CN111732584B - 二芳基取代稠杂环类化合物及其制备方法和在制药中的用途 - Google Patents
二芳基取代稠杂环类化合物及其制备方法和在制药中的用途 Download PDFInfo
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- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明属合成药物化学领域，涉及二芳基取代稠杂环类化合物，具体涉及二芳基取代咪唑并[4,5‑c]吡啶和咪唑并[4,5‑c]吡啶‑2‑酮类化合物或其药学盐化合物及其在制药中的应用。本发明还包括所述化合物、其药用盐及其药物组合物在制备预防或治疗与肿瘤相关疾病药物中的应用。本发明提供的化合物或其在药学上可接受的盐具有优秀的Tubulin/Katanin双重作用、多种肿瘤细胞增殖抑制活性以及体内抗肿瘤活性，可应用于制备预防或治疗与肿瘤相关疾病的药物；所述与肿瘤相关疾病包括良、恶性肿瘤以及肿瘤引起的其他疾病。
Description
技术领域
本发明属化学制药领域,涉及二芳基取代稠杂环类化合物，具体涉及二芳基取代咪唑并[4,5-c]吡啶和咪唑并[4,5-c]吡啶-2-酮类化合物、制备方法及其在制备预防和治疗肿瘤相关疾病药物的应用。
背景技术
现有技术公开了已批准上市的抗肿瘤药物有近百种，主要包括：(1)作用于DNA的抗肿瘤药物：如烷化剂、金属铂配合物、DNA拓扑异构酶抑制剂和抗代谢抗肿瘤药等；(2)作用于激酶的抗肿瘤药物：如酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂等；(3)作用于微管(Microtubule)的抗肿瘤药物：包括微管聚集抑制剂(即微管去稳定剂，以长春碱类、秋水仙碱类、鬼臼毒素和Combretastatins为代表)和微管聚集促进剂(即微管稳定剂，以紫杉醇和埃博霉素类为代表)；其中，微管聚集抑制剂既具有抑制微管蛋白(Tubulin)聚合的能力、又具有针对肿瘤血管的特异性靶向和破坏已生成的肿瘤血管、使肿瘤“饿死”的作用，且多数该类药物不具有多药耐药性，因此成为业内关注的一类抗肿瘤药物。
有研究公开了靶向秋水仙碱结合位点的微管蛋白聚集抑制剂康普立停(Combretastatin A-4，简称CA-4)是1982年从非洲灌木矮柳树(Combretum caffrum)的树皮或茎中分离得到的一系列顺式二苯乙烯类天然产物，具有较强的抑制微管蛋白聚集和选择性抑制肿瘤血管增生的活性，其结构改造已经取得了重要进展。例如，具有显著抗肿瘤活性的手性β-内酰胺类CA-4类似物(J.Med.Chem.2016,59,10329-10334；Eur.J.Med.Chem.2018,144,817-842)。
Katanin是一种微管剪切蛋白(Microtubule severing proteins)，可通过水解ATP剪切微管、使微管解聚，导致细胞周期阻滞和细胞凋亡，从而对细胞分裂、生长等过程进行调节，在微管动态平衡调节中发挥了重要作用(Proc.Natl.Acad.Sci.2009,106,6363-6368；Science 2018,361)，Katanin在肿瘤的生长过程中也扮演了重要角色，研究表明，通过Katanin1 cDNA转染诱导的Katanin p60高表达胰腺癌细胞株PNT-1a与PC-3的细胞增殖能力受到了大幅的抑制(The Prostate 2012,72,291-300)；还有研究表明，具有抑制肿瘤细胞增殖和转移作用的抑癌因子LAPSER1需要通过Katanin p80亚基的协助进行定位从而发挥作用，使用siRNA沉默Katanin p80亚基表达后，LAPSER1的抑癌作用受到明显抑制(TheFASEB Journal 2018,21,2086-2100)；因此，Katanin极具潜力作为肿瘤治疗药物的新靶标。有文献报道了作用于微管剪切蛋白Katanin的二芳基嘌呤类化合物对多种肿瘤细胞株具有增殖抑制作用(J.Med.Chem.2016,59,8521-8534)，进一步的机制研究发现该类化合物能诱导微管碎片化(Microtubule fragmentation)，并产生细胞G2/M期阻滞和凋亡。
由于肿瘤的发病原因与调节机制十分复杂，因此单靶点药物往往作用不理想，而多靶点药物可以同时作用于调控网络的多个位点，相较于单靶点药物可能获得更优良的抗肿瘤效果；同时由于协同效应，多靶点药物可以使用较低的剂量，从而降低毒副作用，因此多靶点药物在肿瘤治疗中备受青睐，如伊马替尼、索拉非尼、拉帕替尼等分子靶向药物均为多靶点药物。
Katanin同样作用于微管，因此同时作用于微管蛋白秋水仙碱位点和Katanin的双靶点类化合物可能通过协同作用发挥更强的微管聚集抑制和抗肿瘤作用。
基于现有技术的现状与基础，本申请的发明人拟提供一类新型二芳基取代稠杂环类化合物，其具有优秀的Tubulin/Katanin双重作用、多种肿瘤细胞增殖抑制活性以及体内抗肿瘤活性，可制备一类结构新颖、机理独特的微管蛋白聚集抑制剂以及血管生成抑制剂类抗肿瘤候选化合物。
发明内容
本发明的目的是提供新型微管蛋白聚集抑制剂以及血管生成抑制剂，具体涉及具有显著抗肿瘤活性的新型二芳基取代稠杂环类化合物及其制备方法和该类化合物及其药学盐或以其为成分的复方药物在制备预防和治疗肿瘤相关疾病药物中的应用。
本申请根据作用于秋水仙碱位点和Katanin的化合物结构特点，将它们的结构进行融合，设计并合成了一类新型二芳基取代稠杂环类化合物。
本发明提供了下述通式结构的二芳基取代稠杂环类化合物或其药学盐，
其中，R1取自烷基、取代烷基、酰基、烷氧酰基；R2取自氨甲酰基、氨乙酰基、氨丙酰基。R3和R4取自氢原子、烷基、取代烷基、烷氧基、酰氧基、羟基、氨基、苯基、取代苯基、吡啶基、乙烯基。
本发明中优选的化合物为：
本发明中，所述的“药学上可接受的盐”，具体地可列举为与氢卤酸、硫酸、磷酸、硝酸等无机酸，以及枸橼酸、富马酸、马来酸、草酸、苹果酸、乳酸、樟脑磺酸等有机酸形成的盐。
本发明的另一个目的是提供上述化合物或这些化合物在药学上可接受的盐以及包含该化合物或其盐的组合物用于制备预防或治疗与肿瘤相关疾病的药物中的应用。
所述的与肿瘤相关疾病具体可列举为甲状腺癌、头颈部鳞状细胞癌、宫颈癌、卵巢癌、乳腺癌、结直肠癌、胰腺癌、食管癌、骨肉瘤、肾癌、胃癌、肺癌、肝癌、黑色素瘤、淋巴瘤、前列腺癌、膀胱癌、脑胶质瘤、鼻咽癌，神经内分泌癌、未分化癌、间质肉瘤、绒癌、恶性葡萄胎、恶性畸胎瘤等，以及良性肿瘤，但不受限于此。
本发明目标化合物(本发明的实施例中以化合物36为例)进行了体外抑制人肿瘤细胞增殖活性测试实验，结果显示，所述的二芳基取代稠杂环类化合物抑制肿瘤细胞增殖活性；经抑制微管蛋白聚集实验：体外微管蛋白自组装实验结果显示，所述的化合物能明显抑制微管蛋白聚集；抑制微管蛋白聚集实验：免疫荧光检测微管蛋白形态实验结果显示所述的能明显抑制微管的聚集；经生物素探针下拉实验，通过连接生物素考察化合物36与Katanin的相互作用，免疫荧光显色证实，化合物可以和Katanin蛋白发生结合作用；经微量热泳动实验：测定目标化合物与Katanin蛋白结合的热力学常数结果表明所述化合物和Katanin有明显的结合；经siRNA转染实验，结果表明Katanin蛋白为所述化合物发挥抗肿瘤作用的直接靶点之一；经抑制血管生成实验表明所述化合物能明显抑制HUVEC细胞生成毛细血管样结构；集落抑制实验结果显示所述化合物能明显抑制肿瘤细胞集落的形成；体外细胞周期实验，结果显示所述化合物能明显将细胞阻滞于G2/M期；经体外细胞周期相关蛋白检测实验，结果显示所述化合物能明显促进磷酸化组蛋白H3、细胞周期蛋白B1及有丝分裂相关蛋白P21的表达；经体外细胞凋亡实验结果显示所述化合物能明显促进细胞凋亡；经体外凋亡相关蛋白检测实验结果显示所述化合物能明显促进促凋亡蛋白Bad、抑癌蛋白p53、DNA修复酶-1的表达；进一步惊醒了动物水平的肿瘤治疗作用实验，结果显示化合物在体内能明显抑制肿瘤生长，并且对小鼠体重无明显影响。
本发明提供并证明了具有显著抗肿瘤作用的二芳基取代稠杂环类化合物或其在药学上可接受的盐，通过作用于Tubulin/Katanin双靶点抑制微管蛋白聚集、抑制肿瘤细胞生长的调控机制，在体外、体内的抗肿瘤实验中对肿瘤的生长具有良好的抑制作用。
附图说明
图1.化合物36体外抑制微管蛋白聚集曲线图，显示化合物36能明显抑制微管蛋白聚集。
图2.共聚焦显微镜观察的微管蛋白的形态，显示化合物36明显抑制微管蛋白聚集。
图3.下拉实验显示生物素附着探针分子44可以和Katanin蛋白发生结合。
图4.微量热泳动实验显示化合物36和Katanin有明显的结合，其Kd值为12.7±2.0μM。
图5.Katna(Katanin蛋白)沉默实验，结果表明化合物36的IC50值从0.34增加到1.48μM，说明Katanin蛋白为化合物发挥抗肿瘤作用的直接靶点之一。
图6.倒置相差显微镜下观察的毛细血管形成情况，显示化合物36明显抑制HUVEC细胞生成毛细血管样结构。
图7.集落抑制实验结果，显示化合物36明显抑制肿瘤细胞集落的形成。
图8.体外细胞周期实验结果，显示化合物36明显将细胞阻滞于G2/M期。
图9.体外细胞周期相关蛋白检测实验结果，显示化合物36明显促进磷酸化组蛋白H3、细胞周期蛋白B1和有丝分裂相关蛋白P21表达。
图10.体外细胞凋亡实验结果，显示化合物36能明显促进细胞凋亡。
图11.体外凋亡相关蛋白检测实验结果，显示化合物36能明显促进促凋亡蛋白Bad、抑癌基因p53和剪切的DNA修复酶的表达。
图12.动物水平的肿瘤治疗作用，实验结果显示化合物36在体内明显抑制肿瘤生长，对小鼠体重无明显影响。
具体实施方式
下面结合实施例进一步说明本发明。这些实施例只是用于进一步说明本发明，并不改变本发明的保护范围。本发明目标化合物的制备方法可以进一步用代表性化合物制备过程体现如下：
实施例1化合物7-(4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(1)的合成
本发明按如下路线合成目标化合物1：
1.1 3-溴-5-硝基-4-(3,4,5-三甲氧基苯基氨基)吡啶(1c)的合成
100mL三口瓶中加入3-溴-4-氯-5-硝基吡啶(1a，2.4g，10mmol)、3,4,5-三甲氧基苯胺(1b，2.0g，11mmol)、无水THF(15mL)和无水三乙胺(1.5mL,11mmol)，室温搅拌18小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝50:1，v/v)，收集对应的洗脱液，蒸干溶剂得橙黄色固体化合物(1c)3.0g，收率78％；Mp:159.3-161.5℃.1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.79(s,1H),8.74(s,1H),6.40(s,2H),3.69(s,6H),3.61(s,3H).13C NMR(150MHz,DMSO-d6)δ154.3,152.7,146.2,141.0,135.8,135.6,134.0,112.1,97.6,59.9,55.5.ESI-MS(m/z):384.2(M+H+).ESI-HRMS(m/z):calcd forC14H15BrN3O5(M+H+),384.019；found,384.0183.
