CN113461666A - Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure and preparation method thereof - Google Patents

Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure and preparation method thereof Download PDF

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CN113461666A
CN113461666A CN202110491425.7A CN202110491425A CN113461666A CN 113461666 A CN113461666 A CN 113461666A CN 202110491425 A CN202110491425 A CN 202110491425A CN 113461666 A CN113461666 A CN 113461666A
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acid
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陈芬儿
庄春林
定力
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Fudan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl methylpyrimidine derivative containing an aromatic heterocyclic structure and a preparation method thereof. The invention optimizes the structure and salification of diaryl pyrimidine non-nucleoside reverse transcriptase inhibitor, examines the pharmacological and toxicological theory, and obtains the novel high-efficiency non-nucleoside reverse transcriptase inhibitor with excellent antiviral activity and pharmacokinetic characteristic, namely biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure, including medicinal salt, stereochemical isomer, hydrate or solvate. The in vitro cell level anti-HIV-1 activity experiment result shows that the compound has stronger anti-HIV-1 biological activity, can obviously inhibit virus replication in MT-4 cells infected by HIV-1 virus, and has lower cytotoxicity. The invention also comprises a pharmaceutical composition containing the compound for preventing and treating AIDS.

Description

Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound for resisting HIV-1 virus strains, namely a biphenyl diaryl methylpyrimidine derivative containing an aromatic heterocyclic structure and a preparation method thereof.
Background
AIDS (Acquired immunodeficiency syndrome), which is Acquired immunodeficiency syndrome (AIDS), is an immunodeficiency caused by infection of Human immunodeficiency virus (HIV-l), and thus causes a series of serious epidemic diseases such as pathogenic infection and tumor. Since the first case was confirmed by the united states Centers for Disease Control (CDC) in 1981, aids has spread rapidly around the world, becoming a major public health problem worldwide, and has caused 3200 more than ten thousand deaths to date.
Reverse Transcriptase (RT) plays a key role in the life cycle of HIV virus replication, and is responsible for Reverse transcription of viral RNA into DNA-RNA hybrids and degradation of RNA in the hybrids to form single-stranded viral DNA, and then viral DNA is integrated into host cells by integrase, so that Reverse transcriptase becomes one of important targets for anti-AIDS drug design. Currently, more than half of the anti-HIV marketed drugs are Reverse Transcriptase Inhibitors (RTIs).
Among the existing anti-HIV-1 drugs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the clinical treatment of AIDS due to the advantages of high efficiency and low toxicity, and become a main component of high-efficiency antiretroviral therapy (HAART). By the end of 2019, over 50 non-nucleoside reverse transcriptase inhibitors of HIV-1 with different chemical structures have been discovered, 6 of which have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of aids are Nevirapine (NVP), Delavirdine (DLV), efavirenz (efavirenz, EFV), etravirine (etravirine, ETR), Rilpivirine (RPV) and doraviline (doravirine, DOR), respectively. Currently clinically used NNRTIs are primarily second generation HIV inhibitors: diarylpyrimidines, Rilpivirine (RPV) and Etravirine (Etravirine, ETR). However, the rapid emergence of viral mutants, the poor water solubility (ETR, < <1 μ g/mL; RPV,20ng/mL) of these compounds, and the side effects caused by long-term administration limit their clinical use, and further development of novel highly potent non-nucleoside reverse transcriptase inhibitors with broad-spectrum antiviral activity and excellent pharmacokinetic properties has become one of the hot spots of research by medicinal chemists.
Disclosure of Invention
The invention aims to provide a biphenyl diaryl methyl pyrimidine derivative with aromatic heterocyclic structure, high biological activity, low cytotoxicity and good water solubility for resisting HIV virus strains, a preparation method thereof and application of the derivative in resisting HIV virus strains.
The invention optimizes the structure and salification of diaryl pyrimidine non-nucleoside reverse transcriptase inhibitor, and examines the pharmacological and toxicological factors of diaryl pyrimidine non-nucleoside reverse transcriptase inhibitor, so as to obtain a novel high-efficiency non-nucleoside reverse transcriptase inhibitor with excellent antiviral activity and pharmacokinetic properties.
