CN106008532A - Alkoxy pyrimidine-spiced 3-pyrrolidinylspirooxindole derivative and preparation method and application thereof - Google Patents
Alkoxy pyrimidine-spiced 3-pyrrolidinylspirooxindole derivative and preparation method and application thereof Download PDFInfo
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- CN106008532A CN106008532A CN201610573327.7A CN201610573327A CN106008532A CN 106008532 A CN106008532 A CN 106008532A CN 201610573327 A CN201610573327 A CN 201610573327A CN 106008532 A CN106008532 A CN 106008532A
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- Prior art keywords
- pyrrole
- alkoxypyrimidine
- splicing
- derivatives
- spirooxindole
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种烷氧基嘧啶拼接3‑吡咯螺环氧化吲哚衍生物，本发明以各种取代的烷氧基嘧啶拼接3‑烯键氧化吲哚衍生物与肌氨酸，多聚甲醛，在有机溶剂中回流，进行1,3‑偶极子3+2环加成反应，获得烷氧基嘧啶拼接3‑吡咯螺环氧化吲哚衍生物，该类骨架包含潜在的生物活性嘧啶骨架和3‑吡咯螺环氧化吲哚骨架，是一类重要的医药中间体类似物和药物分子类似物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值，本发明针对这些衍生物对三种肿瘤细胞株进行肿瘤生长抑制活性筛选，证明这些衍生物发现具有一定的抑制肿瘤细胞生长活性，可预期作为抗肿瘤药物用途。
The invention discloses an alkoxypyrimidine splicing 3-pyrrole spirooxindole derivative. The invention uses various substituted alkoxypyrimidines to splice 3-ethylenic indole derivatives and sarcosine. Polyoxymethylene, refluxed in an organic solvent, 1,3-dipole 3+2 cycloaddition reaction, to obtain alkoxypyrimidine splice 3-pyrrole spirooxindole derivatives, this type of backbone contains potential biological The active pyrimidine skeleton and the 3-pyrrole spirooxindole skeleton are an important class of pharmaceutical intermediate analogs and drug molecule analogs, which can provide a compound source for biological activity screening, and are of great importance to drug screening and the pharmaceutical industry. For application value, the present invention screens the tumor growth inhibitory activity of three tumor cell lines for these derivatives, and proves that these derivatives have a certain tumor cell growth inhibitory activity, and can be expected to be used as antitumor drugs.
Description
技术领域technical field
本发明涉及药物化学技术领域，尤其是一种烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物及其制备方法与应用。The invention relates to the technical field of medicinal chemistry, in particular to an alkoxypyrimidine splice 3-pyrrole spirooxindole derivative and a preparation method and application thereof.
背景技术Background technique
把具有生物活性基团拼接到一个分子骨架中在有机化学和医药化学中是极其重要的研究领域。(1)多官能团氧化吲哚广泛存在天然产物和合成药物分子中，其中，尤其3-吡咯螺环氧化吲哚因为具有广泛的生物活性，吸引了许多化学工作者及医药化学团队的广泛关注，例如,天然产物螺环氧化吲哚horsfiline和elacomine具有多重生物活性；重要的是，甚至非天然产物螺环氧化吲哚III和IV已被证明完全抑制tsFT210细胞，在阻断细胞分裂的G2/M期，是一种重要的非肽p53-MDM2结合抑制剂。p53-MDM2结合抑制剂是一种治疗癌症的新疗法。(2)目前上市或即将上市的抗肿瘤或抗病毒感染的药物相当多都是烷氧基嘧啶衍生而成。例如：齐多夫定(zidovudine,AZT)、ddC(双脱氧胞苷)及Lamivudine(拉米夫定)等是HIV逆转录酶抑制剂；烷氧基嘧啶化合物V-X为药物分子或具有广泛的生物活性分子。鉴于3-烯键氧化吲哚骨架化合物和烷氧基嘧啶骨架化合物具有潜在的生物活性。因此，把烷氧基嘧啶骨架拼接到3-烯键氧化吲哚骨架化合物上，合成一系列新的潜在多活性官能团取代的嘧啶拼接3-吡咯螺环氧化吲哚衍生物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。(如附图7所示)。The splicing of biologically active groups into a molecular scaffold is an extremely important research area in organic and medicinal chemistry. (1) Multifunctional oxindole widely exists in natural products and synthetic drug molecules, among which, especially 3-pyrrole spirooxindole has attracted extensive attention of many chemists and medicinal chemistry teams because of its wide range of biological activities , for example, the natural products spirooxindole horsfiline and elacomine have multiple biological activities; importantly, even the non-natural products spirooxindole III and IV have been shown to completely inhibit tsFT210 cells, in blocking cell division G2/M phase, is an important non-peptide p53-MDM2 binding inhibitor. Inhibitors of p53-MDM2 binding are a novel therapy for cancer. (2) Many anti-tumor or anti-viral drugs currently on the market or to be on the market are derived from alkoxypyrimidines. For example: zidovudine (zidovudine, AZT), ddC (dideoxycytidine) and Lamivudine (lamivudine) are HIV reverse transcriptase inhibitors; alkoxypyrimidine compounds V-X are drug molecules or have a wide range of biological active molecule. In view of the potential biological activity of 3-alkene oxide indole skeleton compound and alkoxypyrimidine skeleton compound. Therefore, the alkoxypyrimidine skeleton is spliced onto the 3-ene bonded oxindole skeleton compound, and a series of new potential multi-active functional group substituted pyrimidine spliced 3-pyrrole spirooxindole derivatives can be synthesized for biological activity. Screening provides a compound source, which has important application value for drug screening and pharmaceutical industry. (As shown in accompanying drawing 7).
发明内容Contents of the invention
本发明的目的是：提供一种烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。The object of the present invention is to provide a kind of alkoxy pyrimidine splicing 3-pyrrole spiro-epoxy indole derivative and its preparation method and application. It is a class of important pharmaceutical intermediate analogs and drug molecule analogs. Drug screening and pharmaceutical industry have important application value, and its synthesis method is very economical and simple.
本发明是这样实现的：一种烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物，该化合物具有如下通式(Ⅰ)的结构：The present invention is achieved in this way: an alkoxy pyrimidine splice 3-pyrrole spiro-epoxy indole derivative, the compound has the following structure of general formula (I):
式中，R1为烷基或氢或苯基；R2为烷基或卤素或H；R3为烷基；R4为卤素或烷氧基或H；R5为卤素或烷氧基。 In the formula, R1 is alkyl or hydrogen or phenyl; R2 is alkyl or halogen or H; R3 is alkyl ; R4 is halogen or alkoxy or H ; R5 is halogen or alkoxy.
烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物的制备方法，由各种取代的烷氧基嘧啶拼接3-烯键氧化吲哚衍生物与肌氨酸及多聚甲醛，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物。The preparation method of alkoxypyrimidine splicing 3-pyrrole spiroepoxide indole derivatives, splicing 3-alkene oxide indole derivatives, sarcosine and paraformaldehyde by various substituted alkoxypyrimidines, molar The ratio of 2:3:6 is refluxed in an organic solvent, and a 1,3-dipole 3+2 cycloaddition reaction is performed to obtain an alkoxypyrimidine splice 3-pyrrole spirooxindole derivative.
