CN117229257A - 间氨磺酰苯甲酰胺类化合物及制法、药物组合物和应用 - Google Patents
间氨磺酰苯甲酰胺类化合物及制法、药物组合物和应用 Download PDFInfo
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- CN117229257A CN117229257A CN202210628353.0A CN202210628353A CN117229257A CN 117229257 A CN117229257 A CN 117229257A CN 202210628353 A CN202210628353 A CN 202210628353A CN 117229257 A CN117229257 A CN 117229257A
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Abstract
本发明公开了一种间氨磺酰苯甲酰胺类化合物及制法、药物组合物和应用。该化合物结构如式I，包含其立体异构体、药学上可接受的盐或它们的混合物。该类化合物及其药物组合物可特异性抑制丁酰胆碱酯酶活性，最优达到纳摩尔浓度水平；同时具有优异的血脑屏障渗透性，可有效送达至病灶，并且在有效抑制剂量下几乎无毒性；此外具有良好的神经保护作用，并且显著改善记忆和认知功能，通过多种作用机制实现治疗阿尔兹海默症的疗效。
Description
技术领域
本发明涉及一种间氨磺酰苯甲酰胺类化合物及制法、药物组合物和应用，尤其涉及一种可制备为高选择性丁酰胆碱酯酶抑制剂药物的间氨磺酰苯甲酰胺类化合物及制法、药物组合物和应用。
背景技术
神经退行性疾病是一类影响大脑中神经元存活和功能的医学病症。神经元损失通常会导致认知功能下降并发展为痴呆。痴呆症是神经退行性疾病的共同特征。阿尔茨海默症(Alzheimer's disease，AD)是老年人痴呆的常见原因，导致严重的残疾和生活依赖。寻找对AD治疗有效的药物及治疗策略已成为世界医药领域内亟待解决的关键性难题。
AD发病因素极为复杂，目前对AD确切病因尚未定论。前期大量研究表明，AD主要是由于遗传基因、衰老和外界环境因素共同的作用后所诱发的，已经提出了几种假设，包括胆碱能功能障碍，淀粉样蛋白β肽(Aβ)斑块，神经原纤维缠结和氧化应激。其中胆碱能假说相关的药物是临床中能够改善AD症状的主要治疗手段。
乙酰胆碱(ACh)是一种胆碱能传递介质，广泛分布于外周和中枢神经系统。在神经元水平，胆碱能神经传递主要通过乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)。在健康成年人中，AChE对胆碱活性起主要调节作用，BChE起辅助调节作用。但是BChE的辅助调节功能随着AD病程的发展发生变化，晚期AD患者BChE/AChE显著上升。BChE代替AChE起水解胆碱的作用。目前，AChE抑制剂广泛应用于恢复ACh水平，但是患者服用AChE抑制剂可能会产生恶心等副作用和呕吐，甚至发生一些罕见的致命事件，例如多奈哌齐引起的横纹肌溶解症，这些不良反应与AChE广泛的生理功能相关，特别是外周AChE。
当前高选择性的丁酰胆碱酯酶结构类型较少，目前仅有一款处于临床研究中。该化合物为bisnorcymserine，是一种氨基甲酸酯类结构，为BChE共价抑制剂，目前尚未有可逆的BChE抑制剂进入临床。
发明内容
发明目的：针对现有AChE抑制剂药物存在的对AD晚期患者疗效不佳、不良反应严重等问题以及现有BChE抑制剂化合物存在的结构类型单一、选择特异性较低等问题，本发明旨在提供一种对丁酰胆碱酯酶具有特异性抑制活性的间氨磺酰苯甲酰胺类化合物及制法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的间氨磺酰苯甲酰胺类化合物具有式I的结构，包含其立体异构体、药学上可接受的盐或它们的混合物：
其中：
n＝0～2；
A环选自6元芳环、6～9元芳杂环、6～7元环杂基或7元环杂基取代的酰基；所述芳杂基或环杂基环系C被一个或多个N取代；所述6元芳环被一个或多个氢、卤素或C1～C3烷氧基取代；
X选自-C(O)-或-S(O)2-；
R1选自C1～C4烷基、6元芳基或者N与所连接的基团共同形成的6元环杂基；所述C1～C4烷基为一个或多个直链或支链烷基，被一个或多个氢、6～10元芳基或9元芳杂基取代；所述环杂基或芳杂基环系C被一个或多个N取代；
R2选一个或多个自氢、卤素、C1～C3烷氧基、C1～C3烷基或者与苯环并环形成的6元环杂基；所述环杂基环系C被一个或多个O取代；
R3选自一个或多个氢或C1～C3烷基；当R3连接手性C时，手性C的构型为R、S或消旋体。
上述化合物为选择性BChE抑制剂，可以规避现有胆碱能抑制剂药物毒性，相比选择性抑制乙酰胆碱酯酶疗效将更显著，尤其适于中晚期AD患者。
优选，上述结构中：
n＝1～2；
A环选自被一个或多个氢、氟、氯、甲氧基取代的苯基、吡啶基、吲哚基、6～7元含氮环杂环或7元含氮环杂基取代的甲酰基；
R1选自C1～C4烷基、苯基或者N与所连接的基团共同形成的6元环杂基；所述C1～C4烷基为1～2个直链或支链烷基，被一个或多个氢、苯基、萘基或吲哚基取代；
R2选一个或多个自氢、卤素、甲氧基、甲基或乙基；
R3选自一个或多个氢、甲基或乙基；当R3连接手性C时，手性C的构型为R、S或消旋体。
进一步优选，上述结构中：
A环选自：
R1选自：
更进一步优选，上述结构中：
n＝1；
A环选自：
R1选自：
最优选为以下任一化合物：
上述间氨磺酰苯甲酰胺类化合物药学上可接受的盐为所述化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
作为本发明涉及的第二方面，上述间氨磺酰苯甲酰胺类化合物的制备方法选自以下任一方法：
(1)当n＝1，A环为吡啶基，X为-S(O)2-，R2为甲氧基，R3为氢，R1的定义如前所述时，
化合物A1经两步酰化、水解、酰化反应得化合物I；
(2)当n＝1，X为-S(O)2-，R1为丙基，R2为甲氧基，R3为氢，A环的定义如前所述时，
化合物A1经两步酰化、水解、酰化反应得化合物I；
(3)当n＝1，A环为X为-S(O)2-，R1为乙基，R2、R3为氢时，
化合物A7经酯化、卤代、酰化、水解、酰化反应的化合物I；
(4)当n＝1，A环为X为-C(O)-，R1为丙基，R2、R3为氢时，
化合物A14经酰化、水解、酰化反应的化合物I；
(5)当n＝1，A环为X为-S(O)2-，R1为丙基或/>R2为甲基，R3为氢时，
化合物A17a～A17l经酰化、酯化、酰化、水解、酰化反应得化合物I；
(6)当n＝0，A环为X为-S(O)2-，R1为丙基，R2为甲基，R3为氢时，
化合物A22经酰化、脱保护反应得化合物A24，化合物A14a经两步酰化得化合物A26，化合物A24与A26经酰化反应得化合物I；
(7)当n＝1～2，A环为X为-S(O)2-，R1为丙基，R2为甲基，R3为氢、甲基或乙基时，
化合物C26经酰化、卤代、取代反应得化合物I；
将相应的酸与以上方法制备的化合物I成盐，即得上述间氨磺酰苯甲酰胺类化合物的药学上可接受的盐。
作为本发明涉及的第三方面，上述间氨磺酰苯甲酰胺类与药学上可接受的载体形成药物组合物。
具体地，可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面，上述间氨磺酰苯甲酰胺类化合物或者其药物组合物应用于制备丁酰胆碱酯酶抑制剂药物，具体应用于制备治疗神经退行性疾病的药物，尤其是治疗阿尔茨海默症的药物。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类化合物及其药物组合物可特异性抑制丁酰胆碱酯酶活性，IC50值均达到微摩尔浓度水平甚至是纳摩尔浓度水平，最优小于5nM，丁酰胆碱酯酶抑制选择系数最优大于20；同时具有优异的血脑屏障渗透性，可有效送达至病灶，此外在有效抑制剂量下几乎无毒性；
(2)该类化合物及其药物组合物具有良好的神经保护作用，并且显著改善记忆和认知功能，通过多种作用机制实现治疗阿尔兹海默症的疗效；
(3)制备方法适用于多种化学结构类型，通用性强。
附图说明
图1为化合物对人神经母细胞瘤细胞SH-SY5Y和小鼠小胶质细胞BV-2的细胞毒性；
图2为化合物30和44(R)对谷氨酸诱导的对人神经母细胞瘤细胞SH-SY5Y的细胞毒性的神经保护效力，结果表示为3个独立实验的平均值±SEM；
图3为水迷宫实验小鼠到达平台的时间(s)，数据表示为平均值±SEM(n＝8；**P＜0.01，***P＜0.001，****P＜0.0001VS模型组)。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
通过核磁共振(NMR)确定化合物的结构。仪器为Bruker AVANCE-300核磁共振仪，测定溶剂是CDCl3，内标为TMS，化学位移是10-6ppm。
实施例1：化合物1的制备
3-(氯磺酰基)-4-甲氧基苯甲酸甲酯(A2)
在干燥的反应瓶中加入氯磺酸(10eq)，置于冰浴下，分批加入茴香酸甲酯(10mmol)。加毕，将反应液移至室温下反应过夜。反应完全后，将反应液倒入冰水中，剧烈搅拌，有白色固体析出。抽滤，滤饼用冰水洗涤。烘干滤饼，柱层析(PE:EA＝15:1)。
白色固体，收率38％。M.p.114～116℃。1H NMR(300MHz,DMSO)δ8.33(dd,J＝5.6,2.3Hz,1H),7.96(dd,J1＝8.6,J2＝2.3Hz,1H),7.13(d,J＝8.6Hz,1H),3.87(s,3H),3.85(s,3H).
4-甲氧基-3-(N-(2-(吡啶-2-基)乙基)氨磺酰)苯甲酸甲酯(A3)
将2-吡啶基乙胺置于干燥的二氯甲烷中，加入三乙胺(1.2eq)。C2(1.1eq)溶于二氯甲烷，冰浴下逐渐加入到反应瓶中。加毕，室温搅拌2h。柱层析(DCM)。
白色固体，收率62％。M.p.142～144℃1H NMR(300MHz,DMSO)δ8.44(d,J＝4.8Hz,1H),8.30(d,J＝2.2Hz,1H),8.18(dd,J1＝8.7,J2＝2.3Hz,1H),7.68(td,J1＝7.7,J2＝1.8Hz,1H),7.58(t,J＝5.8Hz,1H),7.34(d,J＝8.8Hz,1H),7.23–7.16(m,2H),3.96(s,3H),3.88(s,3H),3.20(dd,J1＝13.2,J2＝7.1,2H),2.84(t,J＝7.2Hz,2H).
