Heteroarylpyrimidine derivatives containing pyridine-benzene ring structures, their preparation methods and uses

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to heteroarylpyrimidine derivatives containing a pyridine-benzene ring structure, their preparation methods, and uses. The compounds of this invention are heteroarylpyrimidine derivatives containing a pyridine-benzene ring structure, and also include their pharmaceutical salts, hydrates, and solvates, as well as their polycrystalline or cocrystalline forms, and their precursors and derivatives with similar biological functions. These compounds or combinations thereof 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 these small molecules possess 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 pyrimidine derivative compounds with 5-position aromatic heterocyclic substitution containing a pyridine-benzene ring structure, their preparation methods, and uses. Background Technology

[0002] AIDS remains a major infectious disease threatening human life and health worldwide. Characterized by a long window period, high mortality rate, and incurable disease, it has received extensive research and continuous attention. The first AIDS patient was reported in the United States in 1981, and the HIV virus was identified as the causative agent in 1983. This marked the beginning of humanity's protracted war against AIDS. According to data from UNAIDS in 2023, there were 39 million people living with HIV globally, with 1.3 million new infections in 2022 and 630,000 deaths from AIDS in 2022.

[0003] HIV attacks human T lymphocytes, disrupting cellular and humoral immune processes, thereby causing the immune system to lose its function. The HIV life cycle can be summarized as follows: (1) it adsorbs to and gradually fuses with host T lymphocytes, releasing genomic RNA into the host cell; (2) it reverse transcription the genetic material into DNA and integrates it into the host's genome; (3) it uses enzymes and substances within the host cell to transcribe and translate, synthesizing the genome and proteins required by the virus; (4) it completes assembly within the host and is released outside the host cell. These viruses continue to infect new host cells, thereby disrupting the host's immune system. HIV-1 reverse transcriptase plays an important role in the HIV life cycle and has three main functions: (1) RNA-dependent DNA polymerization; (2) DNA-dependent DNA polymerization; (3) RNA hydrolysis, i.e., RNase H activity, is one of the important targets in the development of HIV-1 inhibitors. RT inhibitors can be divided into nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nucleoside reverse transcriptase inhibitors (NRTIs) competitively bind to the active site of reverse transcriptase (RT) receptors, resulting in poor selectivity and high toxicity. Non-nucleoside reverse transcriptase inhibitors, on the other hand, bind non-competitively to an allosteric binding pocket approximately 10 Å away from the active site, known as the non-nucleoside reverse transcriptase inhibitor binding pocket (NNIBP). NNRTIs are characterized by high selectivity and activity. Currently, the most commonly used NNRTIs in clinical practice are second-generation inhibitors: diarylpyrimidine compounds, such as rilpivirine (RPV) and etravirine (ETR). However, their poor water solubility (ETR, << 1 μg / mL; RPV, 20 ng / mL), low patient response rates (ETR, 36.5%; RPV, 27.3%), and the toxic side effects associated with long-term use limit their clinical application. Furthermore, the emergence of drug-resistant viral strains significantly reduces the efficacy of these drugs. Therefore, developing novel and highly efficient non-nucleoside reverse transcriptase inhibitors with broad-spectrum anti-drug resistance has become one of the hot topics of research for medicinal chemists.

[0004] The present invention aims to optimize the structure of RPV and ETR by introducing aromatic heterocycles to enhance the interaction between the compound and surrounding amino acids, thereby improving the compound’s bioactivity against drug-resistant viral strains and improving its drug-likeness. Summary of the Invention

[0005] The purpose of this invention is to provide a pyrimidine derivative with a 5-position aromatic heterocyclic substituted pyridine ring structure, which has strong anti-HIV-1 biological activity, can significantly inhibit viral replication in MT-4 cells infected with HIV-1, and has low cytotoxicity, as well as its preparation method and uses.

[0006] The pyridine derivative with a 5-position aromatic heterocyclic substitution provided by the present invention has the following structural formula (I) or (II):

[0007]

[0008] Wherein, R is selected from, but not limited to, substituted or unsubstituted pyridyl, furanyl, pyrroleyl, thiophenyl, and pyrazolyl.

