Deuterated-methyl-containing pyrimidino ring compounds, methods of making and uses thereof

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a pyrimidine cyclic compound containing deuterated methyl groups, its preparation method, and its uses. The compound structure of this invention is shown in general formula I, and also includes its pharmaceutical salt, hydrate, and solvate, its polycrystalline or cocrystalline forms, and its precursors and derivatives with similar biological functions. This compound or its composition can be used to prepare drugs for the prevention or treatment of AIDS and related diseases. In vitro cellular level anti-HIV-1 activity experiments show that this type of small molecule has strong anti-HIV-1 biological activity, significantly inhibiting viral replication in HIV-1-infected MT-4 cells, and exhibiting low cytotoxicity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pyrimidine cyclic compound containing deuterated methyl groups, its preparation method, and its uses. Background Technology

[0002] Human immunodeficiency virus (HIV) is the culprit behind AIDS (acquired immunodeficiency syndrome). HIV attacks the body's T lymphocytes, disrupting cellular and humoral immune processes, thus causing the immune system to lose its function. According to data from UNAIDS in 2019, there were 37.9 million people living with HIV globally, with 1.7 million new infections in 2018, and 770,000 deaths from AIDS in 2018.

[0003] The HIV life cycle consists of the following five steps: (1) adsorption and gradual fusion with host T lymphocytes, releasing genomic RNA into the host cell; (2) reverse transcription of RNA into DNA under the action of reverse transcriptase; (3) integration of viral DNA into the host genome; (4) transcription and translation using enzymes and substances within the host cell to synthesize the genome and proteins required by the virus; (5) assembly within the host and release outside the host cell. These viruses continue to infect new host cells, thereby damaging the host's immune system. Several key enzymes are involved in the entire life cycle: fusion enzymes, reverse transcriptases, proteases, and integrases. Among them, reverse transcriptase (RT) plays a crucial role and is an important target for designing anti-HIV-1 drugs. Currently, there are 14 marketed reverse transcriptase inhibitors.

[0004] RT inhibitors can be divided into nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nucleoside reverse transcriptase inhibitors competitively bind to the RT active site with the substrate, resulting in poor selectivity and high toxicity. Non-nucleoside reverse transcriptase inhibitors, on the other hand, bind non-competitively to the RT active site at a distance of approximately [missing information]. The allosteric binding pocket of the distance, also known as the non-nucleoside reverse transcriptase inhibitor binding pocket (NNIBP). NNRTIs are characterized by high selectivity and high activity. Currently, the NNRTIs used clinically are mainly second-generation inhibitors: diarylpyrimidine compounds, such as rilpivirine (RPV) and etravirine (ETR).

[0005] However, poor water solubility (ETR, << 1 μg / mL; RPV, 20 ng / mL), low patient response rates (ETR, 36.5%; RPV, 27.3%), and the emergence of drug-resistant viral strains during long-term use significantly reduce the efficacy of the drug. Furthermore, toxic side effects observed in clinical use (such as cardiotoxicity of ETR (hERG toxicity, IC50)) 50 The limited use of non-nucleoside reverse transcriptase inhibitors (NSTs) due to their high concentration (0.5 μM) and inhibitory activity against CYP enzymes (RPV) restricts their clinical application. Therefore, developing novel, highly effective, and low-toxicity non-nucleoside reverse transcriptase inhibitors with broad-spectrum anti-drug resistance has become a hot research topic for medicinal chemists.

[0006] The present invention aims to optimize the structure of RPV and ETR by introducing deuterated methyl and pyrimidine cyclic skeletons to improve the safety and drug-likeness of the compound, enhance the interaction between the compound and the amino acids on the inner wall of NNIBP, and improve the bioactivity of the compound against drug-resistant virus strains. Summary of the Invention

[0007] The present invention aims to provide a pyrimidine cyclopentadienyl ...