The invention is based on the binding mode of biphenyl diaryl pyrimidine derivatives containing aromatic heterocyclic structures and HIV reverse transcriptase, adopts computer-aided drug design and utilizes a classical biological electron isostere strategy to replace p-cyanophenyl segments in biphenyl segments of difluorobiphenyl DPAY inhibitors into aromatic heterocyclic segments so as to keep pi-pi accumulation between original compounds and aromatic amino acid residues Y181 and Y188 in a binding pocket. Meanwhile, hetero atoms are introduced to improve the water solubility of the whole molecule and improve the drug forming parameters of the inhibitor molecule. In addition, in the optimized compound molecular skeleton, the central pyrimidyl mother ring can maintain to form hydrogen bonds with amino acid residues E138 and K101, so that the binding conformation is stabilized. Further improving the bioactivity of the optimized compound molecule against HIV strain. The in vitro cell level anti-HIV-1 activity experiment result shows that the optimized compound has obvious anti-HIV-1 activity and lower cytotoxicity. Meanwhile, salifying transformation is carried out on optimized compound molecules, and solubility experiments prove that the medicinal salt of the optimized compound shows excellent water solubility in various pH ranges, so that the compound has a good clinical application prospect.
Based on the research, experiment and exploration, the compound for resisting HIV strains provided by the invention is a biphenyl diaryl methylpyrimidine derivative containing aromatic heterocyclic structures, and the structural formula of the compound is shown as the formula (I):
Figure BDA0003052396350000021
wherein R is1Is substituted or unsubstituted furyl, thienyl, pyridyl, pyrimidyl, C7～10An aromatic heterocyclic group.
In some embodiments, the compound is selected from compounds of the following structural formula:
Figure BDA0003052396350000022
Figure BDA0003052396350000031
the compounds of the present invention, further include pharmaceutically acceptable salts, stereochemically isomeric forms, hydrates or solvates of said derivatives;
in the invention, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, formate, methanesulfonate, trifluoromethanesulfonate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate or malate.
The invention also provides a preparation method of the biphenyl diaryl methylpyrimidine derivative containing the aromatic heterocyclic structure, which comprises the following steps:
in Pd (dppf) Cl2、Cs2CO3In the presence of (a), carrying out Suzuki-coupling reaction on the compound shown in the structural formula (II) and heterocyclic boric acid in a solvent to obtain the compound shown in the structural formula (I), wherein the reaction formula is as follows:
Figure BDA0003052396350000032
wherein R is1Is substituted or unsubstituted furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, C7～10An aromatic heterocyclic group.
The solvent is at least one selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane and ethyl acetate.
The heterocyclic boronic acid is selected from at least one of 4-pyridineboronic acid, 3-pyridineboronic acid, 5-pyrimidineboronic acid, 2-furanboronic acid, 3-furanboronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, 2-fluoro-4-pyridineboronic acid, 2, 6-difluoro-4-pyridineboronic acid, 5-trifluoromethyl-3-pyridineboronic acid, 5-cyano-3-pyridineboronic acid and 4-cyano-3-pyridineboronic acid.
The molar ratio of the compound (II) to the heterocyclic boronic acid is 1:1 to 1:8 (1-8)), preferably 1 (2-4).
The compound (II) is reacted with Pd (dppf) Cl2Is 1:0.01 to 1:0.10(1 (0.01 to 0.10)), preferably 1 (0.02 to 0.05).
The compound (II) and Cs2CO3The molar ratio of (1: 1) - (1: 2).
The reaction temperature is 40-180 ℃, and the preferable reaction temperature is 80-170 ℃.
The reaction time is 4-24 h.
The invention also provides application of the compound shown as the structural formula (I) or a medicinal salt, a stereochemical isomer, a hydrate or a solvate thereof in preparing a medicament for preventing or treating AIDS.
The invention also provides a pharmaceutical composition, which comprises the compound shown as the structural formula (I) or a pharmaceutically acceptable salt, a stereochemically isomeric form, a hydrate or a solvate thereof, and a pharmaceutically acceptable carrier.
The pharmaceutical composition comprises an effective dose of the compound or a pharmaceutically acceptable salt, a stereochemically isomeric form, a hydrate or a solvate thereof, and a pharmaceutically acceptable carrier.
