CN109824574B - 吲哚-3-甲酰胺类化合物及其应用 - Google Patents
吲哚-3-甲酰胺类化合物及其应用 Download PDFInfo
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- CN109824574B CN109824574B CN201910274912.0A CN201910274912A CN109824574B CN 109824574 B CN109824574 B CN 109824574B CN 201910274912 A CN201910274912 A CN 201910274912A CN 109824574 B CN109824574 B CN 109824574B
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- indole
- carboxamide
- oxoethoxy
- ethyl
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Abstract
本发明属于医药技术领域，涉及吲哚‑3‑甲酰胺类化合物及其应用。所述的吲哚‑3‑甲酰胺类化合物的结构通式如下所示：其中，R1、R2、R3、R如权利要求书和说明书所述。本发明的吲哚‑3‑甲酰胺类化合物以及该类化合物药学上适用的酸加成的盐可以作为抗氧化剂，用于制备治疗或预防与蛋白质氧化损伤引起的相关疾病药物，与蛋白质氧化损伤引起的相关疾病是阿尔茨海默症、帕金森氏病、糖尿病和慢性肾衰等。
Description
技术领域
本发明属于医药技术领域，涉及吲哚-3-甲酰胺类化合物及其制备方法和其作为抗氧化剂的应用。
背景技术
由自由基介导的蛋白质氧化产物作为体内氧化性损伤的特异性标志物，是近几年自由基生物学研究的热点之一。在细胞内、外环境中，蛋白质都是自由基和其他氧化剂作用的主要目标。据估计，细胞内的大分子中，由蛋白质清除的自由基占活性自由基总量的50％～75％。由于某些蛋白质具有较长的半衰期，容易造成氧化性损伤的积累，因此蛋白质氧化性损伤的形成可能是哺乳动物氧化性损伤的高度敏感指标。
细胞内氧化性蛋白的水平反映了蛋白质氧化水平和氧化蛋白降解之间的动态平衡。这种平衡与产生活性氧(reactive oxygen species,ROS)的多种因素有关，也与降解氧化性损伤蛋白的蛋白酶体的活性和浓度有关。各种不同的生理条件和环境因素均可以导致ROS的产生，而ROS及其衍生物均可以启动蛋白质的修饰。但ROS及其衍生物能否发挥损伤作用，取决于各种抑制ROS产生或使其转变为无活性衍生物的酶和非酶性抗氧化剂。
现有研究表明，蛋白质氧化损伤与许多疾病相关，包括阿尔茨海默症(AD)、帕金森氏病(PD)、糖尿病、慢性肾衰、先兆子痫、严重感染等。(1)蛋白质氧化与神经退行性疾病：AD是最常见的神经退行性疾病，主要临床表现为进行性记忆丧失和痴呆。对AD患者的研究发现，AD的发生与氧化应激有关，其海马回和海马旁回组织切片中氧化性蛋白的水平升高，也有报告AD患者脑组织羰基还原酶的水平升高。羰基还原酶可以使具有细胞毒性的羰基被还原而解毒，该酶水平升高可能与蛋白质羰基化水平升高，从而诱导酶的生成增加有关(Markesbery WR.Protein oxidation in the brain in Alzheimer'sdisease.Neuroscience.2001,103(2):373-383.)。对AD患者的尸体解剖发现，其脑组织与脑脊液中3-硝基酪氨酸水平较相应的对照组分别升高5～8倍和6倍，并且其脑脊液中硝基化Mn-SOD水平升高，而线粒体蛋白中Mn-SOD的硝基化可以使该酶失活，从而导致其清除自由基的能力降低(Beal MF.Oxidatively modified proteins in aging anddisease.Free Radic Biol Med.2002,32(9):797-803.)。此外，有人发现，和正常对照相比，AD患者血浆中总氧化蛋白的水平升高，并且通过Western印迹显示，血浆蛋白中被氧化的蛋白在电泳时只出现一条带，而这种蛋白在体外对氧化修饰更敏感，提示该种蛋白可能是一个特异的蛋白质氧化损伤的指标。Korolainen MA等的研究则认为，AD患者体内的蛋白质氧化和降解之间的平衡发生了改变。以上证据都提示，蛋白质羰基的形成可能参与了AD的发生(Korolainen MA,Goldsteins G,Alafuzoff I,Koistinaho J,
T.Proteomicanalysis of protein oxidation in Alzheimer's diseasebrain.Electrophoresis.2002Sep；23(19):3428-3433.)。PD也是较常见的神经退行性疾病，以进行性运动障碍为主要临床表现。研究发现，PD患者脑黑质、基底神经节、苍白球、额部皮质、小脑等脑部组织中蛋白质羰基水平均升高，并且通过免疫组化染色发现患者脑脊液中硝化的SOD水平明显升高，这提示蛋白质氧化损伤与PD的发生有关。(2)蛋白质氧化与慢性肾功能衰竭和透析治疗：大量研究表明，慢性肾功能衰竭与氧化应激有关，近期的研究还发现，慢性肾功能衰竭患者的透析治疗也可能影响患者的氧化应激。对慢性肾功能衰竭患者和健康志愿者的研究表明，慢性肾功能衰竭患者血浆中总蛋白羰基的水平高于健康对照组，采用Western印迹进一步分析发现，与健康对照相比，慢性肾衰患者血浆中的血清蛋白更容易被氧化，提示不同的蛋白质对氧化损伤的敏感性可能有差异。对慢性肾衰患者采用透析治疗的研究发现，血液透析、腹膜透析和未采用透析治疗的慢性肾衰患者血浆中蛋白质羰基水平依次降低，即采用血液透析者高于腹膜透析者，后者又高于未用透析者。近期的研究也表明，血液透析过程中患者机体的抗氧化能力降低，氧化性蛋白和脂类的水平均升高，这也可能是经血液透析后血清脂类和蛋白质对氧化性修饰的敏感性增加所致。(3)蛋白质氧化与其他疾病：Zusterzeel PL等对孕妇的观察发现，孕妇血浆中蛋白质羰基水平明显高于未怀孕的妇女，提示怀孕时可能处于一定程度的氧化应激状态。此外，还发现先兆子痫的孕妇血浆中蛋白质羰基水平也明显高于健康孕妇，提示该病的发生可能与蛋白质氧化损伤有关(Zusterzeel PL,Mulder TP,Peters WH,Wiseman SA,Steegers EA.Plasmaprotein carbonyls in nonpregnant,healthy pregnant and preeclamptic women.FreeRadic Res.2000Nov；33(5):471-476.)。近期的研究还发现，先兆子痫伴有溶血、肝酶升高和低血小板综合征的患者，蜕膜和胎盘组织中蛋白质羰基含量较健康孕妇明显升高，并且血浆总抗氧化能力也降低，这说明由ROS介导的损伤可能参与了这种疾病的发生。此外，研究还发现，类风湿性关节炎患儿血浆中蛋白质羰基水平较健康儿童升高，并且处于疾病活动期的患儿血浆中蛋白羰基水平要高于缓解期的对照组患儿，提示蛋白质氧化与该病的发生和发展有关。对脓毒血症患者的研究发现，其血浆蛋白质羰基的含量明显高于相应的对照组，并且这一过程与人体蛋白的丢失有关。
所以，抗氧化剂的作用已引起人们广泛的关注，生物学家和临床学家对抗氧化剂感兴趣是因为抗氧化剂能保护人体免于活性氧的损伤。抗氧化剂多用于在人体内调节氧化造成的损伤。抗氧化剂是指在低浓度下能有效延缓或阻止底物氧化的物质。被氧化的底物包括蛋白质、脂质、糖和DNA。
发明内容
本发明所解决的技术问题是提供一种如式I所示的化合物、其前体药物和药物活性代谢物及其药学上可接受的盐，并提供了其在制备预防和/或治疗蛋白质氧化损伤相关的疾病的药物中的应用。
其中，
R1可以独立地选自氢、C1-C4烷基；
R2、R3可以独立地选自H，C1-C4烷基；或R2、R3与它们相连的氮原子一起组成1-哌啶基，1-吡咯烷基，4-吗啉基，2-(4-吗啉基)乙胺基，3-(4-吗啉基)丙胺基，苄胺基或取代苄胺基，苯胺基或取代苯胺基，取代或未取代的2-(2-甲氧基苯氧基)乙胺基；所述的取代基为：C1-C4烷基、C1-C4烷氧基、卤素。
R可以独立地选自苯基或取代苯基，呋喃基，苄基或取代苄基，苯氧甲基或取代苯氧甲基，取代氨基C1-C4烷基，或(4-吗啉基)C1-C4烷基，所述取代基为：C1-C4烷基、C1-C4烷氧基、卤素。
优选为苯基、4-氟苯基，4-氯苯基，4-甲基苯基，4-甲氧基苯基，2-呋喃基，(2-甲氧基苯氧基)甲基，3,4-二甲氧基苄基，(4-吗啉基)甲基，或2-(4-吗啉基)乙基。
“药物可接受的盐”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、果胶脂酸盐等。碱盐包括铵盐，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，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等。优选用于生成酸加成盐的酸包括盐酸、对甲苯磺酸、甲磺酸、顺丁烯二酸、苹果酸、苦味酸、柠檬酸、对氨基苯磺酸。
“药学上可接受的”如药学上可接受地载体、赋形剂、前体药物等，指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。
“药学活性代谢物”指药学上可接受并有效的式I化合物的代谢产物。
本发明也涉及抑制蛋白质氧化损伤的药用组合物，该组合物含有式I化合物，其前体药物和药物活性代谢物或其药学上适用的酸加成盐以及药学上适用的载体。
本发明所述化合物作为全新结构类型的抗氧化剂，具有结构类型新颖，药效作用与现有药物相当或优于现有药物的特点，可用于治疗或预防与蛋白质氧化损伤引起的相关疾病如AD、PD、糖尿病、慢性肾衰、先兆子痫、严重感染等，具有良好的应用价值和开发应用前景。
本发明化合物可以通过不同的方法给患者服用，例如以胶囊剂或片剂口服，以无菌溶液剂或混悬剂给药，并且在某些情况下，可以以溶液剂形式静脉注射。可以将本发明的游离碱化合物以其药学上适用的酸加成盐形式进行配制和服用。
具体实施方式
如下反应流程概括了制备本发明化合物的合成步骤。
反应流程
以下述实例详细叙述本发明。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-苄基-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z01)的制备
步骤A：3-甲胺基-2-丁烯酸乙酯的制备
将乙酰乙酸乙酯(15.01g,0.12mol)置于100mL茄形瓶中，搅拌下缓慢滴加甲胺水溶液0.36mol，滴加完毕后室温条件下继续反应3h，静置分层，有机相水洗一次，无水硫酸钠干燥，过滤，得到淡黄色液体15.08g，收率：91.4％。
步骤B：1,2-二甲基-5-羟基-1H-吲哚-3-羧酸乙酯的制备
将对苯醌(11.89g,0.11mol)和丙酮120mL置于250mL茄形瓶中，搅拌下滴加3-甲胺基-2-丁烯酸乙酯0.11mol，滴加完毕后控温30℃继续反应2h，蒸除溶剂，产物粗品丙酮重结晶，得到白色色固体18.92g，收率：73.7％,M.p.:208-210℃.ESI-MS,m/z:calcd.233.11(M+)；found 234.1([M+H]+),356.1([M+Na]+)。
步骤C：1,2-二甲基-5-羟基-1H-吲哚-3-甲酸的制备
将1,2-二甲基-5-羟基-1H-吲哚-3-羧酸乙酯0.043mol、氢氧化钠(17.15g,0.43mol)、乙醇100mL及水50mL置于250mL茄形瓶中，加热回流反应12h，反应液凉至室温，用6mol/L的盐酸水溶液调pH＝2，析出大量固体，抽滤，产物粗品以乙醇重结晶，得到黄色固体6.79g，收率76.98％,M.p.:216-217℃；ESI-MS,m/z:calcd.205.07(M+)；found 204.1([M-H]-)；1H NMR(400MHz,DMSO-d6):δ11.76(s,1H),8.84(s,1H),7.38(d,J＝2.3Hz,1H),7.25(d,J＝8.7Hz,1H),6.63(dd,J＝8.7,2.4Hz,1H),3.63(s,3H),2.65(s,3H)。
步骤D：N-苄基-1,2-二甲基-5-羟基-1H-吲哚-3-甲酰胺的制备
将1,2-二甲基-5-羟基-1H-吲哚-3-甲酸0.020mol、苄胺(6.42g,0.060mol)、N,N-二甲基甲酰胺10mL和二氯甲烷100mL置于250mL茄形瓶中，依次将HOBt(4.05g,0.030mol)、三乙胺(6.07g,0.060mol)、EDCI(5.75g,0.030mol)分别加入其中，室温搅拌反应16h，反应液以2mol/L盐酸水溶液和饱和碳酸氢钠溶液洗涤，加入大量水搅拌使析出固体，抽滤，产物粗品乙醇重结晶，得到白色固体3.41g，收率58.0％,M.p.:211-213℃；ESI-MS,m/z:calcd.294.14(M+)；found 295.1([M+H]+),317.1([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ8.81(s,1H),7.94(d,J＝2.3Hz,1H),7.37(d,J＝8.6Hz,1H),7.36–7.22(m,5H),7.16(dd,J＝8.7,2.3Hz,1H),4.47(d,J＝6.0Hz,2H),3.61(s,3H),2.56(s,3H)。
步骤E：N-苄基-1,2-二甲基-5-羟基-1H-吲哚-3-甲酰胺的制备
将N-苄基-1,2-二甲基-5-羟基-1H-吲哚-3-甲酰胺0.020mol、苄胺(6.42g,0.060mol)、N,N-二甲基甲酰胺10mL和二氯甲烷100mL置于250mL茄形瓶中，依次将HOBt(4.05g,0.030mol)、三乙胺(6.07g,0.060mol)、EDCI(5.75g,0.030mol)分别加入其中，室温搅拌反应16h，反应液以2mol/L盐酸水溶液和饱和碳酸氢钠溶液洗涤，加入大量水搅拌使析出固体，抽滤，产物粗品乙醇重结晶，得到白色固体3.41g，收率58.0％,M.p.:211-213℃；ESI-MS,m/z:calcd.294.14(M+)；found 295.1([M+H]+),317.1([M+Na]+).；1H NMR(400MHz,DMSO-d6):δ8.81(s,1H),7.94(d,J＝2.3Hz,1H),7.37(d,J＝8.6Hz,1H),7.36–7.22(m,5H),7.16(dd,J＝8.7,2.3Hz,1H),4.47(d,J＝6.0Hz,2H),3.61(s,3H),2.56(s,3H)。
