CN115141197B - 一种3-芳杂环取代苯基衍生物及其制备方法与用途 - Google Patents
一种3-芳杂环取代苯基衍生物及其制备方法与用途 Download PDFInfo
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- CN115141197B CN115141197B CN202210891482.9A CN202210891482A CN115141197B CN 115141197 B CN115141197 B CN 115141197B CN 202210891482 A CN202210891482 A CN 202210891482A CN 115141197 B CN115141197 B CN 115141197B
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- A61P35/02—Antineoplastic agents specific for leukemia
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种3‑芳杂环取代苯基衍生物及其制备方法与用途，涉及药物化学技术领域，本发明借助计算机药物辅助设计技术，通过化合物分子库的筛选和基于化学结构修饰，发现并确定了以3‑芳杂环取代苯基为核心的结构骨架进行“CDK8Type II型抑制剂”的研发，所述3‑芳杂环取代苯基衍生物经体外CDK8激酶活性筛选，结果显示其对CDK8表现出较强的抑制活性；经体外肿瘤细胞活性筛选，结果显示其对肿瘤细胞表现出较强的抑制活性；经体内抗肿瘤活性筛选，结果显示其对结肠癌模型有效的治疗作用。
Description
技术领域：
本发明涉及药物化学技术领域，具体涉及一种3-芳杂环取代苯基衍生物及其制备方法与用途。
背景技术：
目前癌症的治疗主要是化疗，CAR-T细胞免疫疗法和使用靶向抑制剂。化疗导致病人免疫力降低，容易感染，副作用大。CAR-T治疗具有许多不良反应，如细胞因子释放综合征CRS、脱靶效应、神经毒性、过敏反应、移植物抗宿主病、肿瘤溶解综合征等。其中最严重的就是CRS，这是一种致命的失控的全身炎症反应。TRM风险的增加常常使这些患者无法接受最佳的化疗或干细胞移植。因此，新的靶向治疗提供了有效的抗肿瘤活性的希望，减少了脱靶效应的毒性。
细胞周期依赖性蛋白酶8(cyclin-dependent kinase 8，CDK8)最初被称为蛋白K35，被发现作为细胞周期蛋白C的假定激酶伙伴。CDK8基因位于人染色体13q12.13，被转录成含有464个氨基酸的53kDa蛋白，它的激酶活性通过与Cyc-C联系被调节，13q12.13染色体区域在大部分结肠癌中被放大。在CDK8众多细胞功能中，最值得注意的是参与转录。CDK8和MED12、MED13、Cys-C组成中介复合物，一个大的多亚基蛋白复合体，是真核生物中调节转录的中心。2008年，美国丹娜-法伯癌症研究所的Hahn和他的合作者首次提出CDK8通过调控β-catenin作为结直肠癌的致癌基因，此后的研究显示CDK8在黑色素瘤、乳腺癌、急性髓系白血病、胰腺癌、前列腺癌等癌症中都过度表达。研究显示CDK8激酶活性削弱了自然杀伤细胞对恶性细胞的防御，并抑制了对前细胞的肿瘤监视。通过基因敲除验证CDK8对这些癌症存活具有重要的作用。这些证据表明CDK8在这些癌症中的致癌作用以及抑制CDK8蛋白活性能抑制肿瘤发生。因此，发现有效和选择性的小分子CDK8抑制剂用于癌症的治疗，可以作为一种新的癌症治疗新策略。
发明内容：
本发明借助计算机药物辅助设计技术，通过化合物分子库的筛选和基于化学结构修饰，发现并确定了以3-芳杂环取代苯基为核心的结构骨架进行“CDK8 Type II型抑制剂”的研发，从中筛选得到具有高活性的CDK8抑制剂并丰富靶向CDK8的小分子库。
本发明的目的之一是提供一种3-芳杂环取代苯基衍生物，其结构式如下所示：
其中，R2选自脂肪基、苯基、取代苯基、苄基、取代苄基、苯乙基、取代苯乙基、吡啶基、嘧啶基、哒嗪基中的任一种基团；
X选自亚甲基、乙基、乙烯基、甲氨基、甲氧基、甲硫基中的任一种基团；
Y选自O、N、S中的任一种基团或不存在；
R3选自吡啶、吡啶并吡唑、吡啶并吡咯、吡嗪并吡咯、异喹啉、吲哚及其衍生物中的任一种基团。
所述的3-芳杂环取代苯基衍生物结构式如下所示(化合物1-91)：
本发明的目的之二是提供一种所述的3-芳杂环取代苯基衍生物的制备方法，包括以下步骤：
(1)5-溴-7-氮杂吲哚和频那醇酯发生Suzuki-Miyaura反应，得到中间体M0；
(2)R2-NH2和3-溴苯甲酸或3-溴苯乙酸发生酰胺缩合反应，得到中间体M1；
(3)中间体M1和中间体M0经Suzuki反应，得到化合物1-39，67-68；
(4)化合物22发生卤代反应，得到化合物76-78；
(5)R2-COOH和3-溴苯乙胺发生酰胺缩合反应，得到中间体M2；
(6)中间体M2和中间体M0经Suzuki反应，得到化合物40-51；
(7)R2-NH2和三光气反应，得到R2-NCO；
(8)3-溴苯乙胺和R2-NCO发生脲缩合反应，得到中间体M3；
(9)中间体M3和中间体M0经Suzuki反应，得到化合物52-66；
(10)R2-NH2和氯乙酰氯反应，得到中间体M4；
(11)和中间体M4发生亲核取代反应，得到中间体M5；
(12)中间体M5和中间体M0经Suzuki反应，得到化合物69-71；
(13)和膦酰乙酸三乙酯发生Witting反应，得到中间体M6；
(14)中间体M6发生水解，得到中间体M7；
(15)中间体M7和R2-NH2发生酰胺缩合反应，得到中间体M8；
(16)中间体M8和中间体M0经Suzuki反应，得到化合物73-75；
(17)化合物75发生双键还原反应，得到化合物72；
(18)经Suzuki-Miyaura反应得到中间体M9，再与R3-Br经suzuki反应，得到化合物79-90；
(19)与1H-吡咯并[2,3-b]吡啶-5-醇经buchwald-hawting反应得到化合物91。
本发明的目的之三是提供一种药物组合物，含有所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐。
本发明的目的之四是提供一种药物制剂，包括有效成分和药学上可接受的辅料和/或载体，所述有效成分含有所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐。
本发明的目的之五是提供所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐在制备CDK8抑制剂中的用途。
本发明的目的之六是提供所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐在制备抗肿瘤药物中的用途。所述肿瘤选自黑色素瘤、乳腺癌、急性髓系白血病、胰腺癌、前列腺癌、结直肠癌等。
本发明的有益效果是：
(1)本发明的3-芳杂环取代苯基衍生物经体外CDK8激酶活性筛选，结果显示其对CDK8表现出较强的抑制活性，同时毒性较低；
(2)本发明的3-芳杂环取代苯基衍生物经体外肿瘤细胞活性筛选，结果显示其对肿瘤细胞表现出较强的抑制活性，同时毒性较低；
(3)本发明的3-芳杂环取代苯基衍生物经体内抗肿瘤活性筛选，结果显示其对结肠癌模型有效的治疗作用，同时毒性较低；
(4)本发明所述3-芳杂环取代苯基衍生物的结构新颖、合成工艺简单、产品纯度高，具有良好的应用前景。
附图说明：
图1为本发明化合物22的体内抗肿瘤活性测试结果。
具体实施方式：
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例，进一步阐述本发明。
实施例1
5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯并[2,3-b]吡啶(中间体M0)的合成：
将化合物7-氮杂吲哚(10g，50.75mmol)，联硼酸频那醇酯(19.3g，76.13mmol)，醋酸钾(25g，253.75mmol)，二氯[1,1'-二(二苯基膦)二茂铁]钯(1.3g，1.78mmol)，N,N-二甲基甲酰胺(80mL)，氮气置换，80℃反应12小时。反应结束加水和乙酸乙酯搅拌，硅藻土助滤，乙酸乙酯洗涤滤饼；静置分液，水相用乙酸乙酯再萃取依次，合并有机相，饱和食盐水洗，无水硫酸钠干燥，抽滤旋干得黑色油状物。柱层析EA(70％)过出产物，得黄色油状物，石油醚打浆抽滤得淡白色固体7.9g；收率61.1％。
3-(3-溴苯基)-N-苯基丙酰胺(中间体M1)的合成：
将化合物3-溴苯丙酸(362mg，1.58mmol)，草酰氯(218mg，1.72mmol)，二氯甲烷(8mL)，N,N-二甲基甲酰胺(2滴)，25℃反应1小时。直接浓缩，加二氯甲烷2mL配成溶液；化合物苯胺(160mg，1.72mmol)，三乙胺(320mg，2.86mmol)，二氯甲烷8mL，冰浴搅拌，滴加现制备的酰氯，滴毕，25℃反应1小时；直接浓缩得固体560mg投下一步。
3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-苯基丙酰胺(化合物1)的合成：
将化合物M0(1.58mmol)，化合物M1(271mg，1.11mmol)，碳酸钾(655mg，4.74mmol)，二氯[1,1'-二(二苯基膦)二茂铁]钯(95mg，0.13mmol)，1,4-二氧六环10mL，加水(2.5mL)，氮气置换，85℃反应15小时。反应结束加水和乙酸乙酯搅拌，加食盐水分液，无水硫酸钠干燥，旋干得黑色油状物。柱层析，洗脱剂EA(65％)过出产物，得白色固体，乙酸乙酯和石油醚打浆抽滤得白色固体220mg；收率40.74％。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.96(s,1H),8.51(d,J＝2.2Hz,1H),8.16(d,J＝2.0Hz,1H),7.60(d,J＝7.5Hz,3H),7.52(dd,J＝7.4,4.8Hz,2H),7.39(t,J＝7.6Hz,1H),7.33–7.21(m,3H),7.03(t,J＝7.4Hz,1H),6.48(dd,J＝3.4,1.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.71(t,J＝7.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ170.95,148.50,142.36,141.96,139.71,139.57,129.44,129.17(2C),128.67,127.41,127.35,127.29,126.50,125.03,123.50,120.12,119.50(2C),100.58,38.41,31.39.HRMS(ESI):m/z[M+H]+calcd for C22H19N3O:342.1601；found:342.1601.鉴于篇幅原因，以下化合物2-91只提供其氢谱数据。
实施例2：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-苄基丙酰胺(化合物2)的合成
合成步骤同实施例1，用苄胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.51(d,J＝2.0Hz,1H),8.36(t,J＝6.0Hz,1H),8.19(d,J＝2.0Hz,1H),7.60–7.50(m,3H),7.38(t,J＝7.6Hz,1H),7.25–7.16(m,4H),7.12(d,J＝6.8Hz,2H),6.50(dd,J＝3.6,2.0Hz,1H),4.27(d,J＝6.0Hz,2H),2.96(t,J＝7.6Hz,2H),2.55(t,J＝7.6Hz,2H).