1.2 5-溴-N4-(3,4,5-三甲氧基苯基)吡啶-3,4-二胺(1d)的合成
在50mL三口瓶中加入1c(0.76g，2.0mmol)、氯化亚锡(1.7g,12.0mmol)和甲醇(10mL)，回流搅拌5小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥，蒸干溶剂得黄色固体化合物(1d)0.53g，收率76％；Mp:121.2-122.6℃.1H NMR(400MHz,DMSO-d6)δ7.98(s,2H),7.66(s,1H),5.93(s 1H),5.32(s,2H),3.65(s,6H),3.56(s,3H).13C NMR(100MHz,DMSO-d6)δ153.5,141.9,139.4,138.7,134.9,132.7,118.0,93.8,60.6,59.9,56.0.ESI-MS(m/z):354.2(M+H+).ESI-HRMS(m/z):calcd for C14H17BrN3O3(M+H+),354.0448；found,354.0457.
1.3 7-溴-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(1e)的合成
在50mL茄型瓶中加入化合物1d(0.43g,1.2mmol)和二氯甲烷(30mL)搅拌溶解，冰浴下分批加入三光气(0.57g,1.9mmol)，搅拌5min，撤去冰浴室温反应。5h后TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1,v/v)，收集对应的洗脱液，蒸干溶剂得橙色固体化合物(1e)0.30g，收率78％；Mp:310.2-310.8℃.1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.23(d,J＝6.5Hz,2H),6.85(s,2H),3.76(s,6H),3.73(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,152.4,144.2,137.9,133.7,128.5,128.3,127.4,107.7,99.0,60.0,56.0.ESI-MS(m/z):380.2(M+H+).ESI-HRMS(m/z):calcd forC15H15BrN3O4(M+H+),380.0240；found,380.0235.
1.4化合物7-(4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(1)的合成
在25mL史莱克管中加入化合物1e(57mg,0.15mmol)，对甲氧基苯硼酸(27mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(1)0.047g，收率78％；Mp:200.2-201.3℃.1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),8.27(s,1H),8.06(s,1H),6.92(d,J＝6.8Hz,2H),6.61(d,J＝6.9Hz,2H),6.33(s,2H),3.65(s,3H),3.56(s,3H).13C NMR(150MHz,DMSO-d6)δ158.1,153.3,152.1,143.2,136.9,133.1,129.8,129.5,128.2,126.1,119.4,112.6,105.9,59.8,55.6,54.9.ESI-MS(m/z):408.3(M+H+).ESI-HRMS(m/z):calcd for C22H22N3O5(M+H+),408.1554；found,408.1547..
实施例2化合物7-(3-羟基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(2)的合成
在25mL史莱克管中加入化合物1e(57mg,0.15mmol)，3-羟基-4-甲氧基苯硼酸(30mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(2)0.046g，收率73％；Mp:193.2-194.1℃.1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.79(s,1H),8.25(s,1H),8.02(s,1H),6.58(d,J＝8.3Hz,1H),6.42(d,J＝2.1Hz,1H),6.35(dd,J＝8.2,2.1Hz,1H),6.32(s,2H),3.65(s,3H),3.57(s,6H),3.56(s,3H).13C NMR(150MHz,DMSO-d6)δ153.3,152.0,146.6,145.5,143.1,136.8,133.0,129.5,128.1,126.6,126.1,119.8,116.3,111.1,105.7,59.7,55.6,55.5.ESI-MS(m/z):424.3(M+H+).ESI-HRMS(m/z):calcd for C22H22N3O6(M+H+),424.1503；found,424.1496.。
实施例3 7-(3-氟-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(3)的合成
在25mL史莱克管中加入化合物1e(57mg,0.15mmol)，对3-氟-4-甲氧基苯硼酸(30mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(3)0.045g，收率71％；Mp:183.2-184.4℃.1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.29(d,J＝4.7Hz,1H),8.07(d,J＝4.6Hz,1H),6.89(s,2H),6.80(d,J＝13.8Hz,1H),6.39(d,J＝4.7Hz,2H),3.74(s,3H),3.58(s,4H),3.57(s,6H).13C NMR(150MHz,DMSO-d6)δ153.3,152.2,150.9,149.3,146.1,146.1,143.0,136.9,133.3,129.5,128.5,126.7,126.7,126.1,125.0,118.4,116.8,116.7,112.8,106.0,59.6,55.9,55.7.ESI-MS(m/z):426.2(M+H+).ESI-HRMS(m/z):calcdfor C22H21FN3O5(M+H+),426.1387；found,426.1392.。
实施例4 7-(4-甲氧基苯基)-1-(3,4,5-三甲氧基苄基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(4)的合成
本发明按如下路线合成目标化合物4：
4.1 3-溴-5-硝基-4-(3,4,5-三甲氧基苯甲氨基)吡啶(4c)的合成
在100mL三口瓶中加入3-溴-4-氯-5-硝基吡啶(1a，2.4g，10mmol)、3,4,5-三甲氧基苄胺(4b，2.2g，11mmol)、无水THF(15mL)和无水三乙胺(1.5mL,11mmol)，室温搅拌18小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝50:1，v/v)，收集对应的洗脱液，蒸干溶剂得黄色固体化合物(4c)3.4g，收率85％；Mp:123.6-124.5℃.1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.58(s,1H),7.55(s,1H),6.53(s,2H),4.43(s,2H),3.70(d,J＝3.0Hz,6H),3.62(d,J＝3.0Hz,4H).13C NMR(150MHz,DMSO-d6)δ153.5,152.7,146.4,144.4,136.6,134.1,132.8,109.7,104.7,59.8,55.6,48.6.ESI-MS(m/z):398.0(M+H+).ESI-HRMS(m/z):calcd for C15H17BrN3O5(M+H+),398.0346；found,398.0340.
4.2 7-溴-1-(3,4,5-三甲氧基苄基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(4e)的合成
在50mL三口瓶中加入化合物4c(0.78g，2.0mmol)、氯化亚锡(1.7g,12.0mmol)和甲醇(10mL)，回流搅拌5小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥，蒸干溶剂得黄色固体化合物(4d)0.52g，收率72％；ESI-MS(m/z):368.7(M+H+).
在50mL茄型瓶中加入5-溴-N4-(3,4,5-三甲氧基苄基)吡啶-3,4-二胺(4d,0.45g,1.2mmol)，二氯甲烷(30mL)搅拌溶解，冰浴下分批加入三光气(0.57g,1.9mmol)，搅拌5min，撤去冰浴室温反应。5h后TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(4e)0.34g，收率72％；Mp:294.2-295.3℃.1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.28(s,1H),8.26(s,1H),6.89(s,2H),4.40(s,2H),3.8(s,6H),3.76(s,3H).13C NMR(150MHz,DMSO-d6)δ153.1,152.3,14402,137.7,133.5,128.3,128.1,127.2,107.5,98.8,59.8,56.6,48.6.ESI-MS(m/z):394.2(M+H+).ESI-HRMS(m/z):calcd for C16H17BrN3O4(M+H+),394.0133；found,394.0135.4.3 7-苯基-1-(3,4,5-三甲氧基苄基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(4)的合成
在25mL史莱克管中加入化合物4e(59mg,0.15mmol)，对甲氧基苯硼酸(27mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(4)47mg，收率75％；Mp:164.1-164.5℃.1H NMR(400MHz,DMSO-d6)δ11.43(br s,1H),8.24(s,1H),7.91(s,1H),7.16-7.18(m,2H),6.92(d,J＝7.9Hz,2H),5.76(s,2H),4.73(s,2H),3.79(s,3H),3.56(s,3H),3.52(s,6H).13C NMR(150MHz,DMSO-d6)δ158.7,154.4,152.4,143.4,136.3,132.5,132.1,130.9,128.3,126.4,126.0,119.5,113.2,103.1,59.7,55.3,54.9,44.3.ESI-MS(m/z):422.2(M+H+).ESI-HRMS(m/z):calcd for C23H24N3O5(M+H+),422.1710；found,422.1704.。
实施例5 7-(3-羟基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苄基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(5)的合成
在25mL史莱克管中加入化合物4e(57mg,0.15mmol)，3-羟基-4-甲氧基苯硼酸(30mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(5)42mg，收率64％；Mp:164.1-164.5℃.1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),9.24(s,1H),8.21(s,1H),7.91(s,1H),6.93(d,J＝7.8Hz,1H),6.67-6.71(m,2H),5.85(s,2H),4.77(s,2H),3.81(s,3H),3.54(s,9H).13C NMR(150MHz,DMSO-d6)δ154.4,152.4,147.4,145.9,143.3,132.1,128.1,121.0,116.9,111.3,103.5,59.7,55.3,44.4.ESI-MS(m/z):438.2(M+H+).ESI-HRMS(m/z):calcdfor C23H24N3O6(M+H+),438.1660；found,438.1653.。
实施例6 2-甲氧基-5-[1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶-7-基]苯酚(6)的合成
本发明按如下路线合成目标化合物6：
6.1 7-溴-1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶(6e)的合成
在50mL茄型瓶中加入化合物1d(0.43g,1.2mmol)和10mL甲酸，回流反应。4h后TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得米白色固体化合物(6e)0.24g，收率55％；Mp:199.1-199.6℃.1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.59(s,1H),8.47(s,1H),7.02(s,2H),3.78(s,6H),3.72(s,3H).13C NMR(150MHz,DMSO-d6)δ152.4,147.4,144.2,141.4,141.2,138.0,136.0,129.7,106.4,101.4,60.0,56.1.ESI-MS(m/z):364.2(M+H+).ESI-HRMS(m/z):calcdfor C15H15BrN3O3(M+H+),364.0219；found,364.0211.