步骤F：N-苄基-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z01)的制备
将氯乙酰基二乙胺(2.38g,0.016mol)、N-苄基-1,2-二甲基-5-羟基-1H-吲哚-3-甲酰胺(0.89g,0.0030mol)、无水碳酸钾(4.28g,0.031mol)、碘化钾(0.05g,0.00031mol)及N,N-二甲基甲酰胺20mL置于100mL茄形瓶中，控温80℃反应16h，反应液凉至室温并将其倾入250mL水中，搅拌3h，抽滤得黄色固体，经硅胶柱层析分离(v(石油醚):v(乙酸乙酯)＝5:1)得到白色粉末0.87g，收率：71.3％。M.p.:119-120℃；IR:(KBr,cm-1):υ3444.3,2927.6,1660.6,1620.2,1431.2,1383.6,1257.3,1190.8,1085.3,834.3,776.2,745.1,701.8；ESI-MS,m/z:calcd.407.22(M+)；found 408.3([M+H]+),430.2([M+Na]+),446.2([M+K]+).；1HNMR(400MHz,CDCl3):δ7.43(d,J＝2.3Hz,1H),7.37–7.27(m,5H),7.21(d,J＝8.9Hz,1H),6.91(dd,J＝8.9,2.4Hz,1H),4.71(d,J＝5.7Hz,2H),4.66(s,2H),3.66(s,3H),3.38(dd,J＝7.1,2.9Hz,2H),3.35(dd,J＝7.1,2.9Hz,2H),2.72(s,2H),1.17(t,J＝7.1Hz,3H),1.11(t,J＝7.1Hz,3H)。
实施例2：N-苄基-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z02)的制备
参照实施例1的制备方法，得到白色固体0.62g，收率：49.2％。M.p.:105-106℃；IR:(KBr,cm-1):υ3434.3,2925.2,1661.7,1617.5,1530.2,1478.3,1347.7,1259.2,1189.2,1139.2,1082.9,835.4,756.0,704.4；ESI-MS,m/z:calcd.421.24(M+)；found 422.3([M+H]+),444.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.43(d,J＝2.3Hz,1H),7.36–7.27(m,5H),7.21(d,J＝8.9Hz,1H),6.90(dd,J＝8.9,2.4Hz,1H),4.71(d,J＝5.7Hz,2H),4.65(s,2H),4.12(q,J＝7.2Hz,2H),3.36(q,J＝7.0Hz,4H),2.72(s,3H),1.33(t,J＝7.2Hz,3H),1.17(t,J＝7.1Hz,3H),1.11(t,J＝7.1Hz,3H)。
实施例3：N-苄基-5-(2-二正丙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z03)的制备
参照实施例1的制备方法参照实施例1的制备方法，得到白色固体1.08g，收率：82.4％。M.p.:123-125℃；IR:(KBr,cm-1):υ3349.0,2964.9,2871.1,1656.2,1484.3,1382.6,1270.8,1190.0,1143.3,1084.6,926.2,839.0,798.2,741.2,697.8；ESI-MS,m/z:calcd.435.25(M+)；found 436.2([M+H]+),458.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.43(d,J＝2.3Hz,1H),7.38–7.26(m,5H),7.20(d,J＝8.9Hz,1H),6.90(dd,J＝8.9,2.4Hz,1H),4.71(d,J＝5.7Hz,2H),4.67(s,2H),3.66(s,3H),3.26(q,J＝7.0Hz,4H),2.72(s,2H),1.56–1.48(m,4H),0.89(t,J＝7.4Hz,3H),0.84(t,J＝7.4Hz,3H)。
实施例4：N-苄基-5-(2-二正丙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z04)的制备
参照实施例1的制备方法参照实施例1的制备方法，得到白色固体1.07g，收率：79.3％。M.p.:129-130℃；IR:(KBr,cm-1):υ3444.2,2930.3,1657.5,1618.2,1482.3,1383.6,1272.0,1193.7,1145.4,1090.3,795.4,698.8；ESI-MS,m/z:calcd.449.27(M+)；found 450.2([M+H]+),472.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.42(d,J＝2.2Hz,1H),7.37–7.27(m,5H),7.20(d,J＝8.9Hz,1H),6.89(dd,J＝8.9,2.3Hz,1H),4.70(d,J＝5.8Hz,2H),4.67(s,2H),4.11(q,J＝7.1Hz,2H),3.29–3.21(m,4H),2.71(s,3H),1.60–1.52(m,4H),1.34(t,J＝7.3Hz,3H),0.89(t,J＝7.4Hz,3H),0.84(t,J＝7.4Hz,3H)。
实施例5：N-苄基-5-(2-二异丁胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z05)的制备
参照实施例1的制备方法，得到黄色固体1.12g，收率：80.6％。M.p.:105-106℃；IR:(KBr,cm-1):υ3425.2,2919.0,2850.0,1621.9,1485.5,1384.5,1194.7,1120.5,821.2,778.6,697.9；ESI-MS,m/z:calcd.463.28(M+)；found 464.3([M+H]+)；1H NMR(400MHz,CDCl3):δ7.43(d,J＝2.3Hz,1H),7.38–7.27(m,5H),7.19(d,J＝8.9Hz,1H),6.90(dd,J＝8.8,2.4Hz,1H),4.71(d,J＝5.6Hz,2H),4.70(s,2H),3.65(s,3H),3.20–3.11(m,2H),2.72(s,3H),1.29–1.25(m,4H),0.92(d,J＝6.7Hz,6H),0.78(t,J＝6.7Hz,6H)。
实施例6：N-苄基-5-(2-二异丁胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z06)的制备
参照实施例1的制备方法，得到白色固体0.75g，收率：52.4％。M.p.:101-103℃；IR:(KBr,cm-1):υ3423.1,2959.1,2920.8,1656.7,1621.6,1543.7,1484.8,1422.4,1384.8,1209.4,1143.3,1091.9,817.5,744.8,698.8；ESI-MS,m/z:calcd.477.30(M+)；found478.4([M+H]+),500.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.43(d,J＝2.3Hz,1H),7.38–7.25(m,5H),7.20(d,J＝8.9Hz,1H),6.89(dd,J＝8.8,2.3Hz,1H),4.71(d,J＝5.8Hz,2H),4.66(s,2H),4.12(q,J＝7.1Hz,2H),3.21–3.14(m,4H),2.72(s,3H),2.02–1.67(m,4H),1.33(t,J＝7.1Hz,3H),0.92(d,J＝6.7Hz,6H),0.79(t,J＝6.7Hz,6H)。
实施例7：N-苄基-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z07)的制备
参照实施例1的制备方法，得到白色固体0.86g，收率：68.3％。M.p.:78-80℃；IR:(KBr,cm-1):υ3429.6,2923.2,2853.6,1641.2,1618.1,1488.8,1440.1,1212.0,1163.4,1082.8,1017.8,874.0,699.6；ESI-MS,m/z:calcd.419.22(M+)；found 420.4([M+H]+),442.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.43(d,J＝2.4Hz,1H),7.38–7.26(m,5H),7.20(d,J＝8.9Hz,1H),6.91(dd,J＝8.9,2.4Hz,1H),4.71(d,J＝5.8Hz,1H),4.66(s,2H),3.66(s,3H),3.52(t,J＝5.3Hz,2H),3.45(t,J＝5.0Hz,2H),2.72(s,3H),1.61-1.53(m,6H)。
实施例8：N-苄基-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z08)的制备
参照实施例1的制备方法，得到白色固体0.83g，收率：58.0％。M.p.:89-90℃；IR:(KBr,cm-1):υ3551.3,3404.6,3336.9,1646.8,1613.0,1546.0,1488.7,1419.9,1384.5,1214.2,1164.4,1977.0,984.4,850.0,806.9,727.7,695.2；ESI-MS,m/z:calcd.433.24(M+)；found 434.7([M+H]+)；1H NMR(400MHz,CDCl3):δ7.43(d,J＝2.3Hz,1H),7.38–7.25(m,5H),7.21(d,J＝8.9Hz,1H),6.90(dd,J＝8.8,2.4Hz,1H),4.71(d,J＝5.7Hz,2H),4.66(s,2H),4.12(q,J＝7.2Hz,2H),3.52(t,J＝5.3Hz,2H),3.44(t,J＝5.0Hz,2H),2.71(s,3H),1.66–1.48(m,6H),1.33(t,J＝7.2Hz,3H)。
实施例9：N-苄基-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z09)的制备
参照实施例1的制备方法，得到黄色固体0.78g，收率：61.9％。M.p.:110-112℃；IR:(KBr,cm-1):υ3442.6,2856.0’1653.8,1483.8,1384.1,1274.2,1207.7,1162.8,1031.3,923.2,850.8,698.4；ESI-MS,m/z:calcd.421.20(M+)；found 422.2([M+H]+),444.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.44(d,J＝2.3Hz,1H),7.38–7.27(m,5H),7.21(d,J＝8.9Hz,1H),6.89(dd,J＝8.9,2.4Hz,1H),4.71(d,J＝5.7Hz,2H),4.68(s,2H),3.67(s,3H),3.63–3.57(m,8H),2.72(s,3H)。
实施例10：N-苄基-5-[2-(4-吗啉基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z10)的制备
参照实施例1的制备方法，得到白色固体1.08g，收率：82.4％。M.p.:161-162℃；IR:(KBr,cm-1):υ3338.5,2969.3,2931.8,1663.5,1546.4,1481.6,1440.8,1279.5,1196.4,1161.6,1112.1,1035.4,970.1,851.3,758.6,707.8；ESI-MS,m/z:calcd.435.22(M+)；found 436.7([M+H]+)；1H NMR(400MHz,CDCl3):δ7.44(d,J＝2.3Hz,1H),7.38–7.27(m,5H),7.22(d,J＝8.8Hz,1H),6.88(dd,J＝8.8,2.3Hz,1H),4.71(d,J＝5.4Hz,2H),4.67(s,2H),4.16(q,J＝7.1Hz,2H),3.64–3.52(m,8H),2.72(s,3H),1.34(t,J＝7.2Hz,3H)。
实施例11：N-苄基-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z11)的制备
参照实施例1的制备方法，得到白色固体0.99g，收率：66.0％。M.p.:180-181℃；IR:(KBr,cm-1):υ3426.8,2923.0,2852.3,1628.8,1384.4,1253.4,1124.5,777.8,618.2；ESI-MS,m/z:calcd.501.23(M+)；found 502.4([M+H]+),524.4([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝2.3Hz,1H),7.38–7.27(m,5H),7.22(d,J＝8.9Hz,1H),6.90–6.81(m,5H),4.68(d,J＝5.6Hz,2H),4.50(s,2H),4.10(t,J＝5.1Hz,2H),3.76(s,3H),3.74–3.71(m,2H),3.66(s,3H),2.72(s,3H)。
实施例12：N-苄基-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z12)的制备
