CN117586233A - N-[(1h-吲哚-4-基)烷基]苯甲酰胺类化合物的制备及其应用 - Google Patents
N-[(1h-吲哚-4-基)烷基]苯甲酰胺类化合物的制备及其应用 Download PDFInfo
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- CN117586233A CN117586233A CN202311546359.4A CN202311546359A CN117586233A CN 117586233 A CN117586233 A CN 117586233A CN 202311546359 A CN202311546359 A CN 202311546359A CN 117586233 A CN117586233 A CN 117586233A
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- Prior art keywords
- indol
- benzamide
- acetamido
- ethyl
- methyl
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- -1 1H-indol-4-yl Chemical group 0.000 title claims abstract description 273
- 238000002360 preparation method Methods 0.000 title claims abstract description 98
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 21
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 82
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 68
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- 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims description 23
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 11
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 5
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- 238000003032 molecular docking Methods 0.000 description 4
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical class C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 2
- XBARKDQKGSJDLG-UHFFFAOYSA-N 2-(1h-indol-4-yl)ethanamine Chemical compound NCCC1=CC=CC2=C1C=CN2 XBARKDQKGSJDLG-UHFFFAOYSA-N 0.000 description 2
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
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- DQVWAEMRCAYLKH-FNORWQNLSA-N 4-[(e)-2-nitroethenyl]-1h-indole Chemical compound [O-][N+](=O)\C=C\C1=CC=CC2=C1C=CN2 DQVWAEMRCAYLKH-FNORWQNLSA-N 0.000 description 2
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Abstract
本发明的N‑[(1H‑吲哚‑4‑基)烷基]苯甲酰胺类化合物的制备及其应用，属于医药技术领域。具体为结构式如式I所示的N‑[(1H‑吲哚‑4‑基)烷基]苯甲酰胺类化合物或其药学上可接受的盐，其中G如权利要求书和说明书中所述。相应的N‑[(1H‑吲哚‑4‑基)烷基]苯甲酰胺类化合物以及该类化合物药学上适用的酸和药学上可接受的盐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N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物的制备及其作为抗流感病毒药物的应用。
背景技术
流感是由流感病毒引起的传染性呼吸系统疾病，其症状主要表现为发热、咽喉肿痛、流涕、咳嗽等，多数伴有十分严重的肺炎，甚至能够引起心、肾等多种脏器的衰竭而造成死亡。它既可以通过空气传播，也可以通过直接接触禽类的分泌物或污染物表面而感染。每次流感的爆发，都会有新的毒株被发现，这些新的毒株通常是由已经存在的毒株从其它动物传播到人类，或是由已有的人流感病毒组装了禽类或猪流感病毒的基因而形成。流感的爆发给人类带来严重危害性，造成的死亡率很高(Smith GJD,Vijaykrishna D,Bahl J,Lycett SJ,Worobey M,Pybus OG,Ma SK,Cheung CL,Raghwani J,Bhatt S,Peiris JS,Guan Y,Rambaut A.Origins and evolutionary genomics of the 2009swine-OriginH1N1 influenza A apidemic.Nature,2009,459(7250):1122-1125；Galen RJ,Davis CT,Russell CA,Shu B,Lindstrom S,Balish A,Sessions WM,Xu X,Skepner E,Deyde V,Okomo-Adhiambo M,Gubareva L,Barnes J,Smith CB,Emery SL,Hillman MJ,RivaillerP,Smagala J,de Graaf M,Burke DF,Fouchier RA,Pappas C,Alpuche-Aranda CM,López-Gatell H,Olivera H,López I,Myers CA,Faix D,Blair PJ,Yu C,Keene KM,Dotson PDJr,Boxrud D,Sambol AR,Abid SH,St George K,Bannerman T,Moore AL,Stringer DJ,Blevins P,Demmler-Harrison GJ,Ginsberg M,Kriner P,Waterman S,Smole S,GuevaraHF,Belongia EA,Clark PA,Beatrice ST,Donis R,Katz J,Finelli L,Bridges CB,ShawM,Jernigan DB,Uyeki TM,Smith DJ,Klimov AI,Cox NJ.Antigenic and geneticcharacteristics of swine-origin 2009A(H1N1)influenza viruses circularing inhumans.Science,2009,325(5937):197-201.)。因此，预防与治疗流感是医学界一项重要的挑战。
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。但流感疫苗存在的许多缺点(流感病毒变异易失效、研发滞后性、研发周期长、成本高和接种者的年龄及健康状态受限等)使得小分子药物成为防治流感的主要手段。目前，已上市的抗流感药物主要有三类(M2蛋白抑制剂：金刚烷胺(amantadine)、金刚乙胺(rimantidine)；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)等)，但这些药物的耐药性病毒株所占的比例呈上升趋势(Poland G,Jacobson R,OvsyannikovaI.Influenza virus resistance to antiviral agents:a plea for rationaluse.Clinical Infectious Diseases an Official Publication of the InfectiousDiseases Society of America,2009,48(9):1254–1256；Deyde V,Xu X,Bright R,ShawM,Smith CB,Zhang Y,Shu Y,Gubareva LV,Cox NJ,Klimov AI.Surveillance ofresistance to adamantanes among influenza A (H3N2)and A(H1N1)viruses isolatedworldwide.Journal of Infectious Diseases,2007,196(2):249–257.)。因此，研制高效、稳定、经济和作用于新靶标的抗流感病毒药物具有重要意义。
新型流感病毒亚型的产生，主要是由于病毒包膜的血凝素和神经氨酸酶而产生的变化，位于内层的核蛋白和RNA聚合酶较为稳定，很少发生变异，因此，针对该靶标的抗流感病毒药物不易产生抗药性。在病毒的繁殖过程中，RNA聚合酶均起着重要作用，是病毒RNA复制、转录翻译所必须的。RNA聚合酶由PA、PB1和PB2组成。PA具有聚合酶活性，发挥激酶或解旋酶作用，而PB1、PB2则对病毒RNA的延伸和诱导宿主细胞凋亡有关键的作用，PB1负责识别和切割宿主mRNA5’端帽子结构引物。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。同时，组成流感病毒的RNA聚合酶在流感病毒A、B、C中高度保守，在哺乳动物细胞中没有同源蛋白，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(Kawaguchi A,Naito T.,Nagata K.Involvement of influenza virusPA subunit in assembly of functional RNA polymerase complexes.Journal ofVirology,2005,79(2):732–744.)。RNA聚合酶的PB1氨基端(PB1N)和PA羧基端(PAC)之间，通过非共价键相互作用，形成稳定的复合物。它们通过相互结合发挥功能，从而在流感病毒的转录复制全过程中发挥着重要的作用。基于此，我们设计目标化合物，通过与RNA聚合酶PAC活性位点片段产生相互作用，影响了PB1N和PAC的相互结合，从而抑制PA-PB1之间的相互作用，影响流感病毒RNA聚合酶的功能，抑制流感病毒的活性。2013年，意大利Tabarrini课题组(Kessler U,Castagnolo D,Pagano M,Deodato D,Bernardini M,Pilger B,RanadheeraC,Botta M.Discovery and synthesis of novel benzofurazan derivatives asinhibitors of influenza Avirus.Bioorganic&Medicinal Chemistry Letters,2013,23:5575–5577.Pagano M,Castagnolo D,Bernardini M,Fallacara AL,Laurenzana I,Deodato D,Kessler U,Pilger B,Stergiou L,Strunze S,Tintori C,Botta M.The fightagainst the influenza A virus H1N1:synthesis,molecular modeling,andbiological evaluation of benzofurazan derivatives as viral RNA polymeraseinhibitors.ChemMedChem,2014,9:129–150.)利用高通量筛选方法发现部分含有苯并[c][1,2,5]噁二唑结构的衍生物可在微摩尔水平抑制病毒复制，此类化合物还可抑制RNA聚合酶的PA-PB1相互作用，但这些化合物也显示出一定的细胞毒性作用。因此，我们用吲哚环代替苯并[c][1,2,5]噁二唑结构，设计了41个N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物。
