z 274.09 (M+1).

6-(1,2,3,4-tetrahydroquinolinylmethyl)-2-mercapto-5-methyl-4(3H)pyrimidinone (5b): white solid, yield: 70.3%, mp: 227-228°C (dec). ¹ H NMR (DMSO-d ₆ , ppm) δ: 12.01 (s, 1H, N ₃ H), 11.99 (s, 1H, N ₁ H), 6.57-6.99 (m, 4H , quinoline-H), 5.41 (s, 1H, C ₅ -H), 4.21 (s, 2H, NCH ₂ ) 3.15-3.17 (m, 2H, quinoline-H ₂ ), 2.68-2.70 (m, 2H, quinoline -H ₄ ), 1.86-1.88 (m, 2H, quinoline-H ₃ ), 1.79 (s, 3H, C ₅ -CH ₃ ). ESI-MS: m/z 288.11 (M+1). C ₁₅ H ₁₇ N ₃ OS (287.38).

6-(1,2,3,4-tetrahydroquinolinylmethyl)-2-mercapto-5-ethyl-4(3H)pyrimidinone (5c): white solid, yield: 69.7%, mp: 210-211°C (dec). ¹ H NMR (DMSO-d ₆ , ppm) δ: 12.03 (s, 1H, N ₃ H), 12.01 (s, 1H, N ₁ H), 6.45-6.97 (m, 4H , quinoline-H), 4.20 (s, 2H, NCH ₂ ) 3.30-3.37 (m, 2H, quinoline-H ₂ ), 2.37-2.45 (m, 2H, quinoline-H ₄ ), 2.28-2.31 (q, 2H , J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.68-1.79 (m, 2H, quinoline-H ₃ ), 1.79 (s, 3H, C ₅ -CH ₃ ), 1.62-1.71 (m, 2H, _quinolineH3 ), 1.05 (t, 3H, J=7.2Hz, _{C5 - CH2CH3} ). ESI-MS: m/z 302.12 (M+1).

6. Preparation method of 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives

The above-mentioned intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one is subjected to an alkylation reaction with each substituted benzyl halide and substituted α-halogenated acetophenone, and then Purified by crystallization to obtain 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives The derivative 6, the substituent is selected from: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2- Chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl , p-chlorobenzyl chloride, p-nitrobenzyl chloride, p-cyanobenzyl chloride, p-methoxybenzyl chloride or p-fluorobenzyl chloride, the obtained target compounds 6a1-6c14, the structures are shown in Table 1. the

The following provides the preferred operation steps:

Put 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a-c) (2mmol) and K ₂ CO ₃ (2.2mmol) in a reaction flask, add anhydrous Dimethylformamide (DMF), after stirring at room temperature for 30min, add 2.0mmol substituents (substituted chloroacetanilide or substituted benzyl chloride), stir at room temperature, TLC tracking until the raw material point disappears, stop the reaction; add ice water, white Precipitation occurred; filtered and recrystallized with EtOH or EtOH-DMF mixed solvent to obtain the target compound; the obtained target compound 6a1-6c14 (see Table 1).

7.5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives pharmaceutical composition

An anti-HIV-1 pharmaceutical composition, containing the above-mentioned 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]- 3H-pyrimidin-4-one derivatives and pharmaceutical excipients are used to make medicines in different dosage forms. the

8. Application of 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives

5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives of the present invention It can be used as an HIV-1 non-nucleoside inhibitor. Specifically, it is used as an HIV-1 inhibitor for the preparation of anti-AIDS drugs. the

In the present invention, on the basis of molecular simulation, C2 _- uses active groups to replace halobenzyl and α-halogenated acetophenone, and introduces more flexible 1,2,3,4-tetrahydro in the _C6- side chain Quinoline-1-methyl, in order to increase the hydrophobicity and hydrogen bonding between the inhibitor molecule and the surrounding amino acid residues, a series of 5-alkyl-2-arylmethylthio-6-[(1,2 , 3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives. The series of compounds have high anti-HIV activity and low cytotoxicity, and have further medicinal development value.

Detailed ways:

The present invention will be further described below in conjunction with embodiment, and the numbering of all target compounds is identical with table 1. The percentages are all percentages by mass. the

The synthesis of embodiment 1 intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-ketone

Preparation of intermediate 1,2,3,4-tetrahydroquinoline-1-acetic acid

Put 30.37mmol of 1,2,3,4-tetrahydroquinoline and 60.78mmol of K ₂ CO ₃ in 80mL of toluene, add 29.94mmol of ethyl bromoacetate dropwise under stirring condition, react at 90°C for 24h, detect by TLC The reaction was carried out; after the reaction was completed, the reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure, and the remaining liquid was extracted three times with chloroform, and washed with brine; after drying over anhydrous magnesium sulfate, the oily crude product was obtained, and the volume ratio was 1:4 ethyl acetate Purified by ester-petroleum ether column chromatography, the pure product was obtained as a brown oil. Add directly to 1mol/L NaOH aqueous solution without purification and reflux for 12h, drop in 1mol/L HCl after cooling, a brown precipitate appears, filter and dry to obtain the crude product.

1,2,3,4-Tetrahydroquinoline-1-acetic acid (3), brown solid, yield 46.5%, mp: 45-46°C (dec). MS (ESI): m/z192.31 (M +1).

Preparation of β-ketoesters (4a-c)

Put 0.5 mol of substituted diethyl malonate in 800 mL of anhydrous acetonitrile, add 0.595 mol of anhydrous MgCl ₂ , 0.717 mol of Et ₃ N, and stir at room temperature for 2 hours; add 0.25 mol of 1, 2, 3 , 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N,N-carbonyldiimidazole were placed in 300mL acetonitrile for 15 minutes, and then the reaction mixture was poured into substituted diethyl malonate, anhydrous MgCl ₂ , Et ₃ N mixture; stirred at room temperature overnight, heated to reflux for 2h, followed by TLC until the reaction was complete; 150mL of 13% HCl was added dropwise in an ice-bath environment, stirred for 10min after dropping, and the organic layer was separated and evaporated to dryness , add 150ml ethyl acetate; wash the ethyl acetate mixture three times with NaHCO ₃ , 150ml each time, then wash three times with NaCl solution, 150ml each time, then dry with anhydrous MgSO ₄ , and distill under reduced pressure to obtain β-keto acid Crude esters (4a-c) were used in the next step without purification.

Ethyl 3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4a): yellow transparent oil, yield: 15.1%, MS (ESI): m/ z 262.30(M+1). the

Ethyl 2-methyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4b): yellow transparent oil, yield: 12.1%, MS ( ESI): m/z 276.41 (M+1). the

Ethyl 2-ethyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4c): yellow transparent oil, yield: 10.7%, MS ( ESI): m/z 290.33 (M+1). the

Synthesis of 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one:

Sodium (6.9g, 0.3mol) was added in 100mL of absolute ethanol in batches, and after the sodium was dissolved and cooled, thiourea (17.1g, 0.225mol) was added in one go, and then the crude product β-ketoester 4a-c (0.15 mol), the mixture was heated to reflux, followed by TLC until the β-ketoester raw material point disappeared, and the heating was stopped. After cooling, the solvent was evaporated under reduced pressure, and the residue was dissolved in water (100mL), filtered, and 1mol/L hydrochloric acid was used. Adjust the pH to 4 with glacial acetic acid, and a white precipitate occurs. Filter and wash the filter cake with glacial ethanol and glacial ether to obtain 5a-c white solids. It can be directly used in the next step without purification (about 90% pure product). the

6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-2-mercapto-4(3H)pyrimidinone (5a): white solid, yield: 67.1%, mp: 238-240°C (dec). ¹ H NMR (DMSO-d ₆ , ppm) δ: 12.41 (s, 1H, N ₃ H), 12.37 (s, 1H, N ₁ H), 6.35-6.95 (m, 4H , quinoline-H), 5.41 (s, 1H, C ₅ -H), 4.19 (s, 2H, NCH ₂ ) 3.31-3.33 (m, 2H, quinoline-H ₂ ), 2.71-2.73 (m, 2H, quinoline -H ₄ ), 1.89-1.90 (m, 2H, quinoline-H ₃ ); ESI-MS: m/z 274.09 (M+1). 6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-2-mercapto-5-methyl-4(3H)pyrimidinone (5b): white solid, yield: 70.3%, mp: 227-228°C (dec). ¹ H NMR (DMSO-d ₆ , ppm) δ: 12.01 (s, 1H, N ₃ H), 11.99 (s, 1H, N ₁ H), 6.57- 6.99 (m, 4H, quinoline-H), 5.41 (s, 1H, C ₅ -H), 4.21 (s, 2H, NCH ₂ ) 3.15-3.17 (m, 2H, quinoline-H ₂ ), 2.68-2.70 ( m, 2H, quinoline-H ₄ ), 1.86-1.88 (m, 2H, quinoline-H ₃ ), 1.79 (s, 3H, C ₅ -CH ₃ ). ESI-MS: m/z 288.11 (M+1) _.C15H17N3OS ( _287.38 ) _.

