CN112624983B - Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof - Google Patents

Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof Download PDF

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CN112624983B
CN112624983B CN202011476606.4A CN202011476606A CN112624983B CN 112624983 B CN112624983 B CN 112624983B CN 202011476606 A CN202011476606 A CN 202011476606A CN 112624983 B CN112624983 B CN 112624983B
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陈芬儿
庄春林
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl pyrimidine derivative containing an alkyl structure, and preparation and application thereof. The biphenyl diaryl pyrimidine derivative with the compound structure containing the alkyl structure comprises medicinal salt, stereochemical isomer, hydrate and solvate, polycrystal or eutectic crystal and single-enantiomer X-ray diffraction single crystal, and precursor and derivative with the same biological function; the invention also discloses a preparation method thereof and application of a composition containing one or more compounds in preparation of related medicines for treating AIDS and the like. The in vitro cell level anti-HIV-1 activity experiment result shows that the small molecules have stronger anti-HIV-1 biological activity, can obviously inhibit virus replication in MT-4 cells infected by HIV-1 viruses, have lower cytotoxicity and are expected to become anti-HIV candidate drugs.

Description

Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl pyrimidine derivative containing an alkyl structure, and a preparation method and application 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 disease control center (CDC) in 1981, aids has spread rapidly around the world and has become a major public health problem worldwide, resulting in the death of over 3200 thousands of people.
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, etrr), Rilpivirine (RPV) and doraviline (doravirine, DOR), respectively. Currently clinically used NNRTIs are mainly 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.
The invention aims to optimize the structure of diaryl pyrimidine non-nucleoside reverse transcriptase inhibitors, split chiral molecules, investigate the biological activity of different single enantiomers and the pharmacological and toxicological properties so as to obtain novel high-efficiency non-nucleoside reverse transcriptase inhibitors with excellent antiviral activity and pharmacokinetic properties.
Disclosure of Invention
The invention aims to provide a biphenyl diaryl pyrimidine compound with strong biological activity and small cytotoxicity and containing an alkyl structure, and a preparation method and application thereof.
The biphenyl diaryl pyrimidine derivative containing an alkyl structure provided by the invention has a structural formula shown as the following formula (I):
Figure BDA0002835660960000021
wherein R is 1 And R 2 Are independently selected from hydrogen, cyano, amino, nitro, hydroxyl, halogen, C3-6 cycloalkoxy, C3-6 cycloalkamino, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl or C1-6 alkoxy, carbonyl, carboxyl, ester group, amide group and sulfonamide group.
The biphenyl diaryl pyrimidine derivative with alkyl structure also includes its medicinal salt, its stereochemical isomer, its hydrate and solvate, its polycrystal or eutectic crystal and single enantiomer X-ray diffraction monocrystal, and its precursor and derivative with the same biological function.
The medicinal salt of the biphenyl diaryl pyrimidine derivative containing the alkyl structure comprises hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, citrate, fumarate or malate.
The invention also provides a preparation method of the biphenyl diaryl pyrimidine derivative with the alkyl structure, which comprises the following steps:
in a solvent, compound II (4- ((4- ((4-bromo-2, 6-difluorophenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile) in Pd (dppf) Cl 2 Obtaining the compound I through Suzuki-coupling reaction under the action of cesium carbonate, wherein the reaction general formula of the preparation is as follows:
Figure BDA0002835660960000022
the reaction conditions and the resolution method are as follows:
the solvent is one or more of 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 molar ratio of the compound II to the p-cyanophenylboronic acid is 1: 1-1: 3 ((1-3);
the reaction temperature is 0-200 ℃, preferably 50-150 ℃;
the reaction time is 4-14 h, preferably 5-10 h.
The invention also relates to a pharmaceutical composition comprising an effective amount of the above compound and an associated pharmaceutically acceptable carrier. The invention also relates to application of the compound or the composition in preparation of drugs for preventing and treating AIDS.
The invention is based on the combination mode of biphenyl diaryl pyrimidine derivatives containing alkyl structures and HIV reverse transcriptase, combines computer-aided drug design, introduces alkyl at a connecting arm and a central pyrimidine ring, enhances the hydrogen bond interaction of the compound and a combination pocket and provides effective space occupying effect. A biphenyl structure is introduced into the left wing of the pyrimidine ring, so that the pi-pi stacking effect between the compound and aromatic amino acid residues Tyr181 and Tyr188 in a binding pocket is enhanced. The cyano group on the left wing can deeply bind to the pocket to strengthen the binding force between the highly conserved amino acid residues Phe227 and Trp 229. In addition, the single enantiomer with a certain configuration is beneficial to effectively combining the molecule with a target, and the biological activity of the target compound against HIV strains is further improved. The in vitro cell level anti-HIV-1 activity experiment result shows that the series of compounds have more remarkable anti-HIV-1 activity and lower cytotoxicity.