参照实施例1的制备方法，得到白色固体1.43g，收率：92.3％。M.p.:157-159℃；IR:(KBr,cm-1):υ3455.6,2922.3,1686.6,1619.2,1508.6,1482.9,1384.0,1253.7,1209.9,1127.8,1027.1,975.5,745.5,698.1；ESI-MS,m/z:calcd.515.24(M+)；found 516.3([M+H]+),538.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝2.4Hz,1H),7.38–7.27(m,5H),7.23(d,J＝8.8Hz,1H),6.89–6.84(m,5H),4.68(d,J＝5.7Hz,2H),4.50(s,2H),4.14–4.09(m,4H),3.76(s,3H),3.73(t,J＝5.3Hz,2H),2.72(s,3H),1.34(t,J＝7.2Hz,3H)。
实施例13：N-(4-氟苄基)-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z13)的制备
参照实施例1的制备方法，得到白色固体0.86g，收率：67.2％。M.p.:133-134℃；IR:(KBr,cm-1):υ3442.8,2972.6,2931.4,1658.0,1619.9,1487.1,1383.6,1218.2,1143.2,1086.9,974.6,822.1,757.6,568.6；ESI-MS,m/z:calcd.425.21(M+)；found 426.3([M+H]+),448.4([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.41(dd,J＝8.6,5.4Hz,2H),7.29(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.03(t,J＝8.7Hz,2H),6.91(dd,J＝8.8,2.4Hz,1H),4.68(s,2H),4.66(d,J＝5.6Hz,2H),3.66(s,3H),3.37(q,J＝6.9Hz,4H),2.72(s,3H),1.17(t,J＝7.1Hz,3H),1.10(t,J＝7.1Hz,3H)。
实施例14：N-(4-氟苄基)-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z14)的制备
参照实施例1的制备方法，得到白色固体0.85g，收率：64.4％。M.p.:135-137℃；IR:(KBr,cm-1):υ3423.8,3278.3,2925.4,1646.1,1625.0,1510.1,1482.6,1383.4,1263.2,1207.6,1155.5,1070.6,822.5,791.0,706.7；ESI-MS,m/z:calcd.439.23(M+)；found440.4([M+H]+)；1H NMR(400MHz,CDCl3):δ7.40(dd,J＝8.5,5.5Hz,2H),7.29(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.02(t,J＝8.7Hz,2H),6.89(dd,J＝8.8,2.3Hz,1H),4.66(d,J＝5.8Hz,4H),4.11(q,J＝7.2Hz,2H),3.38(q,J＝7.1Hz,4H),2.71(s,3H),1.32(t,J＝7.2Hz,3H),1.17(t,J＝7.1Hz,3H),1.10(t,J＝7.1Hz,3H)。
实施例15：N-(4-氟苄基)-5-(2-二正丙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z15)的制备
参照实施例1的制备方法，得到白色固体1.06g，收率：77.9％。M.p.:145-147℃；IR:(KBr,cm-1):υ3446.5,2930.0,2360.9,1655.5,1508.8,1484.3,1383.4,1271.9,1190.1,1095.7,819.2,798.4,777.4；ESI-MS,m/z:calcd.453.24(M+)；found454.4([M+H]+)；1H NMR(400MHz,CDCl3):δ7.40(dd,J＝8.7,5.4Hz,2H),7.28(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.03(t,J＝8.7Hz,2H),6.89(dd,J＝8.8,2.4Hz,1H),4.70(s,2H),4.67(d,J＝5.6Hz,2H),3.66(s,3H),3.29–3.24(m,4H),2.72(s,3H),1.54–1.47(m,4H),0.90(t,J＝7.4Hz,3H),0.83(t,J＝7.4Hz,3H)。
实施例16：N-(4-氟苄基)-5-(2-二正丙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z16)的制备
参照实施例1的制备方法，得到白色固体0.68g，收率：46.9％。M.p.:120-122℃；IR:(KBr,cm-1):υ3304.4,2963.1,2931.9,1658.7,1619.4,1510.7,1483.0,1423.2,1272.9,1207.6,1158.4,1091.3,835.3,794.0,706.7；ESI-MS,m/z:calcd.467.26(M+)；found468.4([M+H]+),490.4([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(dd,J＝8.5,5.4Hz,2H),7.29(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.02(t,J＝8.7Hz,2H),6.88(dd,J＝8.8,2.4Hz,1H),4.69(s,2H),4.67(d,J＝5.8Hz,2H),4.12(q,J＝7.2Hz,2H),3.32–3.21(m,4H),2.72(s,3H),1.59–1.49(m,4H),1.33(t,J＝7.2Hz,3H),0.90(t,J＝7.4Hz,3H),0.83(t,J＝7.4Hz,3H)。
实施例17：N-(4-氟苄基)-5-(2-二异丁胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z17)的制备
参照实施例1的制备方法，得到白色固体0.88g，收率：61.1％。M.p.:137-139℃；IR:(KBr,cm-1):υ3355.2,2961.8,1656.6,1540.3,1485.8,1385.1,1215.7,1145.0,1082.5,821.1,795.3,758.4,712.4,589.9；ESI-MS,m/z:calcd.481.27(M+)；found482.4([M+H]+),504.4([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.41(dd,J＝8.7,5.4Hz,2H),7.30(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),7.02(t,J＝8.7Hz,2H),6.89(dd,J＝8.8,2.4Hz,1H),4.73(s,2H),4.67(d,J＝5.6Hz,2H),3.66(s,3H),3.20–3.13(m,2H),2.72(s,3H),2.01–1.87(m,4H),0.93(d,J＝6.7Hz,6H),0.77(t,J＝6.7Hz,6H)。
实施例18：N-(4-氟苄基)-5-(2-二异丁胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z18)的制备
参照实施例1的制备方法，得到白色固体0.78g，收率：50.7％。M.p.:112-114℃；IR:(KBr,cm-1):υ3444.7,3295.3,2960.1,2921.4,1665.1,1631.3,1509.6,1483.6,1384.2,1213.4,1151.4,1090.2,842.8,821.8,796.1,749.7,691.1；ESI-MS,m/z:calcd.495.29(M+)；found 496.3([M+H]+),518.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(dd,J＝8.6,5.4Hz,2H),7.30(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),7.02(t,J＝8.7Hz,2H),6.88(dd,J＝8.8,2.4Hz,1H),4.73(s,2H),4.66(d,J＝5.9Hz,2H),4.12(q,J＝7.2Hz,2H),3.20–3.15(m,2H),2.71(s,3H),2.08–1.99(m,4H),0.93(d,J＝6.8Hz,6H),0.76(t,J＝6.7Hz,6H)。
实施例19：N-(4-氟苄基)-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z19)的制备
参照实施例1的制备方法，得到白色固体0.56g，收率：42.7％。M.p.:92-94℃；IR:(KBr,cm-1):υ3423.8,2920.5,2851.1,1626.7,1509.2,1445.4,1220.0,1156.9,1014.3,874.3,803.4,714.5；ESI-MS,m/z:calcd.437.21(M+)；found 438.4([M+H]+),560.4([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.41(dd,J＝8.6,5.4Hz,2H),7.29(d,J＝2.4Hz,1H),7.21(d,J＝8.9Hz,1H),7.03(t,J＝8.7Hz,2H),6.90(dd,J＝8.8,2.4Hz,1H),4.69(s,2H),4.67(d,J＝5.8Hz,2H),3.66(s,3H),3.51(t,J＝5.2Hz,2H),3.45(t,J＝5.1Hz,2H),2.72(s,3H),1.55–1.47(m,6H)。
实施例20：N-(4-氟苄基)-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z20)的制备
参照实施例1的制备方法，得到黄色固体0.60g，收率：42.9％。M.p.:126-127℃；IR:(KBr,cm-1):υ3513.3,3308.9,2918.1,2849.7,1655.9,1608.0,1544.5,1510.5,1439.8,1231.5,1210.6,1160.6,1087.6,837.8,809.2,771.2,689.3；ESI-MS,m/z:calcd.451.23(M+)；found 452.2([M+H]+),474.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.41(dd,J＝8.4,5.5Hz,2H),7.28(d,J＝2.3Hz,1H),7.21(d,J＝8.8Hz,1H),7.02(t,J＝8.7Hz,2H),6.89(dd,J＝8.8,2.3Hz,1H),4.68(s,2H),4.66(d,J＝5.9Hz,2H),4.12(q,J＝7.2Hz,2H),3.52(t,J＝5.1Hz,2H),3.44(t,J＝5.0Hz,2H),2.71(s,3H),1.67–1.52(m,6H),1.33(t,J＝7.2Hz,3H)。
实施例21：N-(4-氟苄基)-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z21)的制备
参照实施例1的制备方法，得到黄色固体1.07g，收率：81.1％。M.p.:181-182℃；IR:(KBr,cm-1):υ3422.9,2919.7,2860.2,1677.1,1627.6,1506.2,1444.1,1214.8,1162.4,1117.0,1032.2,845.3,808.7,720.8；ESI-MS,m/z:calcd.439.19(M+)；found 440.3([M+H]+),462.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.41(dd,J＝8.5,5.4Hz,2H),7.28(d,J＝2.4Hz,1H),7.21(d,J＝8.9Hz,1H),7.03(t,J＝8.7Hz,2H),6.88(dd,J＝8.8,2.4Hz,1H),4.70(s,2H),4.67(d,J＝5.8Hz,2H),3.66(s,3H),3.63–3.58(m,8H),2.71(s,3H)。
实施例22：N-(4-氟苄基)-5-[2-(4-吗啉基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z22)的制备
参照实施例1的制备方法，得到白色固体1.11g，收率：79.3％。M.p.:151-153℃；IR:(KBr,cm-1):υ3369.5,2966.9,2851.8,1669.9,1620.5,1510.2,1481.1,1352.4,1188.6,1112.9,1028.0,841.8,777.3,707.4；ESI-MS,m/z:calcd.453.21(M+)；found 454.2([M+H]+),476.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.42(dd,J＝8.7,5.4Hz,2H),7.29(d,J＝2.4Hz,1H),7.23(d,J＝8.9Hz,1H),7.04(t,J＝8.7Hz,2H),6.88(dd,J＝8.8,2.4Hz,1H),4.70(s,2H),4.67(d,J＝5.7Hz,2H),4.13(q,J＝7.2Hz,2H),3.63–3.59(m,8H),2.72(s,3H),1.34(t,J＝7.2Hz,3H)。
实施例23：N-(4-氟苄基)-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z23)的制备