4-甲氧基-3-(N-(2-(吡啶-2-基)乙基)氨磺酰)苯甲酸(A4)
将原料溶于10mL甲醇中，加入氢氧化锂(5eq)，50℃加热6h。反应完毕后，2N盐酸调节pH至5以下。析出固体。抽滤即得。
白色固体，收率80％。M.p.165～167℃1H NMR(300MHz,DMSO)δ8.76(d,J＝4.8Hz,1H),8.43(t,J＝7.8Hz,1H),8.23(d,J＝2.1Hz,1H),8.14(dd,J1＝8.7,J2＝2.1Hz,1H),7.85(d,J＝7.8Hz,2H),7.72(t,J＝5.8Hz,1H),7.30(d,J＝8.8Hz,1H),3.96(s,3H),3.31(dd,J1＝11.9,J2＝5.8Hz,2H),3.18(t,J＝6.1Hz,2H).
实施例2：4-甲氧基-N-苯乙基-3-(N-(2-(吡啶-2-基)乙基)氨磺酰)苯甲酰胺(2)
A4溶于5mL二氯甲烷中，冰浴下加入EDCI-HCl,HOBT,DIEA.。搅拌0.5h后加入二丙胺。随后移置室温下过夜反应。反应液用水洗涤，二氯甲烷萃取，合并有机相。饱和食盐水洗涤，无水硫酸钠干燥。真空除去溶剂，柱层析(DCM：MEOH＝100:1)。
白色固体，收率70％。M.p.121～123℃。1H NMR(300MHz,CDCl3)δ8.48(d,J＝4.1Hz,1H),8.18(s,1H),8.07(dd,J1＝8.7,J2＝2.3Hz,1H),7.58(td,J1＝7.7,J2＝1.8Hz,1H),7.33(dd,J1＝10.7,J2＝3.8Hz,2H),7.24(dd,J1＝5.1,J2＝2.4Hz,3H),7.15(dd,J1＝7.0,J2＝5.4Hz,1H),7.04(d,J＝7.8Hz,1H),6.99(d,J＝8.7Hz,1H),6.43(t,J＝5.6Hz,1H),6.29(t,J＝6.1Hz,1H),3.85(s,3H),3.70(dd,J1＝13.3,J2＝7.0Hz,2H),3.35(q,J＝6.1Hz,2H),3.21–3.16(m,2H),3.16–3.12(m,2H).13C NMR(75MHz,CDCl3)δ165.63,158.73,158.36,148.94,138.95,136.69,134.41,128.82,128.63,128.33,127.14,126.96,126.49,123.61,121.74,112.00,56.41,42.30,41.48,36.16,35.75.ESI:m/z[M+H]+,calcd.for C23H26N3O4S+:440.1639；found:440.1642.
实施例3：化合物3的制备
步骤1～3参见实施例1。
4-甲氧基-N-丙基-3-(N-(2-(吡啶-2-基)乙基)氨磺酰)苯甲酰胺(3)
参考化合物1的合成，将色胺替换成正丙胺。
无色油状物，收率73％。1H NMR(300MHz,CDCl3)δ8.54(d,J＝4.1Hz,1H),8.25(d,J＝2.3Hz,1H),8.17(dd,J1＝8.7,J2＝2.3Hz,1H),7.63(d,J＝1.8Hz,1H),7.23–7.17(m,1H),7.09(d,J＝7.8Hz,1H),7.03(s,1H),6.36(dd,J1＝11.7,J2＝5.6Hz,2H),3.89(s,3H),3.50–3.44(m,2H),3.43–3.37(m,2H),2.95(t,J＝6.1Hz,2H),1.69(dd,J1＝14.6,J2＝7.3Hz,2H),1.03(t,J＝7.4Hz,3H).13C NMR(75MHz,CDCl3)δ165.58,158.78,148.95,136.67,134.56,128.06,127.09,123.60,121.72,111.98,56.39,41.92,36.12,30.32,22.86,11.51.ESI:m/z[M+H]+,calcd.for C18H24N3O4S+:378.1482；found:378.1486.
实施例4：化合物4的制备
步骤1～3参见实施例1。
N-(2-(二甲氨基)乙基)-4-甲氧基-3-(2-(吡啶-2-基)乙基)氨磺酰)苯甲酰胺(4)
参考化合物1的合成，将色胺替换成N,N-二甲基乙胺。
淡黄色油状物，收率51％。1H NMR(300MHz,CD3OD)δ8.41(d,J＝4.3Hz,1H),8.37(d,J＝2.2Hz,1H),8.09(dd,J1＝8.7,J2＝2.2Hz,1H),7.72(td,J1＝7.7,J2＝1.7Hz,1H),7.25(s,2H),7.22(s,1H),3.96(s,3H),3.66(t,J＝6.2Hz,2H),3.29(t,J＝6.9Hz,2H),2.99(t,J＝6.2Hz,2H),2.92(t,J＝6.9Hz,2H),2.66(s,6H).13C NMR(75MHz,MeOD)δ167.33,158.99,158.39,148.38,137.21,133.54,129.09,127.73,125.77,123.82,121.87,112.04,57.66,55.69,43.44,42.37,36.97,36.26.ESI:m/z[M+H]+,calcd.for C19H27N4O4S+:407.1748；found:407.1754.
实施例5：化合物5的制备
步骤1～3参见实施例1。
4-甲氧基-N-(3-甲氧基丙基)-3-(2-(吡啶-2-基)乙基)氨磺酰)苯甲酰胺(5)
参考化合物1的合成，将色胺替换成3-甲氧基丙胺。
淡黄色油状物，收率68％。1H NMR(300MHz,CDCl3)δ8.50(d,J＝4.8Hz,1H),8.20(d,J＝2.2Hz,1H),8.11(dd,J1＝8.6,J2＝2.2Hz,1H),7.59(td,J1＝7.7,J2＝1.7Hz,1H),7.19–7.12(m,2H),7.02(dd,J1＝16.4,J2＝8.2Hz,2H),6.23(t,J＝6.0Hz,1H),3.85(s,3H),3.58(dd,J1＝11.6,J2＝5.9Hz,4H),3.43(s,3H),3.37(dd,J1＝12.2,J2＝6.1Hz,2H),2.91(t,J＝6.0Hz,2H),1.97–1.84(m,2H).13C NMR(75MHz,CDCl3)δ165.21,158.82,158.28,148.99,136.65,134.32,128.09,127.26,127.02,123.61,121.70,111.94,72.31,58.97,56.38,42.23,39.29,36.16,28.73.ESI:m/z[M+H]+,calcd.for C19H25N3O5S+:408.1588；found:408.1592.
实施例6：化合物6的制备
步骤1～3参见实施例1。
4-甲氧基-N，N-二丙基-3-(N-(2-(吡啶-2-基)乙基)氨磺酰)苯甲酰胺(6)
参考化合物1的合成，将色胺替换成二丙胺。
无色油状物，收率65％。1H NMR(300MHz,CDCl3)δ8.54(d,J＝4.2Hz,1H),7.98(d,J＝2.1Hz,1H),7.66–7.56(m,2H),7.19(dd,J1＝7.1,J2＝5.3Hz,1H),7.10(d,J＝7.8Hz,1H),7.02(s,1H),6.32(t,J＝6.0Hz,1H),3.88(s,3H),3.44(d,J＝15.8Hz,2H),3.40–3.34(m,2H),3.22(s,2H),2.95(t,J＝6.0Hz,2H),1.74(s,2H),1.60(s,2H),1.01(s,3H),0.80(s,3H).13C NMR(75MHz,CDCl3)δ169.91,158.86,156.68,148.95,136.64,133.32,129.56,128.60,127.17,123.59,121.67,111.96,56.26,51.01,42.26,36.12,20.68,11.04.ESI:m/z[M+H]+,calcd.for C21H30N3O4S+:420.1952；found:420.1955.
实施例7：化合物7的制备
步骤1参见实施例1。
步骤2：4-甲氧基-3-(N-苯乙基氨磺酰)苯甲酸甲酯(C5a)
参见C3的合成，其中将2-吡啶基乙胺更换为β-苯乙胺。
无色油状物，收率70％。
步骤3：4-甲氧基-3-(N-苯乙基氨磺酰)苯甲酸(C6a)
参见C4的合成，其中将C3更换为C5a。
白色固体，收率70％。M.p.145～147℃。1H NMR(300MHz,DMSO)δ13.08(s,1H),8.28(d,J＝2.2Hz,1H),8.14(dd,J1＝8.7,J2＝2.2Hz,1H),7.49(t,J＝5.8Hz,1H),7.30(d,J＝8.8Hz,1H),7.28–7.14(m,3H),7.13–7.09(m,2H),3.93(s,3H),3.07–2.96(m,2H),2.67(t,J＝7.4Hz,2H).
步骤4：4-甲氧基-3-(N-苯乙基氨磺酰)-N，N-二丙基苯甲酰胺(7)
C6a溶于5mL二氯甲烷中，冰浴下加入EDCI-HCl(1.5eq)，HOBT(1.5eq)和DIEA(3eq)。搅拌0.5h后加入二丙胺(1.1eq)。随后移置室温下过夜反应。反应液用水洗涤，二氯甲烷萃取，合并有机相。饱和食盐水洗涤，无水硫酸钠干燥。真空除去溶剂，柱层析(DCM：MEOH＝100:1)。
淡黄色油状物，收率75％。1H NMR(300MHz,CDCl3)δ8.48(s,1H),7.80(d,J＝2.0Hz,1H),7.43(dd,J1＝8.5,J2＝2.1Hz,1H),7.28–7.18(m,2H),7.08(t,J＝7.6Hz,1H),6.96–6.88(m,2H),6.58(d,J＝8.6Hz,1H),4.75(t,J＝5.9Hz,1H),3.37(s,2H),3.18–3.07(m,3H),3.06(s,4H),2.86(t,J＝6.0Hz,2H),1.60(s,2H),1.48(s,2H),0.90(s,3H),0.68(s,3H).13C NMR(75MHz,CDCl3)δ170.07,156.22,136.66,135.77,133.29,128.60,126.79,125.90,123.25,119.46,111.68,55.38,51.05,43.17,30.33,24.93,11.13.ESI:m/z[M+H]+,calcd.for C22H30N2O4S+:419.1999；found:419.2000.
实施例8：化合物8的合成
3-(N-(2-氟苯乙基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(8)
参见7的合成，其中将C6a更换为C6b。
淡黄色油状物，收率72％。1H NMR(300MHz,CDCl3)δ7.92(d,J＝1.9Hz,1H),7.61(dd,J＝8.5,1.9Hz,1H),7.25–7.18(m,1H),7.15(t,J＝6.7Hz,1H),7.07(t,J＝7.4Hz,1H),7.01(t,J＝8.2Hz,2H),4.86(t,J＝6.2Hz,1H),3.80(s,3H),3.43(s,2H),3.16(dd,J1＝13.5,J2＝6.5Hz,4H),2.85(t,J＝6.7Hz,2H),1.43(s,2H),0.97(s,3H),0.75(s,3H).13CNMR(75MHz,CDCl3)δ169.75,156.48,133.57,131.22,129.72,128.69,126.57,124.82,124.62,124.32,115.54,112.10,56.32,51.00,43.15,29.25,20.70,11.03.ESI:m/z[M+H]+,calcd.for C22H30FN2O4S+:437.1905；found:437.1906.
