CN113620874B - 2-三氟甲基-4-氨基-喹啉衍生物及其用途 - Google Patents
2-三氟甲基-4-氨基-喹啉衍生物及其用途 Download PDFInfo
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- CN113620874B CN113620874B CN202110912405.2A CN202110912405A CN113620874B CN 113620874 B CN113620874 B CN 113620874B CN 202110912405 A CN202110912405 A CN 202110912405A CN 113620874 B CN113620874 B CN 113620874B
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- C07D215/38—Nitrogen atoms
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Abstract
本发明公开了一种2‑三氟甲基‑4‑氨基‑喹啉衍生物及其用途，包括具有如下通式I所示的化合物，
Description
技术领域
本发明涉及一种喹啉衍生物及其应用，特别是一种2-三氟甲基-4-氨基-喹啉衍生物及其用途。
背景技术
肿瘤是严重危害人类健康的因素之一，是目前全世界发病率和死亡率的第二大原因，抗肿瘤的治疗方法主要有手术治疗、放疗、化疗、免疫治疗等，化疗是治疗恶性肿瘤的最有效的手段之一，尽管抗肿瘤药物的研发取得了一些成功，但由于多数药物缺乏选择性而导致各种毒副作用，以及多药耐药等问题，导致现有药物远不能满足临床所需。
喹啉类生物碱，是一类在自然界广泛存在含苯并吡啶氮杂环化合物，具有多种药理和生物活性，如抗肿瘤、抗疟疾、抑菌、抗炎症、抗结核、抗惊厥、降血压、抗HIV和抗糖尿病等作用。喹啉骨架作为药物开发的优势结构被广泛应用于药物研究领域，以喹啉为母核的药物不断涌现，如抗肿瘤药物有拓扑异构酶(TOPO I)抑制剂喜树碱(Camptothecin)及其衍生物(如Topotecan、Belotecan、Irinotecan等)、抗肿瘤用的Bcr-Abl和Src酪氨酸激酶双重抑制剂波舒替尼(Bosutinib)、具有多靶点的小分子酪氨酸激酶抑制剂卡博替尼(Cabozantinib)、多靶点酪氨酸酶抑制乐伐替尼(Lenvatinib)等，抗疟药物有奎宁(Quinine，俗称金鸡纳霜)、氯喹(Chloroquine)、阿莫地喹(Amodiaquine)和甲氟喹(Mefloquine)等，抗菌药物有多药耐药结核分枝杆菌抑制剂富马酸贝达喹啉(Bedaquiline fuMarate)、喹诺酮类(4-quinolones)药物诺氟沙星(Norfloxacin)和氧氟沙星(Ofloxacin)等，结构如下：
但是由于哺乳动物的细胞质中广泛存在醛氧化酶(AOX)，这是一类高度保守的黄素蛋白酶，包括多种不同的化学结构和官能团(醛类，含氮杂环化合物，N-氧化物、硝基等)。以上2-位无取代的喹啉类药物在生物体内代谢过程中，由于AOX的氧化，易代谢为2-喹啉酮化合物，此类化合物易结晶沉淀从而引起物种特异性肾脏毒性。
因此现有的以喹啉为母核的抗肿瘤药物，容易引起物种特异性肾脏毒性，存在一定的安全风险。
发明内容
本发明的目的在于，提供一种2-三氟甲基-4-氨基-喹啉衍生物及其用途。本发明制得的化合物具有良好的抗肿瘤效果，而且安全性高，副作用小。
本发明的技术方案：2-三氟甲基-4-氨基-喹啉衍生物，包括具有如下通式I所示的化合物，
其中R1选自H、F、Cl、Br、I、C1-C6直链或支链烷基、C3-C7环烷基、取代或未取代苯基、羟基、C1-C6直链或支链烷氧基、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、苯甲酰基、取代苯甲酰基、硝基、氨基、C1-C6直链或支链烷基取代的氨基、C1-C6直链或支链烷酰氨基、C1-C6直链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、4-氨基-2-丙烯酰氨基、4-(烷基取代氨基)-2-丙烯酰氨基、 中的任意一个或者两个以上的组合；
R2选自氢、甲基、乙基、丙基、异丙基、3-羟基丙基、N,N-二甲氨基乙基、N,N-二乙氨基乙基、乙酰基、丙酰基和丙烯酰基中的任意一个；
Ar选自中的任意一个；
R3选自H、-NO2、-NH2和-N(CH3)2中的任意一个。
前述的2-三氟甲基-4-氨基-喹啉衍生物中，所述Ra和Rb均选自C1-C6直链或支链烷基、芳环取代基和芳环取代甲基中的任意一个；Rc选自C1-C6直链或支链烷基。
前述的2-三氟甲基-4-氨基-喹啉衍生物中，所述Rd选自H、C1-C6直链或支链烷基、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、中的任意一个或者两个以上的组合。
前述的2-三氟甲基-4-氨基-喹啉衍生物中，所述芳环为苯环、吡啶环、呋喃环或噻吩环。
前述的2-三氟甲基-4-氨基-喹啉衍生物中，所述化合物为下列化合物T1-T60中的任意一种：
前述的2-三氟甲基-4-氨基-喹啉衍生物的制备方法，是将苯胺或苯胺衍生物与三氟乙酰乙酸乙酯在多聚磷酸作用下反应生成2-三氟甲基-4-羟基喹啉中间体M1，M1经硝化反应得M2，将M2与三氯氧磷反应得M3，最后将M3与取代苯胺进行偶联反应，再经催化氢化反应以及烷基化反应即可得到目标产物T1-T14。将M1与三氯氧磷反应得M4，再将M4分别与取代芳胺进行偶联反应即得中间体M17-M36，再将分别进行烷基化反应即得目标化合物2-三氟甲基-4-氨基-喹啉衍生物T15-T36，再经官能团变换可得目标化合物T37-T60。
合成路线的反应方程式如下所示：
前述的制备方法中，(i)表示多聚磷酸，反应温度为110℃；(ii)表示浓硝酸、冰醋酸，反应温度为40℃；(iii)表示三氯氧磷、DMF，反应温度为100℃；(iv)表示a.苯胺衍生物，HCl/异丙醇(或NaH/DMF)；b.氢气、钯碳和甲醇；(v)表示R5X、NaH和DMF；(vi)表示H2，Pd/C，MeOH；或表示RX、K2CO3和DMF；或RX，DIPEA，DCM；或RCOOH，EDCI，DIPEA。
前述的2-三氟甲基-4-氨基-喹啉衍生物中，还包括药学上可接受的盐或水合物。
上述的2-三氟甲基-4-氨基-喹啉衍生物的用途，是用于制备抗肿瘤的活性药物。
前述的2-三氟甲基-4-氨基-喹啉衍生物的用途，是以化合物为活性成份，加入一种或多种药学上可接受的载体或赋形剂，制备成抗肿瘤的药物制剂。
与现有技术相比，由于F具有最强的电负性(4.0)和与氢原子一般大小的原子半径，电负性大、原子半径小，以及很强的C-F键，因此三氟甲基可以改善有机物的极性、偶极矩、稳定性和亲脂性。本发明鉴于喹啉类化合物的2-位是一个潜在的体内代谢位点，结合三氟甲基在药物结构中的生物活性优点，在喹啉的2-位引入三氟甲基取代，设计合成2-三氟甲基取代衍生物，加之在4-氨基上进行甲基等烷基化取代基的引入，其中F与H的原子大小相近，具有拟态效应，使得本专利合成的2-三氟甲基-4-氨基喹啉类化合物，其稳定性与脂溶性大大提高的同时，代谢能力不受影响，药物用量少，副作用小、安全性高，不会引起肾脏毒性。
经体外生物活性测试研究发现：该类化合物具有较强的抗肿瘤活性，部分衍生物体外抗肿瘤活性与阳性对照药紫杉醇活性相当，其抗肿瘤活性作用机制与已有的抗肿瘤药物不同，属于一类新的抗肿瘤活性化合物，具有十分重要的学术研究价值和应用开发前景。
具体实施方式
下面结合实施例对本发明作进一步的说明，但并不作为对本发明限制的依据。
2-三氟甲基-4-氨基-喹啉衍生物中，通式I为
实施例1：
化合物T1的合成：
(1)中间体M3a的合成：
取多聚磷酸22.0g(64.9mmol)于250mL反应瓶中，加入对甲氧基苯胺2.0g(16.2mmol)，置换氩气，于100℃搅拌下缓慢注入三氟乙酰乙酸乙酯2.4mL(16.3mmol)，注入完毕升温至110℃搅拌4h反应完全，将反应体系倒入冰水中并且迅速搅拌，可见有大量沉淀析出，抽滤，滤饼减压烘干，得化合物M1a共3.08g，收率：78％。取化合物M1a 2.00g(8.22mmol)，加入50mL冰醋酸将其溶解，置换氩气，0℃下缓慢注入浓硝酸0.75mL(9.87mmol)注入完毕，40℃搅拌11h后反应完全，反应完全可见反应体系里面有大量固体析出，抽滤，水洗至中性，干燥得到化合物M2a 1.61g，收率：67.9％。取化合物M2a300mg(1.0mmol)，加入DMF 4mL，置换氩气，缓慢注入三氯氧磷285μL(3.12mmol)，100℃搅拌2h反应完毕，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得化合物M3a共298.6mg，收率：93.5％。
(2)目标化合物T1的合成：
取化合物M3a 200mg(0.65mmol)、对甲氧基苯胺120mg(0.98mmol)于反应瓶内，注入冰醋酸3mL，置换氩气，100℃下搅拌29h反应完全，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得黄色固体状目标化合物M5，取M5 100mg(0.25mmol)，加入DMF 2mL溶解，于0℃搅拌下，加入NaH(60％分散于矿物油中)11mg(0.27mmol)，继续搅拌5min后注入碘甲烷18μL(0.28mmol)，室温搅拌至反应完全，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，即可制备得黄色固体状化合物T1，收率：84.2％。1H NMR(600MHz,CDCl3)δ8.17(d,J＝9.3Hz,1H),7.51(dd,J＝9.3,2.8Hz,1H),7.06(d,J＝2.7Hz,1H),6.88–6.80(m,2H),6.80–6.71(m,2H),3.78(s,3H),3.76(s,3H),3.42(s,3H)；13C NMR(151MHz,CDCl3)δ160.66,154.50,145.74,144.06,141.32,140.91,136.91(q,J＝36.3Hz),132.68,129.15,125.39,120.38(q,J＝276.2Hz),117.57,114.84,102.54,55.76,55.59,39.81；19F NMR(565MHz,CDCl3)δ-64.44；MS(ESI)m/z:408.1[M+H]+。