The invention also provides a pharmaceutical composition which comprises the polycrystal, the eutectic crystal or the single-enantiomer X-ray diffraction single crystal of the compound shown as the structural formula (I) and a medicinal carrier.
The pharmaceutical composition comprises an effective dose of an X-ray derived single crystal of a polymorph, co-crystal, or single enantiomer of the compound, and a pharmaceutically acceptable carrier.
The pharmaceutical composition can be used for preventing or treating AIDS.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Example 1: preparation of the target product (Ia)
Figure BDA0003052396350000041
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (1.0mmol), Pd (dppf) Cl2(0.01mmol) and 4-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Ia).
Characterization of the target product (Ia): a white powdery solid; the yield is 77%; melting point: 275.0-275.4 ℃.1H NMR (400MHz,DMSO–d6)δ9.66(s,1H,NH),8.74-8.73(m,3H,ArH,NH),8.01(s,1H,ArH),7.93 (d,J＝8Hz,2H,ArH),7.88(d,J＝8Hz,2H),7.65-7.39(dd,J＝8Hz,J＝88Hz,4H,ArH),2.18 (s,3H,CH3)。13C NMR(100MHz，DMSO–d6)δ:160.8,160.7-158.2(dd,JC-F＝5Hz,JC-F＝241 Hz),157.9,156.2,150.6,145.9,145.2,137.1(t,JC-F＝10Hz),133.0,121.7,120.1,118.1,117.8(t, JC-F＝20Hz),111.1-110.9(dd,JC-F＝6Hz,JC-F＝12Hz),107.2,101.7,13.8。HRMS(ESI-):m/z calcd for C23H16F2N6[M-H]-414.1405,found 413.1332。HPLC:tR＝5.43min,99.86％,(λ＝254 nm)。
Example 2: preparation of the target product (Ib)
Figure BDA0003052396350000051
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 3-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxane (5mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 150 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Ib).
Characterization of the target product (Ir): a white powdery solid; the yield is 80%; melting point: 229.1-229.5 ℃.1H NMR (400MHz,DMSO–d6)δ9.64(s,1H,NH),9.11(s,1H,ArH),8.67(d,J＝8Hz,1H,ArH),8.64(s, 1H,NH),8.28(d,J＝8Hz,1H,ArH),8.01(s,1H,ArH),7.80(d,J＝8Hz,2H,ArH),7.96-7.41 (dd,J＝8Hz,J＝96Hz,4H,ArH),7.56(q,J＝4Hz,1H,ArH),2.19(s,3H,CH3)。13C NMR(100MHz，DMSO–d6)δ:160.8,160.7-158.3(dd,JC-F＝5Hz,JC-F＝240Hz),158.1,156.4, 150.0,148.2,146.0,137.3(t,JC-F＝10Hz),134.7,133.4,132.9,124.4,120.1,118.0,116.6(t, JC-F＝17Hz),110.9(d,JC-F＝25Hz),107.1,101.6,13.8。HRMS(ESI-):m/z calcd for C23H16F2N6[M-H]-414.1405413.1332。HPLC:tR＝5.41min,99.36％,(λ＝254nm)。
Example 3: preparation of the target product (ic)
Figure BDA0003052396350000061
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 5-pyrimidineboronic acid (1.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 80 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ic).
Characterization of the target product (Ic): a white powdery solid; the yield is 93 percent; melting point: 248.1-248.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.64(s,1H,NH),9.35(s,2H,ArH),9.28(s,1H,ArH),8.67(s,1H,NH), 8.01(s,1H,ArH),7.90(d,J＝12Hz,2H,ArH),7.69-7.44(dd,J＝8Hz,J＝92Hz,4H,ArH), 2.19(s,3H,CH3)。13C NMR(100MHz，DMSO–d6)δ:160.7,160.8-158.2(dd,JC-F＝7Hz,JC-F＝ 239Hz),158.5,158.1,156.5,155.4,145.9,133.9(t,JC-F＝10Hz),133.0,131.3,120.2,118.0, 117.4(t,JC-F＝16Hz),110.1(d,JC-F＝25Hz),107.1,101.6,13.8。HRMS(ESI-):m/z calcd forC22H15F2N7[M-H]-415.1357,found 414.1284。HPLC:tR＝4.47min,98.60％,(λ＝254nm)。
Example 4: preparation of the target product (Id)
Figure BDA0003052396350000062
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 2-Furanboronic acid (8.0mmol) were added to toluene (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 100 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (Id).