实施例9：化合物9的合成
3-(N-(3-氟苯乙基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(9)
参见7的合成，其中将C6a更换为C6c。
淡黄色油状物，收率75％。1H NMR(300MHz,CDCl3)δ7.97(t,J＝2.3Hz,1H),7.73–7.64(m,1H),7.32(d,J＝2.6Hz,2H),7.09–6.98(m,2H),6.96(d,J＝7.3Hz,1H),6.84(d,J＝9.7Hz,1H),4.89(s,1H),3.82(t,J＝7.2Hz,3H),3.49(s,2H),3.26–3.16(m,4H),2.86(dd,J1＝8.3,J2＝4.4Hz,2H),1.70(s,2H),1.03(s,3H),0.82(s,3H).13C NMR(75MHz,CDCl3)δ169.74,164.54,156.42,140.48,133.59,130.32,129.83,128.69,126.51,124.53,124.50,115.59,113.89,56.25,51.00,44.13,35.09,35.07,21.96,11.44.ESI:m/z[M+H]+,calcd.for C22H30FN2O4S+:437.1905；found:437.1905.
实施例10：化合物10的合成
3-(N-(4-氟苯乙基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(10)
参见7的合成，其中将C6a更换为C6d。
淡黄色油状物，收率66％。1H NMR(300MHz,CDCl3)δ7.92(d,J＝2.0Hz,1H),7.60(dd,J＝8.5,2.1Hz,1H),7.06(dd,J1＝8.4,J2＝5.5Hz,2H),7.02–6.96(m,2H),6.94(d,J＝8.6Hz,1H),5.03(t,J＝6.0Hz,1H),3.76(s,3H),3.43(s,2H),3.26–3.04(m,4H),2.76(t,J＝6.7Hz,2H),1.62(d,J＝26.4Hz,4H),0.97(s,3H),0.76(s,3H).13C NMR(75MHz,CDCl3)δ169.77,163.31,156.45,133.59,133.49,130.16,129.72,128.68,126.54,115.58,112.07,56.27,51.00,44.49,34.59,21.94,11.43.ESI:m/z[M+H]+,calcd.for C22H30FN2O4S+:437.1905；found:437.1906.
实施例11：化合物11的合成
4-甲氧基-3-(N-(3-甲氧基苯乙基)氨磺酰)-N，N-二丙基苯甲酰胺(11)
参见7的合成，其中将C6a更换为C6e。
淡黄色油状物，收率63％。1H NMR(300MHz,CDCl3)δ7.91(s,1H),7.60(d,J＝8.5Hz,1H),7.20(t,J＝7.8Hz,1H),6.97(d,J＝8.5Hz,1H),6.77(d,J＝8.2Hz,1H),6.67(d,J＝7.5Hz,1H),6.60(s,1H),4.93(t,J＝6.0Hz,1H),3.76(s,3H),3.69(s,3H),3.43(s,2H),3.27–3.11(m,4H),2.76(t,J＝6.5Hz,2H),1.62(d,J＝26.0Hz,4H),0.97(s,3H),0.77(s,3H).13C NMR(75MHz,CDCl3)δ169.81,159.87,156.45,139.36,133.53,129.77,129.65,128.68,126.37,120.96,114.23,112.20,111.98,56.19,55.19,51.04,44.32,35.18,21.97,11.49.ESI:m/z[M+H]+,calcd.for C23H33N2O5S+:449.2105；found:449.2106.
实施例12：化合物12的合成
3-(N-(3-氯苯乙基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(12)
参见7的合成，其中将C6a更换为C6f。
淡黄色油状物，收率61％。1H NMR(300MHz,CDCl3)δ7.90(d,J＝2.0Hz,1H),7.59(dd,J1＝8.5,J2＝2.0Hz,1H),7.25–7.15(m,2H),7.00(dd,J1＝9.1,J2＝6.9Hz,3H),5.02(t,J＝6.1Hz,1H),3.75(s,3H),3.41(s,2H),3.13(dd,J1＝12.9,J2＝6.5Hz,4H),2.74(t,J＝6.6Hz,2H),1.59(d,J＝23.5Hz,4H),0.94(s,3H),0.74(s,3H).13C NMR(75MHz,CDCl3)δ169.77,156.45,139.98,134.39,133.57,130.02,129.72,128.65,127.14,127.05,126.99,126.54,112.12,56.30,51.03,44.13,35.02,21.97,11.44.ESI:m/z[M+H]+,calcd.forC22H30ClN2O4S+:453.1609；found:453.1610.
实施例13：化合物13的合成
3-(N-(2-溴苯基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(13)
参见7的合成，其中将C6a更换为C6g。
淡黄色油状物，收率64％。1H NMR(300MHz,CDCl3)δ7.71(d,J＝2.0Hz,1H),7.39(dd,J＝8.5,2.0Hz,1H),7.29(d,J＝7.9Hz,1H),7.09–6.95(m,2H),6.93–6.84(m,1H),6.79(d,J＝8.6Hz,1H),4.76(t,J＝6.1Hz,1H),3.60(s,3H),3.21(s,2H),2.94(dd,J＝13.2,6.7Hz,4H),2.72(t,J＝6.9Hz,2H),1.39(d,J＝25.2Hz,4H),0.75(s,3H),0.58(d,J＝22.0Hz,4H).13C NMR(75MHz,CDCl3)δ169.77,156.49,137.09,133.58,132.99,131.19,129.77,128.86,128.60,127.72,126.51,124.40,112.10,56.38,51.01,42.72,35.87,21.98,11.14.ESI:m/z[M+H]+,calcd.for C22H30BrN2O4S+:497.1104；found:497.1108.
实施例14：化合物14的合成
3-(N-(3-溴苯基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(14)
参见7的合成，其中将C6a更换为C6h。
淡黄色油状物，收率64％。1H NMR(300MHz,CDCl3)δ7.71(d,J＝2.0Hz,1H),7.39(dd,J＝8.5,2.0Hz,1H),7.29(d,J＝7.9Hz,1H),7.09–6.95(m,2H),6.93–6.84(m,1H),6.79(d,J＝8.6Hz,1H),4.76(t,J＝6.1Hz,1H),3.60(s,3H),3.21(s,2H),2.94(dd,J＝13.2,6.7Hz,4H),2.72(t,J＝6.9Hz,2H),1.39(d,J＝25.2Hz,4H),0.75(s,3H),0.58(d,J＝22.0Hz,4H).13C NMR(75MHz,CDCl3)δ169.77,156.44,140.29,133.58,131.57,130.32,129.95,129.74,128.64,127.53,126.53,122.70,112.14,56.35,51.02,44.15,35.00,21.98,11.50.ESI:m/z[M+H]+,calcd.for C22H30BrN2O4S+:497.1104；found:497.1103.
实施例15：化合物15的合成
3-(N-(2-(1H-吲哚-3-基)乙基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(15)
参见7的合成，其中将C6a更换为C6i。
淡黄色油状物，收率69％。1H NMR(300MHz,CDCl3)δ7.92(s,1H),7.60(d,J＝8.5Hz,1H),7.35–7.21(m,3H),7.09(d,J＝7.3Hz,2H),6.96(d,J＝8.5Hz,1H),4.91(t,J＝5.9Hz,1H),3.66(s,3H),3.50–3.03(m,6H),2.79(t,J＝6.5Hz,2H),1.60(d,J＝23.3Hz,4H),0.96(s,3H),0.76(s,3H).13C NMR(75MHz,CDCl3)δ169.77,156.49,137.09,133.58,132.99,131.19,129.77,128.86,128.60,127.72,126.51,124.40,112.10,56.38,51.01,42.72,35.87,21.98,11.14.ESI:m/z[M+H]+,calcd.for C24H31N3O4S+:458.2108；found:458.2109.
实施例16：化合物16的合成
4-甲氧基-3-(N-(2-(哌啶-1-基)乙基)氨磺酰)-N，N-二丙基苯甲酰胺(16)
参见7的合成，其中将C6a更换为C6j。
淡黄色油状物，收率60％。1H NMR(300MHz,CDCl3)δ7.98(s,1H),7.67(d,J＝8.3Hz,1H),7.10(d,J＝8.5Hz,1H),4.07(s,3H),3.48(s,2H),3.22(s,2H),2.97(t,J＝5.6Hz,2H),2.37(dd,J1＝13.1,J2＝7.6Hz,2H),2.28(s,4H),1.78–1.42(m,10H),1.02(s,3H),0.82(s,3H).13C NMR(75MHz,CDCl3)δ169.89,156.79,133.50,129.63,128.90,126.66,112.05,56.53,56.49,54.02,51.06,39.90,26.01,24.26,21.94,11.48.ESI:m/z[M+H]+,calcd.forC21H36N3O4S+:426.2421；found:426.2425.
实施例17：化合物17的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-甲氧基-N，N-二丙基苯甲酰胺(17)
参见7的合成，其中将C6a更换为C6k。
无色油状物，收率68％。1H NMR(300MHz,CDCl3)δ7.93(d,J＝2.1Hz,1H),7.62(dd,J1＝8.5,J2＝2.1Hz,1H),7.05(d,J＝8.5Hz,1H),4.00(s,3H),3.43(s,2H),3.19(s,2H),2.95–2.86(m,2H),2.56(s,2H),2.53(d,J＝5.1Hz,4H),1.64(s,2H),1.57(s,10H),0.96(s,3H),0.77(s,3H).13C NMR(75MHz,CDCl3)δ169.92,156.80,133.50,128.89,126.68,125.52,112.07,56.46,55.50,55.06,51.07,40.88,30.31,28.00,21.97,11.40.ESI:m/z[M+H]+,calcd.for C22H38N3O4S+:440.2578；found:440.2579.HPLC:0～16min(A:B＝80:20),tR＝5.34min,Purity:97.54％.
实施例18：化合物18的合成
3-(甲氧羰基)苯磺酸钠的合成(C8)
3-羧基苯磺酸钠溶于甲醇中，加入浓盐酸，加热回流12h。反应结束后，真空除去大半溶剂，析出白色固体，抽滤，少量冰甲醇洗涤滤饼，烘干即得。
白色固体，收率94％。M.p.198～200℃。1H NMR(300MHz,DMSO)δ8.24(t,J＝1.5Hz,1H),7.97–7.92(m,1H),7.92–7.87(m,1H),7.53(t,J＝7.7Hz,1H),3.90(s,3H).