[0009] In the compounds of this invention, an aromatic heterocycle is introduced at the 5-carbon position of the pyrimidine core. The aim is to enhance the antiviral activity of the target compound by increasing hydrogen bonding or polar interactions with surrounding amino acids (especially I180). Simultaneously, the left-wing aryl structure penetrates deep into the binding pocket, strengthening the binding force with highly conserved amino acid residues Phe227 and Trp229, further enhancing the bioactivity of the target compound against drug-resistant viral strains.

[0010] These compounds are HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), which not only have strong biological activity, but also low cytotoxicity and a high selectivity.

[0011] The compounds of the present invention also include pharmaceutically acceptable salts, stereochemical isomers, hydrates or solvates of derivatives.

[0012] 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.

[0013] This invention provides a method for preparing the above-mentioned pyrimidine derivative compound containing a 5-position aromatic heterocyclic substitution of a pyridine-benzene ring structure, the specific steps of which are as follows:

[0014] Compound I or II is obtained by reacting 5-iodopyrimidine derivatives IIIa or IIIb with corresponding aromatic heterocyclic compounds, as shown in the following general reaction formula:

[0015] .

[0016] in:

[0017] The solvent is one or more of the following: dioxane, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, isopropanol, n-butanol, and isobutanol, mixed with water in a volume ratio of 1:1 to 10:1.

[0018] The alkali is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium phosphate, LDA, LiHMDS, and NaHMDS.

[0019] The catalyst is selected from: Pd(dppf)Cl2, Pd(PPh4)3, Pd2(dba)3, PdCl2, Pd(OAc)2, Pd(dba)2;

[0020] The molar ratio of the raw material compound IIIa or IIIb to the corresponding aromatic heterocyclic boric acid, catalyst, and base is 1:(1.0~2.0):(0.005~0.2):(1~5), and the optimal molar ratio is 1:1.2:0.1:2;

[0021] The reaction temperature is 50~180 ℃; the preferred reaction temperature is 100~120 ℃.

[0022] The reaction time is 2 to 24 hours, with a preferred reaction time of 16 hours.

[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 pyrimidine compounds to HIV reverse transcriptase and combined with computer-aided drug design, introduces an aromatic heterocycle at the 5-carbon position of the pyrimidine core. The aim is to enhance the antiviral activity of the target compound by increasing hydrogen bonding or polar interactions with surrounding amino acids (especially I180). Simultaneously, the left-wing aryl group extends into the binding pocket, strengthening the binding affinity with highly conserved amino acid residues Phe227 and Trp229, further enhancing the bioactivity of the target compound against drug-resistant viral strains. 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] Compound IIIa (1 mmol), 2-furanboronic acid (1.3 mmol), and cesium carbonate (2 mmol) were added to a mixed solvent of dioxane (12 mL) and water (3 mL), and stirred for 10 min. Then, Pd(dppf)Cl2 (0.1 mmol) was added. The mixture was degassed three times and purged with nitrogen for protection. The reaction mixture was stirred at 120 °C for 6 h. TLC monitoring showed complete consumption of the starting material. The reaction mixture was concentrated and then subjected to silica gel column chromatography (ethyl acetate: petroleum ether (5%–100%) as eluent) to give compound Ia.

[0029]

[0030] Yield: 89%, yellow solid, mp: 264.9-266.4 ℃. 1 H NMR (400 MHz, DMSO-d6): δ10.00 (s, 1H), 9.14-8.63 (m, 2H), 8.60 (s, 1H), 8.49 (s, 1H), 8.06-7.89 (m,2H), 7.88-7.81 (m, 2H), 7.81 (s, 1H), 7.61-7.59 (m, 2H), 7.37-7.35 (m, 2H), 6.89 (d, J = 4 Hz, 1H), 6.67 (d, J = 4 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ159.74 (dd, J1= 247 Hz, J2= 6 Hz), 158.24, 157.71, 155.71, 150.86, 148.46,145.20, 144.74, 143.23, 137.84 (t, J = 9 Hz), 132.91, 121.92, 119.85, 118.65,117.64 (t, J = 17 Hz), 112.17, 110.85 (dd, J1= 18 Hz, J2= 8 Hz), 107.47,102.97, 102.56. 19 F NMR (376 MHz, DMSO-d6): δ -116.26. HRMS calcd for C 26 H 16 F2N6O[M+Na] + : 489.1246, found 489.1245. HPLC analysis: retention time = 10.68 min; peak area, 98.34% (λ = 254 nm).