因此，靶向流感病毒RNA聚合酶PA-PB1抑制剂在抗流感病毒方面具有显著优势。N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物作为流感病毒抑制剂的发现对流感病毒抑制剂分子库的扩充和新型流感病毒抑制剂的研究具有重要意义。
发明内容
本发明所解决的技术问题是，提供一种N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物及其制备方法和应用，具体为如式Ⅰ所示的N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物或其药学上可接受的盐，并提供了所述化合物在制备治疗与流感相关的疾病的药物中的应用。
结构式如式I所示的N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物或其药学上可接受的盐：
其中，n为1或2，G选自(1H-苯并咪唑-2-基)硫基、(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基、[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基、苯氧基、C1-C3烷基取代苯氧基、C1-C3烷氧基取代苯氧基、硝基苯氧基、4-乙氧甲酰基苯氧基、萘氧基、C1-C3烷基取代苯胺基、C1-C3烷氧基取代苯胺基、卤素取代烷基苯胺基、卤素取代苄胺基、C1-C4烷基氨基、环己基氨基、吗啉基、[3-(吗啉-4-基)丙基]氨基、甲基哌嗪基、甲基取代苯基哌嗪基、卤素取代苯基哌嗪基、甲氧基取代苯基哌嗪基。
进一步地，G选自(1H-苯并咪唑-2-基)硫基、(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基、[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基、4-乙氧甲酰基苯氧基、2-甲氧基苯氧基、4-甲氧基苯氧基、苯氧基、4-甲苯基氧基、4-硝基苯氧基、萘-1-基氧基、吗啉-4-基、[3-(吗啉-4-基)丙基]氨基、环己基氨基、(4-氟苄基)氨基、(2,5-二甲氧基苯基)氨基、[3-(三氟甲基)苯基]氨基、2-二乙基氨基、甲基(苯基)氨基、(4-氟苄基)氨基、正丁基氨基、(2-甲基苯基)氨基、4-甲基哌嗪-1-基、4-(4-甲基苯基)哌嗪-1-基、4-(4-氟苯基)哌嗪-1-基、4-(4-甲氧基苯基)哌嗪-1-基。
更进一步地，所述N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物为如下化合物中任意一个或其药学上可接受的盐：
N-[(1H-吲哚-4-基)甲基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-{[(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺；
{2-{{4-{[(1H-吲哚-4-基)甲基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯；
N-[(1H-吲哚-4-基)甲基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-(吗啉-4-基)苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-[(对甲苯基氧基)乙酰氨基]苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-(苯氧基)苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-{[(5-甲氧基-3H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-(吗啉-4-基)苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲苯基氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(4-硝基苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(萘-1-基氧基)乙酰氨基]苯甲酰胺；
{2-{{4-{[2-(1H-吲哚-4-基)乙基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(2,5-二甲氧基苯基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(三氟甲基)苯基]氨基}乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[甲基(苯基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(4-甲基哌嗪-1-基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-氟苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲氧基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(正丁基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺。
本发明还提供一种药物组合物，包含如式Ⅰ所示的N-[(1H-吲哚-4-基)烷基]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。
对于口服给药途径，除片剂或胶囊的形式，还可以采用水溶液或混悬液的形式给予。通过口服给药时，活性药物成分与可口服，无毒，药学上可接受的惰性载体组合形成药物组合物，对片剂或胶囊形式的口服给药来说，载体包括乳糖，淀粉，蔗糖，葡萄糖，甲基纤维素，硬脂酸镁，磷酸二钙，硫酸钙，甘露醇，山梨醇；对液体形式的口服给药来说，载体包括乙醇，甘油，水及其组合。
本发明的N-[(1H-吲哚-4-基)烷基]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。
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、氢溴酸盐、氢碘酸盐、硝酸盐、磷酸盐、硫酸盐、高氯酸盐、硫氰酸盐、硫酸氢盐、过硫酸盐、硼酸盐、甲酸盐、乙酸盐、丙酸盐、戊酸盐、新戊酸盐、己酸盐、庚酸盐、辛酸盐、异辛酸盐、十一烷酸盐、月桂酸盐、棕榈酸盐、硬脂酸盐、油酸盐、环丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、己二酸盐、壬二酸盐、丙烯酸盐、草莓盐、巴豆酸盐、惕格酸盐、衣康酸盐、山梨酸盐、肉桂酸盐、乙醇酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、亚酒石酸盐、扁桃酸盐、二苯乙醇酸盐、托品酸盐、抗坏血酸盐、葡萄糖酸盐、葡庚糖酸盐、葡萄糖二酸盐、甘露糖酸盐、乳糖酸盐、苯甲酸盐、酞酸盐、对酞酸盐、糠酸盐、烟酸盐、异烟酸盐、水杨酸盐、乙酰水杨酸盐、酪酸盐、没食子酸盐、咖啡酸盐、阿魏酸盐、苦味酸盐、樟脑酸盐、樟脑磺酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、苯磺酸盐、对甲苯磺酸盐、对氨基苯磺酸盐、氨基磺酸盐、牛磺酸盐、2-羟基乙磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、色氨酸盐、酪氨酸盐、天冬氨酸盐、天冬酰胺盐、谷氨酸盐、赖氨酸盐、谷氨酰胺盐、甲硫氨酸盐、丝氨酸盐、苏氨酸盐、半胱氨酸盐、脯氨酸盐、组氨酸盐、精氨酸盐、依地酸盐、丙酮酸盐、α-酮戊二酸盐、藻酸盐、环戊烷丙酸盐、3-苯基丙酸盐、3-环己基丙酸、2-萘甲酸盐、2-萘磺酸盐、双羟萘酸盐、月桂基硫酸盐、甘油磷酸盐、月桂基硫酸盐、果胶脂酸盐。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，N-甲基-D-葡糖胺盐，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、二丁酯和二戊酯；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。
本发明还提供通式I所示N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物的制备方法，包括以下步骤：
对于目标化合物与流感病毒RNA聚合酶的作用模式，通过对目标化合物与流感病毒RNA聚合酶的分子对接得到初步验证。2008年Obayashi E等人报道了流感病毒RNA聚合酶的晶体结构(PDB ID:2ZNL)(Obayashi E,Yoshida H,Kawai F,Shibayama N,Kawaguchi A,Nagata K,Tame JR,Park SY.The structural basis for an essential subunitinteraction in influenza virus RNA polymerase.Nature,2008,454:1127-1131)，现以目标化合物N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺和N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺与流感病毒RNA聚合酶(PDB ID:2ZNL)的分子对接对其结合模式进行了预测(图1)，结果表明N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺的酰胺基团中的氨基(-NH)与流感病毒RNA聚合酶中TRP706形成氢键相互作用；吲哚环可与TRP706形成π-π堆积作用。目标化合物N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)巯基]乙酰氨基}苯甲酰胺与2ZNL的分子对接结果(图2)表明，苯环可与流感病毒RNA聚合酶中PHE411和TRP706形成π-π堆积作用；GLN408、CYS415、ILE621和GLU623均可与N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺的基团形成氢键相互作用。由分子对接结果可得，N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺和N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺均可与流感病毒RNA聚合酶PAC结合，阻断PA-PB相互作用，进而抑制病毒的复制。