实施例3：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2-氟苄基)丙烯酰胺(化合物3)的合成
合成步骤同实施例1，用2-氟苄胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.50(d,J＝2.1Hz,1H),8.38(t,J＝5.8Hz,1H),8.18(d,J＝2.0Hz,1H),7.57(s,1H),7.56–7.50(m,2H),7.37(t,J＝7.6Hz,1H),7.28–7.22(m,1H),7.20(d,J＝7.6Hz,1H),7.13(d,J＝9.5Hz,1H),7.11–7.06(m,1H),7.05–6.98(m,1H),6.50(dd,J＝3.3,1.8Hz,1H),4.30(d,J＝5.7Hz,2H),2.94(t,J＝7.5Hz,2H),2.56(t,J＝7.6Hz,2H).
实施例4：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(1-甲基-1H-吲哚-5-基)丙烯酰胺(化合物4)的合成
合成步骤同实施例1，用1-甲基-1H-吲哚-5-胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.79(s,1H),8.52(s,1H),8.16(s,1H),7.91(s,1H),7.63-7.52(m,3H),7.45–7.08(m,5H),6.45-6.36(m,2H),3.75(s,3H),3.03(s,2H),2.71(s,2H).
实施例5：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2-氟苯基)丙烯酰胺(化合物5)的合成
合成步骤同实施例1，用2-氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.76(s,1H),8.52(d,J＝2.0Hz,1H),8.18(d,J＝2.0Hz,1H),7.89(td,J＝8.0,3.6Hz,1H),7.62(s,1H),7.53(dd,J＝8.4,5.6Hz,2H),7.40(t,J＝7.6Hz,1H),7.24(ddd,J＝7.6,6.0,2.8Hz,2H),7.18–7.11(m,2H),6.49(dd,J＝3.6,1.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.79(t,J＝7.6Hz,2H).
实施例6：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2-(三氟甲基)苯基)丙烯酰胺(化合物6)的合成
合成步骤同实施例1，用2-三氟甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.61(s,1H),8.53(d,J＝2.0Hz,1H),8.21(d,J＝2.0Hz,1H),7.73(d,J＝7.6Hz,1H),7.68–7.59(m,2H),7.57–7.50(m,2H),7.42(dt,J＝12.0,8.0Hz,3H),7.26(d,J＝7.6Hz,1H),6.51(dd,J＝3.6,2.0Hz,1H),3.01(t,J＝7.6Hz,2H),2.76(t,J＝7.6Hz,2H).
实施例7：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-氟苯基)丙烯酰胺(化合物7)的合成
合成步骤同实施例1，用3-氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.18(s,1H),8.50(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.67–7.59(m,2H),7.53(dd,J＝7.6,5.2Hz,2H),7.39(dd,J＝14.0,6.4Hz,1H),7.31(dt,J＝10.4,7.6Hz,2H),7.24(d,J＝7.6Hz,1H),6.93–6.80(m,1H),6.49(dd,J＝3.6,2.0Hz,1H),3.02(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,2H).
实施例8：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-氯苯基)丙烯酰胺(化合物8)的合成
合成步骤同实施例1，用3-氯苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.16(s,1H),8.50(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.85(t,J＝2.0Hz,1H),7.60(s,1H),7.53(dd,J＝7.6,4.8Hz,2H),7.46–7.42(m,1H),7.39(t,J＝7.6Hz,1H),7.32(t,J＝8.0Hz,1H),7.24(d,J＝7.6Hz,1H),7.09(ddd,J＝8.0,2.0,0.8Hz,1H),6.49(dd,J＝3.6,2.0Hz,1H),3.01(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,2H).
实施例9：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-甲基苯基)丙烯酰胺(化合物9)的合成
合成步骤同实施例1，用3-甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),9.87(s,1H),8.50(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.60(s,1H),7.52-7.50(m,2H),7.43(s,1H),7.37(dd,J＝7.6,4.4Hz,2H),7.24(d,J＝7.2Hz,1H),7.16(t,J＝8.0Hz,1H),6.84(d,J＝7.6Hz,1H),6.48(dd,J＝3.2,2.0Hz,1H),3.00(t,J＝8.0Hz,2H),2.69(t,J＝8.0Hz,2H),2.26(s,3H).
实施例10：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-乙基苯基)丙烯酰胺(化合物10)的合成
合成步骤同实施例1，用3-乙基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.90(s,1H),8.52(d,J＝2.1Hz,1H),8.16(d,J＝2.0Hz,1H),7.61(s,1H),7.53(dd,J＝6.8,4.0Hz,2H),7.43(dd,J＝13.5,5.3Hz,2H),7.38(d,J＝7.6Hz,1H),7.25(d,J＝7.6Hz,1H),7.19(t,J＝7.8Hz,1H),6.88(d,J＝7.6Hz,1H),6.49(dd,J＝3.4,1.8Hz,1H),3.02(t,J＝7.6Hz,2H),2.71(t,J＝7.6Hz,2H),2.55(q,J＝7.6Hz,2H),1.18–1.11(m,3H).
实施例11：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-异丙基苯基)丙烯酰胺(化合物11)的合成
合成步骤同实施例1，用3-异丙基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.90(s,1H),8.51(d,J＝2.1Hz,1H),8.16(d,J＝2.0Hz,1H),7.61(s,1H),7.52(dd,J＝7.4,4.8Hz,2H),7.45(d,J＝6.5Hz,2H),7.39(t,J＝7.6Hz,1H),7.27–7.17(m,2H),6.91(d,J＝7.7Hz,1H),6.48(dd,J＝3.3,1.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.82(dt,J＝13.8,6.9Hz,1H),2.70(t,J＝7.6Hz,2H),1.17(d,J＝6.9Hz,6H).
实施例12：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-甲氧基苯基)丙烯酰胺(化合物12)的合成
合成步骤同实施例1，用3-甲氧基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),9.97(s,1H),8.52(d,J＝2.1Hz,1H),8.16(d,J＝2.0Hz,1H),7.61(s,1H),7.53(dd,J＝6.6,3.6Hz,2H),7.39(t,J＝7.6Hz,1H),7.35–7.31(m,1H),7.24(d,J＝7.6Hz,1H),7.20(t,J＝8.0Hz,1H),7.14(d,J＝8.2Hz,1H),6.62(dd,J＝8.0,1.5Hz,1H),6.49(dd,J＝3.3,1.8Hz,1H),3.72(s,3H),3.02(t,J＝7.6Hz,2H),2.71(t,J＝7.6Hz,2H).
实施例13：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-三氟甲基苯基)丙烯酰胺(化合物13)的合成
合成步骤同实施例1，用3-三氟甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.31(s,1H),8.51(d,J＝2.0Hz,1H),8.25–8.04(m,2H),7.78(d,J＝8.4Hz,1H),7.61(s,1H),7.58–7.48(m,3H),7.40(t,J＝7.6Hz,2H),7.25(d,J＝7.6Hz,1H),6.48(dd,J＝3.6,2.0Hz,1H),3.03(t,J＝7.6Hz,2H),2.76(t,J＝7.6Hz,2H).
实施例14：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-氟苯基)丙烯酰胺(化合物14)的合成
合成步骤同实施例1，用4-氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),10.04(s,1H),8.50(s,1H),8.16(s,1H),7.67–7.58(m,3H),7.52(s,2H),7.39(t,J＝7.5Hz,1H),7.24(d,J＝7.2Hz,1H),7.14(t,J＝8.7Hz,2H),6.49(s,1H),3.01(t,J＝7.2Hz,2H),2.70(t,J＝7.4Hz,2H).
实施例15：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-氯苯基)丙烯酰胺(化合物15)的合成
合成步骤同实施例1，用4-氯苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),10.12(s,1H),8.51(s,1H),8.15(s,1H),7.64(d,J＝8.4Hz,2H),7.60(s,1H),7.52(s,2H),7.38(dd,J＝17.3,8.1Hz,3H),7.24(d,J＝7.1Hz,1H),6.49(s,1H),3.01(t,J＝7.0Hz,2H),2.71(dd,J＝14.2,7.0Hz,2H).
实施例16：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-三氟甲基苯基)丙烯酰胺(化合物16)的合成
合成步骤同实施例1，用4-三氟甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.37(s,1H),8.53(d,J＝2.0Hz,1H),8.19(d,J＝1.6Hz,1H),7.84(d,J＝8.4Hz,2H),7.70(d,J＝8.8Hz,2H),7.64(s,1H),7.57-7.54(m,2H),7.42(t,J＝7.2Hz,1H),7.27(d,J＝7.6Hz,1H),6.51(dd,J＝2.8,1.6Hz,1H),3.05(t,J＝7.6Hz,2H),2.79(t,J＝7.6Hz,2H).
实施例17：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基苯基)丙烯酰胺(化合物17)的合成
合成步骤同实施例1，用4-甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.88(s,1H),8.51(d,J＝1.9Hz,1H),8.16(s,1H),7.69–7.44(m,5H),7.39(t,J＝7.6Hz,1H),7.24(d,J＝7.5Hz,1H),7.09(d,J＝8.2Hz,2H),6.49(d,J＝0.9Hz,1H),3.01(t,J＝7.6Hz,2H),2.70(t,J＝7.6Hz,2H),2.24(s,3H).