[0031] Example 2: Synthesis of final product Ib

[0032] The operation is the same as in Example 1.

[0033]

[0034] Yellow solid, yield: 83%, mp: 251.3-252.4 ℃. 1 H NMR (400 MHz, DMSO-d6): δ9.88 (s, 1H), 8.72-8.71 (m, 2H), 8.45 (s, 1H), 8.21 (s, 1H), 7.89-7.88 (m,2H), 7.84-7.82 (m, 2H), 7.74-7.73 (m, 2H), 7.66-7.64 (m, 2H), 7.40-7.38 (m,3H). 13 C NMR (100 MHz, DMSO-d6): δ 159.73 (dd, J1= 246 Hz, J2= 6 Hz), 159.35,158.28, 156.94, 150.95, 145.54, 144.79, 137.52 (t, J = 9 Hz), 134.59, 132.94,128.42, 127.55, 124.05, 121.57, 119.97, 118.45, 117.93 (t, J = 17 Hz), 110.82(dd, J1= 19 Hz, J2= 6 Hz), 108.19, 102.21. 19 F NMR (376 MHz, DMSO-d6): δ -116.34.

[0035] HRMS calcd for C 26 H 16 F2N6S [M+H] + : 483.1198, found 483.1194. HPLC analysis: retention time = 10.56 min; peak area, 99.42% (λ = 254 nm).

[0036] Example 3: Synthesis of final product Ic

[0037] The operation is the same as in Example 1.

[0038]

[0039] Yield: 85%, yellow solid, mp: 281.5-283.1 ℃. 1H NMR (400 MHz, DMSO-d6): δ9.95 (s, 1H), 8.75-8.70 (m, 3H), 8.39 (s, 1H), 8.14-8.10 (m, 2H), 7.88-7.87(m, 2H), 7.84-7.82 (m, 2H), 7.69-7.67 (m, 2H), 7.43-7.41 (m, 2H), 7.34 (d, J= 8 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 163.07 (d, J = 235 Hz), 159.77,159.49 (dd, J1= 246 Hz, J2= 5 Hz), 159.01, 157.66, 150.93, 148.15 (d, J = 16Hz), 145.42, 144.75, 143.53 (d, J = 8 Hz), 137.49 (t, J = 9 Hz), 132.98, 129.26 (d, J = 4 Hz), 121.56, 119.93, 118.62, 117.56 (t, J = 17 Hz), 111.89 (dd, J1=19 Hz, J2= 7 Hz), 110.30 (d, J = 38 Hz), 108.67, 102.47. 19 F NMR (376MHz, DMSO-d6): δ -70.41, -116.35. HRMS calcd for C 27 H 16 F3N7 [M+H] + : 496.1492, found 496.1496. HPLC analysis: retention time = 9.65 min; peak area, 98.17%(λ = 254 nm).

[0040] Example 4: Synthesis of final product Id

[0041] The operation is the same as in Example 1.

[0042]

[0043] Yield: 59%, yellow solid, mp: >300 ℃.

