CN114436975B - 2-三氟甲基-4-氨基喹唑啉类化合物及其应用 - Google Patents

2-三氟甲基-4-氨基喹唑啉类化合物及其应用 Download PDF

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CN114436975B
CN114436975B CN202210091078.3A CN202210091078A CN114436975B CN 114436975 B CN114436975 B CN 114436975B CN 202210091078 A CN202210091078 A CN 202210091078A CN 114436975 B CN114436975 B CN 114436975B
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徐必学
骆衡
余刚
余佳
孟雪玲
曾晓萍
吴辉
韦娇梅
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Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences
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Abstract

本发明公开了一种2‑三氟甲基‑4‑氨基喹唑啉类化合物及其应用，该化合物具有如下通式I所示的结构式：

Description

2-三氟甲基-4-氨基喹唑啉类化合物及其应用
技术领域
本发明涉及一种喹唑啉类化合物，特别是一种2-三氟甲基-4-氨基喹唑啉类化合物及其应用。
背景技术
肿瘤是严重危害人类健康的因素之一，是目前导致人类死亡的第二大原因。当前肿瘤的治疗主要以手术治疗、放疗、化疗和免疫治疗为主，而化疗是治疗恶性肿瘤的最有效方式之一，尽管目前的抗肿瘤药物层见叠出，但多数药物存在因缺乏选择性、专一性而产生一些毒副作用、多药耐药等问题，导致了当下的抗肿瘤药物远远不能满足临床所需。
喹唑啉类生物碱是一类广泛存在于自然界并具有多种药理和生物活性的含苯并嘧啶氮杂环化合物。喹唑啉骨架作为药物开发的优势结构被广泛应用于抗肿瘤药物研究领域，且已有吉非替尼、阿法替尼等上市的以4-氨基喹唑啉为母核的第一代、第二代EGFR-TKIs，以及奥希替尼、奥姆替尼等以2-氨基嘧啶为母核的第三代EGFR-TKIs，但此类药物在临床运用中均会产生耐药。
因此，以喹唑啉为母核，引入新的药效基团，设计合成具有独特化学结构、新的作用机制的新型抗肿瘤药物，以延缓或克服抗肿瘤药物的耐药问题具有极其深远的意义。
基于文献调研发现，当4-氨基喹唑啉类化合物的氨基被甲基化，且2-位被取代后的化合物具备较好的抗肿瘤活性，且其作用机制可能是作用于秋水仙碱作用位点的微管抑制剂，例如4-氨基被甲基化，2-位被甲基取代的喹唑啉类临床新药Verubulin(MPC-6827)就是一种可渗透血脑屏障的具有诱导细胞凋亡作用机理的微管阻断剂，在人MX-1乳腺癌和其他小鼠异种移植瘤模型中，其表现出了高效的抗癌活性。目前，MPC-6827盐酸盐作为治疗复发性恶性胶质瘤的抗肿瘤新药已完成了Ⅱ期临床研究。此外，Cai等人报道了4-氨基被甲基化，2-位被氯取代的喹唑啉类化合物(EP128265)，其作为诱导细胞凋亡的微管聚合抑制剂在体内外均具有较强的抗肿瘤作用。
三氟甲基是一种优异的含氟基团，将其引入到化合物分子中能够显著改变化合物的化学稳定性、亲脂亲油性、生物膜通透性、体内代谢稳定性及其与生物蛋白酶结合的能力等。而目前对于2-三氟甲基-4-氨基喹唑啉类化合物类型以及在抗肿瘤方面的公开报道和应用极少。因此，对于2-三氟甲基-4-氨基喹唑啉类化合物的深入研究还是极具价值。
发明内容
本发明的目的在于，提供一种2-三氟甲基-4-氨基喹唑啉类化合物及其应用。本发明不仅结构新颖，而且还具有高效、广谱的抗肿瘤活性。
本发明的技术方案：2-三氟甲基-4-氨基喹唑啉类化合物，所述化合物具有如下通式I所示的结构式：
其中，R1选自H、F、Cl、Br、I、C1-C6直连或支链烷基、C3-C7环烷基、羟基、C1-C6直连或支链烷氧基、C1-C6直连或支链烷酰氧基、N,N-二甲氨基乙氧基、N,N-二乙氨基乙氧基、硝基、氨基、C1-C6直连或支链烷基取代的氨基、C1-C6直连或支链烷酰氨基、C1-C6直连或支链烷基磺酰氨基、取代或未取代苯甲酰氨基、取代或未取代呋喃甲酰氨基、取代或未取代噻吩甲酰氨基、取代或未取代吡啶甲酰氨基、丙烯酰氨基、4-氨基-2-丙烯酰氨基、4-(烷基取代氨基)-2-丙烯酰氨基、 中的任意一个或两个以上的组合；R1中的n＝1～5；
R2选自 中的任意一个。
前述的2-三氟甲基-4-氨基喹唑啉类化合物中，当R1为H时，R2≠
前述的2-三氟甲基-4-氨基喹唑啉类化合物中，Ra选自H、C1-C6直连或支链烷基、三氟甲基、羟基、C1-C6烷氧基、卤素(氟、氯、溴、碘)、三氟甲氧基、硝基、氨基、N,N-二苄氨基、N,N-二甲氨基、N,N-二乙氨基、C1-C6烷酰氨基、取代或未取代苯甲酰氨基、取代或未取代呋喃甲酰氨基、取代或未取代噻吩甲酰氨基、取代或未取代吡啶甲酰氨基、丙烯酰氨基、 中的任意一个或两个以上的组合，Ra中的n＝1～5；
Ra1选自H、C1-C6直连或支链烷基、C1-C6直连或支链甲酯基、C1-C6直连或支链醇羟基、C3-C7环烷基、取代或未取代苯基、取代或未取代苯甲酰基、取代或未取代苄基、取代或未取代呋喃甲酰基、取代或未取代噻吩甲酰基、取代或未取代吡啶甲酰基、丙烯酰基、 中的任意一个，Ra1中的n＝1～5。
前述的2-三氟甲基-4-氨基喹唑啉类化合物中，Rb选自H、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、3-羟基丙基、N,N-二甲氨基乙基、N,N-二乙氨基乙基、乙酰基、丙酰基、丙烯酰基中的任意一个。
前述的2-三氟甲基-4-氨基喹唑啉类化合物中，Rc和Rd均选自H、C1-C6直连或支链烷基、三氟甲基、羟基、C1-C6直连或支链烷氧基、N,N-二甲氨基乙氧基、卤素(氟、氯、溴、碘)、三氟甲氧基、硝基、氨基、C1-C6直连或支链烷基取代氨基、C1-C6直连或支链烷酰氨基、丙烯酰氨基、3-(N,N-二甲基)氨基丙烯酰氨基中的任意一个或两个以上的组合；当R1＝H时，Rc和Rd均不能为4-Cl。
前述的2-三氟甲基-4-氨基喹唑啉类化合物中，Re和Rf均选自C1-C6直链、支链烷基、芳环取代基或芳环取代甲基中的任意一个；Rg为C1-C6直链或支链烷基；芳环为苯环、吡啶环、呋喃环或噻吩环。
前述的2-三氟甲基-4-氨基喹唑啉类化合物中，所述化合物选自以下化合物中的任一种：
本发明的方案还公开了具有通式I的2-三氟甲基-4-氨基喹唑啉类化合物在制备抗肿瘤活性药物中的应用。
本发明的方案公开了一种药用组合物，包括具有通式I的2-三氟甲基-4-氨基喹唑啉类化合物或其药学上可接受的盐或水合物。
本发明的方案公开了一种药物制剂，包括具有通式I的2-三氟甲基-4-氨基喹唑啉类化合物及其药学上可接受的载体或赋形剂。
与现有技术相比，本发明的有益效果为：
本发明将化学性能优越的三氟甲基引入到4-氨基喹唑啉化合物的2-位，对4-氨基进行修饰，设计合成系列结构新颖的2-三氟甲基-4-氨基喹唑啉类衍生物，增加化合物与靶标之间相互作用的几率，从而提高化合物的生物活性，还提高4-氨基喹唑啉类化合物的化学稳定性，改善其成药性。
本发明对合成的2-三氟甲基-4-氨基喹唑啉类目标化合物进行抗肿瘤活性测试，结果显示，所测目标化合物中大多数化合物具有良好的抗肿瘤活性，部分活性较好的目标化合物的体外抗增值活性(n＝3)以及毒性测试结果显示，化合物A3和A20对人正常肝细胞(L-02细胞)毒性较低，其对人前列腺癌细胞(PC3)和人慢性髓系白血病细胞(K562)的治疗指数均高于阳性对照药紫杉醇和阿霉素。化合物A20对PC3和K562的IC50分别为33nM和22nM，优于阳性对照药紫杉醇(IC50值分别为275nM和302nM)和阿霉素(IC50值分别为513nM和938nM)。
因此，本发明所涉及的化合物不仅结构新颖，而且还具有高效、广谱的抗肿瘤活性。
具体实施方式
实施例1：中间体M3的合成：
取邻氨基苯甲酰胺S12g(14.7mmol)、碳酸钾2.44g(17.6mmol)于反应瓶中，加入15mL无水二氯甲烷，冰水浴搅拌下缓慢滴入2.17mL(15.4mmol)三氟乙酸酐，继续搅拌至反应完全，加入二氯甲烷和水各15mL，萃取，有机相用无水硫酸镁干燥、减压蒸干，所得粗品以硅胶柱层析纯化得2.98g白色固体M1，收率为87.4％。1H NMR(600MHz,DMSO-d6)δ13.70(s,1H),8.55(s,1H),8.40(dd,J＝8.3,0.7Hz,1H),8.03(s,1H),7.97(dd,J＝7.9,1.3Hz,1H),7.63(t,J＝7.8Hz,1H),7.32(t,J＝7.6Hz,1H)。取中间体M12g(8.60mmol)，氢氧化钾483mg(8.60mmol)于反应瓶中，加入20mL乙腈，80℃搅拌4h至反应完全，将反应液倒入50mL水中，用盐酸调至近中性，有固体析出，抽滤，滤饼经干燥得1.67g白色固体M2，收率为90.5％。1HNMR(600MHz,DMSO-d6)δ13.60(s,1H),8.20(dd,J＝7.9,1.2Hz,1H),7.96–7.91(m,1H),7.83(d,J＝8.1Hz,1H),7.72–7.67(m,1H)。取中间体M21.14g(5.30mmol)，DMF77.8mg(1.06mmol)于反应瓶中，加入15mL氯仿，搅拌下缓慢加入1.16mL(16.0mmol)氯化亚砜，于100℃搅拌6h至反应完全，将反应液倒入水中，萃取，有机相依次以饱和碳酸氢钠、水洗涤、无水硫酸镁干燥，减压蒸干得1.05g白色固体M3，收率为84.8％。1H NMR(600MHz,CDCl3)δ8.41–8.36(m,1H),8.24(d,J＝8.5Hz,1H),8.14–8.08(m,1H),7.94–7.87(m,1H)。
实施例2：化合物A1的合成：
取苯胺120mg(1.29mmol)，中间体M3330mg(1.42mmol)于反应瓶中，加入4mL异丙醇、218μL(2.58mmol)浓盐酸，80℃搅拌6h至反应完全，待反应液冷却后有固体析出，抽滤，滤饼经石油醚洗涤，干燥得351mg白色固体M4，收率为94.1％。1H NMR(600MHz,DMSO-d6)δ10.41(s,1H),8.80(d,J＝8.2Hz,1H),7.98(t,J＝7.5Hz,1H),7.95–7.89(m,3H),7.79(t,J＝7.5Hz,1H),7.43(t,J＝7.9Hz,2H),7.19(t,J＝7.4Hz,1H)。取中间体M4180mg(622μmol)于反应瓶中，加入5mL无水DMF，冰水浴中搅拌下加入30mg(1.24mmol)钠氢，搅拌至无气泡产生，再注入77μL(1.24mmol)碘甲烷，缓慢升至室温搅拌过夜至反应完全，将反应液倒入20mL水中，抽滤析出的固体，滤饼用少量石油醚和乙醇混合液洗涤、真空干燥，得白色固体A1，收率80.4％。1H NMR(600MHz,DMSO-d6)δ7.89(d,J＝8.2Hz,1H),7.78–7.74(m,1H),7.49(t,J＝7.7Hz,2H),7.44–7.37(m,3H),7.26–7.21(m,1H),6.91(d,J＝8.5Hz,1H),3.62(s,3H).13CNMR(151MHz,DMSO-d6)δ162.07,151.24(d,J＝34.7Hz),150.89,147.24,133.80,130.84,129.17,128.09,127.38,126.64,126.42,120.44(q,J＝275.9Hz),116.25,42.89.19F NMR(565MHz,DMSO-d6)δ-69.40。
实施例3：化合物A2的合成：参照实施例2中A1的制备，用4-二氟甲氧基苯胺代替苯胺，得白色固体，收率为85.3％。1H NMR(600MHz,DMSO-d6)δ7.91(d,J＝8.3Hz,1H),7.78(ddd,J＝8.3,7.0,1.2Hz,1H),7.50–7.44(m,2H),7.44–7.17(m,4H),6.97(d,J＝8.0Hz,1H),3.60(s,3H).13C NMR(151MHz,DMSO-d6)δ162.14,151.19(q,J＝34.7Hz),150.93,150.11(t,J＝3.3Hz),144.18,133.85,129.23,128.38,127.59,126.34,120.81,120.42(q,J＝275.6Hz),118.40,116.69,116.20,114.98.19F NMR(565MHz,DMSO-d6)δ-69.40,-82.46。
实施例4：化合物A3的合成：参照实施例2中A1的制备，用3-乙炔基苯胺代替苯胺，得白色固体，收率为81.0％。1H NMR(600MHz,DMSO-d6)δ7.92(d,J＝8.2Hz,1H),7.82-7.75(m,1H),7.58(s,1H),7.52-7.39(m,3H),7.31(t,J＝7.8Hz,1H),6.97(d,J＝8.5Hz,1H),4.29(s,1H),3.61(s,3H).13C NMR(151MHz,DMSO-d6)δ162.18,151.20(q,J＝34.7Hz),150.97,147.61,133.91,131.16,131.12,129.54,129.29,127.63,127.35,126.36,124.13,120.44(q,J＝276.0Hz),116.28,82.93,82.54,42.69.19F NMR(565MHz,DMSO-d6)δ-69.36。
实施例5：化合物A4的合成：参照实施例2中A1的制备，用4-三氟甲氧基苯胺代替苯胺，得淡黄色固体，收率为84.6％。1H NMR(600MHz,DMSO-d6)δ7.93(d,J＝8.3Hz,1H),7.80(t,J＝7.5Hz,1H),7.53(d,J＝8.8Hz,2H),7.46(d,J＝8.5Hz,2H),7.31(t,J＝7.7Hz,1H),6.96(d,J＝8.5Hz,1H),3.62(s,3H).13C NMR(151MHz,DMSO-d6)δ162.34,151.17(q,J＝34.9Hz),150.99,147.21,146.38,133.99,129.31,128.47,127.67,126.26,123.31,120.49(q,J＝256.2Hz),120.41(q,J＝275.6Hz),116.22,42.73.19F NMR(565MHz,DMSO-d6)δ-56.99,-69.38。
实施例6：化合物A5的合成：参照实施例2中A1的制备，用4-三氟甲基苯胺代替苯胺，得淡黄色固体，收率为85.6％。1H NMR(600MHz,DMSO-d6)δ7.97(d,J＝8.1Hz,1H),7.86–7.81(m,1H),7.79(d,J＝8.5Hz,2H),7.57(d,J＝8.4Hz,2H),7.40–7.33(m,1H),7.07(d,J＝8.2Hz,1H),3.67(s,3H).13C NMR(151MHz,DMSO-d6)δ162.82,151.42(q,J＝34.8Hz),151.05,134.26,129.40,128.10,127.65(q,J＝3.5Hz),127.23(q,J＝32.2Hz),126.49,126.31,124.46(q,J＝272.0Hz),120.39(q,J＝275.8Hz),116.56,42.32.19F NMR(565MHz,DMSO-d6)δ-60.77,-69.28。
实施例7：化合物A6的合成：参照实施例2中A1的制备，用3-氯-4-氟甲基苯胺代替苯胺，得淡黄色固体，收率为86.1％。1H NMR(600MHz,DMSO-d6)δ7.93(d,J＝8.1Hz,1H),7.84–7.78(m,2H),7.51(t,J＝8.9Hz,1H),7.47–7.41(m,1H),7.41–7.35(m,1H),7.03(d,J＝8.4Hz,1H),3.60(s,3H).13C NMR(151MHz,DMSO-d6)δ162.19,157.29,155.65,151.32(q,J＝34.8Hz),150.99,144.40(d,J＝3.0Hz),133.98,129.10(d,J＝63.3Hz),127.85,127.46(d,J＝7.5Hz),126.29,121.28(d,J＝18.6Hz),120.41(q,J＝275.2Hz),118.70(d,J＝22.2Hz),116.20,42.82.19F NMR(565MHz,DMSO-d6)δ-69.37,-117.33。
实施例8：化合物A7的合成：参照实施例2中A1的制备，用3,5-二三氟甲基苯胺代替苯胺，得淡黄色固体，收率为86.0％。1H NMR(600MHz,DMSO-d6)δ8.18(s,2H),8.03–7.97(m,2H),7.88(t,J＝7.5Hz,1H),7.42(t,J＝7.6Hz,1H),7.10(d,J＝8.5Hz,1H),3.74(s,3H).13CNMR(151MHz,DMSO-d6)δ162.93,151.31,151.04(q,J＝37.5Hz),149.09,134.38,132.15(q,J＝33.5Hz),129.51,128.09,127.35(q,J＝110.2Hz),127.12(q,J＝83.2Hz),126.55(q,J＝2.8Hz),126.16,124.28,122.47,120.40(q,J＝275.9Hz),120.03–119.86(m),116.53,42.27.19F NMR(565MHz,DMSO-d6)δ-61.38,-69.25。
实施例9：化合物A8的合成：参照实施例2中A1的制备，用4-甲硫基苯胺代替苯胺，得黄色固体，收率为90.1％。1H NMR(600MHz,DMSO-d6)δ7.89(d,J＝7.7Hz,1H),7.80–7.73(m,1H),7.36–7.25(m,1H),7.08–7.01(m,5H),3.58(s,3H),2.50(s,3H).13C NMR(151MHz,DMSO-d6)δ162.03,151.22(q,J＝34.7Hz),150.89,144.05,138.13,133.80,129.18,127.73,127.52,127.10,126.41,120.44(q,J＝272.7Hz),116.28,42.88,15.05.19F NMR(565MHz,DMSO-d6)δ-69.40。
实施例10：化合物A9的合成：参照实施例2中A1的制备，用3,4-亚甲二氧基苯胺代替苯胺，得棕黄色固体，收率为86.4％。1H NMR(600MHz,DMSO-d6)δ7.89(d,J＝7.7Hz,1H),7.80–7.73(m,1H),7.36–7.25(m,1H),7.08–7.01(m,5H),3.58(s,3H),2.50(s,3H).13C NMR(151MHz,DMSO-d6)δ162.03,151.22(q,J＝34.7Hz),150.89,144.05,138.13,133.80,129.18,127.73,127.52,127.10,126.41,120.44(q,J＝272.7Hz),116.28,42.88,15.05.19FNMR(565MHz,DMSO-d6)δ-69.40。
实施例11：化合物A10的合成：参照实施例2中A1的制备，用3,4-二甲氧基苯胺代替苯胺，得白色固体，收率为75.1％。1H NMR(600MHz,DMSO-d6)δ7.86(d,J＝7.7Hz,1H),7.78–7.73(m,1H),7.32–7.24(m,1H),7.10(d,J＝2.5Hz,1H),7.00(t,J＝9.5Hz,2H),6.87(dd,J＝8.5,2.5Hz,1H),3.80(s,3H),3.70(s,3H),3.59(s,3H).13C NMR(151MHz,DMSO-d6)δ161.73,151.23(q,J＝34.5Hz),150.81,150.39,148.65,139.84,133.62,129.02,127.28,126.48,120.47(q,J＝275.5Hz),118.70,116.30,112.82,110.80,56.26,56.13,43.15.19FNMR(565MHz,DMSO-d6)δ-69.44。