参照实施例1的制备方法，得到白色固体0.72g，收率：46.2％。M.p.:187-189℃；IR:(KBr,cm-1):υ3453.5,3238.6,2912.8,1681.0,1627.1,1506.3,1485.9,1384.4,1252.9,1222.8,1126.3,1026.5,829,.6,790.9,736.4；ESI-MS,m/z:calcd.519.22(M+)；found520.3([M+H]+),542.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.35(dd,J＝8.6,5.4Hz,2H),7.23(d,J＝2.3Hz,1H),7.19(d,J＝8.9Hz,1H),7.03(t,J＝8.7Hz,2H),6.95(dd,J＝3.8,1.2Hz,1H),6.89–6.83(m,4H),4.64(d,J＝5.8Hz,2H),4.53(s,2H),4.10(t,J＝5.1Hz,2H),3.75(s,3H),3.74–3.70(m,2H),3.66(s,3H),2.71(s,3H)。
实施例24：N-(4-氟苄基)-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z24)的制备
参照实施例1的制备方法，得到白色固体1.07g，收率：64.9％。M.p.:166-168℃；IR:(KBr,cm-1):υ3268.1,1673.3,1622.3,1507.4,1482.0,1254.0,1220.4,1125.7,1026.3,831.0,739,8,720.1；ESI-MS,m/z:calcd.533.23(M+)；found 534.2([M+H]+),556.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.35(dd,J＝8.6,5.4Hz,2H),7.23(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.03(t,J＝8.7Hz,2H),6.94(dd,J＝8.9,2.3Hz,1H),6.89–6.82(m,5H),4.64(d,J＝5.8Hz,2H),4.53(s,2H),4.14–4.10(m,4H),3.76(s,3H),3.74–3.70(m,2H),2.71(s,3H),1.34(t,J＝7.2Hz,3H)。
实施例25：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z25)的制备
参照实施例1的制备方法，得到白色固体0.70g，收率：53.4％。M.p.:164-165℃；IR:(KBr,cm-1):υ3441.3,3274.6,2932,3,1648.8,1551.8,1482.8,1383.1,1256.1,1203.5,1162.1,1119.4,1048.3,1048.3,872.5,794.0,754.4；ESI-MS,m/z:calcd.467.24(M+)；found 468.2([M+H]+),490.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.39(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),7.00(dd,J＝7.7,1.8Hz,1H),6.97–6.86(m,4H),4.62(s,2H),4.26(t,J＝5.1Hz,2H),3.89(dd,J＝10.5,5.4Hz,2H),3.73(s,3H),3.66(s,3H),3.36(q,J＝7.1Hz,2H),3.25(q,J＝7.1Hz,2H),2.70(s,3H),1.13–1.08(m,6H)。
实施例26：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z26)的制备
参照实施例1的制备方法，得到白色固体0.64g，收率：49.2％。M.p.:138-139℃；IR:(KBr,cm-1):υ3440.6,2931.5,1647.3,1547.0,1504.4,1465.7,1383.4,1224.3,1120.2,871.4,751.4,619.7；ESI-MS,m/z:calcd.481.26(M+)；found 482.3([M+H]+),504.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.39(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.00(dd,J＝7.7,1.7Hz,1H),6.96–6.86(m,4H),4.61(s,2H),4.26(t,J＝5.1Hz,2H),4.13(q,J＝7.2Hz,2H),3.89(dd,J＝10.5,5.4Hz,2H),3.73(s,3H),3.37(q,J＝7.1Hz,2H),3.25(q,J＝7.1Hz,2H),2.70(s,3H),1.34(t,J＝7.2Hz,3H),1.11–1.07(m,6H)。
实施例27：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二正丙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z27)的制备
参照实施例1的制备方法，得到白色固体1.10g，收率：73.8％。M.p.:101-103℃；IR:(KBr,cm-1):υ3328.1,2921.1,1650.6,1626.7,1547.4,1458.7,1250.8,1210.7,1124.3,1025.5,931.6,835.9,746.3；ESI-MS,m/z:calcd.495.27(M+)；found 496.3([M+H]+)；1HNMR(400MHz,CDCl3):δ7.38(d,J＝2.2Hz,1H),7.20(d,J＝8.8Hz,1H),7.00(dd,J＝7.7,1.6Hz,1H),6.96–6.85(m,4H),4.64(s,2H),4.26(t,J＝5.1Hz,2H),3.91–3.87(m,2H),3.72(s,3H),3.66(s,3H),3.30–3.25(m,2H),3.16–3.11(m,2H),1.54(dd,J＝15.0,7.5Hz,4H),0.88–0.82(m,6H)。
实施例28：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二正丙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z28)的制备
参照实施例1的制备方法，得到黄色固体0.82g，收率：53.6％。M.p.:91-92℃；IR:(KBr,cm-1):υ3288.5,2918.3,1644.0,1533.6,1504.4,1464.0,1419.4,1279.0,1250.9,1122.6,1025.2,848.8,802.4,748.8；ESI-MS,m/z:calcd.509.29(M+)；found 510.3([M+H]+),532.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.00(dd,J＝7.7,1.8Hz,1H),6.95–6.86(m,4H),4.63(s,2H),4.25(t,J＝5.1Hz,2H),4.12(q,J＝7.2Hz,2H),3.89(q,J＝5.2Hz,2H),3.29–3.25(m,2H),3.16–3.12(m,2H),2.70(s,3H),1.58–1.50(m,4H),1.33(t,J＝7.2Hz,3H),0.87–0.82(m,6H)。
实施例29：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二异丁胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z29)的制备
参照实施例1的制备方法，得到白色固体0.87g，收率：55.4％。M.p.:85-87℃；IR:(KBr,cm-1):υ3424.4,2920.5,1649.2,1626.5,1505.2,1484.7,1384.1,1250.8,1212.0,1122.0,1024.7,837.8,797.8,745.8；ESI-MS,m/z:calcd.523.3(M+)；found 524.3([M+H]+),546.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),7.00(dd,J＝7.6,1.4Hz,1H),6.97–6.86(m,4H),4.68(s,2H),4.25(t,J＝5.1Hz,2H),3.88(q,J＝5.1Hz,2H),3.72(s,3H),3.65(s,3H),3.19(d,J＝7.6Hz,2H),3.06(d,J＝7.6Hz,2H),2.70(s,3H),1.97–1.70(m,4H),0.87–0.81(m,12H)。
实施例30：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二异丁胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z30)的制备
参照实施例1的制备方法，得到黄色固体0.84g，收率：52.2％。M.p.:95-97℃；IR:(KBr,cm-1):υ3447.0,2920.2,1655.7,1543.8,1482.9,1384.3,1256.8,1204.8,1123.6,1026.5,777.7,741.8；ESI-MS,m/z:calcd.537.32(M+)；found 538.3([M+H]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝2.3Hz,1H),7.21(d,J＝8.9Hz,1H),7.00(dd,J＝7.7,1.7Hz,1H),6.96–6.86(m,4H),4.69(s,2H),4.26(t,J＝5.1Hz,2H),4.12(q,J＝7.2Hz,2H),3.72(s,3H),3.19(d,J＝7.6Hz,2H),3.06(d,J＝7.6Hz,2H),2.70(s,3H),2.02–1.86(m,4H),1.33(t,J＝7.2Hz,3H),0.87–0.80(m,12H)。
实施例31：N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z31)的制备
参照实施例1的制备方法，得到白色固体0.78g，收率：54.2％。M.p.:152-153℃；IR:(KBr,cm-1):υ3465.3,2931.0,2854.9,1644.2,1549.1,1504.7,1406.3,1252.2,1219.9,1124.7,1020.5,934.8,851.7,745.3；ESI-MS,m/z:calcd.479.24(M+)；found 480.2.2([M+H]+),502.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝2.4Hz,1H),7.20(d,J＝8.9Hz,1H),7.00(dd,J＝7.6,1.7Hz,1H),6.96–6.86(m,4H),4.63(s,2H),4.26(t,J＝5.1Hz,2H),3.89(dd,J＝10.4,5.4Hz,2H),3.73(s,3H),3.66(s,3H),3.53–3.50(m,2H),3.36–3.32(m,2H),2.70(s,3H),1.60–1.45(m,6H)。
实施例32：N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z32)的制备
参照实施例1的制备方法，得到黄色固体0.84g，收率：56.8％。M.p.:78-79℃；IR:(KBr,cm-1):υ3427.9,2930.7,1638.2,1538.3,1503.7,1467.9,1254.7,1202.3,1163.3,1124.3,1027.0,877.8,852.6,745.9；ESI-MS,m/z:calcd.493.26(M+)；found 494.3([M+H]+),516.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝2.4Hz,1H),7.21(d,J＝8.9Hz,1H),7.00(dd,J＝7.7,1.7Hz,1H),6.95–6.87(m,4H),4.63(s,2H),4.26(t,J＝5.1Hz,2H),4.13(q,J＝7.2Hz,2H),3.89(dd,J＝10.4,5.4Hz,2H),3.74(s,3H),3.54–3.50(m,2H),3.36–3.33(m,2H),2.70(s,3H),1.64–1.56(m,6H),1.34(t,J＝7.2Hz,3H)。
实施例33：N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z33)的制备
参照实施例1的制备方法，得到白色固体0.93g，收率：64.6％。M.p.:111-113℃；IR:(KBr,cm-1):υ3455.0,1653.7,1547.2,1486.1,1384.1,1252.0,1217.3,1125.5,1111.0,1032.6,849.6,743.5；ESI-MS,m/z:calcd.481.22(M+)；found 482.2([M+H]+),504.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝2.4Hz,1H),7.21(d,J＝8.9Hz,1H),7.01(dd,J＝7.7,1.7Hz,1H),6.98–6.89(m,4H),4.64(s,2H),4.27(t,J＝5.0Hz,2H),3.89(dd,J＝10.3,5.4Hz,2H),3.73(s,3H),3.67(s,3H),3.61–3.43(m,8H),2.71(s,3H)。