6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-2-mercapto-5-ethyl-4(3H)pyrimidinone (5c): white solid, yield: 69.7%, mp: 210-211°C (dec). ¹ H NMR (DMSO-d ₆ , ppm) δ: 12.03 (s, 1H, N ₃ H), 12.01 (s, 1H, N ₁ H), 6.45- 6.97(m, 4H, quinoline-H), 4.20(s, 2H, NCH ₂ ) 3.30-3.37(m, 2H, quinoline-H ₂ ), 2.37-2.45(m, 2H, quinoline-H ₄ ), 2.28- 2.31 (q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.68-1.79 (m, 2H, quinoline-H ₃ ), 1.79 (s, 3H, C ₅ -CH ₃ ), 1.62-1.71 (m, 2H, _quinolineH3 ), 1.05 (t, 3H, J=7.2Hz, _{C5 - CH2CH3} ). ESI-MS: m/z 302.12 (M+1).

Example 22-Benzylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a1)

Put 6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a) (2mmol) and K ₂ CO ₃ (2.2mmol) in a reaction flask, add anhydrous DMF, and stir at room temperature for 30min, Substituent 2-bromoacetophenone (2.0 mmol) was added, stirred at room temperature, followed by TLC until the starting point disappeared, and the reaction was stopped. Ice water was added, and a white precipitate was formed. Filter and recrystallize with EtOH or EtOH-DMF mixed solvent to obtain the target compound. Yield: 48.6%, mp: 160-163°C (dec).

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.72 (s, 1H, NH), 8.04 (d, 2H, J = 7.8 Hz, PhH), 7.69 (t, 1H, J1 = 7.8 Hz, J ₂ = 15.6Hz, PhH), 7.58(t, 2H, _J1 =7.8Hz, _J2 =15.6Hz, PhH), 6.23-6.86(m, 4H, quinoline-H), 5.86(s, 1H, _C5 -H ), 4.77 (s, 2H, SCH ₂ ), 3.99 (s, 2H, NCH ₂ ), 3.24-3.26 (m, 2H, quinoline-H ₂ ), 2.61-2.63 (m, 2H, quinoline-H ₄ ), 1.75-1.77 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v3315 (NH), 2945, 2846 (CH ₂ ), 1703 (C=O), 1654 (C=O), 1598 , 1575, 1541, 1499 (aryl), 1239 (CN), 1204 (CN). ESI-MS: m/z 392.47 (M+1). C ₂₂ H ₂₁ N ₃ O ₂ S (391.49).

Example 32-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a2)

The preparation method is the same as in Example 2, except that the substituent is p-methyl-2-chloroacetophenone. the

The resulting product 2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a2) Yield 54.1%, mp: 165-166°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.68 (s, 1H, NH), 7.93 (d, 2H, J=7.8Hz, PhH), 7.36 (d, 2H, J=7.8Hz, PhH), 6.24-6.87 (m, 4H, quinoline-H), 5.87 (s, 1H, C ₅ -H), 4.74 (s, 2H, SCH ₂ ), 4.02 (s, 2H, NCH ₂ ), 3.26-3.31 (m , 2H, quinoline-H ₂ ), 2.71-2.73 (m, 2H, quinoline-H ₄ ), 2.39 (s, 3H, PhCH ₃ ), 1.76-1.78 (m, 2H, quinoline-H ₃ ).IR(KBr , cm ^-1 )v 3421(NH), 2927, 2841(CH ₃ , CH ₂ ), 1675(C=O), 1655(C=O), 1602, 1538, 1506, 1459(aryl), 1315(CN ), 1200 (CN). ESI-MS: m/z 406.47 (M+1). C ₂₃ H ₂₃ N ₃ O ₂ S (405.51).

Example 42-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a3)

The preparation method is the same as in Example 2, except that the substituent is p-chloro-2-chloroacetophenone. the

The resulting product 2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a3) Yield 37.9%, mp: 193-195°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d6, ppm) δ: 12.79 (s, 1H, NH), 8.05 (d, 2H, J=8.4Hz, PhH), 7.64 (d, 2H, J=8.4Hz, PhH), 6.22 -6.86(m, 4H, quinoline-H), 5.87(s, 1H, C ₅ -H), 4.75(s, 2H, SCH ₂ ), 3.99(s, 2H, NCH ₂ ), 3.25-3.33(m, 2H, quinoline-H ₂ ), 2.62-2.64 (m, 2H, quinoline-H ₄ ), 1.76-1.78 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v 3522 (NH), 2927, ₂₈₄₃ (CH2), 1690(C=O), 1656(C=O), 1600, 1587, 1545, 1503(aryl), 1310(CN), 1195(CN).ESI-MS: m/z 426.87(M+1).C ₂₂ H ₂₀ ClN ₃ O ₂ S(425.93).

Example 5 2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a4)

The preparation method is the same as in Example 2, except that the substituent is p-nitro-2-chloroacetophenone. the

The resulting product 2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a4) yield 45.1%, mp: 215-216°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.37 (s, 1H, NH), 8.27 (d, 2H, J=8.4Hz, PhH), 8.03 (d, 2H, J=8.4Hz, PhH), 6.35-6.95 (m, 4H, quinoline-H), 5.41 (s, 1H, C ₅ -H), 4.65 (s, 2H, SCH ₂ ), 4.19 (s, 2H, NCH ₂ ), 3.32-3.34 (m , 2H, quinoline-H ₂ ), 2.71-2.73 (m, 2H, quinoline-H ₄ ), 1.89-1.90 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v 3405 (NH) , 2923, 2856(CH ₂ ), 1703(C=O), 1640(C=O), 1579, 1508, 1458(aryl), 1308(CN), 1185(CN).ESI-MS: m/z 437.51 (M+1).C ₂₂ H ₂₀ N ₄ O ₄ S (436.48).

Example 62-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a5)

The preparation method is the same as in Example 2, except that the substituent is p-cyano-2-chloroacetophenone. the

The resulting product 2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a5) yield 43.3%, mp: 174-175°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.73 (s, 1H, NH), 7.67-7.98 (m, 4H, PhH), 6.73-7.01 (m, 4H, quinoline-H), 5.41 (s, 1H, C ₅ -H), 4.66 (s, 2H, SCH ₂ ), 4.12 (s, 2H, NCH ₂ ), 3.27-3.31 (m, 2H, quinoline-H ₂ ), 2.41-2.53 (m, 2H, quinoline-H ₄ ), 1.79-1.90 (m, 2H, quinoline-H ₃ ). IR (KBr, cm ^-1 ) v3391 (NH), 2925, 2848 (CH ₂ ), 2229 (C≡N), 1662 ( C=O), 1601(C=O), 1581, 1504, 1458(aryl), 1272(CN), 1198( _CN ).ESI-MS: m/z 417.52(M+1) _{.C23H20N 4} O ₂ S (416.50).

Example 72-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a6)

The preparation method is the same as in Example 2, except that the substituent is p-cyano-2-chloroacetophenone. the

The resulting product 2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a6) Yield 39.1%, mp: 163-165°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.72 (s, 1H, NH), 8.02 (d, 2H, J=8.4Hz, PhH), 7.07 (d, 2H, J=8.4Hz, PhH), 6.28-6.87 (m, 4H, quinoline-H), 5.82 (s, 1H, C ₅ -H), 4.69 (s, 2H, SCH ₂ ), 4.03 (s, 2H, NCH ₂ ), 3.85 (s, 3H , PhOCH3).3.28-3.38(m, 2H, quinoline-H ₂ ), 2.63-2.65(m, 2H, quinoline-H ₄ ), 1.78-1.80(m, 2H, quinoline-H ₃ ).1R(KBr, cm ^-1 )v 3416(NH), 2931, 2838(CH ₃ , CH ₂ ), 1656(C=O), 1610(C=O), 1599, 1574, 1535, 1507(aryl), 1259(CN) , 1172 (CN). ESI-MS: m/z 422.54 (M+1). C ₂₃ H ₂₃ N ₃ O ₃ S (421.51).