3-(氯磺酰基)苯甲酸甲酯的合成(C9)
将3-(甲氧羰基)苯磺酸钠(10mmol)置于反应瓶中，加入10mL二氯亚砜，加热回流。反应完毕，将反应液旋干，残余物即为3-(氯磺酰基)苯甲酸甲酯，未经纯化，直接下一步。
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)苯甲酸甲酯(C11)
C10置于干燥的反应瓶中，加入DCM 40mL，三乙胺(1.5eq)。C9(1.2eq)溶于DCM10mL，冰浴下逐滴加入反应瓶内。加毕，移至室温搅拌2h。反应液直接柱层析(DCM:MeOH＝100:1)。
淡黄色油状物，收率64.5％。1H NMR(300MHz,CDCl3)δ8.54(t,J＝1.6Hz,1H),8.26(dd,J1＝4.5,J2＝3.3Hz,1H),8.09(ddd,J1＝7.8,J2＝1.8,J3＝1.2Hz,1H),7.64(dt,J1＝7.8,J2＝3.9Hz,1H),2.95(d,J＝5.9Hz,2H),2.56–2.50(m,2H),2.48–2.42(m,4H),1.54(s,8H).
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)苯甲酸(C12)
将C11溶于(10mmol)30mL甲醇，加入LiOH(50mmol)，50℃加热反应6h。反应结束后，真空除去大半溶剂，2N盐酸调节pH＝5，析出白色固体，抽滤，滤饼用水洗涤，烘干滤饼即得。
白色固体，收率78％。M.p.170～172℃。
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N，N-二丙基苯甲酰胺(18)
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将C12(0.5mmol)溶于10mL二氯甲烷，冰浴下加入EDCI-HCl(1.5eq)，HOBT(1.5eq)，DIPEA(3eq)，搅拌30min后，加入C13a(1.1eq)，转移至室温下反应过夜。反应液用水洗涤，水相使用二氯甲烷萃取1～2次，合并有机相，无水硫酸钠干燥。真空除去溶剂，柱层析(DCM:MeOH＝100:1)。
淡黄色油状物，收率74.1％。1H NMR(300MHz,CDCl3)δ7.97–7.92(m,1H),7.90(s,1H),7.65–7.57(m,2H),3.55–3.46(m,2H),3.21–3.13(m,2H),3.02–2.94(m,2H),2.59–2.53(m,2H),2.50(s,4H),1.74(d,J＝6.7Hz,2H),1.58(s,10H),1.03(t,J＝7.1Hz,3H),0.79(t,J＝7.1Hz,3H).13C NMR(75MHz,CDCl3)δ169.82,140.05,138.27,130.65,129.44,127.48,125.14,55.30,54.91,50.79,40.26,28.06,26.85,21.92,11.46.ESI:m/z[M+H]+,calcd.for C21H36N3O3S+:410.2472；found:410.2474.
实施例19：化合物19的合成
3-(2-(氮杂环丙烷-1-基)乙基)氨甲酰)苯甲酸甲酯(C15)
将C14(0.5mmol)溶于10mL二氯甲烷，冰浴下加入EDCI-HCl(1.5eq)，HOBT(1.5eq)，DIPEA(3eq)，搅拌30min后，加入C10(1.1eq)，转移至室温下反应过夜。反应液用水洗涤，水相使用二氯甲烷萃取1～2次，合并有机相，无水硫酸钠干燥。真空除去溶剂，柱层析(DCM:MeOH＝100:1)。
无色油状物，收率80％。1H NMR(300MHz,CDCl3)δ8.47(t,J＝1.5Hz,1H),8.24–8.18(m,1H),8.12–8.08(m,1H),7.58(t,J＝7.7Hz,1H),3.98(s,4H),3.55(dd,J1＝10.9,J2＝5.7Hz,2H),2.82–2.77(m,2H),2.77–2.72(m,4H),1.69(s,8H).
3-(2-(氮杂环丙烷-1-基)乙基)氨甲酰)苯甲酸(C16)
参见C12的合成，其中C11更换为C15。
无色油状物，收率72％。
N1-(2-(氮杂环丙烷-1-基)乙基)-N3，N3-二丙基二苯甲酰胺(19)
参见18的合成，其中C12更换为C16。
淡黄色油状物，收率65％。1H NMR(300MHz,CDCl3)δ7.84(ddd,J1＝5.1,J2＝3.1,J3＝1.7Hz,1H),7.78(s,1H),7.47(dd,J1＝3.6,J2＝2.0Hz,2H),7.29(s,1H),3.51(dt,J1＝11.7,J2＝5.8Hz,4H),3.16(s,2H),2.82–2.66(m,6H),1.76–1.59(m,10H),1.52(d,J＝6.3Hz,2H),0.99(s,3H),0.74(s,3H).13C NMR(75MHz,CDCl3)δ170.93,166.62,137.62,134.88,129.28,128.77,127.59,125.08,55.92,55.12,50.70,37.20,27.88,26.99,21.87,11.44.ESI:m/z[M+H]+,calcd.for C22H36N3O2S+:374.2802；found:374.2804.
实施例20：化合物20的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N，N-二乙基苯甲酰胺(20)
参见18的合成，其中将C13a更换为C13b。
无色油状物，收率68％。1H NMR(300MHz,CDCl3)δ7.97–7.91(m,2H),7.66–7.57(m,2H),3.59(d,J＝6.8Hz,2H),3.26(d,J＝6.7Hz,2H),3.04–2.95(m,2H),2.63–2.55(m,2H),2.52(s,4H),1.58(s,8H),1.30(t,J＝6.9Hz,3H),1.16(t,J＝6.4Hz,3H).13C NMR(75MHz,CDCl3)δ169.35,140.10,138.17,130.44,129.48,127.55,125.02,55.33,54.93,43.46,40.19,27.92,26.85,14.19.ESI:m/z[M+H]+,calcd.for C19H32N3O3S+:382.2159；found:382.2159.
实施例21：化合物21的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N，N-二丁基苯甲酰胺(21)
参见18的合成，其中将C13a更换为C13c。
无色油状物，收率75％。1H NMR(300MHz,CDCl3)δ7.97–7.91(m,1H),7.90(s,1H),7.62(dd,J1＝4.2,J2＝1.1Hz,1H),7.59(dd,J1＝6.0,J2＝4.6Hz,1H),3.53(t,J＝7.2Hz,2H),3.25–3.11(m,2H),3.03–2.94(m,2H),2.60–2.53(m,2H),2.50(s,4H),1.76–1.63(m,2H),1.58(s,10H),1.44(dd,J1＝14.2,J2＝7.0Hz,2H),1.17(dd,J1＝14.2,J2＝7.2Hz,2H),1.02(t,J＝7.0Hz,3H),0.83(t,J＝7.0Hz,3H).13C NMR(75MHz,CDCl3)δ169.64,140.03,138.23,130.59,129.39,127.45,125.10,55.34,54.89,48.87,40.21,30.74,27.95,26.82,20.26,13.90.ESI:m/z[M+H]+,calcd.for C23H32N3O3S+:438.2785；found:438.2785.
实施例22：化合物22的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N，N-二异丁基苯甲酰胺(22)
参见18的合成，其中将C13a更换为C13d。
无色油状物，收率68％。1H NMR(300MHz,CDCl3)δ8.11–8.00(m,1H),7.95(s,1H),7.68(s,1H),7.67(s,1H),3.48(d,J＝7.4Hz,2H),3.20–3.12(m,4H),2.79(t,J＝9.5Hz,6H),2.32–2.14(m,1H),2.03–1.90(m,1H),1.71(s,8H),1.11(d,J＝6.3Hz,6H),0.86(d,J＝6.4Hz,6H).13C NMR(151MHz,CDCl3)δ170.59,140.17,138.47,131.17,129.51,127.56,125.45,56.58,55.84,55.07,51.35,39.65,26.82,26.60,20.22.ESI:m/z[M+H]+,calcd.for C23H32N3O3S+:438.2785；found:438.2786.
实施例23：化合物23的合成
N-(2-(氮杂环丙烷-1-基)乙基)-3-(哌啶-1-羰基)苯磺酰胺(23)
参见18的合成，其中将C13a更换为C13e。
无色油状物，收率66％。1H NMR(300MHz,CDCl3)δ7.97–7.91(m,2H),7.68–7.57(m,2H),3.75(s,2H),3.35(s,2H),3.04–2.92(m,2H),2.60–2.54(m,2H),2.50(s,4H),1.73(s,4H),1.57(s,10H).13C NMR(75MHz,CDCl3)δ168.31,140.14,137.47,130.91,129.45,125.44,55.34,54.91,48.80,40.25,27.96,26.84,26.44,24.40.ESI:m/z[M+H]+,calcd.for C20H32N3O3S+:394.2159；found:394.2160.
实施例24：化合物24的合成
N-(2-(氮杂-1-基)乙基)-3-(4-甲基哌嗪-1-羰基)苯磺酰胺(24)
参见18的合成，其中将C13a更换为C13f。
无色油状物，收率66％。1H NMR(300MHz,CDCl3)δ8.01–7.97(m,1H),7.95(s,1H),7.67–7.59(m,2H),3.85(s,2H),3.45(s,2H),3.13(dd,J1＝9.5,J2＝4.1Hz,2H),2.79(dd,J1＝11.4,J2＝6.8Hz,6H),2.54(s,2H),2.41(s,2H),2.37(s,3H),1.71(s,4H),1.65(s,4H).13C NMR(75MHz,CDCl3)δ168.35,140.29,136.73,131.09,129.64,128.17,125.63,56.13,55.08,53.71,53.52,45.88,39.18,26.71,25.49.ESI:m/z[M+H]+,calcd.for C20H33N4O3S+:409.2268；found:409.2268.
实施例25：化合物25的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N-苯甲酰胺(25)
参见18的合成，其中将C13a更换为C13g。
黄色油状物，收率71％。1H NMR(300MHz,CDCl3)δ8.71(s,1H),8.40(s,1H),8.15(d,J＝7.5Hz,1H),7.98(d,J＝7.4Hz,1H),7.70(d,J＝7.8Hz,2H),7.60(td,J1＝7.7,J2＝3.3Hz,1H),7.35(dd,J1＝10.0,J2＝5.3Hz,2H),7.15(t,J＝7.3Hz,1H),5.32–5.18(m,1H),2.97(s,2H),2.51(d,J＝13.6Hz,6H),1.52(s,8H).13C NMR(75MHz,CDCl3)δ164.35,140.17,137.91,136.21,132.24,129.77,129.64,129.00,125.35,124.82,120.72,55.29,54.85,39.99,27.03,26.91.ESI:m/z[M+H]+,calcd.for C21H28N3O3S+:402.1846；found:402.1846.