所述的烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物的制备方法，其特征在于：所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。The preparation method of the alkoxypyrimidine splice 3-pyrrole spiroepoxide indole derivative is characterized in that: the organic solvent is acetonitrile, methanol, ethanol, propanol, isopropanol, ether, tetrahydrofuran, Benzene, toluene, xylene, mesitylene, dioxane, ethylene glycol dimethyl ether, isopropyl ether, chloroform, methylene chloride, or nitrobenzene.
所述的烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物的制备方法，其特征在于：各种取代的烷氧基嘧啶拼接3-烯键氧化吲哚衍生物与肌氨酸，多聚甲醛，按摩尔比为2:3:6的比例，在有机溶剂中的反应温度为50-100℃，反应时间为5-20小时。The preparation method of the described alkoxypyrimidine splicing 3-pyrrole spiroepoxide indole derivatives is characterized in that: various substituted alkoxypyrimidines are splicing 3-olefinic indole derivatives and sarcosine, For paraformaldehyde, the molar ratio is 2:3:6, the reaction temperature in the organic solvent is 50-100°C, and the reaction time is 5-20 hours.
所述的烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物，其特征在于：在制备防治肿瘤疾病药物中的应用。The alkoxypyrimidine spliced 3-pyrrole spiroepoxide indole derivative is characterized in that it is used in the preparation of drugs for preventing and treating tumor diseases.
本发明的反应原理如下：The reaction principle of the present invention is as follows:
式中，R1为烷基或氢或苯基；R2为烷基或卤素或H；R3为烷基；R4为卤素或烷氧基或H；R5为卤素或烷氧基。 In the formula, R1 is alkyl or hydrogen or phenyl; R2 is alkyl or halogen or H; R3 is alkyl ; R4 is halogen or alkoxy or H ; R5 is halogen or alkoxy.
通过采用上述技术方案，以各种取代的烷氧基嘧啶拼接3-烯键氧化吲哚衍生物与肌氨酸及多聚甲醛，按特定比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物，该类骨架包含多重生物活性的3-吡咯螺环氧化吲哚骨架拼接到烷氧基嘧啶骨架，可以为生物活性筛选提供化合物源，对多靶点多用途药的筛选和制药行业具有重要的应用价值。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。By adopting the above-mentioned technical scheme, various substituted alkoxypyrimidines are used to splice 3-ene bonded oxide indole derivatives with sarcosine and paraformaldehyde, and reflux in an organic solvent according to a specific ratio to perform 1,3-dipolar 3+2 cycloaddition reaction to obtain alkoxypyrimidine spliced 3-pyrrole spirooxindole derivatives, which contain multiple biologically active 3-pyrrole spirooxindole skeletons spliced into alkoxy The pyrimidine skeleton can provide a compound source for biological activity screening, and has important application value for the screening of multi-target multi-purpose drugs and the pharmaceutical industry. The invention has simple and easy operation, cheap and easy-to-obtain raw material synthesis, can be carried out in various organic solvents, has good air stability, wide applicability, and good compatibility with various substituents.
附图说明Description of drawings
附图1及附图2为本发明的实施例1的化合物3a谱图数据；Accompanying drawing 1 and accompanying drawing 2 are the compound 3a spectrogram data of the embodiment 1 of the present invention;
附图3及附图4为本发明的实施例1的化合物3b谱图数据；Accompanying drawing 3 and accompanying drawing 4 are the spectrum data of compound 3b of embodiment 1 of the present invention;
附图5及附图6为本发明的实施例1的化合物3c谱图数据；Accompanying drawing 5 and accompanying drawing 6 are the spectrum data of compound 3c of embodiment 1 of the present invention;
附图7为本发明的化合物的合成应用；Accompanying drawing 7 is the synthetic application of compound of the present invention;
附图8为本发明的实施例1的化合物3g,3j和3o单晶图。Accompanying drawing 8 is the single crystal diagram of compounds 3g, 3j and 3o of Example 1 of the present invention.
具体实施方式detailed description
本发明的实施例1：在反应管中依次加入89.1mg双甲氧基嘧啶拼接3-烯键氧化吲哚1a(0.3mmol)，53.4mg肌氨酸2(0.6mmol)和27.0mg多聚甲醛(0.9mmol)和8.0mL甲苯溶液，加热回流反应12h，直接上样经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯)＝3:1)纯化得94.5mg化合物3a，白色固体，熔点：107.5-109.3℃；产率89％，>20:1dr。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.48(s,3H),2.63(d,J＝8.0Hz,1H),3.08-3.10(m,1H),3.14-3.17(m,4H),3.69-6.70(m,1H),3.78(s,6H),4.14-4.18(m,1H),6.62(d,J＝8.0Hz,1H),6.76-6.79(m,1H),7.03-7.09(m,2H),8.04(s,1H)；13C NMR(CDCl3,100MHz)δ:26.3,42.4,44.8,53.9,58.3,59.7,66.8,102.3,107.2,121.7,124.1,127.9,131.4,143.4,154.7,168.3,168.4,180.4；HRMS(ESI-TOF)m/z:Calcd.for C19H22N4NaO3[M+Na]+:377.1590；Found:377.1591.Embodiment 1 of the present invention: Add 89.1 mg of bismethoxypyrimidine splice 3-ethylenic indole 1a (0.3 mmol), 53.4 mg of sarcosine 2 (0.6 mmol) and 27.0 mg of paraformaldehyde in the reaction tube (0.9mmol) and 8.0mL toluene solution, heated to reflux for 12h, directly loaded and purified by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = 3:1) to obtain 94.5 mg of compound 3a , white solid, melting point: 107.5-109.3°C; yield 89%, >20:1dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.48 (s, 3H), 2.63 (d, J = 8.0Hz, 1H), 3.08-3.10 (m, 1H), 3.14-3.17(m,4H),3.69-6.70(m,1H),3.78(s,6H),4.14-4.18(m,1H),6.62(d,J＝8.0Hz,1H),6.76-6.79( m,1H),7.03-7.09(m,2H),8.04(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:26.3,42.4,44.8,53.9,58.3,59.7,66.8,102.3,107.2, 121.7, 124.1, 127.9, 131.4, 143.4, 154.7, 168.3, 168.4, 180.4; HRMS (ESI-TOF) m/z: Calcd.for C 19 H 22 N 4 NaO 3 [M+Na] + :377.1590; Found: 377.1591.
化合物3b-3t的制备方法同化合物1，投料比与化合物3a相同，可得到化合物3b-3t，反应产率和dr值见表1和表2，但需强调的是本发明的化合物不限于表1和表2所表示的内容。The preparation method of compound 3b-3t is the same as that of compound 1, and the feeding ratio is the same as that of compound 3a. Compound 3b-3t can be obtained. The reaction yield and dr value are shown in Table 1 and Table 2, but it should be emphasized that the compound of the present invention is not limited to Table 2. 1 and Table 2 show the content.