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，是一类作用于流感病毒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，作用在流感病毒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。且所述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。
附图说明
图1化合物N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺与RNA聚合酶(PDB ID:2ZNL)的结合模式图；
图2化合物N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺与RNA聚合酶(PDB ID:2ZNL)的结合模式图。
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施例。
实施例1：N-[(1H-吲哚-4-基)甲基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺(Z01)的制备
步骤A:(Z)-1H-吲哚-4-甲醛肟的制备
于100mL圆底烧瓶中，加入氢氧化钠(0.33g，8.30mmol)，水(10mL)，待溶清后，加入盐酸羟胺(0.60g，8.30mmol)，室温搅拌0.5h。滴加1H-吲哚-4-甲醛(1.00g，6.90mmol)的甲醇(30mL)溶液，加热回流3h。减压蒸除甲醇，加入20mL水，乙酸乙酯萃取，无水硫酸镁干燥，减压蒸干溶剂，得红棕色固体0.96g，收率86.5％。
步骤B:(1H-吲哚-4-基)甲胺的制备
于100mL圆底烧瓶中，加入氢氧化钠(1.00g，25.00mmol)，水(10mL)，待溶清后，加入(Z)-1H-吲哚-4-甲醛肟(0.50g，3.12mmol)的乙醇(20mL)溶液，分批加入镍铝合金5.00g，回流5h。过滤，减压蒸除乙醇，加入水(20mL)，乙酸乙酯萃取，无水硫酸钠干燥，布氏漏斗抽滤，减压蒸干溶剂，得黄色固体0.32g，收率70.5％，ESI-MS(m/z):147.1([M+H]+)。步骤C:4-氨基-N-[2-(1H-吲哚-4-基)甲基]苯甲酰胺的制备
于500mL圆底烧瓶中，分别加入对氨基苯甲酸(4.71g，34.35mmol)，EDCI(7.18g，37.48mmol)，HOBt(5.06g，37.48mmol)，Et3N(9.48g，93.69mmol)，二氯甲烷(300mL)，室温搅拌1h，再加入(1H-吲哚-4-基)甲胺(4.56g，31.23mmol)，室温搅拌16h，反应液分别用水，5％NaHCO3溶液，饱和食盐水洗两次，用无水硫酸镁干燥，过滤，减压蒸干溶剂得到残渣，经柱层析[V(乙酸乙酯):V(石油醚)＝1:3]得到淡黄色固体5.98g，收率72.2％，ESI-MS(m/z):266.1([M+H]+)。
步骤D:4-(2-氯乙酰氨基)-N-[2-(1H-吲哚-4-基)甲基]苯甲酰胺的制备
于250mL圆底烧瓶中，加入4-氨基-N-(2-(1H-吲哚-4-基)甲基)苯甲酰胺(5.00g，18.80mmol)，二氯甲烷(100mL)，Et3N(5.72g，56.54mmol)，冰浴条件下滴加氯乙酰氯(2.55g，22.56mmol)的二氯甲烷(50mL)溶液，待滴加完毕，撤去冰水浴，室温搅拌8h，反应液分别用5％盐酸，水洗两次，无水硫酸镁干燥，过滤，减压蒸干溶剂得到粉红色固体4.42g，收率68.9％，ESI-MS(m/z):342.1([M+H]+)。
步骤E:N-[(1H-吲哚-4-基)甲基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺(Z01)的制备
于50mL圆底烧瓶中，加入4-(2-氯乙酰氨基)-N-[2-(1H-吲哚-4-基)乙基]苯甲酰胺(0.5g，1.41mmol)，碳酸钾(0.97g，7.05mmol)，1H-苯并咪唑-2-硫醇(0.32g,2.12mmol)，四氢呋喃(20mL)，搅拌加热回流10h，减压浓缩溶剂，加入乙酸乙酯(30mL)，用水洗两次，无水硫酸镁干燥，过滤，蒸干溶剂得到粗品，经柱层析[V(乙酸乙酯):V(石油醚)＝1:3]得到白色固体产物，收率为76.7％；m.p.:168.5–170.0℃；1H NMR(400MHz,DMSO-d6)δ12.67(s,1H),11.11(s,1H),10.72(s,1H),8.87(s,2H),7.88(d,J＝8.3Hz,2H),7.65(d,J＝8.6Hz,2H),7.51(s,1H),7.37–7.27(m,2H),7.12(d,J＝6.9Hz,2H),6.91(d,J＝7.2Hz,1H),6.55(d,J＝10.7Hz,2H),4.72(d,J＝5.9Hz,2H),4.30(s,2H)；ESI-MS(m/z):456.3([M+H]+)。
实施例2：N-[(1H-吲哚-4-基)甲基]-4-{[(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺(Z02)的制备
参考实施例1的制备方法，得到N-[(1H-吲哚-4-基)甲基]-4-{[(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺白色固体，收率为80.2％；m.p.:190.3–191.8℃；1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),11.13(s,1H),10.88(s,1H),8.88(s,1H),7.89(d,J＝8.3Hz,2H),7.76(d,J＝8.5Hz,1H),7.67(d,J＝8.4Hz,2H),7.39–7.25(m,2H),7.10–7.00(m,1H),6.92(d,J＝7.2Hz,1H),6.58(dd,J＝5.5,2.9Hz,2H),4.73(d,J＝5.8Hz,2H),4.26(s,2H),3.84(s,3H)；ESI-MS(m/z):485.2([M-H]-)。
实施例3：N-[(1H-吲哚-4-基)甲基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺(Z03)的制备
参考实施例1的制备方法，得到N-[(1H-吲哚-4-基)甲基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺白色固体，收率为70.9％；m.p.:140.6–142.0℃；1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),11.11(s,1H),10.68(s,1H),8.92–8.84(m,1H),7.88(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,1H),7.41–7.26(m,3H),7.23–7.13(m,1H),7.07–6.88(m,3H),6.57(s,1H),4.72(d,J＝5.7Hz,2H),4.31(d,J＝3.2Hz,2H)；ESI-MS(m/z):520.2([M-H]-)。
实施例4：{2-{{4-{[(1H-吲哚-4-基)甲基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯(Z04)的制备
参考实施例1的制备方法，得到{2-{{4-{[(1H-吲哚-4-基)甲基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯白色固体，收率为68.3％；m.p.:180.2–181.5℃；1H-NMR(400MHz,DMSO-d6):δ1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.37(s,1H),8.89(s,1H),7.94–7.82(m,3H),7.71(d,J＝8.4Hz,2H),7.37–7.28(m,2H),7.11(d,J＝8.7Hz,2H),7.05–7.00(m,1H),6.92(d,J＝7.1Hz,1H),6.56(d,J＝12.7Hz,2H),4.84(s,2H),4.73(d,J＝5.8Hz,2H),4.28(q,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H)；ESI-MS(m/z):470.2([M-H]-)。
实施例5：N-[(1H-吲哚-4-基)甲基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺(Z05)的制备
参考实施例1的制备方法，得到N-[(1H-吲哚-4-基)甲基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺白色固体，收率为86.2％；m.p.:128.0–129.5℃；1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.28(s,1H),8.89(s,1H),7.89(d,J＝8.6Hz,2H),7.71(d,J＝8.6Hz,2H),7.36–7.28(m,2H),7.06–6.86(m,6H),6.58(s,1H),4.74–4.70(d,4H),3.80(s,3H)；ESI-MS(m/z):428.2([M-H]-)。
实施例6：N-[(1H-吲哚-4-基)甲基]-4-(吗啉-4-基)苯甲酰胺(Z06)的制备
参考实施例1的制备方法，得到N-[(1H-吲哚-4-基)甲基]-4-(吗啉-4-基)苯甲酰胺白色固体，收率为83.8％；m.p.:108.5–110.2℃；1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.95(s,1H),8.89–8.87(m,1H),7.88(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.35–7.25(m,2H),7.07–6.98(m,1H),6.92(d,J＝7.1Hz,1H),6.57(s,1H),4.73(d,J＝5.8Hz,2H),3.64(t,J＝4.6Hz,4H),3.15(s,2H),2.51(s,4H)；ESI-MS(m/z):393.3([M+H]+)。
