CN114773267B - [(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物及其制备与应用 - Google Patents
[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物及其制备与应用 Download PDFInfo
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- CN114773267B CN114773267B CN202210422377.0A CN202210422377A CN114773267B CN 114773267 B CN114773267 B CN 114773267B CN 202210422377 A CN202210422377 A CN 202210422377A CN 114773267 B CN114773267 B CN 114773267B
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- trifluoromethylquinolin
- benzamide
- amino
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- benzoyl
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Abstract
本发明的[(7‑三氟甲基喹啉‑4‑基)氨基]苯甲酰胺类化合物及其制备与应用，属于医药技术领域。具体为结构通式如下(I)所示的[(7‑三氟甲基喹啉‑4‑基)氨基]苯甲酰胺类化合物、其前体药物和药物活性代谢物和药学上可接受的盐，其中R1、R2如权利要求书和说明书中所述，可以与现有药物合并或单独使用作为流感病毒抑制剂，用于治疗流感，尤其是对各种A型流感具有较好的疗效。
Description
技术领域
本发明属于医药技术领域，具体涉及一种[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物及其制备与应用，具体作为抗流感病毒药物应用。
背景技术
流感是由流感病毒引起的具有传染性的疾病。流感病毒是一种RNA病毒。根据流感病毒核蛋白(nucleoprotein,NP)和表面基质蛋白(matrix protein,MP)的抗原性不同，可将其分为以下几种类型：A、B、C和D(也称甲、乙、丙和丁)。其中，A型是历次流行流感病毒的最主要元凶。2009年爆发的甲型H1N1流感病毒和目前致死率最高的H5N1禽流感病毒均属于A型流感病毒。A型流感病毒的宿主范围广泛，在人、家禽、猪、马体内都能够分离到。因此，迫切需要高效的流感病毒抑制剂。
目前临床上最为有效的预防和治疗流感的有效手段主要是流感疫苗和抗流感药物。与抗流感药物相比，接种流感疫苗是预防流感最有效的手段，可以显著降低接种者罹患流感的风险。但是，由于流感病毒的快速变异，需要每年接种疫苗才能产生有效的保护；并且疫苗预防的有效性是建立在疫苗的病毒株与正在流行的流感病毒株一致的基础上的。如果流行的优势病毒株与疫苗的病毒株不匹配，流感就会显著高发。
虽然已有多种抗流感病毒药物上市，包括M2蛋白抑制剂：金刚烷胺(Amantadine)、金刚乙胺(Rimantidine)(Deyde V,Xu X,Bright R,et al.Surveillance of resistanceto adamantanes among influenza A(H3N2)and A(H1N1)viruses isolatedworldwide.Journal of Infectious Diseases,2007,196(2):249-257.)；神经氨酸酶(neuraminidase,NA)抑制剂：扎那米韦(Zanamivir)、奥司他韦(Oselmitevir)、帕拉米韦(Peramivir)；RNA聚合酶抑制剂：法匹拉韦(Favipiravir)(Sidwell R,Barnard D,Day C,et al.Efficacy of orally administered T-705on lethal avian influenza A(H5N1)virus infections in mice.Antimicrobial Agents&Chemotherapy,2007,51(3):845-851.；Kiso M,Takahashi K,Sakai-Tagawa Y,et al.T-705(favipiravir)activityagainst lethal H5N1 influenza A viruses.Proceedings of the National Academyof Sciences of the United States of America,2010,107(2):882-887.)。然而，针对这些药物有耐药性的病毒株所占的比例越来越大。
已上市的抗流感病毒药物的作用靶点，主要是针对位于病毒包膜层的M2蛋白和NA流感病毒亚型。然而，针对这两个靶点的药物极易产生耐药性。在流感病毒的繁殖过程中，流感病毒RNA聚合酶起着重要作用，是病毒RNA复制、转录和翻译所必须的。它包含聚合酶酸性蛋白(polymerase acid protein A,PA)、聚合酶碱性蛋白1(polymerase basic protein1,PB1)和聚合酶碱性蛋白2(polymerase basic protein 2,PB2)三个蛋白亚基，PA蛋白亚基具有聚合酶活性，发挥激酶或解旋酶作用，而PB1、PB2蛋白亚基则对病毒RNA的延伸和诱导宿主细胞凋亡有关键的作用，PBl蛋白亚基负责识别和切割宿主mRNA 5'端帽子结构引物，PB2蛋白亚基负责催化新合成RNA链的延伸反应(Hagiwarak K,Kondoh Y,Ueda A,etal.Discovery of novel antiviral agents directed against the influenza A virusnucleoprotein using photo-cross-linked chemical arrays.Biochemical andBiophysical Research Communications,2010,394(3):721-727.)。它们相互结合发挥功能，在流感病毒的转录复制全过程中发挥着必不可少的作用。位于流感病毒内层的RNA聚合酶(RNA polymerase)，较为稳定，很少发生变异。因此，该靶标成为开发广谱流感病毒抑制剂的理想靶标。一些研究表明，作用RNA聚合酶上的流感病毒抑制剂具有潜在的成药性。同时，RNA聚合酶在哺乳动物细胞中却没有同游蛋白，因此，选择性作用于RNA聚合酶的抗病毒药物，对人体无严重的毒副反应。
由于选择性作用于NP和RNA聚合酶的流感病毒抑制剂不会受到病毒变异的影响，具有稳定性。因此，新型的NP蛋白和RNA聚合酶抑制剂是开发新型流感病毒抑制剂研究的重要方向。
发明内容
本发明所解决的技术问题是，提供一种[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物及其制备与应用，具体包括如式I所示的[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物、其前体药物和药物活性代谢物，以及该化合物的立体异构体及其药学上可接受的盐，并提供了其在制备治疗与流感相关的疾病的药物中的应用。
如下式I所示的[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物、其前体药物和药物活性代谢物，以及该化合物的立体异构体及其药学上可接受的盐；
其中R1、R2可以独立地选自氢，C1-C8烷基，羟基取代的C2-C8烷基，苯基取代的C1-C4烷基，环己基，羟基取代环己基，金刚烷-1-基，苯基，C1-C4烷基取代的苯基，卤素取代的苯基，硝基取代的苯基，苄氧基苯基，C1-C4酰基取代的苯基，苄基，卤素取代的苄基，吗啉基，或1,2,3,4-四氢萘-1-基；或R1和R2与它们相连的氮原子一起组成哌啶基，吗啉基，苯基哌嗪基，C1-C6烷基取代的苯基哌基，C1-C6烷氧基取代的苯基哌嗪基，卤素取代的苯基哌嗪基，卤素取代的C1-C4烷氧基取代的苯基哌嗪基，或二苯甲基哌嗪基。
进一步，R1、R2可以独立地选自氢，甲基，乙基，丙基，异丙基，2-羟乙基，3-羟丙基，2-苯乙基，环己基，4-羟基环己基，金刚烷-1-基，苯基，2-甲基苯基，3-甲基苯基，4-氯苯基，4-溴苯基，3-硝基苯基，4-苄氧基苯基，4-乙酰基苯基，苄基，4-氟苄基，吗啉-4-基，或1,2,3,4-四氢萘-1-基；或R2和R3与它们相连的氮原子一起组成哌啶基，吗啉基，4-苯基哌嗪基，4-(2-甲基苯基)哌嗪基，4-(3-甲基苯基)哌嗪基，4-(4-甲基苯基)哌嗪基，4-(4-甲氧基苯基)哌嗪基，4-(4-乙氧基苯基)哌嗪基，4-(3-氯苯基)哌嗪基，4-(4-氯苯基)哌嗪基，4-(4-溴苯基)哌嗪基，4-(2,3-二氯苯基)哌嗪基，4-[3-(三氟甲基)苯基]哌嗪，或4-(二苯甲基)哌嗪。
更进一步地，所述[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物为如下化合物中的任一个：
N-(2-甲基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-甲基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-硝基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-氯苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-溴苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-[4-(苯甲氧基)苯基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-乙酰苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-甲基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-异丙基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-羟丙基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-环己基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-羟基环己基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(吗啉-4-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(金刚烷-1-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苄基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-氟苄基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}吗啉；
1-[3-(三氟甲基)苯基]-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(3-氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(2,3-二氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-苯基-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-溴苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-甲氧基苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(二苯甲基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
N-乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-异丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-正丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苯乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(2-羟乙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-羟丙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N,N-二乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-环己基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-羟基环己基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苯基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(2-甲苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-甲基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-硝基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-溴苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
(哌啶-1-基){3-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮；
1-苯基-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(3-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-三氟甲氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-氯苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(二苯甲基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
N-乙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-异丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-正丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(2-羟乙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-羟丙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-环己基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-羟基环己基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苄基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
(吗啉-4-基){4-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮；
1-(2-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-三氟甲氧基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(3-三氟甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-氯苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-乙氧基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪。
本发明还提供一种药物组合物，包含式I所示[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物和药学上可接受的载体或稀释剂。
该药物组合物用于制备治疗流感病毒疾病的药物。例如采用盐水的水溶液作为载体，pH值为7.4，则该药物组合物以溶液形式通过局部推注而被引入到患者的血流中。
本发明的化合物可以单独给予或依据常规的制药习惯与药学上可接受的载体或稀释剂等辅剂联合，以药物组合物的形式给予。给药途径包括经口服给予或经非胃肠道包括静脉内、肌肉内、腹膜内、皮下、直肠和局部途径给予。
所述的药物组合物中还可以包括甜味剂或矫味剂。对肌内，腹膜内，皮下和静脉内使用来说，通常制备成活性成分的无菌溶液，溶液的pH值应该作适当的调节和缓冲。对静脉内使用来说，应当控制溶质的总浓度以使制剂维持等渗。