实施例34：N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(4-吗啉基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z34)的制备
参照实施例1的制备方法，得到白色固体1.04g，收率：69.8％。M.p.:84-85℃；IR:(KBr,cm-1):υ3431.3,2925.5,1633.6,1482.6,1384.1,1251.3,1201.6,1122.6,1028.7,876.8,754.8；ESI-MS,m/z:calcd.495.24(M+)；found 496.2([M+H]+),518.2([M+Na]+)；1HNMR(400MHz,CDCl3):δ7.40(d,J＝2.4Hz,1H),7.22(d,J＝8.9Hz,1H),7.01(dd,J＝7.7,1.7Hz,1H),6.97–6.86(m,4H),4.64(s,2H),4.26(t,J＝5.0Hz,2H),4.13(q,J＝7.2Hz,2H),3.89(dd,J＝10.4,5.4Hz,2H),3.73(s,3H),3.61–3.42(m,8H),2.70(s,3H),1.34(t,J＝7.2Hz,3H)。
实施例35：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-苄胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z35)的制备
参照实施例1的制备方法，得到黄色固体0.70g，收率：46.7％。M.p.:172-174℃；IR:(KBr,cm-1):υ3395.2,2933.0,1676.4,1646.3,1544.7,1503.1,1384.7,1252.5,1206.5,1164.2,1125.1,1050.9,927.1,839.3,749.6；ESI-MS,m/z:calcd.501.23(M+)；found502.2([M+H]+),524.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝2.3Hz,1H),7.33–7.27(m,5H),7.21(d,J＝8.9Hz,1H),6.97(dd,J＝7.4,1.8Hz,1H),6.93–6.84(m,4H),4.55(s,2H),4.52(d,J＝6.0Hz,2H),4.22(t,J＝5.0Hz,2H),3.89(dd,J＝10.3,5.3Hz,2H),3.72(s,3H),3.67(s,3H),2.70(s,3H)。
实施例36：N-[2-(2-甲氧基苯氧基)乙基]-5-(2-苄胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z36)的制备
参照实施例1的制备方法，得到白色固体0.84g，收率：54.2％。M.p.:128-129℃；IR:(KBr,cm-1):υ3434.2,3297.7,2927.7,1626.2,1540.0,1481.4,1384.5,1259.3,1230.7,1122.0,1089.5,1037.0,841.7,736.2,703.2；ESI-MS,m/z:calcd.515.24(M+)；found516.2([M+H]+),538.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.39(d,J＝2.3Hz,1H),7.33–7.27(m,5H),7.22(d,J＝8.8Hz,1H),6.97(dd,J＝7.5,2.0Hz,1H),6.94–6.84(m,4H),4.55(s,2H),4.52(d,J＝6.0Hz,2H),4.22(t,J＝4.9Hz,2H),4.13(q,J＝7.2Hz,2H),3.89(dd,J＝10.1,5.2Hz,2H),3.71(s,3H),2.70(s,3H),1.34(t,J＝7.2Hz,3H)。
实施例37：N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z37)的制备
参照实施例1的制备方法，得到白色固体0.86g，收率：55.1％。M.p.:169-171℃；IR:(KBr,cm-1):υ3414.8,2928.3,1675.1,1642.7,1542.5,1503.5,1252.7,1221.7,1166.2,1124.2,1048.9,1025.8,843.0,823.5,748.9；ESI-MS,m/z:calcd.519.22(M+)；found520.2([M+H]+)；1H NMR(400MHz,CDCl3):δ7.39(d,J＝2.4Hz,1H),7.22(d,J＝3.1Hz,2H),7.20(d,J＝3.0Hz,1H),7.00–6.90(m,5H),6.84(d,J＝7.8Hz,2H),4.54(s,2H),4.47(d,J＝6.1Hz,2H),4.23(t,J＝5.0Hz,2H),3.89(dd,J＝10.3,5.5Hz,2H),3.72(s,3H),3.66(s,3H),2.70(s,3H)。
实施例38：N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z38)的制备
参照实施例1的制备方法，得到白色固体1.08g，收率：67.5％。M.p.:131-132℃；IR:(KBr,cm-1):υ3436.0,2929.7,1629.8,1543.9,1509.2,1482.1,1384.3,1259.9,1230.9,1211.0,1122.9,1037.5,841.1,735.8；ESI-MS,m/z:calcd.533.23(M+)；found 534.2([M+H]+),556.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝2.3Hz,1H),7.24–7.20(m,4H),6.99–6.86(m,6H),4.55(s,2H),4.47(d,J＝6.1Hz,2H),4.23(t,J＝5.0Hz,2H),4.14(q,J＝7.2Hz,2H),3.90(dd,J＝10.3,5.3Hz,2H),3.72(s,3H),2.70(s,3H),1.34(t,J＝7.2Hz,3H)。
实施例39：N-[3-(4-吗啉基)丙基]-5-(2-苄胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z39)的制备
参照实施例1的制备方法，得到白色固体0.53g，收率：37.1％。M.p.:135-137℃；IR:(KBr,cm-1):υ3425.9,2921.4,2852.3,1665.3,1623.0,1539.2,1484.2,1273.8,1202.5,1161.7,917.6,862.4,799.3,700.3；ESI-MS,m/z:calcd.478.26(M+)；found479.3([M+H]+),501.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.33(d,J＝1.5Hz,1H),7.31–7.27(m,5H),7.22(d,J＝8.8Hz,1H),6.85(dd,J＝8.8,2.4Hz,1H),4.61(s,2H),4.56(d,J＝6.0Hz,2H),3.67(s,3H),3.61–3.58(m,2H),3.56–3.53(m,4H),2.70(s,3H),2.53–2.41(m,6H),1.86–1.78(m,2H)。
实施例40：N-[3-(4-吗啉基)丙基]-5-(2-苄胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z40)的制备
参照实施例1的制备方法，得到白色固体0.54g，收率：37.8％。M.p.:156-157℃；IR:(KBr,cm-1):υ3453.3,2931.3,1628.9,1545.7,1484.2,1437.8,1383.8,1271.3,1207.6,1164.4,1114.9,872.1,697.4；ESI-MS,m/z:calcd.492.27(M+)；found 493.3([M+H]+),515.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.32(d,J＝1.6Hz,1H),7.31–7.27(m,5H),7.23(d,J＝8.8Hz,1H),6.84(dd,J＝8.8,2.3Hz,1H),4.61(s,2H),4.56(d,J＝6.0Hz,2H),4.13(q,J＝7.2Hz,2H),3.62–3.57(m,4H),3.57–3.54(m,2H),2.70(s,3H),2.56–2.40(m,6H),1.86–1.79(m,2H),1.34(t,J＝7.2Hz,3H)。
实施例41：N-[3-(4-吗啉基)丙基]-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z41)的制备
参照实施例1的制备方法，得到白色固体0.53g，收率：35.6％。M.p.:208-209℃；IR:(KBr,cm-1):υ3336.6,3303.7,2859.7,1633.3,1532.3,1509.5,1485.7,1384.3,1210.3,1168.3,1119.4,1059.0,873.4,770.8；ESI-MS,m/z:calcd.496.25(M+)；found 497.3([M+H]+)；1H NMR(400MHz,CDCl3):δ7.28(d,J＝1.6Hz,1H),7.21(d,J＝8.9Hz,1H),6.99(t,J＝8.6Hz,4H),6.84(dd,J＝8.9,2.4Hz,1H),4.62(s,2H),4.51(d,J＝6.1Hz,2H),3.67(s,3H),3.64–3.57(m,6H),2.71(s,3H),2.62–2.42(m,6H),1.31–1.19(m,2H)。
实施例42：N-[3-(4-吗啉基)丙基]-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z42)的制备
参照实施例1的制备方法，得到白色固体1.08g，收率：73.0％。M.p.:182-184℃；IR:(KBr,cm-1):υ3429.1,2926.6,2856.3,1651.3,1511.7,1482.2,1383.6,1338.7,1270.6,1228.6,1210.1,1164.3,1117.8,859.6,768.4；ESI-MS,m/z:calcd.510.26(M+)；found511.3([M+H]+),533.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.29(d,J＝2.2Hz,1H),7.22(d,J＝9.7Hz,1H),7.03–6.99(m,4H),6.83(dd,J＝8.8,1.7Hz,1H),4.60(s,2H),4.51(d,J＝6.0Hz,2H),4.13(q,J＝7.1Hz,2H),3.58(d,J＝6.1Hz,2H),3.56–3.53(m,4H),2.69(s,3H),2.51–2.41(m,6H),1.86–1.78(m,2H),1.33(t,J＝7.1Hz,3H)。
实施例43：N-[3-(4-吗啉基)丙基]-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z43)的制备
参照实施例1的制备方法，得到白色固体0.94g，收率：58.4％。M.p.:91-92℃；IR:(KBr,cm-1):υ3448.0,2919.7,1653.0,1595.9,1485.2,1384.7,1256.5,1202.8,1117.8,1023.6,872.5,741.6；ESI-MS,m/z:calcd.538.28(M+)；found 539.3([M+H]+),561.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.18(d,J＝8.8Hz,1H),6.98–6.88(m,5H),6.87–6.85(m,1H),4.59(s,3H),4.13(t,J＝5.2Hz,2H),3.80(s,3H),3.76(dd,J＝10.8,5.5Hz,2H),3.65(s,3H),3.63–3.55(m,6H),2.70(s,3H),2.58–2.35(m,6H),1.93–1.78(m,2H)。
实施例44：N-[3-(4-吗啉基)丙基]-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z44)的制备
参照实施例1的制备方法，得到白色固体1.10g，收率：68.8％。M.p.:97-98℃；IR:(KBr,cm-1):υ3424.3,2921.2,1668.9,1628.6,1541.7,1505.7,1481.8,1418.9,1254.5,1161.9,1124.5,1026.4,863.9,799.7,746.4；ESI-MS,m/z:calcd.552.29(M+)；found553.3([M+H]+),575.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.30(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),6.96–6.87(m,1H),4.56(s,2H),4.15–4.10(m,4H),3.80(s,3H),3.76(dd,J＝10.6,5.5Hz,2H),3.59–3.53(m,6H),2.69(s,3H),2.49–2.41(m,6H),1.85–1.77(m,2H),1.33(t,J＝7.2Hz,3H)。
实施例45：N-(呋喃-2-甲基)-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z45)的制备