实施例18：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲氧基苯基)丙烯酰胺(化合物18)的合成
合成步骤同实施例1，用4-甲氧基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),9.84(s,1H),8.51(d,J＝2.1Hz,1H),8.16(d,J＝1.9Hz,1H),7.61(s,1H),7.56–7.47(m,4H),7.39(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.87(d,J＝9.0Hz,2H),6.49(dd,J＝3.3,1.8Hz,1H),3.71(s,3H),3.01(t,J＝7.6Hz,2H),2.68(dd,J＝9.7,5.5Hz,2H).
实施例19：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3,4-二甲基苯基)丙烯酰胺(化合物19)的合成
合成步骤同实施例1，用3,4-二甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.79(s,1H),8.51(s,1H),8.16(s,1H),7.56(d,J＝34.3Hz,3H),7.35(dd,J＝28.4,9.9Hz,3H),7.24(d,J＝7.2Hz,1H),7.03(d,J＝8.0Hz,1H),6.48(s,1H),3.00(t,J＝7.1Hz,2H),2.68(t,J＝7.3Hz,2H),2.16(d,J＝6.4Hz,6H).
实施例20：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-氯-4-甲基苯基)丙烯酰胺(化合物20)的合成
合成步骤同实施例1，用3-氯-4-甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.06(s,1H),8.51(d,J＝2.1Hz,1H),8.15(d,J＝2.0Hz,1H),7.83(d,J＝2.0Hz,1H),7.60(s,1H),7.52(dd,J＝6.6,3.5Hz,2H),7.42–7.32(m,2H),7.24(dd,J＝7.8,5.5Hz,2H),6.48(dd,J＝3.4,1.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.71(t,J＝7.6Hz,2H),2.26(s,3H).
实施例21：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-氟-4-甲基苯基)丙烯酰胺(化合物21)的合成
合成步骤同实施例1，用3-氟-4-甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.09(s,1H),8.52(d,J＝1.8Hz,1H),8.16(d,J＝1.8Hz,1H),7.60(d,J＝11.0Hz,2H),7.57–7.48(m,2H),7.38(t,J＝7.6Hz,1H),7.29–7.11(m,3H),6.49(dd,J＝3.1,1.7Hz,1H),3.02(t,J＝7.5Hz,2H),2.72(t,J＝7.6Hz,2H).
实施例22：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物22)的合成
合成步骤同实施例1，用3-三氟甲基-4-甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.20(s,1H),8.50(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),8.02(d,J＝2.0Hz,1H),7.70(dd,J＝8.4,2.0Hz,1H),7.60(s,1H),7.53(dd,J＝7.2,4.8Hz,2H),7.44–7.31(m,2H),6.48(dd,J＝3.6,2.0Hz,1H),3.02(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,2H),2.36(t,J＝7.6Hz,3H).
实施例23：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-氟-3-(三氟甲基)苯基)丙烯酰胺(化合物23)的合成
合成步骤同实施例1，用3-三氟甲基-4-氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.34(s,1H),8.50(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),8.12(dd,J＝6.4,2.4Hz,1H),7.86–7.79(m,1H),7.60(s,1H),7.53(dd,J＝7.2,4.8Hz,2H),7.46(t,J＝9.6Hz,1H),7.39(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.48(dd,J＝3.6,1.6Hz,1H),3.02(t,J＝7.6Hz,2H),2.74(t,J＝7.6Hz,2H).
实施例24：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-氯-3-(三氟甲基)苯基)丙烯酰胺(化合物24)的合成
合成步骤同实施例1，用3-三氟甲基-4-氯苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.41(s,1H),8.50(d,J＝2.4Hz,1H),8.20(d,J＝2.4Hz,1H),8.15(d,J＝2.0Hz,1H),7.84(dd,J＝8.8,2.4Hz,1H),7.65(d,J＝8.8Hz,1H),7.60(s,1H),7.53(dd,J＝7.2,4.8Hz,2H),7.39(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.48(dd,J＝3.6,2.0Hz,1H),3.02(t,J＝7.6Hz,2H),2.75(t,J＝7.6Hz,2H).
实施例25：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲氧基-3-(三氟甲基)苯基)丙烯酰胺(化合物25)的合成
合成步骤同实施例1，用3-三氟甲基-4-甲氧基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.09(s,1H),8.51(d,J＝2.0Hz,1H),8.15(d,J＝2.0Hz,1H),7.96(d,J＝2.4Hz,1H),7.76(dd,J＝9.2,2.4Hz,1H),7.60(s,1H),7.53(dd,J＝7.2,4.8Hz,2H),7.39(t,J＝7.6Hz,1H),7.23(t,J＝8.0Hz,2H),6.48(dd,J＝3.6,2.0Hz,1H),3.85(s,3H),3.01(t,J＝7.6Hz,2H),2.70(t,J＝7.6Hz,2H).
实施例26：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-氰基-3-(三氟甲基)苯基)丙烯酰胺(化合物26)的合成
合成步骤同实施例1，用3-三氟甲基-4-氰基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.76(s,1H),8.50(d,J＝2.0Hz,1H),8.27(d,J＝1.2Hz,1H),8.16(d,J＝1.8Hz,1H),8.09(d,J＝8.6Hz,1H),8.03–7.95(m,1H),7.60(s,1H),7.53(dd,J＝8.1,5.6Hz,2H),7.39(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.48(dd,J＝3.2,1.7Hz,1H),3.03(t,J＝7.5Hz,2H),2.81(t,J＝7.6Hz,2H).
实施例27：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2-氟-5-(三氟甲基)苯基)丙烯酰胺(化合物27)的合成
合成步骤同实施例1，用5-三氟甲基-2-氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),10.10(s,1H),8.52(d,J＝2.0Hz,1H),8.45(d,J＝6.8Hz,1H),8.18(d,J＝2.0Hz,1H),7.62(s,1H),7.58–7.45(m,4H),7.40(t,J＝7.6Hz,1H),7.25(d,J＝7.6Hz,1H),6.49(dd,J＝3.2,2.0Hz,1H),3.02(t,J＝7.6Hz,2H),2.86(t,J＝7.6Hz,2H).
实施例28：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2-氟-3-(三氟甲基)苯基)丙烯酰胺(化合物28)的合成
合成步骤同实施例1，用3-三氟甲基-2-氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.29(s,1H),8.49(d,J＝2.0Hz,1H),8.15(d,J＝2.0Hz,1H),7.82(ddd,J＝13.2,7.6,2.4Hz,1H),7.59(s,1H),7.52(dd,J＝6.8,4.4Hz,2H),7.42–7.32(m,2H),7.32–7.26(m,1H),7.23(d,J＝7.6Hz,1H),6.49(dd,J＝3.2,1.6Hz,1H),3.01(t,J＝7.6Hz,2H),2.72(t,J＝7.6Hz,2H).
实施例29：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2,3-二氟苯基)丙烯酰胺(化合物29)的合成
合成步骤同实施例1，用2,3-二氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.50(s,1H),8.50(d,J＝2.1Hz,1H),8.16(d,J＝2.0Hz,1H),7.87–7.75(m,2H),7.60(s,1H),7.53(dd,J＝8.2,5.5Hz,2H),7.39(t,J＝7.6Hz,1H),7.33(d,J＝8.5Hz,1H),7.24(d,J＝7.6Hz,1H),6.48(dd,J＝3.4,1.8Hz,1H),3.02(t,J＝7.6Hz,2H),2.76(t,J＝7.6Hz,2H).
实施例30：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2,4-二氟苯基)丙烯酰胺(化合物30)的合成
合成步骤同实施例1，用2,4-二氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.78(s,1H),8.52(d,J＝2.1Hz,1H),8.18(d,J＝2.0Hz,1H),7.81(td,J＝9.0,6.3Hz,1H),7.61(s,1H),7.53(dd,J＝7.8,5.4Hz,2H),7.39(t,J＝7.6Hz,1H),7.35–7.21(m,2H),7.12–7.00(m,1H),6.50(dd,J＝3.4,1.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.77(t,J＝7.6Hz,2H).
实施例31：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(2,5-二氟苯基)丙烯酰胺(化合物31)的合成
合成步骤同实施例1，用2,5-二氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.97(s,1H),8.52(d,J＝2.1Hz,1H),8.18(d,J＝2.1Hz,1H),7.68(t,J＝7.0Hz,1H),7.62(s,1H),7.53(dd,J＝8.3,5.6Hz,2H),7.40(t,J＝7.6Hz,1H),7.25(d,J＝7.6Hz,1H),7.22–7.10(m,2H),6.50(dd,J＝3.2,1.3Hz,1H),3.01(t,J＝7.6Hz,2H),2.81(t,J＝7.6Hz,2H).
实施例32：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3,4-二氟苯基)丙烯酰胺(化合物32)的合成
合成步骤同实施例1，用3,4-二氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.22(s,1H),8.49(d,J＝2.0Hz,1H),8.15(d,J＝2.0Hz,1H),7.81(ddd,J＝13.2,7.6,2.4Hz,1H),7.59(s,1H),7.52(dd,J＝7.2,4.8Hz,2H),7.43–7.32(m,2H),7.25(dd,J＝14.8,8.4Hz,2H),6.49(dd,J＝3.2,2.0Hz,1H),3.01(t,J＝7.6Hz,2H),2.71(t,J＝7.6Hz,2H).
实施例33：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3,5-二氟苯基)丙烯酰胺(化合物33)的合成
合成步骤同实施例1，用3,5-二氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.36(s,1H),8.50(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.60(s,1H),7.53(dd,J＝8.4,5.6Hz,2H),7.40(t,J＝7.6Hz,1H),7.36–7.32(m,1H),7.32–7.29(m,1H),7.24(d,J＝7.6Hz,1H),6.90(tt,J＝9.2,2.4Hz,1H),6.48(dd,J＝3.6,2.0Hz,1H),3.01(t,J＝7.6Hz,2H),2.74(t,J＝7.6Hz,2H).
实施例34：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3-氟-5-(三氟甲基)苯基)丙烯酰胺(化合物34)的合成
合成步骤同实施例1，用3-氟-5-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.96(s,1H),8.52(d,J＝2.1Hz,1H),8.18(d,J＝1.9Hz,1H),8.02–7.84(m,1H),7.61(s,1H),7.53(dd,J＝7.5,5.2Hz,2H),7.39(t,J＝7.6Hz,1H),7.30(ddd,J＝10.5,9.3,5.2Hz,1H),7.25(d,J＝7.6Hz,1H),7.00–6.85(m,1H),6.49(dd,J＝3.3,1.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.84(t,J＝7.6Hz,2H).