Detailed Description
The invention will be better understood by the following examples of implementation, without however limiting the scope of the invention.
Example 1: preparation of the target product (I)
Compound II in Pd (dppf) Cl 2 And carrying out Suzuki-coupling reaction under the action of cesium carbonate to obtain the compound I. Wherein the solvent isOne or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane, ethyl acetate, etc.; the reaction temperature is 0-200 ℃, and the reaction time is 4-14 h.
The target compounds are prepared from raw materials containing different substituents by the method respectively, and partial results are as follows:
4- ((4- ((4-bromo-2, 6-difluorophenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol) and p-cyanobenzoic acid (1.2mmol) were added to 1, 4-dioxane (6mL) at room temperature over N 2 The reaction solution is replaced for three times, the reaction temperature is adjusted to 110 ℃, and the reaction solution is stirred 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 (I). Specific compounds are listed below:
compound 1: r is 1 Is CH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000041
a white powdery solid; the yield is 95 percent; melting point: 267.2-268.4 ℃. 1H NMR (400MHz, DMSO-d 6, 70 ℃ C.) delta: 9.60(s,1H, NH),8.04(d, J ═ 8.0Hz,2H, ArH),7.97(d, J ═ 4.0Hz,2H, ArH),7.77(d, J ═ 8.0Hz,2H, ArH),7.72-7.44(m,2H, ArH),8.18(d, J ═ 4.0Hz,1H, pyrimidane-H), 6.27(s,1H, pyrimidane-H), 3.42(s,3H, CH ═ 4.0Hz,1H, pyrimidane-H), 3.42(s,3H, CH ═ 8.0Hz, pyrimidane-H), and pharmaceutically acceptable salts thereof 3 )。 13 C NMR(400MHz，DMSO–d 6 ,CH 3 COCH 2 CH 3 )δ：161.2(d,J＝264Hz),159.9(d,J＝24Hz),157.3(d,J＝24Hz),156.9,149.5,142.0,137.3(t,J＝36Hz),133.4,132.5,128.0,125.5,119.5(d,J＝136Hz),116.4(t,J＝64Hz),111.4,111.1(d,J＝28Hz),110.9(d,J＝28Hz),105.4,98.8,37.2。HRMS(ESI + ):m/z calcd for C 25 H 16 F 2 N 6 [M-Na] + 438.1405,found 461.1291。HPLC:t R ＝7.12min,99.2％。
Compound 2: r 1 Is CH 2 CH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000042
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 242.5-242.7 ℃. 1 H NMR(400MHz,CDCl 3 –d 3 )δ8.06(s,1H,NH),7.83(d,J＝8.0Hz,2H,ArH),7.71(d,J＝8.0Hz,2H,ArH),5.72-8.03(m,6H,ArH),7.31(m,1H,pyrimidine-H),7.29(m,1H,pyrimidine-H),3.91(m,2H,CH 2 )，1.30(m,3H,CH 3 )。 13 C NMR(103MHz，DMSO–d 6 ,CH 3 COCH 2 CH 3 )δ：162.1,161.3(d,J＝20Hz),159.3,158.8(d,J＝24Hz),158.4,157.4,145.6,141.9,139.9,133.5,128.3,120.0,119.1,118.4,111.9,102.1,96.1,44.6,13.0。HRMS(ESI + ):m/z calcd for C 26 H 18 F 2 N 6 [M-Na] + 452.1561,found 475.1456。HPLC:t R ＝8.03min,97.4％。
Compound 3: r 1 Is CH 2 CH 2 CH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000051
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 228.5-229.1 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.26(s,1H,NH),8.36(d,J＝8.0Hz,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝16.0Hz,4H,ArH),7.88(s,4H,ArH),7.32(dd,J＝8.0Hz,J＝16.0Hz,2H,ArH),7.03(d,J＝8.0Hz,1H,pyrimidine-H),3.88(m,2H,CH 2 ),1.65(m,2H,CH 2 ),0.94(m,3H,CH 3 ). 13 C NMR(103MHz，DMSO–d 6 ,)δ：163.4,160.3,157.8,152.3,148.7(d，J＝13Hz),141.7(t,J＝50Hz),133.5，133.0,128.3，121.2，120.4,120.0，119.0，117.2，114.3，112.1，111.4，105.5，97.0，52.2，21.2，11.0。HRMS(ESI + ):m/z calcd for C 27 H 20 F 2 N 6 [M-Na] + 466.1718,found 489.1610。HPLC:t R ＝8.64min,98.0％。