实施例7：N-[(1H-吲哚-4-基)甲基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺(Z07)的制备
参考实施例1的制备方法，得到N-[(1H-吲哚-4-基)甲基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺棕色固体，收率为92.5％；m.p.:166.0–168.0℃；1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.25(s,1H),8.95–8.83(m,1H),7.89(d,J＝8.6Hz,2H),7.73(d,J＝8.5Hz,2H),7.34–7.25(m,2H),7.06–7.00(m,1H),6.99–6.83(m,5H),6.68–6.44(m,1H),4.73(d,J＝5.8Hz,2H),4.65(s,2H),3.70(s,3H)；ESI-MS(m/z):429.2([M-H]-)。
实施例8：N-[(1H-吲哚-4-基)甲基]-4-[(对甲苯基氧基)乙酰氨基]苯甲酰胺(Z08)的制备
参考实施例1的制备方法，得到N-[(1H-吲哚-4-基)甲基]-4-[(对甲苯基氧基)乙酰氨基]苯甲酰胺白色固体，收率为79.5％；m.p.:162.3–164.0℃；1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.27(s,1H),8.92–8.83(m,1H),7.88(d,J＝8.7Hz,2H),7.75–7.69(m,2H),7.35–7.28(m,2H),7.11(d,J＝8.3Hz,2H),7.05–7.01(m,1H),6.93–6.77(m,3H),6.57(s,1H),4.77–4.63(m,4H),2.23(s,3H)；ESI-MS(m/z):414.4([M+H]+)。
实施例9：N-[(1H-吲哚-4-基)甲基]-4-(苯氧基)苯甲酰胺(Z09)的制备
参考实施例1的制备方法，得到N-[(1H-吲哚-4-基)甲基]-4-(苯氧基)苯甲酰胺白色固体，收率为77.2％；m.p.:114.6–116.2℃；1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.31(s,1H),8.89(t,J＝5.8Hz,1H),7.89(d,J＝8.8Hz,2H),7.73(d,J＝8.7Hz,2H),7.36–7.28(m,4H),7.03–6.92(m,4H),6.58(s,1H),4.73(d,J＝4.6Hz,4H)；ESI-MS(m/z):400.4([M+H]+)。
实施例10：N-[2-(1H-吲哚-4-基)乙基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺(Z10)的制备
步骤F:(E)-4-(2-硝基乙烯基)-1H-吲哚的制备
于250mL圆底烧瓶中，加入1H-吲哚-4-甲醛(10.00g，68.92mmol)、硝基甲烷(100mL)，醋酸铵(0.50g，6.48mmol)，搅拌回流3.5h，TLC监测原料完全反应完后，加入乙酸乙酯稀释，饱和食盐水洗涤。有机层用无水硫酸镁干燥，减压蒸干溶剂，得到残余固体，向残余固体中加入石油醚，过滤，洗涤，得到橙红色固体10.00g，收率72.9％。
步骤G:2-(1H-吲哚-4-基)乙胺的制备
于250ml圆底烧瓶中，将LiAlH4(1.21g，31.90mmol)投入四氢呋喃(60mL)中得到悬浮液，冰浴降温至0℃，慢慢滴加(E)-4-(2-硝基乙烯基)-1H-吲哚(1.00g，5.30mmol)的四氢呋喃(20mL)溶液至反应瓶中，滴加完毕后，撤去冰浴，搅拌加热回流6h，冰浴降温至0℃，向反应液中慢慢滴加1mL水，用硅藻土过滤，浓缩母液，用乙酸乙酯萃取，有机层用无水硫酸镁干燥，过滤，蒸干溶剂得到浅黄色固体0.55g，收率65.3％，ESI-MS(m/z):161.1([M+H]+)。
步骤H:4-氨基-N-[2-(1H-吲哚-4-基)乙基]苯甲酰胺的制备
于500mL圆底烧瓶中，分别加入4-氨基苯甲酸(4.71g，34.35mmol)，EDCI(7.18g，37.48mmol)，HOBt(5.06g，37.48mmol)，Et3N(9.48g，93.69mmol)，二氯甲烷300mL，室温搅拌1h。再加入2-(1H-吲哚-4-基)乙胺(5.00g，31.23mmol)，室温搅拌16h，反应液分别用水，5％NaHCO3溶液，饱和食盐水洗两次，用无水硫酸镁干燥，过滤，减压蒸干溶剂得到残渣，经柱层析[V(乙酸乙酯):V(石油醚)＝1:3]得到淡黄色固体6.76g，收率77.5％，ESI-MS(m/z):280.1([M+H]+)。
步骤I:4-(2-氯乙酰氨基)-N-[2-(1H-吲哚-4-基)乙基]苯甲酰胺的制备
于250mL圆底烧瓶中，加入4-氨基-N-[2-(1H-吲哚-4-基)乙基]苯甲酰胺(5.00g，17.90mmol)，二氯甲烷(100mL)，三乙胺(5.43g，53.71mmol)，冰浴条件下滴加氯乙酰氯(2.43g，21.48mmol)的二氯甲烷(50mL)溶液，待滴加完毕，撤去冰水浴，室温搅拌8h，反应液分别用5％盐酸，水洗两次，用无水硫酸钠干燥，布氏漏斗抽滤，减压蒸干溶剂得到粉红色固体4.15g，收率65.3％，ESI-MS(m/z):356.1([M+H]+)。
步骤J：N-[2-(1H-吲哚-4-基)乙基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺(Z10)的制备
于50mL圆底烧瓶中，加入4-(2-氯乙酰氨基)-N-[2-(1H-吲哚-4-基)乙基]苯甲酰胺(0.5g，1.41mmol)，碳酸钾(0.97g，7.05mmol)，1H-苯并咪唑-2-硫醇(0.32g,2.12mmol)，四氢呋喃(20mL)，搅拌加热回流10h，减压浓缩溶剂，加入乙酸乙酯(30mL)，用水洗两次，无水硫酸镁干燥，过滤，蒸干溶剂得到粗品，经柱层析[V(乙酸乙酯):V(石油醚)＝1:3]得到白色固体产物，收率为89.2％；m.p.:136.2–137.5℃；1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),11.07(s,1H),10.74(s,1H),8.54–8.52(m,1H),7.83(d,J＝8.7Hz,2H),7.66(d,J＝8.7Hz,2H),7.46(s,2H),7.36–7.31(m,1H),7.25(d,J＝8.1Hz,1H),7.18–7.11(m,2H),7.04–6.96(m,1H),6.84(d,J＝7.0Hz,1H),6.59(s,1H),4.31(s,2H),3.36(s,2H),3.07(dd,J＝9.0,6.4Hz,2H)；ESI-MS(m/z):470.2([M+H]+)。
实施例11：N-[2-(1H-吲哚-4-基)乙基]-4-{[(5-甲氧基-3H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺(Z11)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-{[(5-甲氧基-3H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺白色固体，收率为73.7％；m.p.:168.2–170.0℃；1H NMR(400MHz,DMSO-d6)δ13.13(s,1H),12.82(s,1H),11.07(s,1H),10.67(s,1H),8.53(s,1H),7.82(d,J＝8.7Hz,2H),7.66(d,J＝8.4Hz,2H),7.36–7.31(m,1H),7.25(d,J＝8.1Hz,1H),7.04–6.98(m,1H),6.84(d,J＝7.1Hz,1H),6.60(d,J＝8.6Hz,2H),3.85(s,3H),3.60–3.49(m,2H),3.35(s,2H),3.07(dd,J＝9.0,6.4Hz,2H)；ESI-MS(m/z):499.2([M-H]+)。
实施例12：N-[2-(1H-吲哚-4-基)乙基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺(Z12)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺白色固体，收率为74.2％；m.p.:110.3–111.6℃；1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),12.83(s,1H),11.07(s,1H),10.67(s,1H),8.60–8.48(m,1H),7.88–7.74(m,3H),7.66(d,J＝8.4Hz,2H),7.36–7.30(m,1H),7.25(d,J＝8.1Hz,1H),7.05–6.97(m,1H),6.84(d,J＝7.1Hz,1H),6.66–6.57(m,2H),3.85(s,3H),3.61–3.49(m,2H),3.07(dd,J＝9.0,6.4Hz,2H)；ESI-MS(m/z):534.3([M-H]+)。
实施例13：N-[2-(1H-吲哚-4-基)乙基]-4-(吗啉-4-基)苯甲酰胺(Z13)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-(吗啉-4-基)苯甲酰胺白色固体，收率为90.7％；m.p.:210.5–212.1℃；1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.95(s,1H),8.61–8.43(m,1H),7.82(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.33(s,1H),7.25(d,J＝8.1Hz,1H),7.04–6.97(m,1H),6.84(d,J＝7.0Hz,1H),6.59(s,1H),3.64(t,J＝4.6Hz,4H),3.58–3.51(m,2H),3.16(s,2H),3.07(dd,J＝9.0,6.4Hz,2H),2.51-2.49(m,4H)；ESI-MS(m/z):405.4([M-H]+)。
实施例14：N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲苯基氧基)乙酰氨基]苯甲酰胺(Z14)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲苯基氧基)乙酰氨基]苯甲酰胺白色固体，收率为68.1％；m.p.:142.4–143.6℃；1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.27(s,1H),8.54(s,1H),7.82(d,J＝8.8Hz,2H),7.72(d,J＝8.8Hz,2H),7.33–7.32(m,1H),7.25(d,J＝8.1Hz,1H),7.11(d,J＝8.3Hz,2H),7.02–6.99(m,1H),6.90(d,J＝8.6Hz,2H),6.84(d,J＝7.0Hz,1H),6.65–6.58(m,1H),4.68(s,2H),3.55(dt,J＝8.9,6.1Hz,2H),3.07(dd,J＝9.0,6.4Hz,2H),2.24(s,3H)；ESI-MS(m/z):426.4([M-H]+)。