本发明的[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物还可与已知的可用于治疗或预防流感的药剂组合使用；优选的组合包括本发明化合物和M2离子通道蛋白抑制剂、本发明化合物和神经氨酸酶抑制剂、本发明化合物和干扰素诱导剂、本发明化合物和反义寡核苷酸、以及本发明化合物和肌苷单磷酸脱氢酶抑制剂。
有关本发明的术语“给予”及其变体(例如：“给予”化合物)的意思是：将[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或该化合物的前药引入需要治疗的动物系统中。当[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或其前药与一种或多种其他活性剂组合提供时，“给予”及其变体都可以被理解为包括同时和相继引入[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或其前药以及其他药剂。通常，所述前药是[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物的官能衍生物，其在体内易于转变为所需的化合物。在本发明中，术语“给予”将包含用具体公开的[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或可能未被具体公开的化合物，但是其能在给予患者后于体内转化为特定的化合物。
当本发明的化合物被给予人类受试中，日剂量将通常由处方医师确定，剂量一般根据患者个体的年龄、体重和反应以及患者症状的严重程度而变化。在一个示例性应用中，将适宜量的化合物给予接受治疗的哺乳动物。当用于所指示的作用时，本发明的口服剂量将为约0.01mg每kg体重每天(mg/kg/天)到约100mg/kg/天，优选0.01mg/kg/天到10mg/kg/天，最优选0.1mg/kg/天到5.0mg/kg/天。对口服给药来说，组合物优选以片剂的形式被提供，其中片剂包含0.01，0.05，0.1，0.5，1.0，2.5，5.0，10.0，15.0，25.0，50.0，100和500mg的活性成分，优选1mg到100mg活性成分。对于静脉注射，在恒速输注期间，最优选的剂量为0.1mg/kg/min到10mg/kg/min。本发明的化合物或包含该化合物的药物组合物可以以每日一次的剂量给予，或者是可以将每日总剂量分为每日两次、三次或四次的剂量给予。对于经皮给药系统的形式进行的给药来说，剂量给药在整个给药方案中当然将是连续的而不是间断的。
使用本发明化合物的剂量方案将根据多种因素进行选择，包括患者的类型，种属，年龄，体重，性别和医学状况；受治状况的严重程度；给药途径；患者的肾和肝功能；以及所用的特定化合物或其盐。普通技术医师，兽医或临床医师可容易地确定和开具需要预防、抗击或阻止状况发展的有效药量。
在本发明的方法中，在此详细描述的化合物能形成活性成分，并根据给药形式即口服片剂，胶囊，酏剂，糖浆剂等而与适当选择的适宜的药学稀释剂，赋形剂或载体(在此统称为“载体”物质)混合，并符合常规的药学习惯。
本发明化合物的药学上可接受的盐类指保留了式I化合物的生物效力和性质，并与合适的非毒性有机酸或无机酸或有机碱或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐包括盐酸盐、硝酸盐、磷酸盐、硫酸盐、乙酸盐、硬脂酸盐、草酸盐、琥珀酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、葡萄糖酸盐、苯甲酸盐、烟酸盐、水杨酸盐、乙酰水杨酸盐、甲磺酸盐、苯磺酸盐、氨基磺酸盐、牛磺酸盐、甘氨酸盐、赖氨酸盐、精氨酸盐等。碱加成盐包括铵盐，碱金属盐，例如钠和钾盐，碱土金属盐，例如钙和镁盐，有机碱的盐，例如二环己胺盐等，而且，碱性含氮基团可以用这样的试剂季铵化，例如低级烷基卤化物，如甲基、乙基、丙基和丁基的氯、溴和碘化物；硫酸二烷基酯，如硫酸二甲酯、二乙酯；长链卤化物，如癸基、月桂基、肉豆蔻基和硬脂酰基的氯、溴和碘化物；芳烷基卤化物，如苄基和苯乙基的溴化物等。
本发明还提供通式I所示[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物的制备方法，包括以下步骤：
其中，R选自C1-C8烷基，卤素，硝基，苯甲氧基，乙酰基。
进一步，R选自甲基，硝基，氯，溴，苯甲氧基，乙酰基。
本发明的有益效果：
本发明提供的化合物用于抑制流感病毒，是一类作用于NP蛋白和RNA聚合酶的新型流感病毒抑制剂，与现已上市的作用于其他靶点的抗流感病毒药物相比，作用在NP蛋白和RNA聚合酶的流感病毒抑制剂具有稳定性。这类流感病毒抑制剂化合物对流感具有广泛的治疗作用。且化合物制备方法简单，收率稳定，制备的化合物能较好地治疗流感相关的疾病。
具体实施方式
以下述实施例详细叙述本发明技术方案。但是，应当明白，本发明不限于具体叙述的下述实例。
实施例1：N-(2-甲基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH01)的制备
步骤A：2-{[(3-三氟甲基苯基)氨基]亚甲基}丙二酸二乙酯的制备
于100mL的茄形瓶中加入3-三氟甲基苯胺1.70g(0.01mol)、乙氧基亚甲基丙二酸二乙酯2.20g(0.01mol)，分别在30℃、50℃、70℃、75℃反应1.0h、1.5h、1.5h、2h。反应停止后，将茄形瓶中的液体冷却至有固体析出，抽滤，得到2-{[(3-三氟甲基苯基)氨基]亚甲基}丙二酸二乙酯白色固体2.84g，收率为85.81％；m.p.:44.5–45.3℃；MS(ESI):332.0([M+H]+)。(文献(Snyder H R,Freier H E,Kovacic P,et al.Synthesis of 4-Hydroxyquinolines.VIII.Some Halogen Containing 4-AminoquinolineDerivatives1.Journal of the American Chemical Society,1947,69(2):371-374.)值：45–46℃)。
步骤B：4-羟基-7-三氟甲基喹啉-3-羧酸乙酯的制备
于250mL的三颈瓶中加入2-{[(3-三氟甲基苯基)氨基]亚甲基}丙二酸二乙酯6.60g(0.02mol)、二苯醚20mL，回流反应40min，静置析出固体。用20ml石油醚打浆，抽滤，得到4-羟基-7-三氟甲基喹啉-3-羧酸乙酯白色固体5.19g，收率为91.05％；MS(ESI):286.3([M+H]+)。
步骤C：4-羟基-7-三氟甲基喹啉-3-羧酸的制备
于250mL茄形瓶中加入4-羟基-7-三氟甲基喹啉-3-羧酸乙酯8.55g(0.03mol)，氢氧化钠12.0g(0.3mol)，5滴无水乙醇以及100mL蒸馏水，回流直至反应完全后，静置冷却，用3mol/L的盐酸调pH值至2-3，析出大量白色固体，抽滤，得到4-羟基-7-三氟甲基喹啉-3-羧酸白色固体6.88g，收率为89.28％；熔点为249.5–251.2℃；MS(ESI):255.8([M-H]-)。(文献(Snyder H R,Freier H E,Kovacic P,et al.Synthesis of 4-Hydroxyquinolines.VIII.Some Halogen Containing 4-AminoquinolineDerivatives1.Journal of the American Chemical Society,1947,69(2):371-374.)值：250℃)。
步骤D：4-羟基-7-三氟甲基喹啉的制备
于250mL的三颈瓶中加入9.80g 4-羟基-7-三氟甲基喹啉-3-羧酸和30mL二苯醚，设定加热温度为260℃。25min后，停止反应，加入30mL石油醚，搅拌10min，抽滤，得到4-羟基-7-三氟甲基喹啉棕黄色固体7.69g，收率为94.78％；m.p.:268.8–270.6℃；MS(ESI):211.9([M+H]+)。(文献(Snyder H R,Freier H E,Kovacic P,et al.Synthesis of 4-Hydroxyquinolines.VIII.Some Halogen Containing 4-AminoquinolineDerivatives1.Journal of the American Chemical Society,1947,69(2):371-374.)值：268–270℃)。
步骤E：4-氯-7-三氟甲基喹啉的制备
于100mL的茄形瓶中加入4-羟基-7-三氟甲基喹啉2.13g(0.01mol)，三氯氧磷4.60g(0.03mol)，加热至105℃反应3h。之后抽真空条件下蒸除剩余的三氯氧磷，得到黑色油状物。向反应瓶中加入饱和碳酸氢钠溶液，边加入边搅拌，抽滤，用蒸馏水洗涤一次滤饼，得黑色固体。经柱层析分离[V(乙酸乙酯):V(石油醚)＝1:10]得到4-氯-7-三氟甲基喹啉白色固体1.39g，收率为64.23％；m.p.:71.4–73.2℃。(文献(Snyder H R,Freier H E,Kovacic P,etal.Synthesis of4-Hydroxyquinolines.VIII.Some Halogen Containing 4-Aminoquinoline Derivatives1.Journal of the American Chemical Society,1947,69(2):371-374.)值：71–72℃)。
步骤F：2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酸的制备
于100mL的茄形瓶中依次加入4-氯-7-三氟甲基喹啉4.64g(0.02mol)，10mL无水乙醇，3.62g 2-氨基苯甲酸(0.024mol)，再滴加15滴浓盐酸，回流反应2h。反应结束向茄形瓶中再加入饱和碳酸氢钠溶液，直至析出固体，此时反应液为碱性，抽滤，蒸馏水洗涤三次滤饼，得到2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酸白色固体5.92g，收率为85.41％；MS(ESI):332.0([M+H]+)；1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),9.06–9.03(m,1H),8.64–8.60(m,2H),8.18(d,J＝9.0Hz,1H),8.11(d,J＝7.8Hz,1H),7.84–7.80(m,1H),7.66–7.60(m,2H),6.65(d,J＝6.9Hz,1H)。
步骤G：N-(邻甲苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH01)的制备
向100mL的茄形瓶中，依次加入2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酸0.66g(0.002mol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride，EDCI)0.41g(0.0025mol)，1-羟基苯并三唑(1-Hydroxybenzotriazole，HOBt)0.34g(0.0025mol)，三乙胺0.40g(0.004mol)以及20mL N,N-二甲基甲酰胺，室温搅拌1h后，加入含有0.0015mol甲胺的甲胺甲醇溶液与15mL N,N-二甲基甲酰胺的混合溶液，室温搅拌12h，停止反应。将反应液缓慢滴入150mL饱和碳酸氢钠溶液中，搅拌下有大量固体析出，抽滤，滤饼以蒸馏水洗涤三次，得粗产品，经柱层析[V(甲醇):V(二氯甲烷)＝1:100]分离,得到N-(邻甲苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为47.36％；m.p.:212.8–214.6℃；HRMS(ESI):422.14682([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.86–8.81(m,1H),8.42(d,J＝9.0Hz,2H),8.22–7.96(m,3H),7.75–7.70(m,2H),7.30–7.08(m,6H),2.12(s,3H)；13C NMR(101MHz,DMSO-d6)δ167.75,165.80,153.34,139.36,136.33,132.67,130.75,130.27,126.47,123.81,122.53,120.92,120.26,65.13,52.89,18.19；IR:(KBr,cm-1)υ3310.55,1678.65,1631.34,1578.47,1512.57,1447.52,1380.58,1319.83,1253.56,1158.27,1114.83,1073.98,906.35,827.03,752.18。
实施例2：N-(3-甲基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH02)的制备
参照实施例1的制备方法，得到N-(3-甲基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺淡黄色固体，收率为47.26％；m.p.:150.3–152.1℃；MS(ESI):422.2([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),10.03(s,1H),8.70(d,J＝5.4Hz,1H),8.60(s,1H),8.46–8.43(m,1H),8.18(s,1H),8.05–8.04(m,1H),7.92–7.86(m,2H),7.62–7.60(m,2H),7.40–7.31(m,2H),7.17–7.13(m,1H),6.87(d,J＝7.7Hz,1H),2.23(s,3H)；IR:(KBr,cm-1)υ3428,2924,1648,1580,1523,1453,1323,1158,1128,830,751。
实施例3：N-(3-硝基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH03)的制备
参照实施例1的制备方法，得到N-(3-硝基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为30.79％；m.p.:>300℃；MS(ESI):453.1([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.32(s,1H),8.68(s,1H),8.59–8.55(m,2H),8.22(s,1H),7.97–7.89(m,4H),7.73–7.69(m,1H),7.63(s,1H),7.58–7.54(m,1H),7.48(s,1H),6.85(s,1H).；IR:(KBr,cm-1)υ3440,2924,1654,1580,1525,1384,1324,1123,893,740。
实施例4：N-(4-氯苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH04)的制备
参照实施例1的制备方法，得到N-(4-氯苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为54.96％；m.p.:214.8–216.6℃；MS(ESI):442.09241([M+H]+)；1HNMR(400MHz,DMSO)δ10.61(s,1H),9.98(s,1H),8.61(s,1H),8.45(s,1H),8.19(s,1H),7.88–7.86(m,3H),7.66–7.63(m,3H),7.34(d,J＝8.0Hz,3H),7.07(s,1H)；13C NMR(101MHz,DMSO-d6)δ152.77,138.08,132.65,130.21,128.95,127.95,127.13,124.17,123.36,122.29,120.92,104.34；IR:(KBr,cm-1)υ3215.64,2924.76,1647.78,1577.31,1514.10,1452.23,1395.42,1320.63,1248.44,1158.49,1130.16,1075.01,920.58,900.28,822.43,748.77,683.10,508.99,474.83,434.74。
实施例5：N-(4-溴苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH05)的制备
参照实施例1的制备方法，得到N-(4-溴苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为62.22％；m.p.:212.8–214.6℃；MS(ESI):486.04251([M+H]+)；1HNMR(400MHz,DMSO-d6)δ10.61(s,1H),8.87–8.83(m,1H),8.53–8.51(m,3H),8.17(s,2H),7.92–7.90(m,1H),7.85–7.83(m,1H),7.63–7.61(m,1H),7.47–7.45(m,2H),7.333–7.31(m,2H),7.03–7.00(m,1H)；13C NMR(101MHz,DMSO-d6)δ167.02,153.34,138.60,132.62,131.83,130.33,124.30,124.00,123.36,122.63,120.69,115.95,104.03,52.90；IR:(KBr,cm-1)υ1578.14,1509.97,1449.19,1378.76,1320.35,1118.79,899.18,821.99,739.13,468.47。