参照实施例1的制备方法，得到白色固体0.74g，收率：62.2％。M.p.:145-147℃；IR:(KBr,cm-1):υ3425.1,2921.9,2851.8,1657.1,1631.4,1483.8,1465.4,1384.3,1162.0,838.0,700.6,666.4；ESI-MS,m/z:calcd.397.20(M+)；found 398.2([M+H]+),420.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝5.6Hz,1H),7.29(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),6.92(dd,J＝8.9,2.4Hz,1H),6.34(dd,J＝5.6,3.0Hz,1H),6.32(d,J＝3.0Hz,1H),4.72(d,J＝5.7Hz,2H),4.65(s,2H),3.65(s,3H),3.40(q,J＝7.0Hz,4H),2.70(s,3H),1.21(t,J＝7.1Hz,3H),1.13(t,J＝7.1Hz,3H)。
实施例46：N-(呋喃-2-甲基)-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z46)的制备
参照实施例1的制备方法，得到白色固体0.62g，收率：50.4％。M.p.:120-121℃；IR:(KBr,cm-1):υ3426.7,2922.1,1636.2,1536.4,1481.4,1419.4,1383.7,1263.8,1191.2,1162.4,1146.0,1084.7,1015.0,921.8,801.0,744.3；ESI-MS,m/z:calcd.411.22(M+)；found 412.2([M+H]+)；1H NMR(400MHz,CDCl3):δ7.37(d,J＝5.5Hz,1H),7.29(d,J＝2.3Hz,1H),7.20(d,J＝8.7Hz,1H),6.90(dd,J＝8.7,2.3Hz,1H),6.32(dd,J＝5.5,3.1Hz,1H),6.21(d,J＝3.0Hz,1H),4.71(d,J＝5.7Hz,2H),4.69(s,2H),4.11(d,J＝7.1Hz,2H),3.39(q,J＝6.9Hz,4H),2.69(s,3H),1.32(t,J＝6.9Hz,3H),1.21(t,J＝6.8Hz,3H),1.13(t,J＝6.8Hz,3H)。
实施例47：N-(呋喃-2-甲基)-5-(2-二正丙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z47)的制备
参照实施例1的制备方法，得到白色固体0.92g，收率：71.9％。M.p.:123-124℃；IR:(KBr,cm-1):υ3439.7,3346.9,2921.0,1659.8,1622.1,1519.3,1484.4,1383.6,1281.7,1198.5,1146.2,1085.1,1017.9,927.0,832.2,752.2；ESI-MS,m/z:calcd.397.20(M+)；found 398.2([M+H]+),420.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.37(d,J＝5.7Hz,1H),7.28(d,J＝2.2Hz,1H),7.19(d,J＝8.9Hz,1H),6.90(dd,J＝8.8,2.2Hz,1H),6.33(dd,J＝5.7,3.0Hz,1H),6.31(d,J＝3.0Hz,1H),4.71(d,J＝5.6Hz,2H),4.69(s,2H),3.64(s,3H),3.29–3.21(m,4H),2.70(s,3H),1.68–1.52(m,4H),0.92(t,J＝7.4Hz,3H),0.86(t,J＝7.4Hz,3H)。
实施例48：N-(呋喃-2-甲基)-5-(2-二正丙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z48)的制备
参照实施例1的制备方法，得到白色固体0.72g，收率：54.5％。M.p.:96-97℃；IR:(KBr,cm-1):υ3424.3,3279.9,2924.6,1656.8,1619.3,1482.4,1424.1,1383.1,1273.3,1200.9,1162.4,1089.5,1009.7,917.9,832.5,794.6,726.2；ESI-MS,m/z:calcd.439.25(M+)；found 440.2([M+H]+),462.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.37(d,J＝5.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.20(d,J＝8.8Hz,1H),6.90(dd,J＝8.8,2.3Hz,1H),6.33(dd,J＝5.7,3.1Hz,1H),6.31(d,J＝3.2Hz,1H),4.71(s,2H),4.69(d,J＝5.5Hz,2H),4.11(q,J＝7.1Hz,2H),3.29–3.22(m,4H),2.70(s,3H),1.64–1.53(m,4H),1.32(t,J＝7.2Hz,3H),0.92(t,J＝7.4Hz,3H),0.86(t,J＝7.4Hz,3H)。
实施例49：N-(呋喃-2-甲基)-5-(2-二异丁胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z49)的制备
参照实施例1的制备方法，得到白色固体0.72g，收率：52.9％。M.p.:102-104℃；IR:(KBr,cm-1):υ3424.8,2921.9,1662.7,1624.9,1482.6,1384.4,1281.8,1158.6,1141.8,1076.2,1015.3,917.3,883.2,839.9,795.6,752.7；ESI-MS,m/z:calcd.453.26(M+)；found454.2([M+H]+),476.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.37(d,J＝5.9Hz,1H),7.29(d,J＝2.3Hz,1H),7.18(d,J＝8.9Hz,1H),6.90(dd,J＝8.8,2.3Hz,1H),6.33(dd,J＝5.9,3.1Hz,1H),6.31(d,J＝3.1Hz,1H),4.74(d,J＝5.7Hz,2H),4.68(s,2H),3.63(s,3H),3.23–3.20(m,2H),2.69(s,3H),2.05–1.70(m,4H),0.93(d,J＝6.7Hz,6H),0.81(d,J＝6.7Hz,6H)。
实施例50：N-(呋喃-2-甲基)-5-(2-二异丁胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z50)的制备
参照实施例1的制备方法，得到黄色固体0.69g，收率：49.3％。M.p.:68-70℃；IR:(KBr,cm-1):υ3417.0,2955.8,2922.0,1661.0,1625.5,1529.4,1480.5,1421.1,1385.1,1347.0,1283.1,1271.2,1190.8,1159.4,1142.4,1077.2,1016.8,919.0,840.7,791.8,758.9；ESI-MS,m/z:calcd.467.28(M+)；found 468.2([M+H]+),490.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.37(d,J＝5.6Hz,1H),7.29(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),6.90(dd,J＝8.8,2.3Hz,1H),6.33(dd,J＝5.8,3.2Hz,1H),6.31(d,J＝3.1Hz,1H),4.75(s,2H),4.68(d,J＝5.6Hz,2H),4.11(q,J＝6.9Hz,2H),3.21–3.19(m,2H),2.70(s,3H),1.99–1.79(m,4H),1.32(t,J＝7.2Hz,3H),0.94(d,J＝6.6Hz,6H),0.81(d,J＝6.7Hz,6H)。
实施例51：N-(呋喃-2-甲基)-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z51)的制备
参照实施例1的制备方法，得到白色固体0.71g，收率：57.7％。M.p.:79-80℃；IR:(KBr,cm-1):υ3424.1,2929.9,2854.9,1639.4,1487.0,1443.2,1384.1,1208.2,1140.5,1079.9,1010.0,839.7,803.8,758.4,602.8；ESI-MS,m/z:calcd.409.20(M+)；found 410.2([M+H]+),432.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝5.9Hz,1H),7.29(d,J＝2.3Hz,1H),7.20(d,J＝8.9Hz,1H),6.92(dd,J＝8.9,2.4Hz,1H),6.34(dd,J＝5.8,3.1Hz,1H),6.32(d,J＝3.1Hz,1H),4.73(d,J＝5.8Hz,2H),4.64(s,2H),3.65(s,3H),3.54(t,J＝5.3Hz,2H),3.46(t,J＝5.0Hz,2H),2.70(s,3H),1.61-1.53(m,6H)。
实施例52：N-(呋喃-2-甲基)-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z52)的制备
参照实施例1的制备方法，得到白色固体0.84g，收率：66.1％。M.p.:81-82℃；IR:(KBr,cm-1):υ3527.8,3414.4,3936.2,2855.6,1647.5,1618.6,1545.0,1487.3,1441.5,1383.9,1207.6,1165.7,1140.5,1074.8,1006.4,878.0,852.9,812.7,745.8；ESI-MS,m/z:calcd.423.22(M+)；found 424.2([M+H]+),446.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝5.7Hz,1H),7.30(d,J＝2.4Hz,1H),7.21(d,J＝8.9Hz,1H),6.91(dd,J＝8.9,2.4Hz,1H),6.34(dd,J＝5.7,3.1Hz,1H),6.32(d,J＝3.1Hz,1H),4.70(d,J＝5.7Hz,2H),4.69(s,2H),4.12(q,J＝7.2Hz,2H),3.56(t,J＝5.2Hz,2H),3.50(t,J＝5.2Hz,2H),2.70(s,3H),1.64–1.61(m,6H),1.33(t,J＝7.2Hz,3H)。
实施例53：N-(呋喃-2-甲基)-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z53)的制备
参照实施例1的制备方法，得到白色固体0.98g，收率：79.7％。M.p.:181-183℃；IR:(KBr,cm-1):υ3423.2,2923.5,2853.5,1654.1,1616.3,1483.7,1412.5,1356.8,1269.4,1191.1,1158.7,1029.9,1002.5,841.6,799.0,741.7；ESI-MS,m/z:calcd.411.18(M+)；found 412.1([M+H]+),434.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.38(d,J＝5.9Hz,1H),7.28(d,J＝2.4Hz,1H),7.19(d,J＝8.9Hz,1H),6.88(dd,J＝8.8,2.4Hz,1H),6.34(dd,J＝5.8,3.1Hz,1H),6.32(d,J＝3.1Hz,1H),4.71(s,2H),4.68(d,J＝5.5Hz,2H),3.64(s,3H),3.62–3.59(m,8H),2.68(s,3H)。
实施例54：N-(呋喃-2-甲基)-5-[2-(4-吗啉基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z54)的制备
参照实施例1的制备方法，得到白色固体0.83g，收率：64.8％。M.p.:128-129℃；IR:(KBr,cm-1):υ3322.6,2973.1,1666.4,1639.9,1544.6,1440.6,1357.3,1308.3,1278.5,1202.0,1161.5,1113.3,1037.7,966.3,879.1,851.8,801.8,757.0；ESI-MS,m/z:calcd.425.20(M+)；found 426.1([M+H]+)；1H NMR(400MHz,CDCl3):δ7.37(d,J＝5.8Hz,1H),7.29(d,J＝2.4Hz,1H),7.20(d,J＝8.9Hz,1H),6.87(dd,J＝8.8,2.4Hz,1H),6.33(dd,J＝5.8,3.2Hz,1H),6.31(d,J＝3.2Hz,1H),4.70(s,2H),4.68(d,J＝5.6Hz,2H),4.10(q,J＝7.2Hz,2H),3.66–3.58(m,8H),2.68(s,3H),1.31(t,J＝7.2Hz,3H)。
实施例55：N-(呋喃-2-甲基)-5-(2-苄胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z55)的制备
参照实施例1的制备方法，得到黄色固体0.69g，收率：53.5％。M.p.:169-170℃；IR:(KBr,cm-1):υ3402.6,2918.1,2849.8,1681.3,1616.2,1545.0,1485.0,1383.9,1213.9,1164.4,1054.6,917.8,827.2,795.7,729.6,696.2；ESI-MS,m/z:calcd.431.18(M+)；found432.2([M+H]+),454.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝5.6Hz,1H),7.33–7.29(m,5H),7.23(d,J＝2.2Hz,1H),7.20(d,J＝8.9Hz,1H),6.83(dd,J＝8.8,2.3Hz,1H),6.34(dd,J＝5.6,3.0Hz,1H),6.30(d,J＝3.1Hz,1H),4.67(d,J＝5.5Hz,2H),4.57(s,2H),4.55(d,J＝6.1Hz,2H),3.65(s,3H),2.68(s,3H)。