表1为烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物的化学结构及其体外活性测试结果Table 1 is the chemical structure and in vitro activity test results of alkoxypyrimidine splice 3-pyrrole spiroepoxide indole derivatives
表2为烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物的化学结构及其体外活性测试结果Table 2 is the chemical structure and in vitro activity test results of alkoxypyrimidine splice 3-pyrrole spiroepoxide indole derivatives
本实施例制备化合物3b:白色固体，产率79％；18:1dr；熔点：82.9-84.6℃；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.93-2.95(m,3H),3.62-3.65(m,2H),3.84(s,7H),4.27-4.32(m,2H),6.76-6.79(m,1H),6.85-6.86(m,1H),6.94(d,J＝8.0Hz,1H),7.02-7.06(m,1H),8.14(s,1H),9.30(brs,1H)；13C NMR(CDCl3,100MHz)δ:29.7,42.7,43.2,54.1,57.9,58.9,109.9,122.0,124.2,128.7,130.9,141.0,155.5,168.1；HRMS(ESI-TOF)m/z:Calcd.forC18H20N4NaO3[M+Na]+:363.1433；Found:363.1430.Compound 3b prepared in this example: white solid, yield 79%; 18: 1dr; melting point: 82.9-84.6°C; NMR and high-resolution mass spectrometry results are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.93- 2.95(m,3H),3.62-3.65(m,2H),3.84(s,7H),4.27-4.32(m,2H),6.76-6.79(m,1H),6.85-6.86(m,1H), 6.94 (d, J=8.0Hz, 1H), 7.02-7.06 (m, 1H), 8.14 (s, 1H), 9.30 (brs, 1H); 13 C NMR (CDCl 3 , 100MHz) δ: 29.7, 42.7, 43.2, 54.1, 57.9, 58.9, 109.9, 122.0, 124.2, 128.7, 130.9, 141.0, 155.5, 168.1; HRMS (ESI-TOF) m/z: Calcd.forC 18 H 20 N 4 NaO 3 [M+Na] + :363.1433; Found: 363.1430.
本实施例制备化合物3c:白色固体，产率90％；>20:1dr；熔点：144.4-145.8℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.56(s,3H),2.80(d,J＝9.6Hz,1H),3.11-3.19(m,1H),3.25(d,J＝9.6Hz,1H),3.78(s,7H),4.30-4.35(m,1H),4.74(d,J＝15.6Hz,1H),5.04(d,J＝15.6Hz,1H),6.53(d,J＝7.9Hz,1H),6.78-6.81(m,1H),6.96-6.98(m,1H),7.19-7.22(m,3H),7.23-7.30(m,3H),8.12(s,1H)；13C NMR(CDCl3,100MHz)δ:42.3,43.7,44.1,53.8,58.4,59.2,66.8,101.8,108.2,121.6,124.5,127.1,127.5,127.8,128.7,136.0,142.6,154.8,168.3,180.0；HRMS(ESI-TOF)m/z:Calcd.for C25H26N4NaO3[M+Na]+:453.1903；Found:453.1907.Compound 3c prepared in this example: white solid, yield 90%; >20: 1dr; melting point: 144.4-145.8°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.56 (s, 3H), 2.80 (d, J = 9.6Hz, 1H), 3.11-3.19 (m, 1H), 3.25(d,J=9.6Hz,1H),3.78(s,7H),4.30-4.35(m,1H),4.74(d,J=15.6Hz,1H),5.04(d,J=15.6Hz,1H ),6.53(d,J＝7.9Hz,1H),6.78-6.81(m,1H),6.96-6.98(m,1H),7.19-7.22(m,3H),7.23-7.30(m,3H), 8.12(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:42.3,43.7,44.1,53.8,58.4,59.2,66.8,101.8,108.2,121.6,124.5,127.1,127.5,127.8,128.7,136.0, 142.6, 154.8, 168.3, 180.0; HRMS (ESI-TOF) m/z: Calcd. for C 25 H 26 N 4 NaO 3 [M+Na] + :453.1903; Found: 453.1907.
本实施例制备化合物3d:黄色固体，产率87％；>20:1dr；熔点：133.3-134.5℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.51(s,3H),2.89(d,J＝9.6Hz,1H),3.11-3.14(m,1H),3.32(d,J＝9.6Hz,1H),3.83-3.84(m,7H),4.30-4.35(m,1H),6.71(d,J＝8.1Hz,1H),6.84-6.86(m,1H),7.01-7.02(m,1H),7.26-7.27(m,1H),7.38-7.41(m,3H),7.48-7.52(m,2H),8.13(s,1H)；13C NMR(CDCl3,100MHz)δ:42.2,45.0,54.0,58.9,59.2,66.8,101.8,108.6,122.0,124.6,125.8,127.5,127.7,129.3,130.9,134.8,142.9,154.8,168.3,179.1；HRMS(ESI-TOF)m/z:Calcd.for C24H24N4NaO3[M+Na]+:439.1746；Found:439.1747.Compound 3d prepared in this example: yellow solid, yield 87%; >20: 1dr; melting point: 133.3-134.5°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.51 (s, 3H), 2.89 (d, J = 9.6Hz, 1H), 3.11-3.14 (m, 1H), 3.32(d,J=9.6Hz,1H),3.83-3.84(m,7H),4.30-4.35(m,1H),6.71(d,J=8.1Hz,1H),6.84-6.86(m,1H) ,7.01-7.02(m,1H),7.26-7.27(m,1H),7.38-7.41(m,3H),7.48-7.52(m,2H),8.13(s,1H); 13 C NMR (CDCl 3 ,100MHz) δ: 42.2, 45.0, 54.0, 58.9, 59.2, 66.8, 101.8, 108.6, 122.0, 124.6, 125.8, 127.5, 127.7, 129.3, 130.9, 134.8, 142.9, 154.8, 168.3, 179.1; )m/z: Calcd.for C 24 H 24 N 4 NaO 3 [M+Na] + : 439.1746; Found: 439.1747.
本实施例制备化合物3e:黄色固体，产率86％；>20:1dr；熔点：152.5-154.0℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.51(s,3H),2.73(d,J＝9.6Hz,1H),2.95-2.99(m,1H),3.09-3.13(m,1H),3.15(s,3H),3.74-3.77(m,1H),3.85(s,6H),4.22-4.26(m,1H),6.52(d,J＝7.8Hz,1H),7.03-7.06(m,1H),7.27-7.31(m,1H),8.10(s,1H)；13C NMR(CDCl3,100MHz)δ:26.3,42.0,44.7,53.9,58.6,58.7,65.8,101.7,107.8,125.0,126.8,127.5,133.1,141.8,154.9,168.1,179.2；HRMS(ESI-TOF)m/z:Calcd.for C19H21ClN4NaO3[M+Na]+:411.1200；Found:411.1202.Compound 3e prepared in this example: yellow solid, yield 86%; >20: 1dr; melting point: 152.5-154.0°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.51 (s, 3H), 2.73 (d, J = 9.6Hz, 1H), 2.95-2.99 (m, 1H), 3.09-3.13(m,1H),3.15(s,3H),3.74-3.77(m,1H),3.85(s,6H),4.22-4.26(m,1H),6.52(d,J＝7.8Hz, 1H),7.03-7.06(m,1H),7.27-7.31(m,1H),8.10(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:26.3,42.0,44.7,53.9,58.6,58.7 ,65.8,101.7,107.8,125.0,126.8,127.5,133.1,141.8,154.9,168.1,179.2; HRMS (ESI-TOF) m/z: Calcd.for C 19 H 21 ClN 4 NaO 3 [M+Na] + :411.1200; Found: 411.1202.