实施例35：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(3,5-双(三氟甲基)苯基)丙烯酰胺(化合物35)的合成
合成步骤同实施例1，用3,5-双(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.64(s,1H),8.52(d,J＝1.4Hz,1H),8.28(s,2H),8.15(d,J＝1.8Hz,1H),7.70(s,1H),7.62(s,1H),7.55–7.49(m,2H),7.38(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.48(dd,J＝3.2,1.7Hz,1H),3.05(t,J＝7.5Hz,2H),2.79(t,J＝7.6Hz,2H).
实施例36：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)丙烯酰胺(化合物36)的合成
合成步骤同实施例1，用3-三氟甲基-4-[(4-甲基哌嗪-1-基)甲基]苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),10.33(s,1H),8.50(d,J＝2.2Hz,1H),8.16(d,J＝2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.78(dd,J＝8.5,1.8Hz,1H),7.67–7.57(m,2H),7.52(dd,J＝7.8,5.5Hz,2H),7.39(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.48(dd,J＝3.4,1.8Hz,1H),3.52(s,2H),3.37(s,4H),3.01(t,J＝7.6Hz,2H),2.74(t,J＝7.6Hz,2H),2.35(s,4H),2.14(s,3H).
实施例37：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-(2-羟基乙氧基)-3-(三氟甲基)苯基)丙烯酰胺(化合物37)的合成
合成步骤同实施例1，用4-(2-羟基乙氧基)-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),10.12(s,1H),8.54(d,J＝2.0Hz,1H),8.16(d,J＝1.8Hz,1H),8.00(d,J＝2.4Hz,1H),7.77(dd,J＝9.0,2.2Hz,1H),7.63(s,1H),7.57–7.48(m,2H),7.38(t,J＝7.6Hz,1H),7.24(dd,J＝8.2,4.1Hz,2H),6.50(dd,J＝3.3,1.7Hz,1H),4.92(t,J＝5.3Hz,1H),4.09(t,J＝5.1Hz,2H),3.75(dd,J＝10.2,5.1Hz,2H),3.04(t,J＝7.5Hz,2H),2.73(t,J＝7.6Hz,2H).
实施例38：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-((2-吗啉代乙基)氨基)-3-(三氟甲基)苯基)丙烯酰胺(化合物38)的合成
合成步骤同实施例1，用4-((2-吗啉代乙基)氨基)-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),9.87(s,1H),8.51(d,J＝2.1Hz,1H),8.15(d,J＝2.0Hz,1H),7.81(d,J＝2.4Hz,1H),7.62–7.55(m,2H),7.52(dd,J＝6.9,4.5Hz,2H),7.39(t,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),6.79(d,J＝9.0Hz,1H),6.48(dd,J＝3.4,1.8Hz,1H),5.27(t,J＝4.3Hz,1H),3.62–3.53(m,4H),3.16(dd,J＝10.9,5.8Hz,2H),3.00(t,J＝7.5Hz,2H),2.67(t,J＝7.6Hz,2H),2.56(t,J＝6.1Hz,2H),2.39(s,4H).
实施例39：3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-((3-吗啉丙基)氨基)-3-(三氟甲基)苯基)丙烯酰胺(化合物39)的合成
合成步骤同实施例1，用4-((2-吗啉代丙基)氨基)-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.84(s,1H),8.50(s,1H),8.15(d,J＝1.8Hz,1H),7.78(d,J＝2.2Hz,1H),7.59(s,1H),7.53(dd,J＝11.6,2.2Hz,3H),7.38(t,J＝7.6Hz,1H),7.22(d,J＝7.6Hz,1H),6.77(d,J＝9.0Hz,1H),6.50–6.44(m,1H),5.63(t,J＝4.8Hz,1H),3.64–3.53(m,4H),3.16(dd,J＝11.4,5.8Hz,2H),2.99(t,J＝7.5Hz,2H),2.65(t,J＝7.6Hz,2H),2.40–2.28(m,6H),1.77–1.65(m,2H).
实施例40
N-(3-溴苯乙基)环丙烷甲酰胺(中间体M2)的合成
将化合物环丙基甲酸(136mg，1.58mmol)，草酰氯(218mg，1.72mmol)，二氯甲烷(8mL)，N,N-二甲基甲酰胺(2滴)，25℃反应1小时。直接浓缩，加二氯甲烷2mL配成溶液；化合物苯胺(160mg，1.72mmol)，三乙胺(320mg，2.86mmol)，二氯甲烷8mL，冰浴搅拌，滴加现制备的酰氯，滴毕，25℃反应1小时；直接浓缩得固体400mg投下一步。
N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)环丙烷甲酰胺(化合物40)的合成
将化合物M0(1.58mmol)，化合物M2(400mg，1.58mmol)，碳酸钾(655mg，4.74mmol)，二氯[1,1'-二(二苯基膦)二茂铁]钯(95mg，0.13mmol)，1,4-二氧六环10mL，加水(2.5mL)，氮气置换，85℃反应15小时。反应结束加水和乙酸乙酯搅拌，加食盐水分液，无水硫酸钠干燥，旋干得黑色油状物。柱层析，洗脱剂EA(65％)过出产物，得白色固体，乙酸乙酯和石油醚打浆抽滤得白色固体300mg；收率62.4％。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.52(d,J＝2.0Hz,1H),8.20(d,J＝2.0Hz,2H),7.62–7.47(m,3H),7.40(t,J＝8.0Hz,1H),7.20(d,J＝7.6Hz,1H),6.51(dd,J＝3.6,1.6Hz,1H),3.43–3.33(m,2H),2.82(t,J＝7.2Hz,2H),1.60–1.50(m,1H),0.70–0.65(m,2H),0.64–0.59(m,2H).
实施例41：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)环己烷甲酰胺(化合物41)的合成
合成步骤同实施例40，用环己酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.51(d,J＝2.0Hz,1H),8.19(d,J＝2.0Hz,1H),7.80(t,J＝5.6Hz,1H),7.56–7.50(m,3H),7.39(t,J＝8.0Hz,1H),7.17(d,J＝7.6Hz,1H),6.50(dd,J＝3.6,2.0Hz,1H),3.35–3.28(m,2H),2.79(t,J＝7.2Hz,2H),2.07(tt,J＝11.4,3.2Hz,1H),1.69–1.55(m,5H),1.29(dt,J＝12.0,7.2Hz,2H),1.24–1.06(m,3H).
实施例42：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)呋喃甲酰胺(化合物42)的合成
合成步骤同实施例40，用2-呋喃甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.50(dd,J＝9.2,4.0Hz,2H),8.14(d,J＝2.0Hz,1H),7.83(d,J＝0.8Hz,1H),7.62–7.45(m,3H),7.43(dd,J＝30.3,22.7Hz,1H),7.22(d,J＝7.6Hz,1H),7.09(dd,J＝3.6,0.8Hz,1H),6.62(dd,J＝3.6,1.6Hz,1H),6.50(dd,J＝3.6,1.6Hz,1H),3.53(dd,J＝13.6,6.8Hz,2H),2.92(t,J＝7.2Hz,2H).
实施例43：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)苯甲酰胺(化合物43)的合成
合成步骤同实施例40，用苯甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.63(t,J＝5.2Hz,1H),8.50(d,J＝1.6Hz,1H),8.15(s,1H),7.85(d,J＝7.2Hz,2H),7.61–7.50(m,4H),7.50–7.37(m,3H),7.24(d,J＝7.2Hz,1H),6.48(s,1H),3.58(dd,J＝12.8,6.8Hz,2H),2.95(t,J＝7.2Hz,2H).
实施例44：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-2-氟苯甲酰胺(化合物44)的合成
合成步骤同实施例40，用2-氟苯甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.52(d,J＝2.2Hz,1H),8.47–8.40(m,1H),8.19(d,J＝1.9Hz,1H),7.60(s,1H),7.56(ddd,J＝7.3,4.4,1.8Hz,2H),7.54–7.48(m,2H),7.41(t,J＝7.6Hz,1H),7.31–7.20(m,3H),6.50(dd,J＝3.4,1.8Hz,1H),3.57(dd,J＝13.1,6.9Hz,2H),2.94(t,J＝7.2Hz,2H).
实施例45：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-氟苯甲酰胺(化合物45)的合成
合成步骤同实施例40，用3-氟苯甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.74(t,J＝5.3Hz,1H),8.49(d,J＝1.8Hz,1H),8.14(d,J＝1.7Hz,1H),7.71(d,J＝7.7Hz,1H),7.64(d,J＝9.9Hz,1H),7.58(s,1H),7.53(dt,J＝14.1,5.8Hz,3H),7.39(dt,J＝9.7,5.0Hz,2H),7.23(d,J＝7.5Hz,1H),6.48(d,J＝1.1Hz,1H),3.58(dd,J＝13.0,6.7Hz,2H),2.95(t,J＝7.1Hz,2H).
实施例46：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-氯苯甲酰胺(化合物46)的合成
合成步骤同实施例40，用3-氯苯甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.77(t,J＝5.3Hz,1H),8.49(d,J＝1.9Hz,1H),8.14(d,J＝1.7Hz,1H),7.88(s,1H),7.81(d,J＝7.7Hz,1H),7.64–7.56(m,2H),7.52(dt,J＝19.3,8.0Hz,3H),7.40(t,J＝7.6Hz,1H),7.23(d,J＝7.5Hz,1H),6.48(dd,J＝3.1,1.7Hz,1H),3.58(dd,J＝12.9,6.7Hz,2H),2.95(t,J＝7.1Hz,2H).
实施例47：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(三氟甲基)苯甲酰胺(化合物47)的合成
合成步骤同实施例40，用3-(三氟甲基)苯甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.90(t,J＝5.6Hz,1H),8.49(d,J＝2.0Hz,3H),8.16(dd,J＝12.8,4.8Hz,1H),7.91(d,J＝7.6Hz,1H),7.72(t,J＝7.8Hz,1H),7.59(s,1H),7.56–7.48(m,1H),7.41(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.47(dd,J＝3.2,1.6Hz,1H),3.61(dd,J＝13.2,6.8Hz,2H),2.97(t,J＝7.2Hz,2H).