实施例6：N-[4-(苯甲氧基)苯基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH06)的制备
参照实施例1的制备方法，得到N-[4-(苯甲氧基)苯基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺白色固体，收率为34.74％；m.p.:198.4–201.1℃；MS(ESI):514.2([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),10.20(s,1H),8.63(d,J＝5.3Hz,1H),8.41(d,J＝8.8Hz,1H),8.21(s,1H),7.89–7.87(m,2H),7.68–7.59(m,2H),7.51(d,J＝8.9Hz,2H),7.44–7.39(m,2H),7.38–7.36(m,2H),7.34–7.29(m,2H),7.15(d,J＝5.3Hz,1H),6.95(d,J＝9.0Hz,2H),5.06(s,2H).；IR:(KBr,cm-1)υ3432,3310,2918,1632,1578,1511,1451,1322,1246,1126,742。
实施例7：N-(4-乙酰苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH07)的制备
参照实施例1的制备方法，得到N-(4-乙酰苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺淡黄色固体，收率为35.05％；m.p.:80.9–83.1℃；MS(ESI):450.2([M+H]+)；1HNMR(400MHz,DMSO-d6)δ10.74(s,1H),9.82(s,1H),8.60–8.59(m,1H),8.49–8.46(m,1H),8.18(s,1H),7.89–7.87(m,3H),7.74–7.72(m,2H),7.68–7.64(m,1H),7.36(s,1H),7.05–7.02(m,1H),6.55(d,J＝8.7Hz,1H),6.02(s,1H),4.05(s,3H)；IR:(KBr,cm-1)υ3331,2922,2851,1663,1593,1517,1323,1251,1123,1073,832,740。
实施例8：N-甲基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH08)的制备
参照实施例1的制备方法，得到N-甲基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为64.7％；m.p.:151.8–152.9℃；HRMS(ESI):346.11533([M+H]+)；1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.77(s,1H),8.69(s,1H),8.36(d,J＝8.8Hz,1H),8.25(s,1H),7.92(d,J＝8.9Hz,1H),7.80(d,J＝7.9Hz,1H),7.71(d,J＝8.2Hz,1H),7.58–7.54(m,1H),7.34(s,1H),7.21–7.17(m,1H),2.78(s,3H)；13C NMR(101MHz,DMSO-d6)δ169.31,153.04,148.32,146.11,140.84,132.39,129.40,127.31,123.67,123.55,122.85,121.33,120.61,104.47,26.70；IR:(KBr,cm-1):υ3598.76,3063.55,2924.43,1632.85,1583.51,1523.94,1447.92,1376.60,1322.57,1254.68,1193.63,1154.73,1098.94,1072.57,895.24,873.07,829.81,738.81,682.09,586.34,513.11,473.37。
实施例9：N-异丙基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH09)的制备
参照实施例1的制备方法，得到N-异丙基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为51.4％；m.p.:212.8–214.6℃；HRMS(ESI):374.14670([M+H]+)；1HNMR(400MHz,DMSO-d6)δ10.73(s,1H),8.58(s,1H),8.41(s,1H),8.33–8.30(m,1H),8.17(s,1H),7.83(d,J＝8.0Hz,1H),7.73(d,J＝8.0Hz,1H),7.60–7.56(m,1H),7.51–7.47(m,1H),7.16–7.13(m,2H),4.01–3.98(m,1H),1.00(d,J＝6.5Hz,6H)；13C NMR(101MHz,DMSO-d6)δ167.73,152.97,148.30,146.50,140.29,132.20,129.77,127.27,125.31,123.66,123.21,122.64,121.37,121.13,104.32,41.44,22.46；IR:(KBr,cm-1):υ3309.44,2970.25,1625.48,1579.39,1521.69,1450.94,1383.20,1324.59,1256.73,1155.80,1114.21,1073.93,906.73,870.22,812.02,771.59,748.74,671.81,622.21,566.90,471.09。
实施例10：N-(3-羟丙基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH10)的制备
参照实施例1的制备方法，得到N-(3-羟丙基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为43.35％；m.p.:166.8–168.7℃；HRMS(ESI):390.13511([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.75(s,1H),8.68(d,J＝5.3Hz,1H),8.36(d,J＝8.8Hz,1H),8.25(s,1H),7.92(d,J＝8.7Hz,1H),7.80(d,J＝7.8Hz,1H),7.70(d,J＝8.2Hz,1H),7.58–7.56(m,1H),7.29(d,J＝5.3Hz,1H),7.22–7.19(m,1H),4.48(t,J＝5.1Hz,1H),3.44–3.39(m,2H),3.31–3.26(m,2H),1.65-1.58(m,2H)；13C NMR(101MHz,DMSO-d6)δ168.75,153.01,146.22,140.58,132.33,129.52,127.29,124.38,123.58,123.02,121.29,120.91,104.42,58.98,55.36,37.08,32.53。
实施例11：N-环己基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH11)的制备
参照实施例1的制备方法，得到N-环己基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺淡黄色固体，收率为43.13％；m.p.:205.3–206.3℃；HRMS(ESI):414.17816([M+H]+)；1HNMR(400MHz,DMSO-d6)δ10.85(s,1H),8.62(s,2H),8.38(d,J＝8.8Hz,1H),8.22(s,1H),7.90(d,J＝8.7Hz,1H),7.79(d,J＝7.8Hz,1H),7.64(d,J＝8.2Hz,1H),7.57–7.53(m,1H),7.22–7.17(m,2H),3.69(s,1H),1.71–1.64(m,2H),1.56–1.53(m,2H),1.25–1.18(m,4H),1.10–1.03(m,2H)；13C NMR(101MHz,DMSO-d6)δ167.60,132.19,129.87,125.34,123.79,123.17,121.41,121.08,104.11,48.64,39.84,32.50,25.60,25.16；IR:(KBr,cm-1):υ3313.95,2937.97,2860.10,1624.85,1578.64,1519.61,1450.74,1382.69,1323.34,1256.85,1156.29,1115.53,1072.49,906.93,813.25,771.49,749.15,674.53,471.70。
实施例11：N-(4-羟基环己基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH12)的制备
参照实施例1的制备方法，得到N-(4-羟基环己基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺淡黄色固体，收率为42.53％；m.p.:212.8–214.6℃；HRMS(ESI):430.17255([M+H]+)；1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.69–8.60(m,2H),8.23(s,1H),8.11(d,J＝7.8Hz,1H),7.95–7.80(m,3H),7.43(d,J＝8.7Hz,2H),7.22(d,J＝5.3Hz,1H),4.57(d,J＝4.4Hz,1H),3.81–3.66(m,2H),1.92–1.79(m,4H),1.46–1.13(m,4H)；IR:(KBr,cm-1):υ3305.10,2927.16,2858.52,2858.52,1625.49,1579.11,1522.41,1452.32,1383.78,1325.08,1257.58,1157.23,1116.19,1075.53,1047.39,906.44,873.75,813.42,749.01,677.06 625.18,567.10,510.13,473.34。
实施例13：N-(吗啉-4-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH13)的制备
参照实施例1的制备方法，得到N-(吗啉-4-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺白色固体，收率为48.60％；m.p.:232–237℃；HRMS(ESI):417.1([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.66(s,1H),8.64(d,J＝5.3Hz,1H),8.41(d,J＝8.7Hz,1H),8.23(s,1H),7.90(d,J＝8.9Hz,1H),7.70(d,J＝7.8Hz,1H),7.64(d,J＝7.5Hz,1H),7.60–7.56(m,1H),7.27–7.23(m,1H),7.11(d,J＝5.3Hz,1H),3.58(t,J＝4.6Hz,4H),2.72(t,J＝4.6Hz,4H)；IR:(KBr,cm-1):υ3208,1632,1592,1681,1530,1328,1159,1113,872,750。
实施例14：N-(金刚烷-1-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH14)的制备
参照实施例1的制备方法，得到N-(金刚烷-1-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为43.45％；m.p.:176.8–177.7℃；HRMS(ESI):466.20953([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.54(s,1H),8.44(d,J＝8.8Hz,1H),8.20(s,1H),7.88–7.83(m,2H),7.70(d,J＝7.8Hz,1H),7.53–7.52(m,2H),7.26–7.22(m,1H),6.89(s,1H),1.89(s,3H),1.79(d,J＝2.9Hz,6H),1.56–1.45(m,6H)；13C NMR(101MHz,DMSO-d6)δ167.47,131.81,130.33,129.07,124.22,123.28,120.76,104.03,51.97,40.97,36.36,29.17；IR:(KBr,cm-1):υ2908.20,2853.11,1644.70,1595.69,1578.84,1518.71,1450.83,1373.84,1327.07,1258.88,1152.15,1122.01,892.39,823.04,744.87。
实施例15：N-苄基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH15)的制备
参照实施例1的制备方法，得到N-苄基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺白色固体，收率为37.64％；m.p.:180.0–182.5℃；MS:422.14615[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.32(s,1H),8.64(s,1H),8.36(d,J＝8.8Hz,1H),8.24(s,1H),7.90-7.88(m,2H),7.66(s,1H),7.60–7.56(m,1H),7.24–7.19(m,7H),4.46–4.45(d,J＝8.8Hz,2H)；13C NMR(101MHz,DMSO-d6)δ168.64,139.42,132.50,129.98,129.67,128.66,127.53,127.20,124.91,123.77,123.41,122.67,121.57,121.18,104.34,42.98；IR:(KBr,cm-1):υ3299.58,1631.25,1579.79,1526.37,1450.33,1384.55,1324.87,1256.64,1153.17,1118.24,902.65,871.88,813.74,740.53,699.78,627.65,511.38,474.79。
实施例16：N-(4-氟苄基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH16)的制备
参照实施例1的制备方法，得到N-(4-氟苄基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺淡黄色色固体，收率为30.63％；m.p.:186–187℃；HRMS(ESI):440.1([M+H]+)；1HNMR(400MHz,DMSO-d6)δ10.65(s,1H),9.25–9.22(m,1H),8.65(d,J＝8.8Hz,1H),8.35(d,J＝8.8Hz,1H),8.24(s,1H),7.89–7.83(m,2H),7.68–7.66(m,1H),7.60–7.56(m,1H),7.26–7.23(m,3H),7.17(d,J＝5.3Hz,1H),7.01–6.97(m,2H),4.40(d,J＝5.9Hz,2H).；IR:(KBr,cm-1):υ3289,2920,2851,1631,1581,1528,1437,1328,1111,869,750。
实施例17：N-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}吗啉(ZH17)的制备
参照实施例1的制备方法，得到N-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}吗啉黄色固体，收率为67.25％；m.p.:165.7–166.6℃；HRMS(ESI):402.14145([M+H]+)；1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.64(d,J＝8.8Hz,1H),8.49(d,J＝5.4Hz,1H),8.19(s,1H),7.83–7.80(m,1H),7.58–7.54(m,1H),7.47–7.43(m,2H),7.40–7.36(m,1H),6.54(d,J＝5.4Hz,1H),3.37–3.23(m,8H)；13C NMR(101MHz,DMSO-d6)δ167.57,152.22,149.24,147.97,137.40,132.44,131.20,130.10,129.39,126.96,126.40,124.78,121.90,120.24,120.21,103.78,66.40,66.31,47.53,41.98；IR:(KBr,cm-1):υ3316.93,1607.79,1565.90,1530.94,1462.69,1377.77,1322.14,1152.73,1111.90,1071.10,1018.34,915.50,869.82,820.82,767.55,732.69,681.27,555.12,488.92,425.07。
实施例18：1-[3-(三氟甲基)苯基]-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH18)的制备