6.2 2-甲氧基-5-[1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶-7-基]苯酚(6)的合成
在25mL史莱克管中加入化合物6e(55mg,0.15mmol)，3-羟基-4-甲氧基苯硼酸(30mg,0.18mmol)，碳酸铯(96mg,0.3mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(6)47mg，收率77％；Mp:244.4-244.5℃.1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.87(s,1H),8.54(s,1H),8.23(s,1H),6.64(d,J＝8.2Hz,1H),6.52(d,J＝2.0Hz,1H),6.46(s,2H),6.41(dd,J＝8.2,2.0Hz,1H),3.67(s,3H),3.59(s,3H),3.56(s,6H).13C NMR(150MHz,DMSO-d6)δ152.3,146.9,146.4,145.8,142.3,140.6,137.0,135.4,130.8,126.9,122.5,120.0,116.4,111.4,104.1,59.8,55.6.ESI-MS(m/z):408.2(M+H+).ESI-HRMS(m/z):calcd for C22H22N3O5(M+H+),408.1554；found,408.1544.。
实施例7 6-(4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(7)的合成
本发明按如下路线合成目标化合物7：
7.1 2-氯-5-硝基-N-(3,4,5-三甲氧基苯基)吡啶-4-胺(7c)的合成
在100mL三口瓶中加入2,4-二氯-5-硝基吡啶(7a，2.4g，10mmol)、3,4,5-三甲氧基苯胺(1b，2.0g，11mmol)、无水乙酸(15mL)和无水乙酸钠(3.2g,40mmol)，75℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝70:1，v/v)，收集对应的洗脱液，蒸干溶剂得黄色固体化合物(7c)2.5g，收率75％；Mp:241.4-241.5℃.1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.77(s,1H),8.72(s,1H),6.38(s,2H),3.66(s,6H),3.59(s,3H).13CNMR(150MHz,DMSO-d6)δ154.4,152.8,149.2,141.1,135.8,135.6,134.1,112.1,97.7,60.0,55.6,55.3.ESI-MS(m/z):340.1(M+H+).ESI-HRMS(m/z):calcd for C14H15ClN3O5(M+H+),340.0695；found,340.0692.
7.2 6-氯-N4-(3,4,5-三甲氧基苯基)吡啶-3,4-二胺(7d)的合成
50mL三口瓶中加入化合物7c(0.76g，2.0mmol)、氯化亚锡(1.7g,12mmol)和甲醇(10mL)，回流搅拌5小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥，蒸干溶剂得黄色固体化合物(7d)0.47g，收率77％；Mp:129.2-129.5℃.1H NMR(400MHz,DMSO-d6)δ7.69(s,1H),7.58(s,1H),6.75(s,1H),6.48(s2H),5.02(s,2H),3.75(s,6H),3.64(s,3H).13C NMR(100MHz,DMSO-d6)δ153.8,140.9,139.1,136.7,134.5,133.9,132.9,99.6,60.6,56.3.ESI-MS(m/z):310.2(M+H+).ESI-HRMS(m/z):calcd for C14H17ClN3O3(M+H+),310.0953；found,310.0962.
7.3 6-氯-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(7e)的合成
在50mL茄型瓶中加入化合物7d(0.38g,1.2mmol)，二氯甲烷30mL搅拌溶解，冰浴下分批加入三光气(0.57g,1.9mmol)，搅拌5min，撤去冰浴室温反应。5h后TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得橙白色固体化合物(7e)0.28g，收率70％；Mp:307.2-307.5℃.1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.03(s,1H),7.03(s,1H),6.82(s,2H),3.77(s,6H),3.70(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,141.6,139.1,137.2,128.5,128.1,125.8,104.3,103.3,59.9,56.0.ESI-MS(m/z):336.1(M+H+).ESI-HRMS(m/z):calcd forC15H15ClN3O4(M+H+),336.0743；found,336.0746.
7.4化合物6-(4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(7)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，对甲氧基苯硼酸(27mg,0.18mmol)，碳酸铯(96mg,0.3mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(7)44mg，收率72％；Mp:265.3-265.7℃.1H NMR(600MHz,DMSO-d6)δ11.34(s,2H),8.32(s,1H),7.96(d,J＝8.7Hz,2H),7.41(s,1H),6.97(d,J＝8.7Hz,2H),6.89(s,2H),3.82(s,6H),3.79(s,3H),3.75(s,3H).13C NMR(150MHz,DMSO-d6)δ159.3,153.2,153.1,149.5,137.7,136.9,131.7,129.0,128.9,127.5,124.6,113.7,104.3,99.2,59.9,56.0,55.0.ESI-MS(m/z):408.1(M+H+).ESI-HRMS(m/z):calcd for C22H22N3O5(M+H+),408.1554；found,408.1548.。
实施例8 6-(3-羟基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(8)的合成
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8.1 6-(3-苄氧基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(8a)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，3-苄氧基-4-甲氧基苯硼酸(46mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2.CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(8a)73mg，收率77％；Mp:246.1-246.5℃.1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.40(s,1H),8.40(s,1H),7.77(s,1H),7.61(d,J＝7.3Hz,2H),7.46(d,J＝7.0Hz,2H),7.41-7.27(m,3H),7.14(d,J＝8.5Hz,1H),6.95(s,2H),5.26(s,2H),3.84(s,3H),3.81(s,6H),3.76(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,151.6,150.3,149.6,146.3,137.1,136.6,131.6,128.7,124.3,120.0,112.3,111.8,104.2,99.8,79.2,78.1,77.6,75.5,59.9,56.0,55.9,55.4.ESI-MS(m/z):514.2(M+H+).ESI-HRMS(m/z):calcd for C29H28N3O6(M+H+),514.1973；found,514.1970.
8.2 6-(3-羟基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(8)的合成
将70mg化合物8a溶于15mL EtOH中，向混合物中加入10％Pd/C(7mg)，将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(8)50mg，收率88％；Mp:325.3-325.5℃.1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.06(s,1H),8.30(s,1H),7.46(s,1H),7.39(d,J＝8.6Hz,1H),7.31(s,1H),6.92(d,J＝8.4Hz,1H),6.88(s,2H),3.81(s,6H),3.78(s,3H),3.74(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,153.1,149.6,147.9,146.3,137.6,136.9,132.0,129.1,128.8,124.5,117.1,113.3,111.9,104.3,103.9,99.1,59.9,56.0,55.4.ESI-MS(m/z):424.2(M+H+).ESI-HRMS(m/z):calcd forC22H22N3O6(M+H+),424.1503；found,424.1496.。
实施例9 6-(3-氟-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(9)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，3-氟-4-甲氧基苯硼酸(29mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(9)42mg，收率67％；Mp:228.1-228.7℃.1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.06(s,1H),8.30(s,1H),7.46(s,1H),7.39(d,J＝8.6Hz,1H),7.31(s,1H),6.92(d,J＝8.4Hz,1H),6.88(s,2H),3.81(s,6H),3.78(s,3H),3.74(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,153.1,149.6,147.9,146.3,137.6,136.9,132.0,129.1,128.8,124.5,117.1,113.3,111.9,104.3,103.9,99.1,59.9,56.0,55.4.ESI-MS(m/z):426.2(M+H+).ESI-HRMS(m/z):calcd for C22H21FN3O5(M+H+),426.1460；found,426.1454.。
实施例10 3-[2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-6-基]苯甲酸甲酯(10)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，3-(甲氧基羰基)苯基硼酸(32mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(10)50mg，收率77％；Mp:264.5-264.7℃.1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.39(s,1H),8.24(d,J＝7.7Hz,1H),7.91(d,J＝7.6Hz,1H),7.55(d,J＝7.1Hz,2H),6.88(s,2H),3.85(s,3H),3.79(s,6H),3.72(s,3H).13C NMR(150MHz,DMSO-d6)δ166.1,153.2,153.1,148.2,139.5,137.6,137.0,130.7,129.8,129.2,128.9,128.9,128.5,126.8,125.4,104.3,100.3,59.9,56.0,52.0.ESI-MS(m/z):436.1(M+H+).ESI-HRMS(m/z):calcd for C22H22N3O5(M+H+),435.1554；found,436.1448.。
实施例11 6-(6-甲氧基吡啶-3-基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(11)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，(6-甲氧基吡啶-3-基)硼酸(28mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得棕色固体化合物(11)46mg，收率75％；Mp:259.0-259.5℃.1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.79(s,1H),8.35(s,1H),8.31(d,J＝9.0Hz,1H),7.52(s,1H),6.88(s,2H),6.84(s,1H),3.88(s,3H),3.81(s,6H),3.74(s,3H).13C NMR(150MHz,DMSO-d6)δ163.3,153.2,153.1,147.4,144.8,137.6,136.9,129.1,128.9,128.6,124.9,109.9,104.0,99.6,59.9,55.9,53.0.ESI-MS(m/z):409.2(M+H+).ESI-HRMS(m/z):calcd for C29H28N3O6(M+H+),409.1506；found,409.1498.。
实施例12 6-(4-乙氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(12)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，对乙氧基苯硼酸(30mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(12)47mg，收率74％；Mp:215.2-215.5℃.1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.31(s,1H),7.93(d,J＝8.7Hz,2H),7.40(s,1H),6.94(d,J＝8.7Hz,2H),6.88(s,2H),4.04(d,J＝6.9Hz,2H),3.81(s,6H),3.74(s,3H),1.33(t,J＝6.9Hz,3H).13C NMR(150MHz,DMSO-d6)δ158.6,153.2,153.1,149.5,137.7,136.9,131.6,129.1,128.9,127.5,124.5,114.2,104.3,99.2,62.9,59.9,56.0,14.5.ESI-MS(m/z):422.2(M+H+).ESI-HRMS(m/z):calcd for C23H24N3O5(M+H+),422.1710；found,422.1701.。