Characterization of the target product (Id): a white powdery solid; the yield is 90 percent; melting point: 201.3-201.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.58(s,1H,NH),8.56(s,1H,NH),7.99(s,1H,ArH),7.86(d,J＝4Hz, 1H,ArH),7.67-7.63(m,4H,ArH),7.42(dd,J＝8Hz,J＝28Hz,2H,ArH),7.24(s,1H,ArH), 2.16(s,3H,CH3)。13C NMR(100MHz，DMSO–d6)δ:160.9,160.8-158.3(dd,JC-F＝7Hz,JC-F＝ 238Hz),158.0,156.3,146.0,145.3,141.3,132.9,132.7(t,JC-F＝11Hz),124.7,120.2,118.0, 115.0(t,JC-F＝17Hz),109.5-109.2(dd,JC-F＝6Hz,JC-F＝13Hz),109.1,107.0,101.5,13.7。 HRMS(ESI-):m/z calcd for C22H15F2N5O[M-H]-403.1245,found 402.1175。HPLC:tR＝6.59 min,99.32％,(λ＝254nm)。
Example 5: preparation of the target product (ie)
Figure BDA0003052396350000071
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol)Cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 3-Furanboronic acid (8.0mmol) were added to methanol (6mL) over N2The replacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 24 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ie).
Characterization of the target product (Ie): a white powdery solid; the yield is 80%; melting point: 230.8-231.5 ℃.1H NMR (400MHz,DMSO–d6)δ9.58(s,1H,NH),8.53(s,1H,NH),8.43(s,1H,ArH),7.98(s,1H,ArH), 7.83(s,1H,ArH),7.66-7.62(m,4H,ArH),7.38(dd,J＝8Hz,2H,ArH),7.16(s,1H,ArH),2.16 (s,3H,CH3)。13C NMR(100MHz，DMSO–d6)δ:160.9,160.8-158.3(dd,JC-F＝7Hz,JC-F＝238 Hz),158.0,156.3,146.0,145.3,141.3,132.9,132.7(t,JC-F＝11Hz),124.7,120.2,118.0,115.0(t, JC-F＝17Hz),109.5-109.2(dd,JC-F＝6Hz,JC-F＝13Hz),109.1,107.0,101.5,13.7。HRMS(ESI-): m/z calcd forC22H15F2N5O[M-H]-403.1245,found 402.1172。HPLC:tR＝6.56min,99.04％, (λ＝254nm)。
Example 6: preparation of the target product (if)
Figure BDA0003052396350000081
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 2-thiopheneboronic acid (4.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 14 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperatureThe reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (if).
Characterization of the target product (If): a white powdery solid; the yield is 90 percent; melting point: 210.5-211.7 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.57(s,1H,NH),7.99(s,1H,ArH),7.76-7.69(dd,J ＝4Hz,J＝20Hz,2H,ArH),7.67-7.61(dd,J＝4Hz,J＝16Hz,4H,ArH),7.49(d,J＝8Hz,2H, ArH),7.23(t,J＝4Hz,1H,ArH),2.17(s,3H,CH3)。13C NMR(100MHz，DMSO–d6)δ:165.6, 165.5-163.0(dd,JC-F＝6Hz,JC-F＝240Hz),162.8,161.1,150.7,145.9,139.0(t,JC-F＝10Hz), 137.6,134.1,132.6,130.9,124.9,122.8,120.5(t,JC-F＝17Hz),114.2(d,JC-F＝25Hz),111.8, 106.3,18.5。HRMS(ESI+):m/z calcd for C22H15F2N5S[M-H]-419.1016,found 418.0943。 HPLC:tR＝7.23min,100％,(λ＝254nm)。
Example 7: preparation of the target product (Ig)
Figure BDA0003052396350000091
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.05mmol) and 3-thiopheneboronic acid (4.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ig).