实施例48：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-甲基苯甲酰胺(化合物48)的合成
合成步骤同实施例40，用3-甲基苯甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.58(t,J＝5.4Hz,1H),8.50(d,J＝2.0Hz,1H),8.15(d,J＝1.9Hz,1H),7.66(s,1H),7.65–7.62(m,1H),7.58(s,1H),7.55(s,1H),7.53–7.51(m,1H),7.40(t,J＝7.6Hz,1H),7.33(d,J＝5.5Hz,2H),7.23(d,J＝7.5Hz,1H),6.48(dd,J＝3.1,1.5Hz,1H),3.57(dd,J＝13.0,6.8Hz,2H),2.95(t,J＝7.1Hz,2H),2.32(s,3H).
实施例49：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-甲氧苯甲酰胺(化合物49)的合成
合成步骤同实施例40，用3-甲氧苯甲酰氯替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.63(t,J＝5.2Hz,1H),8.50(d,J＝1.7Hz,1H),8.14(d,J＝1.3Hz,1H),7.58(s,1H),7.53(dd,J＝9.5,6.3Hz,2H),7.46–7.33(m,4H),7.24(d,J＝7.4Hz,1H),7.08(dd,J＝7.9,1.6Hz,1H),6.48(d,J＝1.2Hz,1H),3.77(s,3H),3.57(dd,J＝12.6,6.5Hz,2H),2.95(t,J＝7.0Hz,2H).
实施例50：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-4-氯-3-(三氟甲基)苯甲酰胺(化合物50)的合成
合成步骤同实施例40，用4-氯-3-(三氟甲基)苯甲酸替换环丙甲酸。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.97(t,J＝5.4Hz,1H),8.50(d,J＝2.1Hz,1H),8.28(d,J＝1.7Hz,1H),8.14(dd,J＝6.6,1.8Hz,2H),7.84(d,J＝8.4Hz,1H),7.61–7.53(m,2H),7.53–7.50(m,1H),7.40(t,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),6.47(dd,J＝3.3,1.8Hz,1H),3.60(dd,J＝13.0,6.8Hz,2H),2.96(t,J＝7.2Hz,2H).
实施例51：N-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-4-甲基-3-(三氟甲基)苯甲酰胺(化合物51)的合成
合成步骤同实施例40，用4-甲基-3-(三氟甲基)苯甲酸替换环丙甲酸。1H NMR(500MHz,DMSO-d6)δ11.70(s,1H),8.81(t,J＝5.4Hz,1H),8.50(d,J＝2.1Hz,1H),8.14(s,2H),8.03(d,J＝7.9Hz,1H),7.58(s,1H),7.54(dd,J＝7.8,3.4Hz,2H),7.52–7.50(m,1H),7.40(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.48(dd,J＝3.3,1.8Hz,1H),3.60(dd,J＝13.1,6.9Hz,2H),2.97(t,J＝7.2Hz,2H),2.49(s,3H).
实施例52：
1-(3-溴苯乙基)-3-苯基脲(中间体M3)的合成：
将三光气(297mg，1.0mmol)，四氢呋喃(6mL)，冰浴搅拌下，加DIPEA(517mg，4.0mmol)，滴加苯胺(322mg，2.0mmol)的四氢呋喃(2mL)溶液，维持冰浴2小时，体系黄色悬浮液；加化合物3-溴苯乙胺(392mg，1.96mmol)，加毕，体系固体逐渐减少，室温23℃下反应1小时；反应结束加水和乙酸乙酯搅拌，加食盐水分液，无水硫酸钠干燥，旋干得黄色固体730mg，直接投下一步。
1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-苯基脲(化合物52)的制备：
将化合物M0(342mg，1.4mmol)，化合物M3(730mg，2.0mmol)，碳酸钾(830mg，6.0mmol)，二氯[1,1'-二(二苯基膦)二茂铁]钯(74mg，0.1mmol)，1,4-二氧六环10mL，加水(2.5mL)，氮气置换，85℃反应15小时。反应结束加水和乙酸乙酯搅拌，加食盐水分液，无水硫酸钠干燥，旋干得黑色油状物。柱层析，洗脱剂EA(70％)过出产物，得白色固体，乙酸乙酯和石油醚打浆抽滤得淡黄色固体135mg；收率22.8％。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.58–8.46(m,2H),8.21(d,J＝1.8Hz,1H),8.01(s,2H),7.61–7.54(m,2H),7.53–7.50(m,1H),7.41(dd,J＝15.8,7.8Hz,3H),7.22(dd,J＝14.4,7.0Hz,1H),6.88(t,J＝7.3Hz,1H),6.48(dd,J＝3.2,1.7Hz,1H),6.15(t,J＝5.5Hz,1H),3.43(dd,J＝12.7,6.6Hz,2H),2.85(t,J＝6.9Hz,2H).
实施例53：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-苄脲(化合物53)的合成：
合成步骤同实施例52，用苄胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.53(d,J＝2.2Hz,1H),8.21(d,J＝2.0Hz,1H),7.58–7.53(m,2H),7.52(dd,J＝5.9,3.1Hz,1H),7.43–7.38(m,1H),7.31–7.25(m,2H),7.24–7.15(m,4H),6.50(dd,J＝3.4,1.8Hz,1H),6.39(t,J＝5.9Hz,1H),5.98(t,J＝5.7Hz,1H),4.21(d,J＝6.0Hz,2H),3.35(s,2H),2.79(t,J＝7.0Hz,2H).
实施例54：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(2-氟苯基)脲(化合物54)的合成：
合成步骤同实施例52，用2-氟胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.53(d,J＝2.2Hz,1H),8.36(d,J＝2.4Hz,1H),8.21(d,J＝1.8Hz,1H),8.16(td,J＝8.3,1.5Hz,1H),7.63–7.55(m,2H),7.52(dd,J＝3.2,2.7Hz,1H),7.43(t,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),7.17(ddd,J＝11.8,8.2,1.4Hz,1H),7.07(t,J＝7.8Hz,1H),6.97–6.87(m,1H),6.67(t,J＝5.6Hz,1H),6.48(dd,J＝3.4,1.9Hz,1H),3.45(dd,J＝12.7,6.8Hz,2H),2.85(t,J＝6.9Hz,2H).
实施例55：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(2-甲基苯基)脲(化合物55)的合成：
合成步骤同实施例52，用2-甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.54(d,J＝2.2Hz,1H),8.22(d,J＝1.9Hz,1H),7.81(d,J＝6.7Hz,2H),7.60(s,1H),7.56(d,J＝7.8Hz,1H),7.53–7.48(m,1H),7.42(t,J＝7.6Hz,1H),7.25(d,J＝7.6Hz,1H),7.08(dd,J＝15.2,7.6Hz,2H),6.85(td,J＝7.4,1.1Hz,1H),6.80(t,J＝5.5Hz,1H),6.47(dd,J＝3.4,1.9Hz,1H),3.42(dd,J＝12.8,6.8Hz,2H),2.85(t,J＝7.0Hz,2H),2.16(s,3H).
实施例56：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(3-氟苯基)脲(化合物56)的合成
合成步骤同实施例52，用3-氟苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.78(s,1H),8.54(s,1H),8.21(s,1H),7.61–7.54(m,2H),7.54–7.46(m,2H),7.42(t,J＝7.6Hz,1H),7.28–7.18(m,2H),7.02(d,J＝8.0Hz,1H),6.69(t,J＝7.4Hz,1H),6.48(s,1H),6.25(t,J＝5.1Hz,1H),3.44(dd,J＝12.3,6.2Hz,2H),2.86(t,J＝6.7Hz,2H).
实施例57：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(3-氯苯基)脲(化合物57)的合成
合成步骤同实施例52，用3-氯苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.76(s,1H),8.54(s,1H),8.21(s,1H),7.70(s,1H),7.60–7.54(m,2H),7.52(s,1H),7.42(t,J＝7.5Hz,1H),7.27–7.20(m,2H),7.17(d,J＝8.1Hz,1H),6.93(d,J＝7.5Hz,1H),6.48(s,1H),6.26(d,J＝5.1Hz,1H),3.43(dd,J＝12.2,6.2Hz,2H),2.85(t,J＝6.7Hz,2H).
实施例58：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(3-甲基苯基)脲(化合物58)的合成
合成步骤同实施例52，用3-甲基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.53(d,J＝2.2Hz,1H),8.42(s,1H),8.21(d,J＝1.8Hz,1H),7.57(dd,J＝7.1,6.1Hz,2H),7.53–7.50(m,1H),7.42(t,J＝7.6Hz,1H),7.28–7.20(m,2H),7.17(d,J＝8.3Hz,1H),7.08(t,J＝7.7Hz,1H),6.70(d,J＝7.4Hz,1H),6.48(dd,J＝3.4,1.9Hz,1H),6.14(t,J＝5.7Hz,1H),3.42(dd,J＝12.9,6.8Hz,2H),2.84(t,J＝7.0Hz,2H),2.23(s,3H).
实施例59：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(3-甲氧基苯基)脲(化合物59)的合成
合成步骤同实施例52，用3-甲氧基苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.54(s,2H),8.21(d,J＝1.2Hz,1H),7.62–7.54(m,2H),7.54–7.50(m,1H),7.42(t,J＝7.6Hz,1H),7.23(d,J＝7.4Hz,1H),7.17(s,1H),7.11(t,J＝8.1Hz,1H),6.86(d,J＝7.9Hz,1H),6.51–6.42(m,2H),6.15(t,J＝5.4Hz,1H),3.70(s,3H),3.43(dd,J＝12.4,6.3Hz,2H),2.85(t,J＝6.8Hz,2H).
实施例60：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(3-(三氟甲基)苯基)脲(化合物60)的合成
合成步骤同实施例52，用3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.91(s,1H),8.53(d,J＝2.0Hz,1H),8.21(d,J＝2.0Hz,1H),8.00(s,1H),7.61–7.54(m,2H),7.53–7.51(m,1H),7.45(dt,J＝14.8,8.0Hz,3H),7.23(t,J＝7.6Hz,2H),6.48(dd,J＝3.6,1.6Hz,1H),6.31(t,J＝5.6Hz,1H),3.44(dd,J＝12.8,6.8Hz,2H),2.86(t,J＝7.2Hz,2H).