Example 8 2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a7)

The preparation method is the same as in Example 2, except that the substituent is p-fluoro-2-chloroacetophenone. the

The resulting product 2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a7) Yield 47.1%, mp: 180-181°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.73 (s, 1H, NH), 8.10-8.13 (m, 2H, PhH), 7.37-7.40 (m, 2H, PhH), 6.23-6.86 (m, 4H, quinoline-H), 5.85 (s, 1H, C ₅ -H), 4.74 (s, 2H, SCH ₂ ), 4.19 (s, 2H, NCH ₂ ) 3.26-3.33 (m, 2H, quinoline-H ₂ ), 2.62-2.64 (m, 2H, quinoline-H ₄ ), 1.77-1.81 (m, 2H, quinoline-H ₃ ). IR (KBr, cm ^-1 ) v 3318 (NH), 2940, 2852 (CH ₂ ), 1702(C=O), 1655(C=O), 1597, 1575, 1539, 1502(aryl), 1220(CN), 1154(CN).ESI-MS: m/z 410.49(M+1) .C ₂₂ H ₂₀ FN ₃ O ₂ S (409.48).

Example 92-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a8)

The preparation method is the same as in Example 2, except that the substituent is benzyl bromide. the

The resulting product 2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a8) yield 49.6%, mp ：200-203℃(dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.70 (s, 1H, NH), 7.39 (d, 2H, J = 7.2 Hz, PhH), 7.30 (t, 1H, J ₁ = 7.2 Hz, J ₂ =14.4Hz, PhH), 7.26(t, 2H, J ₁ =7.2Hz, J ₂ =14.4Hz, ,PhH), 6.35-6.90(m, 4H, quinoline-H), 5.84(s, 1H, C ₅ -H), 4.38 (s, 2H, SCH ₂ ), 4.29 (s, 2H, NCH ₂ ), 3.42-3.44 (m, 2H, quinoline-H ₂ ), 2.70-2.72 (m, 2H, quinoline-H ₄ ), 1.90-1.92 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v3426 (NH), 2928, 2844 (CH ₂ ), 1656 (C=O), 1602, 1574, 1547, 1508(aryl), 1310(CN), 1246(CN). ESI-MS: m/z 364.57(M+1). C ₂₁ H ₂₁ N ₃ OS (363.48).

Example 10 2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a9)

The preparation method is the same as in Example 2, except that the substituent is p-methyl benzyl chloride. the

Gained product 2-[(4-methylphenyl) methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a9) Yield 53.2%, mp: 185-186°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.60 (s, 1H, NH), 7.27 (d, 2H, J=7.8Hz, PhH), 7.10 (d, 2H, J=7.8Hz, PhH), 6.34-6.91 (m, 4H, quinoline-H), 5.89 (s, 1H, C ₅ -H), 4.33 (s, 2H, SCH ₂ ), 4.28 (s, 2H, NCH ₂ ), 3.41-3.44 (m , 2H, quinoline-H ₂ ), 2.70-2.73 (m, 2H, quinoline-H ₄ ), 2.27 (s, 3H, PhCH ₃ ), 1.90-1.91 (m, 2H, quinoline-H ₃ ).IR(KBr , cm ^-1 )v 3418(NH), 2921, 2849(CH ₃ , CH ₂ ), 1651(C=O), 1602, 1579, 1534, 1508(aryl), 1310(CN), 1194(CN). ESI-MS: m/z 378.57 (M+1). C ₂₂ H ₂₃ N ₃ OS (377.50).

Example 11 2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a10 )

The preparation method is the same as in Example 2, except that the substituent is p-chlorobenzyl chloride. the

The resulting product 2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a10 ) yield 57.9%, mp: 190-193°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.65 (s, 1H, NH), 7.41 (d, 2H, J=8.4Hz, PhH), 7.33 (d, 2H, J=8.4Hz, PhH), 6.33-6.90 (m, 4H, quinoline-H), 5.90 (s, 1H, C ₅ -H), 4.36 (s, 2H, SCH ₂ ), 4.28 (s, 2H, NCH ₂ ), 3.41-3.44 (m , 2H, quinoline-H ₂ ), 2.70-2.72 (m, 2H, quinoline-H ₄ ), 1.88-1.92 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v 3413 (NH) , 2921, 2850 (CH ₂ ), 1648 (C=O), 1602, 1581, 1535 (aryl), 1310 (CN), 1194 (CN). ESI-MS: m/z 398.74 (M+1).C ₂₁ H ₂₀ ClN ₃ OS(397.92).

Example 12 2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a11)

The preparation method is the same as in Example 2, except that the substituent is p-nitrobenzyl chloride. the

The resulting product 2-[(4-nitrophenyl) methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a11) Yield 51.5%, mp: 180-182°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.70 (s, 1H, NH), 8.13 (d, 2H, J=8.4Hz, PhH), 7.66 (d, 2H, J=8.4Hz, PhH), 6.30-6.89 (m, 4H, quinoline-H), 5.90 (s, 1H, C ₅ -H), 4.47 (s, 2H, SCH ₂ ), 4.28 (s, 2H, NCH ₂ ), 3.39-3.43 (m , 2H, quinoline-H ₂ ), 2.68-2.71 (m, 2H, quinoline-H ₄ ), 1.87-1.91 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v 3370 (NH) , 2930, 2841(CH ₂ ), 1660(C=O), 1600, 1583, 1518(aryl), 1310(CN), 1240(CN).ESI-MS: m/z 409.51(M+1).C ₂₁ H ₂₀ N ₄ O ₃ S (408.47).

Example 13 2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a12)

The preparation method is the same as in Example 2, except that the substituent is p-cyanobenzyl chloride. the

Gained product 2-[(4-cyanophenyl) methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a12) Yield 54.0%, mp: 186-188°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.71 (s, 1H, NH), 7.73 (d, 2H, J=7.8Hz, PhH), 7.59 (d, 2H, J=7.8Hz, PhH), 6.30-6.90 (m, 4H, quinoline-H), 5.90 (s, 1H, C ₅ -H), 4.43 (s, 2H, SCH ₂ ), 4.27 (s, 2H, NCH ₂ ), 3.38-3.40 (m , 2H, quinoline-H ₂ ), 2.69-2.71 (m, 2H, quinoline-H ₄ ), 1.87-1.91 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v 3419 (NH) , 2927, 2840 (CH ₂ ), 2227 (C≡N), 1656 (C=O), 1601, 1581, 1533, 1504 (aryl), 1311 (CN), 1235 (CN).ESI-MS: m/ z 389.52(M+1).C ₂₂ H ₂₀ N ₄ OS(388.49).

Example 142-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a13)

The preparation method is the same as in Example 2, except that the substituent is p-methoxybenzyl chloride. the

The resulting product 2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a13) yield 48.7%, mp: 194-196°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.60 (s, 1H, NH), 7.31 (d, 2H, J=9.0Hz, PhH), 6.91 (d, 2H, J=9.0Hz, PhH), 6.35-6.84 (m, 4H, quinoline-H), 5.89 (s, 1H, C ₅ -H), 4.32 (s, 2H, SCH ₂ ), 4.29 (s, 2H, NCH ₂ ), 3.72 (s, 3H , PhOCH3), 3.42-3.45 (m, 2H, quinoline-H ₂ ), 2.70-2.73 (m, 2H, quinoline-H ₄ ), 1.89-1.93 (m, 2H, quinoline-H ₃ ).1R (KBr, cm ^-1 )v 3426(NH), 2928, 2835(CH ₃ , CH2), 1649(C=O), 1603, 1579, 1534, 1510(aryl), 1311(CN), 1246(CN).ESI- MS: m/z 394.53 (M+1). C ₂₂ H ₂₃ N ₃ O ₂ S (393.50).