本实施例制备化合物3f:黄色固体，产率89％；>20:1dr；熔点：146.5-148.4℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.47(s,3H),2.70(d,J＝9.6Hz,1H),2.90-2.95(m,1H),3.08(d,J＝9.5Hz,1H),3.12(s,3H),3.71-3.74(m,1H),3.83(s,6H),4.18-4.22(m,1H),6.46(d,J＝8.4Hz,1H),7.14-7.17(m,1H),7.42(d,J＝4.0Hz,1H),8.08(s,1H)；13C NMR(CDCl3,100MHz)δ:26.4,42.2,44.8,54.1,58.7,58.8,65.9,101.8,108.5,114.3,127.9,130.6,133.6,142.4,155.0,168.2,179.2；HRMS(ESI-TOF)m/z:Calcd.for C19H21BrN4NaO3[M+Na]+:455.0695；Found:455.0697.Compound 3f prepared in this example: yellow solid, yield 89%; >20: 1dr; melting point: 146.5-148.4°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.47 (s, 3H), 2.70 (d, J = 9.6Hz, 1H), 2.90-2.95 (m, 1H), 3.08(d,J=9.5Hz,1H),3.12(s,3H),3.71-3.74(m,1H),3.83(s,6H),4.18-4.22(m,1H),6.46(d,J= 8.4Hz, 1H), 7.14-7.17(m, 1H), 7.42(d, J=4.0Hz, 1H), 8.08(s, 1H); 13 C NMR (CDCl 3 , 100MHz) δ: 26.4, 42.2, 44.8 ,54.1,58.7,58.8,65.9,101.8,108.5,114.3,127.9,130.6,133.6,142.4,155.0,168.2,179.2; HRMS (ESI-TOF) m/z: Calcd.for C 19 H 21 BrN 4 NaO 3 [M+Na] + :455.0695; Found: 455.0697.
本实施例制备化合物3g:黄色固体，产率80％；>20:1dr；熔点：88.5-90.2℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.47-2.49(m,3H),2.73(d,J＝9.2Hz,1H),3.03-3.08(m,1H),3.17(d,J＝9.6Hz,1H),3.70-3.73(m,1H),3.75(s,6H),4.25-4.30(m,1H),5.25(d,J＝16.2Hz,1H),5.41(d,J＝16.2Hz,1H),6.68-6.73(m,1H),6.92-6.95(m,1H),7.12-7.17(m,2H),7.22-7.26(m,4H),8.13(s,1H)；13C NMR(CDCl3,100MHz)δ:42.3,44.7,44.8,53.9,58.2,59.2,67.6,101.9,114.5,122.6,123.4,126.5,127.1,128.6,130.4,134.3,138.0,138.7,155.0,168.3,180.6；HRMS(ESI-TOF)m/z:Calcd.for C25H25ClN4O3[M+Na]+:464.1615；Found:464.1617.Compound 3g prepared in this example: yellow solid, yield 80%; >20: 1dr; melting point: 88.5-90.2°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.47-2.49 (m, 3H), 2.73 (d, J=9.2Hz, 1H), 3.03-3.08 (m, 1H ),3.17(d,J=9.6Hz,1H),3.70-3.73(m,1H),3.75(s,6H),4.25-4.30(m,1H),5.25(d,J=16.2Hz,1H) ,5.41(d,J＝16.2Hz,1H),6.68-6.73(m,1H),6.92-6.95(m,1H),7.12-7.17(m,2H),7.22-7.26(m,4H),8.13 (s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:42.3,44.7,44.8,53.9,58.2,59.2,67.6,101.9,114.5,122.6,123.4,126.5,127.1,128.6,130.4,134.3,138.0 , 138.7, 155.0, 168.3, 180.6; HRMS (ESI-TOF) m/z: Calcd.for C 25 H 25 ClN 4 O 3 [M+Na] + :464.1615; Found: 464.1617.
本实施例制备化合物3h:黄色固体，产率87％；19:1dr；熔点：69.5-71.2℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.91(s,3H),2.80(d,J＝9.6Hz,1H),2.93-2.96(m,1H),3.14(d,J＝9.4Hz,1H),3.78-3.80(m,7H),4.35-4.39(m,1H),4.77-4.89(m,2H),6.36(d,J＝7.8Hz,1H),6.90-6.97(m,1H),7.07-7.10(m,2H),7.24-7.28(m,4H),7.42-7.43(m,1H),8.13(s,1H)；13C NMR(CDCl3,100MHz)δ:42.2,43.9,44.2,54.0,58.3,58.9,66.4,101.5,109.1,125.7,127.0,127.1,127.7,128.9,129.0,133.1,135.6,141.2,155.2,168.3,168.4,179.1；HRMS(ESI-TOF)m/z:Calcd.for C25H25ClN4NaO3[M+Na]+:487.1513；Found:487.1513.Compound 3h prepared in this example: yellow solid, yield 87%; 19: 1dr; melting point: 69.5-71.2°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.91 (s, 3H), 2.80 (d, J = 9.6Hz, 1H), 2.93-2.96 (m, 1H), 3.14(d,J=9.4Hz,1H),3.78-3.80(m,7H),4.35-4.39(m,1H),4.77-4.89(m,2H),6.36(d,J=7.8Hz,1H) , 6.90-6.97(m,1H), 7.07-7.10(m,2H), 7.24-7.28(m,4H), 7.42-7.43(m,1H), 8.13(s,1H); 13 C NMR (CDCl 3 ,100MHz)δ:42.2,43.9,44.2,54.0,58.3,58.9,66.4,101.5,109.1,125.7,127.0,127.1,127.7,128.9,129.0,133.1,135.6,141.2,155.2,168.3,1798.1; (ESI-TOF)m/z: Calcd.for C 25 H 25 ClN 4 NaO 3 [M+Na] + :487.1513; Found: 487.1513.
本实施例制备化合物3i:黄色固体，产率84％；>20:1dr；熔点：138.3-140.1℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.18(s,3H),2.56(s,3H),2.81(d,J＝9.6Hz,1H),3.09-3.13(m,1H),3.25(d,J＝9.6Hz,1H),3.78-3.80(m,7H),4.30-4.33(m,1H),4.74(d,J＝15.6Hz,1H),4.99(d,J＝15.6Hz,1H),6.40(d,J＝7.9Hz,1H),6.75-6.78(m,1H),7.07(s,1H),7.17-7.19(m,2H),7.26-7.28(m,3H),8.12(s,1H)；13C NMR(CDCl3,100MHz)δ:21.0,42.3,43.7,44.1,53.8,58.4,59.0,66.7,101.8,107.9,125.5,127.0,127.4,128.0,128.6,130.9,136.1,140.2,154.8,168.3,179.9；HRMS(ESI-TOF)m/z:Calcd.for C26H28N4NaO3[M+Na]+:467.2059；Found:467.2057.Compound 3i prepared in this example: yellow solid, yield 84%; >20: 1dr; melting point: 138.3-140.1°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.18(s, 3H), 2.56(s, 3H), 2.81(d, J=9.6Hz, 1H), 3.09- 3.13(m,1H),3.25(d,J=9.6Hz,1H),3.78-3.80(m,7H),4.30-4.33(m,1H),4.74(d,J=15.6Hz,1H),4.99 (d,J=15.6Hz,1H),6.40(d,J=7.9Hz,1H),6.75-6.78(m,1H),7.07(s,1H),7.17-7.19(m,2H),7.26- 7.28(m,3H),8.12(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:21.0,42.3,43.7,44.1,53.8,58.4,59.0,66.7,101.8,107.9,125.5,127.0,127.4 ,128.0,128.6,130.9,136.1,140.2,154.8,168.3,179.9; HRMS (ESI-TOF) m/z: Calcd.for C 26 H 28 N 4 NaO 3 [M+Na] + :467.2059; Found: 467.2057 .