实施例61：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(2-氟-5-(三氟甲基)苯基)脲(化合物61)的合成
合成步骤同实施例52，用2-氟-5-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.74(d,J＝2.6Hz,1H),8.65(dd,J＝7.4,2.0Hz,1H),8.53(d,J＝2.2Hz,1H),8.21(d,J＝1.9Hz,1H),7.60(s,1H),7.57(d,J＝7.8Hz,1H),7.53–7.49(m,1H),7.42(dt,J＝8.9,6.8Hz,2H),7.32–7.26(m,1H),7.25(d,J＝7.6Hz,1H),6.81(t,J＝5.6Hz,1H),6.48(dd,J＝3.4,1.9Hz,1H),3.47(dd,J＝12.7,6.7Hz,2H),2.86(t,J＝6.9Hz,2H).
实施例62：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(2-氟-3-(三氟甲基)苯基)脲(化合物62)的合成
合成步骤同实施例52，用2-氟-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.67(d,J＝2.1Hz,1H),8.53(d,J＝2.1Hz,1H),8.47(dd,J＝11.1,4.7Hz,1H),8.21(d,J＝2.0Hz,1H),7.64–7.54(m,2H),7.53–7.49(m,1H),7.43(t,J＝7.6Hz,1H),7.33–7.20(m,3H),6.75(t,J＝5.6Hz,1H),6.48(dd,J＝3.4,1.8Hz,1H),3.47(dd,J＝12.7,6.7Hz,2H),2.86(t,J＝6.9Hz,2H).
实施例63：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(4-氟-3-(三氟甲基)苯基)脲(化合物63)的合成
合成步骤同实施例52，用4-氟-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.90(s,1H),8.53(d,J＝2.2Hz,1H),8.20(d,J＝1.9Hz,1H),7.98(dd,J＝6.5,2.7Hz,1H),7.63–7.49(m,4H),7.39(dt,J＝19.6,8.5Hz,2H),7.23(d,J＝7.6Hz,1H),6.48(dd,J＝3.4,1.9Hz,1H),6.31(t,J＝5.6Hz,1H),3.44(dd,J＝12.9,6.8Hz,2H),2.86(t,J＝7.0Hz,2H).
实施例64：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(4-氯-3-(三氟甲基)苯基)脲(化合物64)的合成
合成步骤同实施例52，用4-氯-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),9.04(s,1H),8.53(d,J＝2.2Hz,1H),8.20(d,J＝1.9Hz,1H),8.09(d,J＝2.3Hz,1H),7.62–7.53(m,4H),7.52(t,J＝2.9Hz,1H),7.42(t,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),6.48(dd,J＝3.4,1.9Hz,1H),6.37(t,J＝5.6Hz,1H),3.44(dd,J＝12.9,6.8Hz,2H),2.86(t,J＝7.0Hz,2H).
实施例65：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(4-甲基-3-(三氟甲基)苯基)脲(化合物65)的合成
合成步骤同实施例52，用4-甲基-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.78(s,1H),8.53(d,J＝2.1Hz,1H),8.20(d,J＝1.9Hz,1H),7.90(d,J＝2.0Hz,1H),7.60–7.54(m,2H),7.53–7.50(m,1H),7.42(dd,J＝9.3,5.5Hz,2H),7.29–7.20(m,2H),6.48(dd,J＝3.3,1.8Hz,1H),6.24(t,J＝5.5Hz,1H),3.43(dd,J＝12.9,6.7Hz,2H),2.85(t,J＝7.0Hz,2H),2.34(d,J＝1.2Hz,3H).
实施例66：1-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯乙基)-3-(4-甲氧基-3-(三氟甲基)苯基)脲(化合物66)的合成
合成步骤同实施例52，用4-甲氧基-3-(三氟甲基)苯胺替换苯胺。1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.63(s,1H),8.53(d,J＝2.0Hz,1H),8.21(d,J＝2.0Hz,1H),7.82(d,J＝2.4Hz,1H),7.61–7.54(m,2H),7.53–7.46(m,2H),7.42(t,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),7.14(d,J＝9.2Hz,1H),6.48(dd,J＝3.2,2.0Hz,1H),6.18(t,J＝5.6Hz,1H),3.82(s,3H),3.42(dd,J＝12.8,6.8Hz,2H),2.85(t,J＝7.2Hz,2H).
实施例67：2-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-氯-3-(三氟甲基)苯基)乙酰胺(化合物67)的合成
合成步骤同实施例1，用3-溴苯乙酸替换3-溴苯丙酸。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),10.67(s,1H),8.51(d,J＝2.0Hz,1H),8.21(dd,J＝6.8,2.4Hz,2H),7.87(dd,J＝8.8,2.4Hz,1H),7.72–7.64(m,2H),7.61(d,J＝8.0Hz,1H),7.55–7.50(m,1H),7.44(t,J＝7.6Hz,1H),7.32(d,J＝7.6Hz,1H),6.52(dd,J＝3.6,2.0Hz,1H),3.78(s,2H).
实施例68：2-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)乙酰胺(化合物68)的合成
合成步骤同实施例1，用3-溴苯乙酸替换3-溴苯丙酸。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),10.45(s,1H),8.51(d,J＝2.1Hz,1H),8.20(d,J＝2.1Hz,1H),8.04(d,J＝2.0Hz,1H),7.73(dd,J＝8.3,1.8Hz,1H),7.69(s,1H),7.60(d,J＝7.8Hz,1H),7.54–7.51(m,1H),7.44(t,J＝7.6Hz,1H),7.37(d,J＝8.4Hz,1H),7.33(d,J＝7.6Hz,1H),6.52(dd,J＝3.4,1.8Hz,1H),3.75(s,2H),2.37(d,J＝1.3Hz,3H).
实施例69
2-氯-N-(4-甲基-3-(三氟甲基)苯基)乙酰胺(中间体M4)的合成：
将化合物3-三氟甲基-4-甲基苯胺(1.2g,6.85mmol)和三乙胺(831mg,8.22mmol)溶解在二氯甲烷(30mL)，然后冰浴下滴加氯乙酰氯(812mg,7.19mmol)在CH2Cl2(5mL)的溶液。在25℃搅拌3小时.反应结束后，向反应加二氯甲烷(30mL).稀盐酸洗，柱层析，65％乙酸乙酯洗脱得到化合物M4(1.41g,yield:82％).
2-((3-溴苯基)氨基)-N-(4-甲基-3-(三氟甲基)苯基)乙酰胺(中间体M5)的合成：
将化合物M4(300mg,1.19mmol)和3-溴苯胺(246mg,1.43mmol)溶解在N,N-二甲基甲酰胺(10mL)，然后加碳酸钾(329mg,2.38mmol).反应液在90℃搅拌6h。反应结束后，冷却加入乙酸乙酯(60mL)。有机相用饱和食盐水洗，然后柱层析，55％乙酸乙酯洗脱得到化合物M5(236mg,yield:65％).
2-((3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)氨基)-N-(4-甲基-3-(三氟甲基)苯基)乙酰胺(化合物69)的合成：
合成步骤同实施例1，用M5替换M1。1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),10.31(s,1H),8.44(d,J＝2.0Hz,1H),8.08(dd,J＝11.4,1.8Hz,2H),7.77(dd,J＝8.3,1.3Hz,1H),7.56–7.46(m,1H),7.37(d,J＝8.4Hz,1H),7.21(t,J＝8.1Hz,1H),7.00–6.85(m,2H),6.66–6.55(m,1H),6.48(dd,J＝3.3,1.8Hz,1H),6.18(t,J＝6.0Hz,1H),3.99(d,J＝6.0Hz,2H),2.37(s,3H).
实施例70：2-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯氧基)-N-(4-甲基-3-(三氟甲基)苯基)乙酰胺(化合物70)的合成
合成步骤同实施例69，用3-溴苯酚替换3-溴苯胺。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.36(s,1H),8.54(d,J＝2.1Hz,1H),8.22(d,J＝2.0Hz,1H),8.09(d,J＝1.9Hz,1H),7.84(dd,J＝8.3,1.7Hz,1H),7.60–7.50(m,1H),7.45–7.29(m,4H),7.02(dd,J＝8.1,2.0Hz,1H),6.51(dd,J＝3.3,1.8Hz,1H),4.84(s,2H),2.39(d,J＝1.2Hz,3H).
实施例71：2-((3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)硫代)-N-(4-甲基-3-(三氟甲基)苯基)乙酰胺(化合物71)的合成
合成步骤同实施例69，用3-溴苯硫酚替换3-溴苯胺。1H NMR(500MHz,DMSO-d6)δ11.73(s,1H),10.50(s,1H),8.51(d,J＝2.1Hz,1H),8.17(d,J＝1.9Hz,1H),7.99(d,J＝1.8Hz,1H),7.73(s,1H),7.70(dd,J＝8.3,1.6Hz,1H),7.58–7.51(m,2H),7.43(t,J＝7.7Hz,1H),7.40–7.32(m,2H),6.47(dd,J＝3.3,1.8Hz,1H),3.98(s,2H),2.38(d,J＝1.1Hz,3H).
实施例72：3-(2-氯-5-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物72)的合成
将化合物75(200mg,0.77mmol)溶解在甲醇(15mL)，然后加钯/碳(20mg)。氢气置换三次，氢气球的压力下在35℃反应6h。反应结束后，反应液抽滤，滤液柱层析，75％的乙酸乙酯洗脱得到化合物72(89mg,yield:45％).1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),10.24(s,1H),8.50(s,1H),8.14(s,1H),8.02(s,1H),7.70(d,J＝10.9Hz,2H),7.58(d,J＝8.1Hz,1H),7.55–7.45(m,2H),7.34(d,J＝8.2Hz,1H),6.47(s,1H),3.12(t,J＝7.1Hz,2H),2.75(t,J＝7.2Hz,2H),2.36(s,3H).
实施例73
3-(3-溴苯基)丙烯酸乙酯(中间体M7)的合成：
膦酰基乙酸三乙酯(2.0g,9.57mmol)溶解在四氢呋喃(40mL)，然后-10℃下分批加氢化钠(0.57g,13.67mmol,W＝60％)。-5℃搅拌1h后，加入3-溴苯甲醛(2g,9.11mmol)在四氢呋喃(10mL)的溶液。反应液30℃搅拌15h.。反应结束后，氯化铵水溶液淬灭，加乙酸乙酯萃取后柱层析，55％乙酸乙酯洗脱得到化合物M7(1.32g,yield:50％).