参照实施例1的制备方法，得到1-[3-(三氟甲基)苯基]-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为27.45％；m.p.:158–163℃；HRMS(ESI):544.5([M+H]+)；1H NMR(400MHz,DMSO-d6)δ:11.32(s,1H),9.03(s,1H),8.65(d,J＝6.9Hz,1H),8.45(s,1H),8.09(d,J＝8.7Hz,1H),7.74–7.69(m,1H),7.6–7.63(m,2H),7.58(d,J＝7.8Hz,1H),7.44–7.40(m,1H),7.16(d,J＝8.6Hz,1H),7.10–7.09(m,2H),6.53(d,J＝6.8Hz,1H),3.54–3.41(m,4H),3.18–3.08(m,4H)；IR:(KBr,cm-1):υ3425,2919,1615,1540,1448,1367,1321,1164,1129,945,780,741。
实施例19：1-(3-氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH19)的制备
参照实施例1的制备方法，得到1-(3-氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为25.73％；m.p.:212–219℃；HRMS(ESI):511.1([M+H]+)；1H NMR(400MHz,DMSO-d6)δ:9.14(s,1H),8.58(d,J＝8.7Hz,1H),8.51(d,J＝5.3Hz,1H),8.15(s,1H),7.76–7.74(m,1H),7.60–7.56(m,1H),7.50–7.46(m,2H),7.42–7.38(m,1H),7.18(d,J＝9.0Hz,2H),6.79(d,J＝9.0Hz,2H),6.58(d,J＝5.3Hz,1H),3.42–3.32(m,4H),2.92–2.85(m,4H)；IR:(KBr,cm-1):υ3435,2921,1622,1586,1529,1496,1435,1323,1117,1013,819,756。
实施例20：1-(2,3-二氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH20)的制备
参照实施例1的制备方法，得到1-(2,3-二氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为32.93％；m.p.:202–209℃；HRMS(ESI):545.1([M+H]+)；1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),9.11(d,J＝8.9Hz,1H),8.67(d,J＝7.0Hz,1H),8.49(s,1H),8.18(d,J＝8.9Hz,1H),7.74–7.68(m,1H),7.65–7.63(m,2H),7.57(d,J＝7.8Hz,1H),7.37–7.27(m,2H),6.98–6.95(m,1H),6.53(d,J＝6.9Hz,1H),3.56–3.45(m,4H),3.02–2.69(m,4H)；IR:(KBr,cm-1):υ3422,3060,2920,1613,1538,1448,1319,1136,1089,781,741。
实施例21：1-苯基-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH21)的制备
参照实施例1的制备方法，得到1-苯基-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为43.12％；m.p.:167–168℃；HRMS(ESI):477.2([M+H]+)；1H NMR(400MHz,DMSO-d6)δ:11.53(s,1H),9.16(d,J＝8.9Hz,1H),8.64(d,J＝7.0Hz,1H),8.50(s,1H),8.13–8.10(m,1H),7.74–7.70(m,1H),7.68–7.61(m,2H),7.61–7.57(m,1H),7.30–7.24(m,2H),7.08–7.07(m,1H),7.00–6.93(m,1H),6.88–6.85(m,1H),6.51(d,J＝7.0Hz,1H),3.62–3.50(m,2H),3.39–3.35(m,2H),3.20(s,4H)；IR:(KBr,cm-1):υ3425,3058,2921,1614,1539,1447,1319,1133,1002,827,761,741。
实施例22：1-(4-溴苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH22)的制备
参照实施例1的制备方法，得到1-(4-溴苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为33.41％；m.p.:232–235℃；HRMS(ESI):557.1([M+H]+)；1H NMR(400MHz,DMSO-d6)δ:9.13(s,1H),8.57(d,J＝8.8Hz,1H),8.51(d,J＝5.3Hz,1H),8.15(s,1H),7.76–7.74(m,1H),7.60–7.56(m,1H),7.50–7.46(m,2H),7.42–7.38(m,1H),7.30(d,J＝9.0Hz,2H),6.75(d,J＝9.1Hz,2H),6.58(d,J＝5.3Hz,1H),3.42–3.32(m,4H),2.94–2.85(m,4H)；IR:(KBr,cm-1):υ3284,2809,1626,1588,1436,1325,1233,1018,898,821,755,526。
实施例23：1-(4-甲氧基苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH23)的制备
参照实施例1的制备方法，得到1-(4-甲氧基苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪淡黄色固体，收率为52.26％；m.p.:216–217℃；HRMS(ESI):507.2([M+H]+)；1H NMR(400MHz,DMSO-d6)δ:9.14(s,1H),8.60(d,J＝8.9Hz,1H),8.51(d,J＝5.3Hz,1H),8.16(s,1H),7.77(d,J＝8.8Hz,1H),7.60–7.56(m,1H),7.50–7.46(m,2H),7.42–7.38(m,1H),6.76–6.68(m,4H),6.59(d,J＝5.3Hz,1H),3.66(s,3H),3.44–3.32(m,4H),2.75–2.68(m,4H)；IR:(KBr,cm-1):υ3420,3290,2922,1735,1623,1586,1511,1323,1250,1015,830,756。
实施例24：1-(二苯甲基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH24)的制备
参照实施例1的制备方法，得到1-(二苯甲基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪淡黄色固体，收率为31.8％；m.p.:181–186℃；HRMS(ESI):567.2([M+H]+)；1H NMR(400MHz,DMSO-d6)δ:9.03(s,2H),8.64(d,J＝6.6Hz,1H),8.42(s,1H),8.19(s,1H),7.88(s,2H),7.68(s,1H),7.61–7.56(m,3H),7.44–7.31(m,8H),6.49(s,1H),5.53(s,1H),3.46–3.37(m,8H)；IR:(KBr,cm-1):υ3422,2923,1614,1539,1453,1319,1134,1088,919,708。
实施例25：N-乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH25)的制备
参照实施例1的制备方法，得到N-乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为33.35％；m.p.:210.7–213.6℃；HRMS(ESI):360.13110([M+H]+),382.11264([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.67(d,J＝8.9Hz,1H),8.62(d,J＝5.4Hz,1H),8.58-8.55(m,1H),8.22(s,1H),7.89–7.84(m,2H),7.68–7.66(m,1H),7.55–7.53(m,2H),7.08(d,J＝5.4Hz,1H),3.32(q,J＝7.5,5.7Hz,2H),1.14(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ165.93,152.92,148.44,148.14,140.68,136.49,129.89,127.03,125.45,124.81,123.14,122.23,121.82,120.34,103.54,49.05,34.57,15.24；IR:(KBr,cm-1)υ3265.29,2973.14,2873.46,1637.10,1577.60,1538.57,1442.35,1379.33,1326.98,1255.77,1199.84,1152.59,1113.29,1078.51,899.86,866.10,826.97,682.44,586.67,478.69。
实施例26：N-异丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH26)的制备
参照实施例1的制备方法，得到N-异丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为34.32％；m.p.:242.5–245.3℃；HRMS(ESI):374.14661([M+H]+),396.12841([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.66(d,J＝8.8Hz,1H),8.61(d,J＝5.4Hz,1H),8.28(d,J＝7.7Hz,1H),8.21(s,1H),7.87–7.82(m,2H),7.68–7.66(m,1H),7.55–7.50(m,2H),7.05(d,J＝5.3Hz,1H),4.12(dq,J1＝13.4Hz,J2＝6.7Hz,1H),1.17(d,J＝6.6Hz,6H)；13C NMR(101MHz,DMSO-d6)δ165.36,152.91,148.44,148.27,140.60,136.73,129.78,127.03,125.48,124.80,123.40,122.11,120.34,120.31,103.49,41.52,22.78；IR:(KBr,cm-1)υ3237.22,2974.53,1634.40,1573.01,1537.87,1443.28,1380.93,1327.30,1253.68,1165.71,1126.49,1078.18,901.29,871.11,826.54,738.02,587.83,471.08。
实施例27：N-正丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH27)的制备
参照实施例1的制备方法，得到N-正丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为43.56％；m.p.:225.6–226.4℃；HRMS(ESI):374.14673([M+H]+),396.12827([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.65(d,J＝8.8Hz,1H),8.60(d,J＝5.5Hz,1H),8.53–8.50(m,1H),8.20(s,1H),7.87(s,1H),7.84–7.81(m,1H),7.67–7.64(m,1H),7.55–7.49(m,2H),7.06(d,J＝5.3Hz,1H),3.25-3.20(m,2H),1.58–1.49(m,2H),0.89(t,J＝7.4Hz,3H)；13C NMR(101MHz,DMSO-d6)δ166.18,152.78,148.31,148.27,140.68,136.58,129.88,126.89,125.46,124.83,123.21,122.23,121.88,120.37,120.33,103.55,41.50,22.83,11.91；IR:(KBr,cm-1)υ3295.58,2957.88,2872.53,1631.01,1549.89,1484.36,1381.56,1324.38,1154.45,1116.81,1076.22,1033.33,892.41,831.44,746.00,682.83,590.94,470.60。
实施例28：N-(2-苯乙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH28)的制备
照实施例1的制备方法，得到N-(2-苯乙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为40.05％；m.p.:200.0–202.4℃；HRMS(ESI):436.16248([M+H]+),464.25830([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.67(d,J＝8.6Hz,2H),8.63(d,J＝8.6Hz,1H),8.23(s,1H),7.89(s,1H),7.87–7.84(m,1H),7.66–7.64(m,1H),7.54(d,J＝5.8Hz,2H),7.32–7.25(m,4H),7.23–7.19(m,1H),7.09(d,J＝5.3Hz,1H),3.54–3.49(m,2H),2.87(t,J＝7.4Hz,2H)；13C NMR(101MHz,DMSO-d6)δ166.19,152.88,148.42,148.12,140.72,139.98,136.40,129.95,129.14,128.80,127.02,126.56,125.50,124.83,123.13,122.26,121.69,120.34,103.58,41.39,35.52；IR:(KBr,cm-1)υ3330.27,1637.94,1572.91,1538.21,1484.69,1381.14,1320.98,1266.72,1126.51,1076.37,895.14,860.88,827.70,804.61,740.40,696.30,635.66,570.51,475.02。
实施例29：N-(2-羟乙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH29)的制备
参照实施例1的制备方法，得到N-(2-羟乙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为36.69％；m.p.:217.8–218.6℃；HRMS(ESI):376.12595([M+H]+),398.10760([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.67(d,J＝8.9Hz,1H),8.63(d,J＝5.3Hz,1H),8.55-8.53(m,1H),8.23(s,1H),7.91(s,1H),7.85(d,J＝8.2Hz,1H),7.69(d,J＝6.6Hz,1H),7.55–7.52(m,2H),7.09(d,J＝5.4Hz,1H),4.80–4.79(m,1H),3.57–3.52(m,2H),3.41–3.36(M,2H)；13C NMR(101MHz,DMSO-d6)δ166.34,152.93,148.45,148.13,140.68,136.37,129.89,127.05,125.53,124.82,123.23,122.24,121.91,120.34,103.56,60.17,42.69；IR:(KBr,cm-1):υ3342.13,2922.86,2849.74,1634.46,1575.51,1533.88,1483.29,1379.82,1324.14,1260.13,1180.04,1158.98,1116.29,1065.70,902.04,867.67,825.29,738.29,693.16,592.43,568.52,518.27,472.21。
实施例30：N-(3-羟丙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH30)的制备
参照实施例1的制备方法，得到N-(3-羟丙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为34.56％；m.p.:197.8–198.9℃；HRMS(ESI):390.14136([M+H]+),412.12299([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.68(d,J＝8.9Hz,1H),8.63(d,J＝5.3Hz,1H),8.57(s,1H),8.24(s,1H),7.91(s,1H),7.85(d,J＝8.8Hz,1H),7.68(d,J＝6.9Hz,1H),7.56–7.52(m,2H),7.10(d,J＝5.3Hz,1H),4.57(s,1H),3.45–3.35(m,4H),1.76–1.69(m,2H)；13C NMR(101MHz,DMSO-d6)δ166.26,152.91,148.46,148.11,140.70,136.47,129.88,127.04,125.41,124.81,123.22,123.13,122.24,121.81,120.30,103.55,59.08,37.13,32.85；IR:(KBr,cm-1):υ3281.88,2929.82,2859.89,1641.29,1582.13,1535.86,1442.63,1380.65,1321.21,1254.25,1160.33,1120.40,1052.24,894.23,869.84,828.33,714.35,585.26,474.80。