Example 15 2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a14 )

The preparation method is the same as in Example 2, except that the substituent is p-fluorochlorobenzyl. the

The resulting product 2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a14 ) yield 53.9%, mp: 203-205°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.66 (s, 1H, NH), 7.31 (d, 2H, J=9.0Hz, PhH), 6.91 (d, 2H, J=9.0Hz, PhH), 6.35-6.84 (m, 4H, quinoline-H), 5.89 (s, 1H, C ₅ -H), 4.36 (s, 2H, SCH ₂ ), 4.29 (s, 2H, NCH ₂ ), 3.41-3.43 (m , 2H, quinoline-H ₂ ), 2.70-2.72 (m, 2H, quinoline-H ₄ ), 1.90-1.91 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v 3319 (NH) , 2923, 2844 (CH ₂ ), 1649 (C=O), 1600, 1577, 1545, 1508 (aryl), 1313 (CN), 1229 (CN). ESI-MS: m/z 382.49 (M+1) .C ₂₁ H ₂₀ FN ₃ OS(381.47).

Example 16 5-methyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b1)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is 2-bromoacetophenone. the

The resulting product 5-methyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b1) Rate 45.4%, mp: 188-189°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.77 (s, 1H, NH), 7.86 (d, 2H, J = 7.8 Hz, PhH), 7.69 (t, 1H, J ₁ = 7.8 Hz, J ₂ =15.6Hz, PhH), 7.54(t, 2H, J ₁ =7.8Hz, J ₂ =15.6Hz,, PhH), 6.29-6.82(m, 4H, quinoline-H), 4.61(s, 2H, SCH ₂ ), 4.21 (s, 2H, NCH ₂ ), 3.16-3.18 (m, 2H, quinoline-H ₂ ), 2.43-2.45 (m, 2H, quinoline-H ₄ ), 1.95 (s, 3H, C ₅ CH ₃ ), 1.60-1.61 (m, 2H, quinoline-H ₃ ). IR (KBr, cm ^-1 ) v3420 (NH), 2922, 2842 (CH ₃ , CH ₂ ), 1682 (C=O), 1637 (C =O), 1601, 1572, 1506, 1449(aryl), 1262(CN), 1194(CN).ESI-MS: m/z 406.47(M+1).C ₂₃ H ₂₃ N ₃ O ₂ S (405.51 ).

Example 17 5-methyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b2)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methyl-2-chloroacetophenone. the

The resulting product 5-methyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b2) is 52.3%, mp: 203-204°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.71 (s, 1H, NH), 7.76 (d, 2H, J=8.4Hz, PhH), 7.31 (d, 2H, J=8.4Hz, PhH), 6.31-6.83 (m, 4H, quinoline-H), 4.56 (s, 2H, SCH ₂ ), 4.21 (s, 2H, NCH ₂ ), 3.16-3.18 (m, 2H, quinoline-H ₂ ), 2.39 (s , 3H, PhCH3), 2.47-2.50 (m, 2H, quinoline-H ₄ ), 1.95 (s, 3H, C ₅ -CH ₃ ), 1.62-1.66 (m, 2H, quinoline-H ₃ ).IR(KBr , cm ^-1 )v 3428(NH), 2940, 2920, 2832(CH ₃ , CH ₂ ), 1704(C=O), 1633(C=O), 1603, 1571, 1550, 1505(aryl), 1265 (CN), 1198(CN). ESI-MS: m/z 420.74 (M+1). C ₂₄ H ₂₅ N ₃ O ₂ S (419.54).

Example 18 5-methyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b3)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-chloro-2-chloroacetophenone. the

The resulting product 5-methyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3h-pyrimidine -4-ketone (6b3) yield 36.7%, mp: 187-188°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.79 (s, 1H, NH), 7.85 (d, 2H, J=8.4Hz, PhH), 7.58 (d, 2H, J=8.4Hz, PhH), 6.28-6.81 (m, 4H, quinoline-H), 4.58 (s, 2H, SCH ₂ ), 4.20 (s, 2H, NCH ₂ ), 3.15-3.17 (m, 2H, quinoline-H ₂ ), 2.43-2.50 (m, 2H, quinoline-H ₄ ), 1.95 (s, 3H, C ₅ -CH ₃ ), 1.62-1.68 (m, 2H, quinoline-H ₃ ).IR (KBr, cm ^-1 ) v 3434 (NH ), 2929, 2842 (CH ₃ , CH ₂ ), 1681 (C=O), 1637 (C=O), 1600, 1587, 1550, 1504 (aryl), 1256 (CN), 1193 (CN).ESI- MS: m/z 440.87 (M+1). C ₂₃ H ₂₂ ClN ₃ O ₂ S (439.96).

Example 19 5-methyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b4)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-nitro-2-chloroacetophenone. the

The resulting product 5-methyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b4) is 39.1%, mp: 189-190℃(dec)

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.81 (s, 1H, NH), 8.27 (d, 2H, J=7.8Hz, PhH), 8.09 (d, 2H, J=7.8Hz, PhH), 6.28-6.79 (m, 4H, quinoline-H), 4.65 (s, 2H, SCH ₂ ), 4.18 (s, 2H, NCH ₂ ), 3.40-3.43 (m, 2H, quinoline-H ₂ ), 2.50-2.51 (m, 2H, quinoline-H ₄ ), 1.89-1.94 (m, 2H, quinoline-H ₃ ), 1.620 (s, 3H, C ₅ -CH ₃ ).IR(KBr, cm ^-1 ) v 3406 (NH ), 2918, 2842 (CH ₃ , CH ₂ ), 1696 (C=O), 1641 (C=O), 1602, 1524, 1505, 1458 (aryl), 1344 (CN), 1189 (CN).ESI- _MS : m/z 451.43 (M+1 ₎ . _C23H22N4O4S ( _450.51 ).

Example 205-methyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b5)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-cyano-2-chloroacetophenone. the

The resulting product 5-methyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b5) is 36.6%, mp: 179-180℃(dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.73 (s, 1H, NH), 7.63-7.96 (m, 4H, PhH), 6.30-6.80 (m, 4H, quinoline-H), 4.62 (s, 2H, SCH ₂ ), 4.19 (s, 2H, NCH ₂ ), 3.14-3.23 (m, 2H, quinoline-H ₂ ), 2.44-2.50 (m, 2H, quinoline-H ₄ ), 1.94 (s, 3H, C ₅ -CH ₃ ), 1.62-1.78 (m, 2H, quinoline-H ₃ ). IR (KBr, cm ^-1 ) v3442 (NH), 2919, 2840 (CH ₃ , CH ₂ ), 2231 (C≡N ), 1690(C=O), 1643(C=O), 1602, 1544, 1505(aryl), 1267(CN), 1195(CN).ESI-MS: m/z 431.59(M+1).C ₂₄ H ₂₂ N ₄ O ₂ S (430.52).

Example 215-methyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -pyrimidin-4-one (6b6)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methoxy-2-chloroacetophenone. the

The resulting product 5-methyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -Pyrimidin-4-one (6b6) yield 38.9%, mp: 210-211°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.72 (s, 1H, NH), 7.83 (d, 2H, J=8.4Hz, PhH), 7.03 (d, 2H, J=8.4Hz, PhH), 6.31-6.83 (m, 4H, quinoline-H), 4.54 (s, 2H, SCH ₂ ), 4.23 (s, 2H, NCH ₂ ), 3.86 (s, 3H, PhOCH3), 3.20-3.22 (m, 2H, quinoline-H ₂ ), 2.47-2.50 (m, 2H, quinoline-H ₄ ), 1.95 (s, 3H, C ₅ -CH ₃ ), 1.64-1.66 (m, 2H, quinoline-H ₃ ).IR(KBr , cm ^-1 )v 3225(NH), 2932, 2839(CH ₃ , CH ₂ ), 1667(C=O), 1646(C=O), 1599, 1574, 1546, 1502(aryl), 1266(CN ), 1165 (CN). ESI-MS: m/z 436.71 (M+1). C ₂₄ H ₂₅ N ₃ O ₃ S (435.54).