[0008] The pyrimidine cyclic compounds containing a deuterated methyl structure provided by this invention have the following structural formula:

[0009]

[0010] R1 is selected from hydrogen, methyl, and deuterated methyl;

[0011] R2 is selected from substituted or unsubstituted benzene rings, pyridines, pyrimidines, azines and their oxides, thiophene(ran) (sulfoxides and sulfones), (iso)thiazoles and their oxides, pyrroles and their oxides, pyrazole(ran) and their oxides, imidazoles and their oxides, (iso)oxazoles and their oxides, pyrazolone, furan, cyclopentadiene, dihydrothiophene and other cyclic sulfides (sulfoxides and sulfones), dihydrofurans and other epoxides, and cycloalkanes;

[0012] R3 is one of SO2NH2, CONH2, SO2CH3, COOH, B(OH)2, CN, CF3, OCF3, CH3, OCH3, N(CH3)2, NO2, F, Cl, Br, I, SO2NHR, CONHR, CONHR and COOR.

[0013] In the compounds of this invention, a deuterated methyl group (D3C) is introduced onto the left-hand benzene ring. The purpose is to improve the drug-likeness and safety of the compound by blocking the metabolic sites of related enzymes in vivo. At the same time, the substitution of the deuterated methyl group maintains the binding conformation of the compound to the target protein, thereby ensuring the interaction with the target protein is maintained.

[0014] This compound is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), which not only has strong biological activity, but also low cytotoxicity and a high selectivity.

[0015] The compounds of the present invention also include pharmaceutically acceptable salts, stereochemical isomers, hydrates or solvates of derivatives.

[0016] In this invention, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, formate, methanesulfonate, trifluoromethanesulfonate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate, or malate.

[0017] This invention also provides a method for preparing the above-mentioned pyrimidine cyclic compounds containing deuterated methyl groups, the specific steps of which are as follows:

[0018] In a solvent, 2,4-dichloropyrimidine derivative II and 2-deuterated methyl-4-cyanophenol and its derivatives were reacted under alkaline conditions to give compound III. Subsequently, the isolated compound III reacted with 1-Boc-4-aminopiperidine under appropriate solvent and alkaline conditions to give compound IV. After separation of compound IV, the Boc protecting group was removed in a mixed solvent of trifluoroacetic acid and dichloromethane to give compound V. Finally, compound V reacted with the corresponding benzyl bromide or benzyl chloride under alkaline catalysis in a solvent to give pyrimidine cyclic compound I containing deuterated methyl groups, the general reaction formula of which is as follows:

[0019]

[0020] The solvents used in compounds II to III and compounds III to IV are one or more of the following: acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-butanol, and isobutanol, with N,N-dimethylformamide being the most preferred. The bases used are one of the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide, N,N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide, and sodium tert-butoxide. One or more types of bases are used, with potassium carbonate being the best. The molar ratio of compound II, 2-deuterated methyl-4-cyanophenol and its derivatives to base is 1:1:1 to 1:2:3 (1:(1-2):(1-3)), with 1:1.1:1.2 being the best. The molar ratio of compound III, 1-Boc-4-aminopiperidine to base is 1:1:1 to 1:2:3 (1:(1-2):(1-3)), with 1:1.5:2 being the best. The reaction temperature is 15 to 150 °C, and the reaction time is 0.5 to 5 h.

[0021] In compounds IV to V, the volume ratio of trifluoroacetic acid to dichloromethane is 1:1 to 1:10, with 1:2 being optimal; the ratio of compound IV (a mmol) to trifluoroacetic acid (b ml) is a:b = 1:10 to 10:1, with 1:1 being optimal; the reaction temperature is room temperature, and the reaction time is 0.5 to 5 h.

[0022] The solvent used in compounds V to I is one or more of acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-butanol, and isobutanol, with N,N-dimethylformamide being the most preferred. The base used is one or more of the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen hydride, N,N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide, and sodium tert-butoxide, with potassium carbonate being the most preferred. The molar ratio of compound V, benzyl bromide, or benzyl chloride to the base is 1:1:1 to 1:2:3 (1:(1-2):(1-3)), with 1:1.2:1.5 being the most preferred. The reaction temperature is 15 to 150 °C, and the reaction time is 0.5 to 5 h.

[0023] The present invention also provides a pharmaceutical composition comprising an effective dose of the above-described compound and a related pharmaceutical carrier.