实施例2：
化合物T2的合成：
参照实施例1中T1的合成方法，以4-氟苯胺替代4-甲氧基苯胺，即可制备得红色固体状化合物T2，收率：48.4％。1H NMR(600MHz,CDCl3)δ8.19(d,J＝9.3Hz,1H),7.53(dd,J＝9.3,2.8Hz,1H),6.98(d,J＝2.7Hz,1H),6.97–6.91(m,2H),6.69–6.63(m,2H),3.76(s,3H),3.39(s,3H)；13C NMR(151MHz,CDCl3)δ161.06,157.51(d,J＝240.6Hz),144.94,144.24,143.15,141.82,136.78(q,J＝36.9Hz),132.83,129.10,125.73,120.25(q,J＝275.9Hz),116.40(d,J＝8.1Hz),116.11(d,J＝22.5Hz),102.09,55.82,39.68；19F NMR(565MHz,CDCl3)δ-64.39。
实施例3：
化合物T3的合成：
参照实施例1中T1的合成方法，以对甲苯胺替代4-甲氧基苯胺，碘乙烷替代碘甲烷，即可制备得橘红色固体状化合物T3，收率：60.0％。1H NMR(600MHz,CDCl3)δ8.16(d,J＝9.3Hz,1H),7.49(dd,J＝9.3,2.7Hz,1H),7.09–6.96(m,3H),6.61(d,J＝8.5Hz,2H),3.81(q,J＝7.1Hz,2H),3.71(s,3H),2.25(s,3H),1.31(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ160.74,145.00,144.18,143.57,136.76(q,J＝36.5Hz),132.59,130.14,130.12,129.98,125.47,119.99(q,J＝275.8Hz),116.13,102.72,55.80,47.15,20.47,13.51；19FNMR(565MHz,CDCl3)δ-64.47。
实施例4：
化合物T4的合成：
参照实施例1中T1的合成方法，以对甲苯胺替代4-甲氧基苯胺，碘丙烷替代碘甲烷，即可制备得即可制备得橘红色固体状化合物T4，收率：27.1％。1H NMR(600MHz,CDCl3)δ8.20(d,J＝9.3Hz,1H),7.54(dd,J＝9.3,2.8Hz,1H),7.08(d,J＝8.7Hz,2H),6.93(d,J＝2.7Hz,1H),6.69–6.59(m,2H),3.82(q,J＝7.1Hz,2H),3.73(s,3H),1.32(t,J＝7.1Hz,3H)；13CNMR(151MHz,CDCl3)δ160.71,144.93,144.17,144.11,142.18,136.79(q),132.60,130.13,130.00,129.97,125.41,120.34(q,J＝276.1Hz),116.15,102.83,55.72,54.65,21.49,20.45,11.20；19F NMR(565MHz,CDCl3)δ-58.35,-64.47；MS(ESI)m/z:420.1[M+H]+。
实施例5：
化合物T5的合成：
参照实施例1中T1的合成方法，以4-三氟甲氧基苯胺替代4-甲氧基苯胺，即可制备得黄色固体状化合物T5，收率：39.8％。1H NMR(600MHz,CDCl3)δ8.22(d,J＝9.3Hz,1H),7.56(dd,J＝9.3,2.8Hz,1H),7.10(d,J＝8.8Hz,2H),6.92(t,J＝4.6Hz,1H),6.66(d,J＝8.9Hz,2H),3.75(s,3H),3.40(s,3H)；13C NMR(151MHz,CDCl3)δ161.32,145.44,144.34,144.20,142.69,142.00,136.65(q,J＝36.2Hz),132.90,128.97,125.98,122.46,120.92(q,J＝255.5Hz),120.29(q,J＝276.5Hz),115.30,101.83,55.79,39.47；19F NMR(565MHz,CDCl3)δ-58.35,-64.45；MS(ESI)m/z:462.1[M+H]+。
实施例6：
化合物T6的合成：
参照实施例1中T1的合成方法，以4-三氟甲氧基苯胺替代4-甲氧基苯胺，碘乙烷替代碘甲烷即可制备得黄色固体状化合物T6，收率：75.5％。1H NMR(600MHz,DMSO-d6)δ9.69(s,1H),8.07(d,J＝9.2Hz,1H),7.74(d,J＝2.6Hz,1H),7.62(dd,J＝9.2,2.6Hz,1H),7.31(d,J＝8.4Hz,2H),7.21(dd,J＝9.5,2.6Hz,2H),3.88(s,3H)；13C NMR(151MHz,DMSO-d6)δ160.09,145.14,141.71,141.35,139.58,136.48(q,J＝34.6Hz),132.39,131.09,125.28,124.64,123.38,122.24,124.17–118.23(m),123.21–117.74(m),103.46,56.47；19F NMR(565MHz,DMSO-d6)δ-57.16,-63.20。
实施例7：
化合物T7的合成：
参照实施例1中T1的合成方法，以4-三氟甲氧基苯胺替代4-甲氧基苯胺，碘丙烷替代碘甲烷即可制备得橘黄色固体状化合物T7，收率：41.1％。1H NMR(600MHz,CDCl3)δ8.19(d,J＝9.3Hz,1H),7.53(dd,J＝9.3,2.8Hz,1H),6.98(d,J＝2.7Hz,1H),6.97–6.91(m,2H),6.69–6.63(m,2H),3.76(s,3H),3.39(s,3H)；13C NMR(151MHz,CDCl3)δ161.18,144.61,144.32,143.67,142.51,136.68(q,J＝36.9Hz),132.82,129.74,125.84,122.49,120.73(q,J＝250.8Hz),120.65(q,J＝235.5Hz),115.85,114.50,102.24,55.72,47.37,13.25；19FNMR(565MHz,CDCl3)δ-64.39；MS(ESI)m/z:476.1[M+H]+。
实施例8：
化合物T8的合成：
参照实施例1中T1的合成方法，以3,4-二氯苯胺替代4-甲氧基苯胺，即可制备得红色固体状化合物T8，收率：80.0％。1H NMR(600MHz,CDCl3)δ8.23(d,J＝9.3Hz,1H),7.58(dd,J＝9.3,2.7Hz,1H),7.22(d,J＝8.9Hz,1H),6.91(d,J＝2.7Hz,1H),6.78(s,1H),6.39(d,J＝7.4Hz,1H),3.81(s,3H),3.36(s,3H)；13C NMR(151MHz,CDCl3)δ161.58,146.03,144.38,143.20,141.99,136.61(q,J＝36.7Hz),133.42,133.02,130.89,128.90,126.08,123.58,120.14(q,J＝275.7Hz),115.41,113.88,101.55,55.98,39.36；19F NMR(565MHz,CDCl3)δ-64.39；MS(ESI)m/z:446.1[M+H]+。
实施例9：
化合物T9的合成：
参照实施例1中T1的合成方法，以4-叔丁基苯胺替代4-甲氧基苯胺，即可制备得橘红色固体状化合物T9，收率：65.6％。1H NMR(600MHz,CDCl3)δ8.17(d,J＝9.3Hz,1H),7.50(dd,J＝9.3,2.8Hz,1H),7.27(s,1H),7.00(d,J＝2.8Hz,1H),6.69(d,J＝8.8Hz,2H),3.70(s,3H),3.41(s,3H),1.28(s,9H)；13C NMR(151MHz,CDCl3)δ160.81,145.47,144.53,143.26,143.84,141.71,136.77(q,J＝36.3Hz),132.65,129.25,126.25,125.64,120.37(q,J＝275.7Hz),115.26,102.49,55.69,39.40,34.08,31.37；19F NMR(565MHz,CDCl3)δ-64.38；MS(ESI)m/z:434.1[M+H]+。
实施例10：
化合物T10的合成：
参照实施例1中T1的合成方法，以苯胺替代4-甲氧基苯胺，即可制备得褐色固体状化合物T10，收率：77.0％。1H NMR(600MHz,CDCl3)δ8.19(d,J＝9.3Hz,1H),7.52(dd,J＝9.3,2.8Hz,1H),7.23(dd,J＝8.5,7.5Hz,2H),6.98(d,J＝2.7Hz,1H),6.92(t,J＝7.4Hz,1H),6.70(d,J＝8.0Hz,2H),3.72(s,3H),3.41(s,3H)；13C NMR(151MHz,CDCl3)δ161.01,146.81,145.04,144.25,141.98,138.83–135.79(m),132.73,129.45,129.28,125.76,120.71,124.05–116.59(m),115.00,102.24,55.79,39.26；19F NMR(565MHz,CDCl3)δ-64.41。
实施例11：
化合物T11的合成：
取化合物T1 100mg(0.254mmol)于反应瓶内，加入2mL甲醇使其溶解，加入钯碳(10％)14.1mg(0.127mmol)，置换氢气，RT搅拌24h反应完全，抽滤去除钯碳，滤液减压回收溶剂，残余物经硅胶柱层析纯化，得可制备得白色固体状化合物T11，收率：65.6％。1H NMR(600MHz,CDCl3)δ7.99(d,J＝9.2Hz,1H),7.15(dd,J＝9.2,2.7Hz,1H),6.84(d,J＝9.2Hz,2H),6.69(d,J＝2.7Hz,1H),6.60(d,J＝8.9Hz,2H),4.46(s,2H),3.78(s,3H),3.73(s,3H),3.32(s,3H)；13C NMR(151MHz,CDCl3)δ159.92,152.73,141.33,138.19,136.01,134.04(q,J＝33.2Hz),133.17,132.37,130.01,122.48(q,J＝290.7Hz),119.55,115.20,113.80,99.66,55.73,55.42,37.03；19F NMR(565MHz,CDCl3)δ-66.37；MS(ESI)m/z:378.1[M+H]+。