Example 225-Methyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-keto(6b7)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-fluoro-2-chloroacetophenone. the

The resulting product 5-methyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b7) yield 47.6%, mp: 179-180°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.73 (s, 1H, NH), 7.90-7.93 (m, 2H, PhH), 7.33-7.36 (m, 2H, PhH), 6.29-6.81 (m, 4H, quinoline-H), 4.58 (s, 2H, SCH ₂ ), 4.21 (s, 2H, NCH ₂ ), 3.16-3.18 (m, 2H, quinoline-H ₂ ), 2.43-2.45 (m, 2H, quinoline -H ₄ ), 1.95(s, 3H, C ₅ -CH ₃ ), 1.61-1.63(m, 2H, quinoline-H ₃ ).IR(KBr, cm ^-1 )v 3467(NH), 2951, 2893, 2845(CH ₃ , CH ₂ ), 1703(C=O), 1654(C=O), 1600, 1575, 1551, 1508(aryl), 1263(CN), 1195(CN).ESI-MS: m/ z 424.56(M+1).C ₂₃ H ₂₂ FN ₃ O ₂ S(423.50).

Example 23 5-methyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b8)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is benzyl bromide. the

The resulting product 5-methyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b8) Rate 51.7%, mp: 224-225°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.63 (s, 1H, NH), 7.20 (d, 2H, J = 7.2 Hz, PhH), 7.17 (t, 1H, J ₁ = 7.2 Hz, J ₂ =14.4Hz, PhH), 7.14(t, 2H, J ₁ =7.2Hz, J ₂ =14.4Hz,, PhH), 6.42-6.90(m, 4H, quinoline-H), 4.39(s, 2H, SCH ₂ ), 4.15 (s, 2H, NCH ₂ ), 3.43-3.45 (m, 2H, quinoline-H ₂ ), 2.61-2.63 (m, 2H, quinoline-H ₄ ), 1.98 (s, 3H, C ₅ -CH ₃ ), 1.84-1.86 (m, 2H, quinoline-H ₃ ). IR (KBr, cm ^-1 ) v3427 (NH), 2942, 2838 (CH ₃ , CH ₂ ), 1640 (C=O), 1602, 1573, 1554, 1508 (aryl), 1264 (CN), 1197 (CN). ESI-MS: m/z 378.56 (M+1). C ₂₂ H ₂₃ N ₃ OS (377.50).

Example 24 5-methyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b9)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methylbenzyl chloride. the

The resulting product 5-methyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b9) yield 35.0%, mp: 223-225°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.35 (s, 1H, NH), 7.01 (d, 2H, J=7.8Hz, PhH), 6.96 (d, 2H, J=7.8Hz, PhH), 6.58-6.61 (m, 4H, quinoline-H), 4.22 (s, 2H, SCH ₂ ), 4.12 (s, 2H, NCH ₂ ), 3.43-3.45 (m, 2H, quinoline- _{H 2} ), 2.61-2.63 (m , 2H, quinoline-H ₄ ), 2.24 (s, 3H, PhCH ₃ ), 1.97 (s, 3H, C ₅ -CH ₃ ), 1.84-1.86 (m, 2H, quinoline-H ₃ ).IR(KBr, cm ^-1 )v 3334(NH), 2926, 2853(CH ₃ , CH ₂ ), 1683(C=O), 16001, 1538, 1497(aryl), 1239(CN), 1190(CN).ESI-MS : m/z 392.53(M+1).C ₂₃ H ₂₅ N ₃ OS(391.53).

Example 255-Methyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6b10)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-chlorobenzyl. the

The resulting product 5-methyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6b10) yield 56.3%, mp: 220-222°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.64 (s, 1H, NH), 7.15 (d, 2H, J=7.8Hz, PhH), 7.11 (d, 2H, J=7.8Hz, PhH), 6.40-6.91(m, 4H, quinolineH), 4.38(s, 2H, SCH ₂ ), 4.17(s, 2H, NCH ₂ ), 3.41-3.43(m, 2H, quinolineH ₂ ), 2.60-2.62(m, 2H , quinolineH ₄ ), 1.98(s, 3H, C ₅ CH ₃ ), 1.82-1.86(m, 2H, quinolineH ₃ ).IR(KBr, cm ^-1 )v 3426(NH), 2941, 2840(CH ₃ , CH ₂ ), 1641 (C=O), 1601, 1573, 1554, 1507 (aryl), 1265 (CN), 1197 (CN). ESI-MS: m/z 412.56 (M+1). C ₂₂ H ₂₂ ClN ₃ OS(411.95).

Example 26 5-methyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b11)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-nitrobenzyl chloride. the

The resulting product 5-methyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b11) yield 52.9%, mp: 209-210°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.69 (s, 1H, NH), 7.93 (d, 2H, J=8.4Hz, PhH), 7.34 (d, 2H, J=8.4Hz, PhH), 6.39-6.91 (m, 4H, quinoline-H), 4.39 (s, 2H, SCH ₂ ), 4.32 (s, 2H, NCH ₂ ), 3.39-3.40 (m, 2H, quinoline-H ₂ ), 2.57-2.59 (m, 2H, quinoline-H ₄ ), 1.98 (s, 3H, C ₅ -CH ₃ ), 1.80-1.84 (m, 2H, quinoline-H ₃ ).IR(KBr, cm ^-1 ) v 3334 (NH ), 2936, 2842 (CH ₃ , CH ₂ ), 1643 (C=O), 1599, 1573, 1516 (aryl), 1344 (CN), 1263 (CN). ESI-MS: m/z 423.57 (M+ 1). C ₂₂ H ₂₂ N ₄ O ₃ S (422.50).

Example 27 5-methyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b12)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-cyanobenzyl chloride. the

The resulting product 5-methyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b12) yield 50.4%, mp: 195-197°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.70 (s, 1H, NH), 7.54 (d, 2H, J=7.8Hz, PhH), 7.27 (d, 2H, J=7.8Hz, PhH), 6.40-6.90 (m, 4H, quinoline-H), 4.38 (s, 2H, SCH ₂ ), 4.25 (s, 2H, NCH ₂ ), 3.37-3.39 (m, 2H, quinoline-H ₂ ), 2.57-2.59 (m, 2H, quinoline-H ₄ ), 1.98 (s, 3H, C ₅ -CH ₃ ), 1.80-1.84 (m, 2H, quinoline-H ₃ ).IR(KBr, cm ^-1 ) v 3433 (NH ), 2935, 2842 (CH ₃ , CH ₂ ), 2225 (C≡N), 1642 (C=O), 1601, 1572, 1541, 1505 (aryl), 1260 (CN), 1196 (CN).ESI- _MS : m _/ z 403.57 (M+1). _C23H22N4OS (402.51).

Example 28 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b13)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methoxybenzyl chloride. the

The resulting product 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b13) is 39.8%, mp: 180-182°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.59 (s, 1H, NH), 7.05 (d, 2H, J=8.4Hz, PhH), 6.91 (d, 2H, J=8.4Hz, PhH), 6.41-6.84 (m, 4H, quinoline-H), 4.38 (s, 2H, SCH ₂ ), 4.10 (s, 2H, NCH ₂ ), 3.68 (s, 3H, PhOCH3), 3.44-3.47 (m, 2H, quinoline-H ₂ ), 2.62-2.64 (m, 2H, quinoline-H ₄ ), 1.98 (s, 3H, C ₅ -CH ₃ ), 1.85-1.89 (m, 2H, quinoline-H ₃ ).IR(KBr , cm ^-1 )v 3413(NH), 2928, 2833(CH ₃ , CH ₂ ), 1641(C=O), 1601, 1571, 1545, 1511(aryl), 1253(CN), 1198(CN). ESI-MS: m/z 408.57 (M+1). C ₂₃ H ₂₅ N ₃ O ₂ S (407.53).

Example 29 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b14)

The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methoxybenzyl chloride. the

The resulting product 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b14) is 55.8%, mp: 215-217℃(dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.63 (s, 1H, NH), 7.14 (m, 2H, PhH), 6.93 (m, 2H, PhH), 6.41-6.90 (m, 4H, quinoline- H), 4.38 (s, 2H, SCH ₂ ), 4.16 (s, 2H, NCH ₂ ), 3.42-3.44 (m, 2H, quinoline-H ₂ ), 2.61-2.63 (m, 2H, quinoline-H ₄ ) , 1.98 (s, 3H, C ₅ -CH ₃ ), 1.83-1.87 (m, 2H, quinoline-H ₃ ). IR (KBr, cm ^-1 ) v 3459 (NH), 2939, 2840 (CH ₃ , CH ₂ ), 1641(C=O), 1601, 1573, 1554, 1508(aryl), 1265(CN), 1222(CN).ESI-MS: m/z 396.53(M+1).C ₂₂ H ₂₂ FN ₃ OS(395.49).