3-(3-溴苯基)丙烯酸(中间体M8)的合成：
将化合物M7(1.32g,4.56mmol)溶解在乙醇(25mL)，然后加入氢氧化钠水溶液(365mg,9.12mmol)/H2O(4mL)，70℃搅拌2h。反应结束后，加入乙酸乙酯和水，用2M HCl调pH<8。T混合物分液，柱层析，65％乙酸乙酯洗脱得到化合物M8(1g,yield:85％).
(E)-3-(3-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物73)的合成
合成步骤同实施例40，用3-(3-溴苯基)丙烯酸替换环丙基甲酸。1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.48(s,1H),8.59(d,J＝2.1Hz,1H),8.28(d,J＝1.9Hz,1H),8.16(d,J＝1.7Hz,1H),7.99(s,1H),7.82(d,J＝8.3Hz,1H),7.75(dd,J＝17.7,11.7Hz,2H),7.63(d,J＝7.7Hz,1H),7.59–7.51(m,2H),7.40(d,J＝8.4Hz,1H),6.94(d,J＝15.7Hz,1H),6.53(dd,J＝3.3,1.8Hz,1H),2.39(s,3H).
实施例74：(E)-3-(2-氟-5-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物74)的合成
合成步骤同实施例72，用2-氟-5-溴苯甲醛替换3-溴苯甲醛。1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.54(s,1H),8.57(d,J＝2.1Hz,1H),8.25(d,J＝1.9Hz,1H),8.15(d,J＝1.7Hz,1H),8.02(dd,J＝7.1,2.1Hz,1H),7.86–7.70(m,3H),7.56–7.50(m,1H),7.39(t,J＝9.8Hz,2H),7.05(d,J＝15.9Hz,1H),6.52(dd,J＝3.3,1.8Hz,1H),2.38(s,3H).
实施例75：(E)-3-(2-氯-5-(1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物75)的合成
合成步骤同实施例72，用2-氯-5-溴苯甲醛替换3-溴苯甲醛。1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.54(s,1H),8.60(d,J＝2.2Hz,1H),8.29(d,J＝2.1Hz,1H),8.16(d,J＝1.9Hz,1H),8.07(d,J＝2.2Hz,1H),7.93(d,J＝15.6Hz,1H),7.85–7.71(m,2H),7.62(d,J＝8.4Hz,1H),7.58–7.52(m,1H),7.39(d,J＝8.4Hz,1H),7.04(d,J＝15.6Hz,1H),6.53(dd,J＝3.4,1.8Hz,1H),2.39(d,J＝1.2Hz,3H).
实施例76：3-(3-(3-氯-1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物76)的合成
将化合物22(200mg,0.47mmol)溶解在N,N二甲基甲酰胺(10mL)里，然后加N-氯代琥珀酰亚胺，在30℃搅拌2h。反应结束后，加硫代硫酸钠淬灭，然后加乙酸乙酯萃取，柱层析，65％乙酸乙酯洗脱得到化合物76(61mg,yield:30％)。1H NMR(500MHz,DMSO-d6)δ12.06(s,1H),10.17(s,1H),8.62(d,J＝1.1Hz,1H),8.10(s,1H),8.02(s,1H),7.77–7.69(m,2H),7.66(s,1H),7.58(d,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.35(d,J＝8.3Hz,1H),7.28(d,J＝7.5Hz,1H),3.04(t,J＝7.5Hz,2H),2.75(t,J＝7.6Hz,2H),2.37(s,3H).
实施例77：3-(3-(3-溴-1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物77)的合成
合成步骤同实施例76，用N-溴代琥珀酰亚胺替换N-氯代琥珀酰亚胺。1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),10.21(s,1H),8.59(d,J＝2.1Hz,1H),8.01(t,J＝2.2Hz,2H),7.78(d,J＝2.6Hz,1H),7.70(dd,J＝8.3,1.5Hz,1H),7.66(s,1H),7.58(d,J＝7.8Hz,1H),7.41(t,J＝7.6Hz,1H),7.35(d,J＝8.4Hz,1H),7.27(d,J＝7.6Hz,1H),3.03(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,2H),2.36(s,3H).
实施例78：3-(3-(3-碘-1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物78)的合成
合成步骤同实施例76，用N-碘代琥珀酰亚胺替换N-氯代琥珀酰亚胺。1H NMR(400MHz,DMSO-d6)δ12.22(d,J＝1.6Hz,1H),10.20(s,1H),8.55(d,J＝2.1Hz,1H),8.01(d,J＝2.0Hz,1H),7.84(d,J＝1.8Hz,1H),7.78(d,J＝2.5Hz,1H),7.75–7.61(m,2H),7.57(d,J＝7.8Hz,1H),7.45–7.31(m,2H),7.27(d,J＝7.7Hz,1H),3.03(t,J＝7.6Hz,2H),2.73(t,J＝7.7Hz,2H),2.36(s,3H).
实施例79：3-(3-(6-氨基吡啶-3-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙酰胺(化合物79)的合成
合成步骤同实施例1，用N-(4-甲基-3-(三氟甲基)苯基)-3-(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)丙酰胺替换5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯并[2,3-b]吡啶，2-氨基-5-溴吡啶替换3-(3-溴苯基)-N-苯基丙酰胺。white solid:62％.1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.04(s,1H),7.70(d,J＝8.1Hz,1H),7.42(s,1H),7.30(dt,J＝15.2,9.2Hz,5H),7.09(d,J＝7.3Hz,1H),6.62(d,J＝8.4Hz,2H),5.23(s,2H),2.95(t,J＝7.5Hz,2H),2.68(t,J＝7.6Hz,2H),2.37(s,3H).
实施例80：3-(3-(6-氨基-5-氟吡啶-3-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙酰胺(化合物80)的合成
合成步骤同实施例79，用2-氨基-3-氟-5-溴吡啶替换2-氨基-5-溴吡啶。whitesolid:67％.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.12(d,J＝1.3Hz,1H),8.02(d,J＝1.9Hz,1H),7.74–7.62(m,2H),7.52(s,1H),7.44(d,J＝7.9Hz,1H),7.33(dd,J＝14.6,7.3Hz,2H),7.18(d,J＝7.6Hz,1H),6.36(s,2H),2.96(t,J＝7.6Hz,2H),2.70(t,J＝7.7Hz,2H),2.37(d,J＝1.2Hz,3H).
实施例81：3-(3-(6-氨基-5-氯吡啶-3-基)苯基)-N-(4-甲基-3(三氟甲基)苯基)丙烯酰胺(化合物81)的合成
合成步骤同实施例79，用2-氨基-3-氯-5-溴吡啶替换2-氨基-5-溴吡啶。yellowsolid:41％.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.47(s,1H),8.41(s,1H),8.05(s,1H),7.73(d,J＝7.9Hz,1H),7.64(s,1H),7.53(d,J＝7.4Hz,1H),7.36(dd,J＝17.8,8.1Hz,2H),7.28(d,J＝7.3Hz,1H),2.97(t,J＝7.3Hz,2H),2.73(t,J＝7.4Hz,2H),2.36(s,3H).
实施例82：3-(3-(6-氨基-5-甲基吡啶-3-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物82)的合成
合成步骤同实施例79，用2-氨基-3-甲基-5-溴吡啶替换2-氨基-5-溴吡啶。whitesolid:62％.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.11(d,J＝2.2Hz,1H),8.03(d,J＝1.7Hz,1H),7.75–7.65(m,1H),7.52(d,J＝1.5Hz,1H),7.46(s,1H),7.43–7.26(m,3H),7.14(d,J＝7.5Hz,1H),5.86(s,2H),2.96(t,J＝7.6Hz,2H),2.69(t,J＝7.6Hz,2H),2.37(d,J＝1.2Hz,3H),2.09(s,3H).
实施例83：3-(3-(6-氨基-5-氰基吡啶-3-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙酰胺(化合物83)的合成
合成步骤同实施例79，用2-氨基-3-氰基-5-溴吡啶替换2-氨基-5-溴吡啶。whitesolid:49％.1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.56(d,J＝2.5Hz,1H),8.20(d,J＝2.5Hz,1H),8.01(d,J＝1.9Hz,1H),7.69(dd,J＝8.3,1.6Hz,1H),7.56(s,1H),7.47(d,J＝7.9Hz,1H),7.39–7.29(m,2H),7.21(d,J＝7.6Hz,1H),7.06(s,2H),2.97(t,J＝7.6Hz,2H),2.71(t,J＝7.7Hz,2H),2.36(d,J＝1.3Hz,3H).
实施例84：N-(4-甲基-3-(三氟甲基)苯基)-3-(3-(6-(甲基氨基)吡啶-3-基)苯基)丙酰胺(化合物84)的合成
合成步骤同实施例79，用5-溴-2-(甲基氨基)吡啶替换2-氨基-5-溴吡啶。whitesolid:60％.1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.31(d,J＝2.2Hz,1H),8.03(d,J＝1.9Hz,1H),7.74–7.62(m,2H),7.45(s,1H),7.43–7.25(m,3H),7.15(d,J＝7.5Hz,1H),6.65(q,J＝4.6Hz,1H),6.51(d,J＝8.7Hz,1H),2.96(t,J＝7.6Hz,2H),2.81(d,J＝4.8Hz,3H),2.70(t,J＝7.7Hz,2H),2.37(s,3H).
实施例85：3-(3-(1H-吡唑并[3,4-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物85)的合成
合成步骤同实施例79，用5-溴-1H-吡唑并[3,4-b]吡啶替换2-氨基-5-溴吡啶。white solid:64％.1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),10.29(s,1H),8.83(d,J＝2.1Hz,1H),8.44(d,J＝2.1Hz,1H),8.18(s,1H),8.03(d,J＝1.9Hz,1H),7.70(dd,J＝8.3,1.7Hz,1H),7.65(s,1H),7.58(d,J＝7.9Hz,1H),7.42(t,J＝7.6Hz,1H),7.35(d,J＝8.3Hz,1H),7.29(d,J＝7.6Hz,1H),3.02(t,J＝7.6Hz,2H),2.74(t,J＝7.7Hz,2H),2.36(d,J＝1.3Hz,3H).