实施例12：
化合物T12的合成：
参照实施例11中T11的合成方法，取化合物T9为原料制备得黄色固体状化合物T12，收率：51.4％。1H NMR(600MHz,CDCl3)δ8.05–7.97(m,1H),7.29(d,J＝8.6Hz,2H),7.17(dt,J＝9.2,2.2Hz,1H),6.74(d,J＝5.0Hz,1H),6.63(d,J＝5.5Hz,2H),4.47(s,2H),3.72(s,3H),3.35(d,J＝2.4Hz,3H),1.32(dd,J＝3.4,1.3Hz,9H)；13C NMR(151MHz,CDCl3)δ160.04,144.62,141.40,138.21,136.05,134.04(q,J＝32.6Hz),132.96,132.37,130.09,126.49,122.03(q,J＝277.2Hz),119.62,112.46,99.75,55.38,36.79,33.93,31.51；19FNMR(565MHz,CDCl3)δ-66.18；MS(ESI)m/z:404.0[M+H]+。
实施例13：
化合物T13的合成：
参照实施例11中T11的合成方法，取化合物T10为原料制备得褐色固体状化合物T13，收率：60.0％。1H NMR(600MHz,CDCl3)δ8.03(d,J＝9.2Hz,1H),7.28(d,J＝6.4Hz,2H),7.18(dd,J＝9.2,2.7Hz,1H),6.87(t,J＝7.3Hz,1H),6.71(dd,J＝15.6,3.2Hz,3H),4.51(s,2H),3.74(s,3H),3.38(s,3H)；13C NMR(151MHz,CDCl3)δ160.14,147.02,138.17,136.04,134.02(q,J＝32.7Hz),132.64,132.38,129.97,129.72,122.62(q,J＝275.0Hz),119.64,118.67,112.69,99.62,55.39,36.73；19F NMR(565MHz,CDCl3)δ-66.22；MS(ESI)m/z:348.1[M+H]+。
实施例14：
化合物T14的合成：
参照实施例11中T11的合成方法，即可制备得黄色固体状化合物M16，收率：90.0％；取M16 72.6mg(0.2mmol)，加入无水DMF 3mL溶解，0℃搅拌下加入NaH(60％分散于矿物油中)26.4mg(0.66mmol)，继续搅拌5min后注入碘甲烷41μL(0.66mmol)，室温搅拌至反应完全，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，即可制备得黄色固体状化合物T14，收率：84％。。1HNMR(600MHz,CDCl3)δ8.08(d,J＝9.2Hz,1H),7.31(dd,J＝9.2,2.7Hz,1H),6.85–6.77(m,3H),6.53(d,J＝6.0Hz,2H),3.76(d,J＝11.3Hz,3H),3.72(d,J＝11.4Hz,3H),3.38(s,3H),2.74(s,6H)；13C NMR(151MHz,CDCl3)δ159.46,152.42,149.53,146.30(q,J＝30.6Hz),143.22,142.37,141.57,132.30,130.41,122.12(q,J＝276.2Hz),121.88,114.93,114.71,114.14,101.21,55.66,55.45,43.36,39.76；19F NMR(565MHz,CDCl3)δ-64.95；MS(ESI)m/z:406.1[M+H]+。
实施例15：
化合物T15的合成：
(1)中间体M4a的合成：
取化合物M1a2.33 g(9.58mmol)于反应瓶内，加入DMF 10mL，置换氩气，缓慢注入三氯氧磷2.62mL(28.7mmol)，100℃搅拌3h反应完毕，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得化合物M4a共1.63g，收率：65.0％。
(2)目标化合物T15的合成：
取化合物M4a 200mg(0.765mmol)、3,4-二甲氧基苯胺117mg(0.764mmol)于反应瓶内，注入异丙醇3mL，置换氩气，注入HCl 80μL，80℃搅拌至反应完全，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得白色固体状化合物M17共174mg，收率：60.3％。取M17 100mg，加入NaH 15.6mg，注入DMF 2mL，Ar保护下，缓慢注入碘甲烷36μL,12h后反应完毕，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得黄色固体状化合物T15，收率：35.4％。1H NMR(600MHz,CDCl3)δ8.02(d,J＝9.2Hz,1H),7.29–7.24(m,3H),6.89(d,J＝2.7Hz,1H),6.81(d,J＝8.6Hz,1H),6.62(d,J＝2.5Hz,1H),6.59(dd,J＝8.5,2.6Hz,1H),3.88(s,3H),3.75(s,3H),3.52(s,3H),3.51(s,3H)；13CNMR(151MHz,CDCl3)δ157.56,153.72,149.94,146.19(q,J＝33.8Hz),146.08,144.76,143.62,131.87,124.26,122.55,122.46(q,J＝275.4Hz),115.24,111.91,107.48,105.77,103.37,56.20,56.08,55.13,43.35；19F NMR(565MHz,CDCl3)δ-67.34；MS(ESI)m/z:393.1[M+H]+。
实施例16：
化合物T16的合成：
参照实施例15中T15的合成方法，以4-甲氧基苯胺替换3,4-二甲氧基苯胺，即可制备得白色固体状化合物T16，收率：76.9％。1H NMR(600MHz,CDCl3)δ8.02(d,J＝9.2Hz,1H),7.26(d,J＝2.8Hz,1H),7.09–6.94(m,2H),6.93–6.80(m,3H),3.80(s,3H),3.50(s,6H).；13CNMR(151MHz,CDCl3)δ157.46,156.40,153.81,146.22(q,J＝33.6Hz),144.80,143.44,131.88,124.63,123.33(q,J＝274.5Hz),122.50,114.96,105.46,103.53,55.57,55.10,43.42；19FNMR(565MHz,CDCl3)δ-67.36；MS(ESI)m/z:363.1[M+H]+。
实施例17：
化合物T17的合成：
参照实施例15中T15的合成方法，以4-硝基苯胺替换3,4-二甲氧基苯胺，即可制备得黄色固体状化合物T17，收率：77.8％。1H NMR(600MHz,CDCl3)δ8.22(d,J＝9.3Hz,1H),8.13(d,J＝9.3Hz,2H),7.63(s,1H),7.52(dd,J＝9.3,2.7Hz,1H),6.93(d,J＝2.7Hz,1H),6.74–6.66(m,2H),3.79(s,3H),3.61(s,3H)；13C NMR(151MHz,CDCl3)δ160.06,152.81,151.51,146.53(q,J＝33.8Hz),145.65,139.88,132.72,127.28,125.84,124.46,121.44(q,J＝274.7Hz),115.31,113.78,100.64,55.71,40.51；19F NMR(565MHz,CDCl3)δ-67.13；MS(ESI)m/z:398.1[M+H]+。
实施例18：
化合物T18的合成：
参照实施例15中T15的合成方法，以4-吗啉基苯胺替换3,4-二甲氧基苯胺，即可制备得白色固体状化合物T18，收率：50.0％。1H NMR(600MHz,CDCl3)δ7.75(d,J＝9.1Hz,1H),7.43(d,J＝8.5Hz,2H),7.34(dd,J＝9.0,2.0Hz,1H),7.26(s,1H),7.20(s,1H),6.98(d,J＝8.5Hz,2H),6.75(s,1H),3.93(s,2H),3.92–3.86(m,4H),3.19(s,4H)；13C NMR(151MHz,CDCl3)δ155.54,155.04,149.71,144.65,137.96,133.65(q,J＝30.4Hz),128.77,127.70,123.58(q,J＝274.8Hz),121.73,118.05,116.84,109.74,103.29,66.90,55.52,49.23,38.90；19F NMR(565MHz,CDCl3)δ-62.63；MS(ESI)m/z:440.1[M+Na]+。
实施例19：
化合物T19的合成：
参照实施例15中T15的合成方法，以嘧啶-2-胺替换3,4-二甲氧基苯胺，即可制备得白色固体状化合物T19，收率：72.3％。1H NMR(600MHz,CDCl3)δ8.39(d,J＝4.4Hz,1H),8.19(d,J＝9.2Hz,1H),7.66(s,1H),7.47(dd,J＝9.2,2.3Hz,1H),6.98(d,J＝2.0Hz,1H),6.72(t,J＝4.6Hz,1H),3.83(s,3H),3.68(d,J＝30.6Hz,3H)；13C NMR(151MHz,CDCl3)δ161.93,159.57,157.98,151.26,146.19(q,J＝34.7Hz),145.48,132.37,128.13,123.87,122.09(q,J＝275.1Hz),115.98,112.09,100.87,55.61,38.52；19F NMR(565MHz,CDCl3)δ-67.04；MS(ESI)m/z:335.1[M+H]+。
实施例20：
化合物T20的合成：