实施例31：N,N-二乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH31)的制备
参照实施例1的制备方法，得到N,N-二乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为43.98％；m.p.:159.2–162.0℃；HRMS(ESI):388.16232([M+H]+),410.14383([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.63–8.60(m,2H),8.20(s,1H),7.83(dd,J1＝8.8,J2＝2.0Hz,1H),7.51–7.44(m,2H),7.31–7.30(m,1H),7.14–7.11(m,1H),7.08(d,J＝5.3Hz,1H),3.43–3.34(m,4H),1.21–1.11(s,6H)；13C NMR(101MHz,DMSO-d6)δ169.85,152.83,148.40,148.04,140.74,139.05,130.10,126.97,125.92,124.86,123.04,122.34,122.03,120.35,103.73,43.34,14.58,13.30；IR:(KBr,cm-1)υ2981.53,2940.51,1639.73,1570.96,1540.34,1439.71,1379.00,1325.06,1277.681162.35,1122.52,1075.52,901.21,864.43,824.85,767.14,738.97,701.93,683.12,629.51,584.52,468.11。
实施例32：N-环己基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH32)的制备
参照实施例1的制备方法，得到N-环己基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为28.76％；m.p.:239.8–241.6℃；HRMS(ESI):414.17804([M+H]+),436.16190([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.65(d,J＝8.8Hz,1H),8.61(d,J＝5.5Hz,1H),8.26(d,J＝7.9Hz,1H),8.21(s,1H),7.86–7.82(m,2H),7.68-7.65(m,1H),7.56–7.48(m,2H),7.05(d,J＝5.3Hz,1H),3.81–3.73(m,1H),1.81–1.73(m,4H),1.62–1.60(m,2H),1.33–1.27(m,2H),1.16–1.09(m,2H)；13C NMR(101MHz,DMSO-d6)δ165.34,152.85,148.37,148.29,140.57,136.77,129.76,126.95,125.44,124.81,123.43,122.16,120.35,120.32,103.47,48.88,32.86,25.72,25.42；IR:(KBr,cm-1)υ3346.09,2938.83,2856.10,1633.57,1572.65,1541.15,1483.91,1380.19,1322.69,1261.17,1155.97,1125.88,1077.34,892.69,858.52,828.66,807.35,747.47,682.21,624.71,550.26,467.56。
实施例33：N-(4-羟基环己基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH33)的制备
参照实施例1的制备方法，得到N-(4-羟基环己基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为34.27％；m.p.:277.8–278.6℃；HRMS(ESI):430.17273([M+H]+),452.15427([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.71(d,J＝8.7Hz,1H),8.60(d,J＝5.5Hz,1H),8.27–8.23(m,2H),7.87–7.84(m,2H),7.69–7.67(m,1H),7.57–7.50(m,2H),7.02(d,J＝5.5Hz,1H),4.58(s,1H),3.78–3.68(m,1H),3.41–3.35(m,1H),1.87–1.79(m,4H),1.43–1.33(m,2H),1.28–1.17(m,2H)；13C NMR(101MHz,DMSO-d6)δ165.49,151.96,149.06,147.29,140.28,136.70,129.84,125.80,125.05,123.78,122.43,121.98,120.61,103.30,68.80,48.48,34.70,30.74；IR:(KBr,cm-1)υ3339.15,2923.87,2854.45,1634.05,1573.69,1525.52,1484.87,1382.02,1321.33,1266.67,1126.77,1084.16,1054.42,895.74,857.56,806.39,748.32,683.00,628.06,570.44,467.97。
实施例34：N-苯基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH34)的制备
参照实施例1的制备方法，得到N-苯基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为35.57％；m.p.:237.8–239.9℃；HRMS(ESI):408.13110([M+H]+)；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.43(s,1H),8.69–8.63(m,2H),8.23(s,1H),7.99(s,1H),7.87–7.78(m,4H),7.64–7.58(m,2H),7.39–7.35(m,2H),7.16–7.10(m,2H)；13C NMR(101MHz,DMSO-d6)δ165.57,152.88,148.41,148.07,140.89,139.54,136.79,130.23,130.02,129.07,126.99,125.72,124.84,124.21,123.59,122.32,121.98,120.89,120.40,120.37,103.73；IR:(KBr,cm-1)υ3265.78,1650.13,1572.95,1532.47,1443.75,1379.37,1325.30,1266.69,1152.621114.09,1077.80,899.64,825.47,741.30,690.46,573.45,471.23。
实施例35：N-(2-甲基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH35)的制备
参照实施例1的制备方法，得到N-(2-甲基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为34.67％；m.p.:233.4–235.5℃；HRMS(ESI):422.14667([M+H]+),444.12830([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.42(s,1H),8.69–8.63(m,2H),8.23(s,1H),7.99(s,1H),7.86(d,J＝8.8Hz,1H),7.79–7.78(m,1H),7.64–7.58(m,4H),7.26–7.22(m,1H),7.16–7.15(m,1H),6.93(d,J＝7.4Hz,1H),2.32(s,3H)；13CNMR(101MHz,DMSO-d6)δ165.49,152.90,148.44,148.06,140.88,139.46,138.21,136.81,130.00,128.90,127.02,125.71,124.89,124.84,123.57,122.32,121.96,121.42,120.38,120.35,118.08,103.73,21.67；IR:(KBr,cm-1)υ3283.78,2924.96,2854.99,1650.82,1571.62,1536.10,1485.56,1378.06,1322.20,1264.91,1159.17,1113.64,1074.50,896.30,825.69,777.54,739.50,683.11,574.49,470.49。
实施例36：N-(3-甲基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH36)的制备
参照实施例1的制备方法，得到N-(3-甲基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为35.45％；m.p.:257.9–260.8℃；HRMS(ESI):422.14648([M+H]+),444.12808([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.45(s,1H),8.66(s,2H),8.22(s,1H),8.00(s,1H),7.82(s,2H),7.61(s,2H),7.36–7.18(m,5H),2.26(s,3H)；13CNMR(101MHz,DMSO-d6)δ165.38,152.94,148.50,148.01,140.93,136.82,136.38,134.21,130.78,130.03,127.09,126.49,125.63,124.92,123.47,122.34,122.00,120.33,103.78,18.39；IR:(KBr,cm-1)υ2931.20,1646.13,1577.88,1536.35,1440.95,1378.18,1324.16,1256.94,1163.811125.09,1076.64,901.98,824.81,748.41,700.83,587.14,472.05。
实施例37：N-(3-硝基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH37)的制备
参照实施例1的制备方法，得到N-(3-硝基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为35.48％；m.p.:143.4–145.3℃；HRMS(ESI):453.11597([M+H]+),475.09778([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.45(s,1H),8.81(s,1H),8.68–8.64(m,2H),8.23–8.20(m,2H),8.02–7.97(m,2H),7.86(d,J＝8.4Hz,1H),7.82(d,J＝6.8Hz,1H),7.69–7.62(m,3H),7.17(d,J＝5.2Hz,1H)；13C NMR(101MHz,DMSO-d6)δ166.10,152.89,148.37,148.03,141.05,140.74,136.00,130.57,130.21,126.99,126.71,126.21,124.85,123.68,122.34,121.96,120.44,118.71,114.89,103.80；IR:(KBr,cm-1)υ2796.90,1657.50,1577.38,1522.76,1445.43,1381.27,1328.96,1251.68,1154.50,1120.15,1078.10,1025.21,897.41,871.46,815.72,741.94,672.02,588.77,517.47,473.75。
实施例38：N-(4-溴苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH38)的制备
参照实施例1的制备方法，得到N-(4-溴苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为34.56％；m.p.:258.6–260.9℃；HRMS(ESI):486.04163([M+H]+),507.25586([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.87–8.83(m,1H),8.52(d,J＝8.7Hz,2H),8.17(s,1H),7.91(d,J＝7.6Hz 1H),7.84(d,J＝8.4Hz 1H),7.76–7.69(m,1H),7.63–7.61(m,3H),7.47–7.45(m,1H),7.33–7.31(m,1H),7.19–7.10(m,1H),7.03–6.99(m,1H)；13C NMR(101MHz,DMSO-d6)δ167.02,153.34,138.60,132.62,131.83,130.33,124.30,124.00,123.36,122.63,120.69,115.95,104.03,52.90；IR:(KBr,cm-1)υ2908.96,2851.80,1638.35,1568.56,1530.98,1376.42,1323.74,1262.51,1159.291126.35,901.39,816.55,738.15,695.28,473.84。
实施例39：(哌啶-1-基){3-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮(ZH39)的制备
参照实施例1的制备方法，得到(哌啶-1-基){3-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮黄色固体，收率为23.35％；m.p.:214.0–214.8℃；HRMS(ESI):400.16257([M+H]+),422.14398([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.65–8.62(m,2H),8.22(s,1H),7.84(d,J＝8.9Hz,1H),7.53–7.49(m,2H),7.36(s,1H),7.14(d,J＝6.4Hz,1H),7.11(d,J＝5.2Hz,1H),3.60–3.41(m,4H),1.62–1.52(s,6H)；13C NMR(101MHz,DMSO-d6)δ168.83,152.89,148.48,147.94,140.75,138.25,130.08,127.05,127.01,124.84,123.25,122.47,122.35,120.70,120.34,103.77,48.53,42.82,26.46,25.75,24.51；IR:(KBr,cm-1)υ2922.63,2855.38,1631.22,1567.23,1537.74,1441.72,1375.62,1323.39,1250.59,1162.52,1121.75,1075.34,902.33,848.26,823.98,738.26,699.08,682.11,631.80,584.21,467.40。
实施例40：1-苯基-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH40)的制备
参照实施例1的制备方法，得到1-苯基-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为29.88％；m.p.:183.7–184.9℃；HRMS(ESI):477.18906([M+H]+),499.17053([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.65–8.62(m,2H),8.22(s,1H),7.86–7.83(m,1H),7.55–7.50(m,2H),7.43(s,1H),7.26–7.22(m,3H),7.15(d,J＝5.3Hz,1H),6.98–6.96(d,J＝8.9Hz,2H),6.84-6.80(m,1H),3.77–3.57(m,4H),3.19(m,4H)；13C NMR(101MHz,DMSO-d6)δ168.98,152.93,151.20,148.48,147.86,140.85,137.54,130.15,129.45,127.08,127.03,124.84,123.49,122.78,122.38,120.99,120.38,119.86,116.38,103.91,49.00；IR:(KBr,cm-1)υ1645.24,1575.72,1539.30,1445.46,1376.35,1325.46,1270.30,1226.53,1162.05,1122.79,1076.22,1022.04,904.93,868.86,825.17,761.34,697.72,583.25,466.07。