Compound 4: r 1 Is CH 2 CH 2 CH 2 CH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000052
the operation is the same as above. A white powdery solid; the yield is 95%; melting point: 215.3-216.1 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.2(s,1H,NH),8.35(d,J＝4.0Hz,1H,pyrimidine-H)，8.03(dd,J＝8.0Hz,J＝16.0Hz,4H,ArH),7.86(s,4H,ArH)7.32(dd,J＝8.0Hz,J＝28.0Hz,2H,ArH),7.02(d,J＝4.0Hz,1H,pyrimidine-H),3.94-3.89(m,2H,CH 2 ),1.63-1.59(m,2H,CH 2 ),1.41-1.18(m,2H,CH 2 ),0.91-0.84(m,3H,CH 3 ). 13 C NMR(103MHz，DMSO–d 6 ,)δ：163.4,160.2，157.7,151.8，147.9,142.0，141.7,133.5，133.0，128.3，121.7，120.8，119.9，118.9，117.0，114.2，111.3，105.8，97.0，50.7，29.9，19.5，14.0。HRMS(ESI + ):m/z calcd for C 28 H 22 F 2 N 6 [M-H] + 480.1874,found 481.1940。HPLC:t R ＝9.30min,100.0％。
Compound 5: r 1 Is CH 2 CH(CH 3 ) 2 ，R 2 Is H, and the structural formula is:
Figure BDA0002835660960000061
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 229.1-229.8 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.1(s,1H,NH),8.35(d,J＝8.0Hz,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝20.0Hz,4H,ArH),7.89(s,4H,ArH)，7.33(dd,J＝8.0Hz,J＝20.0Hz,2H,ArH),7.07(d,J＝8.0Hz,1H,pyrimidine-H),3.76(d,J＝8.0Hz,2H,CH 2 ),1.92(m,1H,CH),0.93(m,6H,CH 3 ). 13 C NMR(103MHz，DMSO–d 6 ,)δ：163.8,160.2(d,J＝5Hz),157.7(d,J＝5Hz),152.4,148.6(t，J＝37Hz),133.5，128.3，120.5(d,J＝14Hz)，120.0，119.0，117.1，114.3，112.1，111.4，105.5，97.3，57.4，30.3(d,J＝31Hz)，28.2，19.8.HRMS(ESI + ):m/z calcd for C 28 H 22 F 2 N 6 [M-H] + 480.1874,found 481.1940。HPLC:t R ＝9.17min,97.75％。
Compound 6: r is 1 Is CH (CH) 3 ) 2 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000062
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 248.2-249.3 deg.C. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.16(s,1H,NH),8.37(d,J＝8.0Hz,1H,pyrimidine-H)，8.06(dd,J＝8.0Hz,J＝12.0Hz,4H,ArH),7.88(s,2H,ArH),7.24(dd,J＝8.0Hz,J＝32.0Hz,2H,ArH),7.02(d,J＝8.0Hz,1H,pyrimidine-H),4.74(m,1H,CH),1.24(m,6H,CH 3 ). 13 C NMR(103MHz，DMSO–d 6 ,CH 3 COCH 2 CH 3 )δ：163.3,161.1,158.6,152.2,148.7,142.3,141.6,133.5，132.9,128.3，121.1，120.2(d,J＝14Hz),120.1，119.0，117.2，114.3，112.2，111.4，105.4，97.2，51.0，21.4.HRMS(ESI + ):m/z calcd for C 27 H 20 F 2 N 6 [M-Na] + 466.1718,found 489.161。HPLC:t R ＝8.35min,96.88％。
Compound 7: r 1 Is CH 2 CH(CH 3 )CH 2 CH 3 ，R 2 Is H, the structural formula is：
Figure BDA0002835660960000071
The operation is the same as above. A white powdery solid; the yield is 82 percent; melting point: 224.9-225.8 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.14(s,1H,NH),8.35(d,J＝4.0Hz,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝24.0Hz,4H,ArH),7.87(s,4H,ArH),7.31(d,J＝8.0Hz,J＝32.0Hz,2H,ArH),7.21(d,J＝8.0Hz,1H,pyrimidine-H),3.88-3.75(m,2H,CH 2 ),1.67-1.45(m,2H,CH 2 ),1.28-1.16(m,1H,CH),0.95-0.78(m,6H,CH 3 ). 13 C NMR(103MHz，DMSO–d 6 )δ：163.8,160.3(dd,J＝6Hz,J＝3Hz),157.8(dd,J＝6Hz,J＝4H),152.8,148.2,141.6(t,J＝12Hz),133.5,128.3，121.2,120.4，120.2，119.0,117.3，114.4，112.4，112.1，111.5,105.2，97.2，56.2，34.6,26.4,16.5,11.5.HRMS(ESI + ):m/z calcd for C 27 H 20 F 2 N 6 [M-H] + 494.2031,found 495.2097。HPLC:t R ＝9.83min,99.30％。
Compound 8: r is 1 Is cyclopentyl, R 2 Is H, the structural formula is:
Figure BDA0002835660960000072