参照实施例15中T15的合成方法，以5-氨基吲哚替换3,4-二甲氧基苯胺，即可制备得白色固体状化合物T20，收率：72.3％。1H NMR(600MHz,CDCl3)δ7.57(d,J＝1.8Hz,1H),7.43(d,J＝8.5Hz,1H),7.34(dd,J＝9.2,2.7Hz,1H),7.23(s,1H),7.17(d,J＝3.0Hz,1H),7.13(dd,J＝8.5,1.9Hz,1H),6.98(s,1H),6.54(d,J＝3.0Hz,1H),3.93(s,3H),3.87(s,3H),3.67(s,3H)；13C NMR(151MHz,CDCl3)δ155.63,155.35,144.68,138.01,135.44,133.51(q,J＝30.8Hz),130.14,129.51,128.70,122.87(q,J＝275.1Hz),121.60,121.12,119.42,117.89,110.82,109.98,103.36,101.27,55.52,39.50,33.11；19F NMR(565MHz,CDCl3)δ-62.59；MS(ESI)m/z:409.1[M+H]+。
实施例21：
化合物T21的合成：
(1)中间体M4b的合成：
以苯胺为原料，参照实施例1中M1a的合成方法即可制备的白色粉末状化合物M1b；再以M1b为原料，参照实施例15中M4a的合成方法即可制备的白色粉末状化合物M4b，收率：90％。
(2)化合物T21的合成：
参照实施例15中T15的合成方法，以M4b为原料，以4-甲氧基苯胺替换3,4-二甲氧基苯胺，即可制备得白色固体状化合物T21，收率：80.5％。1H NMR(600MHz,CDCl3)δ8.12(d,J＝8.4Hz,1H),7.69–7.53(m,2H),7.28–7.24(m,2H),7.06–6.95(m,2H),6.91–6.82(m,2H),3.81(s,3H),3.50(s,3H)；13C NMR(151MHz,CDCl3)δ156.63,155.28,149.01,148.50(q,J＝33.6Hz),143.45,130.48,129.71,126.28,125.37,124.75,122.98,122.68(q,J＝275.6Hz),115.01,104.76；19F NMR(565MHz,CDCl3)δ-67.72；MS(ESI)m/z:333.1[M+H]+。
实施例22：
化合物T22的合成：
参照实施例15中T15的合成方法，以M4b为原料，以苯胺替换3,4-二甲氧基苯胺，即可制备得黄色油状化合物T22，收率：80.0％。1H NMR(600MHz,CDCl3)δ8.15(d,J＝8.4Hz,1H),7.68–7.52(m,2H),7.38(s,1H),7.35–7.31(m,1H),7.28(t,J＝8.4,7.6Hz,2H),7.06(t,J＝7.4Hz,1H),6.97(d,J＝7.7Hz,2H),3.54(s,3H)；13C NMR(151MHz,CDCl3)δ155.33,149.59,149.07,148.68(q,J＝33.9Hz),130.60,130.11,129.64,126.92,125.03,124.02,123.37,122.24(q,J＝275.6Hz),121.39,107.70,42.68；19F NMR(565MHz,CDCl3)δ-67.66；MS(ESI)m/z:514.1[M+H]+。
实施例23：
化合物T23的合成：
(1)中间体M4c的合成：
以3,4-二甲氧基苯胺为原料，参照实施例1中M1a的合成方法即可制备的白色粉末状化合物M1c；再以M1c为原料，参照实施例15中M4a的合成方法即可制备的白色粉末状化合物M4c，收率：85％。
(2)化合物T23的合成：
参照实施例15中T15的合成方法，以M4c为原料，以4-甲氧基苯胺替换3,4-二甲氧基苯胺，即可制备得棕色固体状化合物T23，收率：97.7％。1H NMR(600MHz,CDCl3)δ7.41(s,1H),7.19(s,1H),6.97(d,J＝9.0Hz,2H),6.83(d,J＝8.9Hz,2H),6.79(s,1H),3.97(s,3H),3.77(s,3H),3.50(s,3H),3.46(s,3H)；13C NMR(151MHz,CDCl3)δ156.38,153.44,152.24,149.06,146.53(q,J＝33.5Hz),146.08,143.53,124.73,122.05(q,J＝275.3Hz),117.96,114.97,108.75,104.05,103.71,56.15,55.57,55.53,43.28；19F NMR(565MHz,CDCl3)δ-67.36。
实施例24：
化合物T24的合成：
(1)中间体M4d的合成：
以4-甲基苯胺为原料，参照实施例1中M1a的合成方法即可制备的白色粉末状化合物M1d；再以M1d为原料，参照实施例15中M4a的合成方法即可制备的白色粉末状化合物M4d，收率：86％。
(2)化合物T24的合成：
参照实施例15中T15的合成方法，以M4d为原料，以4-甲氧基苯胺替换3,4-二甲氧基苯胺，即可制备得黄色固体状化合物T24，收率：55.0％。1H NMR(600MHz,151MHz,CDCl3)δ8.03(d,J＝8.6Hz,1H),7.47(dd,J＝8.7,1.9Hz,1H),7.39(s,1H),7.26(s,1H),6.98(d,J＝8.9Hz,2H),6.86(d,J＝8.9Hz,2H),3.82(s,3H),3.49(s,3H),2.31(s,3H)；13C NMR(151MHz,151MHz,CDCl3)δ156.4,154.8,147.7(q,J＝33.8Hz),147.5,143.4,136.5,132.0,130.2,124.3,124.2,123.3,121.9(q,J＝275.4Hz),114.9,105.6,55.5,43.4,22.0。
实施例25：
化合物T25的合成：
(1)中间体M4e的合成：
以4-氯苯胺为原料，参照实施例1中M1a的合成方法即可制备的白色粉末状化合物M1e；再以M1e为原料，参照实施例15中M4a的合成方法即可制备的白色粉末状化合物M4e。
(2)化合物T25的合成：
参照实施例15中T15的合成方法，以M4e为原料，以4-甲氧基苯胺替换3,4-二甲氧基苯胺，即可制备得黄色固体状化合物T25，收率：64.0％。1H NMR(600MHz,CDCl3)δ8.04(d,J＝8.9Hz,1H),7.66–7.41(m,2H),7.25(s,1H),7.02–6.98(m,1H),6.90–6.87(m,2H),3.83(s,3H),3.49(s,3H)；13C NMR(151MHz,CDCl3)δ157.0,154.5,148.7(q,J＝34.0Hz),147.4,142.8,132.1,132.0,130.7,124.9,124.6,123.6,121.7(q,J＝275.5Hz),115.2,105.2,105.2,55.6,43.8。
实施例26：
化合物T26的合成：
(1)中间体M4f的合成：
以4-硝基苯胺为原料，参照实施例1中M1a的合成方法即可制备的白色粉末状化合物M1f；再以M1f为原料，参照实施例15中M4a的合成方法即可制备的白色粉末状化合物M4f，收率：79.4％。
(2)化合物T26的合成：
参照实施例15中T15的合成方法，以M4f为原料，以4-甲氧基苯胺替换3,4-二甲氧基苯胺，即可制备得黄色固体状化合物T26，收率：99.0％。1H NMR(600MHz,CDCl3)δ8.46(d,J＝2.4Hz,1H),8.32(dd,J＝9.2,2.5Hz,1H),8.16(d,J＝9.2Hz,1H),7.24(s,1H),7.11(d,J＝8.9Hz,2H),6.95(d,J＝8.9Hz,2H),3.85(s,3H),3.57(s,3H).13C NMR(151MHz,CDCl3)δ158.24,156.45,151.64,151.37(q,J＝34.7Hz),144.15,142.19,132.05,132.04,126.12,122.88,121.93(q,J＝275.8Hz),120.89,115.84,103.73,55.65,44.16.19F NMR(565MHz,CDCl3)δ-68.34。
实施例27：
化合物T27的合成：
参照实施例15中T15的合成方法，以M4f为原料，以5-氨基吲哚替换3,4-二甲氧基苯胺，即可制备得橙色固体状化合物T27，收率：92.0％。1H NMR(600MHz,CDCl3)δ8.39(d,J＝2.5Hz,1H),8.22(dd,J＝9.2,2.5Hz,1H),8.09(d,J＝9.2Hz,1H),7.39(d,J＝8.6Hz,1H),7.34(d,J＝2.1Hz,1H),7.22(s,1H),7.10(td,J＝3.8,2.2Hz,2H),6.40(dd,J＝3.1,0.8Hz,1H),3.83(s,3H),3.61(s,3H).13C NMR(151MHz,CDCl3)δ156.93,151.77,151.26(q,J＝34.1Hz),143.86,141.81,135.29,131.76,130.82,129.54,123.36,122.79,120.93,121.37(q,J＝275.5Hz).,119.13,117.34,111.34,103.08,101.39,44.78,33.13.19F NMR(565MHz,CDCl3)δ-68.32。
实施例28：
化合物T28的合成：
(1)中间体M4g的合成：
以4-氟苯胺为原料，参照实施例1中M1a的合成方法即可制备的白色粉末状化合物M1g；再以M1e为原料，参照实施例15中M4a的合成方法即可制备的白色粉末状化合物M4g，收率：88.5％。
(2)化合物T28的合成：
参照实施例15中T15的合成方法，以M4g为原料，以4-甲氧基苯胺替换3,4-二甲氧基苯胺，即可制备得黄色固体状化合物T28，收率：88.0％。1HNMR(600MHz,CDCl3)δ8.10(dd,J＝9.3,5.6Hz,1H),7.37(ddd,J＝9.3,7.7,2.8Hz,1H),7.25(s,1H),7.14(dd,J＝10.7,2.8Hz,1H),6.97(d,J＝9.0Hz,2H),6.85(d,J＝9.0Hz,2H),3.80(s,3H),3.47(s,3H)；13CNMR(151MHz,CDCl3)δ159.91(d,J＝248.2Hz),156.92,154.82(d,J＝5.0Hz),148.03(q,J＝36.2Hz),146.01,142.75,133.04(d,J＝9.8Hz),124.84,124.02(d,J＝9.9Hz),121.76(q,J＝275.4Hz),119.98(d,J＝25.0Hz),115.18,109.35(d,J＝24.8Hz),105.15,55.51,43.76；19F NMR(565MHz,CDCl3)δ-67.74,-110.73。