实施例12：化合物A11的合成：参照实施例2中A1的制备，用4-甲基苯胺代替苯胺，得白色固体，收率为80.9％。1H NMR(600MHz,DMSO-d6)δ7.88(d,J＝8.1Hz,1H),7.75(t,J＝7.2Hz,1H),7.33–7.19(m,5H),6.96(d,J＝8.4Hz,1H),3.57(s,3H),2.36(s,3H).13C NMR(151MHz,DMSO-d6)δ161.98,151.24(q,J＝69.6,34.9Hz),150.85,144.70,137.57,133.72,131.30,129.12,127.35,126.42,120.44(q,J＝551.8,275.6Hz),116.26,42.98,21.11.19FNMR(565MHz,DMSO-d6)δ-69.43。
实施例13：化合物A12的合成：参照实施例2中A1的制备，用5-氨基-1-甲基-1H-吲哚代替苯胺，得白色固体，收率为61.4％。1H NMR(600MHz,DMSO-d6)δ7.83(d,J＝7.8Hz,1H),7.69–7.65(m,1H),7.58–7.54(m,2H),7.43(d,J＝3.0Hz,1H),7.16(dd,J＝8.6,2.1Hz,1H),7.09–7.06(m,1H),6.83(d,J＝8.2Hz,1H),6.44(d,J＝2.9Hz,1H),3.84(s,3H),3.63(s,3H).13C NMR(151MHz,DMSO-d6)δ161.89,151.32(q,J＝34.4Hz),150.86,139.07,135.77,133.43,131.96,129.20,128.95,127.01,126.60,120.51(q,J＝275.7Hz),119.95,118.31,116.38,112.01,101.50,43.85,33.18.19F NMR(565MHz,DMSO-d6)δ-69.46。
实施例14：化合物A13的合成：参照实施例2中A1的制备，用对氨基苯甲酸代替苯胺，得白色固体，收率为95.8％。1H NMR(600MHz,CDCl3)δ8.07(d,J＝2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.99(dd,J＝8.3,1.2Hz,1H),7.71–7.68(m,1H),7.24(d,J＝2.0Hz,1H),7.23(d,J＝2.0Hz,1H),7.19–7.16(m,1H),7.07(dd,J＝8.5,1.4Hz,1H),3.94(s,3H),3.74(s,3H).13C NMR(151MHz)δ166.13,162.50,152.09(q,J＝35.1Hz),151.61,151.26,133.08,131.54,129.50,128.12,127.02,126.03,125.05,119.95(q,J＝276.5Hz),116.53,52.30,42.18。
实施例15：化合物A14的合成：参照实施例2中A1的制备，用对甲氧基苯胺代替苯胺，用碘乙烷代替碘甲烷，得淡黄色固体，收率为88.0％。1H NMR(600MHz,CDCl3)δ7.90(dd,J＝8.3,1.2Hz,1H),7.60(ddd,J＝8.3,6.8,1.3Hz,1H),7.14(d,J＝2.2Hz,1H),7.13(d,J＝2.3Hz,1H),7.08(ddd,J＝8.4,6.8,1.3Hz,1H),6.96(d,J＝2.3Hz,1H),4.18(q,J＝7.0Hz,2H),3.87(s,3H),1.30(t,J＝7.0Hz,3H).13C NMR(151MHz)δ161.18,158.77,152.13(q,J＝35.5Hz),151.44,138.14,132.40,129.18,128.37,126.26,126.17,120.11(q,J＝275.9Hz),116.24,115.37,55.56,49.97,11.49.19F NMR(565MHz)δ-71.10。
实施例16：化合物A15的合成：参照实施例2中A1的制备，用对甲氧基苯胺代替苯胺，用碘丙烷代替碘甲烷，得淡黄色固体，收率为47.0％。1H NMR(600MHz,CDCl3)δ7.90(dd,J＝8.4,1.2Hz,1H),7.60(ddd,J＝8.4,6.9,1.3Hz,1H),7.14(d,J＝2.2Hz,1H),7.13(d,J＝2.2Hz,1H),7.08(ddd,J＝8.3,6.8,1.3Hz,1H),6.96(d,J＝2.3Hz,1H),6.95(d,J＝2.2Hz,1H),6.93(d,J＝1.2Hz,1H),4.10–4.05(m,2H),3.86(s,3H),1.82–1.74(m,2H),0.96(t,J＝7.4Hz,3H).13C NMR(151MHz,CDCl3)δ161.36,158.71,152.11(q,J＝35.7Hz),151.50,138.58,132.39,129.17,128.17,126.24,126.15,120.11(q,J＝275.5Hz),116.23,115.36,56.60,55.55,19.71,11.39.19F NMR(565MHz,CDCl3)δ-71.12。
实施例17：化合物A16的合成：
取中间体M3100mg(859μmol)和74mg(781μmol)2-氨基吡啶于反应瓶中，以5mL无水DMF溶解完全，加入93.8mg(2.35mmol)钠氢，氩气保护下室温搅拌2h至反应完全，将反应液倒入20mL水中，用乙酸乙酯萃取，有机相用无水硫酸镁干燥、减压蒸干得194mg黄色固体M5，收率为85.8％。1H NMR(600MHz,CDCl3)δ8.77(d,J＝13.8Hz,2H),8.33(d,J＝4.8Hz,1H),8.08(dt,J＝8.4,2.4Hz,2H),7.91(ddd,J＝8.3,6.9,1.3Hz,1H),7.84(ddd,J＝8.8,7.3,2.0Hz,1H),7.70(ddd,J＝8.1,6.9,1.2Hz,1H),7.10(dd,J＝7.3,4.9Hz,1H).13C NMR(151MHz,CDCl3)δ157.41,151.29(q,J＝35.5Hz),149.53,147.84,138.75,134.08,129.86,128.83,119.95(q,J＝275.1Hz),119.8,115.17。以M5为原料，参照由M4合成A1的制备方法，得黄色固体A16，收率为90.4％。1H NMR(600MHz,CDCl3)δ8.50(dd,J＝8.1,1.5Hz,1H),8.4(dd,J＝5.4,1.5Hz,1Hl),7.92(dd,J＝8.,1.5Hz,1H),7.77(ddd,J＝8.4,6.8,1.5Hz,1H),7.59–7.50(m,3H),6.51(td,J＝6.7,1.4Hz,1H),3.91(s,3H).13C NMR(151MHz,CDCl3)δ165.17,156.65,152.30(q,J＝33.6Hz),150.30,139.55,139.23,133.01,127.95,127.10,125.85,122.44,122.25(q,J＝274.65Hz),119.35,110.88,41.81.19F NMR(565MHz,CDCl3)δ-70.65。
实施例18：化合物A17的合成：参照实施例17中A16的制备，用2-氨基嘧啶代替2-氨基吡啶。得黄色固体，收率51.3％。1H NMR(600MHz,CDCl3)δ8.40(s,1H),8.40(s,1H),8.14(d,J＝8.4Hz,1H),7.87(ddd,J＝8.4,6.7,1.5Hz,1H),7.52(dd,J＝8.6,1.5Hz,1H),7.48(ddd,J＝8.4,6.7,1.2Hz,1H),6.87(t,J＝4.8Hz,1H),3.88(s,3H).13C NMR(151MHz,CDCl3)δ165.37,162.60,157.87,152.49(q,J＝35.4Hz),151.32,134.08,129.57,128.25,126.02,121.19(q,J＝273.75Hz),114.89,37.72.19F NMR(565MHz,CDCl3)δ-70.19。
实施例19：化合物A18的合成：参照实施例17中A16的制备，用4-(4-氨基苯基)吗啉代替2-氨基吡啶，得黄色固体，收率为79.0％。1H NMR(600MHz,CDCl3)δ7.92(dd,J＝8.4,1.2Hz,1H),7.62(ddd,J＝8.2,6.8,1.4Hz,1H),7.14(d,J＝2.1Hz,1H),7.12(d,J＝2.1Hz,1H),7.12–7.10(m,1H),7.07(dd,J＝8.7,1.4Hz,1H),6.94(d,J＝2.3Hz,1H),6.93(d,J＝2.3Hz,1Hs,1H),3.90–3.87(m,4H),3.64(s,3H),3.24–3.19(m,4H).13C NMR(151MHz,CDCl3)δ161.89,152.24(q,J＝34.8Hz),151.15,150.29,139.15,132.45,129.16,127.11,119.19(q,J＝276.0Hz),116.59,116.39,66.78,48.93.42.99.19F NMR(565MHz,CDCl3)δ-70.95。
实施例20：化合物A19的合成：参照实施例2中A1的制备，用4-甲氧基-3-硝基苯胺代替苯胺，得黄色固体，收率为93.7％。1H NMR(600MHz,DMSO-d6)δ8.12(d,J＝2.7Hz,1H),7.94(d,J＝8.9Hz,1H),7.85(dd,J＝8.9,2.3Hz,1H),7.78(dd,J＝9.0,2.7Hz,1H),7.50(d,J＝9.1Hz,1H),6.88(d,J＝2.3Hz,1H),3.99(s,3H),3.61(s,3H).13C NMR(151MHz,DMSO-d6)δ161.20,151.45(q,J＝34.9Hz),151.41,149.71,140.33,138.75,134.22,132.75,131.42,131.37,125.53,123.35,120.29(q,J＝275.6Hz),116.90,116.41,57.70,42.83.19F NMR(565MHz,DMSO-d6)δ-69.49。
实施例21：化合物A20的合成：
取A19300mg(793μmol)和钯碳25mg(238μmol)于反应管中，加入20mL乙酸乙酯，室温搅拌过夜至反应完全，抽滤除去固体，滤液减压蒸干得247mg黄色固体A20，收率为89.5％。1H NMR(600MHz,DMSO-d6)δ7.86–7.83(m,1H),7.76–7.72(m,1H),7.30–7.26(m,1H),7.15–7.12(m,1H),6.86(d,J＝8.4Hz,1H),6.58(d,J＝2.6Hz,1H),6.51(dd,J＝8.4,2.6Hz,1H),5.00(s,2H),3.81(s,3H),3.53(s,3H).13C NMR(151MHz,DMSO-d6)δ161.67,151.29(q,J＝34.5Hz),150.71,146.07,140.24,139.89,133.60,128.92,127.22,126.75,120.46(q,J＝275.8Hz),116.39,113.58,111.76,111.09,55.96,43.19.19F NMR(565MHz,DMSO-d6)δ-69.50。
实施例22：化合物A21的合成：参照实施例2中A1的制备，用4-甲氧基-2-硝基苯胺代替苯胺，得黄色固体，收率为76.5％。1H NMR(600MHz,DMSO-d6)δ7.92(d,J＝8.2Hz,1H),7.82(t,J＝7.4Hz,1H),7.73(d,J＝8.8Hz,1H),7.71(d,J＝2.9Hz,1H),7.47(dd,J＝8.8,2.9Hz,1H),7.36(t,J＝7.7Hz,1H),6.98(d,J＝6.2Hz,1H),3.93(s,3H),3.57(s,3H).13CNMR(151MHz,DMSO-d6)δ161.47,159.57,150.92(q,J＝35.8Hz),150.79,146.55,134.16,131.95,131.91,129.34,128.23,125.07,121.87,120.33(q,J＝275.6Hz),115.51,111.27,56.88,42.92.19F NMR(565MHz,DMSO-d6)δ-69.47。
实施例23：化合物A22的合成：以A21为原料参照实施例21中A20的制备，得黄色固体，收率为93.6％。1H NMR(600MHz,DMSO-d6)δ7.84(dd,J＝8.3,0.8Hz,1H),7.76–7.72(m,1H),7.30–7.27(m,1H),7.21(d,J＝7.9Hz,1H),6.79(d,J＝8.6Hz,1H),6.47(d,J＝2.8Hz,1H),6.11(dd,J＝8.6,2.8Hz,1H),5.57(s,2H),3.72(s,3H),3.39(s,3H).13C NMR(151MHz,DMSO-d6)δ161.97,160.40,151.21(q,J＝34.5Hz),150.61,146.03,133.49,128.81,128.47,127.34,126.18,124.67,120.53(q,J＝276.1Hz),116.43,103.10,100.82,55.44,40.88.19F NMR(565MHz,DMSO-d6)δ-69.43。
实施例24：化合物A23的合成：以A22和醋酸酐为原料参照实施例1中M1的制备，得黄色固体，收率为64.3％。1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),7.88(dd,J＝8.3,0.7Hz,1H),7.79–7.73(m,1H),7.32–7.25(m,1H),7.10(d,J＝8.7Hz,1H),6.96(d,J＝8.6Hz,1H),6.70(dd,J＝8.7,2.9Hz,1H),3.79(s,1H),3.40(s,1H),2.03(s,1H).13C NMR(151MHz,DMSO-d6)δ169.76,162.45,159.31,151.07(q,J＝34.5Hz),150.63,136.17,133.60,130.69,128.97,128.67,127.47,126.09,120.51(q,J＝275.6Hz),116.53,110.78,110.08,55.90,41.53,24.13.19F NMR(565MHz,DMSO-d6)δ-69.39。
实施例25：化合物A24的合成：以4-甲氨基苯酚参照实施例2中A1的制备，得白色固体，收率为96.5％。1H NMR(600MHz,DMSO-d6)δ7.86(dd,J＝8.3,1.3Hz,1H),7.75(ddd,J＝8.3,6.9,1.3Hz,1H),7.28–7.25(m,1H),7.22–7.19(m,2H),6.97(dd,J＝8.5,1.2Hz,1H),6.88–6.85(m,2H),3.55(s,3H).13C NMR(151MHz,DMSO-d6)δ161.68,157.36,151.25(q,J＝34.8Hz),150.87,138.26,133.55,129.07,128.06,127.18,126.52,120.47(q,J＝275.5Hz),117.29,116.24,43.25.19F NMR(565MHz,DMSO-d6)δ-69.49。
实施例26：化合物A25的合成：
以M3和4-甲氧基-2-硝基苯胺为原料参照实施例2中M4的制备方法合成M6，将M6催化氢化还原所得M7，再将M7与氯乙酰氯反应即得M8。取M8450mg(1.10mmol)和无水碳酸钾303mg(2.19mmol)于反应管中，加入5mL DMF，于100℃搅拌3h至反应完全，将反应液分散至15mL水中，有固体析出，抽滤，滤饼干燥得333mg黄色固体状A25，收率为81.2％。1H NMR(600MHz,DMSO-d6)δ10.87(s,1H),8.01(d,J＝8.4Hz,1H),7.97–7.86(m,1H),7.53–7.49(m,2H),6.87(d,J＝8.9Hz,1H),6.71(d,J＝2.7Hz,1H),6.45(dd,J＝8.9,2.7Hz,1H),4.61(s,2H),3.75(s,3H).13C NMR(151MHz,DMSO-d6)δ167.78,160.50,157.75,151.26,151.19(q,J＝34.9Hz),134.76,132.67,129.40,128.24,126.19,122.75,121.92,120.31(q,J＝275.7Hz),116.96,108.19,102.62,55.85,51.46.19F NMR(565MHz,DMSO-d6)δ-69.21。
实施例27：化合物A26的合成：以A25和碘甲烷为原料参照实施例2中A1的制备，得白色固体，收率为71.8％。1H NMR(600MHz,DMSO-d6)δ7.99(d,J＝8.4Hz,1H),7.92–7.87(m,1H),7.53–7.38(m,2H),7.01–6.86(m,2H),6.55(dd,J＝8.8,2.6Hz,1H),5.26(q,J＝7.0Hz,1H),3.82(s,3H),3.40(s,3H),1.31(d,J＝7.0Hz,3H).13C NMR(151MHz,DMSO-d6)δ168.93,159.80,158.06,151.28,151.24(q,J＝35.2Hz),134.70,134.22,129.42,128.15,126.26,123.04,121.48,120.30(q,J＝275.5Hz),116.63,108.52,103.14,57.14,56.03,29.65,13.97.19F NMR(565MHz,DMSO-d6)δ-69.38。
实施例28：化合物A27的合成：以M3和N1-甲基-4-硝基苯胺为原料参照实施例17中M5的制备，得黄色固体，收率为83.0％。1H NMR(600MHz,DMSO-d6)δ8.24(d,J＝2.1Hz,1H),8.23(d,J＝2.2Hz,1H),8.03(dd,J＝8.4,1.2Hz,1H),7.90(ddd,J＝8.3,6.9,1.3Hz,1H),7.56(d,J＝2.1Hz,1H),7.55(d,J＝2.2Hz,1H),7.46(ddd,J＝8.4,6.9,1.3Hz,1H),7.23(dd,J＝8.6,1.3Hz,1H),3.73(s,3H).13C NMR(151MHz,DMSO-d6)δ163.33,153.22,151.29(q,J＝35.5Hz),144.70,134.66,129.55,128.70,126.40,125.84,125.18,119.45(q,J＝275.1Hz),117.23,41.86.19F NMR(565MHz,DMSO-d6)δ-69.53。
实施例29：化合物A28的合成：以A27为原料参照实施例21中A20的制备，得淡黄色固体，收率为91.0％。1H NMR(600MHz,DMSO-d6)δ7.83(d,J＝8.2Hz,1H),7.73(ddd,J＝8.4,6.9,1.3Hz,1H),7.25(ddd,J＝8.5,6.9,1.3Hz,1H),7.07(d,J＝8.6Hz,1H),7.04(d,J＝1.8Hz,1H),7.03(d,J＝1.8Hz,1H),6.67(d,J＝2.0Hz,1H),6.66(d,J＝2.0Hz,1H),5.65(s,2H),3.53(s,3H).13C NMR(151MHz,DMSO-d6)δ161.54,151.18(q,J＝35.5Hz),150.85,148.31,135.44,133.42,128.98,127.44,126.98,126.68,120.48(q,J＝275.3Hz),116.34,115.69,43.31.19F NMR(565MHz,DMSO-d6)δ-69.53。