实施例15：N-[2-(1H-吲哚-4-基)乙基]-4-[(苯氧基)乙酰氨基]苯甲酰胺(Z15)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-[(苯氧基)乙酰氨基]苯甲酰胺白色固体，收率为90.9％；m.p.:118.5–120.0℃；1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.31(s,1H),8.54(s,1H),7.83(d,J＝8.7Hz,2H),7.73(d,J＝8.7Hz,2H),7.34–7.30(m,3H),7.25(d,J＝8.1Hz,1H),7.03–6.95(m,4H),6.84(d,J＝7.0Hz,1H),6.59(s,1H),4.73(s,2H),3.35(s,1H),3.07(dd,J＝9.0,6.4Hz,2H),2.81(d,J＝62.7Hz,1H)；ESI-MS(m/z):414.4([M+H]+)。
实施例16：N-[2-(1H-吲哚-4-基)乙基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺(Z16)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺白色固体，收率为78.4％；m.p.:164.2–163.8℃；1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.28(s,1H),8.54(s,1H),7.83(d,J＝8.7Hz,2H),7.70(d,J＝8.5Hz,2H),7.33(s,1H),7.25(d,J＝8.1Hz,1H),7.06–6.94(m,4H),6.91–6.81(m,2H),6.59(s,1H),4.70(s,2H),3.81(s,3H),3.55(q,J＝6.7Hz,2H),3.07(dd,J＝9.0,6.4Hz,2H)；ESI-MS(m/z):444.4([M+H]+)。
实施例17：N-[2-(1H-吲哚-4-基)乙基]-4-[(4-硝基苯氧基)乙酰氨基]苯甲酰胺(Z17)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-[(4-硝基苯氧基)乙酰氨基]苯甲酰胺白色固体，收率为80.4％；m.p.:174.4–176.2℃；1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.43(s,1H),8.55(s,1H),8.25(d,J＝9.2Hz,2H),7.84(d,J＝8.4Hz,2H),7.70(d,J＝8.4Hz,2H),7.33(s,1H),7.23(dd,J＝12.9,8.7Hz,3H),7.04–6.97(m,1H),6.84(d,J＝7.1Hz,1H),6.59(s,1H),4.95(s,2H),3.55(q,J＝6.8Hz,2H),3.07(t,J＝7.7Hz,2H)；ESI-MS(m/z):457.3([M-H]-)。
实施例18：N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺(Z18)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺白色固体，收率为76.8％；m.p.:150.2–152.0℃；1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.25(s,1H),8.54(s,1H),7.83(d,J＝8.5Hz,2H),7.73(d,J＝8.5Hz,2H),7.33(s,1H),7.25(d,J＝8.1Hz,1H),7.02–6.95(m,2H),6.91–6.81(m,3H),6.77–6.65(m,1H),6.59(s,1H),4.66(s,2H),3.70(s,3H),3.55(q,J＝6.9Hz,2H),3.34(s,1H),3.07(dd,J＝9.0,6.4Hz,1H)；ESI-MS(m/z):442.3([M-H]-)。
实施例19：N-[2-(1H-吲哚-4-基)乙基]-4-[(萘-1-基氧基)乙酰氨基]苯甲酰胺(Z19)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-4-[(萘-1-基氧基)乙酰氨基]苯甲酰胺白色固体，收率为78.0％；m.p.:184.5–186.0℃；1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.45(s,1H),8.63–8.52(m,1H),8.37–8.30(m,1H),7.92–7.88(m,1H),7.84(d,J＝8.8Hz,2H),7.73(d,J＝8.7Hz,2H),7.57–7.52(m,,3H),7.47–7.40(m,1H),7.36–7.31(m,1H),7.25(d,J＝8.1Hz,1H),7.05–6.93(m,2H),6.84(d,J＝7.1Hz,1H),6.59(s,1H),4.96(s,2H),3.34(s,2H),3.07(dd,J＝9.0,6.4Hz,2H)；ESI-MS(m/z):462.4([M-H]-)。
实施例20：{2-{{4-{[2-(1H-吲哚-4-基)乙基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯(Z20)的制备
参考实施例10的制备方法，得到{2-{{4-{[2-(1H-吲哚-4-基)乙基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯白色固体，收率为74.5％；m.p.:190.0–192.0℃；1HNMR(400MHz,DMSO-d6)δ11.07(s,1H),10.37(s,1H),8.59–8.51(m,1H),7.94(d,J＝8.9Hz,2H),7.83(d,J＝8.8Hz,2H),7.71(d,J＝8.8Hz,2H),7.36–7.31(m,1H),7.25(d,J＝8.1Hz,1H),7.11(d,J＝8.9Hz,2H),7.04–6.98(m,1H),6.84(d,J＝7.1Hz,1H),6.59(s,1H),4.85(s,2H),4.27(t,J＝7.1Hz,2H),3.55(q,J＝6.6Hz,2H),3.07(dd,J＝9.0,6.4Hz,2H),1.31(t,J＝7.1Hz,3H)；ESI-MS(m/z):484.3([M-H]-)。
实施例21：N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺(Z21)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺白色固体，收率为80.3％；m.p.:118.5–120.0℃；1H NMR(400MHz,CDCl3)δ11.79(s,1H),8.63(d,J＝8.3Hz,1H),8.53(s,1H),7.46–7.38(m,3H),7.25–7.16(m,2H),7.09–6.99(m,2H),6.62(s,1H),6.46(s,1H),4.91(d,J＝5.2Hz,2H),3.72(s,1H),3.65(t,J＝4.6Hz,4H),3.44(s,2H),2.75(t,J＝6.8Hz,2H),2.45(q,J＝6.6,6.1Hz,6H),1.82–1.76(m,2H)；IR(KBr,cm-1):3293,2924,2855,2814,1644,1598,1581,1515,1446,1283,755；ESI-MS(m/z):450.3([M+H]+)。
实施例22：N-[2-(1H-吲哚-4-基)甲基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺(Z22)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺白色固体，收率为81.4％；m.p.:160.3–162.0℃；1H NMR(400MHz,CDCl3)δ11.73(s,1H),8.66–8.56(m,1H),8.37(s,1H),7.47–7.35(m,3H),7.25(s,2H),7.25–7.16(m,1H),7.10(d,J＝7.2Hz,1H),7.05–6.98(m,1H),6.68–6.63(m,1H),4.93(d,J＝5.2Hz,2H),3.48(d,J＝6.1Hz,6H),1.60(d,J＝11.4Hz,2H),1.43–1.01(m,6H)；IR(KBr,cm-1):3305,2925,2851,1663,1641,1597,1581,1518,1447,754；ESI-MS(m/z):405.3([M+H]+)。
实施例23：N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺(Z23)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺白色固体，收率为77.8％；m.p.:164.2–163.8℃；1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),11.15(s,1H),9.26–9.14(m,1H),8.53(dd,J＝8.4,1.1Hz,1H),7.71(d,J＝9.5Hz,1H),7.55–7.43(m,3H),7.38–7.29(m,2H),7.19–7.12(m,1H),7.07–6.94(m,4H),6.62(s,1H),4.77(d,J＝5.9Hz,2H),3.69(s,1H),3.33(s,2H),3.25(s,2H)；IR(KBr,cm-1):3318,3194,3053,2922,2853,1659,1628,1591,1538,1509,1446,1291,838,747；ESI-MS(m/z):431.2([M+H]+)。