Example 305-Ethyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c1)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is 2-bromoacetophenone. the

The resulting product 5-ethyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c1) Rate 47.5%, mp: 193-194°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.77 (s, 1H, NH), 7.85 (d, 2H, J = 7.8 Hz, PhH), 7.68 (t, 1H, J ₁ = 7.8 Hz, J ₂ =15.6Hz, PhH), 7.53(t, 2H, J ₁ =7.8Hz, J ₂ =15.6Hz, PhH), 6.32-6.82(m, 4H, quinoline-H), 4.60(s, 2H, SCH ₂ ) , 4.24(s, 2H, NCH ₂ ), 3.16-3.18(m, 2H, quinoline-H ₂ ), 2.45-2.50(m, 2H, quinoline-H ₄ ), 2.43(q, 2H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ), 1.60-1.63 (m, 2H, quinoline-H ₃ ), 1.05 (t, 3H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ).IR(KBr, cm ^-1 )v 3462 (NH), 2931, 2840 (CH ₃ , CH ₂ ), 1682 (C=O), 1633 (C=O), 1599, 1573, 1507, 1448 (aryl), 1254 (CN), 1195 ( CN). ESI-MS: m/z 420.21 (M+1). C ₂₄ H ₂₅ N ₃ O ₂ S (419.54).

Example 315-Ethyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c2)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methyl-2-bromoacetophenone. the

The resulting product 5-ethyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c2) is 57.1%, mp: 185-187°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.76 (s, 1H, NH), 7.74 (d, 2H, J=8.4Hz, PhH), 7.32 (d, 2H, J=8.4Hz, PhH), 6.33-6.83 (m, 4H, quinoline-H), 4.56 (s, 2H, SCH ₂ ), 4.24 (s, 2H, NCH ₂ ), 3.16-3.18 (m, 2H, quinoline-H ₂ ), 2.45-2.50 (m, 2H, quinoline-H ₄ ), 2.42 (q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 2.39 (s, 3H, PhCH ₃ ), 1.62-1.65 (m, 2H, quinoline -H ₃ ), 1.02 (t, 3H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ).IR (KBr, cm ^-1 ) v 3437 (NH), 2929, 2842 (CH ₃ , CH ₂ ), 1677(C=O), 1639(C=O), 1602, 1572, 1505, 1456(aryl), 1254(CN), 1193(CN).ESI-MS: m/z 434.57(M+1).C ₂₅ H ₂₇ N ₃ O ₂ S (433.18)

Example 325-Ethyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6c3)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-chloro-2-bromoacetophenone. the

The resulting product 5-ethyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c3) yield 39.2%, mp: 190-192°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d6, ppm) δ: 12.48 (s, 1H, NH), 7.84 (d, 2H, J=8.4Hz, PhH), 7.57 (d, 2H, J=8.4Hz, PhH), 6.31 -7.01 (m, 4H, quinoline-H), 4.57 (s, 2H, SCH ₂ ), 4.24 (s, 2H, NCH ₂ ), 3.24-3.33 (m, 2H, quinoline-H ₂ ), 2.67-2.71 ( m, 2H, quinoline-H ₄ ), 2.31 (q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.87-1.91 (m, 2H, quinoline-H ₃ ), 1.06 (t, 3H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ). IR (KBr, cm ^-1 ) v 3566 (NH), 2962, 2930, 2868 (CH ₃ , CH ₂ ), 1686 (C=O), 1640 ( C=O), 1601, 1571, 1536, 1506 (aryl), 1254 (CN), 1191 (CN). ESI-MS: m/z 454.43 (M+1). C ₂₄ H ₂₄ ClN ₃ O ₂ S ( 454.13)

Example 335-Ethyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c4)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-nitro-2-bromoacetophenone. the

The resulting product 5-ethyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c4) is 43.7%, mp: 191-192°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.78 (s, 1H, NH), 8.27 (d, 2H, J=7.8Hz, PhH), 8.04 (d, 2H, J=7.8Hz, PhH), 6.32-7.01 (m, 4H, quinoline-H), 4.64 (s, 2H, SCH ₂ ), 4.23 (s, 2H, NCH ₂ ), 3.32-3.34 (m, 2H, quinoline-H ₂ ), 2.71-2.73 (m, 2H, quinoline-H ₄ ), 2.43 (q, 2H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ), 1.89-1.90 (m, 2H, quinoline-H ₃ ), 1.07 (t, 3H , J=7.8Hz, C ₅ -CH ₂ CH ₃ ).IR(KBr, cm ^-1 ) v 3467(NH), 2930, 2869(CH ₃ , CH ₂ ), 1693(C=O), 1640(C =O), 1601, 1571, 1536, 1506 (aryl), 1344 (CN), 1189 (CN). ESI-MS: m/z 465.55 (M+1). C ₂₄ H ₂₄ N ₄ O ₄ S (464.15 )

Example 34 5-ethyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c5)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-cyano-2-bromoacetophenone. the

The resulting product 5-ethyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c5) is 49.6%, mp: 192-194°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.80 (s, 1H, NH), 7.60-7.96 (m, 4H, PhH), 6.36-6.80 (m, 4H, quinoline-H), 4.61 (s, 2H, SCH ₂ ), 4.31(s, 2H, NCH ₂ ), 3.33-3.42(m, 2H, quinoline-H ₂ ), 2.43-2.51(m, 2H, quinoline-H ₄ ), 2.39(q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.60-1.61(m, 2H, quinoline-H ₃ ), 1.02(t, 3H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ).IR( KBr, cm ^-1 ) v 3343 (NH), 2937, 2869 (CH ₃ , CH ₂ ), 2230 (C≡N), 1688 (C=O), 1640 (C=O), 1601, 1542, 1506 ( aryl), 1251 (CN), 1195 (CN). ESI-MS: m/z 445.54 (M+1). C ₂₅ H ₂₄ N ₄ O ₂ S (444.16)

Example 355-Ethyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -pyrimidin-4-one (6c6)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methoxy-2-bromoacetophenone. The resulting product 5-ethyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -Pyrimidin-4-one (6c6) yield 39.1%, mp: 196-198°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.75 (s, 1H, NH), 7.82 (d, 2H, J=8.4Hz, PhH), 7.02 (d, 2H, J=8.4Hz, PhH), 6.33-6.83 (m, 4H, quinoline-H), 4.53 (s, 2H, SCH ₂ ), 4.24 (s, 2H, NCH ₂ ), 3.86 (s, 3H, PhOCH3). 3.14-3.19 (m, 2H, quinoline-H ₂ ), 2.45-2.50 (m, 2H, quinoline-H ₄ ), 2.27-2.31 (q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.88-1.90 (m, 2H, quinoline-H ₃ ), 1.05 (t, 3H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ).IR (KBr, cm ^-1 ) v 3476 (NH), 2932, 2839 (CH ₃ , CH ₂ ) , 1667(C=O), 1642(C=O), 1599, 1564, 1541, 1504(aryl), 1264(CN), 1166(CN).ESI-MS: m/z 450.34(M+1). C ₂₅ H ₂₇ N ₃ O ₃ S (449.18).

Example 36 5-ethyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-keto(6c7)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-fluoro-2-bromoacetophenone. the

The resulting product 5-ethyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c7) yield 49.3%, mp: 192-193°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.84 (s, 1H, NH), 7.90-7.92 (m, 2H, PhH), 7.32-7.35 (m, 2H, PhH), 6.32-6.82 (m, 4H, quinoline-H), 4.58 (s, 2H, SCH ₂ ), 4.24 (s, 2H, NCH ₂ ), 3.33-3.44 (m, 2H, quinoline-H ₂ ), 2.39-2.50 (m, 2H, quinoline -H ₄ ), 2.28-2.31(q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.62-1.71(m, 2H, quinoline-H ₃ ), 1.05(t, 3H, J=7.2 Hz, C ₅ -CH ₂ CH ₃ ). IR (KBr, cm ^-1 ) v 3466 (NH), 2933, 2840 (CH ₃ , CH ₂ ), 1680 (C=O), 1638 (C=O), 1598, 1574, 1547, 1506 (aryl), 1253 (CN), 1196 (CN). ESI-MS: m/z 438.56 (M+1). C ₂₄ H ₂₄ FN ₃ O ₂ S (437.16).