Characterization of the target product (Ig): a white powdery solid; the yield is 77%; melting point: 264.9-265.7 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),8.54(s,1H,NH),8.19(d,J＝4Hz,1H,ArH),7.99(s, 1H,ArH),7.77-7.72(m,4H,ArH),7.68-7.37(dd,J＝8Hz,J＝108Hz,4H,ArH),2.17(s,3H, CH3)。13C NMR(100MHz，DMSO–d6)δ:165.7-162.8(dd,JC-F＝28Hz,JC-F＝246Hz),161.0, 165.6,162.8,161.0,150.7,144.3,140.3(t,JC-F＝10Hz),137.7,132.9,131.4,128.1,124.9,122.8, 120.0(t,JC-F＝17Hz),114.7(d,JC-F＝22Hz),111.7,106.3,18.5。HRMS(ESI-):m/z calcd forC22H15F2N5S[M-H]-419.1016,found 418.0935。HPLC:tR＝7.26min,99.71％,(λ＝254nm)。
Example 8: preparation of the target product (ih)
Figure BDA0003052396350000092
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.08mmol) and 3-fluoro-4-pyridineboronic acid (8.0mmol) were added to 1, 4-dioxane (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ih).
Characterization of the target product (Ig): a white powdery solid; the yield is 58 percent; melting point: 273.4-274.1 ℃.1H NMR (400MHz,DMSO–d6)δ9.65(s,1H,NH),8.70(s,1H,NH),8.38(d,J＝4Hz,1H, pyrimidine-H),8.01-7.77(m,5H,ArH),7.67-7.41(dd,J＝8Hz,J＝88Hz,4H,ArH),2.18(s, 3H,CH3)。13C NMR(100MHz,DMSO–d6)δ:161.2-157.8(dd,JC-F＝8Hz,JC-F＝320Hz),160.7, 158.1,156.5,152.1,146.2(d,JC-F＝6Hz),145.9,135.5(t,JC-F＝14Hz),133.8(t,JC-F＝3Hz), 132.9,132.0(q,JC-F＝5Hz),126.3(q,JC-F＝43Hz),120.0,118.0,117.5(t,JC-F＝23Hz), 111.6-111.3(dd,JC-F＝11Hz,JC-F＝12Hz),107.1,101.7,13.7。HRMS(ESI-):m/z calcd for C23H15F3N6[M-H]-432.1310,found 431.1238。HPLC:tR＝5.94min,99.52％,(λ＝254nm)。
Example 9: preparation of the target product (II)
Figure BDA0003052396350000101
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 3, 5-difluoro-4-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 100 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (II). :
characterization of the target product (Ii): a white powdery solid; the yield is 70%; melting point: 269.1-270.0 ℃.1H NMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.69(s,1H,NH),8.81(s,1H,ArH),7.98(d,J＝12 Hz,2H,ArH),7.78(s,2H,ArH),7.66-7.41(dd,J＝12Hz,J＝76Hz,4H,ArH),7.42(d,J＝12 Hz,2H,ArH)2.18(s,3H,CH3)。13C NMR(100MHz,DMSO–d6)δ:163.8(d,JC-F＝22Hz), 161.0-157.6(dd,JC-F＝8Hz,JC-F＝321Hz),160.6,158.0,155.5,145.9,134.7(t,JC-F＝13Hz), 133.0,120.1,119.1(t,JC-F＝22Hz),118.1,111.8(d,JC-F＝34Hz),107.3,104.9,104.3,101.7,13.7。 HRMS(ESI-):m/z calcd for C23H14F4N6[M-H]-450.1216,found 449.1143。HPLC:tR＝6.85 min,98.92％,(λ＝254nm)。
Example 10: preparation of the target product (Ij)
Figure BDA0003052396350000111
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.01mmol) and 5-trifluoromethyl-3-pyridineboronic acid (1.2mmol) were added to methanol (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2), and a saturated brine (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ij).