the operation is the same as above. A white powdery solid; the yield is 87%; melting point: 265.9-266.9 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.17(s,1H,NH),8.37(m,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝24.0Hz,4H,ArH),7.89(d,J＝8Hz,4H,ArH),7.24(d,J＝20Hz,2H,ArH),7.03(m,1H,pyrimidine-H),5.01-4.68(m,1H,CH),2.10-1.45(m,8H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d)δ：163.7,161.0,158.5,152.4,149.0,141.6,133.5,128.4，120.2,119.0，117.3，116.3,114.4,112.2，112.0,111.6，105.2，97.5，60.2，30.0,22.8。HRMS(ESI + ):m/z calcd for C 29 H 22 F 2 N 6 [M-H] + 492.1874,found 419.1937。HPLC:t R ＝9.22min,99.63％。
Compound 9: r 1 Is cyclopentyl ethyl, R 2 Is H, the structural formula is:
Figure BDA0002835660960000081
the operation is the same as above. A white powdery solid; the yield is 82 percent; melting point: 226.5-228.0 deg.C. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d,)δ11.15(s,1H,NH),8.36(d,J＝8Hz,1H,pyrimidine-H)，8.09-7.98(m,4H,ArH),7.92-7.87(m,4H,ArH),7.34(dd,J＝8Hz,J＝16Hz,2H,ArH),7.05(d,J＝4Hz,1H,pyrimidine-H),3.87(d,J＝8Hz,2H),2.21-2.13(m,1H,CH),1.76-1.17(m,8H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d,)δ：163.4,160.3(d,J＝5Hz),157.8(d,J＝5Hz,),152.4,148.8,141.7(t,J＝36Hz),133.5,133.0,128.3，121.2,120.4(d,J＝14Hz)，120.0,119.0,117.2，114.3，112.1，111.4，105.4，97.1，55.0，38.4,30.2,25.1。HRMS(ESI + ):m/z calcd for C 27 H 20 F 2 N 6 [M-H] + 506.2031,found507.2095。HPLC:t R ＝10.20min,98.43％。
Compound 10: r 1 Is CH (CH) 3 )CH 2 CH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000082
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 226.7-227.9 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d,)δ11.18(s,1H,NH),8.36(d,J＝4Hz,1H,pyrimidine-H)，8.09-7.99(m,4H,ArH),7.93-7.87(m,4H,ArH),7.23(dd,J＝8Hz,J＝16Hz,2H,ArH),7.01(d,J＝8Hz,1H,pyrimidine-H),4.51-4.46(m,1H,CH),1.75-1.40(m,2H,CH 2 ),1.00-0.92(m,6H,CH 3 ). 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d)δ：163.5,161.2,158.7,152.6,149.0,142.5,141.6,133.5,132.9，128.3，121.1,119.0，117.4，114.5，112.2,111.6，105.4，97.4，56.6，28.0,17.6,11.2。HRMS(ESI + ):m/z calcd for C 28 H 22 F 2 N 6 [M-H] + 480.1874,found 481.1933。HPLC:t R ＝8.90min,99.85％。
Compound 11: r 1 Is CH 2 CH 2 OH，R 2 Is H, the structural formula is:
Figure BDA0002835660960000091
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 258.0-259.0 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d,)δ11.14(s,1H,NH),8.35(d,J＝8Hz,1H,pyrimidine-H)，8.08-7.98(m,4H,ArH),7.91-7.85(m,4H,ArH),7.34(dd,J＝8Hz,J＝16Hz,2H,ArH),7.03(d,J＝8Hz,1H,pyrimidine-H),4.03-3.98(m,2H,CH 2 ),3.70-3.69(m,2H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d,CH 3 COCH 2 CH 3 )δ：163.9,160.2,157.8,152.2,148.2,142.3,140.8,133.5,133.0，128.3，120.6,119.0，117.2，114.3，112.1,105.5，97.6，59.2，53.1。HRMS(ESI + ):m/z calcd for C 26 H 18 F 2 N 6 O[M-H] + 468.1510,found 469.1574。HPLC:t R ＝6.28min,97.50％。
Compound 12: r is 1 Is CH 2 CN，R 2 Is H, the structural formula is:
Figure BDA0002835660960000092
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 258.0-259.0 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d,)δ10.63(s,1H,NH),8.45-8.21(m,1H,pyrimidine-H)，8.07-7.99(m,4H,ArH),7.91(d,J＝8Hz，4H,ArH),7.83-7.35(m,2H,ArH),6.92-6.11(m,1H,pyrimidine-H),6.11(s,2H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d)δ：162.0,160.8,156.9,144.0,141.7,133.5,128.4,120.1,119.9,119.7,119.0，117.0，116.6,114.1,112.2，111.3，104.2，97.9，65.5，60.2。HRMS(ESI + ):m/z calcd for C 26 H 15 F 2 N 7 [M-Na] + 463.1357,found 486.1237。HPLC:t R ＝6.22min,99.68％。