实施例30：化合物A29的合成：以A28和醋酸酐为原料参照实施例1中M1的制备，得橙黄色固体，收率为50.5％。1HNMR(600MHz,DMSO-d6)δ10.14(s,1H),7.88(dd,J＝8.3,1.3Hz,1H),7.75(ddd,J＝8.3,6.9,1.4Hz,1H),7.69(d,J＝2.1Hz,1H),7.68(d,J＝2.2Hz,1H),7.32(d,J＝2.1Hz,1H),7.31(d,1H),7.27(ddd,J＝8.4,6.9,1.4Hz,1H),6.98(dd,J＝8.7,1.3Hz,1H),3.57(s,3H),2.07(s,3H).13C NMR(151MHz,DMSO-d6)δ168.97,161.91,151.63(q,J＝35.7Hz),150.89,141.80,139.07,133.68,129.15,127.38,127.06,126.44,120.76(q,J＝275.4Hz),116.28,42.99,24.51.19F NMR(565MHz,DMSO-d6)δ-69.43。
实施例31：化合物A30的合成：以A28和氯乙酰氯为原料参照实施例1中M1的制备，得淡黄色固体，收率为56.5％。1H NMR(600MHz,DMSO-d6)δ10.52(s,1H),7.89(dd,J＝8.4,1.3Hz,1H),7.77(ddd,J＝8.3,6.9,1.3Hz,1H),7.71(d,J＝2.4Hz,1H),7.70(d,J＝2.3Hz,1H),7.37(d,J＝2.2Hz,1H),7.36(d,J＝2.2Hz,1H),7.29(ddd,J＝8.4,6.9,1.3Hz,1H),7.00(dd,J＝8.6,1.2Hz,1H),4.30(s,2H),3.59(s,3H).13C NMR(151MHz,DMSO-d6)δ165.30,161.99,151.64(q,J＝35.7Hz),150.91,142.64,138.13,133.73,129.19,127.45,127.19,126.41,121.22(q,J＝275.4Hz),116.29,44.04,42.94.19F NMR(565MHz,DMSO-d6)δ-69.42。
实施例32：化合物A31的合成：以A28和丙烯酰氯为原料参照实施例1中M1的制备，得暗黄色固体，收率为52.0％。1H NMR(600MHz,DMSO-d6)δ10.36(s,1H),7.89(dd,J＝8.3,1.2Hz,1H),7.79(d,J＝2.1Hz,1H),7.78–7.74(m,2H),7.37(d,J＝2.0Hz,1H),7.35(d,1H),7.29(ddd,J＝8.5,6.9,1.3Hz,1H),7.01(dd,J＝8.6,1.3Hz,1H),6.46(dd,J＝17.0,10.1Hz,1H),6.30(dd,J＝17.0,1.9Hz,1H),5.79(dd,J＝10.1,2.0Hz,1H),3.59(s,3H).13CNMR(151MHz,DMSO-d6)δ163.75,161.96,151.71(q,J＝35.7Hz),150.90,142.31,138.70,133.71,132.14,129.17,127.76,127.43,127.13,126.45,121.19,120.46(q,J＝276.0Hz),116.30.19F NMR(565MHz,DMSO-d6)δ-69.42。
实施例33：化合物A32的合成：以A28和苯甲酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为79.5％。1HNMR(600MHz,CDCl3)δ8.04(s,1H),7.95(dd,J＝8.4,1.3Hz,1H),7.89(d,J＝1.5Hz,1H),7.88(d,J＝1.5Hz,1H),7.75(d,J＝2.1Hz,1H),7.73(d,J＝2.1Hz,1H),7.65(ddd,J＝8.3,6.7,1.5Hz,1H),7.59–7.55(q,J＝7.8Hz,1H),7.52–7.44(m,3H),7.23(d,J＝2.2Hz,1H),7.22(d,J＝2.2Hz,1H),7.15(ddd,J＝8.2,6.8,1.3Hz,1H),7.11(dd,J＝8.7,1.4Hz,1H),3.68(s,3H).13C NMR(151MHz,CDCl3)δ165.88,162.10,151.98(q,J＝35.7Hz),151.15,143.53,137.05,134.54,132.74,132.21,130.18,129.25,128.94,128.49,127.05,126.83,126.27,121.46(q,J＝276.0Hz),116.34,42.87.19F NMR(565MHz,CDCl3)δ-70.84。
实施例34：化合物A33的合成：以A28和噻吩-2-甲酰氯为原料参照实施例1中M1的制备，得白色固体，收率为75.0％。1HNMR(600MHz,DMSO-d6)δ10.41(s,1H),8.05(dd,J＝3.8,1.2Hz,1H),7.93–7.87(m,2H),7.86(d,J＝2.1Hz,1H),7.85(s,1H),7.77(ddd,J＝8.3,6.9,1.4Hz,1H),7.40(d,J＝2.1Hz,1H),7.38(d,J＝2.2Hz,1H),7.29(ddd,J＝8.4,6.9,1.3Hz,1H),7.25(dd,J＝5.0,3.7Hz,1H),7.05(dd,J＝8.7,1.2Hz,1H),3.61(s,3H).13C NMR(151MHz,DMSO-d6)δ162.02,160.46,151.88(q,J＝34.5Hz),150.92,142.55,140.21,138.42,133.73,132.61,129.83,129.19,128.58,127.43,126.98,126.47,122.15,121.48(q,J＝273.6Hz),116.34,42.96.19F NMR(565MHz,DMSO-d6)δ-69.41。
实施例35：化合物A34的合成：以A28和对甲苯磺酰氯为原料参照实施例1中M1的制备，得淡黄色固体，收率为74.0％。1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.4,1.2Hz,1H),7.74(d,J＝1.6Hz,1H),7.73(d,J＝1.9Hz,1H),7.65(ddd,J＝8.3,6.9,1.3Hz,1H),7.37(s,1H),7.15(d,J＝2.1Hz,1H),7.14(d,J＝2.3Hz,1H),7.09(d,J＝2.2Hz,1H),7.08(d,J＝2.2Hz,1H),7.03(ddd,J＝8.4,6.9,1.3Hz,1H),6.87(dd,J＝8.6,1.2Hz,1H),3.62(s,3H),2.43(s,3H).13C NMR(151MHz,CDCl3)δ162.05,152.07(q,J＝35.4Hz),151.18,144.38,144.32,135.82,135.60,132.69,129.83,129.36,127.38,127.06,126.37,126.04,122.86(q,J＝276.0Hz),116.24,42.68,21.63.19F NMR(565MHz,CDCl3)δ-70.86。
实施例36：化合物A35的合成：以A28和甲磺酸酐为原料参照实施例1中M1的制备，得淡黄色固体，收率为76.6％。1HNMR(600MHz,CDCl3)δ8.01(d,J＝8.4Hz,1H),7.70(ddd,J＝8.3,6.9,1.3Hz,1H),7.32(d,J＝2.3Hz,1H),7.31(d,J＝2.2Hz,1H),7.25(d,J＝2.4Hz,1H),7.23(d,J＝2.2Hz,1H),7.18(ddd,J＝8.4,6.9,1.3Hz,1H),7.06(dd,J＝8.6,1.3Hz,1H),7.02(s,1H),3.71(s,3H),3.12(s,3H).13C NMR(151MHz,CDCl3)δ162.16,152.07(q,J＝35.9Hz),144.44,135.76,132.96,129.24,127.41,126.73,126.03,122.86(q,J＝276.0Hz),121.96,116.19,42.85,39.79.19F NMR(565MHz,CDCl3)δ-70.80。
实施例37：化合物A36的合成：以A28和碘甲烷为原料参照实施例2中A1的制备，得淡黄色固体，收率为30.0％。1H NMR(600MHz,CDCl3)δ7.90(d,J＝8.3Hz,1H),7.60(ddd,J＝8.3,6.5,1.7Hz,1H),7.08(m,4H),6.73(d,J＝2.1Hz,1H),6.72(d,J＝2.1Hz,1H),3.63(s,3H),3.01(s,6H).13C NMR(151MHz,CDCl3)δ161.78,152.14(q,J＝34.9Hz),151.12,149.64,135.92,132.30,129.01,127.07,126.50,126.19,120.15(q,J＝275.9Hz),116.47,113.28,43.14,40.52.19F NMR(565MHz,CDCl3)δ-70.99。
实施例38：化合物A37的合成：
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取A2880mg(251μmol)和3,4,5-三甲氧基苯甲酸106mg(502μmol)，EDCI 48mg(251μmol)，DMAP 31mg(251μmol)溶于2mL DMF，氩气保护，注入吡啶60μL(754μmol)，室温搅拌25h至反应完全，将反应液倒入水中，加盐酸调节pH＝3～4，乙酸乙酯萃取，有机相无水硫酸镁干燥、减压蒸干，所得粗品经硅胶柱层析纯化，得淡黄色固体，收率为43.0％。1H NMR(600MHz,DMSO-d6)δ10.31(s,1H),7.88(dd,J＝17.8,8.3Hz,3H),7.77(t,J＝7.7Hz,1H),7.40(s,1H),7.29(d,J＝7.8Hz,3H),7.06(d,J＝8.6Hz,1H),3.88(s,6H),3.74(s,3H),3.61(s,3H).13C NMR(151MHz,DMSO-d6)δ165.50,162.03,153.13,151.38(q,J＝34.6Hz),150.93,142.55,140.90,138.74,133.71,130.29,129.19,127.39,126.90,126.47,122.42121.38(q,J＝273.7Hz),116.34,105.80,60.59,56.58,42.96.19F NMR(565MHz,DMSO-d6)δ-69.42。
实施例39：化合物A38的合成：以M3和4-氟苯硫酚为原料参照实施例2中M4的制备，得白色固体，收率为61.1％。1H NMR(600MHz,CDCl3)δ8.28(d,J＝8.3Hz,1H),8.14(d,J＝8.4Hz,1H),8.03–7.98(m,1H),7.82–7.75(m,1H),7.66–7.61(m,2H),7.25–7.18(m,2H).13CNMR(151MHz,CDCl3)δ173.55(s),164.77(s),163.10(s),151.36(q,J＝36.5Hz),147.84(s),137.81(d,J＝8.7Hz),134.96(s),129.56(d,J＝31.0Hz),123.77(s),123.14(s),121.26(d,J＝3.2Hz),119.56(q,J＝275.9Hz),116.62(d,J＝22.3Hz).19F NMR(565MHz,CDCl3)δ-70.58,-110.14。
实施例40：化合物A39的合成：以M3和4-氯苯酚为原料参照实施例17中M5的制备，得白色固体，收率为55.6％。1H NMR(600MHz,DMSO-d6)δ8.49(d,J＝8.1Hz,1H),8.21–8.17(m,2H),7.96(ddd,J＝8.2,5.7,2.5Hz,1H),7.61–7.58(m,2H),7.50–7.46(m,2H)。
实施例41：化合物A40的合成：
以M3和N1,N1-二苄基-6-甲氧基-4-硝基苯-1,3-二胺为原料参照实施例26中A25的制备方法合成M9。将M9催化氢化还原得M10，再将M10与丙烯酰氯反应得黄色固体状A40，收率为37.9％。1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.30(s,1H),8.03(d,J＝8.5Hz,1H),7.93(t,J＝7.6Hz,1H),7.67(d,J＝7.2Hz,1H),7.61(d,J＝8.5Hz,1H),7.52(t,J＝7.8Hz,1H),6.83(s,1H),6.56(dd,J＝16.9,10.2Hz,1H),6.00(dd,J＝16.9,2.0Hz,1H),5.59(d,1H),4.63(s,2H),3.88(s,3H),3.35(s,2H).13C NMR(151MHz)δ167.56,163.47,160.40,151.17(q,J＝35.1Hz),148.52,135.00,132.09,129.35,128.49,128.26,127.10,126.38,122.07,121.67,121.22,119.39,100.42,56.45,51.57.19F NMR(565MHz)δ-69.20。
实施例42：化合物A41的合成：以M10和醋酸酐为原料参照实施例41中A40的制备，得淡黄色固体，收率为46.0％。1H NMR(600MHz,DMSO-d6)δ10.81(s,1H),9.06(s,1H),8.02(d,J＝8.3Hz,1H),7.94(d,1H),7.59(dd,J＝8.6,1.4Hz,1H),7.52(d,J＝7.2Hz 1H),7.50(d,J＝2.7Hz,1H),6.80(s,1H),4.61(s,2H),3.85(s,3H),1.90(s,3H).13C NMR(151MHz)δ168.67,167.54,162.77,160.35,160.16,150.78(q,J＝35.3Hz),148.48,147.34,134.96,129.29,128.46,127.94,126.40,122.36,121.17(q,J＝274.5Hz),119.38,116.94,114.89,100.36,56.35,51.56,36.24,31.23,23.98.19F NMR(565MHz)δ-69.20。
实施例43：化合物A42的合成：以M10和氯乙酰氯为原料参照实施例41中A40的制备，得淡黄色固体，收率为37.0％。1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),9.42(s,1H),8.03(d,J＝8.3Hz,1H),7.94(t,J＝7.8Hz,1H),7.60(d,J＝8.3Hz,1H),7.53(d,J＝8.2Hz,H),6.83(s,1H),4.62(s,2H),4.21(s,2H),3.87(s,2H).13C NMR(151MHz)δ167.56,164.93,160.42,151.04(q,J＝35.4Hz),148.47,135.01,129.33,128.59,128.54,126.36,121.74,121.42,118.47(q,J＝276.2Hz),116.95,114.59,100.51,56.50,51.55,43.55.19F NMR(565MHz)δ-69.19。
实施例44：化合物A43的合成：以M10和苯甲酰氯为原料参照实施例41中A40的制备，得淡黄色固体，收率为42.7％。1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),9.35(s,1H),8.02(dd,J＝8.3,1.2Hz,1H),7.94(dd,J＝6.9,1.5Hz,1H),7.80(d,J＝1.1Hz,1H),7.79(d,J＝1.5Hz,1H),7.66(dd,J＝8.6,1.3Hz,1H),7.54(dd,J＝8.4,1.3Hz,1H),7.53–7.50(m,1H),7.44(t,J＝7.8Hz,2H),7.36(s,1H),4.64(s,2H),3.86(s,3H).13C NMR(151MHz)δ167.62,165.31,160.46,151.14(q,J＝34.9Hz),150.47,134.95,134.53,132.06,129.71,129.35,128.83,128.53,127.90,126.36,121.78,121.67,120.33(q,J＝276.3Hz),117.40,117.08,100.60,56.49,51.59.19F NMR(565MHz)δ-69.16。
实施例45：化合物A44的合成：
以S2为原料参照实施例1中M3的制备方法合成中间体M11。以M11和4-甲氧基苯胺为原料参照实施例2中A1的制备方法合成得黄色固体A44，收率为49.6％。1H NMR(600MHz,CDCl3)δ7.93(dd,J＝9.2,5.6Hz,1H),7.42–7.37(m,1H),7.16(d,J＝2.2Hz,1H),7.15(d,J＝2.2Hz,1H),6.98(d,J＝2.3Hz,1H),6.97(d,J＝2.2Hz,1H),6.57(dd,J＝10.8,2.8Hz,1H),3.87(s,3H),3.64(s,3H).13C NMR(151MHz)δ161.44(d,J＝4.7Hz),159.33(d,J＝249.1Hz),159.05,151.73(q,J＝35.7Hz),148.04,139.28,131.55(d,J＝8.7Hz),127.51,122.28(d,J＝24.8Hz),120.05(q,J＝275.5Hz),116.96(d,J＝8.9Hz),115.65,110.81(d,J＝25.9Hz),55.62,43.16.19F NMR(565MHz)δ-70.94,-109.49。
实施例46：化合物A45的合成：以M11和5-氨基-1-甲基-1H-吲哚为原料参照实施例2中A1的制备，得浅褐色固体，收率为90.1％。1H NMR(600MHz,CDCl3)δ7.91(dd,J＝9.1,5.6Hz,1H),7.49(d,J＝2.1Hz,1H),7.40(d,J＝8.6Hz,1H),7.33(ddd,J＝9.1,7.7,2.8Hz,1H),7.16(d,J＝3.1Hz,1H),7.08(dd,J＝8.6,2.1Hz,1H),6.49(d,J＝5.2Hz,1H),6.48–6.47(m,1H),3.86(s,3H),3.71(s,3H).13C NMR(151MHz)δ161.59(d,J＝4.0Hz),159.17(d,J＝247.2Hz),151.78(q,J＝35.9,35.4Hz),148.00,138.59,135.78,131.23(d,J＝8.7Hz),130.89,129.42,122.02(d,J＝24.9Hz),120.15(q,J＝275.6Hz),119.89,118.55,117.21(d,J＝8.9Hz),111.26,111.09,101.62,43.80,33.16.19F NMR(565MHz)δ-70.89,-110.26。
实施例47：化合物A46的合成：