实施例29：
化合物T29的合成：
参照实施例15中T15的合成方法，以M4g为原料，即可制备得黄色固体状化合物T29，收率：97.8％。1H NMR(600MHz,CDCl3)δ8.10(dd,J＝9.3,5.6Hz,1H),7.39(ddd,J＝9.2,7.6,2.8Hz,1H),7.27(s,1H),7.17(dd,J＝10.7,2.8Hz,1H),6.79(d,J＝8.5Hz,1H),6.60(d,J＝2.5Hz,1H),6.55(dd,J＝8.5,2.6Hz,1H),3.88(s,3H),3.77(s,3H),3.49(s,3H)；13CNMR(151MHz,CDCl3)δ159.96(d,J＝249.1Hz),154.66(d,J＝5.9Hz),150.03,148.03(q,J＝34.7Hz),146.68,145.96,142.92,133.04(d,J＝8.8Hz),124.11(d,J＝9.8Hz),121.74(q,J＝275.5Hz),120.07(d,J＝25.9Hz),115.62,111.88,109.22(d,J＝24.7Hz),107.61,105.31,56.09,56.06,43.74；19F NMR(565MHz,CDCl3)δ-67.74,-110.47。
实施例30：
化合物T30的合成：
参照实施例15中T15的合成方法，以M4g为原料，以5-氨基吲哚替换3,4-二甲氧基苯胺，制备得黄色固体状化合物T30，收率：62.1％。1H NMR(600MHz,CDCl3)δ8.07(dd,J＝9.2,5.7Hz,1H),7.31(ddd,J＝9.2,7.6,2.8Hz,1H),7.29-7.27(m,2H),7.25(s,1H),7.15(dd,J＝11.0,2.8Hz,1H),7.08(d,J＝3.1Hz,1H),6.99(dd,J＝8.7,2.1Hz,1H),6.38(dd,J＝3.1,0.8Hz,1H),3.80(s,3H),3.53(s,3H)；13C NMR(151MHz,CDCl3)δ159.62(d,J＝248.1Hz),155.32(d,J＝5.0Hz),147.99(q,J＝34.7Hz),146.04,142.49,134.61,132.79(d,J＝8.8Hz),130.29,129.23,123.99(d,J＝9.9Hz),121.89(q,J＝275.4Hz),119.70(d,J＝26.0Hz),118.92,116.39,110.65,109.72(d,J＝24.4Hz),104.22,101.15,44.62,33.05；19F NMR(565MHz,CDCl3)δ-67.72,-111.27。
实施例31：
化合物T31的合成：
取化合物M4g 125mg(0.5mmol)、N-甲基-4-硝基苯胺76mg(0.5mmol)，加入DMF 5mL溶解完全，搅拌下加入NaH(60％分散于矿物油中)20mg(0.5mmol)，反应液于80℃反应12h，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，制备得黄色固体状化合物T31，收率：47.8％。1H NMR(600MHz,CDCl3)δ8.33(dd,J＝9.3,5.3Hz,1H),8.12(d,J＝9.3Hz,2H),7.66(s,1H),7.63(ddd,J＝9.3,7.8,2.8Hz,1H),7.35(dd,J＝9.1,2.8Hz,1H),6.70(d,J＝9.3Hz,2H),3.59(s,3H)；13C NMR(151MHz,CDCl3)δ162.11(d,J＝254.2Hz),153.05(d,J＝6.2Hz),152.65,148.69(q,J＝35.9Hz),146.61,140.41,134.11(d,J＝9.8Hz),127.10(d,J＝9.8Hz),125.90,121.16(q,J＝275.3Hz),122.09(d,J＝26.2Hz).115.40,114.26,107.09(d,J＝23.6Hz),40.88；19F NMR(565MHz,CDCl3)δ-67.47,-106.86。
实施例32：
化合物T32的合成：
参照实施例31中T31的合成方法，以2-氨基嘧啶替换N-甲基-4-硝基苯胺，制备得黄色固体状化合物T32，收率：44.8％。1H NMR(600MHz,CDCl3)δ8.35(d,J＝4.8Hz,2H),8.29(dd,J＝9.3,5.3Hz,1H),7.68(s,1H),7.57(ddd,J＝9.2,7.9,2.8Hz,1H),7.36(dd,J＝9.3,2.8Hz,1H),6.73(t,J＝4.8Hz,1H),3.65(s,3H)；13C NMR(151MHz,CDCl3)δ161.84(d,J＝252.0Hz),161.71,157.99,152.68(d,J＝5.8Hz),148.30(q,J＝34.8Hz),146.30,133.63(d,J＝8.9Hz),128.12(d,J＝9.6Hz),121.42(d,J＝27.0Hz),121.36(q,J＝275.3Hz),116.04,112.49,107.36(d,J＝23.6Hz),38.75；19F NMR(565MHz,CDCl3)δ-67.42,-108.86。
实施例33：
化合物T33的合成：
参照实施例15中T15的合成方法，以M4g为原料，以3,4,5-三甲氧基苯胺替换3,4-二甲氧基苯胺，制备得白色固体状化合物T33，收率：95.4％。1H NMR(600MHz,CDCl3)δ8.13(dd,J＝9.2,5.6Hz,1H),7.42(ddd,J＝9.2,7.6,2.8Hz,1H),7.32(s,1H),7.23(dd,J＝10.4,2.8Hz,1H),6.20(s,2H),3.84(s,3H),3.71(s,6H),3.50(s,3H)；13C NMR(151MHz,CDCl3)δ160.28(d,J＝249.4Hz),154.55(d,J＝5.0Hz),154.08,148.08(q,J＝33.6Hz),145.97,145.23,135.32,133.16(d,J＝9.0Hz),124.65(d,J＝9.9Hz),121.67(q,J＝275.5Hz),120.38(d,J＝26.1Hz),108.91(d,J＝24.7Hz),106.82,100.41,61.08,56.26,43.32；19F NMR(565MHz,CDCl3)δ-67.71,-110.03。
实施例34：
化合物T34的合成：
参照实施例15中T15的合成方法，以M4g为原料，以4-苄氧基苯胺替换3,4-二甲氧基苯胺，制备得黄色固体状化合物T34，收率：91.3％。1H NMR(600MHz,CDCl3)δ8.11(dd,J＝9.3,5.6Hz,1H),7.46–7.30(m,6H),7.26(s,1H),7.15(dd,J＝10.7,2.8Hz,1H),6.96(d,J＝9.1Hz,2H),6.93(d,J＝9.0Hz,2H),5.05(s,2H),3.47(s,3H)；13C NMR(151MHz,CDCl3)δ159.96(d,J＝248.1Hz),156.05,154.81(d,J＝5.0Hz),148.05(q,J＝33.9Hz),146.03,142.97,136.69,133.07(d,J＝9.5Hz),128.64,128.11,124.74,124.08(d,J＝9.4Hz),121.75(q,J＝275.3Hz),120.02(d,J＝26.0Hz),116.20,109.34(d,J＝24.5Hz),105.34,70.39,43.70。
实施例35：
化合物T35的合成：
参照实施例15中T15的合成方法，以M4g为原料，以3-甲氧基苯胺替换3,4-二甲氧基苯胺，制备得黄色固体状化合物T35，收率：89.1％。1H NMR(600MHz,CDCl3)δ8.16(dd,J＝9.3,5.5Hz,1H),7.44(ddd,J＝9.3,7.8,2.9Hz,1H),7.39(s,1H),7.27(dd,J＝10.3,2.8Hz,1H),7.19(t,J＝8.1Hz,1H),6.63(dd,J＝8.4,2.4Hz,1H),6.51(dd,J＝8.0,2.2Hz,1H),6.49(t,J＝2.4Hz,1H),3.74(s,3H),3.51(s,3H)；13C NMR(151MHz,CDCl3)δ160.79,160.58(d,J＝249.6Hz),154.83(d,J＝6.0Hz),150.20,148.18(q,J＝33.7Hz),146.09,133.23(d,J＝8.9Hz),130.46,125.42(d,J＝9.3Hz),121.62(q,J＝275.5Hz),120.56(d,J＝26.0Hz),113.75,108.89,108.70(d,J＝8.6Hz),108.50,107.60,55.34,42.57；19F NMR(565MHz,CDCl3)δ-67.71,-109.99。
实施例36：
化合物T36的合成：
取化合物M4g 125mg(0.5mmol)、N-甲基-4-硝基苯胺152mg(1.0mmol)，加入DMF5mL溶解完全，搅拌下加入NaH(60％分散于矿物油中)40mg(1.0mmol)，反应液于80℃反应12h，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，制备得黄色固体状化合物T36，收率：50.7％。1H NMR(600MHz,CDCl3)δ8.27(d,J＝9.2Hz,1H),8.12(d,J＝9.3Hz,2H),8.08(d,J＝9.2Hz,2H),7.68(dd,J＝9.1,2.5Hz,1H),7.63(s,1H),7.36(d,J＝2.5Hz,1H),6.93(d,J＝9.3Hz,2H),6.72(d,J＝9.3Hz,2H),3.58(s,3H),3.40(s,3H)；13C NMR(151MHz,CDCl3)δ152.82,152.54,152.27,148.33(q,J＝34.8Hz),147.11,146.89,140.84,140.37,132.92,128.75,128.68,127.94,126.92,125.82,125.63,121.28(q,J＝275.4Hz),116.70,115.17,114.98,114.43,40.94,40.67；19F NMR(565MHz,CDCl3)δ-67.40。