Compound 13: r 1 Is CH 2 OCH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000101
the operation is the same as above. A white powdery solid; the yield is 65%; melting point: 238.6-239.2 ℃. 1 H NMR(400MHz,DMSO–d 6 ,)δ9.92(s,1H,NH),8.25(m,1H,pyrimidine-H)，8.04(dd,J＝8Hz，J＝20Hz，4H,ArH),7.93-7.22(m,6H,ArH),6.69(m,1H,pyrimidine-H),5.18(s,2H,CH 2 )1.20(s,3H,CH 3 )。 13 C NMR(103MHz，DMSO–d 6 ,)δ：174.8,162.7,159.1,158.7,158.6,145.4,141.9,133.5,133.0,130.0,128.3,119.9,119.1,118.5,111.9,111.7,102.4,97.4,55.6,29.5。HRMS(ESI + ):m/z calcd forC 26 H 18 F 2 N 6 O[M-Na] + 468.1510,found 491.1394。HPLC:t R ＝7.30min,96.70％。
Compound 14: r 1 Is CH 2 CH 2 F，R 2 Is H, the structural formula is:
Figure BDA0002835660960000102
the operation is the same as above. A white powdery solid; the yield is 75%; melting point: 232.8-233.4 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.04(s,1H,NH),8.38-8.37(m,1H,pyrimidine-H)，8.12-7.84(m,8H,ArH),7.42-7.23(m,2H,ArH),7.02-7.00(m,1H,pyrimidine-H),4.76(dd,J＝16Hz,J＝32Hz,2H,CH 2 ),4.30(d,J＝28Hz,2H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d)δ：163.8,160.4,157.9,152.9,149.7,141.7,133.5,128.3,120.4,119.9,119.0,117.1,114.2,112.1,111.7,111.3,105.3,97.2,83.1,81.4.。HRMS(ESI + ):m/z calcd for C 26 H 17 F 3 N 6 [M-H] + 470.1467,found 471.1541。HPLC:t R ＝7.20min,98.72％。
Compound 15: r 1 Is CH 2 CHF 2 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000111
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 237.5-237.8 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.05(s,1H,NH),8.39-8.38(m,1H,pyrimidine-H)，8.05-7.80(m,8H,ArH),7.36-7.31(m,2H,ArH),6.95-6.93(m,1H,pyrimidine-H),4.62-4.50(m,2H,CH 2 ),4.09-3.98(m,2H,CH 2 ),2.10-2.00(m,2H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d)δ：164.0,163.0,160.5,158.0,156.2,154.5,153.4,152.3,143.2,141.7,141.0,133.4,128.3,120.0,119.0,117.1,114.8,114.2,112.1,111.3,104.6,97.3,51.1。HRMS(ESI + ):m/z calcd for C 26 H 16 F 4 N 6 [M-H] + 488.1373,found489.1440。HPLC:t R ＝7.57min,96.16％。
Compound 16: r 1 Is CH 2 CH 2 CH 2 F，R 2 Is H, the structural formula is:
Figure BDA0002835660960000112
the operation is the same as above.A white powdery solid; the yield is 88%; melting point: 240.4-241.0 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ10.74(s,1H,NH),8.40-8.38(m,1H,pyrimidine-H)，8.05-7.97(m,4H,ArH),7.87-7.84(m,4H,ArH),7.33(m,2H,ArH),6.99(m,1H,pyrimidine-H),6.32(dd,J＝56Hz,J＝52Hz,1H,CH),4.44-4.41(m,2H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CH 3 COCH 2 CH 3 )δ：163.3,160.3,157.9,153.6,150.0,142.6,141.7,133.5,128.3，120.7(dd,J＝15Hz,J＝56Hz),120.0，119.0，117.1,114.3，112.1，111.4，105.2，96.7，82.2(dd,J＝51Hz,J＝110Hz)，47.2(d,J＝35Hz),28.8。HRMS(ESI + ):m/z calcd for C 27 H 19 F 3 N 6 [M-H] + 484.1629,found 485.1696。HPLC:t R ＝7.83min,97.66％。
Compound 17: r 1 Is CH 2 CH 2 CH 2 OH，R 2 Is H, the structural formula is:
Figure BDA0002835660960000121