[0044] 1 H NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 8.92 (s, 1H), 8.72-8.71(m, 2H), 8.50 (d, J = 4 Hz, 1H), 8.25 (s, 1H), 7.89-7.84 (m, 4H), 7.67-7.58(m, 4H), 7.41-7.39 (m, 2H). 13 C NMR (100 MHz, DMSO-d6): δ 159.44 (dd, J1= 247Hz, J2= 6 Hz), 159.17, 159.11, 158.08, 151.40, 150.95, 150.76, 146.45,145.15, 144.72, 137.63 (t, J = 9 Hz), 132.98, 124.26, 123.52, 121.58, 119.84,118.79, 117.44 (t, J = 17 Hz), 110.95 (dd, J1= 19 Hz, J2= 6 Hz), 109.14,102.77. 19 F NMR (376 MHz, DMSO-d6): δ -116.43. HRMS calcd for C 27 H 16 ClF2N7 [M+Na] + : 534.1016, found 534.1018. HPLC analysis: retention time = 10.13 min; peak area, 94.83% (λ = 254 nm).

[0045] Example 5: Synthesis of final product IIa

[0046] Compound IIIb (1 mmol), 2-furanboronic acid (1.1 mmol), and cesium carbonate (2 mmol) were added to a mixed solvent of dioxane (12 mL) and water (6 mL), and stirred for 10 min. Then, Pd(dppf)Cl2 (0.1 mmol) was added. The mixture was degassed three times and purged with nitrogen for protection. The reaction solution was stirred at 120 °C for 16 h. The reaction solution was concentrated and then subjected to silica gel column chromatography (ethyl acetate: petroleum ether (5%–100%) as eluent) to give compound IIa.

[0047]

[0048] Yield: 78%, yellow solid, mp: 282.1-283.7 ℃. 1 H NMR (400 MHz, DMSO-d6):9.89 (s, 1H), 8.68-8.67 (m, 2H), 8.44-8.42 (m, 2H), 7.81-7.79 (m, 3H), 7.70 (s, 2H), 7.54-7.52 (m, 2H), 7.25-7.23 (m, 2H), 6.93-6.92 (d, J = 4 Hz, 1H), 6.67- 6.65 (m, 1H), 2.25 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ: 158.34,157.76, 154.95, 150.72, 149.00, 147.17, 145.57, 142.87, 138.86, 137.87,135.80, 132.74, 126.67, 121.63, 119.93, 118.38, 112.13, 106.91, 102.31,102.04, 18.79. HRMS calcd for C 28 H 22 N6O [M+H] + : 459.1928, found 459.1926. HPLC analysis: retention time = 11.61 min; peak area, 99.23% (λ = 254 nm).

[0049] Example 6: Synthesis of final product IIb

[0050] The operation is the same as in Example 5.

[0051]

[0052] Yield: 77%, yellow solid, mp: 269.5-271.6 ℃.

[0053] 1 H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.67-8.64 (m, 2H), 8.51 (s,1H), 8.28-8.26 (m, 1H), 8.09 (s, 1H), 7.79-7.77 (m, 2H), 7.66 (s, 2H), 7.53-7.51 (m, 2H), 7.24-7.19 (m, 3H), 7.01 (s, 1H), 3.90 (s, 3H), 2.23 (s, 6H). 13 CNMR (100 MHz, DMSO-d6): δ 164.64, 159.23, 159.08, 156.77, 150.72, 147.98,147.22, 146.16, 145.62, 138.79, 137.81, 135.66, 132.75, 126.67, 121.52,119.93, 118.42, 117.63, 110.27, 109.52, 102.02, 53.67, 18.84. HRMS calcd forC 30 H 25 N7O [M+H] + : 500.2193, found 500.2198. HPLC analysis: retention time =11.43 min; peak area, 98.97% (λ = 254 nm).

[0054] Example 7: Synthesis of final product IIc

[0055] The operation is the same as in Example 5.

[0056]

[0057] Yield: 35%, yellow solid, mp: >300 ℃. 1H NMR (400 MHz, DMSO-d6): δ 13.11(s, 1H), 9.65 (s, 1H), 8.67-8.65 (m, 2H), 8.10-8.07 (m, 3H), 7.87 (s, 1H),7.80-7.79 (m, 2H), 7.67 (s, 2H), 7.53-7.51 (m, 2H), 7.23-7.21 (m, 2H), 2.23(s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 159.47, 158.10, 155.53, 150.74, 147.26,145.98, 139.20, 137.93, 135.52, 132.72, 126.61, 121.51, 120.05, 118.09,113.71, 104.22, 101.45, 18.85. HRMS calcd for C 27 H 22 N8 [M+H] + : 459.2040, found459.2044. HPLC analysis: retention time = 9.13 min; peak area, 99.41% (λ =254 nm).