本实施例制备化合物3j:白色固体，产率90％；>20:1dr；熔点：177.2-179.0℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.11(s,3H),2.51(s,3H),2.75(d,J＝9.6Hz,1H),3.08-3.10(m,1H),3.23(d,J＝9.4Hz,1H),3.73-3.76(m,1H),3.78(s,6H),4.28-4.32(m,1H),5.02(d,J＝16.8Hz,1H),5.26-5.33(m,1H),6.68-6.71(m,2H),7.02-7.04(m,2H),7.18-7.19(m,1H),7.23-7.26(m,3H),8.11(s,1H)；13C NMR(CDCl3,100MHz)δ:18.8,42.4,44.6,45.0,53.9,57.8,59.4,67.8,102.1,118.8,121.7,122.7,125.7,125.8,125.9,127.1,128.9,129.0,131.8,131.9,138.2,140.7,154.8,168.4,181.2；HRMS(ESI-TOF)m/z:C26H28N4NaO3[M+Na]+:467.2059；Found:467.2062.Compound 3j prepared in this example: white solid, yield 90%; >20: 1dr; melting point: 177.2-179.0°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.11 (s, 3H), 2.51 (s, 3H), 2.75 (d, J=9.6Hz, 1H), 3.08- 3.10(m,1H),3.23(d,J=9.4Hz,1H),3.73-3.76(m,1H),3.78(s,6H),4.28-4.32(m,1H),5.02(d,J= 16.8Hz,1H),5.26-5.33(m,1H),6.68-6.71(m,2H),7.02-7.04(m,2H),7.18-7.19(m,1H),7.23-7.26(m,3H) ,8.11(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:18.8,42.4,44.6,45.0,53.9,57.8,59.4,67.8,102.1,118.8,121.7,122.7,125.7,125.8,125.9,127.1 , 128.9, 129.0, 131.8, 131.9, 138.2, 140.7, 154.8, 168.4, 181.2; HRMS (ESI-TOF) m/z: C 26 H 28 N 4 NaO 3 [M+Na] + :467.2059;
本实施例制备化合物3k:白色固体，产率80％；>20:1dr；熔点：139.1-140.9℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.29-1.34(m,6H),2.50(s,3H),2.76(d,J＝9.2Hz,1H),3.01-3.02(m,1H),3.19-3.21(m,1H),3.79-3.84(m,1H),4.10-4.26(m,4H),4.35-4.39(m,1H),4.73(d,J＝15.6Hz,1H),5.01(d,J＝15.6Hz,1H),6.45(d,J＝8.0Hz,1H),6.75-6.78(m,1H),6.91-6.95(m,1H),7.13-7.15(m,2H),7.22-7.26(m,3H),7.34(d,J＝11.2Hz,1H),8.05(s,1H)；13C NMR(CDCl3,100MHz)δ:14.6,42.2,43.7,44.2,58.6,59.0,62.7,67.2,101.8,102.9,108.4,121.6,124.8,127.0,127.1,127.5,127.8,128.8,131.4,136.1,142.7,154.9,168.1,180.0；HRMS(ESI-TOF)m/z:C27H30N4NaO3[M+Na]+:481.2216；Found:481.2218.Compound 3k prepared in this example: white solid, yield 80%; >20: 1dr; melting point: 139.1-140.9°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 1.29-1.34 (m, 6H), 2.50 (s, 3H), 2.76 (d, J=9.2Hz, 1H), 3.01-3.02(m,1H),3.19-3.21(m,1H),3.79-3.84(m,1H),4.10-4.26(m,4H),4.35-4.39(m,1H),4.73(d,J =15.6Hz,1H),5.01(d,J=15.6Hz,1H),6.45(d,J=8.0Hz,1H),6.75-6.78(m,1H),6.91-6.95(m,1H),7.13 -7.15(m,2H),7.22-7.26(m,3H),7.34(d,J＝11.2Hz,1H),8.05(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:14.6,42.2 ,43.7,44.2,58.6,59.0,62.7,67.2,101.8,102.9,108.4,121.6,124.8,127.0,127.1,127.5,127.8,128.8,131.4,136.1,142.7 )m/z: C 27 H 30 N 4 NaO 3 [M+Na] + :481.2216; Found: 481.2218.
本实施例制备化合物3l:黄色固体，产率82％；>20:1dr；熔点：216.5-217.9℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.96-0.99(m,6H),1.73-1.80(m,4H),2.48(s,3H),2.63-2.66(m,1H),3.13-3.15(m,1H),3.19-3.22(m,1H),3.74-3.76(m,1H),4.10-4.19(m,4H),4.24-4.26(m,1H),6.73-6.77(m,2H),6.96-6.99(m,1H),7.12(d,J＝7.8Hz,1H),8.02(s,1H),9.16(brs,1H)；13C NMR(CDCl3,100MHz)δ:10.8,22.3,34.0,42.2,44.4,51.9,58.7,68.6,103.0,109.4,121.6,124.4,127.9,131.5,141.0,154.7,168.2,183.5；HRMS(ESI-TOF)m/z:C22H28N4NaO3[M+Na]+:419.2059；Found:419.2060.Compound 3l prepared in this example: yellow solid, yield 82%; >20: 1dr; melting point: 216.5-217.9°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 0.96-0.99 (m, 6H), 1.73-1.80 (m, 4H), 2.48 (s, 3H), 2.63-2.66 (m,1H),3.13-3.15(m,1H),3.19-3.22(m,1H),3.74-3.76(m,1H),4.10-4.19(m,4H),4.24-4.26(m,1H) , 6.73-6.77 (m, 2H), 6.96-6.99 (m, 1H), 7.12 (d, J=7.8Hz, 1H), 8.02 (s, 1H), 9.16 (brs, 1H); 13 C NMR (CDCl 3 ,100MHz)δ:10.8,22.3,34.0,42.2,44.4,51.9,58.7,68.6,103.0,109.4,121.6,124.4,127.9,131.5,141.0,154.7,168.2,183.5; HRMS(ESI-TOF)m/ z: C 22 H 28 N 4 NaO 3 [M+Na] + :419.2059; Found: 419.2060.
本实施例制备化合物3m:白色固体，产率80％；>20:1dr；熔点：175.2-177.0℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.90-0.93(m,6H),1.41-1.46(m,4H),1.70-1.75(m,4H),2.48(s,3H),2.64(d,J＝8.4Hz,1H),3.09-3.14(m,1H),3.17-3.21(m,1H),3.71-3.74(m,1H),4.11-4.18(m,3H),4.21-4.26(m,2H),6.72-6.75(m,2H),6.96-7.02(m,1H),7.12(d,J＝8.1Hz,1H),8.03(s,1H),8.72(br s,1H)；13C NMR(CDCl3,100MHz)δ:13.9,19.4,31.0,34.0,42.2,44.5,51.9,58.7,66.8,103.0,109.2,121.7,124.5,127.9,140.8,154.7,168.2,183.2；HRMS(ESI-TOF)m/z:C24H32N4NaO3[M+Na]+:447.2372；Found:447.2375.Compound 3m prepared in this example: white solid, yield 80%; >20: 1dr; melting point: 175.2-177.0°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 0.90-0.93 (m, 6H), 1.41-1.46 (m, 4H), 1.70-1.75 (m, 4H), 2.48 (s,3H),2.64(d,J＝8.4Hz,1H),3.09-3.14(m,1H),3.17-3.21(m,1H),3.71-3.74(m,1H),4.11-4.18(m ,3H),4.21-4.26(m,2H),6.72-6.75(m,2H),6.96-7.02(m,1H),7.12(d,J＝8.1Hz,1H),8.03(s,1H), 8.72 (br s, 1H); 13 C NMR (CDCl 3 , 100MHz) δ: 13.9, 19.4, 31.0, 34.0, 42.2, 44.5, 51.9, 58.7, 66.8, 103.0, 109.2, 121.7, 124.5, 127.9, 140.8, 154.7 , 168.2, 183.2; HRMS (ESI-TOF) m/z: C 24 H 32 N 4 NaO 3 [M+Na] + :447.2372; Found: 447.2375.