the operation is the same as above. A white powdery solid; the yield is 65%; melting point: 209.4-210.0 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.11(s,1H,NH),8.38(d,J＝8Hz,1H,pyrimidine-H)，8.07-7.85(m,8H,ArH),7.34-7.31(m,2H,ArH),6.95(m,d,J＝8Hz,1H,pyrimidine-H),4.06-3.92(m,2H,CH 2 ),3.54-3.51(m,2H,CH 2 ),1.83-1.79(m,2H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 ,CF 3 COOH-d)δ：163.3,160.3,158.0,153.0,149.7,142.7,141.7,133.5,132.9,128.3,120.9,120.2,119.0,117.4,114.5,112.1,105.1,96.8,57.8,48.0,30.9。HRMS(ESI + ):m/z calcd for C 27 H 20 F 2 N 6 O[M-H] + 482.1667,found 483.1738。HPLC:t R ＝6.56min,99.78％。
Compound 18: r is 1 Is CH 2 CH 2 CH 2 Cl，R 2 Is H, the structural formula is:
Figure BDA0002835660960000122
the operation is the same as above. A white powdery solid; the yield is 80%; melting point: 217.4-218.6 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.11(s,1H,NH),8.39(d,J＝8Hz,1H,pyrimidine-H)，8.12-7.79(m,8H,ArH),7.31(s,2H,ArH),6.92(d,J＝8Hz,1H,pyrimidine-H),4.09-3.97(m,2H,CH 2 ),3.75-3.71(m,2H,CH 2 ),2.13-2.11(m,2H,CH 2 )。 13 C NMR(103MHz，DMSO–d 6 )δ：163.1,160.4(d,J＝5Hz),157.9(d,J＝5Hz),153.9,151.1,143.0,141.7,141.0,133.4,128.3，120.3,118.9，117.4,114.5，112.5,112.1(d,J＝56Hz),104.8，96.6,48.1(d,J＝18Hz),42.7(d,J＝54Hz),30.49(d,J＝52Hz)。HRMS(ESI + ):m/z calcd for C 27 H 19 ClF 2 N 6 [M-H] + 500.1328,found 501.1404。HPLC:t R ＝8.33min,97.50％。
Compound 19: r 1 Is CH 2 CHCH 2 ，R 2 Is H, and the structural formula is:
Figure BDA0002835660960000131
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 233.2-233.9 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.07(s,1H,NH),8.37(d,J＝8Hz,1H,pyrimidine-H)，8.06-7.79(m,8H,ArH),7.33(s,2H,ArH),6.86(d,J＝8Hz,1H,pyrimidine-H),6.05-5.89(m,1H,CH＝CH 2 ),5.44-5.26(m,2H,CH＝CH 2 ),4.59-4.53(m,2H,CH 2 ). 13 C NMR(103MHz，DMSO–d 6 )δ：163.2,160.4,157.9,154.6,153.8,150.7,142.9,141.7,140.8,133.4,133.4,132.9,131.8,128.3，120.8,119.5，119.0,117.4,114.5，112.1,111.6,104.8，97.2,53.2。HRMS(ESI + ):m/z calcd for C 27 H 18 F 2 N 6 [M-H] + 464.1561,found 485.1569。HPLC:t R ＝8.10min,97.55％。
Compound 20: r 1 Is CH 2 CH(OH)CH 2 (OH)，R 2 Is H, the structural formula is:
Figure BDA0002835660960000132
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 233.2-233.9 ℃. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.16(s,1H,NH),8.35(d,J＝8.0Hz,1H,pyrimidine-H),8.07(d,J＝8.0Hz,2H,ArH),7.98(d,J＝12.0Hz,2H,ArH),7.81-7.81(m,3H,ArH),7.62-7.45(m,1H,ArH),7.33(dd,2H,J＝8Hz,J＝16Hz,ArH),7.00(d,J＝8.0Hz,1H,pyrimidine-H),4.48-3.70(m,4H,CH 2 OH-CH 2 OH),3.48-3.34(m,2H,CH 2 N)。 13 C NMR(400MHz，DMSO–d 6 )δ：164.0,160.2,157.7,152.2,148.2,142.3,141.8,140.7,134.6,133.8,133.5,133.0,128.3,121.1,120.5,119.0,117.3,112.0,105.5,97.8,70.6,63.6,54.1。HRMS(ESI + ):m/z calcd for C 27 H 20 F 2 N 6 O 2 [M-H] + 498.1616,found 499.1689。HPLC:t R ＝5.78min,98.53％。
Compound 21: r is 1 Is CHCH (OH) CH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000141
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 248.7-249.2 deg.C. 1 H NMR(400MHz,DMSO–d 6 ,CF 3 COOH-d)δ11.16(s,1H,NH),8.33(d,J＝8.0Hz,1H,pyrimidine-H),8.19-7.80(m,8H,ArH),7.34-7.29(m,2H,ArH),7.01(d,J＝8.0Hz,1H,pyrimidine-H),4.15-3.67(m,3H,CH 2 -CHOH),1.17-1.13(m,3H,CH 3 )。 13 C NMR(400MHz，DMSO–d 6 )δ：163.8,160.2,157.8,152.8,149.0,142.6,141.8,140.6,133.5,128.3,121.0,120.2,119.0,117.5,114.6,112.0,111.8,111.6,105.1,97.8,65.4,57.5,21.4。HRMS(ESI + ):m/z calcd for C 27 H 20 F 2 N 6 O[M-H] - 482.1667,found 481.1859。HPLC:t R ＝6.67min,97.45％。