[0058] Example 8: Synthesis of final product IId

[0059] The operation is the same as in Example 5.

[0060]

[0061] Yield: 56%, yellow solid, mp: >300 ℃.

[0062] 1 H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.65-8.66 (m, 2H), 8.46 (s,1H), 8.42 (d, J = 1 Hz), 8.15 (dd, J1= 8 Hz, J2= 4 Hz, 1H), 8.04 (s, 1H),7.78-7.77 (m, 2H), 7.65 (s, 2H), 7.60-7.58 (m, 2H), 7.33 (dd, J1= 8 Hz, J2=1 Hz, 1H), 7.29-7.27 (m, 2H), 2.24 (s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ162.99 (d, J = 234 Hz), 159.92, 159.18, 156.85, 150.73, 148.07 (d, J = 15 Hz),147.20, 145.79, 143.51, 143.47 (d, J = 8 Hz), 138.66, 137.76, 135.64, 132.80,129.77 (d, J = 5 Hz), 126.68, 121.51, 120.00, 118.38, 110.33 (d, J = 38 Hz),108.01, 101.93, 18.88. 19 F NMR (376 MHz, DMSO-d6): δ -70.56. HRMS calcd forC 29 H 22 FN7 [M+H] + : 488.1993, found 488.1993.HPLC analysis: retention time = 9.87min; peak area, 97.73% (λ = 254 nm).

[0063] Example 9: Synthesis of final product IIe

[0064] The operation is the same as in Example 5.

[0065]

[0066] Yield: 71%, yellow solid, mp: 240.7-242.3 ℃.

[0067] 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.67-8.65 (m, 2H), 8.45 (s,1H), 8.41-8.40 (m, 1H), 8.17-8.12 (m, 1H), 8.03 (s, 1H), 7.79-7.77 (m, 2H), 7.66 (s, 2H), 7.59-7.57 (m, 2H), 7.35-7.32 (m, 1H), , 7.28-7.26 (m, 2H), 2.24(s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 162.99 (d, J = 234 Hz), 159.93, 159.18,156.84, 150.70, 148.07 (d, J = 15 Hz), 147.23, 145.78, 143.47 (d, J = 9 Hz),138.66, 137.76, 135.63, 132.78, 129.77 (d, J = 5 Hz), 126.68, 121.52, 119.97,118.39, 110.32 (d, J = 38 Hz), 108.02, 101.94, 18.86. 19 F NMR (376 MHz, DMSO-d6): δ -70.59. HRMS calcd for C 29 H 22 FN7 [M+H] + : 488.1993, found 488.1993. HPLC analysis: retention time = 9.88 min; peak area, 99.40% (λ = 254 nm).

[0068] Example 10: Synthesis of final product IIf

[0069] The operation is the same as in Example 5.

[0070]

[0071] Yield: 77%, yellow solid, mp: 277.6-279.5 ℃.

[0072] 1H NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 8.66-8.65 (m, 2H), 8.21 (s,1H), 8.11 (s, 1H), 7.79-7.78 (m, 2H), 7.74-7.72 (m, 2H), 7.66 (s, 2H), 7.53-7.51 (m, 2H), 7.42(d, J = 4 Hz, 1H), 7.23-7.21 (m, 2H), 2.23(s, 6H). 13 C NMR(100 MHz, DMSO-d6): δ 159.45, 158.37, 156.19, 150.72, 147.26, 145.83, 139.08,137.91, 135.56, 135.12, 132.73, 128.32, 127.50, 126.63, 123.52, 121.52,120.01, 118.20, 107.50, 101.66, 18.87. HRMS calcd for C 28 H 22 N6S [M+H] + :475.1699, found 475.1696. HPLC analysis: retention time = 11.21 min; peak area, 99.60% (λ = 254 nm).