实施例41：1-(3-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]甲酰苯基}哌嗪(ZH41)的制备
参照实施例1的制备方法，得到1-(3-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]甲酰苯基}哌嗪黄色固体，收率为34.32％；m.p.:166.5–168.0℃；HRMS(ESI):491.20493([M+H]+),513.18683([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.65–8.63(m,2H),8.22(s,1H),7.86–7.83(m,1H),7.55–7.49(m,2H),7.43(s,1H),7.25–7.22(m,1H),7.19–7.13(m,3H),7.04–6.96(m,2H),3.79–3.57(m,4H),2.87(m,4H),2.28(s,3H)；13CNMR(101MHz,DMSO-d6)δ169.02,152.84,151.29,148.38,147.94,140.83,137.68,132.40,131.31,130.13,127.03,124.87,123.73,123.45,122.79,122.36,121.02,120.39,119.59,103.86,51.96,18.01；IR:(KBr,cm-1)υ3257.41,2900.99,2854.43,1614.22,1568.10,1536.51,1438.20,1378.37,1322.821265.79,1141.81,1121.06,1070.30,1020.59,896.80,865.06,829.49,806.02,779.71763.63,746.70,721.95,685.45,558.68,462.65。
实施例42：1-(4-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH42)的制备
参照实施例1的制备方法，得到1-(4-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为33.34％；m.p.:221.3–222.1℃；HRMS(ESI):491.19805([M+H]+)；1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.65-8.62(m,2H),8.22(s,1H),7.86–7.83(m,1H),7.53–7.51(m,2H),7.42(s,1H),7.23–7.20(m,1H),7.14(d,J＝5.3Hz,1H),7.05–7.03(d,J＝8.4Hz,2H),6.86(d,J＝8.6Hz,2H),3.76–3.55(m,4H),3.12(m,4H),2.20(s,3H)；13C NMR(101MHz,DMSO-d6)δ168.96,152.92,149.13,148.47,147.86,140.84,137.55,130.14,129.88,128.77,127.07,127.02,124.85,123.47,122.77,122.37,120.98,120.37,116.70,103.90,49.54,20.51；IR:(KBr,cm-1)υ2917.36,1641.72,1574.21,1542.49,1513.89,1444.77,1377.26,1325.97,1267.85,1231.26,1162.72,1122.12,1077.11,1025.16,952.94,904.98,868.32,826.21,809.76,739.96,700.17,585.44,527.56,466.85。
实施例43：1-(4-三氟甲氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH43)的制备
参照实施例1的制备方法，得到1-(4-三氟甲氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为35.43％；m.p.:228.8–230.5℃；HRMS(ESI):561.17133([M+H]+),583.15289([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.65–8.62(m,2H),8.22(s,1H),7.86–7.83(m,1H),7.55–7.50(m,2H),7.44(s 1H),7.24–7.20(m,3H),7.14(d,J＝5.3Hz,1H),7.06–7.02(m,2H),3.77–3.57(m,4H),3.23(m,4H)；13C NMR(101MHz,DMSO-d6)δ169.00,152.91,150.26,148.47,147.86,141.31,140.86,137.48,130.15,127.06,127.02,124.84,123.53,122.77,122.35,120.99,120.37,120.34,117.16,103.89,48.78；IR:(KBr,cm-1)υ2921.72,2852.64,1643.69,1569.28,1543.18,1509.34,1443.43,1377.89,1330.051200.46,1121.90,1075.66,903.57,867.78,825.77,738.55,699.45,624.44,583.04,464.70。
实施例44：1-(4-氯苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH44)的制备
参照实施例1的制备方法，得到1-(4-氯苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为35.68％；m.p.:217.4–220.2℃；HRMS(ESI):511.15060([M+H]+)；1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.66–8.62(m,2H),8.25–8.19(m,1H),7.86–7.83(m,1H),7.55–7.49(m,2H),7.43(s,1H),7.30–7.18(m,3H),7.14(d,J＝5.3Hz,1H),6.99–6.96(m,2H),3.76–3.56(m,4H),3.20(m,4H)；13C NMR(101MHz,DMSO-d6)δ169.01,152.93,150.00,148.48,147.86,140.86,137.48,130.20,130.16,129.88,129.15,127.07,127.03,124.84,123.53,123.34,122.78,122.38,120.99,120.38,117.79,103.91,48.75；IR:(KBr,cm-1):υ1643.39,1569.08,1543.80,1496.03,1444.78,1378.16,1326.09,1276.39,1230.55,1163.88,1124.15,1077.33,1023.24,954.59,904.78,869.35,826.24,748.09,699.77639.84,584.57,467.12。
实施例45：1-(二苯甲基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH45)的制备
参照实施例1的制备方法，得到1-(二苯甲基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为37.86％；m.p.:123.5–125.4℃；HRMS(ESI):567.23529([M+H]+),589.21729([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.64(d,J＝8.8Hz,1H),8.58(d,J＝5.4Hz,1H),8.23(s,1H),7.86–7.83(m,1H),7.50–7.47(m,2H),7.43(d,J＝7.2Hz,4H),7.35(s,1H),7.32–7.28(m,4H),7.20(d,J＝7.4Hz,2H),7.18–7.15(m,1H),7.08(d,J＝5.4Hz,1H),4.35(s,1H),3.65–3.44(m,4H),2.35(m,4H)；13C NMR(101MHz,DMSO-d6)δ168.76,152.44,148.27,147.95,142.87,140.60,137.56,130.10,129.06,128.08,127.45,126.59,124.94,123.64,123.00,122.26,121.13,120.48,103.76,75.22；IR:(KBr,cm-1)υ2918.42,1568.48,1536.49,1440.47,1377.42,1321.28,1263.74,1121.84,1071.53,1028.59,996.15,901.70,869.57,825.22,740.94,703.87,577.77,534.40,466.75。
实施例46：N-乙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH46)的制备
参照实施例1的制备方法，得到N-乙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为35.54％；m.p.:262.8–264.5℃；HRMS(ESI):360.16135([M+H]+),382.11298([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.66–8.62(m,2H),8.43–8.40(m,1H),8.22(s,1H),7.92(d,J＝8.2Hz,2H),7.85–7.82(m,1H),7.44(d,J＝8.2Hz,2H),7.23(d,J＝5.3Hz,1H),3.34–3.29(m,2H),1.14(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ165.78,152.82,148.44,147.38,143.49,129.89,129.02,126.99,124.95,122.64,120.96,120.42,104.83,34.47,15.33；IR:(KBr,cm-1)υ3308.31,2977.60,2937.44,2878.02,1627.76,1582.42,1567.59,1528.22,1431.87,1376.17,1322.23,1260.29,1183.97,1161.45,1119.18,1074.00,920.21,893.54,865.65,822.68 757.59,738.75,681.32,594.89,497.60。
实施例47：N-异丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH47)的制备
参照实施例1的制备方法，得到N-异丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为36.45％；m.p.:243.7–245.9℃；HRMS(ESI):374.14688([M+H]+),396.12848([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.66(d,J＝5.3Hz,1H),8.63(d,J＝8.8Hz,1H),8.23(s,1H),8.16(d,J＝7.8Hz,1H),,7.92(d,J＝8.6Hz,2H),7.85(dd,J＝8.8,1.9Hz,1H),7.44(d,J＝8.6Hz,2H),7.23(d,J＝5.3Hz,1H),4.16–4.08(m,1H),1.18(d,J＝6.6Hz,6H)；13C NMR(101MHz,DMSO-d6)δ165.17,152.92,148.51,147.38,143.40,130.03,129.15,127.09,127.05,124.95,122.62,120.96,120.43,104.79,41.37,22.87；IR:(KBr,cm-1)υ3318.08,2924.08,2853.42,1623.32,1582.64,1527.68,1460.31,1432.30,1375.36,1322.54,1259.37,1185.73,1160.00,1119.55,1074.27,920.08,893.84,865.45,823.29,759.08 739.56,681.47,595.14,505.52,477.08。
实施例48：N-正丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH48)的制备
参照实施例1的制备方法，得到N-正丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为36.95％；m.p.:242.5–243.4℃；HRMS(ESI):374.14731([M+H]+),396.12885([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.67–8.63(m,2H),8.43–8.41(m,1H),8.24(s,1H),7.93(d,J＝8.6Hz,2H),7.85(dd,J＝9.0,2.0Hz,1H),7.46(d,J＝8.7Hz,2H),7.25(d,J＝5.3Hz,1H),3.27–3.23(m,2H),1.61–1.52(m,2H),0.92(t,J＝7.4Hz,3H)；13C NMR(101MHz,DMSO-d6)δ165.97,152.90,148.50,147.36,143.47,129.90,129.05,127.06,124.96,122.65,120.97,120.45,120.42,104.84,41.44,22.95,11.94；IR:(KBr,cm-1)υ3307.72,2965.99,2874.79,1628.12,1582.23,1527.63,1431.97,1375.85,1322.67,1260.19,1184.62,1161.30,1121.06,1074.19,919.75,893.99,864.80,822.59,757.42,738.91 681.53,593.05,478.04。
实施例49：N-(2-羟乙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH49)的制备
参照实施例1的制备方法，得到N-(2-羟乙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为42.55％；m.p.:262.5–264.1℃；HRMS(ESI):376.12628([M+H]+),398.10797([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.70–8.65(m 2H),8.44–8.40(m,1H),8.28–8.22(m,1H),8.00–7.85(m,3H),7.51–7.44(m,2H),7.27–7.23(m,1H),4.78(s,1H),3.39(d,J＝15.2Hz,4H)；13C NMR(101MHz,DMSO-d6)δ166.20,152.61,148.15,147.57,143.48,129.80,129.13,126.75,125.01,122.58,121.03,120.52,104.81,60.33,42.64；IR:(KBr,cm-1)υ3252.15,1637.11,1573.22,1534.13,1434.45,1382.06,1323.99,1265.16,1205.06,1147.49,1123.47,1079.36,1050.80,898.67,876.76,826.05,738.61,682.47,620.69,476.66。
实施例50：N-(3-羟丙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH50)的制备
参照实施例1的制备方法，得到N-(3-羟丙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为35.55％；m.p.:249.6–250.4℃；HRMS(ESI):390.14175([M+H]+),412.12338([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.65–8.63(m,2H),8.44–8.41(m,1H),8.22(s,1H),7.93(d,J＝8.6Hz,2H),7.82(d,J＝9.0Hz,1H),7.45(d,J＝8.6Hz,2H),7.23(d,J＝5.3Hz,1H),4.54(s,1H),3.52–3.49(m,2H),3.38–3.34(m,2H),1.75–1.69(m,2H)；13C NMR(101MHz,DMSO-d6)δ166.13,152.73,148.37,147.42,143.53,129.82,129.04,126.91,124.97,122.63,120.98,120.42,120.39,104.82,59.12,37.04,32.97；IR:(KBr,cm-1)υ3286.63,2941.49,2866.79,1627.10,1533.89,1433.70,1382.91,1326.38,1262.75,1192.02,1155.06,1121.22,1080.00,1048.33,923.23,901.69,866.32,822.06,759.56,681.81 622.15,476.95。