实施例13 6-(4-乙氧基-3-氟苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(13)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，对3-氟-4-乙氧基苯硼酸(32mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(13)47mg，收率72％；Mp:234.2-234.7℃.1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.86(d,J＝13.5Hz,1H),7.78(d,J＝8.2Hz,1H),7.47(s,1H),7.15(d,J＝9.1Hz,1H),6.85(s,2H),4.11(q,J＝6.8Hz,2H),3.79(s,6H),3.73(s,3H),1.33(s,3H).13C NMR(150MHz,DMSO-d6)δ153.1,153.1,148.2,137.7,136.9,129.4,128.9,124.9,122.3,114.4,113.6,113.5,104.3,99.6,64.1,59.9,56.0,14.4.ESI-MS(m/z):440.3(M+H+).ESI-HRMS(m/z):calcd for C23H23FN3O5(M+H+),440.1616；found,440.1612.。
实施例14 6-(4-甲氧基-3-甲基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(14)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，3-甲基-4-甲氧基苯硼酸(30mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(14)44mg，收率67％；Mp:263.2-263.5℃.1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.31(s,1H),7.81(d,J＝5.8Hz,2H),7.39(s,1H),6.95(d,J＝9.2Hz,1H),6.88(s,2H),3.81(s,9H),3.75(s,3H),2.19(s,3H).13C NMR(150MHz,DMSO-d6)δ157.4,153.1,153.1,149.7,137.6,136.9,131.2,129.0,128.8,128.2,125.3,124.9,124.5,110.1,104.3,99.1,59.9,56.0,55.1,15.9.ESI-MS(m/z):422.3(M+H+).ESI-HRMS(m/z):calcd for C23H24N3O5(M+H+),422.1716；found,422.1791.。
实施例15 6-(3-氨基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(15)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，3-氨基-4-甲氧基苯硼酸(30mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(15)42mg，收率65％；Mp:259.1-259.7℃.1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.29(s,1H),7.23(s,1H),7.17(d,J＝8.2Hz,1H),6.86(s,2H),6.79(d,J＝8.6Hz,1H),4.74(s,2H),3.79(s,6H),3.75(s,3H),3.72(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,153.1,150.2,146.6,137.5,137.3,136.9,131.9,129.1,128.7,124.4,114.3,111.5,110.2,104.3,98.8,59.9,56.0,55.1.ESI-MS(m/z):423.3(M+H+).ESI-HRMS(m/z):calcd for C22H23FN4O5(M+H+),423.1663；found,423.1658.。
实施例16 3-[2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-6-基]苯甲酸(16)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，3-羧基苯硼酸(29mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(16)37mg，收率62％；Mp:223.3-224.7℃.1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.29(s,1H),7.87(d,J＝7.5Hz,1H),7.76(d,J＝7.3Hz,1H),7.31(s,1H),7.25(t,J＝7.6Hz,1H),6.79(s,2H),3.70(s,6H),3.64(s,3H).13CNMR(150MHz,DMSO-d6)δ168.9,153.2,149.7,138.3,137.6,137.0,129.1,129.0,128.7,127.4,127.0,126.9,125.2,104.3,99.7,59.9,56.0.ESI-MS(m/z):422.2(M+H+).ESI-HRMS(m/z):calcd for C22H23N3O6(M+H+),422.1254；found,422.15278.。
实施例17 2-甲氧基-5-[2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-6-基]苯甲酸(17)的合成
在25mL史莱克管中加入化合物7e(50mg,0.15mmol)，5-硼-2-甲氧基苯甲酸(32mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(17)49mg，收率76％；Mp:275.3-275.6℃.1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.90(s,1H),7.80(d,J＝8.0Hz,1H),7.30(s,1H),6.91(d,J＝8.0Hz,1H),6.88(s,2H),3.80(s,6H),3.74(s,6H).13C NMR(150MHz,DMSO-d6)δ156.1,153.3,153.2,149.7,137.7,137.0,130.7,129.2,120.0,126.4,125.6,124.7,111.4,104.3,98.9,60.0,56.0,55.3.ESI-MS(m/z):452.1(M+H+).ESI-HRMS(m/z):calcdfor C23H22N3O7(M+H+),452.1334；found,452.1338.。
实施例18 6-(4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶(18)的合成
本发明按如下路线合成目标化合物18：
18.1 6-氯-N4-(3,4,5-三甲氧基苯基)吡啶-3,4-二胺(7d)的合成
在50mL三口瓶中加入2-氯-5-硝基-4-(3,4,5-三甲氧基苯基氨基)吡啶(7c，0.76g，2.0mmol)、氯化亚锡(1.7g,12.0mmol)和甲醇(10mL)，回流搅拌5小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥，蒸干溶剂得黄色固体化合物(7d)0.47g，收率77％；Mp:129.2-129.5℃.1H NMR(400MHz,DMSO-d6)δ7.69(s,1H),7.58(s,1H),6.75(s,1H),6.48(s 2H),5.02(s,2H),3.75(s,6H),3.64(s,3H).13C NMR(100MHz,DMSO-d6)δ153.8,140.9,139.1,136.7,134.5,133.9,132.9,99.6,60.6,56.3.ESI-MS(m/z):310.2(M+H+).ESI-HRMS(m/z):calcd for C14H17ClN3O3(M+H+),310.0953；found,310.0962.
18.2 6-氯-1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶(18e)的合成
在50mL茄型瓶中加入化合物7d(0.38g,1.2mmol)和10mL甲酸，回流反应。10h后TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得棕色固体化合物(18e)0.20g，收率55％；Mp:183.3-183.6℃.1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.33(s,1H),8.15(s,1H),6.53(s,2H),3.76(s,6H),3.66(s,3H).13C NMR(150MHz,DMSO-d6)δ160.6,153.2,147.7,147.6,145.8,134.8,134.4,119.7,106.2,102.0,100.4,59.9,55.8.ESI-MS(m/z):338.1(M+H+).ESI-HRMS(m/z):calcd for C20H17ClN3O3(M+H+),338.0902；found,338.0898.
18.3 6-(4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶(18)的合成
在25mL史莱克管中加入化合物18e(50mg,0.15mmol)，3-羟基-4-甲氧基苯硼酸(27mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(18)42mg，收率72％；Mp:291.3-291.6℃.1H NMR(400MHz,DMSO-d6)δ9.08(d,J＝9.6Hz,2H),8.66(s,1H),7.95(s,1H),7.63(s,1H),7.57(d,J＝7.6Hz,1H),7.07(s,2H),6.98(d,J＝7.6Hz,1H),3.89(s,7H),3.81(s,3H),3.75(s,3H).13C NMR(150MHz,DMSO-d6)δ153.6,150.1,148.0,146.4,145.3,141.5,139.6,139.2,137.0,132.1,130.7,117.7,113.9,112.0,102.0,101.1,60.0,56.2,55.4.ESI-MS(m/z):408.2(M+H+).ESI-HRMS(m/z):calcd for C22H22N3O5(M+H+),408.1554；found,408.1548.。
实施例19 2-甲氧基-5-[1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶-6-基]苯甲酸(19)的合成
在25mL史莱克管中加入化合物18e(50mg,0.15mmol)，5-硼-2-甲氧基苯甲酸(32mg,0.18mmol)，碳酸铯(96mg,0.30mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(19)41mg，收率64％；Mp:283.3-283.6℃.1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.67(s,1H),8.34(s,1H),8.18(d,J＝8.2Hz,1H),8.06(s,1H),7.12(d,J＝8.8Hz,1H),7.07(s,2H),3.88(s,6H),3.83(s,3H),3.75(s,3H).13C NMR(150MHz,DMSO-d6)δ168.2,157.5,153.6,149.4,145.4,141.6,139.7,139.2,137.0,131.0,130.7,129.4,128.4,112.1,102.0,101.5,60.0,56.2,55.6.ESI-MS(m/z):436.3(M+H+).ESI-HRMS(m/z):calcd for C23H22N3O6(M+H+),436.1334；found,436.1438.。
实施例20 1-(3-羟基-4-甲氧基苯基)-6-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(20)的合成
本发明按如下路线合成目标化合物20：
20.1N-(3-[苄氧基)-4-甲氧基苯基]-2-氯-5-硝基吡啶-4-胺(20c)的合成
在100mL三口瓶中加入2,4-二氯-5-硝基吡啶(7a，2.4g，10mmol)、3-(苄氧基)-4-甲氧基苯胺(20b，2.5g，11mmol)、无水乙酸(15mL)和无水乙酸钠(3.2g,40mmol)，75℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝70:1，v/v)，收集对应的洗脱液，蒸干溶剂得橘黄色固体化合物(20c)3.2g，收率78％；Mp:148.3-148.5℃.1HNMR(400MHz,DMSO-d6)δ9.88(s,1H),8.95(d,J＝1.1Hz,1H),7.33-7.45(m,5H),7.09(s,1H)7.08(s,1H),6.92(d,J＝8.4Hz,1H),6.60(s,1H),6.56-6.42(m,1H),5.09(s,2H),3.81(s,3H).13C NMR(150MHz,DMSO-d6)δ154.3,148.9,148.6,148.2,148.1,136.5,129.6,129.2,128.2,127.7,127.6,118.7,112.4,112.1,107.9,69.8,55.6.ESI-MS(m/z):386.1(M+H+).ESI-HRMS(m/z):calcd for C14H15ClN3O5(M+H+),386.0902；found,386.0899.
20.2N4-[3-(苄氧基)-4-甲氧基苯基]-6-氯吡啶-3,4-二胺(20d)的合成
50mL三口瓶中加入化合物20c(0.77g，2.0mmol)、氯化亚锡(1.7g,12mmol)和甲醇(10mL)，回流搅拌5小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥，蒸干溶剂得黄色固体化合物(20d)0.45g，收率73％；ESI-MS(m/z):356.1(M+H+).
20.3 1-[3-(苄氧基)-4-甲氧基苯基]-6-氯-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(20e)的合成
在50mL茄型瓶中加入化合物20d(0.43g,1.2mmol)，二氯甲烷30mL搅拌溶解，冰浴下分批加入三光气(0.57g,1.9mmol)，搅拌5min，撤去冰浴室温反应。5h后TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得黄色固体化合物(20e)0.30g，收率67％；Mp:168.3-168.8℃.1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.05(s,1H),7.50-7.29(m,5H),7.19(d,J＝7.9Hz,1H),7.14(d,J＝7.9Hz,1H),7.06(s,1H),7.06(s,1H),6.78(s,1H),5.11(s,2H),3.84(s,3H).13CNMR(150MHz,DMSO-d6)δ153.1,148.9,147.8,141.6,139.1,136.5,128.2,128.1,127.8,127.7,125.6,125.3,119.1,112.1,111.9,102.9,69.8,55.6.ESI-MS(m/z):382.1(M+H+).ESI-HRMS(m/z):calcd for C20H17ClN3O3(M+H+),382.0880；found,382.0870.