Example 37 5-ethyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c8)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is benzyl bromide. the

The resulting product 5-ethyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c8) Rate 46.9%, mp: 224-226°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.62 (s, 1H, NH), 7.20 (d, 2H, J = 7.2 Hz, PhH), 7.18 (t, 1H, J ₁ = 7.2 Hz, J ₂ =14.4Hz, PhH), 7.14(t, 2H, J ₁ =7.2Hz, J ₂ =14.4Hz, PhH), 6.34-6.91(m, 4H, quinoline-H), 4.42(s, 2H, SCH ₂ ) , 4.14 (s, 2H, NCH ₂ ), 3.42-3.44 (m, 2H, quinoline-H ₂ ), 2.61-2.63 (m, 2H, quinoline-H ₄ ), 2.46-2.51 (q, 2H, J=7.8 Hz, C ₅ -CH ₂ CH ₃ ), 1.84-1.86 (m, 2H, quinoline-H ₃ ), 1.06 (t, 3H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ).IR(KBr, cm ^-1 )v 3361(NH), 2932, 2840(CH ₃ , CH ₂ ), 1635(C=O), 1600, 1570, 1549, 1508(aryl), 1252(CN), 1197(CN).ESI- MS: m/z 392.37 (M+1). C ₂₃ H ₂₅ N ₃ OS (391.53).

Example 38 5-ethyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6c9)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methylbenzyl chloride. the

The resulting product 5-ethyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c9) yield 47.2%, mp: 218-221°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.60 (s, 1H, NH), 7.00 (d, 2H, J=8.4Hz, PhH), 6.97 (d, 2H, J=8.4Hz, PhH), 6.43-6.90 (m, 4H, quinoline-H), 4.41 (s, 2H, SCH ₂ ), 4.09 (s, 2H, NCH ₂ ), 3.42-3.44 (m, 2H, quinoline-H ₂ ), 2.61-2.64 (m, 2H, quinoline-H ₄ ), 2.46-2.51 (q, 2H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ), 2.22 (s, 3H, PhCH3), 1.84-1.88 (m, 2H, quinoline-H ₃ ), 1.07 (t, 3H, J=7.8Hz, C _{5 -CH 2} CH ₃ ).IR (KBr, cm ^-1 ) v 3422 (NH), 2930, 2838, 2796 (CH ₃ , CH ₂ ), 1634(C=O), 1600, 1569, 1546, 1507(aryl), 1251(CN), 1197(CN).ESI-MS: m/z 406.59(M+1).C ₂₄ H ₂₇ N ₃ OS(405.56).

Example 39 5-ethyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6c10)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-chlorobenzyl chloride. the

The resulting product 5-ethyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- The yield of 4-ketone (6c10) is 49.7%, mp: 227-229°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.65 (s, 1H, NH), 7.15 (d, 2H, J=8.4Hz, PhH), 7.11 (d, 2H, J=8.4Hz, PhH), 6.42-6.91 (m, 4H, quinoline-H), 4.41 (s, 2H, SCH ₂ ), 4.16 (s, 2H, NCH ₂ ), 3.40-3.42 (m, 2H, quinoline-H ₂ ), 2.60-2.62 (m, 2H, quinoline-H ₄ ), 2.47-2.50 (q, 2H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ), 1.83-1.85 (m, 2H, quinoline-H ₃ ), 1.06(t , 3H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ).IR (KBr, cm ^-1 ) v 3326(NH), 2932, 2840(CH ₃ , CH ₂ ), 1636(C=O), 1600 , 1570, 1546, 1507 (aryl), 1251 (CN), 1197 (CN). ESI-MS: m/z 426.74 (M+1). C ₂₃ H ₂₄ ClN ₃ OS (425.97).

Example 40 5-ethyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-keto (6c11)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-nitrobenzyl chloride. the

The resulting product 5-ethyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c11) yield 45.1%, mp: 195-197°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.71 (s, 1H, NH), 7.93 (d, 2H, J=8.4Hz, PhH), 7.34 (d, 2H, J=8.4Hz, PhH), 6.42-6.91 (m, 4H, quinoline-H), 4.42 (s, 2H, SCH ₂ ), 4.31 (s, 2H, NCH ₂ ), 3.37-3.39 (m, 2H, quinoline-H ₂ ), 2.56-2.58 (m, 2H, quinoline-H ₄ ), 2.50 (q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.80-1.82 (m, 2H, quinoline-H ₃ ), 1.07 (t, 3H , J=7.2Hz, C ₅ -CH ₂ CH ₃ ).IR(KBr, cm ^-1 ) v 3434(NH), 2931, 2840(CH ₃ , CH ₂ ), 1641(C=O), 1600, 1571 , 1519(aryl), 1250(CN), 1196(CN).ESI-MS: m/z 437.47(M+1).C ₂₃ H ₂₄ ClN ₄ O ₃ S (436.53).

Example 41 5-ethyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6c12)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-cyanobenzyl chloride. the

The resulting product 5-ethyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c12) yield 45.2%, mp: 195-196°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.70 (s, 1H, NH), 7.54 (d, 2H, J=8.4Hz, PhH), 7.27 (d, 2H, J=8.4Hz, PhH), 6.42-6.91 (m, 4H, quinoline-H), 4.41 (s, 2H, SCH ₂ ), 4.24 (s, 2H, NCH ₂ ), 3.36-3.38 (m, 2H, quinoline-H ₂ ), 2.57-2.59 (m, 2H, quinoline-H ₄ ), 2.50 (q, 2H, J=7.8Hz, C ₅ -CH ₂ CH ₃ ), 1.80-1.83 (m, 2H, quinoline-H ₃ ), 1.07 (t, 3H , J=7.8Hz, C ₅ -CH ₂ CH ₃ ).IR(KBr, cm ^-1 ) v 3411(NH), 2932, 2840(CH ₃ , CH ₂ ), 2227(C≡N), 1640(C =O), 1601, 1571, 1542, 1503 (aryl), 1251 (CN), 1195 (CN). ESI-MS: m/z 417.62 (M+1). C ₂₄ H ₂₄ N ₄ OS (416.54).

Example 42 5-ethyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c13)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methoxybenzyl chloride. the

The resulting product 5-ethyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c13) is 48.7%, mp: 187-188°C (dec). 

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.58 (s, 1H, NH), 7.04 (d, 2H, J=8.4Hz, PhH), 6.91 (d, 2H, J=8.4Hz, PhH), 6.43-6.84 (m, 4H, quinoline-H), 4.32 (s, 2H, SCH ₂ ), 4.41 (s, 2H, NCH ₂ ), 3.68 (s, 3H, PhOCH3), 3.45-3.47 (m, 2H, quinoline-H ₂ ), 2.62-2.64 (m, 2H, quinoline-H ₄ ), 2.50 (q, 2H, J=8.4Hz, C ₅ -CH ₂ CH ₃ ), 1.86-1.88 (m, 2H, quinoline- H ₃ ), 1.06 (t, 3H, J=8.4Hz, C ₅ -CH ₂ CH ₃ ).IR (KBr, cm ^-1 ) v 3434 (NH), 2930, 2833, 2763 (CH ₃ , CH ₂ ) , 1637(C=O), 1600, 1569, 1544, 1509(aryl), 1251(CN), 1197(CN).ESI-MS: m/z 422.34(M+1).C ₂₄ H ₂₇ N ₃ O ₂ S(421.56).

Example 435-Ethyl-2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6c14)

The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-fluorochlorobenzyl. the

The resulting product 5-ethyl-2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6c14) yield 59.7%, mp: 224-227°C (dec)

Product spectral analysis data:

¹ H NMR (DMSO-d ₆ , ppm) δ: 12.63 (s, 1H, NH), 7.12 (d, 2H, J=8.4Hz, PhH), 6.93 (d, 2H, J=8.4Hz, PhH), 6.43-6.90 (m, 4H, quinoline-H), 4.42 (s, 2H, SCH ₂ ), 4.15 (s, 2H, NCH ₂ ), 3.42-3.44 (m, 2H, quinoline-H ₂ ), 2.60-2.63 (m, 2H, quinoline-H ₄ ), 2.51 (q, 2H, J=7.2Hz, C ₅ -CH ₂ CH ₃ ), 1.84-1.86 (m, 2H, quinoline-H ₃ ), 1.07 (t, 3H , J=7.2Hz, C ₅ -CH ₂ CH ₃ ).IR(KBr, cm ^-1 ) v 3359(NH), 2932, 2841(CH ₃ , CH ₂ ), 1636(C=O), 1600, 1570 , 1547, 1508(aryl), 1251(CN), 1221(CN). ESI-MS: m/z 410.29(M+1).C ₂₃ H ₂₄ FN ₃ OS (409.52).