实施例26：化合物26的合成
N-((1H-吲哚-3-基)甲基)-3-(N-(2-(氮杂环-1-基)乙基)氨磺酰)-N-丙基苯甲酰胺(26)
参见18的合成，其中将C13a更换为C13h。
淡黄色油状物，收率75％。1H NMR(300MHz,CDCl3)δ8.31(d,J＝23.1Hz,1H),8.03–7.85(m,2H),7.72(d,J＝16.3Hz,1H),7.50(dd,J1＝30.7,J2＝22.6Hz,3H),7.25–7.05(m,2H),4.78(d,J＝104.6Hz,2H),3.49(s,2H),2.99(d,J＝38.1Hz,2H),2.44(t,J＝19.3Hz,6H),1.61(d,J＝54.8Hz,10H),0.84(d,J＝68.9Hz,3H).ESI:m/z[M+H]+,calcd.forC27H37N4O3S+:497.2581；found:497.2581.
实施例27：化合物27的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N-(萘-2-基甲基)-N-丙基苯甲酰胺(27)
参见18的合成，其中将C13a更换为C13i。
淡黄色油状物，收率78％。1H NMR(300MHz,CDCl3)δ8.04–7.75(m,6H),7.65(d,J＝11.7Hz,2H),7.56–7.48(m,3H),7.28(s,1H),4.80(d,J＝95.3Hz,2H),3.33(d,J＝123.2Hz,2H),2.90(d,J＝45.2Hz,2H),2.62–2.35(m,6H),1.64(d,J＝59.4Hz,10H),0.86(d,J＝71.1Hz,3H).13C NMR(75MHz,CDCl3)δ170.30,140.28,137.81,134.47,133.81,133.32,132.85,130.71,130.44,129.51,128.79,127.80,127.75,127.07,126.06,125.33,124.41,55.24,54.88,52.75,47.70,40.25,28.09,26.86,21.52,11.45.ESI:m/z[M+H]+,calcd.forC29H38N3O3S+:508.2628；found:508.2630.
实施例28：化合物28的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N-(萘-1-基甲基)-N-丙基苯甲酰胺(28)
参见18的合成，其中将C13a更换为C13j。
淡黄色油状物，收率71％。1H NMR(300MHz,CDCl3)δ8.15(s,1H),7.99–7.81(m,4H),7.58(dd,J1＝32.6,J2＝16.2Hz,6H),5.11(d,J＝105.4Hz,2H),2.98(s,2H),2.52(d,J＝19.0Hz,4H),2.31(s,2H),1.66(d,J＝62.8Hz,10H),0.84(d,J＝88.8Hz,3H).ESI:m/z[M+H]+,calcd.for C29H38N3O3S+:508.2628；found:508.2627.
实施例29：化合物29的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N-苄基-N-丙基苯甲酰胺(29)
参见18的合成，其中将C13a更换为C13k。
淡黄色油状物，收率70％。1H NMR(300MHz,CDCl3)δ7.92(s,2H),7.57(d,J＝24.0Hz,2H),7.35(s,4H),7.14(s,1H),3.08(s,2H),2.90(d,J＝25.4Hz,2H),2.45(s,6H),1.60(d,J＝42.8Hz,10H),1.26(s,2H),0.84(d,J＝70.3Hz,3H).13CNMR(75MHz,CDCl3)δ170.21,140.21,137.78,136.91,136.32,130.69,129.49,128.93,128.09,127.75,127.63,126.61,125.29,55.26,54.90,52.56,49.92,47.49,40.26,28.08,26.85,21.46,11.41.ESI:m/z[M+H]+,calcd.for C25H36N3O3S+:458.2472；found:458.2471.
实施例30：化合物30的合成
3-(氯磺酰基)-4-甲基苯甲酸(C18a)
在干燥的反应瓶中，加入氯磺酸(5eq)，冰浴下加入C17a，后80℃加热反应8h。反应结束后，反应液倒入冰水中，析出固体，抽滤，滤饼用水洗涤，烘干滤饼即得。
白色固体，收率78％。M.p.173～175℃。1H NMR(300MHz,DMSO)δ12.42(s,1H),8.34(d,J＝1.8Hz,1H),7.79(dd,J＝7.8,1.9Hz,1H),7.28(d,J＝7.9Hz,1H),2.60(s,3H).
3-(氯磺酰基)-4-甲基苯甲酸甲酯(C19a)
将C18a(8mmol)置于干燥的反应瓶中，加入8mL氯化亚砜，加热回流6h。真空除去反应液，残余物溶于干燥的二氯甲烷，于冰浴下缓慢加入冷甲醇中。在该条件下继续搅拌0.5h后转室温搅拌约1h。反应结束后，在不超过40℃下真空除去溶剂，柱层析(PE:EA＝10:1)。
白色固体，收率68％。M.p.113～115℃。1H NMR(300MHz,CDCl3)δ8.73(d,J＝1.7Hz,1H),8.28(dd,J1＝7.9,J2＝1.7Hz,1H),7.55(d,J＝8.0Hz,1H),3.99(s,3H),2.87(s,3H).
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-甲基苯甲酸甲酯(C20a)
C10置于干燥的反应瓶中，加入DCM 40mL，三乙胺(1.5eq)。C19a(1.2eq)溶于DCM10mL，冰浴下逐滴加入反应瓶内，加毕，移至室温搅拌2h。反应液直接柱层析(DCM:MeOH＝100:1)。
淡黄色油状物，收率80％。1H NMR(300MHz,CDCl3)δ8.63(d,J＝1.6Hz,1H),8.14–8.02(m,1H),7.43(d,J＝7.9Hz,1H),3.95(s,3H),3.02–2.92(m,2H),2.75(s,3H),2.51(t,J＝5.4Hz,6H),1.58(s,8H).
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-甲基苯甲酸(C21a)
参见C12的合成，C20a改为C11。
淡黄色固体，收率90％。M.p.167～170℃。
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(30)
参见18的合成，C12改为C21a。
淡黄色油状物，收率74％。1H NMR(300MHz,CDCl3)δ7.98(s,1H),7.48(d,J＝6.2Hz,1H),7.36(d,J＝6.9Hz,1H),3.44(s,2H),3.14(s,2H),2.90(s,2H),2.69(s,3H),2.49(s,6H),1.68(s,2H),1.56(s,12H),0.97(s,3H),0.75(s,3H).13C NMR(75MHz,CDCl3)δ169.96,137.92,137.71,135.26,132.71,130.85,127.55,55.52,55.10,50.83,40.21,27.97,26.80,21.91,20.16,11.44.ESI:m/z[M+H]+,calcd.for C22H38N3O3S+:424.2628；found:424.2628.HPLC:0～16min(A:B＝80:20),tR＝4.253min,Purity:98.92％.
实施例31：化合物31的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-氟-N，N-二丙基苯甲酰胺(31)
参见18的合成，C12改为C21b。
淡黄色油状物，收率78％。1H NMR(300MHz,CDCl3)δ7.92(dd,J1＝6.7,J2＝2.1Hz,1H),7.63(ddd,J1＝8.3,J2＝4.7,J3＝2.2Hz,1H),7.27(dd,J1＝9.5,J2＝8.6Hz,1H),3.46(s,2H),3.16(s,2H),3.03–2.96(m,2H),2.60–2.54(m,2H),2.52(s,4H),1.64(d,J＝30.3Hz,12H),1.00(s,3H),0.79(s,3H).13C NMR(75MHz,CDCl3)δ169.02,157.22,133.90,133.55,128.74,127.87,117.41,55.49,55.10,50.92,40.51,28.16,26.78,21.94,11.45.ESI:m/z[M+H]+,calcd.for C21H35FN3O3S+:428.2378；found:428.2382.
实施例32：化合物32的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-氯-N，N-二丙基苯甲酰胺(32)
参见18的合成，C12改为C21c。
淡黄色油状物，收率71％。1H NMR(300MHz,CDCl3)δ8.08(s,1H),7.65–7.47(m,2H),3.44(s,2H),3.13(s,2H),2.96–2.86(m,2H),2.51(s,6H),1.68(s,2H),1.57(s,10H),0.98(s,3H),0.77(s,3H).13C NMR(75MHz,CDCl3)δ168.95,137.11,136.39,132.17,131.90,131.87,129.24,55.60,55.19,50.86,40.63,28.10,26.81,21.93,11.44.ESI:m/z[M+H]+,calcd.for C21H35ClN3O3S+:444.2082；found:444.2082.
实施例33：化合物33的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-溴-N，N-二丙基苯甲酰胺(33)
参见18的合成，C12改为C21d。
淡黄色油状物，收率78％。1H NMR(300MHz,CDCl3)δ8.28(s,1H),7.95(d,J＝8.0Hz,1H),7.60(d,J＝8.1Hz,1H),3.62(s,2H),3.30(s,2H),3.08(d,J＝4.5Hz,2H),2.69(s,6H),1.85(s,2H),1.75(s,10H),1.15(s,3H),0.94(s,3H).13C NMR(75MHz,CDCl3)δ168.99,138.82,137.00,135.39,131.79,129.40,120.50,55.60,55.22,50.85,40.64,28.11,26.86,21.94,11.46.ESI:m/z[M+2+H]+,calcd.for C21H35BrN3O3S+:490.1575；found:490.1575.
实施例34：化合物34的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-乙基-N，N-二丙基苯甲酰胺(34)
参见18的合成，C12改为C21e。
淡黄色油状物，收率70％。1H NMR(300MHz,CDCl3)δ8.00(d,J＝1.6Hz,1H),7.57(dd,J1＝7.9,J2＝1.7Hz,1H),7.46(d,J＝7.9Hz,1H),3.47(s,2H),3.18(s,2H),3.10(q,J＝7.5Hz,2H),2.97–2.90(m,2H),2.53(t,6H),1.71(s,2H),1.59(s,10H),1.38(d,J＝7.4Hz,3H),1.01(s,3H),0.79(s,3H).13C NMR(75MHz,CDCl3)δ170.04,144.00,137.33,135.03,131.07,130.67,127.62,55.54,55.08,50.85,40.27,29.67,28.07,25.74,21.93,14.78,11.47.ESI:m/z[M+2+H]+,calcd.for C23H40N3O3S+:438.2786；found:438.2786.
实施例35：化合物35的合成
7-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-N，N-二丙基-2,3-二氢苯并[b][1,4]二恶英-5-甲酰胺(35)
参见18的合成，C12改为C21f。
淡黄色油状物，收率79％。1H NMR(300MHz,CDCl3)δ7.38(d,J＝2.2Hz,1H),7.29(d,J＝2.2Hz,1H),4.31(s,4H),3.53–3.41(m,2H),3.07(s,2H),2.92(t,J＝5.7Hz,2H),2.54(d,J＝5.9Hz,2H),2.49(s,4H),1.68(dd,J1＝15.0,J2＝7.5Hz,2H),1.58–1.46(m,10H),0.97(t,J＝7.4Hz,3H),0.76(t,J＝7.4Hz,3H).13C NMR(75MHz,CDCl3)δ166.52,143.80,143.17,132.30,127.25,118.89,116.56,64.67,64.08,55.34,54.94,50.28,40.24,28.15,26.85,21.66,11.36.ESI:m/z[M+H]+,calcd.for C23H38N3O4S+:468.2527；found:468.2531.