Characterization of the target product (Ij): a white powdery solid; the yield is 91%; melting point: 259.4-260.3 ℃.1H NMR (400MHz,DMSO–d6)δ9.61(s,1H,NH),8.67(s,1H,NH),8.38(d,J＝8Hz,1H, pyrimidine-H),8.01(s,1H,ArH),7.92-7.87(m,3H,ArH),7.75(s,1H,ArH),7.67-7.39(dd,J＝ 12Hz,J＝88Hz,4H,ArH),2.18(s,3H,CH3)。13C NMR(100MHz,DMSO–d6)δ:166.2-163.1 (d,JC-F＝310Hz),161.1-157.7(dd,JC-F＝8Hz,JC-F＝320Hz),160.7,158.0,156.5,150.8(d, JC-F＝11Hz),148.9(d,JC-F＝21Hz),145.9,132.9,120.1,120.0,118.4(t,JC-F＝22Hz),118.1, 111.4(dd,JC-F＝10Hz,JC-F＝13Hz),107.6-107.0(d,JC-F＝52Hz),107.2,101.7,13.7。HRMS (ESI-):m/z calcd for C24H15F5N6[M-H]-482.1278,found 491.0366。HPLC:tR＝7.12min, 99.62％,(λ＝254nm)。
Example 11: preparation of the target product (Ik)
Figure BDA0003052396350000112
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.08mmol) and 5-cyano-3-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 170 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (ik).
Characterization of the target product (Ik): a white powdery solid; the yield is 88%; melting point: 294.3-294.9 ℃.1H NMR (400MHz,DMSO–d6)δ9.60(s,1H,NH),9.39(d,J＝4Hz,1H,ArH),9.10(d,J＝4Hz,1H, ArH),8.86(t,J＝4Hz,1H,ArH),8.64(s,1H,NH),8.01(s,1H,ArH),7.91-7.66(dd,J＝8.0Hz, J＝88Hz,4H,ArH),7.44(d,J＝8Hz,2H,ArH),2.19(s,,3H,CH3)。13C NMR(100MHz, DMSO–d6)δ:160.8,160.6,160.5-157.9(dd,JC-F＝6Hz,JC-F＝246Hz),158.0,156.5,151.3(t, JC-F＝3Hz),150.0(d,JC-F＝5Hz),144.6,132.9(d,JC-F＝5Hz),130.5(t,JC-F＝11Hz),120.2,118.0, 116.5(d,JC-F＝27Hz),115.6(t,JC-F＝17Hz),113.0,108.8,107.4,101.6,13.8。HRMS(ESI-):m/z calcd forC24H15F2N7[M-H]-439.1357,found 438.1284。HPLC:tR＝5.22min,99.05％,(λ＝254 nm)。
Example 12: preparation of the target product (il)
Figure BDA0003052396350000121
At room temperature, 4- ((4- ((4-bromo-2, 6-difluorophenyl) amino) 5-methylpyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol), Pd (dppf) Cl2(0.10mmol) and 4-cyano-3-pyridineboronic acid (1.2mmol) were added to 1, 4-dioxan (6mL) over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. The starting material disappeared and the reaction was complete by TLC (PE/EA: 1/1). The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (il).
Characterization of the target product (Il): a white powdery solid; the yield is 88%; melting point: 293.7-294.2 ℃.1H NMR (400MHz,DMSO–d6)δ9.64(s,1H,NH),9.30(s,1H,NH),8.69(s,1H,ArH),8.56-8.21(dd,J ＝8Hz,J＝124Hz,2H,ArH),8.01(s,1H,ArH),7.92(d,J＝8Hz,1H,ArH),7.68-7.43(dd,J＝ 8.0Hz,J＝84Hz,4H,ArH),2.18(s,,3H,CH3)。13C NMR(100MHz,DMSO–d6)δ: 160.6,158.2(d,JC-F＝7Hz),158.1,156.5,149.8,145.9,136.8,136.0,135.2(t,JC-F＝10Hz),133.0, 132.5,129.6,120.2,118.0,111.6-111.4(d,JC-F＝25Hz),107.2,101.6,13.8。HRMS(ESI+):m/z calcd for C24H15F2N7[M-H]-439.1357,found 438.1284。HPLC:tR＝5.63min,95.39％,(λ＝254 nm)。
Example 13: salifying transformation and water solubility measurement of compound
Salification transformation was performed on the target products of examples 1-12 and water solubility measurements were performed over multiple pH ranges on the salified product by a standard curve method.