实施例37：
化合物T37的合成：
参照实施例11中T11的合成方法，以T17为原料，制备得白色固体状化合物T37，收率：46.5％。1H NMR(600MHz,CDCl3)δ7.98(d,J＝9.2Hz,1H),7.24(dd,J＝9.2,2.8Hz,1H),7.21(s,1H),6.93–6.85(m,3H),6.64(d,J＝8.6Hz,2H),3.50(s,3H),3.46(s,3H)；13C NMR(151MHz,CDCl3)δ157.14,153.85,146.13(q,J＝33.6Hz),144.70,143.58,141.68,131.67,125.25,123.76,122.41(q,J＝274.6Hz),122.31,116.06,104.39,103.87,55.08,43.64；19FNMR(565MHz,CDCl3)δ-67.31；MS(ESI)m/z:348.1[M+H]+。
实施例38：
化合物T38的合成：
参照实施例11中T11的合成方法，以T26为原料，制备得黄色固体状化合物T38，收率：86.9％。1H NMR(600MHz,CDCl3)δ7.95(d,J＝9.0Hz,1H),7.25(s,1H),7.08(dd,J＝9.0,2.5Hz,1H),6.91(d,J＝9.0Hz,2H),6.83(d,J＝9.0Hz,2H),6.70(d,J＝2.5Hz,1H),3.88(s,2H),3.80(s,3H),3.44(s,3H)；13C NMR(151MHz,CDCl3)δ155.77,153.10,145.03,144.88(q,J＝33.7Hz),143.71,143.09,131.88,125.56,123.05,122.11(q,J＝274.3Hz),121.70,114.76,107.23(d,J＝2.0Hz),105.22,55.51,43.04。
实施例39：
化合物T39的合成：
参照实施例11中T11的合成方法，以T27为原料，制备得黄色固体状化合物T39，收率：86.9％。1H NMR(600MHz,CDCl3)δ7.94(d,J＝8.9Hz,1H),7.29(d,J＝2.2Hz,1H),7.26–7.22(m,2H),7.08(d,J＝3.1Hz,1H),7.02(dd,J＝8.9,2.6Hz,1H),6.93(dd,J＝8.7,2.2Hz,1H),6.75(d,J＝2.5Hz,1H),6.40(dd,J＝3.1,0.8Hz,1H),3.80(s,3H),3.71(s,2H),3.52(s,3H)；13CNMR(151MHz,DMSO-d6)δ149.01,140.22(q,J＝33.7Hz),139.83,138.96,138.24,129.27,126.96,125.12,124.30,120.63,117.47(q,J＝274.7Hz),116.65,113.57,110.06,105.39,101.29,101.17,96.19,39.41,28.26；19F NMR(565MHz,CDCl3)δ-67.18。
实施例40：
化合物T40的合成：
参照实施例11中T11的合成方法，以T34为原料，制备得黄色固体状化合物T40，收率：94.5％。1H NMR(600MHz,CDCl3)δ8.69(s,1H),8.03(dd,J＝9.3,5.6Hz,1H),7.31(ddd,J＝9.3,7.6,2.9Hz,1H),7.16(s,1H),7.10(dd,J＝11.0,2.8Hz,1H),6.86(d,J＝8.8Hz,2H),6.78(d,J＝8.8Hz,2H),3.42(s,3H)；13C NMR(151MHz,CDCl3)δ159.59(d,J＝248.2Hz),154.95,154.80(d,J＝5.0Hz),147.84(q,J＝32.4Hz),145.91,141.58,132.78(d,J＝9.7Hz),125.35,123.69(d,J＝9.6Hz),121.78(q,J＝275.3Hz),119.76(d,J＝26.0Hz),116.86,109.59(d,J＝24.9Hz),104.15,43.95；19F NMR(565MHz,CDCl3)δ-67.71,-111.13(d,J＝10.4Hz)。
实施例41：
化合物T41的合成：
取化合物T37 60mg、K2CO3100mg，加入DMF 2mL使其溶解，注入碘乙烷56μL，搅拌24h，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，即可制备得白色固体状化合物T41，收率：29.0％。1HNMR(600MHz,CDCl3)δ7.97(d,J＝9.2Hz,1H),7.22(dd,J＝9.2,2.8Hz,1H),7.18(s,1H),7.00–6.93(m,2H),6.90(d,J＝2.7Hz,1H),6.63(d,J＝9.0Hz,2H),3.47(s,3H),3.45(s,3H),3.35(q,J＝7.0Hz,4H),1.15(t,J＝7.0Hz,6H)；13C NMR(151MHz,CDCl3)δ156.87,153.82,146.17(d,J＝33.4Hz),145.30,144.75,138.87,131.65,125.63,123.55,122.20,122.14(d,J＝275.3Hz),112.91,103.99,103.64,54.91,44.56,43.74,12.50；19F NMR(565MHz,CDCl3)δ-67.37。
实施例42：
化合物T42的合成：
参照实施例41中T41的合成方法，以T38为原料，以碘甲烷替换碘乙烷，即可制备得黄色固体状化合物T42，收率：81.4％。1H NMR(600MHz,CDCl3)δ7.98(d,J＝9.3Hz,1H),7.26(dd,J＝9.3,2.8Hz,1H),7.23(s,1H),6.98(d,J＝9.0Hz,2H),6.85(d,J＝9.0Hz,2H),6.53(d,J＝2.8Hz,1H),3.79(s,3H),3.48(s,3H),2.81(s,6H)；13C NMR(151MHz,CDCl3)δ155.92,152.67,148.15,144.12(q,J＝33.4Hz),143.67,142.37,131.16,124.66,124.10,122.27(q,J＝275.1Hz),118.99,114.80,105.98,103.29,55.58,43.22,40.24.19F NMR(565MHz,CDCl3)δ-67.01。
实施例43：
化合物T43的合成：
参照实施例41中T41的合成方法，以T38为原料，即可制备得黄色固体状化合物T43，收率：35.5％。1H NMR(600MHz,CDCl3)δ7.94(d,J＝9.4Hz,1H),7.19(s,1H),7.18(dd,J＝9.5,3.0Hz,1H),6.95(d,J＝9.0Hz,2H),6.82(d,J＝8.9Hz,2H),6.47(d,J＝2.9Hz,1H),3.76(s,3H),3.45(s,3H),3.18(q,J＝7.1Hz,4H),0.96(t,J＝7.1Hz,6H).13C NMR(151MHz,CDCl3)δ156.93,151.77,151.26(q,J＝34.1Hz),143.86,141.81,135.29,131.76,130.82,129.54,123.36,122.79,121.54(q,J＝275.5Hz),120.93,119.13,117.34,111.34,103.08,101.39,44.78,33.13.19F NMR(565MHz,CDCl3)δ-66.92。
实施例44：
化合物T44的合成：
参照实施例41中T41的合成方法，以T39为原料，以碘甲烷替换碘乙烷，即可制备得黄色固体状化合物T44，收率：63.8％。1H NMR(600MHz,CDCl3)δ7.96(d,J＝9.3Hz,1H),7.32(d,J＝2.1Hz,1H),7.26(d,J＝8.7Hz,1H),7.23(s,1H),7.20(dd,J＝9.3,2.9Hz,1H),7.06(d,J＝3.1Hz,1H),7.03(dd,J＝8.7,2.2Hz,1H),6.62(d,J＝2.8Hz,1H),6.38(dd,J＝3.1,0.8Hz,1H),3.79(s,3H),3.53(s,3H),2.66(s,6H)；13C NMR(151MHz,DMSO-D6)δ153.45,147.90,144.15(q,J＝33.4Hz),143.40,142.33,134.01,130.89,129.84,129.10,124.59,122.32(q,J＝273.34Hz),118.90,118.71,115.71,104.92,103.88,100.96,44.11,40.16,32.96；19F NMR(565MHz,CDCl3)δ-66.97。
实施例45：
化合物T45的合成：
取原料T37 80mg于反应瓶内，加入DCM 2mL，置换氩气，注入DIPEA 160μL、0℃下注入4-氯丁酰氯40μL，28h后反应完全，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得黄色固体状化合物T45共63mg，收率:60.5％。1H NMR(600MHz,CDCl3)δ8.04(d,J＝9.2Hz,1H),7.53(s,1H),7.46(d,J＝8.8Hz,2H),7.36(s,1H),7.30(dd,J＝9.2,2.7Hz,1H),6.94(d,J＝8.8Hz,2H),6.87(d,J＝2.6Hz,1H),3.67(t,J＝6.1Hz,2H),3.55(s,3H),3.51(s,3H),2.56(t,J＝7.1Hz,2H),2.27–2.15(m,2H)；19F NMR(565MHz,CDCl3)δ-67.22(s)。
实施例46：
化合物T46的合成：