以S3为原料参照实施例1中M3的制备方法合成中间体M12。以M12和4-甲氧基苯胺为原料参照实施例2中A1的制备方法合成A46，得淡黄色固体，收率为80.2％。1HNMR(600MHz,DMSO-d6)δ7.87(d,J＝8.9Hz,1H),7.78(dd,J＝8.9,2.3Hz,1H),7.37(d,J＝8.9Hz,2H),7.09(d,J＝8.9Hz,2H),6.73(d,J＝2.3Hz,1H),3.82(s,3H),3.58(s,3H).13CNMR(151MHz,DMSO-d6)δ160.73,159.39,151.58(q,J＝34.8Hz),149.55,138.98,133.90,131.09,131.00,128.19,125.85,120.32(q,J＝275.9Hz),116.88,116.14,56.10,43.13.19FNMR(565MHz,DMSO-d6)δ-69.60。
实施例48：化合物A47的合成：以M12和5-氨基-1-甲基-1H-吲哚为原料参照实施例2中A1的制备，得淡黄色固体，收率为75.6％。1H NMR(600MHz,DMSO-d6)δ7.84(d,J＝8.9Hz,1H),7.71(dd,J＝8.9,2.3Hz,1H),7.66–7.58(m,2H),7.47(d,J＝3.1Hz,1H),7.18(dd,J＝8.6,2.1Hz,1H),6.65(d,J＝2.3Hz,1H),6.48(d,J＝3.0Hz,1H),3.86(s,3H),3.64(s,3H).13C NMR(151MHz,DMSO-d6)δ160.85,151.66(q,J＝34.6Hz),149.55,138.18,136.04,133.76,132.23,130.93,130.74,129.28,126.06,120.38(q,J＝276.5Hz),119.76,118.41,117.09,112.11,101.57,43.84,33.23.19F NMR(565MHz,DMSO-d6)δ-69.59。
实施例49：化合物A48的合成：以M12和4-甲氧基-3-硝基苯胺为原料参照实施例2中A1的制备，得淡黄色固体，收率为67.4％。1H NMR(600MHz,DMSO-d6)δ8.12(d,J＝2.7Hz,1H),7.94(d,J＝8.9Hz,1H),7.85(dd,J＝8.9,2.3Hz,1H),7.78(dd,J＝9.0,2.7Hz,1H),7.50(d,J＝9.1Hz,1H),6.88(d,J＝2.3Hz,1H),3.99(s,3H),3.61(s,3H).13C NMR(151MHz,DMSO-d6)δ161.20,151.45(q,J＝34.9Hz),151.41,149.71,140.33,138.75,134.22,132.75,131.42,131.37,125.53,123.35,120.29(q,J＝275.6Hz),116.90,116.41,57.70,42.83.19F NMR(565MHz,DMSO-d6)δ-69.49。
实施例50：化合物A49的合成：以M12和4-甲氧基-2-硝基苯胺为原料参照实施例2中A1的制备，得淡黄色固体，收率为74.5％。1H NMR(600MHz,DMSO-d6)δ7.95(d,J＝8.9Hz,1H),7.87(dd,J＝8.9,2.3Hz,1H),7.80(d,J＝8.8Hz,1H),7.77(d,J＝3.0Hz,1H),7.53(dd,J＝8.9,3.0Hz,1H),6.79(s,1H),3.94(s,3H),3.58(s,3H).13C NMR(151MHz,DMSO-d6)δ160.61(s),160.03(s),151.29(q,J＝35.1Hz),149.47,146.74,134.51,132.04,131.95,131.44,131.07,124.38,121.87,120.19(q,J＝275.6Hz),116.22,111.25,57.09,42.90.19FNMR(565MHz,DMSO-d6)δ-69.58。
实施例51：化合物A50的合成：
以S4为原料参照实施例1中M3的制备方法合成中间体M13。以M13和4-甲氧基苯胺为原料参照实施例2中A1的制备方法合成得淡黄色固体A50，收率为81.9％。1HNMR(600MHz,DMSO-d6)δ7.75(d,J＝8.4Hz,1H),7.59(d,J＝8.3Hz,1H),7.29(d,J＝8.7Hz,2H),7.05(d,J＝8.7Hz,2H),6.60(s,1H),3.80(s,1H),3.55(s,2H),2.06(s,1H).13C NMR(151MHz,DMSO-d6)δ161.31,159.00,150.57(q,J＝34.3Hz),149.09,139.80,136.70,135.20,128.78,128.10,125.91,120.51(q,J＝275.7Hz),116.01,115.83,56.03,42.98,21.88.19F NMR(565MHz,DMSO-d6)δ-69.33。
实施例52：化合物A51的合成：以M13和4-三氟甲基苯胺为原料参照实施例2中A1的制备，得淡黄色固体，收率为72.6％。1H NMR(600MHz,DMSO-d6)δ7.86(d,J＝8.5Hz,1H),7.80(d,J＝8.5Hz,2H),7.67(dd,J＝8.5,1.5Hz,1H),7.55(d,J＝8.4Hz,2H),6.70(s,1H),3.67(s,3H),2.11(s,3H).13C NMR(151MHz,DMSO-d6)δ162.17,150.90,150.56(q,J＝35.0Hz),149.45,137.59,135.86,129.13,127.48(q,J＝3.5Hz),127.26(q,J＝32.2Hz),126.50,125.51,124.49(q,J＝271.7Hz),120.45(q,J＝275.5Hz),116.41,42.05,21.70.19F NMR(565MHz,DMSO-d6)δ-60.88,-69.20。
实施例53：化合物A52的合成：以M13和5-氨基-1-甲基-1H-吲哚为原料参照实施例2中A1的制备，得灰白色固体，收率为79.5％。1H NMR(600MHz,DMSO-d6)δ7.73(d,J＝8.4Hz,1H),7.58(d,J＝8.6Hz,1H),7.54–7.51(m,2H),7.44(d,J＝3.0Hz,1H),7.15(dd,J＝8.6,2.0Hz,1H),6.51(s,1H),6.45(d,J＝2.7Hz,1H),3.85(s,3H),3.62(s,3H),1.86(s,3H).13CNMR(151MHz,DMSO-d6)δ161.48,150.66(q,J＝34.8Hz),149.07,139.01,136.36,135.84,135.02,132.00,129.14,128.63,126.17,120.56(q,J＝275.6Hz),120.04,118.39,116.22,111.77,101.44,43.68,33.20,21.83.19F NMR(565MHz,DMSO-d6)δ-69.31。
实施例54：化合物A53的合成：
以S5为原料参照实施例1中M3的制备方法合成中间体M14。以M14和4-甲氧基苯胺为原料参照实施例2中M4的制备方法合成得黄色固体A53，收率为79.6％。1HNMR(600MHz,DMSO-d6)δ9.83(s,1H),7.94(s,1H),7.67(d,J＝4.4Hz,2H),7.35(s,1H),7.01(d,J＝4.1Hz,2H),3.98(s,3H),3.96(s,3H),3.79(s,3H),2.50(s,3H).13C NMR(151MHz,DMSO-d6)δ157.63,156.53,155.28,150.72,150.26(q,J＝34.0Hz),146.25,131.95,124.67,123.36,121.53,120.66(q,J＝263.1Hz),119.70,118.04,114.23,109.37,108.30,102.57,56.84,56.54,55.70.19F NMR(565MHz,DMSO-d6)δ-69.16(s).
实施例55：化合物A54的合成：以A53和碘甲烷为原料参照实施例2中A1的制备，得白色固体，收率为79.7％。1H NMR(600MHz,DMSO-d6)δ7.32(d,J＝8.8Hz,2H),7.29(s,1H),7.05(d,J＝8.8Hz,2H),6.29(s,1H),3.88(s,3H),3.78(s,3H),3.53(s,3H),3.23(s,3H).13CNMR(151MHz,DMSO-d6)δ160.39,158.63,154.43,149.95(q,J＝34.5Hz),148.51,148.09,140.23,128.47,120.66(q,J＝275.5Hz),115.86,110.12,108.22,105.44,56.44,56.01,55.05,42.54.19F NMR(565MHz,DMSO-d6)δ-69.02。
实施例56：化合物A55的合成：以M14和为3-氨基苯乙炔原料参照实施例2中A1的制备，得淡黄色固体，收率为66.9％。1H NMR(600MHz,DMSO-d6)δ7.53–7.46(m,2H),7.45(d,J＝7.6Hz,1H),7.41(d,J＝7.8Hz,1H),7.33(s,1H),6.29(s,1H),3.90(s,3H),3.59(s,3H),3.24(s,3H).13C NMR(151MHz,DMSO-d6)δ160.52,154.78,149.94(q,J＝34.7Hz),148.95,148.31,147.88,131.06,130.48,129.54,127.43,123.99,120.62(q,J＝275.5Hz),110.35,108.31,105.16,82.87,82.42,56.55,55.11,42.03.19F NMR(565MHz,DMSO-d6)δ-68.90。
实施例57：化合物A56的合成：以M14和4-甲硫基苯胺为原料参照实施例2中A1的制备，白色固体，收率为75.5％。1HNMR(600MHz,DMSO-d6)δ7.40–7.35(m,2H),7.33–7.28(m,3H),6.29(s,1H),3.89(s,3H),3.56(s,3H),3.24(s,3H),2.49(s,3H).13C NMR(151MHz,DMSO-d6)δ160.41,154.59,149.94(q,J＝34.6Hz),148.68,148.16,144.32,137.74,127.98,127.51,120.63(q,J＝275.5Hz),110.20,108.20,105.38,56.49,54.98,42.12,15.37.19F NMR(565MHz,DMSO-d6)δ-68.95。
实施例58：化合物A57的合成：
以S6为原料参照实施例1中M3的制备方法合成M15。以M15和4-甲氧基苯胺为原料参照实施例2中A1的制备方法合成M16。M16经催化氢化制得白色固体A57，收率为86.0％。1HNMR(600MHz,CDCl3)δ7.28(s,1H),7.11(d,J＝2.3Hz,1H),7.10(d,J＝2.3Hz,1H),6.91(d,J＝2.4Hz,1H),6.90(d,J＝2.0Hz,1H),6.44(s,1H),5.99(s,1H),3.95(s,3H),3.82(s,3H),3.60(s,3H).13C NMR(151MHz)δ160.78,158.44,151.78,150.67(q,J＝34.9Hz),147.68,145.04,140.17,127.29,120.24(q,J＝275.6Hz),115.32,111.49,108.56,107.62,56.26,55.53,42.91。
实施例59：化合物A58的合成：
以S7为原料参照实施例1中M3的制备方法合成M17。以M17和4-甲氧基苯胺为原料参照实施例2中A1的制备方法合成M18。M18经催化氢化制得淡黄色固体A58，收率为81.2％。1HNMR(600MHz,DMSO-d6)δ10.68(s,1H),7.68(d,J＝11.5Hz,1H),7.26(d,J＝2.2Hz,1H),7.25(d,J＝2.2Hz,1H),7.03(d,J＝2.2Hz,1H),7.02(d,J＝2.2Hz,1H),6.56(d,J＝9.3Hz,1H),3.81(s,3H),3.52(s,3H).13C NMR(151MHz)δ160.63,158.55,156.76,155.07,150.78(q,J＝35.3Hz),139.76,127.50,121.17(q,J＝274.5Hz),115.91,114.24,114.13,112.16,55.87,43.28。
实施例60：化合物A59的合成：以M15和5-氨基-1-甲基-1H-吲哚为原料参照实施例58中A57的制备，得白色固体，收率为82.0％。1H NMR(600MHz,CDCl3)δ7.43(d,J＝2.1Hz,1H),7.31(d,J＝8.6Hz,1H),7.22(s,1H),7.08(d,J＝3.1Hz,1H),6.41(dd,J＝3.1,0.9Hz,1H),6.38(s,1H),5.98(s,1H),3.89(s,3H),3.79(s,3H),3.66(s,3H).13C NMR(151MHz)δ160.95,151.65,150.68(q,J＝35.1Hz),147.56,144.75,139.48,135.46,130.50,129.26,121.22(q,J＝273.9Hz),120.05,118.37,111.63,110.69,108.92,107.46,101.43,56.14,43.60,33.06.19F NMR(565MHz)δ-70.59。
实施例61：化合物A60的合成：
取化合物A57500mg(1.32mmol)与碳酸钾273mg(1.98mmol)于6mL无水DMF，氩气置换，注入1,3-二溴丙烷1.67mL(13.2mmol)，室温搅拌20h至反应完全，将反应液分散至适量水和乙酸乙酯中，萃取，有机相用水洗涤1次，再经无水硫酸镁干燥，减压蒸干得564mg淡黄色固体M19，收率为94.0％。1H NMR(600MHz,CDCl3)δ7.26(s,1H),7.20(d,J＝1.8Hz,1H),7.18(d,J＝1.9Hz,1H),6.97(d,J＝1.3Hz,1H),6.96(d,J＝1.3Hz,1H),6.40(s,1H),3.92(s,3H),3.83(s,3H),3.63(t,J＝6.6Hz,3H),3.62(s,3H),3.53(t,J＝6.1,1.6Hz,2H),2.10–2.05(m,2H).13Cδ160.48,158.49,154.23,151.05(q,J＝35.2Hz),148.37,140.46,127.90,120.23(q,J＝275.4Hz),115.35,110.34,108.14,106.42,64.76,56.14,55.61,42.56,41.26,31.65。取中间体M1975mg(164μmol)，碳酸钾57mg(411μmol)于反应管，加入3mL乙腈、吗啉57μL(658μmol)，于80℃搅拌16h至反应完全，将反应液分散至水和乙酸乙酯混合液中，萃取，有机相用无水硫酸镁干燥，减压蒸干，所得粗产物经硅胶柱层析纯化得47mg黄色固体A60，收率为56.0％。1H NMR(600MHz,CDCl3)δ7.26(s,1H),7.19(d,J＝2.1Hz,1H),7.18(d,J＝2.3Hz,1H),6.95(d,J＝2.2Hz,1H),6.94(d,J＝2.3Hz,1H),6.37(s,1H),3.92(s,3H),3.82(s,3H),3.73(t,J＝4.7Hz,4H),3.61(s,3H),3.43(t,J＝6.6Hz,2H),2.49(s,4H)2.42(t,J＝7.5Hz,2H),1.88–1.79(m,2H).13C NMR(151MHz)δ174.54,160.44,158.34,154.23,150.96(q,J＝34.8Hz),148.22,147.54,140.59,127.95,120.22(q,J＝275.3Hz),115.30,110.39,108.07,106.13,66.63,66.47,56.17,55.63,55.18,53.42,42.60,25.53.19F NMR(565MHz)δ-70.60。
实施例62：化合物A61的合成：参照实施例61中A60的制备，用四氢吡咯代替吗啉，得黄色固体，收率为85.0％。1H NMR(600MHz,CDCl3)δ7.25(s,1H),7.17(d,J＝2.2Hz,1H),7.16(d,J＝2.4Hz,1H),6.97(d,J＝2.3Hz,1H),6.96(d,J＝2.2Hz,1H),6.34(s,1H),3.90(s,3H),3.86(s,3H),3.61(s,3H),3.47(t,J＝5.7Hz,2H),3.09(t,J＝8.1Hz,2H),2.20(dq,J＝11.4,5.8Hz,2H),2.14–2.06(m,4H),0.91–0.79(m,4H)。
实施例63：化合物A62的合成：参照实施例61中A60的制备，用N-甲基哌嗪代替吗啉，得黄色固体，收率为69.0％。1H NMR(600MHz,CDCl3)δ7.25(s,1H),7.18(d,J＝1.8Hz,1H),7.17(d,J＝2.2Hz,1H),6.94(d,J＝2.0Hz,1H),6.93(d,J＝2.3Hz,1H),6.34(s,1H),3.91(s,3H),3.81(s,3H),3.60(s,3H),3.40(t,J＝6.5Hz,2H),2.96–2.53(m,8H),2.47(q,2H),2.45(s,3H),1.85–1.74(m,2H).13C NMR(151MHz)δ175.74,160.41,158.34,154.22,150.84(q,J＝35.3Hz),148.24,147.46,140.57,127.96,119.30(q,J＝274.3Hz),110.35,108.07,106.12,66.25,56.16,55.66,54.23,53.39,51.08,44.27,42.59,25.63,22.02.19FNMR(565MHz)δ-70.60。
实施例64：化合物A63的合成：参照实施例61中M19的制备，用N,N-二甲基-氨基-1-氯乙烷盐酸盐代替1,3-二溴丙烷，得灰色固体，收率为73.7％。1H NMR(600MHz,CDCl3)δ7.26(s,1H),7.19(d,J＝2.3Hz,1H),7.18(d,J＝2.2Hz,1H),6.97(d,J＝2.3Hz,1H),6.96(d,J＝2.2Hz,1H),6.39(s,1H),3.92(s,3H),3.83(s,3H),3.62(s,3H),3.53(t,J＝5.8Hz,2H),2.71(t,J＝5.8Hz,2H),2.35(s,6H).13CNMR(151MHz)δ160.49,158.38,154.23,151.06(q,J＝35.1Hz),148.43,147.35,140.53,127.92,121.13(q,J＝274.05Hz),115.34,110.33,108.12,106.33,65.60,57.24,56.13,55.55,45.26,42.57,29.69.19F NMR(565MHz)δ-70.62。