实施例36：化合物36的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4,5-二甲基-N，N-二丙基苯甲酰胺(36)
参见18的合成，C12改为C21g。
淡黄色油状物，收率70％。1H NMR(300MHz,CDCl3)δ7.87(s,1H),7.40(s,1H),3.44(s,2H),3.15(s,2H),2.94–2.85(m,2H),2.59(s,3H),2.49(t,J＝5.3Hz,6H),2.37(s,3H),1.69(d,J＝6.5Hz,2H),1.57(s,10H),0.98(s,3H),0.76(s,3H).13C NMR(75MHz,CDCl3)δ168.48,141.26,136.08,134.36,133.20,131.16,128.83,55.64,55.20,50.29,40.57,28.14,26.81,21.72,20.65,18.93,11.50.ESI:m/z[M+H]+,calcd.for C23H40N3O3S+:438.2785；found:438.2789.
实施例37：化合物37的合成
5-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-氯-2-甲基-N，N-二丙基苯甲酰胺(37)
参见18的合成，C12改为C21h。
淡黄色油状物，收率66％。1H NMR(300MHz,CDCl3)δ7.89(s,1H),7.39(s,1H),3.47(s,2H),3.06–2.95(m,2H),2.91(s,1H),2.53(s,6H),2.35(s,3H),1.79–1.65(m,2H),1.58(s,8H),1.48(dt,J1＝15.0,J2＝7.5Hz,2H),0.99(t,J＝7.4Hz,3H),0.75(t,J＝7.4Hz,3H).13C NMR(75MHz,CDCl3)δ168.54,141.14,136.71,136.64,136.09,128.99,119.55,55.67,55.25,50.30,40.57,28.11,26.86,21.74,18.82,11.52.ESI:m/z[M+H]+,calcd.forC22H37ClN3O3S+:458.2239；found:458.2239.
实施例38：化合物38的合成
5-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-溴-2-甲基-N，N-二丙基苯甲酰胺(38)
参见18的合成，C12改为C21i。
淡黄色油状物，收率67％。1H NMR(300MHz,CDCl3)δ7.98(s,1H),7.66(s,1H),3.52(s,2H),3.11–3.01(m,2H),2.94(s,2H),2.58(s,6H),2.40(s,3H),1.77(dt,J1＝15.0,J2＝7.6Hz,2H),1.64(s,8H),1.53(dt,J1＝14.7,J2＝7.4Hz,2H),1.05(t,J＝7.3Hz,3H),0.80(t,J＝7.4Hz,3H).13C NMR(75MHz,CDCl3)δ168.54,141.14,136.71,136.64,136.09,128.99,119.55,55.67,55.25,50.30,40.57,28.11,26.86,21.74,18.82,11.52.ESI:m/z[M+2+H]+,calcd.for C22H37BrN3O3S+:504.1734；found:504.1733.
实施例39：化合物39的合成
5-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-2-甲基-N，N-二丙基苯甲酰胺(39)
参见18的合成，C12改为C21j。
淡黄色油状物，收率60％。1H NMR(300MHz,CDCl3)δ7.81(d,J＝7.9Hz,1H),7.72(s,1H),7.42(d,J＝8.1Hz,1H),3.53(s,2H),3.10–2.98(m,4H),2.67–2.55(m,6H),2.42(s,3H),1.84–1.69(m,2H),1.62(s,8H),1.52(dt,J1＝13.4,J2＝6.8Hz,2H),1.05(t,J＝7.4Hz,3H),0.79(t,J＝7.4Hz,3H).13C NMR(75MHz,CDCl3)δ169.33,139.49,137.79,137.30,131.22,126.98,124.69,55.59,54.96,50.18,39.95,27.44,26.82,21.67,19.13,11.53.ESI:m/z[M+H]+,calcd.for C22H38N3O3S+:424.2628；found:424.2625.
实施例40：化合物40的合成
5-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-2-甲氧基-N，N-二丙基苯甲酰胺(40)
参见18的合成，C12改为C21k。
淡黄色油状物，收率60％。1H NMR(300MHz,CDCl3)δ7.86(dd,J1＝8.7,J2＝1.9Hz,1H),7.70(d,J＝1.9Hz,1H),7.00(d,J＝8.8Hz,1H),3.89(s,3H),3.47(d,J＝25.6Hz,2H),3.01(d,J＝5.2Hz,2H),2.92(t,J＝5.6Hz,2H),2.56–2.51(m,2H),2.48(s,4H),1.76–1.62(m,2H),1.55(s,8H),1.52–1.40(m,2H),0.98(t,J＝7.4Hz,3H),0.73(t,J＝7.4Hz,3H).13CNMR(75MHz,CDCl3)δ167.24,158.30,131.64,129.50,127.47,127.01,111.04,56.00,55.35,54.88,50.13,40.21,28.04,26.84,21.59,11.29.ESI:m/z[M+H]+,calcd.forC22H38N3O4S+:440.2578；found:440.2580.
实施例41：化合物41的合成
5-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-2-氯-N，N-二丙基苯甲酰胺(41)
参见18的合成，C12改为C21l。
淡黄色油状物，收率57％。1H NMR(300MHz,CDCl3)δ7.84(dd,J1＝8.4,J2＝2.2Hz,1H),7.80(d,J＝2.0Hz,1H),7.57(d,J＝8.4Hz,1H),3.76–3.61(m,1H),3.38–3.22(m,1H),3.12–2.93(m,4H),2.64(dd,J1＝10.4,J2＝4.8Hz,6H),1.74(dq,J1＝15.5,J2＝7.6Hz,2H),1.60(s,10H),1.02(t,J＝7.4Hz,3H),0.77(t,J＝7.4Hz,3H).13C NMR(75MHz,CDCl3)δ166.48,139.00,137.51,134.92,130.55,128.22,126.67,55.56,54.99,50.16,39.95,27.34,26.85,20.47,11.16.ESI:m/z[M+H]+,calcd.for C21H35ClN3O3S+:444.2082；found:444.2083.
实施例42：化合物42的合成
3-(N-(2-(氮杂环丙烷-1-基)乙基)氨磺酰)-4-甲基-N-(萘-2-基甲基)-N-丙基苯甲酰胺(42)
参见18的合成，C12改为C13i。
淡黄色油状物，收率57％。1H NMR(300MHz,CDCl3)δ8.19(s,0.5H),8.10(s,1H),7.92(dd,J1＝20.4,J2＝7.6 6.4Hz,2H),7.73–7.47(m,6H),7.41(s,0.5H),5.14(d,J＝103.6Hz,2H),3.70–2.91(m,4H),2.74(s,3H),2.55(s,3H),2.36(t,J＝37.0Hz,4H),1.71(d,J＝58.0Hz,10H),0.87(d,J＝85.7Hz,3H).ESI:m/z[M+H]+,calcd.for C30H40N3O3S+:522.2785；found:522.2787.
实施例43：化合物43的合成
叔丁基(2-(氮杂-1-基)-2-氧乙基)氨基甲酸酯(C23)
N-Boc-甘氨酸(5mmol)溶于20mL DCM中，冰浴下加入EDCI-HCl(1.5eq)，HOBT(1.5eq)，DIEA(3eq)。搅拌0.5h后加入C22，后移至室温反应4h。柱层析(PE:EA＝5:1)，无色油状物，收率65％。
2-氨基-1-(氮杂-1-基)乙烷-1-酮(C24)
C23溶于5mL TFA中，室温搅拌8h。反应完毕后直接真空除去TFA，用于下一步。
4-甲基-N，N-二丙基苯甲酰胺(C25)
C14a(5mmol)溶于20mL DCM中，冰浴下加入EDCI-HCl(1.5eq)，HOBT(1.5eq)，DIEA(3eq)。溶解后加入二丙胺，后移至室温反应2h。柱层析(PE:EA＝20:1)。无色油状物，收率85％。
5-(二丙基氨甲酰)-2-甲苯磺酰氯(C26)
氯磺酸(5eq)置于干燥的反应瓶中，冰浴下加入C25，后100℃加热8h。反应结束后，将反应液投入冰水中，剧烈搅拌，以DCM萃取三次，无水硫酸钠干燥。柱层析(PE:EA＝5:1)，棕色油状物，收率76％。
3-(N-(2-(氮杂环丙烷-1-基)-2-氧乙基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(43)
C26置于干燥的反应瓶中，加入DCM 5mL，三乙胺(2.5eq)。C21a(1.2eq)溶于DCM5mL，冰浴下逐滴加入反应瓶内，加毕，移至室温搅拌2h。反应液直接柱层析(DCM:MeOH＝100:1)。
无色油状物，收率68％。1H NMR(300MHz,CDCl3)δ7.97(s,1H),7.49–7.43(m,1H),7.36(d,J＝7.8Hz,1H),5.95(t,J＝3.7Hz,1H),3.70(d,J＝4.0Hz,2H),3.49–3.40(m,4H),3.25–3.19(m,2H),3.18–3.08(m,2H),2.73(s,3H),1.68(t,J＝10.7Hz,6H),1.56–1.45(m,6H),0.98(t,J＝6.9Hz,3H),0.76(t,J＝6.8Hz,3H).13C NMR(75MHz,CDCl3)δ169.99,166.05,138.61,137.08,135.24,132.97,130.97,127.60,50.81,46.61,43.49,28.55,27.22,21.92,20.09,11.48.ESI:m/z[M+H]+,calcd.for C21H35ClN3O3S+:438.2421；found:438.2424.
实施例44：化合物44的合成
3-(N-(1-羟基丙烷-2-基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(C28a)
C23置于干燥的反应瓶中，加入DCM 5mL，三乙胺(3eq)，对二甲氨基吡啶(0.2eq)。C24a(1.1eq)溶于DCM 5mL，冰浴下逐滴加入反应瓶内，加毕，移至室温搅拌2h。反应液直接柱层析(PE:EA＝5:1,then EA)。手性C25a则采用相应的手性原料C24a。
淡黄色油状物，收率85％。1H NMR(300MHz,CDCl3)δ8.00(d,J＝1.4Hz,1H),7.46(dd,J1＝7.7Hz,J2＝1.5Hz,1H),7.36(d,J＝7.8Hz,1H),5.32(d,J＝6.9Hz,1H),3.52–3.39(m,3H),3.36–3.27(m,2H),3.21–3.06(m,2H),2.77(s,1H),2.68(s,3H),1.69(dd,J＝14.6,7.2Hz,2H),1.54(dd,J＝14.1,7.1Hz,2H),1.07(d,J＝6.3Hz,2H),0.97(d,J＝7.0Hz,3H),0.75(t,J＝7.0Hz,3H).