参照实施例45中T45的合成方法，以T38为原料，以丙烯酰氯替换4-氯丁酰氯，即可制备得黄色固体状化合物T46，收率：54.6％。1HNMR(600MHz,CDCl3)δ8.05(d,J＝9.1Hz,1H),7.98(s,1H),7.81(d,J＝9.1Hz,1H),7.58(s,1H),7.23(s,1H),6.95(d,J＝8.9Hz,2H),6.81(d,J＝9.0Hz,2H),6.39(dd,J＝16.9,1.1Hz,1H),6.19(dd,J＝16.9,10.2Hz,1H),5.73(dd,J＝10.2,1.2Hz,1H),3.76(s,3H),3.44(s,3H).13C NMR(151MHz,CDCl3)δ163.06,154.92,154.69,145.77(q,J＝33.5Hz),145.00,141.75,136.44,130.57,129.71,126.18,123.58,123.32,122.31,119.96(q,J＝275.3Hz),113.89,112.30(d,J＝6.8Hz),106.20,54.46,42.04.19F NMR(565MHz,CDCl3)δ-67.56。
实施例47：
化合物T47的合成：
参照实施例45中T45的合成方法，以T38为原料，以2-呋喃甲酰氯替换4-氯丁酰氯，即可制备得黄色固体状化合物T47，收率：69.1％。1H NMR(600MHz,CDCl3)δ8.17(s,1H),8.15–8.09(m,2H),7.86(dd,J＝9.1,2.4Hz,1H),7.50(s,1H),7.27(s,1H),7.23(d,J＝3.5Hz,1H),7.06–6.97(m,2H),6.93–6.81(m,2H),6.56(dd,J＝3.5,1.7Hz,1H),3.78(s,3H),3.49(s,3H)；13C NMR(151MHz,CDCl3)δ156.38,155.94,155.42,147.56(q,J＝33.8Hz),147.42,146.31,144.41,142.95,135.49,131.44,124.20,124.12,123.71,121.85(q,J＝275.4Hz),115.68,115.03,113.74,112.75,106.51,55.52,43.41；19F NMR(565MHz,CDCl3)δ-67.53。
实施例48：
化合物T48的合成：
参照实施例45中T45的合成方法，以T38为原料，以2-噻吩甲酰氯替换4-氯丁酰氯，即可制备得黄色固体状化合物T48，收率：86.5％。1H NMR(600MHz,CDCl3)δ8.11(d,J＝9.1Hz,1H),8.06(d,J＝2.4Hz,1H),7.84(dd,J＝9.1,2.4Hz,1H),7.80(s,1H),7.59(dd,J＝3.8,1.1Hz,1H),7.56(dd,J＝5.1,1.1Hz,1H),7.26(s,1H),7.12(dd,J＝5.0,3.8Hz,1H),7.00(d,J＝8.9Hz,2H),6.86(d,J＝9.0Hz,2H),3.79(s,3H),3.49(s,3H)；13C NMR(151MHz,CDCl3)δ159.80,156.41,155.38,147.67(q,J＝34.0Hz),146.38,142.90,138.87,135.69,131.49,131.17,128.67,127.89,124.17,124.08,123.88,121.84(q,J＝275.5Hz),115.06,114.04,106.56,55.55,43.37；19F NMR(565MHz,CDCl3)δ-67.58。
实施例49：
化合物T49的合成：
参照实施例45中T45的合成方法，以T39为原料，以丙烯酰氯替换4-氯丁酰氯，即可制备得黄色固体状化合物T49，收率：63.8％。1H NMR(600MHz,DMSO-d6)δ10.29(s,1H),8.29(s,1H),7.99(d,J＝9.1Hz,1H),7.88(dd,J＝9.2,2.3Hz,1H),7.40(d,J＝8.7Hz,1H),7.34(s,1H),7.29(d,J＝3.1Hz,1H),7.17(d,J＝2.1Hz,1H),6.99(dd,J＝8.7,2.2Hz,1H),6.35(dd,J＝17.0,10.1Hz,1H),6.31(dd,J＝3.0,0.8Hz,1H),6.21(dd,J＝16.9,1.9Hz,1H),5.73(dd,J＝10.0,1.9Hz,1H),3.76(s,3H),3.50(s,3H).13C NMR(151MHz,DMSO-d6)δ163.70,156.48,146.20(q,J＝33.1Hz),145.69,142.95,137.57,134.23,132.01,130.98,130.94,128.95,127.88,124.50,121.50(q,J＝274.8Hz),118.51,114.94,113.51,111.31,106.45,100.97,79.65,44.59,33.06.19FNMR(565MHz,DMSO-d6)δ-66.00。
实施例50：
化合物T50的合成：
取化合物T37 173mg(0.5mmol)和N-Boc-L-缬氨酸108mg(0.5mmol)加入10mL反应瓶中，再加入10mL二氯甲烷溶解完全。Ar置换，用注射器加入二异丙基乙胺0.165mL(1.0mmol)，室温搅拌5min后加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)143mg(0.75mmol)，室温搅拌至反应完全。反应液加适量二氯甲烷，依次用水、饱和NaHCO3水溶液、水、稀盐酸(1M)、水各洗一次，有机层经无水MgSO4干燥后浓缩至干，所得物经硅胶柱层析纯化，得白色固体状化合物T50，收率：66.0％。1H NMR(600MHz,CDCl3)δ8.01(d,J＝9.2Hz,1H),7.43(d,J＝8.7Hz,2H),7.31(s,1H),6.87(d,J＝8.5Hz,2H),6.83(d,J＝2.4Hz,1H),5.28(d,J＝8.7Hz,1H),3.55–3.47(m,3H),3.45(s,3H),1.42(s,9H),1.25(t,J＝7.1Hz,1H),1.00(d,J＝6.7Hz,3H),0.98(d,J＝6.7Hz,2H)；19F NMR(565MHz,CDCl3)δ-67.28。
实施例51：
化合物T51的合成：
参照实施例50中T50的合成方法，以T38为原料，即可制备得黄色固体状化合物T51，收率：31.5％。1H NMR(600MHz,CDCl3)δ8.39(s,1H),8.05(d,J＝2.3Hz,1H),7.97(d,J＝8.5Hz,1H),7.49(s,1H),7.17(s,1H),6.98(d,J＝9.0Hz,2H),6.85(d,J＝8.9Hz,2H),5.20(dd,J＝8.5,2.4Hz,1H),4.02(s,1H),3.79(s,3H),3.47(s,3H),2.17(t,J＝7.6Hz,1H),1.46(s,9H),0.98(d,J＝6.5Hz,6H).13C NMR(151MHz,CDCl3)δ170.25,156.34,155.23,146.10,142.92,135.29,131.08,124.20,123.71,123.54,121.83(q,J＝275.7Hz),114.91,113.85,106.14,60.94,55.43,43.19,30.59,28.31,19.21,19.10,18.14,17.56.19F NMR(565MHz,CDCl3)δ-67.52。
实施例52：
化合物T52的合成：
参照实施例50中T50的合成方法，以T38为原料，以N-Boc-L-亮氨酸替换N-Boc-L-缬氨酸，即可制备得黄色固体状化合物T52，收率：47.1％。1H NMR(600MHz,CDCl3)δ8.59(s,1H),8.04(d,J＝2.4Hz,1H),7.99(d,J＝9.1Hz,1H),7.58(d,J＝9.0Hz,1H),7.18(s,1H),6.96(d,J＝8.9Hz,2H),6.84(d,J＝8.9Hz,2H),4.93(s,1H),4.22(s,1H),3.78(s,3H),3.45(s,3H),1.68(d,J＝21.4Hz,2H),1.54(q,J＝9.0,6.6Hz,1H),1.44(s,9H),1.00(d,J＝6.7Hz,3H),0.98(d,J＝6.7Hz,3H).13C NMR(151MHz,CDCl3)δ170.80,156.25,155.45,146.15,142.87,135.87,134.21,131.21,124.10,123.85,123.59,121.82(q,J＝275.6Hz),114.95,113.44,106.73,80.83,55.49,53.84,43.15,40.33,28.31,24.77,22.95,21.88.19FNMR(565MHz,CDCl3)δ-67.55。
实施例53：
化合物T53的合成：
参照实施例45中T45的合成方法，以T38为原料，以4硝基苯磺酰氯替换4-氯丁酰氯，即可制备得白色固体状化合物T53，收率：98.0％。1H NMR(600MHz,DMSO-d6)δ10.99(s,1H),8.37–8.25(m,2H),7.95(d,J＝8.9Hz,1H),7.84–7.67(m,2H),7.50–7.42(m,2H),7.39(s,1H),6.98–6.90(m,2H),6.87–6.81(m,2H),3.71(s,3H),3.39(s,3H)；13C NMR(151MHz,DMSO-d6)δ156.47,155.08,150.31,146.82(q,J＝33.1Hz),145.79,144.97,143.32,135.84,132.03,128.28,125.10,124.89,124.43,123.91,122.22(q,J＝275.1Hz),115.40,113.66,106.34,55.73,44.24；19F NMR(565MHz,DMSO-d6)δ-66.16。
实施例54：
化合物T54的合成：
参照实施例45中T45的合成方法，以T38为原料，以甲磺酸酐替换4-氯丁酰氯，即可制备得黄色固体状化合物T54，收率：94.7％。1H NMR(600MHz,CDCl3)δ8.06(d,J＝9.0Hz,1H),7.44(d,J＝2.4Hz,1H),7.36(dd,J＝9.0,2.5Hz,1H),7.30(s,1H),7.28(s,1H),6.99(d,J＝8.9Hz,2H),6.85(d,J＝8.9Hz,2H),3.78(s,3H),3.49(s,3H),2.67(s,3H)；13C NMR(151MHz,CDCl3)δ156.90,154.53,147.87(q,J＝34.1Hz),146.16,143.08,134.83,132.24,125.22,123.48,123.27,121.80(q,J＝275.3Hz),115.18,112.95,105.25,55.56,43.86,38.86；19F NMR(565MHz,CDCl3)δ-67.58。