实施例65：化合物A64的合成：参照实施例61中M19的制备，用N,N-二甲基-氨基-1-氯丙烷盐酸盐代替1,3-二溴丙烷，得黄色固体，收率为84.0％。1H NMR(600MHz,CDCl3)δ7.27(s,1H),7.20(d,J＝1.7Hz,1H),7.19(d,J＝1.4Hz,1H),6.98(d,J＝1.5Hz,1H),6.97(d,1H),6.35(s,1H),3.93(s,3H),3.85(d,J＝1.3Hz,3H),3.62(s,3H),3.43(t,J＝6.2Hz,2H),2.79–2.69(m,2H),2.51(s,5H),2.00(s,3H).13C NMR(151MHz)δ176.14,160.43,158.43,154.13,151.04(q,J＝35.4Hz),148.35,147.23,140.45,127.99,120.20(q,J＝275.6Hz),115.37,110.31,108.12,106.31,65.87,63.81,56.13,55.70,55.20,43.60,42.57,29.70,25.14,22.31,14.13.19F NMR(565MHz)δ-70.61。
实施例66：化合物A65的合成：参照实施例61中M19的制备，用碘乙烷代替1,3-二溴丙烷，得灰色固体，收率为81.3％。1H NMR(600MHz,CDCl3)δ7.29(s,2H),7.21(d,J＝8.2Hz,2H),6.98(d,J＝8.3Hz,2H),6.40(s,1H),3.96(s,3H),3.85(s,3H),3.64(s,3H),3.53(q,J＝7.2Hz,2H).13C NMR(151MHz)δ160.47,158.43,154.23,150.78(q,J＝35.4Hz),148.15,147.55,140.62,127.84,121.17(q,J＝274.2Hz),115.34,110.53,108.05,105.88,63.74,56.21,55.65,42.60,14.28。
实施例67：化合物A66的合成：
以S8和三氟乙酸酐为原料，参照实施例1中M1的制备方法合成得淡黄色固体M20，收率为77.9％。取中间体M2017.0g(61.1mmol)、EDCI 17.6g(91.7mmol)、DMAP 14.9g(122mmol)于反应瓶中，加入150mLDMF，室温搅拌5min后加入氯化铵32.7g(611mmol)和49mL吡啶，氩气保护下于45℃搅拌约15h至反应完全，将反应液分散至水中，加盐酸调节pH呈弱酸性或中性，固体析出，抽滤，滤饼干燥得淡黄色固体M21(13.8g)，收率为83.1％。1H NMR(600MHz,DMSO-d6)δ13.69(s,1H),8.79(d,J＝1.8Hz,1H),8.60(dd,J＝8.8,2.0Hz,1H),8.00(d,J＝8.9Hz,1H)。中间体M22的合成参照实施例1中M3的制备，用M21代替M2，得淡黄色固体，收率为64.7％。以M22和4-甲氧基苯胺为原料参照实施例2中A1的制备方法合成得淡黄色固体A66，收率为81.7％。1H NMR(600MHz,DMSO-d6)δ8.47(dd,J＝9.2,2.5Hz,1H),8.09(d,J＝9.2Hz,1H),7.96(d,J＝8.4Hz,2H),7.81(d,J＝8.3Hz,2H),7.64(d,J＝2.4Hz,1H),3.74(s,3H).13C NMR(151MHz,DMSO-d6)δ162.66,154.41,153.81(q,J＝35.0Hz),149.48,144.58,130.98,129.16(q,J＝32.4Hz),128.43(q,J＝3.5Hz),127.64,127.27,124.35(q,J＝272.0Hz),123.30,120.12(q,J＝276.4Hz),115.20,42.59.19F NMR(565MHz,DMSO-d6)δ-61.09,-69.85。
实施例68：化合物A67的合成：以M22和5-氨基-1-甲基-1H-吲哚为原料参照实施例2中A1的制备，得黄色固体，收率为87.9％。1HNMR(600MHz,DMSO-d6)δ8.35(dd,J＝9.1,2.4Hz,1H),7.96(d,J＝9.1Hz,1H),7.70(d,J＝1.6Hz,1H),7.67(d,J＝8.6Hz,1H),7.50(dd,J＝12.0,2.6Hz,2H),7.25(dd,J＝8.6,1.8Hz,1H),6.49(d,J＝2.9Hz,1H),3.87(s,3H),3.71(s,3H).13C NMR(151MHz,DMSO-d6)δ162.08,154.50,153.93(q,J＝34.8Hz),144.12,137.39,136.45,132.35,130.43,129.64,126.89,123.93,120.18(q,J＝277.8Hz),119.24,118.21,115.32,112.64,101.67,43.90,33.24.19F NMR(565MHz,DMSO-d6)δ-69.95。
实施例69：化合物A68的合成：以M22和4-三氟甲基基苯胺为原料参照实施例2中A1的制备，得黄色固体，收率为65.7％。1H NMR(600MHz,DMSO-d6)δ8.47(dd,J＝9.2,2.5Hz,1H),8.09(d,J＝9.2Hz,1H),7.96(d,J＝8.4Hz,2H),7.81(d,J＝8.3Hz,2H),7.64(d,J＝2.4Hz,1H),3.74(s,3H).13C NMR(151MHz,DMSO-d6)δ162.66,154.41,153.81(q,J＝35.0Hz),149.48,144.58,130.98,129.16(q,J＝32.4Hz),128.43(q,J＝3.5Hz),127.64,127.27,124.35(q,J＝272.0Hz),123.30,120.12(q,J＝276.4Hz),115.20,42.59.19F NMR(565MHz,DMSO-d6)δ-61.09,-69.85。
实施例70：化合物A69的合成：以M22和3-胺基苯乙炔为原料参照实施例2中A1的制备，得黄色固体，收率为73.0％。1HNMR(600MHz,DMSO-d6)δ8.45(dd,J＝9.1,2.4Hz,1H),8.08–8.02(m,1H),7.71(d,J＝2.3Hz,1H),7.64(s,1H),7.57–7.48(m,3H),3.67(s,3H),2.04(s,3H).13C NMR(151MHz,DMSO-d6)δ162.21,154.42,153.84(q,J＝35.3Hz),146.03,144.41,131.88,131.68,130.81,129.37,127.14,126.47,126.35,123.46,120.13(q,J＝276.5Hz),115.17,89.04,79.12,42.91,4.33.19F NMR(565MHz,DMSO-d6)δ-69.92。
实施例71：化合物A70的合成：以M22和4-甲氧基-3-硝基苯胺为原料参照实施例2中A1的制备，得黄色固体，收率为63.9％。1HNMR(600MHz,CDCl3)δ8.46(dd,J＝9.1,1.5Hz,1H),8.11(d,J＝9.1Hz,1H),7.92(s,1H),7.85(d,J＝2.1Hz,1H),7.57(dd,J＝8.8,2.2Hz,1H),7.32(d,J＝8.9Hz,1H),4.10(s,3H),3.78(s,3H).13C NMR(151MHz,CDCl3)δ162.38,154.80(q,J＝36.4Hz),154.59,153.16,144.63,140.50,137.88,132.09,131.28,126.56,123.74,122.60,119.54(q,J＝276.2Hz),116.21,114.70,57.28,43.11.19F NMR(565MHz,CDCl3)δ-71.30。
实施例72：化合物A71的合成：以A66为原料参照实施例21中A20的制备，得淡黄色固体，收率为85.4％。1H NMR(600MHz,DMSO-d6)δ7.61(d,J＝8.9Hz,1H),7.18–7.10(m,3H),6.97–6.93(m,2H),6.03(d,J＝2.4Hz,1H),5.56(s,1H),3.77(s,3H),3.47(s,3H).13C NMR(151MHz,DMSO-d6)δ160.52,157.98,148.34,146.65(q,J＝34.6Hz),142.97,140.43,129.99,126.99,124.16,120.88(q,J＝274.7Hz),118.63,115.52,105.01,55.76,43.14.19FNMR(565MHz,DMSO-d6)δ-68.50。
实施例73：化合物A72的合成：以A67为原料参照实施例21中A20的制备，得墨绿色固体，收率为74.8％。1H NMR(600MHz,DMSO-d6)δ7.60(d,J＝8.9Hz,1H),7.49(d,J＝8.6Hz,1H),7.38(d,J＝2.9Hz,1H),7.35(d,J＝1.7Hz,1H),7.09(dd,J＝8.9,2.3Hz,1H),7.05(dd,J＝8.6,1.8Hz,1H),6.39(d,J＝2.8Hz,1H),6.05(d,J＝2.2Hz,1H),5.39(s,2H),3.82(s,3H),3.53(s,3H).13C NMR(151MHz,DMSO-d6)δ160.97,148.17,146.75(q,J＝34.9Hz),143.00,140.01,135.34,131.42,129.88,128.99,124.01,120.97(q,J＝275.2Hz),119.63,118.93,117.36,111.50,105.24,101.32,43.97,33.14.19F NMR(565MHz,DMSO-d6)δ-68.48。
实施例74：化合物A73的合成：以A71和醋酸酐为原料参照实施例1中M1的制备，得淡黄色固体，收率为83.0％。1H NMR(600MHz,DMSO-d6)δ10.13(s,1H),7.83(d,J＝9.0Hz,1H),7.79(s,1H),7.75(dd,J＝9.0,2.2Hz,1H),7.20(d,J＝8.9Hz,2H),6.99–6.94(m,2H),3.77(s,3H),3.52(s,3H),1.95(s,3H).13C NMR(151MHz,DMSO-d6)δ168.61,162.01,158.41,149.81(q,J＝34.7Hz),146.98,140.15,138.03,129.44,127.20,126.71,120.60(q,J＝275.5Hz),117.03,116.02,114.48,55.90,43.39,24.36.19F NMR(565MHz,DMSO-d6)δ-69.10。
实施例75：化合物A74的合成：以A72和醋酸酐为原料参照实施例1中M1的制备，得黄色固体，收率为67.9％。1H NMR(600MHz,DMSO-d6)δ9.91(s,1H),7.86–7.75(m,2H),7.67(s,1H),7.50(d,J＝8.5Hz,1H),7.41–7.33(m,2H),7.10(d,J＝8.2Hz,1H),6.37(s,1H),3.80(s,3H),3.56(s,3H),1.85(s,3H).13C NMR(151MHz,DMSO-d6)δ168.45,162.61,149.91(q,J＝34.5Hz),147.07,139.81,137.88,135.58,131.41,129.35,129.16,126.83,120.65(q,J＝275.4Hz),119.57,117.57,117.43,114.88,111.89,101.42,44.14,33.13,24.29.19FNMR(565MHz,DMSO-d6)δ-69.08。
实施例76：化合物A75的合成：以A71和丙烯酰氯为原料参照实施例1中M1的制备，得棕色固体，收率为71.4％。1HNMR(600MHz,DMSO-d6)δ10.20(s,1H),7.87–7.77(m,3H),7.23(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),6.33(dd,J＝16.9,10.1Hz,1H),6.18(dd,J＝16.9,1.4Hz,1H),5.73(dd,J＝10.2,1.4Hz,1H),3.77(s,3H),3.54(s,3H).13C NMR(151MHz,DMSO-d6)δ163.32,161.90,158.58,150.03(q,J＝34.7Hz),147.31,140.00,137.61,131.92,129.56,127.75,127.29,126.89,120.59(q,J＝275.5Hz),116.93,116.09,115.22,55.89,43.36.19F NMR(565MHz,DMSO-d6)δ-69.15。
实施例77：化合物A76的合成：以A72和丙烯酰氯为原料参照实施例1中M1的制备，得黑色固体，收率为75.1％。1HNMR(600MHz,DMSO-d6)δ10.10(s,1H),7.88–7.76(m,2H),7.66(s,1H),7.50(d,J＝8.4Hz,1H),7.37(d,J＝33.4Hz,2H),7.11(d,J＝8.4Hz,1H),6.37(s,1H),6.27–6.16(m,1H),6.07(d,J＝16.9Hz,1H),5.65(d,J＝9.8Hz,1H),3.78(s,3H),3.58(s,3H).13C NMR(151MHz,DMSO-d6)δ163.27,162.42,150.12(q,J＝33.5Hz),147.33,139.52,137.36,135.70,131.74,131.43,129.38,129.17,127.78,127.04,120.60(q,J＝276.5Hz),119.56,117.64,117.23,115.74,111.99,101.42,44.05,33.08.19F NMR(565MHz,DMSO-d6)δ-69.13。
实施例78.化合物A77的合成：以A71和氯乙酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为73.8％。1H NMR(600MHz,DMSO-d6)δ10.37(s,1H),7.86(d,J＝8.9Hz,1H),7.75–7.72(m,2H),7.24(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),4.16(s,2H),3.78(s,3H),3.55(s,3H).13C NMR(151MHz,DMSO-d6)δ164.89,161.90,158.63,150.19(q,J＝34.5Hz),147.48,139.92,137.05,129.70,127.30,126.76,120.56(q,J＝275.7Hz),116.89,116.14,115.26,55.93,43.83,43.37.19F NMR(565MHz,DMSO-d6)δ-69.19。
实施例79：化合物A78的合成：以A72和氯乙酰氯为原料参照实施例1中M1的制备，得紫黑色固体，收率为75.6％。1H NMR(600MHz,DMSO-d6)δ10.22(s,1H),7.86(d,J＝9.0Hz,1H),7.78(dd,J＝9.0,2.2Hz,1H),7.56(d,J＝1.1Hz,1H),7.52(d,J＝8.7Hz,1H),7.41(d,J＝1.9Hz,1H),7.36(d,J＝3.0Hz,1H),7.13(dd,J＝8.6,2.0Hz,1H),6.37(d,J＝3.0Hz,1H),4.05(s,2H),3.81(s,3H),3.59(s,3H).13C NMR(151MHz,DMSO-d6)δ164.76,162.43,150.28(q,J＝34.6Hz),147.54,139.47,136.86,135.73,131.50,129.55,129.18,126.90,120.61(q,J＝275.9Hz),119.54,117.64,117.22,115.79,112.03,101.42,44.07,43.70,33.13.19FNMR(565MHz,DMSO-d6)δ-69.17。
实施例80：化合物A79的合成：以A77和N-甲基哌嗪为原料参照实施例61中A60的制备，得淡黄色固体，收率为71.7％。1H NMR(600MHz,DMSO-d6)δ9.65(s,1H),7.90(dd,J＝9.0,2.2Hz,1H),7.84(d,J＝9.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.25(d,J＝8.8Hz,2H),6.98(d,J＝8.9Hz,2H),3.77(s,3H),3.55(s,3H),3.00(s,2H),2.49–2.21(m,8H),2.20(s,3H).13CNMR(151MHz,DMSO-d6)δ168.47,161.61,158.63,150.05(q,J＝34.7Hz),147.22,139.81,137.02,129.51,127.50,126.92,120.59(q,J＝275.7Hz),116.67,115.90,115.29,62.01,55.87,54.97,53.01,46.15,43.22.19F NMR(565MHz,DMSO-d6)δ-69.17。
实施例81：化合物A80的合成：以A77和吗啉为原料参照实施例61中A60的制备，得黄色固体，收率为71.7％。1H NMR(600MHz,DMSO-d6)δ9.74(s,1H),7.90–7.82(m,2H),7.49(d,J＝1.9Hz,1H),7.25(d,J＝8.9Hz,2H),6.99(d,J＝8.9Hz,2H),3.77(s,3H),3.63–3.59(m,4H),3.56(s,3H),3.03(s,2H),2.46–2.37(m,4H).13C NMR(151MHz,DMSO-d6)δ168.25,161.58,158.65,150.06(q,J＝34.7Hz),147.22,139.80,137.01,129.48,127.55,126.95,120.59(q,J＝275.8Hz),116.65,115.88,115.42,66.55,62.21,55.83,53.41,43.23.19FNMR(565MHz,DMSO-d6)δ-69.17。
实施例82：化合物A81的合成：以A71和氯丙酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为87.6％。1H NMR(600MHz,DMSO-d6)δ10.15(s,1H),7.85(d,J＝9.5Hz,1H),7.78–7.70(m,2H),7.23(d,J＝8.9Hz,2H),6.97(d,J＝8.9Hz,2H),3.79(t,J＝6.2Hz,2H),3.77(s,3H),3.55(s,3H),2.73(t,J＝6.2Hz,2H).13C NMR(151MHz,DMSO-d6)δ168.22,161.88,158.58,149.99(q,J＝34.4Hz),147.20,139.93,137.48,129.54,127.25,126.74,120.59(q,J＝275.7Hz),116.89,116.02,115.09,55.84,43.33,41.02,39.57.19F NMR(565MHz,DMSO-d6)δ-69.15。
实施例83：化合物A82的合成：以A72和氯丙酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为82.3％。1H NMR(600MHz,DMSO-d6)δ10.00(s,1H),7.83(d,J＝9.0Hz,1H),7.74(dd,J＝9.0,2.0Hz,1H),7.57(s,1H),7.50(d,J＝8.6Hz,1H),7.40(d,J＝1.8Hz,1H),7.35(d,J＝3.0Hz,1H),7.11(dd,J＝8.6,2.0Hz,1H),6.37(d,J＝2.9Hz,1H),3.80(s,3H),3.67(t,J＝6.1Hz,2H),3.60(s,3H),2.60(t,J＝6.0Hz,2H).13C NMR(151MHz,DMSO-d6)δ168.04,162.32,150.08(q,J＝34.3Hz),147.23,139.41,137.24,135.75,131.39,129.36,129.20,126.89,120.64(q,J＝275.6Hz),119.54,117.64,117.17,115.72,111.95,101.42,44.00,40.92,39.42,33.10.19F NMR(565MHz,DMSO-d6)δ-69.12。