Compound 22: r 1 Is COCH 3 ，R 2 Is H, the structural formula is:
Figure BDA0002835660960000142
the operation is the same as above. A white powdery solid; the yield is 93 percent; melting point: 245.9-246.4 ℃. 1 H NMR(400MHz,DMSO–d 6 )δ10.21(s,1H,NH),8.13-8.02(dd,J＝8.0Hz,J＝28.0Hz,4H,ArH),7.99(d,J＝8.0Hz,2H,ArH),7.38-7.30(dd,J＝8.0Hz,J＝16.0Hz,4H,ArH),8.57(d,J＝4.0Hz,1H,pyrimidine-H),7.60(d,J＝4.0Hz,1H,pyrimidine-H),2.21(s,3H,CH 3 )。 13 C NMR(400MHz，DMSO–d 6 )δ：171.2,162.8,160.7，160.4(d,J＝24Hz),159.6,159.0,158.0(d,J＝20Hz),144.7,141.9(t,J＝40Hz),141.6,133.6,132.9,128.4,119.6,119.0,118.5,112.2,105.1,102.9,25.0。HRMS(ESI + ):m/z calcd for C 26 H 16 F 2 N 6 O[M-Na] + 466.1354,found 489.1248。HPLC:t R ＝6.78min,98.44％。
Compound 23: r is 1 Is H, R 2 Is CH 3 The structural formula is as follows:
Figure BDA0002835660960000151
the operation is the same as above. A white powdery solid; the yield is 95%; melting point: 209.4-210.3 ℃. 1 H NMR(400MHz,DMSO–d 6 )δ9.58(s,1H,NH),8.62(s,1H,NH),8.08-7.98(dd,J＝8.0Hz,J＝20.0Hz,4H,ArH),7.79(d,J＝8.0Hz,2H,ArH),7.65-7.36(dd,J＝12.0Hz,4H,ArH),7.99(s,1H,pyrimidine-H),2.17(s,3H,CH 3 )。 13 C NMR(400MHz，DMSO–d 6 )δ：160.8,160.7(d,J＝24Hz),158.3(d,J＝24Hz),158.1,156.5,146.0,142.2,138.3(t,J＝40Hz),133.5,133.0,128.1,120.1,119.1,118.1,117.3(t,J＝64Hz),111.6,111.2(d,J＝28Hz),111.0(d,J＝28Hz),107.2,101.6,13.75。HRMS(ESI + ):m/z calcd for C 25 H 16 F 2 N 6 [M-H] + 438.1405,found 439.1472。HPLC:t R ＝6.82min,98.24％。
Example 2: anti-HIV biological Activity assay
The anti-HIV virus activity at the cellular level in vitro was determined by the Rega drug research institute of Katholleke university, Belgium, and mainly included: inhibiting activity and cytotoxicity on HIV-infected MT-4 cells. The method comprises the following steps: the compound was allowed to infect HIV in MT-4 cells at different times, the protective effect of the drug on HIV-mutagenized cytopathic effects was determined by MTT method, and the half effective concentration EC required to protect 50% of the cells from HIV-induced cytopathic effects was calculated 50 Toxicity 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 culture 50 ) And calculating the selectivity index SI ═ CC 50 /EC 50 。
The material and the method are as follows:
the anti-HIV activity of each compound was monitored by the efficiency of the drug's inhibition of the cytopathic effects of 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 in DMSO or water, diluting in phosphate buffered saline solution, and mixing 3 × 10 5 MT-4 cells were pre-incubated with 100. mu.L of each compound in different concentrations in this solution at 37 ℃ for 1h, and then 100. mu.L of an appropriate viral diluent was added to the compound and the cells were incubated at 37 ℃ for 1 h. After three washes, the cells were resuspended in culture medium with or without compound, respectively. Cells were then incubated at 5% CO 2 Incubate at 37 ℃ for 7 more days in an atmosphere and replace the supplemented medium with culture medium with or without compound on the third day post infection. Repeat the procedure for each broth conditionTwice. Cytopathic effects on the virus were monitored daily with a reverse optical microscope. 