本实施例制备化合物3n:白色固体，产率76％；>20:1dr；熔点：182.7-184.7℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.88-0.90(m,12H),1.60-1.68(m,4H),1.70-1.77(m,2H),2.47(s,3H),2.63(d,J＝8.4Hz,1H),3.08-3.12(m,1H),3.18(d,J＝8.1Hz,1H),3.69-3.72(m,1H),4.13-4.18(m,2H),4.23-4.31(m,3H),6.73-6.78(m,2H),6.97-6.99(m,1H),7.10-7.11(m,1H),8.03(s,1H),9.21(br s,1H)；13C NMR(CDCl3,100MHz)δ:22.4,22.7,25.1,37.6,42.2,44.5,58.8,65.5,102.1,109.4,121.6,124.4,127.9,131.7,141.0,154.7,168.2,183.6；HRMS(ESI-TOF)m/z:C26H36N4NaO3[M+Na]+:475.2685；Found:475.2687.Compound 3n prepared in this example: white solid, yield 76%; >20: 1dr; melting point: 182.7-184.7°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 0.88-0.90 (m, 12H), 1.60-1.68 (m, 4H), 1.70-1.77 (m, 2H), 2.47 (s,3H),2.63(d,J=8.4Hz,1H),3.08-3.12(m,1H),3.18(d,J=8.1Hz,1H),3.69-3.72(m,1H),4.13- 4.18(m,2H),4.23-4.31(m,3H),6.73-6.78(m,2H),6.97-6.99(m,1H),7.10-7.11(m,1H),8.03(s,1H), 9.21(br s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:22.4,22.7,25.1,37.6,42.2,44.5,58.8,65.5,102.1,109.4,121.6,124.4,127.9,131.7,141.0,154.7 , 168.2, 183.6; HRMS (ESI-TOF) m/z: C 26 H 36 N 4 NaO 3 [M+Na] + :475.2685; Found: 475.2687.
本实施例制备化合物3o:黄色固体，产率88％；14:1dr；熔点：134.2-136.1℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.48(s,3H),2.79(d,J＝12.4Hz,1H),2.88-2.92(m,1H),3.01(d,J＝12.4Hz,1H),3.53(s,3H),3.77-3.82(m,1H),3.92(s,3H),4.36-4.40(m,1H),6.68-6.72(m,1H),6.97-7.00(m,1H),7.21-7.25(m,1H),8.19(s,1H)；13C NMR(CDCl3,100MHz)δ:30.0,41.9,48.4,54.7,58.4,58.6,66.6,115.1,117.7,122.5,123.1,130.6,133.5,139.3,155.4,160.1,168.5,179.7；HRMS(ESI-TOF)m/z:Calcd.for C18H18Cl2N4NaO2[M+Na]+:415.0705；Found:415.0707.Compound 3o prepared in this example: yellow solid, yield 88%; 14: 1dr; melting point: 134.2-136.1°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.48 (s, 3H), 2.79 (d, J = 12.4Hz, 1H), 2.88-2.92 (m, 1H), 3.01(d,J＝12.4Hz,1H),3.53(s,3H),3.77-3.82(m,1H),3.92(s,3H),4.36-4.40(m,1H),6.68-6.72(m, 1H),6.97-7.00(m,1H),7.21-7.25(m,1H),8.19(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:30.0,41.9,48.4,54.7,58.4,58.6 ,66.6,115.1,117.7,122.5,123.1,130.6,133.5,139.3,155.4,160.1,168.5,179.7; HRMS (ESI-TOF) m/z: Calcd.for C 18 H 18 Cl 2 N 4 NaO 2 [M +Na] + :415.0705; Found: 415.0707.
本实施例制备化合物3p:黄色固体，产率81％；17:1dr；熔点：148.2-150.1℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.46-1.50(m,3H),2.43(s,3H),2.77-2.80(m,2H),2.91-2.93(m,1H),3.09(s,3H),3.75-3.79(m,1H),4.34-4.45(m,3H),6.47-6.51(m,1H),6.70-6.75(m,1H),7.15-7.21(m,1H),8.11(s,1H)；13C NMR(CDCl3,100MHz)δ:14.3,26.7,41.6,48.2,58.2,59.2,63.8,65.9,107.9,112.6,112.9,114.2,114.4,117.5,132.5,132.6,139.4,155.4,155.5,157.5,159.9,160.5,167.9,178.8；HRMS(ESI-TOF)m/z:C19H20ClFN4NaO2[M+Na]+:413.1157；Found:413.1157.Compound 3p prepared in this example: yellow solid, yield 81%; 17: 1dr; melting point: 148.2-150.1°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 1.46-1.50 (m, 3H), 2.43 (s, 3H), 2.77-2.80 (m, 2H), 2.91-2.93 (m,1H),3.09(s,3H),3.75-3.79(m,1H),4.34-4.45(m,3H),6.47-6.51(m,1H),6.70-6.75(m,1H),7.15 -7.21(m,1H),8.11(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:14.3,26.7,41.6,48.2,58.2,59.2,63.8,65.9,107.9,112.6,112.9,114.2, 114.4, 117.5, 132.5, 132.6, 139.4, 155.4, 155.5, 157.5, 159.9, 160.5, 167.9, 178.8; HRMS (ESI-TOF) m/z: C 19 H 20 ClFN 4 NaO 2 [M+Na] + :413.1157 ;Found: 413.1157.
本实施例制备化合物3q:黄色固体，产率79％；>20:1dr；熔点：117.1-118.7℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.49-1.53(m,3H),2.49(s,3H),2.85-2.89(m,2H),3.02-3.03(m,1H),3.81-3.84(m,1H),4.37-4.40(m,1H),4.46-4.53(m,2H),4.68(d,J＝15.8Hz,1H),4.98(d,J＝16.0Hz,1H),6.41-6.43(m,1H),6.63-6.66(m,1H),7.21-7.24(m,6H),8.19(s,1H)；13C NMR(CDCl3,100MHz)δ:14.3,41.7,44.4,47.9,58.2,59.3,63.8,66.5,100.0,109.1,109.2,113.1,114.2,114.5,117.4,127.4,127.8,128.8,128.9,132.5,135.4,138.6,155.5,157.4,159.8,160.7,167.9,168.0,178.8；HRMS(ESI-TOF)m/z:C25H24ClFN4NaO2[M+Na]+:489.1470；Found:489.1474.Compound 3q prepared in this example: yellow solid, yield 79%; >20: 1dr; melting point: 117.1-118.7°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 1.49-1.53 (m, 3H), 2.49 (s, 3H), 2.85-2.89 (m, 2H), 3.02-3.03 (m,1H),3.81-3.84(m,1H),4.37-4.40(m,1H),4.46-4.53(m,2H),4.68(d,J＝15.8Hz,1H),4.98(d,J ＝16.0Hz, 1H), 6.41-6.43(m, 1H), 6.63-6.66(m, 1H), 7.21-7.24(m, 6H), 8.19(s, 1H); 13 C NMR (CDCl 3 , 100MHz) δ: 14.3, 41.7, 44.4, 47.9, 58.2, 59.3, 63.8, 66.5, 100.0, 109.1, 109.2, 113.1, 114.2, 114.5, 117.4, 127.4, 127.8, 128.8, 128.9, 132.5, 135.4, 1558.4, 135.5, 6, 159.8, 160.7, 167.9, 168.0, 178.8; HRMS (ESI-TOF) m/z: C 25 H 24 ClFN 4 NaO 2 [M+Na] + :489.1470; Found: 489.1474.