实施例24：N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(2,5-二甲氧基苯基)氨基]乙酰氨基}苯甲酰胺(Z24)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(2,5-二甲氧基苯基)氨基]乙酰氨基}苯甲酰胺白色固体，收率为77.6％；m.p.:168.2–170.0℃；1H NMR(400MHz,CDCl3)δ11.62(s,1H),8.65–8.57(m,1H),8.31(s,1H),7.48–7.32(m,3H),7.25–7.14(m,2H),7.06–6.97(m,2H),6.74(d,J＝8.6Hz,1H),6.55(s,1H),6.31–6.16(m,3H),5.15(t,J＝5.8Hz,1H),4.74(d,J＝5.1Hz,2H),3.98(d,J＝5.7Hz,2H),3.89(s,3H),3.72(s,3H)；IR(KBr,cm-1):3402,3307,2937,2830,1672,1635,1598,1582,1515,1446,837,757；ESI-MS(m/z):459.2([M+H]+)。实施例25：N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(三氟甲基)苯基]氨基}乙酰氨基}苯甲酰胺(Z25)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(三氟甲基)苯基]氨基}乙酰氨基}苯甲酰胺白色固体，收率为75.0％；m.p.:190.0–192.0℃；1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),11.13(s,1H),9.24–9.09(m,1H),8.47(d,J＝8.3Hz,1H),7.68(dd,J＝7.8,1.5Hz,1H),7.55–7.44(m,1H),7.34 7–.28(m,3H),7.16–7.08(m,1H),7.03–6.75(m,6H),6.49(s,1H),4.54(d,J＝5.7Hz,2H),3.91(d,J＝5.7Hz,2H)；IR(KBr,cm-1):3415,3236,2923,1663,1617,1598,1520,1450,1294,790,752；ESI-MS(m/z):467.2([M+H]+)。
实施例26：N-[2-(1H-吲哚-4-基)甲基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺(Z26)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺白色固体，收率为74.5％；m.p.:142.4–143.6℃；1H NMR(400MHz,CDCl3)δ11.68(s,1H),8.65–8.48(m,2H),7.47–7.33(m,3H),7.26–7.15(m,2H),7.08(d,J＝7.2Hz,1H),7.02–7.00(m,1H),6.62(s,1H),6.34(s,1H),4.91(d,J＝5.3Hz,2H),3.19(s,2H),2.67(q,J＝7.1Hz,4H),1.13(t,J＝7.1Hz,6H)；IR(KBr,cm-1):3258,3093,2965,2872,2823,1663,1597,1581,1516,1448,1291,753；ESI-MS(m/z):379.3([M+H]+)。
实施例27：N-[2-(1H-吲哚-4-基)甲基]-2-{2-[甲基(苯基)氨基]乙酰氨基}苯甲酰胺(Z27)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-[甲基(苯基)氨基]乙酰氨基}苯甲酰胺白色固体，收率为86.7％；m.p.:174.4–176.2℃；1H NMR(400MHz,CDCl3)δ11.62(s,1H),8.62(d,J＝8.4Hz,1H),8.29(s,1H),7.48–7.41(m,1H),7.40–7.27(m,4H),7.23–7.12(m,2H),7.05–6.97(m,2H),6.87–6.78(m,3H),6.49(s,1H),6.20(s,1H),4.68(d,J＝5.1Hz,2H),4.04(s,2H),3.24(s,3H)；IR(KBr,cm-1):3389,3278,3061,2924,2857,1665,1628,1599,1581,1518,1447,1284,753,690；ESI-MS(m/z):413.2([M+H]+)。
实施例28：N-[2-(1H-吲哚-4-基)甲基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺(Z28)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺白色固体，收率为84.2％；m.p.:150.2–152.0℃；1H NMR(400MHz,CDCl3)δ11.84(s,1H),8.62(d,J＝8.3Hz,1H),8.36(s,1H),7.54–7.33(m,4H),7.22–7.15(m,1H),7.12–6.97(m,2H),6.63(s,1H),6.40(s,1H),4.93(d,J＝5.4Hz,2H),3.87(t,J＝4.6Hz,2H),2.63(s,4H),2.17(s,4H)；IR(KBr,cm-1):3317,2923,2858,2829,1646,1598,1582,1512,1447,1291,752；ESI-MS(m/z):393.3([M+H]+)。
实施例29：N-[2-(1H-吲哚-4-基)甲基]-2-[2-(4-甲基哌嗪-1-基)乙酰氨基]苯甲酰胺(Z29)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-[2-(4-甲基哌嗪-1-基)乙酰氨基]苯甲酰胺白色固体，收率为86.4％；m.p.:184.5–186.0℃；1H NMR(400MHz,CDCl3)δ11.69(s,1H),8.60(d,J＝8.2Hz,1H),8.44(s,1H),7.44–7.38(m,3H),7.20–7.16(m,1H),7.10–7.01(m,3H),6.65(s,1H),6.40(s,1H),4.94(d,J＝5.4Hz,2H),3.49(s,8H),3.18(s,2H),2.67(s,3H)；IR(KBr,cm-1):3408,3251,2936,2817,1684,1650,1598,1582,1512,1446,1282,754；ESI-MS(m/z):406.3([M+H]+)。
实施例30：N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺(Z30)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺白色固体，收率为84.3％；m.p.:136.2–137.5℃；1H NMR(400MHz,CDCl3)δ11.77(s,1H),8.62(d,1H,J＝8.3Hz),8.36(s,1H),7.47–7.35(m,3H),7.26(s,1H),7.16–7.12(m,1H),7.06–7.01(m,4H),6.76(d,2H,J＝8.5Hz),6.61(s,1H),6.41–6.38(m,1H),4.89(d,2H,CH2),3.27–3.23(m,6H),2.75(t,4H),2.25(s,3H)；IR(KBr,cm-1):3403,3291,2918,2820,1644,1582,1515,1581,1448,1289,814,754；ESI-MS(m/z):482.2([M+H]+)。
实施例31：N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-氟苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺(Z31)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-氟苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺白色固体，收率为78.9％；m.p.:110.3–111.6℃；1H NMR(400MHz,CDCl3)δ11.76(s,1H),8.61(d,J＝8.2Hz,1H),8.45(s,1H),7.47–7.33(m,3H),7.26(s,1H),7.14–7.01(m,3H),6.90–6.85(m,2H),6.73(dd,J＝9.1,4.6Hz,2H),6.60(s,1H),6.47(d,J＝6.4Hz,1H),3.73(s,2H),3.25–3.11(m,6H),2.75(d,J＝5.1Hz,4H)；IR(KBr,cm-1):3370,3296,2944,2821,1733,1677,1639,1599,1583,1509,1449,1292,822,758；ESI-MS(m/z):486.2([M+H]+)。
实施例32：N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲氧基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺(Z32)的制备
参考实施例1的制备方法，得到N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲氧基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺白色固体，收率为86.1％；m.p.:210.5–212.1℃；1HNMR(400MHz,CDCl3)δ11.76(s,1H),8.62(d,J＝8.4Hz,1H),8.36(s,1H),7.53–7.40(m,2H),7.37(d,J＝8.1Hz,1H),7.26(s,2H),7.17–7.11(m,1H),7.08–7.02(m,2H),6.84–6.74(m,4H),6.41(s,1H),4.91(d,J＝5.4Hz,2H),3.74(s,3H),3.24(s,2H),3.19(t,J＝4.9Hz,4H),2.77(t,J＝4.9Hz,4H)；IR(KBr,cm-1):3347,3266,3170,2992,2941,2829,1671,1636,1598,1582,1553,1511,1447,1295,821,749；ESI-MS(m/z):498.3([M+H]+)。
实施例33：N-[2-(1H-吲哚-4-基)乙基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺(Z33)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺白色固体，收率为83.1％；m.p.:140.6–142.0℃；1H NMR(400MHz,CDCl3)δ11.71(s,1H),8.60-8.57(m,2H),7.41-7.39(m,1H),7.31(d,J＝8.1Hz,1H),7.22–7.13(m,3H),6.98-6.94(m,2H),6.61(s,1H),6.22(s,1H),3.80(q,J＝6.3Hz,2H),3.65(t,J＝4.6Hz,4H),3.47(s,1H),3.41(s,2H),3.21(t,J＝6.6Hz,2H),2.73(t,J＝6.8Hz,2H),2.46–2.42(m,6H),1.99(s,2H)；IR(KBr,cm-1):3272,2930,2854,1663,1632,1596,1581,1515,1446,1320,1290,760；ESI-MS(m/z):464.3([M+H]+)。
实施例34：N-[2-(1H-吲哚-4-基)乙基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺(Z34)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺白色固体，收率为86.4％；m.p.:168.5–170.0℃；1H NMR(400MHz,CDCl3)δ11.67(s,1H),8.61-8.58(m,1H),8.33(s,1H),7.43-7.39(m,1H),7.33(d,1H,J＝8.2Hz),7.26-7.15(m,4H),6.99-6.95(m,1H),6.65(s,1H),6.12(s,1H),3.85-3.81(m,2H),3.49(s,1H),3.45(s,2H),3.25-3.21(m,2H,),2.48-2.43(m,1H),1.99-1.96(m,2H),1.60-1.57(m,2H),1.26-1.12(m,6H)；IR(KBr,cm-1):3324,3263,2928,2852,1664,1629,1581,1543,1518,1447,1320,749,725；ESI-MS(m/z):419.3([M+H]+)。