Embodiment 44: Anti-HIV cell activity screening test

Glossary of terms:

MTT method: thiazolium blue method;

MT-4: human acute lymphoblastic cells;

CCID50: Cell Culture Half Infection Dose;

DMSO: dimethyl sulfoxide;

EC ₅₀ : the concentration of the compound that protects 50% of HIV-1-infected MT-4 cells from cytopathic changes;

CC ₅₀ : the concentration of the compound that makes 50% of the cells not infected with HIV-1 pathological;

SI: selectivity coefficient, that is, the ratio of CC ₅₀ /EC ₅₀ (HIV-1III _B );

HIV-1 (III _B ): HIV-1 virus strain III _B subtype;

HIV-2 (ROD): HIV-2 strain ROD subtype. the

Compound anti-HIV activity test, using the thiazolium blue method (MTT method): on a 96-well cell culture plate, add 50uL of culture medium containing 1× ¹⁰⁴ MT-4 cells (human acute lymphoblastic cells), and then add 20uL respectively to infect HIV -1 (III _B ) or HIV-2 (ROD) MT-4 cell suspension (per milliliter containing 100 times cell culture half infection dose CCID50), then add different concentrations of test compound solution, each concentration 3 Well, after culturing at 37°C for a certain period of time (5 days), add 20uL (5mg/ml) MTT solution to each well, continue to cultivate for 2 hours, then add the dissolving solution dimethyl sulfoxide (DMSO), and mix with On a microplate reader, the absorbance was measured at 540nm, and the cell proliferation rate P% at different concentrations of the compound was calculated. At the same time, a blank group was set up, from which the concentration required for the compound to protect 50% of the cells from HIV-induced cytopathy (EC ₅₀ ) was calculated.

Determination of compound toxicity: in uninfected MT-4 cells, in parallel with the anti-HIV activity test of the compound, the MTT method was used to determine the concentration of the compound that caused 50% of the uninfected cells to undergo cytopathic changes, that is, the toxic concentration (CC ₅₀ ).

Calculation of selection index: SI=CC ₅₀ /EC ₅₀ .

The 42 compounds 6a1-6c14 synthesized above were screened for anti-HIV-1 (III _B ) and HIV-2 (ROD) activity, and their activity and toxicity data are listed in Table 2, wherein the nucleosides of clinical application reverse The transcriptase inhibitors nevirapine (NVP), delavirdine (DLV), efavirenz (EFV) and zidovudine (AZT) were used as positive controls. As can be seen from the table, these compounds have no inhibitory effect on HIV-2 (ROD), but have shown certain inhibitory activity on HIV-1 (III _B ), among which the two compounds 6c1 with the best activity (EC ₅₀ = 0.24±0.05 μM, CC ₅₀ >297.95, SI >1218) and 6c6 (EC ₅₀ =0.38+0.13 μM, CC ₅₀ >61.84 μM, SI >164). It can be used as a lead compound against HIV.

Anti-HIV-1 (III _B ) and HIV-2 (ROD) activity and toxicity (MT-4 cell) of table 2 compound 6a1-6c14

Claims (6)

1.5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives (I) as follows:

in, R ₁ is: H, methyl or ethyl; _R2 is: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano -2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitro Benzyl chloride, p-cyanobenzyl chloride, p-methoxybenzyl chloride or p-fluorobenzyl chloride. 2. 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- as claimed in claim 1 4-ketone derivatives, characterized in that they are one of the following compounds:

3. 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- as claimed in claim 1 The preparation method of 4-keto derivatives, the steps are as follows: The synthetic route is as follows:

Reagents: (i) K ₂ CO ₃ , toluene, reflux for 24h, 90°C; (ii) 15% NaOH, 15h; (iii) MgCl ₂ , Et ₃ N, CH ₃ CN, R ₁ CH(CO ₂ Et)( CO ₂ K), N, N-carbonyldiimidazole, stirred overnight at room temperature and then refluxed for 2 hours; (iv) thiourea, EtONa, refluxed for 6-12 hours; (v) substituted benzyl halides and substituted α-halogenated acetophenones , potassium carbonate (K ₂ CO ₃ ), N,N-dimethylformamide (DMF), at room temperature for 12 hours; Put 2mmol 6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a, 5b, 5c) and 2.2mmol K ₂ CO ₃ in the reaction flask, add anhydrous dimethylformamide, at room temperature After stirring for 30 min, add 2.0 mmol of substituents, stir at room temperature, TLC tracking until the raw material point disappears, stop the reaction; add ice water, a white precipitate occurs; filter, and recrystallize with EtOH or EtOH-DMF mixed solvent to obtain the target compound (6a1- 6c14); The substituents are: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyan Base-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitrogen chlorobenzyl chloride, p-cyanobenzyl chloride, p-methoxybenzyl chloride or p-fluorochlorobenzyl. 4. 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- as claimed in claim 3 The preparation method of 4-ketone derivatives, wherein, the preparation steps of the intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a, 5b, 5c) are as follows: Put 30.37mmol of 1,2,3,4-tetrahydroquinoline and 60.78mmol of K ₂ CO ₃ in 80mL of toluene, add 29.94mmol of ethyl bromoacetate dropwise under stirring condition, react at 90°C for 24h, detect by TLC The reaction was carried out; after the reaction was completed, the reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure, and the remaining liquid was extracted three times with chloroform, and washed with brine; after drying with anhydrous magnesium sulfate, the oily crude product was obtained, and the volume ratio was 1:4 ethyl acetate Purified by ester-petroleum ether column chromatography to obtain a brown oily pure product, which was directly added to 1mol/L NaOH aqueous solution to reflux for 12 hours without purification, and then dropped into 1mol/L HCl after cooling, a brown precipitate appeared, filtered, and dried to obtain a crude product; Put 0.5 mol of substituted diethyl malonate in 800 mL of anhydrous acetonitrile, add 0.595 mol of anhydrous MgCl ₂ , 0.717 mol of Et ₃ N, and stir at room temperature for 2 hours; add 0.25 mol of 1, 2, 3 , 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N,N-carbonyldiimidazole were placed in 300mL acetonitrile for 15 minutes, and then the reaction mixture was poured into substituted diethyl malonate, anhydrous MgCl ₂ , Et ₃ N mixture; stirred at room temperature overnight, heated to reflux for 2h, followed by TLC until the reaction was complete; 150mL of 13% HCl was added dropwise in an ice-bath environment, stirred for 10min after dropping, and the organic layer was separated and evaporated to dryness , add 150ml ethyl acetate; wash the ethyl acetate mixture three times with NaHCO ₃ , 150ml each time, then wash three times with NaCl solution, 150ml each time, then dry with anhydrous MgSO ₄ , and distill under reduced pressure to obtain β-keto acid The crude product of ester (4a-c) was directly used in the next step without purification; Add 0.3 mol of sodium in 100 mL of absolute ethanol in batches, wait for the sodium to dissolve and cool, then add 0.225 mol of thiourea at one time, then add 0.15 mol of the crude product β-ketoester (4a-c), heat the mixture to reflux, and trace it by TLC Stop heating until the β-keto ester raw material point disappears, after cooling, distill off the solvent under reduced pressure, dissolve the residue in 100mL water, filter, adjust the pH to 4 with 1mol/L hydrochloric acid and glacial acetic acid, and a white precipitate appears; Filter and wash the filter cake with ice ethanol and ice ether to obtain (5a-c) white solids; they can be directly used in the next step without purification (about 90% or more of the pure product). 5. 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- as claimed in claim 1 or 2 Application of pyrimidin-4-one derivatives in the preparation of HIV-1 inhibitor drugs. 6. An anti-HIV pharmaceutical composition, characterized in that the 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinone) described in claim 1 or 2 Phenyl)-1-methyl]-3H-pyrimidin-4-one derivatives and pharmaceutical excipients are prepared into pharmaceutical preparations in different dosage forms.