20.4 1-[3-(苄氧基)-4-甲氧基苯基]-6-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(20f)的合成
在25mL史莱克管中加入化合物20e(57mg,0.15mmol)，3,4,5-三甲氧基苯硼酸(36mg,0.18mmol)，碳酸铯(96mg,0.3mmol)和PdCl2(dppf)2·CH2Cl2(12mg,0.015mmol)，置换氮气三次，加入8mL二氧六环和2mL纯净水。加热至回流，反应过夜，TLC显示原料反应完全，停止加热，冷却至室温。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(20f)59mg，收率77％；Mp:211.3-211.7℃.1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.36(s,1H),7.44(d,J＝7.4Hz,2H),7.39-7.32(m,3H),7.29(s,2H),7.21(s,2H),7.15(d,J＝7.4Hz,2H),5.10(s,2H),3.84(s,3H),3.81(s,6H),3.69(s,3H).13C NMR(150MHz,DMSO-d6)δ153.3,152.8,149.6,148.6,148.0,137.7,137.5,136.6,135.1,128.8,128.2,127.8,127.8,126.0,125.0,119.0,112.1,1117,103.9,100.1,70.0,59.9,55.8,55.6.ESI-MS(m/z):514.2(M+H+).ESI-HRMS(m/z):calcd for C29H28N3O6(M+H+),514.1973；found,514.1966.
20.5 1-[3-(苄氧基)-4-甲氧基苯基]-6-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(20)的合成
将50mg化合物20f溶于15mL EtOH中，向混合物中加入10％Pd/C(7mg)，将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(20)40mg，收率95％；Mp:325.1-325.3℃.1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),9.45(s,1H),8.35(s,1H),7.39(s,1H),7.23(s,2H),7.09(d,J＝9.1Hz,1H),7.03-6.91(m,2H),3.85(s,2H),3.84(s,3H),3.83(s,6H),3.69(s,3H).13C NMR(150MHz,DMSO-d6)δ153.3,152.8,149.4,147.3,146.9,137.8,137.5,135.1,128.9,126.1,125.0,116.8,113.5,112.3,103.8,99.9,59.9,55.9,55.6.ESI-MS(m/z):424.2(M+H+).ESI-HRMS(m/z):calcd for C23H23FN3O5(M+H+),424.1503；found,424.1496.。
实施例21 2-甲氧基-5-[1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶-2-基]苯酚(21)的合成
本发明按如下路线合成目标化合物21：
21.1 3-硝基-N-(3,4,5-三甲氧基苯基)吡啶-4-胺(21b)的合成
在100mL三口瓶中加入4-氯-3-硝基吡啶(21a，1.6g，10mmol)、3,4,5-三甲氧基苯胺(2.0g，11mmol)、无水乙酸(15ml)和无水乙酸钠(3.2g,40mmol)，75℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝70:1，v/v)，收集对应的洗脱液，蒸干溶剂得黄色固体化合物(21b)2.3g，收率75％；Mp:169.3-170.5℃.1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.79(s,1H),8.76(s,1H),8.71(s,1H),6.40(s,2H),3.69(s,6H),3.61(s,3H).13C NMR(150MHz,DMSO-d6)δ154.3,152.7,146.2,141.0,135.8,135.6,134.0,112.1,97.6,59.9,55.5.ESI-MS(m/z):306.2(M+H+).ESI-HRMS(m/z):calcd for C14H15BrN3O5(M+H+),306.1011；found,306.1210.
21.2N4-(3,4,5-三甲氧基苯基)吡啶-3,4-二胺(21c)的合成
在50mL三口瓶中加入化合物21b(0.60g，2.0mmol)、氯化亚锡(1.7g,12mmol)和甲醇(10mL)，回流搅拌5小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥，蒸干溶剂得黄色固体化合物(21c)0.46g，收率85％；Mp:131.4-132.8℃.1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.62(d,J＝8Hz,1H),7.41(s1H),6.95(d,J＝8Hz,1H),6.41(s,2H),4.86(s,2H),3.73(s,6H),3.62(s,3H).13C NMR(100MHz,DMSO-d6)δ153.8,139.4,138.1,136.8,133.7,108.9,97.6,60.4,59.1.ESI-MS(m/z):276.2(M+H+).ESI-HRMS(m/z):calcd for C14H18N3O3(M+H+),276.1343；found,276.1353.
21.3 2-甲氧基-5-[1-(3,4,5-三甲氧基苯基)-1H-咪唑并[4,5-c]吡啶-2-基]苯酚(21)的合成
在50mL茄型瓶中加入化合物21c(0.38g,1.2mmol)、3-羟基-4-甲氧基苯甲醛(0.18g,1.2mmol)和H2O(10mL)，回流搅拌5h，TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得灰色固体化合物(21)0.20g，收率55％；Mp:290.4-290.5℃.1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),9.01(s,1H),8.33(d,J＝5.5Hz,1H),7.29(d,J＝5.5Hz,1H),7.19(d,J＝1.8Hz,1H),6.92-6.96(m,2H),6.82(s,2H),3.77(s,3H),3.75(s,3H),3.70(s,6H).13C NMR(150MHz,DMSO-d6)δ153.4,153.1,149.2,145.9,141.9,141.6,141.1,139.4,137.6,131.2,121.3,120.5,116.1,111.4,106.0,105.1,60.0,56.1,55.3.ESI-MS(m/z):408.2(M+H+).ESI-HRMS(m/z):calcd for C22H22N3O5(M+H+),408.1554；found,408.1548.。
实施例22 6-(3-羟基-4-甲氧基苯基)-3-甲基-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(22)的合成
在50mL茄型瓶中加入氢化钠(60％,3.1mg,0.079mmol)、25mL无水THF和化合物8a(38mg,0.075mmol)，加热至50℃，搅拌30min。逐滴加入碘甲烷(10mg，0.083mmol)，50℃下继续搅拌2h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。蒸干溶剂得粗品白色固体化合物30mg。将粗产物溶于15mL EtOH中，向混合物中加入10％Pd/C(3.0mg)。将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(22)20mg，收率75％。Mp:217.3-217.6℃.1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.49(s,1H),7.49(s,1H),7.42(d,J＝8.0Hz,1H),7.34(s,1H),6.93(d,J＝8.0Hz,1H),6.88(s,2H),3.80(s,6H),3.78(s,3H),3.75(s,3H),3.47(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,152.5,150.0,147.9,146.3,137.0,136.3,131.9,129.0,128.2,125.8,117.2,113.3,111.9,104.2,98.9,59.9,56.0,55.4,27.2.ESI-MS(m/z):438.3(M+H+).ESI-HRMS(m/z):calcd for C23H24N3O6(M+H+),438.1660；found,438.1654.。
实施例23 3-乙基-6-(3-羟基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(23)的合成
在50mL茄型瓶中加入氢化钠(60％,3.1mg,0.079mmol)、25mL无水THF和化合物8a(38mg,0.075mmol)，加热至50℃，搅拌30min。逐滴加入溴乙烷(8.9mg，0.083mmol)，50℃下继续搅拌2h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。蒸干溶剂得粗品白色固体化合物33mg。将粗产物溶于15mL EtOH中，向混合物中加入10％Pd/C(3.0mg)。将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(23)23mg，收率65％。Mp:199.4-199.7℃.1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.54(s,1H),7.48(s,1H),7.41(d,J＝8.4Hz,1H),7.35(s,1H),6.93(d,J＝8.5Hz,1H),6.89(s,2H),4.00(d,J＝7.1Hz,2H),3.81(s,6H),3.78(s,3H),3.75(s,3H),1.33(t,J＝7.0Hz,3H).13C NMR(150MHz,DMSO-d6)δ153.2,151.9,149.9,147.9,146.3,137.0,136.4,132.0,129.0,128.2,124.8,117.2,113.3,111.9,104.3,99.0,59.9,56.0,55.4,35.7,13.3.ESI-MS(m/z):452.3(M+H+).ESI-HRMS(m/z):calcd for C24H26N3O6(M+H+),452.1816；found,452.1809.。
实施例24 6-(3-羟基-4-甲氧基苯基)-3-异丙基-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(24)的合成
在50mL茄型瓶中加入氢化钠(60％,3.1mg,0.079mmol)、25mL无水THF和化合物8a(38mg,0.075mmol)，加热至50℃，搅拌30min。逐滴加入2-溴丙烷(8.5mg，0.083mmol)，50℃下继续搅拌2h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。蒸干溶剂得粗品白色固体化合物28mg。将粗产物溶于15mL EtOH中，向混合物中加入10％Pd/C(3.0mg)。将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(24)26mg，收率73％。Mp:136.2-136.7℃.1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.64(s,1H),7.45(s,1H),7.39(d,J＝8.5Hz,1H),7.31(s,1H),6.91(d,J＝8.3Hz,1H),6.87(s,2H),4.78-4.59(m,1H),3.78(s,6H),3.76(s,3H),3.73(s,3H),1.52(d,J＝6.6Hz,6H).13C NMR(150MHz,DMSO-d6)δ153.2,151.5,149.4,147.9,146.3,137.0,136.6,131.9,128.9,124.0,117.1,113.3,111.9,104.4,99.1,59.9,56.0,55.4,44.8,19.8.ESI-MS(m/z):466.4(M+H+).ESI-HRMS(m/z):calcd for C25H28N3O6(M+H+),466.1973；found,466.1966.。
实施例25 3-环丙基-6-(3-羟基-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(25)的合成
在50mL茄型瓶中加入氢化钠(60％,3.1mg,0.079mmol)、25mL无水THF和化合物8a(38mg,0.075mmol)，加热至50℃，搅拌30min。逐滴加入溴代环丙烷(9.9mg，0.083mmol)，50℃下继续搅拌2h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。蒸干溶剂得粗品白色固体化合物28mg。将粗产物溶于15mL EtOH中。向混合物中加入10％Pd/C(3.0mg)。将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(25)24mg，收率64％。Mp:127.2-127.8℃.1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.59(s,1H),7.48(s,1H),7.41(d,J＝8.3Hz,1H),7.36(s,1H),6.94(d,J＝8.4Hz,1H),6.90(s,2H),3.85(d,J＝6.6Hz,2H),3.81(s,6H),3.77(d,J＝8.1Hz,3H),3.75(s,3H),1.27(s,1H),0.54(d,J＝7.1Hz,2H),0.47(s,2H).13C NMR(150MHz,DMSO-d6)δ153.2,152.3,149.9,147.9,146.3,137.0,136.3,131.9,129.0,128.6,125.3,117.2,113.3,111.9,104.2,99.0,59.9,56.0,55.4,45.2,10.0,3.5.ESI-MS(m/z):478.2(M+H+).ESI-HRMS(m/z):calcd for C26H28N3O6(M+H+),478.1973；found,478.1968.。