实施例35：N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺(Z35)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺白色固体，收率为84.4％；m.p.:128.0–129.5℃；1H NMR(400MHz,CDCl3)δ11.80(s,1H),8.60(d,J＝8.4Hz,1H),8.35(s,1H),7.48–7.40(m,3H),7.32(d,J＝8.2Hz,1H),7.26(s,1H),7.22–7.15(m,3H),7.02–6.96(m,3H),6.22(s,1H),6.18(s,1H),3.86(t,J＝6.2Hz,2H),3.83(s,3H),3.45(s,2H),3.23(t,J＝6.6Hz,2H)；IR(KBr,cm-1):3310,3232,2918,2872,1669,1641,1599,1583,1519,1446,1291,825,754；ESI-MS(m/z):445.3([M+H]+)。
实施例36：N-[2-(1H-吲哚-4-基)乙基]-2-[2-(正丁基氨基)乙酰氨基]苯甲酰胺(Z36)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-[2-(正丁基氨基)乙酰氨基]苯甲酰胺白色固体，收率为81.8％；m.p.:114.6–116.2℃；1H NMR(400MHz,CDCl3)δ11.67(s,1H),8.60(d,J＝8.3Hz,1H),8.33(s,1H),7.46–7.38(m,1H),7.33(d,J＝8.2Hz,1H),7.25–7.12(m,3H),7.01–6.94(m,2H),6.63(s,1H),6.13(s,1H),3.83(q,J＝6.3Hz,2H),3.43(s,1H),3.23(t,J＝6.6Hz,2H),2.68(t,J＝7.3Hz,2H),1.57(q,J＝7.6Hz,2H),1.38(q,J＝7.5Hz,4H),0.91(t,J＝7.3Hz,3H)；IR(KBr,cm-1):3305,3259,2925,2869,1664,1630,1596,1581,1518,1446,1289,751；ESI-MS(m/z):393.3([M+H]+)。
实施例37：N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺(Z37)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺白色固体，收率为80.0％；m.p.:108.5–110.2℃；1H NMR(400MHz,CDCl3)δ11.63(s,1H),8.59(d,J＝8.4Hz,1H),8.33(s,1H),7.43–7.38(m,1H),7.31–7.29(m,1H),7.25(s,1H),7.20(s,1H),7.15–7.12(m,2H),7.09–7.06(m,2H),6.97–6.93(m,1H),6.87(d,J＝7.1Hz,1H),6.69–6.65(m,1H),6.56–6.51(m,2H),4.40(t,J＝5.5Hz,1H),4.12(q,J＝7.1Hz,1H),4.00(d,J＝5.3Hz,2H),3.66(q,J＝6.4Hz,2H),3.07(t,J＝6.6Hz,2H),2.33(s,3H)；IR(KBr,cm-1):3393,3274,3088,2927,2858,1741,1676,1632,1600,1584,1523,1448,1297,754；ESI-MS(m/z):427.3([M+H]+)。
实施例38：N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺(Z38)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺棕色固体，收率为87.9％；m.p.:166.0–168.0℃；1H NMR(400MHz,CDCl3)δ11.76(s,1H),11.29(s,1H),8.52(d,J＝8.4Hz,1H),8.47(s,1H),7.46–7.42(m,1H),7.34(d,J＝8.2Hz,1H),7.25–7.15(m,7H),7.06–6.95(m,2H),6.62(s,1H),6.34(s,1H),3.93(s,1H),3.81(q,J＝6.3Hz,2H),3.49(s,1H),3.22(t,J＝6.6Hz,2H)；IR(KBr,cm-1):3305,3000,2928,2907,2169,1669,1612,1588,1514,1446,1347,1299,752；ESI-MS(m/z):470.2([M+H]+)。
实施例39：N-[2-(1H-吲哚-4-基)乙基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺(Z39)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺白色固体，收率为87.3％；m.p.:162.3–164.0℃；1H NMR(400MHz,CDCl3)δ11.62(s,1H),8.55(d,J＝8.4Hz,1H),8.29(s,1H),7.45–7.37(m,1H),7.33(d,J＝8.2Hz,1H),7.25–7.12(m,3H),6.97(t,J＝7.5Hz,2H),6.65(s,1H),6.05(s,1H),3.82(q,J＝6.5Hz,2H),3.32–3.13(m,4H),2.67(q,J＝7.1Hz,4H),1.13(t,J＝7.1Hz,6H)；IR(KBr,cm-1):3258,3089,2971,2931,2859,1661,1631,1598,1581,1519,1447,1288,753；ESI-MS(m/z):393.4([M+H]+)。
实施例40：N-[2-(1H-吲哚-4-基)乙基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺(Z40)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺白色固体，收率为82.4％；m.p.:180.2–181.5℃；1H NMR(400MHz,CDCl3)δ11.80(s,1H),8.59(d,J＝8.4Hz,1H),8.43(s,1H),7.43-7.41(m,1H),7.32(d,J＝8.2Hz,2H),7.26–7.20(m,2H),7.17–7.14(m,1H),7.00–6.95(m,2H),6.65(s,1H),6.19(s,1H),3.92–3.89(m,4H),3.82(q,J＝6.5Hz,2H),3.24–3..20(m,2H),3.16(s,1H),2.61(t,J＝4.5Hz,8H)；IR(KBr,cm-1):3326,3192,3052,2931,2816,1663,1645,1582,1541,1516,1448,1286,754；ESI-MS(m/z):407.3([M+H]+)。
实施例41：N-[2-(1H-吲哚-4-基)乙基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺(Z41)的制备
参考实施例10的制备方法，得到N-[2-(1H-吲哚-4-基)乙基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺白色固体，收率为82.1％；m.p.:190.3–191.8℃；1H NMR(400MHz,CDCl3)δ11.76(s,1H),8.61(d,J＝8.3Hz,1H),8.29(s,1H),7.43-7.39(m,1H),7.30(d,J＝8.2Hz,1H),7.21–7.07(m,5H),7.00–6.86(m,4H),6.60(s,1H),6.11(s,1H),3.77(q,J＝6.5Hz,2H),3.37-3.34(s,4H),3.23–3.17(m,4H),2.77(t,J＝4.9Hz,4H),2.29(s,3H)；IR(KBr,cm-1):3406,3339,3196,2918,2830,1670,1640,1597,1581,1514,1445,1390,1308,820,758；ESI-MS(m/z):496.3([M+H]+)。
实施例42：在细胞水平考察化合物的细胞毒性
使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)测定评估目标化合物的细胞毒性。将犬肾上皮连续细胞系(Madin-Daby canine kidney cells,MDCK)细胞接种在96孔微量滴定板上的生长培养基中。过夜培养后，在每孔中加入化合物，5％ CO2，37℃孵育24h后，将新鲜制备的5mg·mL-1MTT磷酸盐缓冲盐溶液20μL加入到每个孔中，在37℃下继续孵育3h。终止孵育，用溶解在DMSO中的甲臜显色，通过酶联免疫分析仪读取540nm处的吸光度OD值，计算给药物后的细胞存活率。随后计算其CC50(加入的化合物对50％的细胞发生细胞毒性反应时的化合物浓度)。
按照上述方法测定本发明的化合物对正常MDCK细胞的细胞毒性，结果示于下表。
受试目标化合物对MDCK细胞的毒性实验的测试结果表明本发明化合物的细胞毒性相对较小。其中实施例10制备的N-[2-(1H-吲哚-4-基)乙基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺和实施例11制备的N-[2-(1H-吲哚-4-基)乙基]-4-{[(5-甲氧基-3H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺对MDCK细胞的毒性相对较大，CC50值分别为54.15和68.20μM，其余化合物的CC50值均大于100μM，毒性较小。
实施例43：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，吸出病毒，将化合物稀释成多个浓度，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27制备的N-[2-(1H-吲哚-4-基)甲基]-2-{2-[甲基(苯基)氨基]乙酰氨基}苯甲酰胺、实施例35制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺、实施例37制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺、实施例38制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺和实施例40制备的N-[2-(1H-吲哚-4-基)乙基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺对MDCK细胞保护活性较强。尤其是实施例37制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺和实施例38制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺，其EC50值分别为1.64μM和1.41μM。