实施例56：N-(呋喃-2-甲基)-5-(2-苄胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z56)的制备
参照实施例1的制备方法，得到白色固体1.29g，收率：96.3％。M.p.:170-172℃；IR:(KBr,cm-1):υ3397.5,2920.7,2851.2,1672.1,1625.6,1543.2,1482.7,1384.2,1264.4,1199.8,1163.7,1028.1,920.8,804.3,738.8,699.3；ESI-MS,m/z:calcd.445.20(M+)；found 446.2([M+H]+),468.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.40(d,J＝5.8Hz,1H),7.34–7.29(m,5H),7.24(d,J＝2.4Hz,1H),7.22(d,J＝8.9Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),6.34(dd,J＝5.8,3.0Hz,1H),6.30(d,J＝3.1Hz,1H),4.68(d,J＝5.5Hz,2H),4.58(s,2H),4.56(d,J＝6.0Hz,2H),4.12(q,J＝7.2Hz,2H),2.69(s,3H),1.33(t,J＝7.2Hz,3H)。
实施例57：N-(呋喃-2-甲基)-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z57)的制备
参照实施例1的制备方法，得到白色固体1.12g，收率：83.0％。M.p.:198-200℃；IR:(KBr,cm-1):υ3426.1,2923.2,2852.7,1740.5,1630.7,1465.3,1384.0,1259.7,1166.0,1117.4,618.3；ESI-MS,m/z:calcd.449.18(M+)；found 450.2([M+H]+),472.2([M+Na]+)；1HNMR(400MHz,CDCl3):δ7.41(d,J＝5.7Hz,1H),7.24(d,J＝2.4Hz,2H),7.21(d,J＝8.8Hz,1H),7.01(d,J＝8.7Hz,2H),6.98(d,J＝2.3Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),6.35(dd,J＝5.7,3.1Hz,1H),6.31(d,J＝3.2Hz,1H),4.68(d,J＝5.4Hz,2H),4.58(s,2H),4.52(d,J＝6.0Hz,2H),3.66(s,3H),2.70(s,3H)。
实施例58：N-(呋喃-2-甲基)-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z58)的制备
参照实施例1的制备方法，得到白色固体1.22g，收率：87.8％。M.p.:154-156℃；IR:(KBr,cm-1):υ3403.0,2920.5,2850.9,1650.6,1625.0,1510.3,1483.0,1384.1,1339.2,1266.6,1223.2,1159.0,1015.3,796.6,772.3,730.9；ESI-MS,m/z:calcd.463.19(M+)；found 464.2([M+H]+),486.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.41(d,J＝5.7Hz,1H),7.25(d,J＝2.5Hz,2H),7.22(d,J＝8.9Hz,1H),7.03(d,J＝2.2Hz,1H),6.99(d,J＝5.6Hz,2H),6.83(dd,J＝8.8,2.3Hz,1H),6.34(dd,J＝5.7,3.1Hz,1H),6.30(d,J＝3.1Hz,1H),4.68(d,J＝5.3Hz,2H),4.58(s,2H),4.51(d,J＝5.9Hz,2H),4.13(q,J＝7.1Hz,2H),2.69(s,3H),1.33(t,J＝7.2Hz,3H)。
实施例59：N-(呋喃-2-甲基)-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z59)的制备
参照实施例1的制备方法，得到白色固体1.24g，收率：84.4％。M.p.:178-180℃；IR:(KBr,cm-1):υ3456.2,3258.1,2920.9,1680.7,1627.5,1507.2,1486.7,1384.2,1254.0,1230.0,1165.0,1126.2,1024.9,923.0,841.9,788.5,739.0；ESI-MS,m/z:calcd.491.21(M+)；found 492.2([M+H]+),514.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.43(d,J＝5.7Hz,1H),7.24(d,J＝8.7Hz,1H),6.97(dd,J＝8.7,2.3Hz,1H),6.93–6.84(m,4H),6.66(d,J＝2.3Hz,1H),6.41(dd,J＝5.7,3.1Hz,1H),6.27(d,J＝3.0Hz,1H),4.70(d,J＝5.7Hz,2H),4.47(s,2H),4.11(t,J＝5.4Hz,2H),3.77(s,3H),3.76–3.72(m,2H),3.62(s,3H),2.50(s,3H)。
实施例60：N-(呋喃-2-甲基)-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z60)的制备
参照实施例1的制备方法，得到白色固体1.12g，收率：73.7％。M.p.:164-166℃；IR:(KBr,cm-1):υ3443.7,3269.6,2969.7,1679.6,1619.0,1556.4,1508.4,1482.6,1386.5,1254.1,1222.1,1126.2,1076.0,1011.2,924.3,860.7,786.8,738.3,698.6；ESI-MS,m/z:calcd.505.22(M+)；found 506.2([M+H]+),528.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.42(d,J＝5.7Hz,1H),7.20(d,J＝8.9Hz,1H),6.95(dd,J＝8.9,2.2Hz,1H),6.90–6.87(m,4H),6.86(d,J＝2.2Hz,1H),6.33(dd,J＝5.7,3.1Hz,1H),6.29(d,J＝3.2Hz,1H),4.66(d,J＝5.5Hz,2H),4.55(s,2H),4.14(q,J＝7.1Hz,2H),4.12(t,J＝5.5Hz,2H),3.78(s,3H),3.77–3.74(m,2H),2.70(s,3H),1.33(t,J＝7.2Hz,3H)。
实施例61：N-[2-(3,4-二甲氧基苯基)乙基]-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z61)的制备
参照实施例1的制备方法，得到黄色固体0.62g，收率：43.1％。M.p.:112-114℃；IR:(KBr,cm-1):υ3429.8,3324.1,2923.7,1657.9,1613.5,1515.6,1481.3,1383.6,1260.1,1236.4,1187.5,1160.4,1139.3,1028.0,835.7,801.0,763.0；ESI-MS,m/z:calcd.481.26(M+)；found 482.3([M+H]+),504.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.18(d,J＝3.3Hz,1H),7.16(d,J＝3.2Hz,1H),6.89(dd,J＝8.9,2.1Hz,1H),6.82(d,J＝4.8Hz,3H),4.64(s,2H),3.84(s,3H),3.82(s,3H),3.74(dd,J＝12.8,6.8Hz,2H),3.62(s,3H),3.39(q,J＝7.1Hz,4H),2.94(t,J＝7.0Hz,2H),2.64(s,3H),1.19(t,J＝7.0Hz,3H),1.12(t,J＝7.1Hz,3H)。
实施例62：N-[2-(3,4-二甲氧基苯基)乙基]-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z62)的制备
参照实施例1的制备方法，得到白色固体0.62g，收率：41.6％。M.p.:116-117℃；IR:(KBr,cm-1):υ3441.5,2924.5,1641.9,1626.4,1517.0,1483.1,1383.8,1263.0,1235.0,1209.8,1139.8,1030.5,789.3,720.6,704.0；ESI-MS,m/z:calcd.495.27(M+)；found496.2([M+H]+),518.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.20(d,J＝3.3Hz,1H),7.18(d,J＝2.2Hz,1H),6.89(dd,J＝8.8,2.1Hz,1H),6.82(d,J＝6.2Hz,3H),4.65(s,2H),4.10(q,J＝7.2Hz,2H),3.85(s,3H),3.83(s,3H),3.75(dd,J＝12.5,6.5Hz,2H),3.40(q,J＝7.1Hz,4H),2.95(t,J＝7.0Hz,2H),2.66(s,3H),1.32(t,J＝7.2Hz,3H),1.20(t,J＝7.0Hz,3H),1.13(t,J＝7.1Hz,3H)。
实施例63：N-[2-(3,4-二甲氧基苯基)乙基]-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z63)的制备
参照实施例1的制备方法，得到黄色固体0.64g，收率：43.2％。M.p.:62-64℃；IR:(KBr,cm-1):υ3429.7,2930.2,2853.7,1631.9,1514.8,1483.1,1383.9,1259.8,1234.5,1157.0,1138.9,1025.8,798.5,763.9；ESI-MS,m/z:calcd.493.26(M+)；found 494.3([M+H]+)；1H NMR(400MHz,CDCl3):δ7.17(d,J＝8.9Hz,1H),7.15(d,J＝2.3Hz,1H),6.88(dd,J＝8.8,2.4Hz,1H),6.82(t,J＝2.5Hz,3H),4.64(s,2H),3.84(s,3H),3.82(s,3H),3.75(dd,J＝12.8,6.9Hz,2H),3.63(s,3H),3.56–3.52(m,2H),3.50–3.47(m,2H),2.95(t,J＝7.0Hz,2H),2.65(s,3H),1.63–1.51(m,6H)。
实施例64：N-[2-(3,4-二甲氧基苯基)乙基]-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z64)的制备
参照实施例1的制备方法，得到黄色固体0.48g，收率：31.6％。M.p.:96-98℃；IR:(KBr,cm-1):υ3344.3,2930.9,1659.8,1616.8,1513.9,1480.3,1260.6,1235.2,1187.2,1157.8,1087.1,1027.3,845.5,784.1,763.6；ESI-MS,m/z:calcd.507.27(M+)；found508.3([M+H]+),530.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.20(d,J＝8.8Hz,1H),7.15(s,1H),6.89(dd,J＝8.8,2.0Hz,1H),6.83(d,J＝4.5Hz,3H),4.65(s,2H),4.11(dd,J＝7.2Hz,2H),3.85(s,3H),3.83(s,3H),3.76(d,J＝3.5Hz,2H),3.57–3.48(m,4H),2.96(t,J＝6.9Hz,2H),2.67(s,3H),1.73–1.61(m,6H),1.32(t,J＝7.2Hz,3H)。
实施例65：N-[2-(3,4-二甲氧基苯基)乙基]-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z65)的制备
参照实施例1的制备方法，得到黄色固体0.63g，收率：42.3％。M.p.:79-80℃；IR:(KBr,cm-1):υ3438.0,2921.8,2852.3,1631.8,1515.4,1484.3,1384.2,1261.6,1235.8,1158.3,1113.9,1028.8,850.2,801.6；ESI-MS,m/z:calcd.495.24(M+)；found 496.2([M+H]+),518.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.19(d,J＝8.8Hz,1H),7.11(d,J＝1.8Hz,1H),6.87(dd,J＝8.8,2.3Hz,1H),6.82(d,J＝4.6Hz,3H),4.65(s,2H),3.85(s,3H),3.82(s,3H),3.78–3.74(m,2H),3.65(s,3H),3.64–3.59(m,8H),2.96(t,J＝6.9Hz,2H),2.66(s,3H)。
实施例66：N-[2-(3,4-二甲氧基苯基)乙基]-5-[2-(4-吗啉基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z66)的制备