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 such that the drug produces a 50% inhibition of the viral cytopathic effect while having no direct toxicity to the cells (CC) 50 ) And (4) showing. It is emphasized that, when the compounds are poorly water soluble and require DMSO to dissolve, the DMSO specific concentration is generally less than 10% relative to water (the final concentration of DMSO in the MT-4 cell culture medium is less than 2%). Since DMSO can affect the antiviral activity of the test compound, the antiviral activity of solutions containing the same concentration of DMSO should also be performed in parallel to the control blank. In addition, the final concentration of DMSO (1/1000) was much lower than the concentration required for HIV-1 replication in T cells.
The invention uses marketed drugs Nevirapine (NVP), Efavirenz (EFV) and Etravirine (ETRAvirine, ETV) as reference substances, and the result of the HIV inhibition activity of part of target compounds is shown in Table 1 (the anti-HIV activity and cytotoxicity of the compounds 1-23 in MT-4 cells).
Figure BDA0002835660960000161
TABLE 1 [a]
Figure BDA0002835660960000162
Figure BDA0002835660960000171
a All data represent the mean of at least three independent experiments; b EC 50 an effective concentration to protect 50% of the cells from viral infection;
c CC 50 the drug concentration when 50% of cells are diseased; d SI selection index, CC 50 Value and EC 50 The ratio of the values is used for judging the safety range of the drug effect.
Experimental results show that the compounds contained in the chemical general formula generally have stronger anti-HIV-1 virus activity, smaller cytotoxicity and higher selectivity index.
The present invention is not limited to the above examples.

Claims (6)

1. A biphenyl diaryl pyrimidine derivative containing an alkyl structure is characterized in that the structural formula shown in the formula (I) is as follows:
Figure DEST_PATH_IMAGE002
wherein R is 1 Is hydrogen, R 2 Is methyl.
2. The biphenyl diarylpyrimidine derivatives having an alkyl structure as claimed in claim 1, further comprising pharmaceutically acceptable salts thereof.
3. The biphenyl diarylpyrimidine derivatives with alkyl structure as claimed in claim 2, wherein the pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, citrate, fumarate or malate salts.
4. The preparation method of the biphenyl diarylpyrimidine derivatives containing alkyl structure as claimed in claim 1, which comprises the following steps:
in a solvent, compound II is in Pd (dppf) Cl 2 And carrying out Suzuki-coupling reaction under the action of cesium carbonate to obtain the compound I, wherein the reaction general formula is as follows:
Figure DEST_PATH_IMAGE004
the solvent is one or more of 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 molar ratio of the compound II to the p-cyanophenylboronic acid is 1: 1-1: 3;
the reaction temperature is 0-200 ℃;
the reaction time is 4-14 h.
5. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
6. The use of biphenyl diarylpyrimidine derivatives containing alkyl structure as claimed in claim 1 in the preparation of drugs for treating AIDS.
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