本实施例制备化合物3r:黄色固体，产率81％；18:1dr；熔点：163.5-165.2℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.49-1.53(m,3H),2.52(s,3H),2.93-3.00(m,2H),3.14(d,J＝9.2Hz,1H),3.87-3.91(m,1H),4.39-4.54(m,3H),6.63(d,J＝7.8Hz,1H),6.82-6.86(m,1H),6.98-7.02(m,1H),7.35-7.49(m,6H),8.19(s,1H)；13C NMR(CDCl3,100MHz)δ:14.3,41.9,48.6,58.6,59.1,63.8,66.9,109.1,117.9,122.2,124.8,126.4,128.0,128.2,129.6,134.6,143.4,155.4,160.6,168.2,178.7；HRMS(ESI-TOF)m/z:C24H23ClN4NaO2[M+Na]+:457.1407；Found:457.1409.Compound 3r prepared in this example: yellow solid, yield 81%; 18: 1dr; melting point: 163.5-165.2°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 1.49-1.53 (m, 3H), 2.52 (s, 3H), 2.93-3.00 (m, 2H), 3.14 (d ,J=9.2Hz,1H),3.87-3.91(m,1H),4.39-4.54(m,3H),6.63(d,J=7.8Hz,1H),6.82-6.86(m,1H),6.98- 7.02(m,1H),7.35-7.49(m,6H),8.19(s,1H); 13 C NMR(CDCl 3 ,100MHz)δ:14.3,41.9,48.6,58.6,59.1,63.8,66.9,109.1, 117.9, 122.2, 124.8, 126.4, 128.0, 128.2, 129.6, 134.6, 143.4, 155.4, 160.6, 168.2, 178.7; HRMS (ESI-TOF) m/z: C 24 H 23 ClN 4 NaO 2 [M+Na] + :457.1407; Found: 457.1409.
本实施例制备化合物3s:黄色固体，产率80％；>20:1dr；熔点：114.5-116.2℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.49(s,3H),2.73-2.75(m,1H),3.01-3.08(m,1H),3.19-3.23(m,1H),3.67-3.72(m,1H),3.73(s,6H),3.80(s,3H),4.22-4.25(m,1H),4.75(d,J＝15.8Hz,1H),4.96(d,J＝15.2Hz,1H),6.49(d,J＝7.8Hz,1H),6.78-6.80(m,1H),6.93-6.95(m,1H),7.15-7.19(m,3H),7.21-7.26(m,4H)；13C NMR(CDCl3,100MHz)δ:42.5,43.8,44.1,53.8,54.5,58.5,59.3,67.0,94.2,108.3,121.7,124.8,127.1,127.2,127.3,127.5,127.8,128.8,136.2,142.7,162.5,169.9,180.3；HRMS(ESI-TOF)m/z:C26H28N4NaO4[M+Na]+:483.2008；Found:483.2008.Compound 3s prepared in this example: yellow solid, yield 80%; >20: 1dr; melting point: 114.5-116.2°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.49 (s, 3H), 2.73-2.75 (m, 1H), 3.01-3.08 (m, 1H), 3.19-3.23 (m,1H),3.67-3.72(m,1H),3.73(s,6H),3.80(s,3H),4.22-4.25(m,1H),4.75(d,J＝15.8Hz,1H), 4.96(d,J=15.2Hz,1H),6.49(d,J=7.8Hz,1H),6.78-6.80(m,1H),6.93-6.95(m,1H),7.15-7.19(m,3H) ,7.21-7.26(m,4H); 13 C NMR(CDCl 3 ,100MHz)δ:42.5,43.8,44.1,53.8,54.5,58.5,59.3,67.0,94.2,108.3,121.7,124.8,127.1,127.2,127.3 , 127.5, 127.8, 128.8, 136.2, 142.7, 162.5, 169.9, 180.3; HRMS (ESI-TOF) m/z: C 26 H 28 N 4 NaO 4 [M+Na] + :483.2008; Found: 483.2008.
本实施例制备化合物3t:黄色固体，产率75％；17:1dr；熔点：88.3-89.8℃。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.52(s,3H),2.81(d,J＝7.8Hz,1H),2.93-2.96(m,1H),3.17(d,J＝7.8Hz,1H),3.73-3.77(m,1H),3.81(s,6H),3.86(s,3H),4.34-4.38(m,1H),4.82-4.89(m,2H),6.38(d,J＝7.2Hz,1H),6.93-6.94(m,1H),7.10-7.12(m,2H),7.24-7.28(m,3H),7.47-7.48(m,1H)；13C NMR(CDCl3,100MHz)δ:42.1,43.6,43.9,53.8,54.4,58.1,58.8,66.2,93.7,108.9,125.7,126.7,126.8,126.9,127.4,127.5,128.6,128.7,133.2,135.5,141.1,162.5,169.7,179.1；HRMS(ESI-TOF)m/z:C26H27ClN4NaO4[M+Na]+:517.1619；Found:517.1621.Compound 3t prepared in this example: yellow solid, yield 75%; 17: 1dr; melting point: 88.3-89.8°C. The results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR (CDCl 3 , 400MHz) δ: 2.52 (s, 3H), 2.81 (d, J = 7.8Hz, 1H), 2.93-2.96 (m, 1H), 3.17(d,J＝7.8Hz,1H),3.73-3.77(m,1H),3.81(s,6H),3.86(s,3H),4.34-4.38(m,1H),4.82-4.89(m, 2H), 6.38(d, J=7.2Hz, 1H), 6.93-6.94(m, 1H), 7.10-7.12(m, 2H), 7.24-7.28(m, 3H), 7.47-7.48(m, 1H) ; 13 C NMR (CDCl 3 , 100MHz) δ: 42.1, 43.6, 43.9, 53.8, 54.4, 58.1, 58.8, 66.2, 93.7, 108.9, 125.7, 126.7, 126.8, 126.9, 127.4, 127.5, 128.6, 128.7, 133.2, 135.5, 141.1, 162.5, 169.7, 179.1; HRMS (ESI-TOF) m/z: C 26 H 27 ClN 4 NaO 4 [M+Na] + :517.1619; Found: 517.1621.
本发明的式(1)化合物具有重要的生物活性，人前列腺癌细胞(PC-3),人肺癌细胞(A549)以及人白血病细胞(K562)共三株肿瘤细胞的细胞毒性试验表明：此类式(1)所示的结构的烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人肺癌细胞(A549)，人前列腺癌细胞(PC-3)和人白血病细胞(K562)表示的细胞毒性。The compound of formula (1) of the present invention has important biological activity, and the cytotoxicity test of human prostate cancer cell (PC-3), human lung cancer cell (A549) and human leukemia cell (K562) total three tumor cell lines shows: The alkoxypyrimidine spliced 3-pyrrole spirooxindole derivative with the structure shown in formula (1) has an inhibitory effect on tumor cell growth, and may be developed into a new anti-tumor drug. But it should be emphasized that the compounds of the present invention are not limited to the cytotoxicity expressed by human lung cancer cells (A549), human prostate cancer cells (PC-3) and human leukemia cells (K562).