实施例26 2-[6-(3-(苄氧基)-4-甲氧基苯基)-2-氧代-1-(3,4,5-三甲氧基苯基)-1,2-二氢-3H-咪唑并[4,5-c]吡啶-3-基]乙腈(26)的合成
在50mL茄型瓶中加入氢化钠(60％,3.1mg,0.079mmol)、25mL无水THF和化合物8a(38mg,0.075mmol)，加热至50℃，搅拌30min。逐滴加入2-溴乙腈(9.9mg，0.083mmol)，50℃下继续搅拌2h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(26)24mg，收率57％。Mp:133.2-133.3℃.1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.69(s,1H),7.58(d,J＝8.3Hz,1H),7.49-7.41(m,3H),7.40-7.26(m,3H),7.02(d,J＝8.4Hz,1H),6.94(s,2H),5.29(s,2H),5.16(s,2H),3.81(s,9H),3.76(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,151.6,151.0,149.6,147.5,137.3,137.0,136.9,131.5,128.5,128.4,128.1,127.6,123.8,119.4,115.4,111.8,111.8,104.4,99.9,69.7,59.9,56.0,55.4,29.4.ESI-MS(m/z):553.2(M+H+).ESI-HRMS(m/z):calcd for C31H29N4O6(M+H+),553.1009；found,553.2109.。
实施例27 2-[6-(3-(苄氧基)-4-甲氧基苯基)-2-氧代-1-(3,4,5-三甲氧基苯基)-1,2-二氢-3H-咪唑并[4,5-c]吡啶-3-基]乙酰胺(27)的合成
在100mL三口瓶中加入化合物26(56mg，0.1mmol)、碳酸钾(56mg，0.4mmol)、H2O(10ml)和丙酮(10mL)，室温搅拌8小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝30:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(27)38mg，收率66％；Mp:147.3-147.5℃.1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.73(s,1H),7.65(s,1H),7.54(d,J＝9.0Hz,1H),7.44(s,1H),7.42(s,2H),7.38-7.25(m,4H),6.99(d,J＝8.2Hz,1H),6.86(s,2H),5.14(s,2H),4.56(s,2H),3.80(s,6H),3.78(s,3H),3.74(s,3H).13C NMR(150MHz,DMSO-d6)δ168.1,153.2,152.4,150.0,149.4,147.5,137.0,136.3,131.9,128.9,128.7,128.1,127.6,125.8,119.2,111.8,104.0,99.5,69.8,59.9,56.0,55.4,43.2.ESI-MS(m/z):571.4(M+H+).ESI-HRMS(m/z):calcd for C31H31BN4O57(M+H+),571.2113；found,571.2234.。
实施例28 2-[6-(3-羟基-4-甲氧基苯基)-2-氧代-1-(3,4,5-三甲氧基苯基)-1,2-二氢-3H-咪唑并[4,5-c]吡啶-3-基]乙酰胺(28)的合成
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将30mg化合物27溶于15mL EtOH中，向混合物中加入10％Pd/C(3.0mg)，将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(28)22mg，收率94％。Mp:295.2-295.6℃.1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.40(s,1H),7.76(s,1H),7.48(s,1H),7.37(s,3H),6.95(s,1H),6.88(s,1H),4.58(s,2H),3.82(s,6H),3.78(s,3H),3.76(s,3H).13C NMR(150MHz,DMSO-d6)δ168.1,153.2,152.3,150.1,148.0,146.3,137.0,136.3,132.0,128.9,128.7,125.7,117.2,113.4,111.9,104.1,99.1,59.9,56.0,55.4,43.2ESI-MS(m/z):481.2(M+H+).ESI-HRMS(m/z):calcd for C24H25N4O7(M+H+),481.1718；found,481.1710.。
实施例29 6-(3-(苄氧基)-4-甲氧基苯基)-3-(环丙烷羰基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(29)合成
在50mL茄型瓶中加入三乙胺(7.1mL,0.079mmol)、25mL无水THF、环丙基甲酰氯(31mg,0.15mmol)和化合物8a(38mg,0.075mmol)，室温搅拌1h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。蒸干溶剂得粗品白色固体化合物。将粗产物溶于15mL EtOH中。向混合物中加入10％Pd/C(3mg)。将溶液在H2氛围(1atm)下搅拌12h。TLC显示反应完全，过滤Pd/C，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(29)27mg，收率63％。Mp:177.2-177.8℃.1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.54-7.42(m,2H),7.29(d,J＝12.2Hz,1H),6.99(s,1H),6.94(d,J＝6.9Hz,1H),6.88(s,1H),3.89-3.75(m,12H),3.75(s,1H),1.21(d,J＝17.5Hz,4H).13C NMR(150MHz,DMSO-d6)δ173.5,153.3,153.1,153.1,152.4,150.9,149.5,148.4,147.9,146.4,146.3,137.8,137.6,136.9,134.0,132.0,131.1,129.4,129.0,128.8,127.9,124.5,122.6,117.6,117.1,113.4,113.3,111.8,105.0,104.2,99.2,99.0,59.9,56.0,55.4,13.2,10.9.ESI-MS(m/z):582.2(M+H+).ESI-HRMS(m/z):calcd for C33H32N3O7(M+H+),582.2121；found,582.2133.。
实施例30 6-[4-甲氧基-3-(4-硝基苯甲酰氧基)苯基]-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-2-酮(30)的合成
在50mL茄型瓶中加入三乙胺(7.1mL,0.079mmol)、25mL无水DCM、4-硝基苯甲酰氯(34mg,0.15mmol)和化合物8(32mg,0.075mmol)，室温搅拌1h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得黄色固体化合物(30)32mg，收率70％。Mp:186.2-186.8℃.1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.42(d,J＝8.7Hz,2H),8.36(d,J＝8.8Hz,2H),8.32(s,1H),8.01(dd,J＝8.4,5.3Hz,2H),7.50(s,1H),7.24(d,J＝8.8Hz,1H),6.88(s,2H),3.81(s,3H),3.80(s,6H),3.73(s,3H).13C NMR(150MHz,DMSO-d6)δ162.5,153.2,150.7,150.5,148.3,139.0,137.8,137.0,133.9,132.2,131.2,129.0,128.9,125.1,124.9,124.0,120.6,112.7,104.4,99.5,59.9,56.0,55.9.ESI-MS(m/z):573.2(M+H+).ESI-HRMS(m/z):calcd forC29H25N4O9(M+H+),573.1531；found,573.1552.。
实施例31 6-[4-甲氧基-3-(4-氟苯甲酰氧基)苯基]-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-2-酮(31)的合成
在50mL茄型瓶中加入三乙胺(7.1mL,0.079mmol)、25mL无水DCM、4-氟苯甲酰氯(32mg,0.15mmol)和化合物8(32mg,0.075mmol)，室温搅拌1h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(31)29mg，收率76％。Mp:192.2-192.4℃.1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.32(s,1H),8.20(s,2H),8.00(s,1H),7.94(s,1H),7.50(s,1H),7.44(s,2H),7.22(s,1H),6.87(s,2H),3.80(s,9H),3.73(s,3H).13C NMR(150MHz,DMSO-d6)δ166.2,164.5,162.8,153.2,151.0,148.4,139.3,137.1,132.5,132.4,128.8,125.1,124.8,124.6,120.8,115.7,115.5,112.2,103.9,99.5,59.9,55.8,55.6.ESI-MS(m/z):546.3(M+H+).ESI-HRMS(m/z):calcd for C29H25N3O7(M+H+),546.1591；found,546.1592.。
实施例32 6-[4-甲氧基-3-(3-吡啶甲酰氧基)苯基]-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-2-酮(32)的合成
在50mL茄型瓶中加入三乙胺(7.1mL,0.079mmol)、25mL无水DCM、烟酰氯(30mg,0.15mmol)和化合物8(32mg,0.075mmol)，室温搅拌1h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝20:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(32)26mg，收率66％。Mp:164.3-164.4℃.1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),9.23(s,1H),8.89(d,J＝3.2Hz,1H),8.45(d,J＝7.8Hz,1H),8.29(d,J＝11.6Hz,1H),7.97(dd,J＝11.8,5.4Hz,2H),7.64(dd,J＝7.9,5.0Hz,1H),7.48(s,1H),7.21(d,J＝8.7Hz,1H),6.85(s,2H),3.79(s,3H),3.78(s,6H),3.71(s,3H).13C NMR(150MHz,DMSO-d6)δ162.9,154.1,153.1,150.7,150.3,148.3,138.9,137.3,136.9,128.9,124.9,124.8,124.0,120.6,112.6,104.4,99.5,59.9,56.0,55.8.ESI-MS(m/z):529.3(M+H+).ESI-HRMS(m/z):calcd for C28H25N4O7(M+H+),529.1631；found,529.1672.。
实施例33 3-烯丙基-6-(3-(烯丙氧基)-4-甲氧基苯基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(33)的合成
在50mL茄型瓶中加入25mL丙酮、碳酸钾(44mg,0.32mmol)和化合物8(32mg,0.075mmol)，搅拌均匀。逐滴加入烯丙基溴(19mg,0.16mmol)，60℃下继续搅拌12h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝30:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(33)25mg，收率67％。Mp:183.2-183.6℃.1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.60(s,1H),7.52(s,1H),7.46(s,1H),6.97(s,1H),6.90(s,2H),6.00(d,J＝2.2Hz,2H),5.43-5.17(m,4H),4.58(s,4H),3.79(s,9H),3.72(s,3H).13C NMR(150MHz,DMSO-d6)δ153.2,152.0,145.0,149.4,147.4,137.0,136.4,133.8,132.0,131.9,129.0,128.6,125.1,119.1,117.6,117.2,111.7,111.6,104.2,99.6,68.8,59.9,56.0,55.4,43.0.ESI-MS(m/z):504.3(M+H+).ESI-HRMS(m/z):calcd for C28H30N3O6(M+H+),504.2019；found,504.2159.。
实施例34 6-[4-甲氧基-3-(炔丙氧基)苯基]-3-(炔丙基)-1-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(34)的合成