参照实施例1的制备方法，得到黄色固体0.64g，收率：41.8％。M.p.:67-68℃；IR:(KBr,cm-1):υ3439.1,2922.0,2852.1,1631.4,1514.6,1464.5,1384.1,1261.7,1235.1,1156.9,1113.3,1027.6,849.2,798.8,619.1；ESI-MS,m/z:calcd.509.25(M+)；found510.2([M+H]+),532.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.20(d,J＝8.8Hz,1H),7.11(d,J＝1.8Hz,1H),6.86(dd,J＝8.7,2.0Hz,1H),6.82(d,J＝5.6Hz,3H),4.65(s,2H),4.11(q,J＝7.1Hz,2H),3.85(s,3H),3.82(s,3H),3.76(d,J＝5.0Hz,2H),3.66–3.61(m,8H),2.96(t,J＝6.6Hz,2H),2.66(s,3H),1.32(t,J＝7.1Hz,3H)。
实施例67：N-[2-(3,4-二甲氧基苯基)乙基]-5-(2-苄胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z67)的制备
参照实施例1的制备方法，得到白色固体0.71g，收率：45.8％。M.p.:175-176℃；IR:(KBr,cm-1):υ3420.4,2923.7,1647.6,1616.5,1514.9,1481.2,1383.9,1262.4,1232.1,1157.9,1029.3,859.7,799.9,743.5,699.5；ESI-MS,m/z:calcd.515.24(M+)；found 516.2([M+H]+),538.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.34–7.28(m,5H),7.19(d,J＝8.8Hz,1H),6.92(d,J＝2.3Hz,1H),6.85(d,J＝8.2Hz,3H),6.80(d,J＝8.6Hz,1H),4.58(d,J＝6.1Hz,2H),4.53(s,2H),3.81(s,3H),3.75(s,3H),3.73(d,J＝6.7Hz,2H),3.65(s,3H),2.93(t,J＝6.8Hz,2H),2.67(s,3H)。
实施例68：N-[2-(3,4-二甲氧基苯基)乙基]-5-(2-苄胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z68)的制备
参照实施例1的制备方法，得到黄色固体0.81g，收率：50.9％。M.p.:158-159℃；IR:(KBr,cm-1):υ3425.7,2919.6,1678.9,1625.7,1515.1,1481.5,1384.1,1259.7,1236.3,1157.5,1140.3,1027.7,796.0,751.7；ESI-MS,m/z:calcd.529.26(M+)；found 530.2([M+H]+),5552.3([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.34–7.29(m,5H),7.20(d,J＝8.9Hz,1H),6.93(d,J＝2.7Hz,1H),6.85–6.80(m,3H),6.79(d,J＝1.4Hz,1H),4.58(d,J＝6.3Hz,2H),4.53(s,2H),4.11(dd,J＝15.1,7.6Hz,2H),3.81(s,3H),3.75(s,3H),3.73(d,J＝6.7Hz,2H),2.93(t,J＝7.2Hz,2H),2.67(s,3H),1.32(t,J＝7.5Hz,3H)。
实施例69：N-[2-(3,4-二甲氧基苯基)乙基]-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺(化合物Z69)的制备
参照实施例1的制备方法，得到白色固体0.89g，收率：55.6％。M.p.:164-166℃；IR:(KBr,cm-1):υ3411.4,2925.8,1678.4,1629.2,1511.5,1485.6,1260.4,1234.3,1157.0,1023.8,874.9,808.1,774.3,706.6；ESI-MS,m/z:calcd.533.23(M+)；found 534.2([M+H]+)；1HNMR(400MHz,CDCl3):δ7.30–7.27(m,2H),7.18(d,J＝8.1Hz,1H),6.99(t,J＝8.3Hz,2H),6.89(d,J＝2.3Hz,1H),6.84–6.78(m,4H),4.54(d,J＝6.1Hz,2H),4.51(s,2H),3.80(s,3H),3.76(d,J＝6.2Hz,2H),3.74(s,3H),3.65(s,3H),2.93(t,J＝6.7Hz,2H),2.66(s,3H)。
实施例70：N-[2-(3,4-二甲氧基苯基)乙基]-5-[2-(4-氟苄胺基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺(化合物Z70)的制备
参照实施例1的制备方法，得到白色固体0.92g，收率：56.1％。M.p.:131-133℃；IR:(KBr,cm-1):υ3420.6,2921.1,2851.5,1631.6,1546.7,1509.9,1468.2,1384.4,1161.5,1136.7,1026.3,617.9；ESI-MS,m/z:calcd.547.25(M+)；found 548.3([M+H]+),570.2([M+Na]+)；1H NMR(400MHz,CDCl3):δ7.30–7.27(m,2H),7.20(d,J＝8.9Hz,1H),7.01–6.97(m,2H),6.91(d,J＝2.3Hz,1H),6.85–6.79(m,4H),4.54(d,J＝6.1Hz,2H),4.52(s,2H),4.11(q,J＝7.2Hz,2H),3.81(s,3H),3.76(d,J＝6.5Hz,2H),3.75(s,3H),2.93(t,J＝6.7Hz,2H),2.67(s,3H),1.32(t,J＝7.2Hz,3H)。
化合物列表如下：
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。
药理实施例
实施例71：受试化合物抗氧化活性初筛实验方法。
A.实验材料
细胞系：人骨髓神经母细胞瘤细胞株SH-SY5Y，以5000/孔的密度铺于96孔板，每孔100ul，24h后使用。
化合物编号Z01-Z70目标化合物：以DMSO溶解，用培养液稀释配制为50μM、20μM、10μM、5μM、2μM五个不同浓度保存于-20℃待用，DMSO在培养液中的终浓度低于0.1％。
阳性对照药：维生素C(Ascorbic acid)。
MTT：以PBS溶解为5mg/mL，保存于-20℃。
B.实验方法
利用MTT方法，选取SH-SY5Y细胞来评价供试样品的抗氧化活性。细胞株在Dulbecco氏改进的Eagle培养基(DMEM)上进行培养，该培养基包含10％小牛血清(FBS)。当细胞增殖至80-90％时使其合并随后进行不超过20代的传代培养，然后在下一步处置前使它们适应环境达到24h。将这些细胞置于96孔板上(8×104/mL)，然后在含有5％CO2的湿润环境中培养过夜并控温在37℃。24h过后加入不同浓度的发明代表性化合物。再经过24h的培养，加入1mM H2O2继续孵育1h，然后向其中加入20ul MTT并继续培养4h。移除培养基质，将晶体溶解于150ulDMSO中，利用酶标仪(TECAN SPECTRA,Wetzlar,德国)在570nm波长下测量吸光度。
根据公式：细胞活力＝实验测得吸光度/空白对照组平均吸光度，计算相应浓度下的细胞活力，按照上述方法测定本发明代表性化合物，结果示于表1：
表1
制剂实施例
下列制剂实施例仅举例说明本发明的保护范围，但不以任何方式构成限定。
实施例72：明胶胶囊
硬明胶胶囊的制备采用：
可以根据所提供的合理变化来改进上述制剂。
实施例73：片剂
片剂的制备采用
将上述组分混合并压制成片剂。
实施例74：片剂
每片中含有2.5-1000mg活性组分的片剂制备如下：
使活性成分、淀粉和纤维素通过美国45号目筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合，随后经美国14号目筛。将生成的颗粒在50-60℃下干燥并经美国18号目筛。将预先经过美国60号目筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加入到上述颗粒中，随后混合，在压片机上压制得到片剂。
实施例75：混悬液
每5ml含有0.1-1000mg药物的混悬液制备如下：
令药物经美国45号目筛并与羧甲基纤维素钠和糖浆混合形成平滑的糊剂。将苯甲酸溶液、矫味剂和着色剂用一些水稀释并在搅拌下加入上述糊剂。随后加入足量的水以达到所需的体积。
实施例76：组合片剂
使活性成分、淀粉和纤维素通过美国45号目筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合，随后经美国14号目筛。将生成的颗粒在50-60℃下干燥并经美国18号目筛。将预先经过美国60号目筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加入到上述颗粒中，随后混合，在压片机上压制得到片剂。
对于上述说明，本领域技术人员可容易地理解本发明的必要特征，不背离本发明的精神和范围，本发明可进行各种改变和改进以适应不同的应用和条件。
Claims (3)
1.如下的吲哚-3-甲酰胺化合物及其药学上可接受的盐在制备治疗或预防与蛋白质氧化损伤引起的相关疾病药物中的应用：
N-苄基-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-苄基-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-苄基-5-(2-二正丙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-苄基-5-(2-二正丙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-苄基-5-(2-二异丁胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-苄基-5-(2-二异丁胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-苄基-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-苄基-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-苄基-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-苄基-5-[2-(4-吗啉基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-苄基-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-苄基-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-(2-二正丙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-(2-二正丙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-(2-二异丁胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-(2-二异丁胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-[2-(4-吗啉基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-(4-氟苄基)-5-{2-[2-(2-甲氧基苯氧基)乙胺基]-2-氧代乙氧基}-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二乙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二乙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二正丙胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二正丙胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二异丁胺基-2-氧代乙氧基)-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-(2-二异丁胺基-2-氧代乙氧基)-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(1-哌啶基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(1-哌啶基)-2-氧代乙氧基]-2-甲基-1-乙基-1H-吲哚-3-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-5-[2-(4-吗啉基)-2-氧代乙氧基]-1,2-二甲基-1H-吲哚-3-甲酰胺。
2.如权利要求1所述的应用，其特征在于，所述的与蛋白质氧化损伤引起的相关疾病是阿尔茨海默症、帕金森氏病、糖尿病或慢性肾衰。
3.如权利要求1或2所述的应用，其特征在于，所述的吲哚-3-甲酰胺化合物及其药学上可接受的盐与药学上可接受的载体组成药物组合物。
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