[0024] The present invention also provides the use of the said compound or composition in the preparation of medicaments for the prevention and treatment of AIDS.

[0025] This invention, based on the binding mode of diarylpyrimidine compounds to HIV reverse transcriptase and combined with computer-aided drug design, introduces a deuterated methyl group onto the left-hand benzene ring. The aim is to enhance the in vivo safety and stability of the compound by blocking the metabolic sites of related enzymes on the benzene ring, thereby improving its drug-likeness. Simultaneously, the substitution of the deuterated methyl group maintains the binding conformation of the compound to the target protein, thus preserving the interaction with the target protein. Experimental results show that this series of compounds exhibits significant anti-HIV-1 activity, with low cytotoxicity and high selectivity. Detailed Implementation

[0026] The following examples can provide a better understanding of the invention, but they do not limit the scope of the invention.

[0027] Example 1: Synthesis of final product Ia

[0028] (1) At room temperature, 500 mg of 2,4-dichlorothiophene[3,2-D]pyrimidine was added to a 50 mL round-bottom flask, followed by 374 mg of 2,6-dideuterated methyl-4-cyanophenol, 404 mg of potassium carbonate, and 15 mL of N,N-dimethylformamide. After the addition was complete, the mixture was stirred at room temperature for 2 h, and the reaction was monitored for completion. The reaction was stopped, and the mixture was extracted with ethyl acetate and water. The organic layer was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was separated by column chromatography (eluting with petroleum ether and ethyl acetate) to give 700 mg of a white solid, with a yield of 89%, designated as IIa.

[0029] (2) At room temperature, 670 mg of compound IIa was added to a 50 mL round-bottom flask, followed by 625 mg of 1-Boc-4-aminopiperidine, 574 mg of potassium carbonate, and 15 mL of N,N-dimethylformamide. After the addition was complete, the mixture was heated and stirred at 120 °C for 2 h, and the reaction was monitored for completion. The reaction was stopped, and the mixture was extracted with ethyl acetate and water. The organic layer was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was separated by column chromatography (eluting with petroleum ether and ethyl acetate) to give 856 mg of a white solid, with a yield of 85%, which was designated as IIIa.

[0030] (3) At room temperature, 856 mg of compound IIIa was added to a 25 mL round-bottom flask, followed by 3.5 mL of dichloromethane. While stirring, 1.7 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours, and the reaction was monitored for completion. Saturated sodium bicarbonate was added dropwise to the reaction system until the system became alkaline. A suitable amount of dichloromethane and water were added for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. Separation was performed by column chromatography (eluting with dichloromethane and methanol) to obtain 410 mg of a white solid, with a yield of 60%, designated as IVa.

[0031] (4) At room temperature, 300 mg of compound IVa was added to a 25 mL round-bottom flask, followed by 176 mg of 4-bromomethylbenzenesulfonamide, 161 mg of potassium carbonate, and 5 mL of N,N-dimethylformamide. After the addition was complete, the mixture was stirred at room temperature for 1 h, and the reaction was monitored for completion. The reaction was stopped, and the mixture was extracted with ethyl acetate and water. The organic layer was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was separated by column chromatography (eluting with dichloromethane and methanol) to obtain 45 mg of a white solid, with a yield of 10%, which was designated as Ia.

[0032]

[0033] White powder solid, yield: 10%. 1 H NMR (400MHz, DMSO-d6) δ8.20(d,J=5.4Hz,1H),7.79(d,J=7.9Hz,2H),7.73(s,2H),7.48(d,J=7.9Hz,2H),7.34(s,2H),7.27(s,1H) ,6.91(s,1H),3.74(s,1H),3.50(s,2H),2.71(d,J=23.6Hz,2H),2.00(s,1H),1.79(s,2H),1.64(s,1H),1.46(s,2H).HRMS(ESI)m / z C 27 H 22 D6N6O3S2:calcd 554.2041,found 555.2106[M+H] + .