[0073] Example 11: Synthesis of final product IIg

[0074] The operation is the same as in Example 5.

[0075]

[0076] Yield: 73%, yellow solid, mp: 269.1-270.6 ℃.

[0077] 1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.67-8.65 (m, 2H), 8.53 (d,J = 8 Hz, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 7.80-7.78 (m, 2H), 7.67 (s, 2H),7.54-7.52 (m, 2H), 7.46 (s, 1H), 7.40 (d, J = 8 Hz, 1H), 7.24-7.22 (m, 2H),2.54 (s, 3H), 2.24 (s, 6H).

[0078] 13 C NMR (100 MHz, DMSO-d6): δ 159.22, 159.06, 158.94, 156.93, 150.75,149.96, 147.19, 145.65, 143.32, 138.82, 137.84, 135.69, 132.75, 126.69,123.20, 121.52, 121.02, 119.93, 118.40, 109.61, 102.00, 24.72, 18.89. HRMScalcd for C 30 H 25 N7[M+H] + : 484.2244, found 484.2243. HPLC analysis: retentiontime = 10.24 min; peak area, 99.95% (λ = 254 nm).

[0079] Example 12: Synthesis of final product IIh

[0080] The operation is the same as in Example 5.

[0081]

[0082] Yield: 68%, yellow solid, mp: 190.5-192.1 ℃.

[0083] 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.66-8.63 (m, 3H), 8.44 (s,1H), 7.99 (s, 1H), 7.86-7.84 (m, 1H), 7.79-7.77 (m, 2H), 7.65 (s, 2H), 7.57-7.55 (m, 2H), 7.38 (d, J = 8 Hz, 1H), 7.26-7.24 (m, 2H), 2.53 (s, 3H), 2.23(s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 159.86, 158.94, 157.27, 156.67, 150.65,149.16, 147.32, 145.82, 138.89, 137.79, 137.43, 135.53, 132.75, 128.38,126.66, 123.84, 121.53, 119.98, 118.32, 109.07, 101.81, 24.25, 18.86. HRMScalcd for C 30 H 25 N7 [M+H] + : 484.2244, found 484.2243. HPLC analysis: retentiontime = 9.38 min; peak area, 97.48% (λ = 254 nm).

[0084] Example 13: Synthesis of final product IIi

[0085] The operation is the same as in Example 5.

[0086]

[0087] Yield: 56%, yellow solid, mp: 273.2-274.9 ℃.

[0088] 1H NMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 8.71 (s, 1H), 8.66-8.65 (m,2H), 8.64-8.60 (m, 2H), 8.09-8.08 (m, 2H), 7.79-7.77 (m, 2H), 7.66 (s, 2H), 7.57-7.55 (m, 2H), 7.27-7.25 (m, 2H), 2.24 (s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 159.67, 159.22, 157.25, 150.73, 148.38, 147.30, 147.18, 145.66,138.57, 137.72, 136.80, 135.65, 132.98, 132.79, 131.71, 126.69, 121.52,119.93, 118.44, 107.60, 102.04, 18.87. HRMS calcd for C 29 H 22 ClN7 [M+H] + :504.1698, found 504.1694. HPLC analysis: retention time = 10.86 min; peak area, 97.28% (λ = 254 nm).

[0089] Example 14: Synthesis of final product IIj

[0090] The operation is the same as in Example 5.

[0091]

[0092] Yield: 70%, yellow solid, mp: 269.6-271.4 ℃.

[0093] 1H NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 8.66-8.64 (m, 2H), 8.36 (s,1H), 7.98-7.97 (m, 1H), 7.96 (s, 1H), 7.92-7.91 (m, 1H), 7.78-7.77 (m, 2H),7.65 (s, 2H), 7.55-7.53 (m, 2H), 7.25-7.22 (m, 2H), 7.10 (t, J = 4 Hz, 1H),5.47 (s, 2H), 2.23 (s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 159.79, 158.82,156.21, 150.71, 147.27, 145.84, 145.41, 138.99, 137.84, 137.15, 136.01,135.52, 132.75, 131.14, 126.62, 121.51, 120.56, 120.01, 118.28, 109.66,101.73, 18.88. HRMS calcd for C 29 H 24 N8 [M+H] + : 485.2197, found 485.2202. HPLC analysis: retention time = 8.93 min; peak area, 97.88% (λ = 254 nm).