Preparing a salified compound: dissolving the compound in a solvent completely at room temperature or under heating, adding the acid to be salified in N2Stirring for 18-48h under protection until a large amount of solid is separated out. Filtering to obtain the salified compound of the compound. The solvent selected here may be one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane, dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, cyclohexane, petroleum ether. The preparation method of the hydrochloride and the water solubility test results are specifically described below by taking the target product (Ia) as an example.
The expected product (Ia) (100mg) was dissolved in 15ml of ethyl acetate at 33 ℃ and 10 drops of acid were added and stirred at 33 ℃ for 24 h. And (4) filtering to obtain a salt-forming compound of the target product after a large amount of solids are separated out. And respectively taking 5-10mg of the compound, sequentially adding the compound into buffer aqueous solutions with pH values of 2.0, 7.0 and 7.4, stirring for more than 18 hours at 20-25 ℃, filtering to obtain supernate, and testing the water solubility of the compound in various pH ranges by reverse phase HPLC analysis. The water solubility results are shown in table 1:
TABLE 1 Water solubility results for the target product (Ia) and salt-forming complexes thereof
Figure BDA0003052396350000131
Other examples salt formation modification of the target product, as well as water solubility measurements, have similar results to those described above and are not listed.
Example 14: anti-HIV biological Activity assay
Examples 1-12 in vitro cellular anti-HIV viral activity of target products was determined by the Rega pharmaceutical research institute at the university of Katholleke, belgium, and consists essentially of: inhibiting activity and cytotoxicity on HIV-infected MT-4 cells. The method comprises the following steps: the protective effect of test compounds on HIV-induced cytopathic effects was determined by MTT assay in HIV-infected MT-4 cells at various times during HIV infection, and the concentration required to protect 50% of MT-4 cells from HIV-induced cytopathic effects was calculatedDegree-half effective concentration EC50Toxicity assay was performed in parallel with anti-HIV activity assay, and the concentration (CC) at which 50% of uninfected cells were cytopathic was measured by MTT method in MT-4 cell culture50) And calculating the selectivity index SI ═ CC50/EC50。
The material and the method are as follows:
the anti-HIV activity of the test compound is evaluated by the efficiency of the test compound in inhibiting the cytopathy caused by HIV in cells. MT-4 cells were used for cell culture. The viral strains used were: HIV-1 strain IIIB and HIV-2 strain ROD.
The specific operation is as follows: dissolving the compound to be tested in DMSO or water, diluting with phosphate buffer saline solution in gradient, adding 100 μ L of compound solution to be tested with different concentrations into 3 × 105MT-4 cells were pre-cultured at 37 ℃ for 1 hour, and then 100. mu.L of a virus diluent of an appropriate concentration was added to the pre-cultured cells, and the MT-4 cells were cultured at 37 ℃ for 1 hour. After three washes, MT-4 cells are resuspended in culture medium with and without test compound, respectively. MT-4 cells were then incubated in 5% CO2The culture medium was incubated at 37 ℃ for another 7 days in the atmosphere and the previously consumed corresponding culture medium was replaced with culture medium containing and not containing the test compound, respectively, on the third day after infection to supplement the culture medium. Each cultivation process was repeated twice. Virus-induced cytopathic effects were monitored daily by reverse light microscopy. Typically, the viral dilutions used in this experiment often lead to cytopathic effects the fifth day after viral infection. The inhibitory concentration of the drug is that concentration at which the drug produces 50% inhibition of virus-induced cytopathic effects while not being directly toxic to cells (CC)50) And (4) showing. It is emphasized that, when the test compound is poorly water soluble and DMSO is required to dissolve, the DMSO concentration is generally less than 10% relative to water (the final concentration of DMSO in MT-4 cell culture medium is less than 2%). Since DMSO affects the antiviral activity of the test compound, it is necessary to perform the antiviral activity assay using a blank containing the same concentration of DMSO solution. In addition, the final DMSO concentration (1/1000) is much lower than the replication of HIV-1 in T cellsThe desired concentration.