在50mL茄型瓶中加入25mL丙酮、碳酸钾(44mg,0.32mmol)和化合物8(32mg,0.075mmol)，搅拌均匀。逐滴加入炔丙基溴(19mg,0.16mmol)，60℃下继续搅拌12h。TLC显示反应完全。加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥。湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝30:1，v/v)，收集对应的洗脱液，蒸干溶剂得白色固体化合物(34)21mg，收率58％。Mp:194.2-194.3℃.1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),7.72(d,J＝1.9Hz,1H),7.63(dd,J＝8.4,1.9Hz,1H),7.54(s,1H),7.03(d,J＝8.6Hz,1H),6.93(s,2H),4.87(s,4H),3.82(s,6H),3.80(s,3H),3.75(s,3H),3.53(s,1H),3.48(s,1H).13C NMR(150MHz,DMSO-d6)δ153.2,151.6,150.3,149.6,146.3,137.0,136.6,131.6,128.7,124.3,120.0,112.3,111.8,104.2,99.8,79.2,78.1,77.6,75.5,59.9,56.0,55.9,55.4,30.4.ESI-MS(m/z):500.1(M+H+).ESI-HRMS(m/z):calcd for C28H26N3O6(M+H+),500.1119；found,500.1733.。
实施例35 6-(3-氟-4-甲氧基苯基)-2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-4-甲酰胺(35)的合成
在50mL三口瓶中加入化合物9(53mg,0.13mmol)、甲酰胺(2mL)和过硫酸钾(68mg,0.25mmol)，70℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得到白色粉末化合物(35)45mg，收率77％；Mp:313.2-313.6℃.1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.39(s,1H),8.27(d,J＝13.2Hz,1H),7.97(d,J＝8.9Hz,1H),7.73(s,1H),7.61(s,1H),7.14(d,J＝9.4Hz,1H),6.89(s,2H),6.85(s,1H),3.88(s,3H),3.81(s,6H),3.79(s,3H).13C NMR(150MHz,DMSO-d6)δ166.5,165.2,153.2,152.4,150.8,147.4,147.3,146.6,141.3,139.8,137.3,137.1,131.3,129.4,129.1,128.8,128.6,124.7,122.7,114.3,114.2,113.2,105.1,104.6,104.5,101.3,59.9,56.0,55.8.ESI-MS(m/z):469.2(M+H+).ESI-HRMS(m/z):calcd forC23H22FN4O6(M+H+),469.1518；found,469.1519.。
实施例36 6-(3-羟基-4-甲氧基苯基)-2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-4-甲酰胺(36)的合成
在50mL三口瓶中加入化合物8(53mg,0.13mmol)、甲酰胺(2mL)和过硫酸钾(68mg,0.25mmol)，70℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得到白色粉末化合物(36)42mg，收率75％；Mp:306.2-306.7℃.1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),9.00(s,1H),8.13(s,1H),7.78(s,1H),7.61(d,J＝8.1Hz,1H),7.57(s,1H),7.42(s,1H),6.95(d,J＝8.4Hz,1H),6.91(s,2H),3.82(s,6H),3.81(s,3H),3.76(s,3H).13C NMR(150MHz,DMSO-d6)δ166.5,153.2,148.2,148.0,146.3,139.8,137.1,131.0,128.9,129.0,124.4,117.8,113.6,111.8,104.6,101.0,60.0,56.0,55.5.ESI-MS(m/z):467.2(M+H+).ESI-HRMS(m/z):calcd for C23H23N4O7(M+H+),467.1561；found,467.1559.。
实施例37 6-(4-乙氧基苯基)-2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-4-甲酰胺(37)的合成
在50mL三口瓶中加入化合物12(54mg,0.126mmol)、甲酰胺(2mL)和过硫酸钾(68mg,0.25mmol)，70℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝15:1，v/v)，收集对应的洗脱液，蒸干溶剂得到白色粉末化合物(37)42mg，收率75％；Mp:307.3-307.8℃.1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.26(s,1H),8.15(d,J＝8.4Hz,2H),7.74(s,1H),7.52(s,1H),6.95(d,J＝8.6Hz,2H),6.89(s,2H),4.06(q,J＝6.9Hz,2H),3.81(s,6H),3.75(s,3H),1.34(t,J＝6.9Hz,3H).13C NMR(150MHz,DMSO-d6)δ166.5,158.9,153.2,153.2,147.8,139.8,137.0,130.5,129.0,128.9,127.9,124.4,114.1,104.5,100.9,62.9,59.9,56.0,14.4.ESI-MS(m/z):465.2(M+H+).ESI-HRMS(m/z):calcd for C24H25N4O6(M+H+),465.1769；found,465.1766.。
实施例38 5-[4-氨基甲酰基-2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-6-基]-2-甲氧基苯甲酸(38)的合成
在50mL三口瓶中加入化合物17(55mg,0.13mmol)、甲酰胺(2mL)和过硫酸钾(68mg,0.25mmol)，70℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝10:1，v/v)，收集对应的洗脱液，蒸干溶剂得到白色粉末化合物(38)52mg，收率76％；Mp:311.2-311.6℃.1H NMR(400MHz,DMSO-d6)δ11.4(s,1H),8.69(s,1H),8.58(d,J＝12Hz,1H),8.28(d,J＝8Hz,1H),8.03(s,1H),7.91(s,1H),7.47-7.43(m,1H),7.18(s,1H),7.14(s,1H),3.69(s,6H),3.6(s,6H).13C NMR(150MHz,DMSO-d6)δ156.1,153.2,153.1,149.6,137.6,136.9,130.7,129.1,128.9,126.4,125.5,124.7,111.4,104.3,98.8,59.9,56.0,55.2.ESI-MS(m/z):495.3(M+H+).ESI-HRMS(m/z):calcd for C23H23FN3O5(M+H+),495.1438；found,495.1455。
实施例39 6-(3-羟基-4-甲氧基苯基)-N-甲基-2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-4-甲酰胺(39)的合成
50mL三口瓶中加入化合物8(53mg,0.13mmol)、N-甲基甲酰胺(2mL)和过硫酸钾(68mg,0.25mmol)，70℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝10:1，v/v)，收集对应的洗脱液，蒸干溶剂得到白色粉末化合物(39)44mg，收率65％；Mp:296.4-296.7℃.1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.97(s,1H),8.72(d,J＝4.9Hz,1H),7.63(dd,J＝8.4,2.2Hz,1H),7.58(d,J＝2.1Hz,1H),7.40(s,1H),6.96(d,J＝8.5Hz,1H),6.91(s,2H),3.82(s,6H),3.81(s,3H),3.76(s,3H),2.92(d,J＝4.8Hz,3H).13CNMR(150MHz,DMSO-d6)δ164.6,153.2,148.2,148.1,146.3,139.8,137.1,131.1,129.5,129.0,128.9,124.0,117.9,113.7,111.7,104.6,100.9,59.9,56.0,55.5,25.6.ESI-MS(m/z):481.2(M+H+).ESI-HRMS(m/z):calcd for C24H25N4O7(M+H+),481.1718；found,481.1717.。
实施例40N-乙基-6-(3-羟基-4-甲氧基苯基)-2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-4-甲酰胺(40)的合成
在50mL三口瓶中加入化合物8(53mg,0.13mmol)、N-乙基甲酰胺(2mL)和过硫酸钾(68mg,0.25mmol)，70℃搅拌10小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝10:1，v/v)，收集对应的洗脱液，蒸干溶剂得到白色粉末化合物(40)49mg，收率55％；Mp:294.3-294.6℃.1H NMR(400MHz,DMSO-d6)δ8.77(t,J＝5.9Hz,1H),7.61(d,J＝8.4Hz,1H),7.58(s,1H),7.39(s,1H),6.96(d,J＝8.6Hz,1H),6.89(s,2H),3.81(s,9H),3.75(s,3H),2.00(m,2H),1.14(m,3H).13C NMR(150MHz,DMSO-d6)δ174.1,163.9,153.2,139.8,137.1,131.0,129.4,128.9,124.1,117.8,113.7,111.8,104.5,100.9,59.9,56.0,55.5,28.8,28.5,14.9.ESI-MS(m/z):495.2(M+H+).ESI-HRMS(m/z):calcd for C25H27N4O7(M+H+),495.1874；found,495.1876.。
实施例41目标化合物体外抑制人肿瘤细胞增殖活性测试实验
肿瘤细胞接种于96孔板中于37℃、5％CO2的环境下培养24小时，然后加入6个不同浓度的样品，并以CA-4为阳性对照。继续培养48小时后，加入20微升5mg/mL的MTT溶液，继续培养4小时后弃去上清液，加入150μL的DMSO溶解甲瓒，在酶标仪上540nm处测得OD值，并计算抑制率及IC50值。结果如表1所示：
表1.二芳基取代稠杂环类化合物抑制肿瘤细胞增殖活性(IC50,μM)
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其中，抗肿瘤活性由MTT法测定，数据均是三次测量的平均值；A2780是人卵巢癌细胞株；Hela是人宫颈癌细胞株；HCT-116是人结肠癌细胞系；A549是人肺腺癌细胞株。
实施例42抑制微管蛋白聚集实验：体外微管蛋白自组装实验
采用浊度法检测受试化合物36对体外微管聚集的抑制作用，检测试剂盒购自美国Cytoskeleton,Inc.。按如下步骤，微管聚集体系内含0.1M PIPES，pH＝6.6，10mM MgCl2，1mM GTP，1mM EGTA，3.4M甘油，反应液先在冰上预孵育，加入不同浓度的受试化合物，并设置DMSO(4％，v/v)组作为阴性对照组，Colchicine处理组作为阳性对照，加入10mM微管蛋白后，立刻置于37℃进行聚集反应，保持37℃，并用分光光度计在340nm下每隔1min测定吸光度，共测30min，根据吸光度绘制曲线图(如图1所示)；结果显示化合物36能明显抑制微管蛋白聚集，IC50为16.9μM(表2)。
表2.化合物36的微管蛋白聚集抑制活性(IC50，μM)。
a数据均是三次测量的平均值。
实施例43抑制微管蛋白聚集实验：免疫荧光检测微管蛋白形态实验
将人宫颈癌细胞HeLa接种到共聚焦皿中(4000个/皿)，37℃、5％二氧化碳条件下培养24h后，加入不同浓度的受试化合物处理24h，同时设置DMSO处理组作为阴性对照；弃去培养基，PBS洗涤2次，加入甲醇固定15min，PBS洗涤3次，0.1％ Triton通透15min，PBS洗涤3次。用5％ BSA室温封闭1h后一抗4℃孵育过夜，PBST漂洗3次，每次5min；加入荧光二抗，室温避光孵育1h，PBST漂洗3次，每次5min。共聚焦显微镜观察微管蛋白的形态，检测受试化合物对微管结构的影响，并拍摄相关照片，结果显示化合物36能明显抑制微管的聚集(如图2所示)。
实施例44生物素探针下拉实验：通过连接生物素考察化合物36与Katanin的相互作用
本发明按如下路线合成生物素探针分子44：
44.1叔丁基(5-(5-((3aS,4S,6aR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酰氨基)戊基)氨基甲酸酯(42)的合成
在50mL三口瓶中加入化合物41(40mg,0.20mmol)、HBTU(77mg,0.20mmol),DIPEA(50μL,0.20mmol)、D-(+)-biotin(50mg,0.20mmol)和5mL无水THF，室温搅拌24小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝30:1，v/v)，收集对应的洗脱液，蒸干溶剂得到黄色粉末化合物(42)50mg，收率65％。Mp:210.2-210.4℃.1H NMR(400MHz,DMSO-d6)δ7.77(s,1H),6.80(s,1H),6.47(s,1H),6.40(s,1H),4.32(s,1H),4.15(s,1H),3.11(s,1H),3.01(s,2H),2.89-2.83(m,21H).ESI-MS(m/z):429.3(M+H+).