[0094] Example 15: Synthesis of final product ⅠⅠk

[0095] The operation is the same as in Example 5.

[0096]

[0097] Yield: 75%, yellow solid, mp: 166.6-168.1 ℃.

[0098] 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.66-8.65 (m, 2H), 8.25 (s,1H), 7.93 (s, 1H), 7.78-7.77 (m, 2H), 7.65 (s, 2H), 7.58 (s, 1H), 7,56-7.53(m, 2H), 7.26-7.24 (m, 2H), 7.07 (s, 1H), 5.10 (s, 2H), 3.92 (s, 3H), 2.24(s, 6H). 13 C NMR (100 MHz, DMSO-d6): 160.06, 158.68, 155.86, 152.05, 150.70,147.30, 145.95, 139.06, 137.84, 135.47, 133.02, 132.75, 132.51, 126.59,124.96, 121.50, 120.04, 119.88, 118.23, 109.96, 101.62, 53.41, 18.88. HRMScalcd for C 30 H 26 N8O [M+H] + : 515.2302, found 515.2308. HPLC analysis: retentiontime = 9.81 min; peak area, 98.29% (λ = 254 nm).

[0099] Example 16: Synthesis of final product ⅠⅠ l

[0100] The operation is the same as in Example 5.

[0101]

[0102] Yield: 80%, yellow solid, mp: >300 ℃.

[0103] 1H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.66-8.64 (m, 2H), 8.24 (s,1H), 8.10 (d, J = 4 Hz, 1H), 7.91 (s, 1H), 7.78-7.76 (m, 2H), 7.64 (s, 2H),7.57-7.54 (m, 3H), 7.25-7.23 (m, 2H), 6.60 (d, J = 8 Hz, 1H), 6.10 (s, 2H),2.22 (s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 160.11, 159.69, 158.46, 155.87,150.72, 148.13, 147.29, 146.00, 139.13, 138.30, 137.82, 135.44, 132.74,126.59, 121.50, 120.06, 118.79, 118.17, 110.18, 108.66, 101.52, 18.89. HRMScalcd for C 29 H 24 N8 [M+H] + : 485.2197, found 485.2194. HPLC analysis: retentiontime = 7.10 min; peak area, 98.72% (λ = 254 nm).

[0104] Example 17: Synthesis of final product I1m

[0105] The operation is the same as in Example 5.

[0106]

[0107] Yield: 42%, yellow solid, mp: 234.9-236.1 ℃.

[0108] 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.67-8.66 (m, 3H), 8.50 (d,J = 4 Hz, 1H), 8.15 (s, 1H), 7.80-7.79 (m, 2H), 7.70 (s, 1H), 7.68 (s, 2H), 7.64 (d, J = 4 Hz, 1H), 7.54-7.52 (m, 2H), 7.26-7.23 (m, 2H), 2.24 (s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ 159.31, 159.17, 157.43, 151.42, 150.75, 147.16,147.01, 145.50, 138.56, 137.73, 135.76, 132.77, 126.74, 124.11, 123.39,121.52, 119.87, 118.52, 108.37, 102.23, 18.87.HRMS calcd for C 29 H 22 ClN7 [M+H] + :504.1698, found 504.1691. HPLC analysis: retention time = 10.66 min; peak area, 98.02% (λ = 254 nm).