药理实施例1：化合物3a-3t对PC-3细胞的细胞毒性，但需强调的是本发明的化合物不限于化合物3a-3t对PC-3(人前列腺癌)的细胞毒性。Pharmacological Example 1: Cytotoxicity of compounds 3a-3t on PC-3 cells, but it should be emphasized that the compounds of the present invention are not limited to the cytotoxicity of compounds 3a-3t on PC-3 (human prostate cancer).
PC-3(人前列腺癌)细胞用RPMI-1640培养基培养，培养基中含10％的胎牛血清，100U/mL青霉素及100U/mL的链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。PC-3 (human prostate cancer) cells were cultured with RPMI-1640 medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and cultured for 24 hours at 37 °C in an incubator with 5% CO2 humidified air.
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后，分别将新配的化合物3a-3t的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度分别为5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/L。48小时后，每孔加入10μL MTT(5mg/mL)的磷酸盐缓冲液，再继续在37℃培养4小时后，离心5分钟除去未转化的MTT，每孔中加入150μL二甲基亚砜。以溶解还原的MTT晶体甲臜(formazan)，用酶标仪在490nm波长测定OD值。其中化合物3a-3t对PC-3细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3a-3t对PC-3肿瘤细胞的IC50为见表1和表2；而阳性对照顺铂对PC-3肿瘤细胞的IC50为24.4μmol/L。Cell viability was determined by the modified MTT method. After the cells were incubated for 24 hours, the newly prepared dimethyl sulfoxide solutions of compounds 3a-3t were added to each well in a concentration gradient, so that the final concentrations of the compounds in the wells were 5 μmol/L, 10 μmol/L, and 20 μmol /L, 40μmol/L and 80μmol/L. After 48 hours, 10 μL of MTT (5 mg/mL) in phosphate buffer was added to each well, and after further incubation at 37° C. for 4 hours, unconverted MTT was removed by centrifugation for 5 minutes, and 150 μL of dimethyl sulfoxide was added to each well. The reduced MTT crystal formazan was dissolved, and the OD value was measured at a wavelength of 490 nm with a microplate reader. Among them, the half-inhibitory concentration IC 50 of compounds 3a-3t on PC-3 cells was analyzed by spss software (version 19). The IC 50 of compounds 3a-3t against PC-3 tumor cells is shown in Table 1 and Table 2; while the IC 50 of the positive control cisplatin against PC-3 tumor cells is 24.4 μmol/L.
实验结论：PC-3细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物对PC-3细胞具有较强的细胞毒性，部分化合物和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。Experimental conclusion: PC-3 cells are an effective tool and evaluation index for testing the cytotoxicity of compounds on tumor cells. This experiment shows that the alkoxypyrimidine splicing 3-pyrrole spirooxindole derivatives represented by the formula (1) have strong cytotoxicity to PC-3 cells, and some compounds are the same as the first-line drug cisplatin for tumor treatment. Order of magnitude, it is possible to develop into a new drug with anti-tumor effect.
药理实施例2：化合物3a-3t对A549细胞的细胞毒性，但需强调的是本发明的化合物不限于化合物3a-3t对A549细胞的细胞毒性。Pharmacological Example 2: Cytotoxicity of compounds 3a-3t on A549 cells, but it should be emphasized that the compounds of the present invention are not limited to the cytotoxicity of compounds 3a-3t on A549 cells.
A549(人非小细胞肺癌肺癌)用DMEM培养基培养，培养基中含10％的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔4000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。A549 (human non-small cell lung cancer) was cultured with DMEM medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 U/mL streptomycin. Cells were added to 96 wells at a concentration of 4000 cells per well and cultured for 24 hours at 37 °C in an incubator with 5% CO2 humidified air.
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3a-3t对A549肿瘤细胞的IC50为见表1和表2；而阳性照顺铂对A549肿瘤细胞的IC50为28.1μmol/L。Cell viability was determined by the modified MTT method. The specific method is as in Pharmacological Example 1. The IC 50 of compounds 3a-3t against A549 tumor cells is shown in Table 1 and Table 2; while the IC 50 of the positive control cisplatin against A549 tumor cells is 28.1 μmol/L.
实验结论：A549细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物对A549细胞具有较强的细胞毒性，部分化合物和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。Experimental conclusion: A549 cells are an effective tool and evaluation index for testing the cytotoxicity of compounds on tumor cells. This experiment shows that the alkoxypyrimidine splicing 3-pyrrole spirooxindole derivative represented by the formula (1) has strong cytotoxicity to A549 cells, and some compounds are of the same order of magnitude as the first-line drug cisplatin for tumor treatment. It is possible to develop new drugs with anti-tumor effects.
药理实施例3：化合物3a-3t对K562细胞的细胞毒性，但需强调的是本发明的化合物不限于化合物3a-3t对A549细胞的细胞毒性。Pharmacological Example 3: Cytotoxicity of compounds 3a-3t on K562 cells, but it should be emphasized that the compounds of the present invention are not limited to the cytotoxicity of compounds 3a-3t on A549 cells.
K562(人慢性髓系白血病细胞)用RPMI-1640培养基培养，培养基中含10％的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。K562 (human chronic myeloid leukemia cells) were cultured with RPMI-1640 medium containing 10% fetal bovine serum, 100 U/mL penicillin and 100 U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and cultured for 24 hours at 37 °C in an incubator with 5% CO2 humidified air.
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3a-3t对K562细胞的IC50为见表1和表2；而阳性对照顺铂对K562肿瘤细胞的IC50为26.8μmol/L。Cell viability was determined by the modified MTT method. The specific method is as in Pharmacological Example 1. The IC 50 of compounds 3a-3t on K562 cells is shown in Table 1 and Table 2; while the IC 50 of the positive control cisplatin on K562 tumor cells is 26.8 μmol/L.
实验结论：K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物对K562细胞具有较强的细胞毒性，部分化合物和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。Experimental conclusion: K562 cells are an effective tool and evaluation index for testing the cytotoxicity of compounds on tumor cells. This experiment shows that the alkoxypyrimidine splicing 3-pyrrole spirooxindole derivative represented by the formula (1) has strong cytotoxicity to K562 cells, and some compounds are of the same order of magnitude as the first-line drug cisplatin for tumor treatment. It is possible to develop new drugs with anti-tumor effects.
从以上药理实施例中我们可以看出这些化合物对这三株肿瘤细胞都显示有一定的细胞毒性。但需强调的是本发明的化合物不限于人前列腺癌细胞(PC-3),人肺癌细胞(A549)以及人白血病细胞(K562)表示的细胞毒性。可见这些化合物具有开发成为抗肿瘤药物的潜力，值得继续深入研究下去。From the above pharmacological examples, we can see that these compounds have certain cytotoxicity to the three tumor cell lines. But it should be emphasized that the compounds of the present invention are not limited to the cytotoxicity expressed by human prostate cancer cells (PC-3), human lung cancer cells (A549) and human leukemia cells (K562). It can be seen that these compounds have the potential to be developed into anti-tumor drugs, and are worthy of further research.
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