[0034] Example 2: Synthesis of final product Ib

[0035]

[0036] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 28%. 1 H NMR (400MHz, DMSO-d6) δ8.20(d,J=5.4Hz,1H),7.95(s,1H),7.83(d,J=7.8Hz,2H),7.73(s,2H),7.37(s,1H),7.34(s,2H),7.26( s,1H),6.91(s,1H),3.57(s,2H),2.72(d,J=28.9Hz,2H),2.15–1.95(m,1H),1.79(s,2H),1.37(d,J=67.4Hz,4H).HRMS(ESI)m / z C 28 H 22 D6N6O2S:calcd 518.2371,found519.2445[M+H]+ .

[0037] Example 3: Synthesis of final product Ic

[0038]

[0039] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 28%. 1 H NMR (400MHz, DMSO-d6) δ8.20(d,J=5.4Hz,1H),7.79(d,J=8.4Hz,2H),7.73(s,2H),7.47(d,J=8.1Hz,2H),7.34(s,2H),7.31–7.21(m,1H),3.74(s ,1H),3.49(s,2H),2.80–2.59(m,2H),2.11(s,3H),2.02(s,1H),1.95–1 .83(m,1H),1.78(s,1H),1.68–1.55(m,1H),1.45(s,2H).HRMS(ESI)m / zC 27 H 25 D3N6O3S2:calcd551.1853,found 552.1933[M+H] + .

[0040] Example 4: Synthesis of final product Id

[0041]

[0042] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 43%. 1 H NMR (400MHz, DMSO-d6) δ8.21(t,J=8.0Hz,1H),8.17(d,J=5.4Hz,1H),7.95(d,J= 5.7Hz,1H),7.83(dd,J=9.6,7.2Hz,3H),7.73(s,1H),7.39(d,J=7.9Hz,2H),7.34 (q,J=5.4,4.9Hz,3H),4.11–3.94(m,1H),3.54(s,2H),2.85(d,J=11.4Hz,2H),2. 11(s,3H),1.93–1.81(m,2H),1.64(t,J=10.0Hz,2H),1.39(s,2H).HRMS(ESI)m / z C 28 H 25 D3N6O2S:calcd 515.2183,found 516.2252[M+H] + .

[0043] Example 5: Synthesis of final product Ie

[0044]

[0045] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 19%. 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=8.2Hz,2H),7.72(s,2H),7.47(d,J=8.0Hz,2H),7.36(d,J=6.0Hz,2H),7. 34(s,1H),7.27(d,J=6.0Hz,1H),7.12(s,1H),3.71(s,1H),3.56–3.42(m,2H),2.70(d,J=33.1Hz,2H),2.11–

[0046] 2.00(m,1H),1.77(s,1H),1.61(s,1H),1.43(d,J=34.8Hz,2H),1.30(s,1H).HRMS(ESI)m / zC 27 H 22 D6N6O3S2:calcd 554.2041,found 555.2102[M+H] + .

[0047] Example 6: Synthesis of final product If

[0048]

[0049] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 35%. 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=8.3Hz,2H),7.72(s,2H),7.47(d,J=8.0Hz,2 H),7.36(d,J=6.0Hz,1H),7.34(s,2H),7.27(d,J=5.9Hz,1H),7.12(s,1H),3.71 (s,1H),3.50(s,2H),2.74(s,2H),2.65(s,1H),2.11(s,3H),1.78(d,J=11.9Hz, 1H),1.61(s,1H),1.44(d,J=30.9Hz,2H),1.32(d,J=16.2Hz,1H).HRMS(ESI)m / z C 27 H 25 D3N6O3S2:calcd 551.1853,found 552.1916[M+H] + .

[0050] Example 7: Synthesis of final product Ig

[0051]

[0052] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 24%. 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.82(d,J=7.9Hz,2H),7.72(d,J=0.9Hz,2 H),7.40–7.30(m,4H),7.27(d,J=6.0Hz,1H),7.10(s,1H),3.70(s,1H),3.47(s, 2H),2.82(d,J=60.3Hz,2H),2.67(t,J=1.9Hz,1H),2.10(s,3H),2.04–1.92(m, 1H),1.76(s,1H),1.53(d,J=50.4Hz,3H),1.26(d,J=20.4Hz,1H).HRMS(ESI)m / z C 28 H 25 D3N6O2S:calcd 515.2183,found 516.2256[M+H] + .