实施例84：化合物A83的合成：以A81和N-甲基哌嗪为原料参照实施例61中A60的制备，得黄色固体，收率为67.3％。1HNMR(600MHz,DMSO-d6)δ10.16(s,1H),7.83(d,J＝9.6Hz,1H),7.74–7.69(m,2H),7.21(d,J＝8.9Hz,2H),6.96(d,J＝8.9Hz,2H),3.78(s,3H),3.54(s,3H),2.57–2.47(m,4H),2.35(t,J＝7.0Hz,4H),2.14(s,3H).13C NMR(151MHz,DMSO-d6)δ170.46,161.87,158.49,149.85(q,J＝34.5Hz),147.03,140.02,137.82,129.49,127.25,126.75,120.60(q,J＝275.6Hz),116.94,115.97,114.77,55.88,55.17,54.02,52.74,46.17,43.33,34.55.19F NMR(565MHz,DMSO-d6)δ-69.11。
实施例85：化合物A84的合成：以A71和氯丁酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为74.6％。1H NMR(600MHz,DMSO-d6)δ10.07(s,1H),7.83(d,J＝8.9Hz,1H),7.76(s,1H),7.68(dd,J＝9.0,2.2Hz,1H),7.22(d,J＝8.8Hz,2H),6.97(d,J＝8.8Hz,2H),3.78(s,3H),3.64(t,J＝6.5Hz,1H),3.55(s,3H),2.39(t,J＝7.1Hz,2H),1.97–1.91(m,2H).13C NMR(151MHz,DMSO-d6)δ170.32,161.77,158.57,149.88(q,J＝34.3Hz),147.01,139.93,137.70,129.44,127.32,126.68,120.61(q,J＝275.8Hz),116.84,115.96,114.93,55.86,45.19,43.30,33.53,28.20.19F NMR(565MHz,DMSO-d6)δ-69.12。
实施例86：化合物A85的合成：以A72和氯丁酰氯为原料参照实施例1中M1的制备，得黑色固体，收率为66.1％。1H NMR(600MHz,DMSO-d6)δ9.95(s,1H),7.79(d,J＝8.9Hz,1H),7.64–7.59(m,2H),7.49(d,J＝8.6Hz,1H),7.40(d,J＝1.6Hz,1H),7.34(d,J＝2.9Hz,1H),7.07(dd,J＝8.6,1.8Hz,1H),6.37(d,J＝2.9Hz,1H),3.80(s,3H),3.59(s,3H),3.40(t,J＝6.6Hz,2H),2.24(t,J＝6.7Hz,2H),1.80–1.72(m,2H).13C NMR(151MHz,DMSO-d6)δ170.11,162.07,150.00(q,J＝34.8Hz),146.99,139.27,137.33,135.75,131.38,129.20,129.18,126.77,120.63(q,J＝275.8Hz),119.58,117.73,116.98,115.71,111.90,101.39,44.93,43.93,33.20,33.08,28.09.19F NMR(565MHz,DMSO-d6)δ-69.12。
实施例87：化合物A86的合成：以A71和苯甲酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为86.2％。1HNMR(600MHz,DMSO-d6)δ10.33(s,1H),7.94–7.87(m,3H),7.85–7.82(m,2H),7.59(t,J＝7.4Hz,1H),7.56–7.48(m,2H),7.27(d,J＝8.9Hz,2H),6.99(d,J＝8.9Hz,2H),3.74(s,3H),3.57(s,3H).13C NMR(151MHz,DMSO-d6)δ165.70,161.90,158.64,150.12(q,J＝34.4Hz),147.42,139.97,137.79,135.02,132.21,129.32,128.87,128.05,127.83,127.40,120.62(q,J＝275.4Hz),116.77,116.20,116.09,55.87,43.33.19FNMR(565MHz,DMSO-d6)δ-69.13。
实施例88：化合物A87的合成：以A71和对甲苯磺酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为77.8％。1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),7.78(d,J＝9.0Hz,1H),7.47(dd,J＝9.0,2.4Hz,1H),7.44(d,J＝8.3Hz,2H),7.31(d,J＝8.1Hz,2H),7.22(d,J＝8.9Hz,2H),7.06(d,J＝2.3Hz,1H),7.01(d,J＝8.9Hz,2H),3.82(s,3H),3.50(s,3H),2.32(s,3H).13C NMR(151MHz,DMSO-d6)δ161.72,158.76,150.20(q,J＝34.7Hz),147.53,143.91,139.71,136.75,130.35,130.15,127.22,127.03,126.97,120.47(q,J＝275.4Hz),117.10,116.17,115.13,55.93,43.67,21.42.19F NMR(565MHz,DMSO-d6)δ-69.30。
实施例89：化合物A88的合成：以A71和3,4,5-三甲氧基苯甲酸为原料参照实施例38中A37的制备，得淡黄色固体，收率为67.3％。1HNMR(600MHz,DMSO-d6)δ10.19(s,1H),7.95–7.87(m,2H),7.81(d,J＝2.1Hz,1H),7.28(d,J＝8.8Hz,2H),7.15(s,2H),7.01(d,J＝8.9Hz,2H),3.86(s,6H),3.76(s,3H),3.73(s,3H),3.58(s,3H).13C NMR(151MHz,DMSO-d6)δ165.08,161.78,158.72,153.09,150.15(q,J＝35.0Hz),147.44,140.92,139.85,137.68,130.11,129.33,127.97,127.45,120.61(q,J＝275.7Hz),116.75,116.49,116.13,105.68,60.61,56.53,55.89,43.36.19F NMR(565MHz,DMSO-d6)δ-69.16。
实施例90：化合物A89的合成：以A71和碘甲烷为原料参照实施例2中A1的制备，得黄色固体，收率为78.4％。1H NMR(600MHz,DMSO-d6)δ7.70(d,J＝9.2Hz,1H),7.34(dt,J＝21.0,10.6Hz,1H),7.28(d,J＝8.6Hz,2H),7.02(d,J＝8.6Hz,2H),6.07(d,J＝1.8Hz,1H),3.77(s,3H),3.52(s,3H),2.62(s,6H).13C NMR(151MHz,DMSO-d6)δ160.38,158.38,148.50,147.34(q,J＝34.5Hz),142.72,140.62,129.68,128.19,121.47,120.86(q,J＝275.2Hz),117.57,115.66,104.89,55.97,42.96,39.86.19F NMR(565MHz,DMSO-d6)δ-68.64。
实施例91：化合物A90的合成：以A72和碘甲烷为原料参照实施例2中A1的制备，得黄色固体，收率为78.7％。1HNMR(600MHz,DMSO-d6)δ7.67(d,J＝9.2Hz,1H),7.54(d,J＝8.6Hz,1H),7.49(d,J＝1.7Hz,1H),7.42(d,J＝3.0Hz,1H),7.27(dd,J＝9.2,2.7Hz,1H),7.16(dd,J＝8.6,1.9Hz,1H),6.41(d,J＝2.9Hz,1H),5.92(d,J＝2.7Hz,1H),3.81(s,3H),3.59(s,3H),2.34(s,6H).13C NMR(151MHz,DMSO-d6)δ160.57,148.33,147.46(q,J＝34.4Hz),142.66,139.61,135.58,131.83,129.45,129.09,121.16,120.92(q,J＝275.1Hz),120.48,118.63,117.67,111.56,105.38,101.28,43.51,39.65,33.13.19F NMR(565MHz,DMSO-d6)δ-68.65。
实施例92：化合物A91的合成：以A71和碘乙烷为原料参照实施例2中A1的制备，得黄色固体，收率为81.6％。1HNMR(600MHz,DMSO-d6)δ7.70(d,J＝9.3Hz,1H),7.30(dd,J＝9.3,2.8Hz,1H),7.28–7.25(m,2H),7.04–7.00(m,2H),6.08(d,J＝2.7Hz,1H),3.78(s,3H),3.51(s,3H),3.04(q,J＝7.0Hz,4H),0.84(t,J＝7.0Hz,6H).13C NMR(151MHz,DMSO-d6)δ160.07,158.49,146.87(q,J＝34.5Hz),146.14,142.17,140.44,130.07,127.77,121.03,120.91(q,J＝274.7Hz),118.17,115.69,103.65,55.93,44.11,43.27,12.69.19F NMR(565MHz,DMSO-d6)δ-68.56。
实施例93：化合物A92的合成：以A72和碘乙烷为原料参照实施例2中A1的制备，得黄色固体，收率为80.0％。1HNMR(600MHz,DMSO-d6)δ7.65(d,J＝9.2Hz,1H),7.52(d,J＝8.6Hz,1H),7.50(d,J＝1.3Hz,1H),7.20(dd,J＝9.3,2.6Hz,1H),7.11(dd,J＝8.5,1.6Hz,1H),6.41(d,J＝2.8Hz,1H),5.94(d,J＝2.4Hz,1H),3.80(s,3H),3.57(s,3H),2.77(q,J＝6.9Hz,4H),0.55(t,J＝7.0Hz,6H).13C NMR(151MHz,DMSO-d6)δ160.17,146.97(q,J＝34.5Hz),145.93,141.99,139.42,135.70,131.75,129.82,129.23,120.94(q,J＝274.6Hz),120.67,120.11,118.28,118.23,111.58,104.10,101.28,43.84,43.79,33.09,12.22.19F NMR(565MHz,DMSO-d6)δ-68.59。
实施例94：化合物A93的合成：
以S9为原料参照实施例67中M21的制备方法合成M24。以M24为原料参照实施例1中M3的制备方法合成M25。以M25和4-甲氧基苯胺为原料参照实施例2中A1的制备方法合成得黄色固体A93，收率为91.5％。1H NMR(600MHz,DMSO-d6)δ8.55(d,J＝2.4Hz,1H),7.98(dd,J＝9.4,2.5Hz,1H),7.42(d,J＝8.8Hz,2H),7.11(d,J＝9.4Hz,1H),7.08(d,J＝8.9Hz,2H),3.83(s,3H),3.62(s,3H).13C NMR(151MHz,DMSO-d6)δ161.52,159.28,152.88(q,J＝34.9Hz),151.23,149.98,138.97,128.78,128.00,123.92,120.34,120.22(q,J＝266.0Hz),119.82,116.24,55.98,43.46.19F NMR(565MHz,DMSO-d6)δ-69.76。
实施例95：化合物A94的合成：以M25和5-氨基-1-甲基-1H-吲哚为原料参照实施例2中A1的制备，得黄色固体，收率为85.4％。1H NMR(600MHz,DMSO-d6)δ8.50(d,J＝2.4Hz,1H),7.78(dd,J＝9.4,2.5Hz,1H),7.64(d,J＝2.0Hz,1H),7.61(d,J＝8.6Hz,1H),7.47(d,J＝3.1Hz,1H),7.22(dd,J＝8.6,2.1Hz,1H),6.97(d,J＝9.4Hz,1H),6.46(d,J＝2.9Hz,1H),3.86(s,3H),3.68(s,3H).13C NMR(151MHz,DMSO-d6)δ161.52,152.97(q,J＝35.2Hz),151.21,149.83,138.22,136.02,132.18,129.28,128.87,123.77,120.22(q,J＝276.0Hz),119.98,119.97,119.60,118.23,112.33,101.63,44.10,33.21.19F NMR(565MHz,DMSO-d6)δ-69.79。
实施例96：化合物A95的合成：以A93为原料参照实施例21中A20的制备，得黄色固体，收率为93.5％。1HNMR(600MHz,DMSO-d6)δ9.12(s,1H),8.79(s,1H),7.27(d,J＝8.5Hz,2H),7.07–6.95(m,3H),6.72(d,J＝9.4Hz,1H),6.60(s,1H),3.79(d,J＝14.4Hz,3H),3.49(d,J＝17.7Hz,3H).13C NMR(151MHz,DMSO-d6)δ161.40,158.45,155.53,153.09,151.59(q,J＝34.0Hz),140.52,127.91,126.88,120.55(q,J＝276.4Hz),115.81,114.79,108.60,105.64,55.86,42.68.19F NMR(565MHz,DMSO-d6)δ-69.47。
实施例97：化合物A96的合成：以A95和醋酸酐为原料参照实施例1中M1的制备，得黄色固体，收率为75.8％。1HNMR(600MHz,DMSO-d6)δ7.92(d,J＝2.4Hz,1H),7.43(dd,J＝9.5,2.4Hz,1H),7.37(d,J＝8.9Hz,2H),7.06(d,J＝8.9Hz,2H),6.92(d,J＝9.5Hz,1H),3.82(s,4H),3.57(s,3H),2.17(s,3H).13C NMR(151MHz,DMSO-d6)δ169.26,161.20,158.98,152.06(q,J＝34.8Hz),151.66,142.80,139.51,128.12,127.44,120.37(q,J＝276.3Hz),116.08,113.50,55.91,43.17,22.41.19F NMR(565MHz,DMSO-d6)δ-69.58。
实施例98：化合物A97的合成：以A95和丙烯酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为83.2％。1H NMR(600MHz,DMSO-d6)δ7.85(d,J＝2.3Hz,1H),7.46(dd,J＝9.4,2.2Hz,1H),7.37(d,J＝8.8Hz,2H),7.06(d,J＝8.9Hz,2H),6.94(d,J＝9.5Hz,1H),6.69(d,J＝17.4Hz,1H),6.41(dd,J＝16.8,1.4Hz,1H),6.33(d,J＝10.7Hz,1H),6.00–5.93(m,1H),3.82(s,3H),3.57(s,3H).13C NMR(151MHz,DMSO-d6)δ164.06,161.24,159.04,152.18(q,J＝34.5Hz),151.64,142.51,139.41,137.56,132.66,128.12,127.71,127.71,126.82,124.22,120.33(q,J＝276.1Hz),116.10,55.91,43.20.19F NMR(565MHz,DMSO-d6)δ-69.65。
实施例99：化合物A98的合成：以A95和氯乙酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为85.8％。1H NMR(600MHz,DMSO-d6)δ10.71(s,1H),8.18(d,J＝1.4Hz,1H),7.32(d,J＝8.7Hz,2H),7.29(dd,J＝9.3,1.6Hz,1H),7.04(d,J＝8.7Hz,2H),6.86(d,J＝9.3Hz,1H),4.32(s,2H),3.81(s,3H),3.55(s,3H).13C NMR(151MHz,DMSO-d6)δ166.05,161.34,158.79,152.11,151.82(q,J＝34.6Hz),142.62,139.85,128.02,127.38,120.41(q,J＝278.2Hz),119.49,116.08,115.96,112.22,55.91,44.03,42.95.19F NMR(565MHz,DMSO-d6)δ-69.56。
实施例100：化合物A99的合成：以A95和氯丙酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为84.1％。1H NMR(600MHz,DMSO-d6)δ10.49(s,1H),8.19(d,J＝2.1Hz,1H),7.34–7.27(m,3H),7.06–7.01(m,2H),6.84(d,J＝9.3Hz,1H),3.89(t,J＝6.2Hz,2H),3.81(s,3H),3.54(s,3H),3.54(s,3H),2.88(t,J＝6.2Hz,2H).13C NMR(151MHz,DMSO-d6)δ169.48,161.34,158.75,152.17,151.75(q,J＝34.4Hz),143.01,139.91,128.01,127.28,120.44(q,J＝276.0Hz),119.41,115.93,115.67,111.90,55.90,42.90,40.95,37.63.19FNMR(565MHz,DMSO-d6)δ-69.54。
实施例101：化合物A100的合成：以A95和氯丁酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为67.1％。1H NMR(600MHz,DMSO-d6)δ7.93(d,J＝2.4Hz,1H),7.41(dd,J＝9.4,2.4Hz,1H),7.37(t,J＝10.5Hz,2H),7.05(d,J＝8.9Hz,2H),6.92(d,J＝9.4Hz,1H),3.81(s,3H),3.66(t,J＝6.6Hz,2H),3.57(s,3H),2.60(t,J＝6.3Hz,2H),2.04–1.95(m,2H).13C NMR(151MHz,DMSO-d6)δ174.12,171.14,170.79,162.75,161.25,159.02,152.09(q,J＝34.8Hz),151.66,142.71,139.49,128.12,127.47,120.36(q,J＝276.0Hz),116.08,55.91,44.83,43.16,30.67,27.31.19F NMR(565MHz,DMSO-d6)δ-69.60。