实施例55：
化合物T55的合成：
参照实施例45中T45的合成方法，以T38为原料，以乙酸酐替换4-氯丁酰氯，即可制备得黄色固体状化合物T55，收率：67.9％。1H NMR(600MHz,DMSO-d6)δ10.16(s,1H),8.18(d,J＝2.2Hz,1H),7.98(d,J＝9.0Hz,1H),7.81(dd,J＝9.1,2.3Hz,1H),6.96(d,J＝9.0Hz,2H),6.85(d,J＝9.0Hz,2H),3.71(s,3H),3.43(s,3H),2.02(s,3H)；13C NMR(151MHz,DMSO-d6)δ168.99,156.04,155.48,145.98(q,J＝33.4Hz),145.37,138.17,130.93,124.48,124.32,124.13,122.37(q,J＝275.4Hz),115.29,112.42,106.93,60.22,55.67,43.70,24.54；19F NMR(565MHz,CDCl3)δ-67.56。
实施例56：
化合物T56的合成：
取化合物T40 100mg于反应瓶内，注入乙腈3mL使其溶解，置换氩气，注入1-氯-3-溴丙烷30μL，碳酸钾124mg，80℃搅拌20h后反应完全，将反应物分散于乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得化合物T56共78.3mg，收率:66.3％。1H NMR(600MHz,CDCl3)δ8.10(dd,J＝9.2,5.6Hz,1H),7.37(ddd,J＝9.3,7.7,2.9Hz,1H),7.26(s,1H),7.15(dd,J＝10.7,2.8Hz,1H),6.96(d,J＝8.9Hz,2H),6.85(d,J＝9.0Hz,2H),4.10(t,J＝5.9Hz,2H),3.75(t,J＝6.3Hz,2H),3.47(s,3H),2.27–2.20(m,2H)；13C NMR(151MHz,CDCl3)δ159.96(d,J＝248.2Hz),155.99,154.81(d,J＝6.0Hz),148.04(q,J＝33.8Hz),146.02,142.96,133.07(d,J＝9.8Hz),124.76,124.08(d,J＝9.5Hz),121.75(q,J＝275.4Hz),120.02(d,J＝26.0Hz),115.79,109.32(d,J＝24.1Hz),105.35,64.61,43.72,41.46,32.25；19F NMR(565MHz,CDCl3)δ-67.74,-110.63。
实施例57：
化合物T57的合成：
参照实施例56中T56的合成方法，以3-二甲氨基氯丙烷替换1-氯-3-溴丙烷，即可制备得黄色固体状化合物T57，收率：87.4％。1H NMR(600MHz,CDCl3)δ8.08(dd,J＝9.2,5.6Hz,1H),7.36(ddd,J＝9.3,7.8,2.8Hz,1H),7.23(s,1H),7.13(dd,J＝10.7,2.8Hz,1H),6.94(d,J＝8.9Hz,2H),6.84(d,J＝8.9Hz,2H),3.99(t,J＝6.3Hz,2H),3.45(s,3H),2.52(t,J＝7.4Hz,2H),2.30(s,6H),2.01–1.95(m,2H)；13C NMR(151MHz,CDCl3)δ159.89(d,J＝248.2Hz),156.30,154.81(d,J＝5.0Hz),148.01(q,J＝33.0Hz),146.00,142.72,133.03(d,J＝8.8Hz),124.81,124.01(d,J＝9.9Hz),121.75(q,J＝275.4Hz),119.96(d,J＝26.0Hz),115.77,109.36(d,J＝24.7Hz),105.14,66.39,56.24,45.22,43.75,27.22；19FNMR(565MHz,CDCl3)δ-67.74,-110.74。
实施例58：
化合物T58的合成：
参照实施例56中T56的合成方法，以二甲氨基氯乙烷替换1-氯-3-溴丙烷，即可制备得黄色油状化合物T58，收率：89.2％。1H NMR(600MHz,CDCl3)δ8.09(dd,J＝9.2,5.7Hz,1H),7.36(ddd,J＝9.2,7.6,2.8Hz,1H),7.24(s,1H),7.13(dd,J＝10.8,2.8Hz,1H),6.95(d,J＝8.9Hz,2H),6.87(d,J＝8.9Hz,2H),4.04(t,J＝5.7Hz,2H),3.46(s,3H),2.73(t,J＝5.7Hz,2H),2.34(s,6H)；13C NMR(151MHz,CDCl3)δ159.90(d,J＝249.2Hz),156.18,154.80(d,J＝5.0Hz),148.01(q,J＝35.2Hz),146.01,142.79,133.03(d,J＝9.7Hz),124.76,124.02(d,J＝9.8Hz),121.75(q,J＝275.2Hz),119.98(d,J＝26.0Hz),115.85,109.36(d,J＝24.1Hz),105.17,66.27,58.30,45.93,43.72；19F NMR(565MHz,CDCl3)δ-67.75,-110.72。
实施例59：
化合物T59的合成：
参照实施例56中T56的合成方法，以二乙氨基氯乙烷替换1-氯-3-溴丙烷，即可制备得黄色油状化合物T59，收率：86.9％。1H NMR(600MHz,CDCl3)δ8.09(dd,J＝9.3,5.6Hz,1H),7.36(ddd,J＝9.3,7.7,2.8Hz,1H),7.24(s,1H),7.13(dd,J＝10.8,2.8Hz,1H),6.95(d,J＝8.9Hz,2H),6.85(d,J＝9.0Hz,2H),4.03(t,J＝6.2Hz,2H),3.46(s,3H),2.87(t,J＝6.3Hz,2H),2.64(q,J＝7.1Hz,4H),1.07(t,J＝7.1Hz,6H)；13C NMR(151MHz,CDCl3)δ159.89(d,J＝248.4Hz),156.21,154.80(d,J＝5.1Hz),148.02(q,J＝33.9Hz),146.01,142.72,133.02(d,J＝9.6Hz),124.80,124.01(d,J＝9.9Hz),121.75(q,J＝275.4Hz),119.97(d,J＝25.1Hz),115.81,109.37(d,J＝24.8Hz),105.12,66.85,51.69,47.87,43.74,11.7919FNMR(565MHz,CDCl3)δ-67.75,-110.72。
实施例60：
化合物T60的合成：
参照实施例15中M17的合成方法，将3,4-二甲氧基苯胺替换为2-硝基-4-甲氧基苯胺，制备得黄色固体状化合物M37，收率：81.0％；以M37为原料，参照T11的合成方法，即可制备得M38；以M38为原料，参照实施例45中T45的合成方法，以2-氯乙酰氯替换4-氯丁酰氯，制备得M39；取原料M39样品76mg、碳酸钾93mg于反应瓶内，注入DMF 2mL，置换氩气，100℃下搅拌，4h后反应完毕，将反应物分散至乙酸乙酯和水中，萃取，有机层用水洗涤两次，无水硫酸镁干燥，减压回收溶剂，残余物经硅胶柱层析纯化，得白色固体状化合物T60共44mg，收率：45.1％。1H NMR(600MHz,CDCl3)δ8.14(d,J＝9.2Hz,1H),7.43(dd,J＝9.2,2.6Hz,1H),7.32(s,1H),6.92(d,J＝2.5Hz,1H),6.58(d,J＝2.2Hz,1H),6.44(dd,J＝8.7,2.5Hz,1H),6.38(d,J＝8.8Hz,1H)；13C NMR(151MHz,CDCl3)δ167.67,158.67,156.09,149.71,146.22(q,J＝34.0Hz),144.81,132.38,129.42,125.37,124.67,123.78(q,J＝275.6Hz),123.60,119.60,109.09,108.77,102.63,102.35,55.74,55.45,53.59；19F NMR(565MHz,CDCl3)δ-67.28；MS(ESI)m/z:404.1[M+H]+。
2-三氟甲基-4-氨基-喹啉衍生物的体外抗肿瘤活性测试：
选择4类肿瘤细胞模型来筛选目标化合物的生物活性，分别为人慢性髓系白血病细胞K562、前列腺癌细胞LNCaP、PC3以及宫颈癌细胞Hela，以阿霉素(Doxorubicin)为阳性对照。分别取上述4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T1-T60及阿霉素用DMSO溶解，并用无血清的培养基稀释成终浓度为5μmol·L–1的溶液，给药，于培养箱中继续培养24h后加入20μL 5mg/mL MTT溶液继续培养4h。弃去上清液，加入100μL DMSO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，部分目标化合物测试结果见表1。
抑制率(％)＝(对照组OD值-样品组OD值)/对照组OD值×100％。
表1部分目标化合物的肿瘤细胞抑制率
从以上2-三氟甲基-4-氨基-喹啉衍生物的体外抗肿瘤活性测试结果可知，其中部分目标化合物对人慢性髓系白血病细胞K562、前列腺癌细胞LNCaP、PC3以及宫颈癌细胞Hela均具有较好的抑制作用，其抑制率与阳性对照物紫杉醇相当，例如：T60、T51、T42；大部分目标化合物对PC3、K562肿瘤细胞抑制率均与紫杉醇持平，例如：T11、T16、T47。因此，本发明所合成的2-三氟甲基-4-氨基-喹啉衍生物具有十分重要的学术价值和和应用开发前景。
Claims (4)
1.2-三氟甲基-4-氨基-喹啉衍生物，其特征在于：所述衍生物为下列化合物中的任意一种：
2.一种药物组合物，其特征在于：包括权利要求1所述的2-三氟甲基-4-氨基-喹啉衍生物或其药学上可接受的盐。
3.根据权利要求1所述的2-三氟甲基-4-氨基-喹啉衍生物的用途，其特征在于：用于制备抗肿瘤的活性药物。
4.根据权利要求3所述的用途，其特征在于：以所述的2-三氟甲基-4-氨基-喹啉衍生物为活性成份，加入一种或多种药学上可接受的载体或赋形剂，制备成抗肿瘤的药物制剂。
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