[0053] Example 8: Synthesis of final product Ih

[0054]

[0055] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 71%. 1 H NMR(400MHz, DMSO-d6)δ8.17–8.02(m,1H),7.78(d,J=7.4Hz,2H),7.74(s, 2H),7.58–7.38(m,3H),7.33(s,2H),7.25(s,1H),7.11–6.91(m,1H),3.81( s,1H),3.52(s,2H),2.76(s,2H),2.67(s,1H),2.12(s,3H),1.99(s,1H),1 .80(s,1H),1.44(d,J=33.5Hz,2H),1.27(d,J=28.9Hz,1H).HRMS(ESI)m / zC 29 H 27 D3N6O3S:calcd 545.2288,found 546.2369[M+H] + .

[0056] Example 9: Synthesis of final product Ii

[0057]

[0058] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 63%. 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.94(s,1H),7.82(d,J=7.9Hz,2H),7 .74(s,2H),7.62(s,1H),7.46(s,2H),7.36–7.29(m,2H),7.25(s,1H),6.99 (s,1H),3.80(s,1H),3.53(d,J=24.1Hz,2H),2.83(d,J=47.7Hz,2H),2.67 (s,1H),2.12(s,3H),2.03(s,1H),1.80(s,2H),1.48(s,2H).HRMS(ESI)m / z C 30 H 27 D3N6O2:calcd 509.2619,found 510.2697[M+H] + .

[0059] Example 10: Synthesis of final product Ij

[0060]

[0061] The procedure was the same as in Example 1, yielding a white powder solid with a yield of 56%. 1 H NMR (400MHz, DMSO-d6) δ8.27(d,J=8.1Hz,1H),8.22(d,J=7.0Hz,1H),7.97(s,1H),7.86(d,J=8.1Hz,2H),7.73(d,J=9.0Hz,1H),7.66(s ,2H),7.42(s,1H),7.40–7.29(m,4H),3.71(s,1H),3.50(s,2H),2.86–2.71(m,2H),1.94–1.72(m,4H),1.65–1.48(m,2H).HRMS(ESI)m / z C 30 H 24 D6N6O2:calcd512.2807,found513.2879[M+H]+.

[0062] Example 11: Anti-HIV bioactivity test

[0063] The in vitro cellular anti-HIV activity was determined by the Rega Institute of Pharmaceutical Research at the University of Katholleke, Belgium, primarily including inhibitory activity and cytotoxicity against HIV-infected MT-4 cells. The method was as follows: the compound was administered to HIV-infected MT-4 cells at different time points after HIV infection. The protective effect of the drug against HIV-induced cytopathic effects was determined using the MTT assay. The half-maximal effective concentration (EC50) required to protect 50% of the cells from HIV-induced cytopathic effects was calculated. 50 The toxicity assay and anti-HIV activity assay were performed in parallel, also in MT-4 cell culture, using the MTT assay to determine the concentration (CC) that caused cytopathic effects in 50% of uninfected cells. 50 ), and calculate the selectivity index SI = CC 50 / EC 50 .

[0064] Materials and Methods:

[0065] The anti-HIV activity of each compound was monitored by its efficiency in inhibiting HIV-induced cytopathic effects in cells. MT-4 cells were used for cell culture. The viral strains used were HIV-1 strain IIIB and HIV-2 strain ROD.

[0066] The specific procedure is as follows: Dissolve the compound in DMSO or water, then dilute it in a phosphate buffered saline solution, adding 3×10... 5 MT-4 cells were pre-cultured at 37°C for 1 hour with 100 μL of solutions containing different concentrations of various compounds. Then, 100 μL of an appropriate viral dilution was added to each compound, and the cells were incubated at 37°C for another hour. After three washes, the cells were resuspended in culture media containing or without the compounds. The cells were then cultured at 37°C for 7 days in a 5% CO2 atmosphere, with the culture medium being replaced with either compound-containing or compound-free media on the third day post-infection. Each culture medium condition was repeated twice. The cytopathic effect of the virus was monitored daily using a reverse optical microscope. Typically, the viral dilutions used in this experiment often caused cytopathic effects by the fifth day post-infection. The drug inhibitory concentration was defined as the concentration at which the drug produced 50% inhibition of viral cytopathic effects without direct cytotoxicity to cells (CC). 50 It is important to emphasize that when a compound has poor water solubility and requires DMSO to dissolve, the DMSO concentration 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 comparison experiments with blanks containing the same concentration of DMSO should also be performed in parallel. Furthermore, the final concentration of DMSO (1 / 1000) is far lower than the concentration required for HIV-1 replication in T cells.