实施例102：化合物A101的合成：以A95和苯甲酰氯为原料参照实施例1中M1的制备，得淡黄色固体，收率为84.7％。1H NMR(600MHz,DMSO-d6)δ7.80(d,J＝2.3Hz,1H),7.64(d,J＝7.2Hz,2H),7.47(t,J＝7.5Hz,1H),7.39(t,J＝7.6Hz,3H),7.35(d,J＝8.9Hz,2H),7.03(d,J＝8.9Hz,2H),6.90(d,J＝9.4Hz,1H),3.79(s,3H),3.56(s,3H).13C NMR(151MHz,DMSO-d6)δ164.22,161.25,158.99,152.15(q,J＝34.6Hz),151.58,143.45,139.39,135.66,132.29,130.33,128.93,128.07,127.57,125.81,121.59,120.30(q,J＝276.3Hz),116.07,114.18,55.89,43.19.19F NMR(565MHz,DMSO-d6)δ-69.65。
实施例103：化合物A102的合成：以A95和碘甲烷为原料参照实施例2中A1的制备，得黄色固体，收率为66.2％。1HNMR(600MHz,DMSO-d6)δ7.27(d,J＝8.8Hz,2H),7.02(d,J＝8.8Hz,2H),6.81–6.77(m,2H),6.74(d,J＝9.5Hz,1H),3.80(s,3H),3.50(s,3H),2.98(s,6H).13C NMR(151MHz,DMSO-d6)δ161.24,158.45,152.98,152.89,151.60(q,J＝33.7Hz),140.55,128.01,127.21,120.62(q,J＝275.9Hz),115.83,115.02,106.30,105.64,55.85,42.64,39.91.19F NMR(565MHz,DMSO-d6)δ-69.46。
实施例104：化合物A103的合成：参照实施例2中A1的制备，用4(4-氨基苯基)哌嗪-1-羧酸叔丁酯代替苯胺，得黄色固体，收率为88.6％。1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.4,1.4Hz,1H),7.64(ddd,J＝8.4,6.8,1.5Hz,1H),7.13(m,3H),7.08(dd,J＝8.7,1.5Hz,1H),6.97(d,J＝2.2Hz,1H),6.96(d,J＝2.3Hz,1H),3.66(s,3H),3.63(t,J＝4.9Hz,4H),3.22(t,J＝4.9Hz,4H),1.52(s,9H).13C NMR(151MHz,CDCl3)δ161.89,154.68,152.11(q,J＝35.7Hz),151.13,150.24,139.26,132.46,129.14,127.11,126.35,126.32,121.01(q,J＝275.9Hz),117.42,116.38,80.11,48.97,42.98,28.44.19F NMR(565MHz,CDCl3)δ-70.95。
实施例105：化合物A104的合成：
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取A103100mg溶解于0.5mL的无水二氯甲烷中，冰水浴搅拌10min，缓慢注入0.5mL三氟乙酸，室温搅拌3h至反应完全，将反应液倒入冰水中，缓慢加入碳酸钾颗粒调pH至中性，乙酸乙酯萃取，有机相用无水硫酸镁干燥，减压蒸干得黄色固体70mg，收率为88.6％。1HNMR(600MHz,CDCl3)δ7.93(d,J＝8.4Hz,1H),7.64(t,J＝7.6Hz,1H),7.14(m,3H),7.08(d,J＝8.6Hz,1H),6.97(d,J＝2.2Hz,1H),6.96(d,J＝2.3Hz,1H),4.87(s,1H),3.65(s,3H),3.31(t,J＝4.9Hz,4H),3.16(t,J＝4.8Hz,4H).13C NMR(151MHz,CDCl3)δ161.89,152.10(q,J＝35.7Hz),151.11,150.30,139.26,132.48,129.12,127.09,126.39,126.33,120.09(q,J＝276.5Hz),117.25,116.38,49.02,45.21,42.98.19F NMR(565MHz,CDCl3)δ-70.95。
实施例106：化合物A105的合成：以A104和溴化苄参照实施例61中A60的制备，得黄色固体，收率为81.2％。1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.3,1.3Hz,1H),7.64(ddd,J＝8.3,6.8,1.5Hz,1H),7.38(m,3H),7.36(d,J＝7.8Hz,1H),7.31(t,J＝6.9Hz,1H),7.15–7.11(m,3H),7.09(dd,J＝8.7,1.5Hz,1H),6.97(d,J＝2.1Hz,1H),6.95(d,J＝2.2Hz,1H),3.66(s,3H),3.62(s,2H),3.28(t,J＝5.0Hz,4H),2.67(t,J＝5.0Hz,4H).13C NMR(151MHz,CDCl3)δ161.85,152.12(q,J＝34.9Hz),151.12,150.43,138.60,137.86,132.42,129.20,129.10,128.35,127.25,127.02,126.41,126.32,120.12(q,J＝275.7Hz),116.83,116.40,63.03,52.93,48.77,43.00.19F NMR(565MHz,CDCl3)δ-70.94。
实施例107：化合物A106的合成：以A104和4-氰基溴化苄参照实施例61中A60的制备，得黄色固体，收率为84.6％。1HNMR(600MHz,CDCl3)δ7.93(dd,J＝8.4,1.2Hz,1H),7.67–7.62(m,3H),7.52(d,J＝7.9Hz,2H),7.15–7.11(m,3H),7.08(dd,J＝8.6,1.5Hz,1H),6.97(d,J＝2.3Hz,1H),6.95(d,J＝2.2Hz,1H),3.66(s,5H),3.29(t,J＝5.0Hz,4H),2.66(t,J＝5.0Hz,4H).13C NMR(151MHz,CDCl3)δ161.86,152.11(q,J＝34.9Hz),151.13,150.25,143.86,138.84,132.43,132.22,129.52,129.12,127.05,126.37,126.32,120.11(q,J＝275.6Hz),118.91,116.93,116.39,111.10,62.37,53.00,48.78,43.00.19F NMR(565MHz,CDCl3)δ-70.93。
实施例108：化合物A107的合成：
取A10590mg(108μmol)溶解于5mL四氢呋喃中，加入钯碳3.35mg(5.6μmol)，氢气置换，室温搅拌24h至反应完全，滤除钯碳，滤液减压蒸干得到72mg黄色固体，收率为83.1％。1H NMR(600MHz,CDCl3)δ7.90(dd,J＝8.4,1.3Hz,1H),7.61(ddd,J＝8.3,6.9,1.4Hz,1H),7.13–7.08(m,3H),7.03(dd,J＝8.7,1.3Hz,1H),6.93(d,J＝2.2Hz,1H),6.92(d,J＝2.2Hz,1H),3.63(s,3H),3.61(t,J＝4.7Hz,2H),3.30(t,J＝5.0Hz,4H),2.73(t,J＝5.0Hz,4H),2.50(d,J＝5.6Hz,2H),1.77–1.68(m,4H).13C NMR(151MHz,CDCl3)δ161.85,152.08(q,J＝35.4Hz),151.08,150.10,139.02,132.47,129.06,127.04,126.41,126.34,120.10(q,J＝276.1),117.10,116.37,62.64,58.45,52.79,48.33,42.98,32.38,25.12.19F NMR(565MHz,CDCl3)δ-70.94。
实施例109：化合物A108的合成：以A104和碘甲烷为原料参照实施例2中A1的制备，得黄色固体，收率为82.6％。1H NMR(600MHz,CDCl3)δ7.93(d,J＝8.4Hz,1H),7.64(ddd,J＝8.3,6.6,1.6Hz,1H),7.16–7.12(m,3H),7.10(dd,J＝8.8,1.5Hz,1H),6.97(d,J＝2.5Hz,1H),6.96(d,J＝2.5Hz,1H),3.66(s,3H),3.29(t,J＝5.0Hz,4H),2.63(t,J＝4.9Hz,4H),2.40(s,3H).13C NMR(151MHz,CDCl3)δ154.34,145.77(q,J＝30.7Hz),144.90,144.19,134.00,128.49,125.55,123.74,123.19,123.14,117.67(q,J＝242.8Hz),114.82,114.40,60.44,54.92,52.68,49.92.19F NMR(565MHz,CDCl3)δ-70.94。
实施例110：化合物A109的合成：以A104和醋酸酐为原料参照实施例1中M1的制备，得淡黄色固体，收率为90.0％。1HNMR(600MHz,CDCl3)δ7.93(d,J＝8.3Hz,1H),7.64(ddd,J＝8.3,6.7,1.4Hz,1H),7.18–7.10(m,3H),7.07(dd,J＝8.7,1.3Hz,1H),6.96(d,J＝8.9Hz,2H),3.82(t,J＝5.2Hz,2H),3.68(t,J＝5.2Hz,2H),3.65(s,3H),3.29–3.25(m,2H),3.24(t,J＝5.3Hz,2H).13C NMR(151MHz,CDCl3)δ169.05,161.90,152.10(q,J＝35.1Hz),151.14,149.88,139.53,132.49,129.17,127.15,126.37,126.28,121.09(q,J＝276.48Hz),117.47,116.37,49.19,48.93,46.05,42.96,41.20.19F NMR(565MHz,CDCl3)δ-70.92。
实施例111：化合物A110的合成：以A104和噻吩-2-甲酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为87.5％。1H NMR(600MHz,CDCl3)δ7.95(dd,J＝8.4,1.2Hz,1H),7.65(ddd,J＝8.3,6.9,1.4Hz,1H),7.51(dd,J＝5.0,1.1Hz,1H),7.38(dd,J＝3.7,1.2Hz,1H),7.16(d,J＝8.9Hz,2H),7.15–7.12(m,1H),7.10(dd,J＝5.0,3.7Hz,1H),7.08(dd,J＝8.7,1.3Hz,1H),6.98(d,J＝8.9Hz,2H),3.99–3.95(m,4H),3.67(s,3H),3.37–3.30(m,4H).13C NMR(151MHz,CDCl3)δ163.75,161.93,152.12(q,J＝35.0Hz),151.14,139.60,136.66,132.50,129.18,129.00,127.19,126.85,126.38,126.28,120.09(q,J＝276.3Hz),117.44,116.38,49.18,42.98.19F NMR(565MHz,CDCl3)δ-70.93。
实施例112：化合物A111的合成：以A104和呋喃-2-甲酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为83.5％。1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.4,1.3Hz,1H),7.64(ddd,J＝8.2,6.8,1.4Hz,1H),7.54(dd,J＝1.7,0.8Hz,1H),7.16(d,J＝8.9Hz,2H),7.14–7.12(m,1H),7.10(dd,J＝3.5,0.8Hz,1H),7.08(dd,J＝8.8,1.3Hz,1H),6.98(d,J＝8.9Hz,2H),6.54(dd,J＝3.5,1.8Hz,1H),4.10–3.92(m,4H),3.66(s,3H),3.38–3.31(m,4H).13C NMR(151MHz,CDCl3)δ161.91,159.12,152.11(q,J＝35.0Hz),151.14,149.88,147.84,143.89,139.47,132.49,129.16,127.17,126.37,126.29,120.09(q,J＝275.8Hz),117.34,116.96,116.38,111.49,42.97.13C NMR(151MHz,CDCl3)δ161.91,159.12,152.11(q,J＝35.0Hz),151.14,149.88,147.84,143.89,139.47,132.49,129.16,127.17,126.37,126.29,120.09(q,J＝275.8Hz),117.34,116.96,116.38,111.49,42.97.19F NMR(565MHz,CDCl3)δ-70.93。
实施例113：化合物A112的合成：以A104和氯乙酰氯为原料参照实施例1中M1的制备，得黄色固体，收率为81.6％。1HNMR(600MHz,CDCl3)δ7.94(dd,J＝8.4,1.3Hz,1H),7.64(ddd,J＝8.4,6.9,1.4Hz,1H),7.17(d,J＝2.1Hz,1H),7.15(d,J＝2.6Hz,1H),7.13(dd,J＝8.6,1H),7.07(dd,J＝8.6,1.4Hz,1H),6.98(d,J＝2.2Hz,1H),6.97(d,J＝2.2Hz,1H),4.15(s,2H),3.84(t,J＝5.2Hz,2H),3.75(t,J＝5.2Hz,2H),3.66(s,3H),3.33(t,J＝5.2Hz,2H),3.28(t,J＝5.2Hz,2H).13C NMR(151MHz,CDCl3)δ165.19,161.92,152.10(q,J＝35.1Hz),151.14,149.71,139.77,132.51,129.19,127.19,126.39,126.26,121.01(q,J＝275.5Hz),117.62,116.36,49.20,48.83,46.08,42.96,41.95,40.77.19F NMR(565MHz,CDCl3)δ-70.91。
实施例114：化合物A113的合成：以A112和二甲胺盐酸盐为原料参照实施例61中A60的制备，得黄色固体，收率为81.2％。1HNMR(600MHz,CDCl3)δ7.93(dd,J＝8.4,1.2Hz,1H),7.63(ddd,J＝8.3,6.8,1.4Hz,1H),7.15(d,J＝2.2Hz,1H),7.13(d,J＝2.4Hz,1H),7.12(dd,J＝8.7,1.4Hz,1H),7.07(dd,J＝8.7,1.4Hz,1H),6.97(d,J＝2.3Hz,1H),6.96(d,J＝2.3Hz,1H),3.81(t,J＝4.9Hz,4H),3.64(s,3H),3.25(t,J＝4.9Hz,4H),3.23(s,2H),2.35(s,6H).13C NMR(151MHz,CDCl3)δ168.32,161.89,152.08(q,J＝35.1Hz),151.11,149.97,139.43,132.49,129.13,127.13,126.37,126.29,120.09(q,J＝276.3Hz),117.41,116.36,62.35,49.41,45.40,45.23,42.96,41.56.19F NMR(565MHz,CDCl3)δ-70.91。
实施例115：化合物A114的合成：以A112和苯酚为原料参照实施例61中A60的制备，得黄色固体，收率为88.3％。1H NMR(600MHz,CDCl3)δ7.95(dd,J＝8.4,1.2Hz,1H),7.65(ddd,J＝8.2,6.8,1.4Hz,1H),7.36–7.32(m,2H),7.17–7.11(m,3H),7.07(dd,J＝8.6,1.3Hz,1H),7.03(t,J＝7.3,1.1Hz,1H),7.00(d,J＝7.9Hz,2H),6.95(d,J＝8.9Hz,2H),4.77(s,2H),3.84(t,J＝4.8Hz,4H),3.66(s,3H),3.26(t,J＝5.1Hz,4H).13C NMR(151MHz,CDCl3)δ166.69,161.92,157.73,152.12(q,J＝35.6Hz),151.14,149.78,139.62,132.50,129.74,129.18,127.16,126.38,126.27,121.86,120.09(q,J＝275.7Hz),117.49,116.37,114.58,67.89,49.37,48.89,45.22,42.97,41.94.19F NMR(565MHz,CDCl3)δ-70.92。
实施例116：化合物A115的合成：以A112和咪唑为原料参照实施例61中A60的制备，得黄色固体，收率为84.1％。1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.4,1.2Hz,1H),7.64(ddd,J＝8.4,6.9,1.4Hz,1H),7.59(s,1H),7.16(d,J＝2.2Hz,1H),7.15(d,J＝2.3Hz,1H),7.13(d,J＝6.8Hz,2H),7.07(dd,J＝8.6,1.3Hz,1H),7.00(s,1H),6.96(d,J＝2.3Hz,1H),6.95(d,J＝2.2Hz,1H),4.88(s,2H),3.85(t,J＝5.2Hz,2H),3.68(t,J＝5.2Hz,2H),3.66(s,3H),3.26(t,J＝5.1Hz,4H).13C NMR(151MHz,CDCl3)δ164.66,161.94,152.10(q,J＝35.8Hz),151.14,149.52,139.93,137.96,132.54,129.36,129.20,127.20,126.41,126.25,120.17,120.09(q,J＝276.0Hz),117.66,116.36,49.08,48.87,48.11,44.95,42.96,42.08.19F NMR(565MHz,CDCl3)δ-70.90。
实施例117：化合物A116的合成：以A104和4-溴代巴豆酸甲酯为原料参照实施例106中A105的制备，得黄色固体，收率为89.3％。1H NMR(600MHz,CDCl3)δ7.93(dd,J＝8.4,1.2Hz,1H),7.64(ddd,J＝8.3,6.8,1.5Hz,1H),7.15–7.11(m,3H),7.08(dd,J＝8.6,1.5Hz,1H),7.01(dt,J＝15.8,6.2Hz,1H),6.96(d,J＝2.3Hz,1H),6.95(d,J＝2.2Hz,1H),6.07(d,J＝15.8,1H),3.78(s,3H),3.65(s,3H),3.29(t,J＝5.0Hz,4H),3.24(d,J＝1.7Hz,2H),2.68(t,J＝5.0Hz,4H).13C NMR(151MHz,CDCl3)δ166.57,161.86,152.11(q,J＝35.7Hz),151.12,150.21,144.84,138.84,132.43,129.11,127.05,126.37,126.34,123.30,120.11(q,J＝275.5Hz),116.93,116.39,59.14,53.08,51.65,48.73,42.99.19F NMR(565MHz,CDCl3)δ-70.95.