44.2N-(5-氨基戊基)-5-[(3aS,4S,6aR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基]戊酰胺(43)的合成
在50mL三口瓶中加入化合物42(50mg,0.12mmol)、2mL TFA和5mL无水CH2Cl2，室温搅拌1小时，旋干溶剂，湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝10:1，v/v)，收集对应的洗脱液，蒸干溶剂得到无色油状液体(43)30mg，收率66％。1H NMR(400MHz,DMSO-d6)δ7.87-7.83(m,2H),6.45(s,1H),6.41(s,1H),4.30-4.22(m,1H),4.12-4.05(m,1H),3.53(s,1H),3.09-3.02(m,1H),3.02-2.92(m,2H),2.78-2.67(m,2H),2.39(s,1H),2.33(s,1H),2.00(t,J＝7.2Hz,2H),1.63-1.53(m,2H),1.52-1.39(m,3H),1.38-1.31(m,2H),1.29-1.20(m,4H),1.19(s,1H).ESI-MS(m/z):329.3(M+H+).
44.3 6-[4-甲氧基-3-((5-(5-((3aS,4S,6aR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酰氨基)戊基)氨基甲酰基)苯基]-2-氧代-1-(3,4,5-三甲氧基苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-4-甲酰胺(44)的合成
在50mL三口瓶中加入化合物38(84mg,0.17mmol)、HBTU(77mg,0.20mmol),DIPEA(50μL,0.20mmol)、化合物43(111mg,0.34mmol)和5mL无水DMF，室温搅拌24小时，加入饱和碳酸氢钠水溶液淬灭反应，分出有机相，水相用DCM萃取三遍，合并有机相，无水硫酸钠干燥；湿法上柱层析分离纯化(展开剂：二氯甲烷/甲醇＝10:1，v/v)，收集对应的洗脱液，蒸干溶剂得到黄色粉末化合物(44)75mg，收率48％。Mp:152.2-152.6℃.1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.69(s,1H),8.49(s,1H),8.23(s,2H),8.09(s,1H),7.78(s,1H),7.20(d,J＝8.4Hz,1H),7.08(s,2H),6.44(s,1H),6.37(s,1H),4.28(s,1H),4.10(s,1H),3.92(s,3H),3.88(s,6H),3.75(s,3H),3.27(s,2H),3.04(s,2H),2.78(s,1H),2.55(d,J＝12.7Hz,1H),2.03(s,2H),1.50-1.42(m,7H),1.30(s,3H),1.23(s,3H).13C NMR(150MHz,DMSO-d6)δ171.6,164.7,162.5,156.9,153.5,149.3,145.5,141.6,139.7,139.2,137.0,131.5,130.6,129.8,128.6,123.6,112.0,102.0,101.5,60.8,60.0,59.0,56.1,55.9,55.2,38.2,35.0,28.7,28.6,28.0,27.8,25.1,23.7.ESI-MS(m/z):805.4(M+H+).ESI-HRMS(m/z):calcd for C39H49N8O9S(M+H+),805.3256；found,805.3221.
裂解A549细胞后，将裂解所得样品与生物素探针分子44和连接链43(Linker，作为阴性对照)于4℃孵育12h。加入链霉亲和素磁珠，室温振荡1h，磁场吸附，弃去上清液，细胞裂解液洗6次，用20μL PBS重悬，加入上样缓冲液，100℃加热10min，用免疫印迹实验(Western blot)检测蛋白。通过免疫荧光显色证实，化合物44可以和Katanin蛋白发生结合作用(如图3所示)。
实施例45微量热泳动实验：测定目标化合物36与Katanin蛋白结合的热力学常数
用Monolith NTTMProtein Labeling Kit RED试剂盒标记人Katanin蛋白，使标记蛋白的终浓度约为800nM。化合物36溶解于蓖麻油和DMSO混合液中(1:1，v/v)，再进一步用8倍体积PBS稀释，制得化合物母液，使其浓度为1mM。在PCR管中用含10％蓖麻油和10％二甲基亚砜的PBS按1:1梯度稀释化合物母液，再在梯度稀释的化合物溶液中加入等体积的标记蛋白并混匀。将样品装载入毛细管中，进行检测。检测试验在Nano Temper MonolithNT.115仪器上以40％ LED和40％ MST power的参数下进行，在MO.Affinity Analysis软件中分析数据。实验结果表明化合物36和Katanin有明显的结合，其Kd值为12.7±2.0μM。
实施例46siRNA转染实验
在6孔板中接种A549细胞(2×105个/孔)，于37℃、5％CO2条件下培养24小时，然后用Lipofectamine 2000转染试剂(10μL/孔)转染人Katna(Katanin)siRNA或其阴性对照。转染6小时后换新鲜培养基培养。24小时后收集转染细胞并进行免疫印迹分析和体外细胞生长抑制试验。采用MTT实验测定化合物36对Control组和siKatanin组细胞的活性。结果表明，化合物36的IC50值从0.34增加到1.48μM(如图5所示)，说明Katanin蛋白为化合物36发挥抗肿瘤作用的直接靶点之一。
实施例47抑制血管生成实验
将含指定浓度化合物36的60μL基质胶加入96孔板中，置于37℃、5％ CO2培养箱中孵育1小时，待凝胶形成后，将100μL含指定浓度化合物的HUVEC细胞悬液加入凝胶孔中，使每孔中含约3×104个细胞。DMSO为阴性对照。于37℃，5％ CO2培养箱中培养12h，倒置相差显微镜下观察毛细血管形成情况，并拍摄相关照片。结果显示化合物36能明显抑制HUVEC细胞生成毛细血管样结构(如图6所示)。
实施例48集落抑制实验
A549细胞(1500个/孔)接种到6孔板中，37℃孵育24小时，待细胞贴壁后，加入不同浓度的化合物36处理细胞48h，并设阳性对照组(CA-4)、阴性对照组(DMSO)，更换新鲜培养基继续培养7-10天后，弃去培养基，用甲醇固定细胞，并用结晶紫染料染色，结果显示化合物36能明显抑制肿瘤细胞集落的形成(如图7所示)。
实施例49体外细胞周期实验
6孔板中，按2×105个/孔的数量接种细胞，37℃孵育24小时，待细胞贴壁后，用不同浓度的化合物36处理细胞24h，同时设阳性对照组(CA-4)、阴性对照组(2％ DMSO)，收集细胞，PBS洗两次，再用75％乙醇-2℃固定过夜后，用PI染色后采用流式细胞仪进行测试，结果显示化合物36能明显将细胞阻滞于G2/M期(如图8所示)。
实施例50体外细胞周期相关蛋白检测实验
选择不同浓度化合物处理肿瘤细胞后(DMSO为阴性对照)，收集并裂解细胞。所得蛋白样品经加热变性后，电泳分离，转膜，封闭，依次经一抗反应、二抗反应后，曝光显色；结果显示化合物36能明显促进磷酸化组蛋白H3、细胞周期蛋白B1及有丝分裂相关蛋白P21的表达(如图9所示)。
实施例51体外细胞凋亡实验
6孔板中，按2×105个/孔的数量接种细胞，37℃孵育24小时，待细胞贴壁后，用不同浓度的受试样品处理细胞48h，同时设阳性对照组(CA-4)、阴性对照组(2％ DMSO)。收集细胞，PBS洗两次后将细胞重悬于100μL 1×细胞凋亡结合液中，用PI和Annexin V双染色后采用流式细胞仪进行测试，结果显示化合物36能明显促进细胞凋亡(如图10所示)。
实施例52体外凋亡相关蛋白检测实验
选择不同浓度化合物处理肿瘤细胞后(DMSO为阴性对照)，收集并裂解细胞。所得蛋白样品经加热变性后，电泳分离，转膜，封闭，依次经一抗反应、二抗反应后，曝光显色；结果显示化合物36能明显促进促凋亡蛋白Bad、抑癌蛋白p53、DNA修复酶-1的表达(如图11所示)。
实施例53动物水平的肿瘤治疗作用
培养卵巢癌细胞系A2780，选择处于生长旺盛生长期的细胞进行接种，按每只2×106个细胞皮下接种于6周龄的Balb/C雌性裸鼠，建立裸鼠肿瘤转移模型。待裸鼠皮下移植瘤长至体积约100mm3，将小鼠随机分为四组，分别为给药组1(50mg/kg化合物36)，给药组2(25mg/kg化合物36)，阳性对照组(10mg/kg紫杉醇)及空白对照组(溶剂)。腹腔注射隔天给药并用游标卡尺测量肿瘤直径。肿瘤体积按以下公式计算：肿瘤体积(mm3)＝a×b2×0.52(这里a代表最长的直径，b代表最短的直径，0.52是经验系数)。当空白对照组肿瘤体积达到2000mm3后，处死裸鼠，剥离瘤组织，称取瘤重量。结果显示化合物36在体内能明显抑制肿瘤生长，并且对小鼠体重无明显影响(如图12所示)。
Claims (4)
1.二芳基取代咪唑并[4,5-c]吡啶-2-酮类化合物或其药学盐，其特征在于，所述化合物为：
2.二芳基取代咪唑并[4,5-c]吡啶类化合物或其药学盐，其特征在于，所述化合物为：
3.权利要求1-2中任一项所述化合物或其药学盐在制备预防和治疗与肿瘤相关疾病的药物中的应用，所述与肿瘤相关疾病是宫颈癌、卵巢癌、结直肠癌、肺癌。
4.一种用于预防和治疗与肿瘤相关疾病的药物组合物，其特征在于，其含有权利要求1-2中任一项所述化合物或其药学盐，所述与肿瘤相关疾病是宫颈癌、卵巢癌、结直肠癌、肺癌。
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