[0067] This invention uses marketed drugs nevirapine (NVP), efavirenz (EFV), and ETR as reference standards. The results of the inhibitory activity of some target compounds against HIV-1 IIIb strain are shown in Table 1.

[0068]

[0069] Table 1

[0070]

[0071] a EC 50 The effective concentration that protects 50% of cells from viral infection; b RES056 represents the K103N / Y181C double mutant strain;

[0072] c A indicates that the compound's EC50 value is between 1 and 10 nM.

Claims

1. A pyrimidine cyclic compound containing a deuterated methyl group, characterized in that, The structure is as follows: ； The compound of formula I is: 。 2. The method for preparing the pyrimidine cyclic compound containing deuterated methyl groups as described in claim 1, characterized in that, The general reaction formula is as follows: ； The specific steps are as follows: In a solvent, 2,4-dichloropyrimidine derivative II and 2-deuterated methyl-4-cyanophenol and its derivatives were reacted under alkaline conditions to obtain compound III. Subsequently, the isolated compound III reacted with 1-Boc-4-aminopiperidine under appropriate solvent and alkaline conditions to obtain compound IV. After separation of compound IV, the Boc protecting group was removed in a mixed solvent of trifluoroacetic acid and dichloromethane to obtain compound V. Finally, compound V reacted with the corresponding benzyl bromide or benzyl chloride under alkaline catalysis in a solvent to obtain pyrimidine cyclic compound I containing deuterated methyl groups. The molar ratio of compound II, 2-deuterated methyl-4-cyanophenol and its derivatives to base is 1:1:1 or 1:2:3; the molar ratio of compound III, 1-Boc-4-aminopiperidine to base is 1:1:1 or 1:2:3; the reaction temperature is 15~150 ℃; the reaction time is 0.5~5 h; In compounds IV to V, the volume ratio of trifluoroacetic acid to dichloromethane is 1:1 to 1:10; the amount of compound IV is in millimoles and the amount of trifluoroacetic acid is in milliliters, and their ratio of a:b is 1:10 to 10:1; the reaction temperature is room temperature and the reaction time is 0.5 to 5 hours. The molar ratio of compound V, benzyl bromide, or benzyl chloride to the base is 1:1:1 or 1:2:3; the reaction temperature is 15~150 ℃; and the reaction time is 0.5~5 h.

3. The preparation method according to claim 2, characterized in that, The solvents used in compounds II to III and compounds III to IV were acetone, acetonitrile, toluene, dichloromethane, and tetrahydrofuran. N,N -Dimethylformamide, N,N - One or more of dimethylacetamide, methanol, ethanol, isopropanol, n-butanol, and isobutanol; the base used is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydroxide. N,N -One or more of dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide, and sodium tert-butoxide.

4. The preparation method according to claim 2, characterized in that, The solvents used in compounds V through I are acetone, acetonitrile, toluene, dichloromethane, and tetrahydrofuran. N,N -Dimethylformamide, N,N - One or more of dimethylacetamide, methanol, ethanol, isopropanol, n-butanol, and isobutanol; the base used is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydroxide. N,N -One or more of dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine, potassium tert-butoxide, and sodium tert-butoxide.

5. A pharmaceutical composition, characterized in that, It contains an effective dose of any of the compounds and pharmaceutical carriers as described in claim 1.

6. A pharmaceutical salt of a pyrimidine cyclic compound containing a deuterated methyl structure as described in claim 1, characterized in that, This includes hydrochloride, hydrobromide, formate, methanesulfonate, trifluoromethanesulfonate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate, or malate.

7. The use of the pyrimidine cyclocyclic compound containing a deuterated methyl structure as described in claim 1 in the preparation of a medicament for the prevention and treatment of AIDS.

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