实施例118.化合物A117的合成：
取A116100mg(206μmol)，13mg(308μmol)氢氧化锂单水合物溶于0.5mL水和1mL四氢呋喃混合液，室温搅拌5h至反应完全，将反应液倒入水中，加乙酸乙酯萃取，有机相用无水硫酸镁干燥，减压蒸干，所得粗产物经硅胶柱层析纯化得到80mg黄色固体，收率为82.3％。1H NMR(600MHz,CDCl3)δ7.94(d,J＝8.4Hz,1H),7.64(ddd,J＝8.2,6.7,1.4Hz,1H),7.16–7.11(m,3H),7.09(d,J＝8.4Hz,1H),7.03(dt,J＝15.6,6.4Hz,1H),6.96(d,J＝8.8Hz,2H),6.08(d,J＝15.6Hz,1H),3.65(s,3H),3.40–3.30(m,6H),2.86–2.75(m,4H).13CNMR(151MHz,CDCl3)δ169.56,161.89,152.11(q,J＝35.3Hz),151.09,149.90,143.17,139.21,132.48,129.10,127.08,126.38,126.33,120.08(q,J＝275.8Hz),117.18,116.37,58.80,52.69,48.20,43.00.19F NMR(565MHz,CDCl3)δ-70.93。
实施例119.化合物A118的合成：
取E-4-二甲氨巴豆酸盐酸盐100mg(603μmol)溶解于1mL无水二氯甲烷中，在0℃搅拌下注入用1mL无水二氯甲烷稀释草酰氯53μL(629μmol)混合液，室温搅拌4h后，再注入将1mL含A104199mg(516μmol)的二氯甲烷溶液，室温搅拌过夜至反应完全，将反应液倒入10mL水中，加15mL乙酸乙酯萃取，有机相用无水硫酸镁干燥，减压蒸干，所得粗产物经硅胶柱层析纯化得155mg黄色固体A118，收率为60.5％。1H NMR(600MHz,DMSO-d6)δ7.86(dd,J＝8.4,1.3Hz,1H),7.74(ddd,J＝8.3,6.9,1.3Hz,1H),7.27–7.22(m,3H),7.04(d,J＝8.9Hz,2H),7.02(dd,J＝8.7,1.2Hz,1H),6.65(d,J＝3.3Hz,2H),3.77–3.64(m,4H),3.55(s,3H),3.26–3.18(m,4H),3.05(d,J＝3.3Hz,2H),2.16(s,6H).13C NMR(151MHz,DMSO-d6)δ164.64,161.77,151.28(q,J＝34.7Hz),150.88,150.22,142.65,138.24,133.55,129.06,127.37,127.23,126.50,122.65,120.47(q,J＝276.4Hz),117.07,116.31,60.39,45.50,43.11.19FNMR(565MHz,DMSO-d6)δ-69.48。
实施例120：化合物A119的合成：以A104和氯甲酸异丁酯为原料参照实施例1中M1的制备，得黄色固体，收率为90.0％。1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.4,1.2Hz,1H),7.64(ddd,J＝8.3,6.7,1.4Hz,1H),7.17–7.11(m,3H),7.08(dd,J＝8.6,1.4Hz,1H),6.98(d,J＝2.3Hz,1H),6.96(d,J＝2.3Hz,1H),3.94(d,J＝6.6Hz,2H),3.70(t,J＝5.2Hz,4H),3.66(s,3H),3.24(t,J＝5.1Hz,4H),2.03–1.95(m,1H),0.99(s,3H),0.98(s,3H).13C NMR(151MHz,DMSO-d6)δ157.15,150.77,147.37(q,J＝35.0Hz),146.40,145.41,134.64,127.70,124.41,122.37,121.59,121.55,115.34(q,J＝276.0Hz),112.73,111.63,67.02,44.22,38.20,23.27,14.36.19F NMR(565MHz,DMSO-d6)δ-75.70。
实施例121：化合物A120的合成：以A104和(S)-1-(2-(((苄氧基)羰基)氨基)乙酰基)吡咯烷-2-羧酸为原料参照实施例38中A37的制备，得黄色固体，收率为83.1％。1HNMR(600MHz,CDCl3)δ7.92(d,J＝8.3Hz,1H),7.62(t,J＝7.7Hz,1H),7.38–7.33(m,4H),7.30(d,J＝4.4Hz,1H),7.17–7.10(m,3H),7.06(d,J＝8.6Hz,1H),6.95(d,J＝8.6Hz,2H),5.75(t,J＝4.4Hz,1H),5.15–5.08(m,2H),4.93(dd,J＝8.3,3.8Hz,1H),4.12(m,1H),4.03–3.96(m,1H),3.95–3.84(m,2H),3.73–3.66(m,3H),3.64(s,3H),3.57–3.50(m,1H),3.40–3.34(m,1H),3.32–3.19(m,3H),2.27–2.15(m,2H),2.07–2.01(m,1H),1.99–1.91(m,1H).13C NMR(151MHz,CDCl3)δ174.11,169.98,166.96,161.91,156.31,152.10(q,J＝35.3Hz),151.12,149.81,139.55,136.45,132.51,129.14,128.50,128.08,127.97,127.15,126.41,126.29,120.09(q,J＝275.7Hz),117.46,116.37,66.88,56.46,49.05,48.93,46.17,45.48,43.40,42.98,42.02,29.02,24.71.19F NMR(565MHz,CDCl3)δ-70.92。
实施例122：化合物A121的合成：以A104和(R)-1-(叔丁氧基羰基)吡咯烷-2-羧酸为原料参照实施例38中A37的制备，然后脱掉Boc保护，得黄色固体，收率为81.1％。1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.5,1.2Hz,1H),7.64(ddd,J＝8.4,6.7,1.4Hz,1H),7.18–7.10(m,3H),7.07(dd,J＝8.6,1.3Hz,1H),6.96(d,J＝8.9Hz,2H),4.37–4.30(m,1H),3.96–3.85(m,1H),3.81–3.73(m,2H),3.70–3.66(m,1H),3.65(s,3H),3.34–3.22(m,5H),3.17–3.07(m,1H),2.36–2.26(m,1H),2.03–1.93(m,1H),1.93–1.74(m,2H).13C NMR(151MHz,CDCl3)δ170.77,161.93,152.10(q,J＝35.5Hz),151.14,149.66,139.82,132.51,129.19,127.18,126.40,126.25,120.08(q,J＝276.0Hz),117.63,116.36,58.02,49.19,48.94,47.25,44.96,42.96,42.24,30.66,25.94.19F NMR(565MHz,CDCl3)δ-70.93。
实施例123：化合物A122的合成：以A104和(R)-2-(叔丁氧基羰基)-4-甲基戊酸为原料参照实施例38中A37的制备，然后脱掉Boc保护，得黄色固体，收率为85.1％。1HNMR(600MHz,Methanol-d4)δ7.88(dd,J＝8.3,1.2Hz,1H),7.72(ddd,J＝8.4,6.9,1.4Hz,1H),7.23(d,J＝2.2Hz,1H),7.22(d,J＝2.2Hz,1H),7.17(ddd,J＝8.4,6.9,1.3Hz,1H),7.14–7.10(m,3H),4.16(d,J＝5.1Hz,1H),3.96–3.89(m,1H),3.86–3.80(m,1H),3.80–3.73(m,2H),3.66(s,3H),3.38–3.30(m,4H),3.30–3.23(m,1H),2.19–2.10(m,1H),1.12(d,J＝7.0Hz,3H),1.04(d,J＝6.9Hz,3H).13C NMR(151MHz,Methanol-d4)δ169.59,161.91,151.74(q,J＝35.2Hz),150.61,150.34,139.00,132.72,127.88,126.93,126.37,126.27,120.09(q,J＝275.7Hz),117.27,78.12,55.07,48.90,48.43,45.35,42.01,41.86,30.57,18.16,15.70.19F NMR(565MHz,Methanol-d4)δ-72.40。
实施例124：化合物A123的合成：参照实施例2中A1的制备，用对氨基苯甲酸代替苯胺，得白色固体，收率为63.9％。1HNMR(600MHz,CDCl3)δ8.07(d,J＝2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.99(dd,J＝8.3,1.2Hz,1H),7.71–7.68(m,1H),7.24(d,J＝2.0Hz,1H),7.23(d,J＝2.0Hz,1H),7.19–7.16(m,1H),7.07(dd,J＝8.5,1.4Hz,1H),3.94(s,3H),3.74(s,3H).13C NMR(151MHz)δ166.13,162.50,152.09(q,J＝35.1Hz),151.61,151.26,133.08,131.54,129.50,128.12,127.02,126.03,125.05,119.95(q,J＝276.5Hz),116.53,52.30,42.18。
实施例125：化合物A124的合成：将A123用氢氧化钾水溶液水解制备，得黄色油状液体，收率为70.5％。1H NMR(600MHz,Pyridine-d5)δ8.41–8.39(m,2H),8.09(dt,J＝8.1,1.9Hz,1H),7.68(ddt,J＝8.3,6.5,1.8Hz,1H),7.36–7.33(m,2H),7.20–7.16(m,2H),3.66(s,3H).13C NMR(151MHz,Pyridine-d5)δ168.03,162.61,162.56,151.80(q,J＝35.2Hz),151.40,151.10,133.35,131.93,129.36,127.17,126.51,125.43,120.41(q,J＝276.48Hz),116.75,41.98。
实施例126：化合物A125的合成：以A124和4-甲氧基苯胺为原料参照实施例38中A37的制备，得黄色固体，收率为68.5％。1H NMR(600MHz,CDCl3)δ8.00(dd,J＝8.4,1.2Hz,1H),7.90(d,J＝8.1Hz,2H),7.78(s,1H),7.70(ddd,J＝8.3,6.9,1.4Hz,1H),7.53(d,J＝8.5Hz,2H),7.28(d,J＝8.3Hz,2H),7.19(ddd,J＝8.4,6.9,1.3Hz,1H),7.11(dd,J＝8.6,1.4Hz,1H),6.93–6.90(m,2H),3.81(s,3H),3.74(s,3H).13C NMR(151MHz,DMSO-d6)δ159.75,157.74,152.09,147.37(q,J＝36.1Hz),146.52,145.85,128.38,128.24,125.96,124.76,124.32,122.35,121.34,120.77,117.53,115.24(q,J＝275.5Hz),111.76,109.54,50.76,37.62.19F NMR(565MHz,CDCl3)δ-70.73。
实施例127：化合物A126的合成：参照实施例38中A37的制备，用氯化铵代替苯胺，得白色固体，收率为50.2％。1H NMR(600MHz,DMSO-d6)δ8.06(s,1H),7.98–7.95(m,2H),7.93(d,J＝8.1Hz,1H),7.80(t,J＝8.0Hz,1H),7.46(d,J＝7.4Hz,2H),7.44(s,1H),7.32(t,J＝8.1Hz,1H),7.02(d,J＝8.8Hz,1H),3.65(s,3H).13C NMR(151MHz,DMSO-d6)δ167.39,162.49,151.22(q,J＝34.7Hz),150.98,149.88,133.99,132.93,129.96,129.29,127.77,126.41,125.81,120.43(q,J＝275.5Hz),116.51,42.48.19F NMR(565MHz,DMSO-d6)δ-69.32。
实施例128：化合物A127的合成：以A124和N-甲基-1H-吲哚-5-胺为原料参照实施例38中A37的制备，得红褐色固体，收率为68.7％。1HNMR(600MHz,DMSO-d6)δ10.20(s,1H),8.08(d,J＝8.0Hz,2H),8.02(s,1H),7.95(d,J＝8.3Hz,1H),7.82(t,J＝7.7Hz,1H),7.52(d,J＝8.1Hz,2H),7.48(d,J＝8.7Hz,1H),7.40(d,J＝8.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.31(d,J＝3.1Hz,1H),7.10(d,J＝8.9Hz,1H),6.41(d,J＝3.0Hz,1H),3.78(s,3H),3.68(s,3H).13C NMR(151MHz,DMSO-d6)δ164.50,162.55,151.24(q,J＝35.0Hz),151.01,149.90,134.09,134.04,133.90,131.50,130.66,130.06,129.33,128.22,127.86,126.48,125.87,120.46(q,J＝275.6Hz),116.57,116.52,112.95,109.83,100.81,42.53,33.00.19FNMR(565MHz,DMSO-d6)δ-69.28。
代表性2-三氟甲基喹唑啉类化合物的体外抗肿瘤活性测试：
本实验选择了10种类型肿瘤细胞株(非小细胞肺癌细胞(A549)、宫颈癌细胞(Hela)、人慢性髓系白血病细胞(K562)、人前列腺癌细胞(PC3)、人前列腺癌细胞(LNCaP)、胶质瘤细胞(LN)、乳腺癌细胞株(MDA-231)、黑色素瘤细胞(WM9)、肾癌细胞(A498)、结肠癌细胞(HCT-116))对A1-A127中部分目标化合物进行抗肿瘤活性测试。以阿霉素(Doxorubicin)和紫杉醇(Taxol)为阳性对照。分别取上述10种处于对数期的癌细胞，制成单细胞悬液，调整细胞密度，接种于96孔板中。将96孔板置于饱和湿度、37℃、5％CO2的培养箱中培养48h。取目标化合物及阿霉素和紫杉醇用DMSO-D6溶解，并用无血清的培养基稀释成终浓度为5μmol/L的溶液，给药，于培养箱中继续培养24h后加入2μL 5mg/mL MTT溶液继续培养4h。弃去上清液，加入100μLDMSO-D6后避光、低速震荡至完全溶解。于490nm波长下用酶联免疫检测仪测量吸光度(OD)值，重复三次，计算抑制率。
抑制率(％)＝(对照组OD值-样品组OD值)/对照组OD值×100％。
本发明部分典型的喹唑啉类化合物的体外抗肿瘤活性数据见表1至表5。
表1.目标化合物A1-A56中部分化合物的体外抗肿瘤活性测试结果
表2.目标化合物A3、A53-A55的体外抗肿瘤活性测试结果
表3.目标化合物A50-A92中部分化合物的体外抗肿瘤活性测试结果
表4.目标化合物A13-A123中部分化合物的体外抗肿瘤活性测试结果
表5.目标化合物A103-A127中部分化合物的体外抗肿瘤活性测试结果
从表1至表5可看出，所测目标化合物中大多数化合物具有良好的抗肿瘤活性，其中，化合物A3对非小细胞肺癌细胞(A549)、人前列腺癌细胞(PC3)、人前列腺癌细胞(LNCaP)的抑制率分别为72.87％、55.55％和60.94％，均高于阳性对照药紫杉醇(分别为71.79％、51.93％、51.41％)，化合物A30、A42、A61对人前列腺癌细胞(PC3)、人前列腺癌细胞(LNCaP)、人慢性髓系白血病细胞(K562)也均高于紫杉醇。从活性数据可看出，本发明所涉及的化合物在制备抗肿瘤药物或抗肿瘤药物添加剂中具有很大用途。
选取部分活性较好的目标化合物进行半数抑制浓度(IC50)和细胞毒性测试，结果见表6。
表6部分活性较好的目标化合物的体外抗增值活性(n＝3)以及毒性测试结果
结果显示，化合物A3和A20对人正常肝细胞(L-02细胞)毒性较低，其对人前列腺癌细胞(PC3)和人慢性髓系白血病细胞(K562)的治疗指数(SI)均高于阳性对照药紫杉醇和阿霉素。化合物A20对PC3和K562的IC50分别为33nM和22nM，优于阳性对照药紫杉醇(IC50值分别为275nM和302nM)和阿霉素(IC50值分别为513nM和938nM)。
本发明还公开了一种药用组合物，包括上述的2-三氟甲基-4-氨基喹唑啉类化合物或其药学上可接受的盐或水合物。
本发明还公开了一种药物制剂，包括上述的2-三氟甲基-4-氨基喹唑啉类化合物及其药学上可接受的载体或赋形剂。

Claims (5)

1.2-三氟甲基-4-氨基喹唑啉类化合物，其特征在于：所述化合物具有如下通式I所示的结构式：
其中，R1选自H、F、Cl、C1-C6直连或支链烷基、羟基、C1-C6直连或支链烷氧基、N,N-二甲氨基乙氧基、N,N-二乙氨基乙氧基、硝基、氨基、C1-C6直连或支链烷基取代的氨基、C1-C6直连或支链烷酰氨基、C1-C6直连或支链烷基磺酰氨基、取代或未取代苯甲酰氨基、丙烯酰氨基、/> 中的任意一个或两个以上的组合；R1中的n＝1～5；
R2选自
当R1为H时，R2≠
Ra选自H、C1-C6直连或支链烷基、三氟甲基、羟基、C1-C6烷氧基、卤素(氟、氯、溴、碘)、三氟甲氧基、硝基、氨基、N,N-二甲氨基、N,N-二乙氨基、C1-C6烷酰氨基、取代或未取代苯甲酰氨基、取代或未取代噻吩甲酰氨基、丙烯酰氨基、中的任意一个或两个以上的组合，Ra中的n＝1～5；
Ra1选自H、C1-C6直连或支链烷基、C1-C6直连或支链甲酯基、C1-C6直连或支链醇羟基、取代或未取代苄基、取代或未取代呋喃甲酰基、取代或未取代噻吩甲酰基、 中的任意一个，Ra1中的n＝1～5；
所述Rb选自甲基、乙基、丙基。
2.一种2-三氟甲基-4-氨基喹唑啉类化合物，其特征在于：所述化合物选自以下化合物中的任一种：
3.一种如权利要求1～2任意一项所述的2-三氟甲基-4-氨基喹唑啉类化合物在制备抗肿瘤活性药物中的应用。
4.一种药用组合物，包括权利要求1～2任意一项所述的2-三氟甲基-4-氨基喹唑啉类化合物或其药学上可接受的盐或水合物。
5.一种药物制剂，包括权利要求1～2任意一项所述的2-三氟甲基-4-氨基喹唑啉类化合物及其药学上可接受的载体或赋形剂。
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