实施例44：受试化合物对多种流感病毒株的抑制率测定
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，多种测试病毒株分别为A/WSN/33(H1N1)、A/PR/8(H1N1)和A/HK/68(H3N2)，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，将流感病毒A/WSN/33(H1N1)、A/PR/8(H1N1)或A/HK/68(H3N2)接种于MDCK细胞，37℃下吸附2h，倾去病毒液。加入不同浓度(100、50、25、12.5、6.25、3.125μmol·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。根据不同浓度下的病毒存活率计算每个化合物对不同病毒株的IC50。
对实施例37制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺和实施例38制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺进行进一步的流感病毒抑制实验，测得其对病毒株A/WSN/33(H1N1)的IC50分别为8.57μM和29.85μM；对病毒株A/PR/8(H1N1)的IC50分别为8.09μM和1.02μM；对病毒株A/HK/68(H3N2)的IC50分别为7.54μM和4.76μM。结果示于下表。因此，实施例37制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺和实施例38制备的N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺可用于制备广谱抗流感病毒抑制剂。
在下述制剂中，“活性组分”是指式I所示化合物，或其药学上可接受的盐。
实施例45：明胶胶囊
实施例46：片剂
实施例47：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48：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49：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50：栓剂
将活性组分通过60目U.S.筛，并将其悬浮于预先熔化的饱和脂肪酸甘油酯类化合物中，然后将混合物倾入至标准的2g腔栓剂模中并冷却。
实施例51：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，任何熟悉本领域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 (9)
1.一种结构式如式Ⅰ所示的N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物或其药学上可接受的盐：
其中，n为1或2，G选自(1H-苯并咪唑-2-基)硫基、(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基、[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基、苯氧基、C1-C3烷基取代苯氧基、C1-C3烷氧基取代苯氧基、硝基苯氧基、4-乙氧甲酰基苯氧基、萘氧基、C1-C3烷基取代苯胺基、C1-C3烷氧基取代苯胺基、卤素取代烷基苯胺基、卤素取代苄胺基、C1-C4烷基氨基、环己基氨基、吗啉基、[3-(吗啉-4-基)丙基]氨基、甲基哌嗪基、甲基取代苯基哌嗪基、卤素取代苯基哌嗪基、甲氧基取代苯基哌嗪基。
2.如权利要求1所述的N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物或其药学上可接受的盐，其特征在于，所述结构式I中，G选自(1H-苯并咪唑-2-基)硫基、(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基、[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基、4-乙氧甲酰基苯氧基、2-甲氧基苯氧基、4-甲氧基苯氧基、苯氧基、4-甲苯基氧基、4-硝基苯氧基、萘-1-基氧基、吗啉-4-基、[3-(吗啉-4-基)丙基]氨基、环己基氨基、(4-氟苄基)氨基、(2,5-二甲氧基苯基)氨基、[3-(三氟甲基)苯基]氨基、2-二乙基氨基、甲基(苯基)氨基、(4-氟苄基)氨基、正丁基氨基、(2-甲基苯基)氨基、4-甲基哌嗪-1-基、4-(4-甲基苯基)哌嗪-1-基、4-(4-氟苯基)哌嗪-1-基、4-(4-甲氧基苯基)哌嗪-1-基。
3.如权利要求1所述的N-[(1H-吲哚-4-基)烷基]苯甲酰胺类化合物或其药学上可接受的盐，其特征在于，所述的化合物选自如下化合物中任意一个或其药学上可接受的盐：
N-[(1H-吲哚-4-基)甲基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-{[(5-甲氧基-1H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺；N-[(1H-吲哚-4-基)甲基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺；{2-{{4-{[(1H-吲哚-4-基)甲基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯；
N-[(1H-吲哚-4-基)甲基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-(吗啉-4-基)苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-[(对甲苯基氧基)乙酰氨基]苯甲酰胺；
N-[(1H-吲哚-4-基)甲基]-4-(苯氧基)苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-{[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-{[(5-甲氧基-3H-咪唑并[4,5-b]吡啶-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-{{[6-(二氟甲氧基)-1H-苯并咪唑-2-基]硫基}乙酰氨基}苯甲酰胺；N-[2-(1H-吲哚-4-基)乙基]-4-(吗啉-4-基)苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲苯基氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(2-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(4-硝基苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(4-甲氧基苯氧基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-4-[(萘-1-基氧基)乙酰氨基]苯甲酰胺；
{2-{{4-{[2-(1H-吲哚-4-基)乙基]氨基甲酰基}苯基}氨基}-2-氧代乙氧基}苯甲酸乙酯；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[(2,5-二甲氧基苯基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-{[3-(三氟甲基)苯基]氨基}乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[甲基(苯基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-[2-(4-甲基哌嗪-1-基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-氟苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)甲基]-2-{2-[4-(4-甲氧基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-{[3-(吗啉-4-基)丙基]氨基}乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(环己基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(4-氟苄基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(正丁基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(2-甲基苯基)氨基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[(1H-苯并咪唑-2-基)硫基]乙酰氨基}苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(二乙基氨基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-[2-(吗啉-4-基)乙酰氨基]苯甲酰胺；
N-[2-(1H-吲哚-4-基)乙基]-2-{2-[4-(4-甲基苯基)哌嗪-1-基]乙酰氨基}苯甲酰胺。
4.一种药物组合物，其特征在于，包括作为活性成分的权利要求1-3任意一项所述的化合物或及所述化合物在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。
5.权利要求1所述的化合物的制备方法，其特征在于，包括以下步骤：
6.权利要求1-3任意一项所述的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。
7.权利要求4所述的药物组合物在制备流感病毒治疗药物中的应用。
8.根据权利要求6所述的应用，其特征在于，所述流感病毒为A/WSN/33、A/PR/8及A/HK/68；以有效量的权利要求1-3任意一项所述的化合物或其药学上可接受的盐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。
9.根据权利要求7所述的应用，其特征在于，所述流感病毒为A/WSN/33、A/PR/8及A/HK/68；以有效量的权利要求4所述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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