实施例51：N-环己基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH51)的制备
参照实施例1的制备方法，得到N-环己基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为33.45％；m.p.:236.5–237.3℃；HRMS(ESI):414.17871([M+H]+),436.16028([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.66–8.62(m,2H),8.23(s,1H),8.14(d,J＝7.9Hz,1H),7.91(d,J＝8.8Hz,2H),7.86–7.83(m,1H),7.43(d,J＝8.6Hz,2H),7.22(d,J＝5.3Hz,1H),3.80–3.76(m 1H),1.82–1.60(m,6H),1.38–1.13(m,4H)；13CNMR(101MHz,DMSO-d6)δ165.14,152.88,148.45,147.43,143.37,130.08,129.19,127.00,124.97,122.60,120.99,120.47,104.76,48.75,32.97,25.76,25.46；IR:(KBr,cm-1)υ3219.24,2934.11,2856.95,1633.01,1582.49,1530.64,1379.21,1323.67,1260.81,1158.83,1125.73,1072.30,919.35,892.37,863.93,816.92,739.71,683.61,568.21,481.12。
实施例52：N-(4-羟基环己基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH52)的制备
参照实施例1的制备方法，得到N-(4-羟基环己基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为25.89％；m.p.:324.0–325.0℃；HRMS(ESI):430.17301([M+H]+)；1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.66–8.62(m,2H),8.23(s,1H),8.11(d,J＝7.8Hz,1H),7.90(d,J＝8.4Hz,2H),7.86–7.83(m,1H),7.43(d,J＝8.7Hz,2H),7.22(d,J＝5.3Hz,1H),4.57(d,J＝4.4Hz,1H),3.78–3.69(m,1H),3.33(s,1H),1.88–1.81(m,4H),1.43–1.21(m,4H)；13C NMR(101MHz,DMSO-d6)δ165.35,152.92,148.52,147.39,143.44,129.97,129.18,127.08,124.98,122.63,120.96,120.46,104.82,68.84,48.34,34.76,30.85；IR:(KBr,cm-1)υ3260.93,2934.68,1642.46,1530.00,1430.77,1379.65,1320.12,1261.47,1180.96,1152.52,1129.93,1081.83,1051.36,892.99,837.04,757.96,685.43,627.19,476.94。
实施例53：N-苄基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺(ZH53)的制备
参照实施例1的制备方法，得到N-苄基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺黄色固体，收率为26.45％；m.p.:263.4–265.8℃；HRMS(ESI):422.14749([M+H]+),444.12921([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.06–9.03(m,1H),8.67–8.64(m,2H),8.25(s,1H),8.02(d,J＝8.3Hz,2H),7.83(d,J＝8.8Hz,1H),7.47(d,J＝8.4Hz,2H),7.37–7.31(m,4H),7.27–7.22(m,2H),4.54(d,J＝5.9Hz,2H)；13C NMR(101MHz,DMSO-d6)δ166.14,152.78,148.48,147.31,143.83,140.31,129.44,129.23,128.69,127.67,127.12,124.95,122.70,120.91,120.40,104.95,43.11；IR:(KBr,cm-1):υ3301.70,3031.23,2871.88,1625.87,1581.37,1525.59,1431.34,1376.87,1321.75,1260.57,1190.03,1155.01,1126.26,1074.94,921.01,895.44,867.80,821.80,751.76,694.17579.52,524.41,501.98,480.82。
实施例54：(吗啉-4-基){4-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮(ZH54)的制备
参照实施例1的制备方法，得到(吗啉-4-基){4-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮黄色固体，收率为35.75％；m.p.:277.9–278.7℃；HRMS(ESI):402.14197([M+H]+),424.12341([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.65–8.62(m,2H),8.23(s,1H),7.85(dd,J＝8.9,2.0Hz,1H),7.50–7.43(m,4H),7.23(d,J＝5.3Hz,1H),3.63(m,4H),3.54(m,4H)；13C NMR(101MHz,DMSO-d6)δ169.28,152.85,148.42,147.56,142.20,130.69,130.24,129.93,129.25,126.98,124.95,122.56,121.48,120.46,120.42,104.57,66.60；IR:(KBr,cm-1):υ3300.39,1605.07,1579.94,1525.28,1460.28,1423.13,1375.23,1320.29,1253.57,1130.02,1074.49,1009.77,914.69,868.78,831.15,775.83,754.96,737.03,684.25,551.59 475.16。
实施例55：1-(2-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH55)的制备
参照实施例1的制备方法，得到1-(2-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为35.49％；m.p.:194.7–195.6℃；HRMS(ESI):491.20551([M+H]+)；1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.66–8.63(m,2H),8.23(s,1H),7.85(dd,J＝8.9,1.9Hz,1H),7.56–7.41(m,4H),7.25(d,J＝5.3Hz,1H),7.05(d,J＝8.3Hz,2H),6.88(d,J＝8.6Hz,2H),3.68(m,4H),3.13(m,4H),2.21(s,3H)；13C NMR(101MHz,DMSO-d6)δ169.21,152.90,149.17,148.50,147.50,142.21,130.91,129.89,129.23,128.76,127.03,124.94,122.57,121.46,120.43,116.70,104.58,49.59,20.52；IR:(KBr,cm-1)υ3161.73,2920.05,2861.80,1624.33,1578.97,1516.33,1427.86,1378.74,1326.49,1236.32,1180.42,1165.03,1124.18,1077.07,1010.84,920.53,905.17,871.23,826.91,749.08 682.76,568.47,475.57。
实施例56：1-(4-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨甲酰基]苯基}哌嗪(ZH56)的制备
参照实施例1的制备方法，得到1-(4-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨甲酰基]苯基}哌嗪黄色固体，收率为52.35％；m.p.:192.0–193.8℃；HRMS(ESI):491.20471([M+H]+),513.18652([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.66–8.63(m,2H),8.23(s,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.56–7.43(m,4H),7.25(d,J＝5.3Hz,1H),7.05(d,J＝8.1Hz,2H),6.88(d,J＝8.3Hz,2H),3.68(m,4H),3.13(m,4H),2.21(s,3H)；13C NMR(101MHz,DMSO-d6)δ169.22,152.92,149.18,148.52,147.50,142.22,130.93,129.89,129.23,128.76,127.07,124.94,122.59,121.47,120.43,120.40,116.71,104.60,49.60,20.52；IR:(KBr,cm-1):υ3061.55,2920.72,2828.32,1626.17,1579.09,1516.46,1427.64,1379.18,1327.32,1235.24,1180.85,1165.51,1123.80,1077.18,1010.69,920.59,905.24,871.15,827.19,749.70 682.65,568.45,476.00。
实施例57：1-(4-三氟甲氧基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH57)的制备
参照实施例1的制备方法，得到1-(4-三氟甲氧基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为34.50％；m.p.:195.9–196.4℃；HRMS(ESI):561.17194([M+H]+),583.15344([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.67–8.63(m,2H),8.23(d,J＝1.9Hz,1H),7.85(dd,J＝8.9,1.9Hz,1H),7.53(d,J＝8.6Hz,2H),7.47(d,J＝8.6Hz,2H),7.26–7.21(m,3H),7.07–7.03(m,2H),3.70(m,4H),3.24(m,4H)；13CNMR(101MHz,DMSO-d6)δ168.23,151.86,149.27,147.47,146.48,141.26,140.29,129.80,129.22,128.23,126.02,124.88,123.92,121.56,121.32,120.42,119.41,119.38,116.14,103.58,47.82；IR:(KBr,cm-1)υ3161.55,2925.20,1625.56,1579.31,1512.13,1428.85,1379.67,1327.92,1259.14,1207.05,1154.27,1122.87,1076.70,1009.67,920.34,871.61,827.07,739.75,611.88,475.55。
实施例58：1-(3-三氟甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH58)的制备
参照实施例1的制备方法，得到1-(3-三氟甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为26.65％；m.p.:217.0–218.5℃；HRMS(ESI):545.17645([M+H]+)；1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.67–8.64(m,2H),8.24(s,1H),7.86(dd,J＝8.9,1.9Hz,1H),7.55(d,J＝8.5Hz,2H),7.50–7.44(m,3H),7.26(dd,J＝9.6,5.0Hz,3H),7.12(d,J＝7.6Hz,1H),3.72(m,4H),3.34(m,4H)；13C NMR(101MHz,DMSO-d6)δ169.30,152.84,151.47,148.49,147.50,142.31,130.77,130.57,130.47,130.26,129.92,129.26,127.03,125.90,124.93,123.19,122.58,121.43,120.40,120.37,119.62,115.56,111.82,104.57,48.33；IR:(KBr,cm-1)υ1620.97,1579.11,1530.60,1429.09,1378.01,1321.85,1256.37,1154.90,1114.82,1074.00,1011.09,946.43,902.88,870.96,825.82,784.66,739.44,682.17,474.80。
实施例59：1-(4-氯苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH59)的制备
参照实施例1的制备方法，得到1-(4-氯苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为24.25％；m.p.:242.0–242.9℃；HRMS(ESI):511.15131([M+H]+),533.13215([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.66–8.62(m,2H),8.23(s,1H),7.86(d,J＝6.9Hz,1H),7.53–7.45(m,4H),7.28–7.24(m,3H),6.99(d,J＝8.8Hz,2H),3.68(m,4H),3.21(m,4H)；13C NMR(101MHz,DMSO-d6)δ169.25,152.88,150.04,148.45,147.53,142.25,130.84,129.25,127.02,124.96,123.32,122.58,121.46,120.46,117.80,104.60,48.79；IR:(KBr,cm-1)υ3159.21,2828.99,1625.71,1579.11,1531.13,1496.65,1427.24,1378.80,1326.80,1234.13,1181.05,1164.67,1123.67,1076.96,1011.72,920.34,871.48,826.80,749.93,651.62 518.84,476.05。
实施例60：1-(4-乙氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪(ZH60)的制备
参照实施例1的制备方法，得到1-(4-乙氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪黄色固体，收率为31.25％；m.p.:210.0–212.3℃；HRMS(ESI):521.21588([M+H]+),543.19975([M+Na]+)；1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.66–8.63(m,2H),8.23(s,1H),7.85(dd,J＝8.9,2.0Hz,1H),7.53–7.45(m,4H),7.24(d,J＝5.3Hz,1H),6.92(d,J＝8.9Hz,2H),6.85(d,J＝8.9Hz,2H),3.97–3.92(m,2H),3.68(m,4H),3.06(m,4H),1.29(t,J＝7.0Hz,3H)；13C NMR(101MHz,DMSO-d6)δ169.19,153.03,152.86,148.43,147.56,145.49,142.19,130.96,129.22,127.00,124.95,122.56,121.49,120.47,120.42,118.52,115.35,104.56,63.56,50.53,15.23；IR:(KBr,cm-1)υ3157.07,2977.56,2820.65,1630.27,1579.43,1511.51,1425.29,1377.65,1325.07,1246.01,1164.49,1123.51,1076.52,1046.55,1012.80,920.37,871.12,824.80,739.39,682.44 474.20。
实施例61：流感病毒核糖核蛋白复合物活化活性测试实验(RNP活化活性测试实验)
流感病毒核糖核蛋白复合物活化活性测试实验使用293T细胞为测试细胞系。以Nucleozin为活性对照药。该核糖核蛋白复合物包含流感病毒NP和RNA聚合酶(包括PA、PB1和PB2亚基)片段。