[0109] Anti-HIV bioactivity test

[0110] The Rega Institute of Pharmaceutical Research at the University of Katholleke, Belgium, determined the anti-HIV activity at the in vitro cellular level, focusing on two main aspects: inhibitory activity against HIV infection in MT-4 cells and cytotoxicity. The specific methods were as follows: the compound was added to MT-4 cells, which were then infected with HIV at different time points. The protective effect of the drug against HIV-induced mutagenesis-induced cell damage was assessed using the MTT assay, and the concentration required to protect 50% of cells from HIV-induced damage (EC50) was calculated. 50 Simultaneously, in toxicity tests conducted concurrently with anti-HIV activity assays, the MTT assay was used to determine the concentration (CC) required to cause damage to 50% of uninfected cells. 50 ), and calculate the selectivity index SI = EC 50 / CC 50 .

[0111] Materials and Methods:

[0112] 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.

[0113] 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, comparative experiments on antiviral activity using a blank solution 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.

[0114] This invention uses the drugs nevirapine (NVP), efavirenz (EFV), and ETR as reference standards. The results of the inhibitory activity of some target compounds against HIV are shown in Table 1, and the inhibitory activity of common clinically resistant strains against HIV-1 is shown in Table 2.

[0115]

[0116] Table 1: Inhibitory activity of HIV-1 against wild-type strains

[0117] .

[0118] Table 2: Inhibitory activity against common clinically resistant HIV-1 strains

[0119] .

[0120] Experimental results show that the target products I and II of the examples have strong anti-HIV-1 virus activity, can significantly inhibit viral replication in MT-4 cells infected with HIV-1 virus, and have low cytotoxicity and high selectivity index.

[0121] It should be noted that although the above embodiments have been described herein, this does not limit the scope of patent protection of the present invention. Even when the technical parameters and raw material components not described in detail are varied within the parameter range listed in the present invention, the same or similar technical effects as the above embodiments can still be obtained, and these effects still fall within the scope of protection of the present invention. Therefore, any changes and modifications made to the embodiments described herein based on the innovative concept of the present invention, or equivalent structural or procedural transformations made using the content of the present invention's specification and drawings, directly or indirectly applying the above technical solutions to other related technical fields, are all included within the scope of patent protection of the present invention.

Claims

1. A heteroarylpyrimidine derivative containing a pyridine-benzene ring structure, characterized in that, The structural formula is shown in either (Ⅰ) or (Ⅱ) below: Wherein, R is selected from pyridyl, furanyl, pyrroleyl, thiophenyl, pyrazolyl, ... , , , , , , , , , , .

2. The method for preparing heteroarylpyrimidine derivatives containing a pyridine-benzene ring structure as described in claim 1, characterized in that, The specific steps are as follows: Using 5-iodopyrimidine derivatives IIIa or IIIb as starting materials, compounds I or II are obtained by reacting with the corresponding aromatic heterocyclic boric acids, as shown in the following general reaction formula: In this reaction: The solvent is one or more of the following: dioxane, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, isopropanol, n-butanol, and isobutanol, mixed with water in a volume ratio of 1:1 to 10:

1. The base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium phosphate, LDA, LiHMDS, and NaHMDS; The catalysts are selected from Pd(dppf)Cl2, Pd(PPh4)3, Pd2(dba)3, PdCl2, Pd(OAc)2, and Pd(dba)2. The molar ratio of raw material compound IIIa or IIIb, aromatic heterocyclic boric acid, catalyst, and base is 1:(1.0~2.0):(0.005~0.2):(1~5); The reaction temperature is 50~180 ℃; The reaction time is 2 to 24 hours.

3. A pharmaceutical salt of a heteroarylpyrimidine derivative containing a pyridine-benzene ring structure as described in claim 1, characterized in that... This includes hydrochloride, hydrobromide, sulfate, formate, methanesulfonate, trifluoromethanesulfonate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate, or malate.

4. A pharmaceutical composition, characterized in that, The compound containing an effective dose of any of the heteroarylpyrimidine derivatives with a pyridine-benzene ring structure as described in claim 1, and a pharmaceutical carrier.

5. The use of the heteroarylpyrimidine derivatives containing a pyridine-benzene ring structure as described in claim 1 in the preparation of drugs for the prevention and treatment of AIDS.

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