实施例86：3-(3-(2,3-二氢-1H-吡咯并[2,3-b]吡啶-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物86)的合成
合成步骤同实施例79，用5-溴-2,3-二氢-7-氮杂吲哚替换2-氨基-5-溴吡啶。white solid:55％.1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.01(dd,J＝14.5,1.6Hz,2H),7.70(dd,J＝8.3,1.6Hz,1H),7.52(d,J＝1.2Hz,1H),7.43(s,1H),7.33(ddd,J＝24.1,10.8,5.8Hz,3H),7.14(d,J＝7.5Hz,1H),6.52(s,1H),3.51(t,J＝8.5Hz,2H),3.06–2.89(m,4H),2.69(t,J＝7.6Hz,2H),2.37(d,J＝1.3Hz,3H).
实施例87：3-(3-(5H-吡咯并[2,3-b]吡嗪-2-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物87)的合成
合成步骤同实施例79，用5-溴-4,7-二氮杂吲哚替换2-氨基-5-溴吡啶。whitesolid:54％.1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),10.29(s,1H),8.83(s,1H),8.07–8.00(m,2H),7.94(d,J＝7.8Hz,1H),7.92–7.88(m,1H),7.70(dd,J＝8.3,1.6Hz,1H),7.42(t,J＝7.7Hz,1H),7.33(dd,J＝12.3,8.1Hz,2H),6.68(dd,J＝3.4,1.1Hz,1H),3.03(t,J＝7.7Hz,2H),2.73(t,J＝7.7Hz,2H),2.36(d,J＝1.3Hz,3H).
实施例88：3-(3-(1-氨基异喹啉-4-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物88)的合成
合成步骤同实施例79，用1-氨基-4-溴异喹啉替换2-氨基-5-溴吡啶。yellowsolid:47％.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.27(dd,J＝6.7,2.9Hz,1H),8.02(d,J＝1.8Hz,1H),7.73(s,1H),7.72–7.63(m,2H),7.52–7.45(m,2H),7.40(t,J＝7.6Hz,1H),7.37–7.31(m,2H),7.26(dd,J＝14.4,7.6Hz,2H),6.91(s,2H),3.00(t,J＝7.5Hz,2H),2.72(t,J＝7.5Hz,2H),2.37(s,3H).
实施例89：3-(3-(1H-吲哚-5-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物89)的合成
合成步骤同实施例79，用5-溴吲哚替换2-氨基-5-溴吡啶。white solid:58％.1HNMR(400MHz,DMSO-d6)δ11.19(s,1H),10.27(s,1H),8.08(s,1H),7.79(s,1H),7.73(d,J＝8.0Hz,1H),7.57(s,1H),7.47(t,J＝7.5Hz,2H),7.35(dd,J＝14.0,7.4Hz,4H),7.18(d,J＝7.3Hz,1H),6.46(s,1H),3.02(t,J＝7.2Hz,2H),2.73(t,J＝7.3Hz,2H),2.38(s,3H).
实施例90：3-(3-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物90)的合成
合成步骤同实施例79，用4-溴-7-氮杂吲哚替换2-氨基-5-溴吡啶。white solid:71％.1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),10.29(s,1H),8.26(d,J＝4.9Hz,1H),8.06(d,J＝1.9Hz,1H),7.71(dd,J＝8.3,1.6Hz,1H),7.67(s,1H),7.58(d,J＝7.7Hz,1H),7.52–7.42(m,2H),7.36(d,J＝8.3Hz,2H),7.15(d,J＝4.9Hz,1H),6.60(dd,J＝3.4,1.8Hz,1H),3.04(t,J＝7.4Hz,2H),2.74(t,J＝7.4Hz,2H),2.37(s,3H).
实施例91：3-(3-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙烯酰胺(化合物91)的合成
3-(3-溴苯基)-N-(4-甲基-3-(三氟甲基)苯基)丙胺(200mg,0.52mmol)，5-羟基-7-氮杂吲哚(83mg,0.62mmol)，碳酸铯(398mg,1.04mmol)，三(二亚苄基丙酮)二钯(45mg,0.05mmol)，2-双环已基膦-2',6'-二异丙氧基联苯(50mg,0.1mmol)和1,4-二氧六环(10mL)，氮气保护下，105℃搅拌22h。反应结束后加水和乙酸乙酯分液，然后柱层析，90％乙酸乙酯洗脱得到化合物91(13.2mg,yield:6％).yellow solid:6％.1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.45(s,1H),8.02(d,J＝1.9Hz,1H),7.92(d,J＝2.6Hz,1H),7.83(d,J＝3.6Hz,1H),7.75(d,J＝7.1Hz,2H),7.70(dd,J＝8.3,1.7Hz,1H),7.44(d,J＝7.5Hz,1H),7.40(d,J＝2.6Hz,1H),7.35(d,J＝8.4Hz,1H),7.19(d,J＝7.6Hz,1H),6.55(d,J＝3.6Hz,1H),3.01(t,J＝7.6Hz,2H),2.72(t,J＝7.7Hz,2H),2.37(d,J＝1.3Hz,3H).
实施例92：体外CDK8激酶抑制活性和体外抗肿瘤活性评价
使用黑色384孔板通过ADP-Glo Kinase Assay(Promega)测试化合物1-91对CDK8激酶的抑制活性。将活性CDK8激酶稀释在混合物中(5ng CDK8激酶、0.5μg底物、50μM DTT、1μL buffer，每孔加入ddH2O至3μL)，然后每孔加入1uL浓度为1uM的化合物溶液(在体系中相当于稀释了5倍，化合物终浓度为200nM)，随后加入1uL ATP(三磷酸腺苷)，使其最终浓度为50μM。在室温下孵育1h后，加入ADP-Glo溶液和激酶检测试剂，数据由酶标仪收集。
本发明所述化合物1-91在浓度200nM下均显示出一定的CDK8激酶抑制活性，优选其中抑制率较高的化合物进行MTT试验，测试这些化合物对正常细胞和结直肠癌细胞的活性。选取索拉非尼为阳性对照物，结果见表1。
MTT试验：分别将HCT-116、HT-29、SW-480、CT-26、GES-1细胞以6000个细胞/孔接种在96孔板中，并在37℃、5％CO2的培养箱中培养24h；弃掉培养基，随后加入100μL的各浓度的化合物溶液(浓度为100、20、4、0.8、0.016μM)，培养48h；再加入MTT(5mg/mL，20μL)，在37℃下孵育4h；除去培养基，加入150μL DMSO溶解；通过酶标仪(PerkinElmer Envision)测量492nm处的吸光度，并计算GI50值。
表1
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由表1可以看出，化合物22的激酶活性和细胞活性显著优于索拉非尼。
实施例93：体内抗肿瘤活性评价
根据上述研究，本发明中化合物22是一种潜在的CDK8抑制剂，并进一步评估了其体内抗肿瘤活性。在Balb/c小鼠中建立同系CRC模型，皮下接种CT-26鼠结肠癌细胞建立模型。在每天口服给予化合物22(20、40和80mg/kg)3周后，与对照组相比，肿瘤体积显着减小。但20和40mg/kg组似乎没有明显差异，两组体重略有下降，主要是治疗效果不满意。高浓度组(80mg/kg)能明显抑制小鼠体重减轻。对照组最重，可能是因为肿瘤较重(图1A、1B)。
结直肠癌与WNT信号通路的失调密切相关。先前的研究表明，化合物22可抑制HCT-116细胞中的WNT信号通路。因此，免疫组织化学用于检测CT-26衍生的宏观肿瘤中β-连环蛋白的表达。β-连环蛋白在对照组中显示出强阳性表达，并随着化合物22的处理逐渐减少(图1C，1D)。在CT-26肿瘤组织中β-连环蛋白的蛋白质印迹分析中也观察到了相同的现象。此外，在CT-26肿瘤组织中观察到STAT1 SER727磷酸化的剂量依赖性抑制，并且致癌基因C-myc的表达也降低(图1E，1F)。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (6)
1.一种3-芳杂环取代苯基衍生物，其特征在于，所述3-芳杂环取代苯基衍生物的结构式如下所示：
2.权利要求1所述的3-芳杂环取代苯基衍生物的制备方法，其特征在于，包括以下步骤：
(1)5-溴-7-氮杂吲哚和频那醇酯发生Suzuki-Miyaura反应，得到中间体M0；
(2)R2-NH2和3-溴苯甲酸或3-溴苯乙酸发生酰胺缩合反应，得到中间体M1；
(3)中间体M1和中间体M0经Suzuki反应，得到化合物1-39，67-68；
(4)化合物22发生卤代反应，得到化合物76-78；
(5)R2-COOH和3-溴苯乙胺发生酰胺缩合反应，得到中间体M2；(6)中间体M2和中间体M0经Suzuki反应，得到化合物40-51；
(7)R2-NH2和三光气反应，得到R2-NCO；
(8)3-溴苯乙胺和R2-NCO发生脲缩合反应，得到中间体M3；
(9)中间体M3和中间体M0经Suzuki反应，得到化合物52-66；
(10)R2-NH2和氯乙酰氯反应，得到中间体M4；
(11)和中间体M4发生亲核取代反应，得到中间体M5；
(12)中间体M5和中间体M0经Suzuki反应，得到化合物69-71；
(13)和膦酰乙酸三乙酯发生Witting反应，得到中间体M6；
(14)中间体M6发生水解，得到中间体M7；
(15)中间体M7和R2-NH2发生酰胺缩合反应，得到中间体M8；
(16)中间体M8和中间体M0经Suzuki反应，得到化合物73-75；
(17)化合物75发生双键还原反应，得到化合物72；
3.一种药物组合物，含有权利要求1所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐。
4.一种药物制剂，包括有效成分和药学上可接受的辅料和/或载体，所述有效成分含有权利要求1所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐。
5.权利要求1所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐在制备CDK8抑制剂中的用途。
6.权利要求1所述的3-芳杂环取代苯基衍生物或其药学上可接受的盐在制备抗肿瘤药物中的用途；所述肿瘤为结直肠癌。
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