首先培养293T细胞：在一个培养皿中(直径6cm)，加入混有1/10T75的培养液，并检查一下对于转染是否有足够的质粒。
将1×105个293T细胞接种在96孔微量滴定板上过夜。将125ng pcDNA3a-PB1，pcDNA3a-PB2，pcDNA3a-PA，pcDNA3a-NP，pPOL-NS-Luci质粒和pEGFP共转染到293T细胞中，用Lipofectamine 2000(Invitrogen)重构RNP复合物。转染6小时后，加入含有被测试化合物的生长培养基。24小时后，通过Steady-Glo荧光素酶底物(Promega)测定荧光素酶活性。使用VICTOR 3Multilabel板读数器(Perkin Elmer)读取GFP表达和发出的荧光。
RNP活化活性测试实验的结果(％)，是将含有被测试化合物的荧光素酶信号(相对发光值)除以阴性对照品(DMSO)的荧光素酶信号(相对发光值)来计算的。RNP活化活性值低，说明被测试化合物与RNP发生了相互作用，具有一定的流感病毒抑制活性。对每一种被测试化合物，本实验均用其最高的非细胞毒性浓度进行测试。
本发明方法制得的部分[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物样品在100μmol·L-1浓度下RNP活化活性测试实验结果列表如下(n＝3)：
从受试目标化合物的流感病毒核糖核蛋白复合物活化活性测试实验的初步筛选结果可以看出，本发明提供的[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物均与RNP存在相互作用，对流感病毒具有抑制活性，其中实施例3制备的N-(3-硝基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例16制备的N-(4-氟苄基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例27制备的N-正丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例32制备的N-环己基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例43制备的1-(4-三氟甲氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪、实施例44制备的1-(4-氯苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪和实施例45制备的1-(二苯甲基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪与RNP存在较强的相互作用。
实施例62：考察化合物对流感病毒感染细胞的存活率的影响。
将MDCK细胞接种在96孔板中，每孔3000个细胞，培养24h。加入100TCID50(50％tissue culture infective dose，引起半数培养细胞病变的病毒量的100倍)的流感病毒，吸附细胞3h后，吸出流感病毒，将化合物稀释成100μmol·L-1、50μmol·L-1、25μmol·L-1、12.5μmol·L-1四个浓度，加到96孔板中，每个浓度做4个复孔。同时设病毒对照组、细胞对照组和空白培养基对照组，培养36h。加入CCK-8试剂，采用MTT法，测试并计算感染了流感病毒、且添加了目标化合物(或对照化合物)的细胞的吸光度与未感染病毒的细胞的吸光度的比值，测试结果表示目标化合物存在下细胞的存活率，通过观察化合物是否能够提高感染病毒后细胞的存活率，来评估化合物对流感病毒感染的细胞的保护作用。
按照上述方法测定本发明的化合物对流感病毒的抑制活性，结果示于下表。
从受试目标化合物对MDCK细胞保护的测试实验的筛选结果表明，本发明化合物能明显保护MDCK细胞，有效地抑制流感病毒的活性，其中实施例3制备的N-(3-硝基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例16制备的N-(4-氟苄基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例32制备的N-环己基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例43制备的1-(4-三氟甲氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪、实施例44制备的1-(4-氯苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪、实施例56制备的1-(4-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨甲酰基]苯基}哌嗪对MDCK细胞具有较强的保护活性。
实施例63：受试化合物对流感病毒的抑制活性
采用标准蚀斑法对部分目标化合物的抗流感病毒活性进行测试，以A/WSN/33(H1N1)流感病毒为测试病毒株，受试化合物以DMSO溶解，用培养液稀释配制为100μM的浓度，以二甲基亚砜为空白对照。
将MDCK细胞按一定浓度接种于96孔细胞培养板，在5％CO2、37℃的环境中培养细胞24h，除去培养液，将A/WSN/33(H1N1)流感病毒接种于MDCK细胞，37℃下吸附2h，倾去病毒液。加入100μmol·L-1的受试化合物，每个化合物做3个复孔，设置病毒对照组(感染病毒，不加化合物)37℃下继续培养24h，用MDCK细胞的标准蚀斑测定法测定细胞的病毒株数量，计算病毒存活率。病毒存活率＝(实验组病毒株数/病毒对照组病毒株数)×100％。
按照上述方法测定本发明的化合物对流感病毒的抑制活性，结果示于下表。
从受试目标化合物对A/WSN/33(H1N1)流感病毒抑制活性测试实验的筛选结果表明本发明化合物能明显减少流感病毒的存活量，有效地抑制流感病毒的活性，其中实施例3制备的N-(3-硝基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例16制备的N-(4-氟苄基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例27制备的N-正丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例32制备的N-环己基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺、实施例43制备的1-(4-三氟甲氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪和实施例44制备的1-(4-氯苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪抑制流感病毒活性最强。
在下述制剂中，“活性组分”是指式I所示化合物，或其盐或溶剂化物。
实施例64：明胶胶囊
实施例65：片剂
实施例66：片剂
将活性组分、淀粉和纤维素通过45目U.S.筛并充分混合，将所得粉末与聚乙烯吡咯烷酮混合，然后通过14目U.S.筛，将这样得到的颗粒在50-60℃干燥，并通过18目U.S.筛。将羧甲基纤维素钠、硬脂酸镁和滑石，先通过60目U.S.筛，然后加入至上述颗粒中，混合后，在压片机上压制成片剂。
实施例67：悬浮剂
将药物通过45目U.S.筛，并与羧甲基纤维素钠及糖浆混合，以形成均匀糊状物，将苯甲酸溶液、矫味剂和着色剂用一些水稀释，并边搅拌边加入，然后加入足够量水，以达到所需的体积。
实施例68：气溶胶
将活性成分与乙醇混合，并将所得混合物加入至抛射剂22中，冷却至30℃，并转移至容器中。然后将所需量加入至不锈钢容器中，并用剩余喷射剂稀释，然后安装阀门装置。
实施例69：可注射制剂
将以上溶液静脉内注射给药至患者，速度约1mL/min。
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其它形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。
Claims (7)
1.N-取代苯基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或其药学上可接受的盐，其特征在于，所述的N-取代苯基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物为以下化合物中的一种：
N-(2-甲基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-甲基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-硝基苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-氯苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-溴苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-[4-(苯甲氧基)苯基]-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-乙酰苯基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-甲基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-异丙基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-羟丙基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-环己基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-羟基环己基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(吗啉-4-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(金刚烷-1-基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苄基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-氟苄基)-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}吗啉；
1-[3-(三氟甲基)苯基]-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(3-氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(2,3-二氯苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-苯基-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-溴苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-甲氧基苯基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(二苯甲基)-4-{2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
N-乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-异丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-正丙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苯乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(2-羟乙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-羟丙基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N,N-二乙基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-环己基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-羟基环己基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苯基-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(2-甲苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-甲基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-硝基苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-溴苯基)-3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
(哌啶-1-基){3-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮；
1-苯基-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(3-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-甲基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-三氟甲氧基苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-氯苯基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(二苯甲基)-4-{3-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
N-乙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-异丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-正丙基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(2-羟乙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(3-羟丙基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-环己基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-(4-羟基环己基)-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
N-苄基-4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺；
(吗啉-4-基){4-[(7-三氟甲基喹啉-4-基)氨基]苯基}甲酮；
1-(2-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-三氟甲氧基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(3-三氟甲基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-氯苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪；
1-(4-乙氧基苯基)-4-{4-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰基}哌嗪。
2.权利要求1中所述的N-取代苯基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物的制备方法，其特征在于，包括以下步骤：
其中，R1、R2如权利要求1所述。
3.一种药物组合物，其特征在于，包括作为活性成分的权利要求1所述的N-取代苯基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或其药学上可接受的盐中任何一个的化合物和药物可接受的载体或稀释剂。
4.权利要求1所述的N-取代苯基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或其药学上可接受的盐在制备流感病毒治疗药物中的应用。
5.权利要求3所述的药物组合物在制备流感病毒治疗药物中的应用。
6.根据权利要求4所述的N-取代苯基-2-[(7-三氟甲基喹啉-4-基)氨基]苯甲酰胺类化合物或其药学上可接受的盐在制备流感病毒治疗药物中的应用，其特征在于，以有效量的该结构式的化合物作用于流感病毒的核蛋白或RNA聚合酶，抑制流感病毒的复制。
7.根据权利要求5所述的应用，其特征在于，以有效量的药物组合物作用于流感病毒的核蛋白或RNA聚合酶，抑制流感病毒的复制。
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