The results of the inhibitory activity of the target products of examples 1-12 on HIV using the marketed drugs Nevirapine (NVP), Efavirenz (Efavirenz, EFV) and Etravirine (Etravirine, ETV) as controls are shown in Table 2 (anti-HIV activity and cytotoxicity of the target products of examples 1-12 in MT-4 cells), and compounds 11a-l in Table 2 correspond to the target products of examples 1-12, respectively.
Figure BDA0003052396350000151
TABLE 2[a]
Figure BDA0003052396350000152
Figure BDA0003052396350000161
aAll data represent the mean of at least three independent experiments;bEC50an effective concentration to protect 50% of the cells from viral infection;cCC50the drug concentration when 50% of cells are diseased;dSI selection index, CC50Value and EC50The ratio of the values is used for judging the safety range of the drug effect.
Experimental results show that the target products of examples 1-12 have strong anti-HIV-1 virus activity, can remarkably inhibit virus replication in MT-4 cells infected by HIV-1 virus, and have small cytotoxicity and high selectivity index.
It should be noted that, although the above embodiments have been described herein, the scope of the present invention is not limited thereby, and the technical parameters and raw material components which are not described in detail herein can still obtain the same or similar technical effects as the above embodiments when they are changed within the range of the parameters recited in the present invention, and still fall within the scope of the present invention. Therefore, based on the innovative concepts of the present invention, the technical solutions of the present invention can be directly or indirectly applied to other related technical fields by making changes and modifications to the embodiments described herein or by using equivalent process changes made by the content of the present specification, and are included in the scope of the present invention.

Claims (9)

1. A compound resisting HIV strain is a biphenyl diarylmethylpyrimidine derivative containing aromatic heterocyclic structure, and the structural formula of the compound is shown as the formula (I):
Figure FDA0003052396340000011
wherein R is1Is substituted or unsubstituted furyl, thienyl, pyridyl, pyrimidyl, C7～10An aromatic heterocyclic group.
2. The compound of claim 1, wherein the compound is selected from the following structural formulas:
Figure FDA0003052396340000012
3. the compound of claim 1 or 2, further comprising a pharmaceutically acceptable salt, a stereochemically isomeric form, a hydrate or a solvate of said chemotrope;
the pharmaceutically acceptable salt is hydrochloride, hydrobromide, formate, methanesulfonate, trifluoromethanesulfonate, sulfate, phosphate, acetate, p-toluenesulfonate, tartrate, citrate, succinate, maleate, fumarate or malate.
4. A method for preparing the compound of claim 1, which comprises the following steps:
in Pd (dppf) Cl2、Cs2CO3In the presence of (a), carrying out Suzuki-coupling reaction on the compound shown in the structural formula (II) and heterocyclic boric acid in a solvent to obtain the compound shown in the structural formula (I), wherein the reaction formula is as follows:
Figure FDA0003052396340000021
wherein R is1Is substituted or unsubstituted furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, C7～10An aromatic heterocyclic group.
5. The process for the preparation of a compound according to claim 4, wherein:
the solvent is at least one selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane and ethyl acetate;
the heterocyclic boronic acid is selected from at least one of 4-pyridineboronic acid, 3-pyridineboronic acid, 5-pyrimidineboronic acid, 2-furanboronic acid, 3-furanboronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, 2-fluoro-4-pyridineboronic acid, 2, 6-difluoro-4-pyridineboronic acid, 5-trifluoromethyl-3-pyridineboronic acid, 5-cyano-3-pyridineboronic acid and 4-cyano-3-pyridineboronic acid.
6. The process for the preparation of a compound according to claim 4, wherein:
the molar ratio of the compound (II) to the heterocyclic boric acid is 1 (1-8);
the compound (II) is reacted with Pd (dppf) Cl2The molar ratio of (1) to (0.01-0.10);
the compound (II) and Cs2CO3The molar ratio of (1) to (2);
the reaction temperature is 40-180 ℃, and the reaction time is 4-24 h.
7. Use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the prophylaxis or treatment of aids.
8. A pharmaceutical composition for preventing or treating aids, comprising a compound according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition for preventing or treating aids comprising a single crystal by X-ray diffraction of a single crystal of a polymorph, cocrystal or single enantiomer of the compound of claim 1, and a pharmaceutically acceptable carrier.
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