3-(N-(1-溴丙烷-2-基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(C29a)
将C25a置于反应瓶中，加入无水DCM，冰浴下加入四溴化碳(1.25eq)，三苯基膦(1.5eq)，移至室温搅拌4h。水洗，无水硫酸钠干燥，柱层析(PE:EA＝5:1,then PE:EA＝2:1)，黄色油状物，收率80％～85％。
3-(N-(1-(氮杂环丙烷-1-基)丙烷-2-基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(44)
C19溶于10mL乙腈，加入碳酸钠(1.5eq)，C26a(1eq)。加热至50℃，反应4h。过滤除去不溶物，滤液真空除去溶剂，柱层析(DCM:MeOH＝100:1)。
淡黄色油状物，收率82％。1H NMR(300MHz,CDCl3)δ8.02(d,J＝1.5Hz,1H),7.50(dd,J1＝7.7Hz,J2＝1.6Hz,1H),7.37(d,J＝7.8Hz,1H),3.47(d,J＝6.5Hz,2H),3.22–3.13(m,2H),3.13–3.05(m,1H),2.73(s,3H),2.58–2.41(m,5H),2.29–2.19(m,1H),1.71(dd,J1＝14.5Hz,J2＝7.1Hz,2H),1.56(s,10H),1.07(d,J＝6.2Hz,3H),1.00(t,J＝6.9Hz,3H),0.77(t,J＝6.8Hz,3H).13C NMR(75MHz,CDCl3)δ170.02,138.22,138.19,135.26,132.70,130.93,127.53,62.50,55.45,50.87,46.99,27.52,26.99,21.96,20.50,19.13,11.49.ESI:m/z[M+H]+,calcd.for C23H40N3O3S+:438.2785；found:438.2790.
(R)-3-(N-(1-(氮杂环丙烷-1-基)丙烷-2-基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(44R)
参见44的合成，C28a改为C28aR。
淡黄色油状物，收率78％。1H NMR(300MHz,CDCl3)δ8.02(s,1H),7.50(d,J＝7.7Hz,1H),7.37(d,J＝7.8Hz,1H),3.46(s,2H),3.21–3.13(m,2H),3.12–3.04(m,1H),2.73(s,3H),2.73(s,3H),2.56(s,1H),2.55–2.42(m,4H),2.29–2.16(m,1H),1.70(s,2H),1.56(s,10H),1.07(d,J＝6.1Hz,3H),1.00(s,3H),0.77(s,3H).13C NMR(75MHz,CDCl3)δ170.01,138.22,138.18,135.25,132.70,130.92,127.53,62.50,55.45,50.87,47.00,27.52,26.99,21.95,20.49,19.13,11.48.ESI:m/z[M+H]+,calcd.for C23H40N3O3S+:438.2785；found:438.2786.HPLC:0～16min(A:B＝80:20),tR＝6.000min,Purity:98.57％.
(S)-3-(N-(1-(氮杂环丙烷-1-基)丙烷-2-基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(44S)
参见44的合成，C28a改为C28aS。
淡黄色油状物，收率75％。1H NMR(300MHz,CDCl3)δ8.02(d,J＝1.5Hz,1H),7.50(dd,J1＝7.7Hz,J2＝1.6Hz,1H),7.37(d,J＝7.8Hz,1H),3.47(d,J＝6.5Hz,2H),3.15(d,J＝7.2Hz,2H),3.09(dd,J1＝11.5Hz,J2＝5.3Hz,1H),2.73(s,3H),2.55(d,J＝12.0Hz,1H),2.47(dd,J1＝15.2Hz,J2＝11.1Hz,4H),2.28–2.16(m,1H),1.71(dd,J1＝14.5Hz,J2＝7.1Hz,2H),1.56(s,10H),1.07(d,J＝6.2Hz,3H),1.00(t,J＝6.9Hz,3H),0.77(t,J＝6.8Hz,3H).ESI:m/z[M+H]+,calcd.for C23H40N3O3S+:438.2785；found:438.2782.
实施例45：化合物45的合成
3-(N-(1-(氮杂环丙烷-1-基)丁烷-2-基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(45)
参见44的合成，C28a改为C28b。
淡黄色油状物，收率75％。1H NMR(300MHz,CDCl3)δ8.02(d,J＝1.4Hz,1H),7.50(dd,J1＝7.7Hz,J2＝1.5Hz,1H),7.37(d,J＝7.8Hz,1H),3.47(s,2H),3.17(s,2H),3.13–3.03(m,1H),2.74(s,3H),2.55(d,J＝4.5Hz,1H),2.49(dd,J1＝15.7Hz,J2＝8.9Hz,4H),2.31(dd,J1＝12.7Hz,J2＝10.1Hz,1H),1.70(s,2H),1.57(s,10H),1.55–1.42(m,2H),1.00(s,3H),0.77(t,J＝7.4Hz,6H).13C NMR(75MHz,CDCl3)δ170.03,138.41,138.25,135.21,132.66,130.88,127.41,59.45,55.62,52.29,50.86,27.63,27.01,25.53,21.95,20.51,11.47,8.66.ESI:m/z[M+H]+,calcd.for C24H42N3O3S+:452.2941；found:452.2938.
实施例46：化合物46的合成
3-(N-(3-(氮杂环丙烷-1-基)丙基)氨磺酰)-4-甲基-N，N-二丙基苯甲酰胺(46)
参见44的合成，C28a改为C28c。
淡黄色油状物，收率70％。1H NMR(300MHz,CDCl3)δ7.95(s,1H),7.46(d,J＝7.7Hz,1H),7.34(d,J＝7.8Hz,1H),3.44(s,2H),3.15(s,2H),3.08–2.98(m,2H),2.69(s,3H),2.68–2.63(m,4H),2.61(d,J＝5.5Hz,2H),1.78–1.51(m,14H),0.98(s,3H),0.76(s,3H).13CNMR(75MHz,CDCl3)δ170.18,138.13,138.12,135.20,132.65,130.51,127.45,58.62,56.03,50.84,44.12,27.50,26.61,24.63,21.94,20.16,11.48.ESI:m/z[M+H]+,calcd.forC23H40N3O3S+:438.2785；found:438.2786.
实施例47：胆碱酯酶抑制活性的测定
药品与试剂：实施例6-18制得的化合物、AChE(E.C.3.1.1.7,Type VI-S,选自电鳗)、BuChE(E.C.3.1.1.8,选自马血清)、5,5’-二硫双(2-硝基苯甲酸)(DTNB)、乙酰硫代胆碱(ATC)碘化物以及丁酰硫代胆碱(BTC)碘化物均购于西格玛公司；他克林由本实验室合成(纯度＞95％)。
仪器：THERMO Varioskan Flash全波长多功能酶标仪。
实验方法：
(1)配制缓冲液：13.6g磷酸二氢钾溶于1L水中，以氢氧化钾调节pH＝8±0.1。溶液于4℃保存，备用。
(2)配制0.01M DTNB溶液：将0.396g DTNB及0.15g碳酸氢钠溶于100mL水中制得0.01M DTNB溶液，于-20℃保存，备用。
(3)配制0.075M ATC、BTC溶液：将0.217g ATC溶于10mL水中制得0.075M ATC及BTC溶液，于-20℃保存，备用；将0.237g BTC溶于10mL水中制得0.075M BTC溶液，于-20℃保存，备用。
(4)配制AChE、BuChE溶液：将5000单位的AChE溶于1mL 1％的凝胶溶液中，然后用水稀释至100mL制得浓度为5单位/mL的AChE溶液，于-20℃保存，备用；将5000单位的BChE溶于1mL 1％的凝胶溶液中，然后用水稀释至100mL制得浓度为5单位/mL的BChE溶液，于-30℃保存，备用。
(5)配制受试物溶液：将受试化合物溶于乙醇中以制得浓度为10-3M的溶液(乙醇不影响测试结果)，然后用水稀释分别制得浓度为10-4、10-5、10-6、10-7、10-8、10-9M的溶液。
实验开始前，所用溶液均加温至室温，并将AChE，BChE溶液用水稀释一倍制成浓度为2.5单位/mL的酶溶液。用空白缓冲液(3mL)测得背景紫外吸收。先将100μL受试化合物溶液、100μL DTNB溶液、100μL酶溶液加至3mL缓冲液中，加入20μL ATC或BTC溶液触发反应后立即计时并同时快速混匀测试溶液，2min后于412nM波长下测量紫外吸收度。空白对照组用等容积的水代替受试物溶液测得。所有测试均平行操作三次。以空白对照组的紫外吸收值作为100％，记录受试化合物在各个浓度下的吸光度(OD值)，所得结果用GraphPad PrismTM(GraphPad Software,San Diego,CA,USA)软件以非线性衰退分析模式(non-linearregression analysis model)计算得相应的IC50值，如表1所示。
表1化合物的胆碱酯酶抑制活性
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NA：no active。
结果分析：本发明化合物的活性分布较广，其中，对eqBChE的抑制活性在0.003±0.0008μM～NA，对eeAChE的抑制活性在0.032±0.008μM～NA，部分优选化合物测试了对hBChE的抑制活性，其中化合物44R的抑制活性最佳，达到了0.005±0.001μM，与此同时其对hAChE的抑制活性仅为0.11±0.06μM，选择性系数达到了22。
实施例48：体外血脑屏障渗透试验
药品与试剂：
结果分析：挑选化合物30，32，33，34，44R，44S和44RS进行了PAMPA-BBB模型的体外血脑屏障渗透实验。由六个阳性药作为验证，测得化合物的渗透性如表4所示。Pe(×106cm/s)>5.0936，表明化合物具备良好的透过BBB的能力，可知所有的测试化合物均具有良好的BBB透过性。
表2PAMPA-BBB分析中的渗透性(Pe×106cm/s)
| Compound | BibLvaluea | Experimentalvalue | CNSpenetration classificationb |
| Hydrocortisone | 1.9 | 3.09 | CNS+/- |
| Piroxicam | 2.5 | 2.55 | CNS+/- |
| Chlorpromazine | 6.5 | 9.24 | CNS+ |
| progesterone | 9.3 | 9.99 | CNS+ |
| β-Estradiol | 12 | 13.83 | CNS+ |
| Verapamil | 13.2 | 13.76 | CNS+ |
| 30 | / | 8.2 | CNS+ |
| 32 | / | 8.8 | CNS+ |
| 33 | / | 9.4 | CNS+ |
| 34 | / | 6.9 | CNS+ |
| 44RS | / | 7.5 | CNS+ |
| 44R | / | 9.9 | CNS+ |
| 45 | / | 7.1 | CNS+ |
a Values are expressed as the mean±SD of three independentexperiments.
b Ranges of permeability of PAMPA-BBB assays(Pe×10-6cm/s).
Compounds of high BBB permeation(CNS+)Pe(×106cm/s)>5.0936
Compounds of uncertain BBB permeation(CNS+/-)5.0936>Pe>3.0476,
Compounds of low BBB permeation(CNS-)<3.0476,
实施例49：MTT实验
药品与试剂：3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)(购自阿拉丁)
仪器：THERMO Varioskan Flash全波长多功能酶标仪。
实验方法：将SH-SY5Y或BV-2细胞(5×103，体积为0.1mL)置于96孔平底培养板中，细胞在37℃下培养过夜达到贴壁状态。后加入待测化合物100μL(终浓度：10，20和50μM)处理细胞24h。每孔中加入20μL MTT试剂，在37℃下孵育4h。每孔中加入50μL DMSO溶解产生的甲瓒，使用酶标仪在490nm测量其紫外吸收。所有实验平行3次进行。实验结果图1所示。
结果分析：所有化合物在10、20和50μM的浓度下均显示出对SH-SY5Y安全性，即便在高浓度下，细胞的存活率也大于75％。44(R)和44(S)的细胞毒作用没有太大差异。与SH-SY5Y相比，化合物对BV-2的毒性略微提升，主要表现在50μM的浓度下，其中优选化合物44R的细胞存活率为50％左右。当然，该剂量远远大于化合物的抑制活性。
实施例50：对谷氨酸诱导的SH-SY5Y细胞损伤的神经保护作用
药品与试剂：3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)(购自阿拉丁)
仪器：THERMO Varioskan Flash全波长多功能酶标仪。
实验方法：将靶细胞(5×103，体积为0.1mL)置于96孔平底培养板中，使细胞在37℃下粘附于板的底部过夜。用各种浓度的化合物处理细胞24h。孔中加入MTT试剂，将板在37℃下孵育4h。在孔中加入0.1mL裂解缓冲液破坏细胞。孵化后将它们在37℃再保持24h，使用酶标仪在490nm测量显色反应。
实验结果分析：鉴于化合物30和44(R)显示出最优的BChE抑制活性并且具有一定的选择性；进一步使用MTT法对谷氨酸诱导的SH-SY5Y细胞损伤的神经保护作用。如图2所示，当SH-SY5Y细胞暴露于31mM谷氨酸时，与未处理组相比，细胞活力急剧下降至48.6±1.4％。当用30和44(R)处理时，细胞的存活率有所上升，低浓度1μM下，未显示出保护作用，化合物30和44(R)为10μM剂量下，细胞活力分别增加至62.1±8.8％和57.9±2.3％。因此，结果表明化合物30和44(R)对Aβ1-42诱导的SH-SY5Y细胞损伤表现出一定的神经保护作用。
实施例51：水迷宫实验
药品与试剂：东莨宕碱(购自阿拉丁，纯度99％)，化合物30和44R，利凡斯的明(购自上海毕得，纯度98％)。
实验仪器：Panlab SMART 3.0行为学视频分析仪
动物：成年雄性ICR小鼠(8-10周，体重20-25克)购自江苏华创信诺医药科技有限公司。
实验方法：将40只小鼠随机分成5个亚组(每组8只小鼠)：(i)空白对照组，(ii)东莨菪碱作为模型组，(iii)利凡斯的明加东莨菪碱作为阳性对照，和(iv)化合物30(5mg/kg)加东莨菪碱作为试验组，(v)化合物44R(1mg/kg)加东莨菪碱作为试验组。模型组小鼠，利凡斯的明组，化合物30组(5mg/kg)，化合物44R组(1mg/kg)腹腔注射东莨菪碱(2mg/kg)，空白对照组注射生理盐水。30min后，将化合物腹腔注射至各自化合物组中，模型组和空白对照组注射生理盐水。
圆形水池(直径120cm，高60cm)中固定一个逃生平台(直径10cm)，并填充40cm深的淡水(保持在2 5℃)构成水迷宫。置于一个明亮的房间里。在学习和记忆训练5天后，在第6天进行探针试验。为了评估认知功能，每只小鼠在可见平台(用小旗标记，5cm高)上单独训练2天，第3天到第5天在隐藏平台(放置在水面下1cm)的水迷宫训练。所有小鼠每天进行2次训练试验，每次试验持续90秒。记录每只小鼠找到平台的时间(成功逃脱)。如果鼠标在90秒内未能到达平台，则终止测试并用手小心地将鼠标放置到平台。无论是成功与否，每只鼠标都将在平台上保持30秒。在最后一天(第6天)，从池中取出平台，对小鼠进行试验，允许每只小鼠90秒以搜索平台。记录小鼠到达失踪平台位置的时间和轨迹。
结果分析：由图3A可知，与对照组相比，模型组小鼠到达平台的平均时间具有显著性差异，表明东莨菪碱能够导致小鼠记忆缺陷，说明造模成功。相对于模型组，利凡斯的明组所耗时间和距离都显著降低，表明利凡斯的明对于小鼠的记忆和认知功能有显著性的改善。而化合物30处理组、化合物44R处理组的小鼠到达平台的平均时间和距离都低于模型组，表明化合物30、化合物44R对小鼠记忆和认知功能的具有改善效果。
实施例52：水迷宫实验
药品与试剂：Aβ(购自碧云天)，化合物30和44R，利凡斯的明(购自上海毕得，纯度98％)。
实验仪器：Panlab SMART 3.0行为学视频分析仪
动物：成年雄性ICR小鼠(8-10周，体重20-25克)购自江苏华创信诺医药科技有限公司。
实验方法：将48只小鼠随机分成6个亚组(每组8只小鼠)：(i)空白对照组，(ii)假手术组，(iii)模型组，(iv)利凡斯的明组，(v)化合物30(5mg/kg)组，(vi)化合物44R(1mg/kg)组。除空白对照组，每组小鼠均在海马区进行手术，其中假手术组注射5μL生理盐水，其他组注射同体积的Aβ(4mg/mL)。手术后2-14天给药，其中空白对照和假手术组给生理盐水。9-13天进行训练，第14天进行探索实验。
结果分析：由图3B可知，与对照组相比，假手术组无显著性差异，表示，手术不影响小鼠的运动及认知水平。模型组小鼠到达平台的平均时间具有显著性差异，表明Aβ能够导致小鼠记忆缺陷，说明造模成功。相对于模型组，利凡斯的明组所耗时间和距离都显著降低，表明利凡斯的明对于小鼠的记忆和认知功能有显著性的改善。而化合物30处理组、化合物44R处理组的小鼠到达平台的平均时间和距离都低于模型组，表明化合物30、化合物44R对小鼠记忆和认知功能的具有改善效果。
化合物44R在相同剂量下与阳性对照的效果相当，表明其良好的体内有效性。
Claims (10)
1.一种间氨磺酰苯甲酰胺类化合物，其特征在于，具有式I的结构，所述化合物包含其立体异构体、药学上可接受的盐或它们的混合物：
其中：
n＝0～2；
A环选自6元芳环、6～9元芳杂环、6～7元环杂基或7元环杂基取代的酰基；所述芳杂基或环杂基环系C被一个或多个N取代；所述6元芳环被一个或多个氢、卤素或C1～C3烷氧基取代；
X选自-C(O)-或-S(O)2-；
R1选自C1～C4烷基、6元芳基或者N与所连接的基团共同形成的6元环杂基；所述C1～C4烷基为一个或多个直链或支链烷基，被一个或多个氢、6～10元芳基或9元芳杂基取代；所述环杂基或芳杂基环系C被一个或多个N取代；
R2选一个或多个自氢、卤素、C1～C3烷氧基、C1～C3烷基或者与苯环并环形成的6元环杂基；所述环杂基环系C被一个或多个O取代；
R3选自一个或多个氢或C1～C3烷基；当R3连接手性C时，手性C的构型为R、S或消旋体。
2.根据权利要求1所述的间氨磺酰苯甲酰胺类化合物，其特征在于，所述结构中：
n＝1～2；
A环选自被一个或多个氢、氟、氯、甲氧基取代的苯基、吡啶基、吲哚基、6～7元含氮环杂环或7元含氮环杂基取代的甲酰基；
R1选自C1～C4烷基、苯基或者N与所连接的基团共同形成的6元环杂基；所述C1～C4烷基为1～2个直链或支链烷基，被一个或多个氢、苯基、萘基或吲哚基取代；
R2选一个或多个自氢、卤素、甲氧基、甲基或乙基；
R3选自一个或多个氢、甲基或乙基；当R3连接手性C时，手性C的构型为R、S或消旋体。
3.根据权利要求1或2所述的间氨磺酰苯甲酰胺类化合物，其特征在于，所述结构中：
A环选自：
R1选自：
4.根据权利要求1或2所述的间氨磺酰苯甲酰胺类化合物，其特征在于，所述结构中：
n＝1；
A环选自：
R1选自：
5.根据权利要求1或2所述的间氨磺酰苯甲酰胺类化合物，其特征在于，选自以下任一化合物：
6.根据权利要求1或2所述的间氨磺酰苯甲酰胺类化合物，其特征在于，所述药学上可接受的盐为所述化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
7.一种权利要求1～6任一所述的间氨磺酰苯甲酰胺类化合物的制备方法，其特征在于，选自以下任一方法：
(1)当n＝1，A环为吡啶基，X为-S(O)2-，R2为甲氧基，R3为氢，R1的定义如权利要求1～5任一所述时，
化合物A1经两步酰化、水解、酰化反应得化合物I；
(2)当n＝1，X为-S(O)2-，R1为丙基，R2为甲氧基，R3为氢，A环的定义如权利要求1～5任一所述时，
化合物A1经两步酰化、水解、酰化反应得化合物I；
(3)当n＝1，A环为X为-S(O)2-，R1为乙基，R2、R3为氢时，
化合物A7经酯化、卤代、酰化、水解、酰化反应的化合物I；
(4)当n＝1，A环为X为-C(O)-，R1为丙基，R2、R3为氢时，
化合物A14经酰化、水解、酰化反应的化合物I；
(5)当n＝1，A环为X为-S(O)2-，R1为丙基或/>R2为甲基，R3为氢时，
化合物A17a～A17l经酰化、酯化、酰化、水解、酰化反应得化合物I；
(6)当n＝0，A环为X为-S(O)2-，R1为丙基，R2为甲基，R3为氢时，
化合物A22经酰化、脱保护反应得化合物A24，化合物A14a经两步酰化得化合物A26，化合物A24与A26经酰化反应得化合物I；
(7)当n＝1～2，A环为X为-S(O)2-，R1为丙基，R2为甲基，R3为氢、甲基或乙基时，
化合物C26经酰化、卤代、取代反应得化合物I；
将相应的酸与以上方法制备的化合物I成盐，即得所述间氨磺酰苯甲酰胺类化合物的药学上可接受的盐。
8.一种药物组合物，其特征在于，包含权利要求1～6任一所述的间氨磺酰苯甲酰胺类化合物以及药学上可接受的载体。
9.一种权利要求1～6任一所述的间氨磺酰苯甲酰胺类化合物或者权利要求8所述的药物组合物在制备丁酰胆碱酯酶抑制剂药物中的应用。
10.根据权利要9所述的应用，其特征在于，所述药物为治疗神经退行性疾病的药物。
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