具体实施方式

本发明提供了一类2-亚氨基噻唑烷酮烯酯类化合物，所述2-亚氨基噻唑烷酮烯酯类化合物结构如通式I所示：

其中，R₁为芳基或含氮烷基，R₂为卤素取代的芳基或烷基取代的芳基。

在本发明中，所述R₁优选为

中的任意一种；所述R₂优选为

中的任意一种。

所述2-亚氨基噻唑烷酮烯酯类化合物优选为以下任意一种：

本发明还提供了一种上述任意一种2-亚氨基噻唑烷酮烯酯类化合物的制备方法，所述方法通过下列反应方案得到：

其中，R₃为卤素或烷基。

在本发明中，所述方法具体为：将摩尔比为1:1:1的氨基取代的R₁-NH₂、R₃取代的异硫氰酸苯酯、乙炔二羧酸二乙酯与2mL乙醇混合，白光下室温反应12h，用TLC分离法分离即得2-亚氨基噻唑烷酮烯酯类化合物。本发明的制备方法操作简便，所得目标化合物的产率高。

本发明还提供了一种上述任意一种2-亚氨基噻唑烷酮烯酯类化合物在制备抗血吸虫药物中的应用。

在本发明中，所述应用优选地用于杀灭血吸虫成虫。

本发明还提供了一种抗血吸虫的药物，所述抗血吸虫药物的活性成分为上述任意一种2-亚氨基噻唑烷酮烯酯类化合物中的一种或几种。

在本发明中，所述药物优选地还包括药学上可接受的盐；所述2-亚氨基噻唑烷酮烯酯类化合物在所述药物中的质量百分含量优选为0.05～99％，更优选为0.1～70％；所述药物的剂型优选为片剂、颗粒剂、散剂、溶液剂、乳剂、混悬剂、糖浆剂、注射剂或胶囊剂。

在本发明中，若无特殊说明，所有的原料组分均为本领域技术人员熟知的市售商品。

下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。

实施例1

(1)化合物1的制备

将0.25mmol化合物1-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到24.9mg化合物1，收率23.9％。对化合物1的进行分析，图谱表征：

IR(KBr,cm^-1)2935.40,2794.11,1720.01,1638.86,1592.61,1388.60,1314.82,1190.96,1028.20,854.21,762.15,695.75,476.40；¹H NMR(400MHz,CDCl₃)δ＝7.34(t,J＝7.9Hz,2H),7.15(t,J＝7.5Hz,1H),6.94(d,J＝7.3Hz,2H),6.87(s,1H),4.23(q,J＝7.1Hz,2H),4.03(t,J＝7.1Hz,2H),2.45(t,J＝7.0Hz,10H),2.24(s,3H),1.94(dd,J＝14.1,7.1Hz,2H),1.28(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.9(s),165.0(s),151.1(s),147.3(s),141.6(s),129.3(s),125.1(s),121.0(s),116.1(s),61.6(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₈N₄O₃S[M+H]⁺417.19549,found417.19727.鉴定数据表明化合物1制备成功。

(2)化合物2的制备

将0.25mmol化合物2-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到21mg化合物2，产率为24.2％。对化合物2的进行分析，图谱表征：

IR(KBr,cm^-1)2942.38,2770.36,1721.20,1641.43,1593.41,1388.39,1315.85,1193.33,1027.68,858.91,764.30,646.49；¹H NMR(400MHz,CDCl₃)δ＝7.35(dd,J＝8.2,7.6Hz,2H),7.17(t,J＝7.5Hz,1H),6.97(d,J＝7.3Hz,2H),6.89(s,1H),4.24(q,J＝7.1Hz,2H),4.10(t,J＝6.7Hz,2H),2.69(t,J＝6.7Hz,2H),2.31(s,6H),1.29(t,J＝7.1Hz,3H).¹³CNMR(100MHz,CDCl₃)δ＝166.0(s),165.0(s),151.0(s),147.3(s),141.5(s),129.3(s),125.1(s),121.0(s),116.4(s),61.6(s),56.0(s),45.6(s),40.8(s),14.1(s).HRMS(ESI):calcd.for C₁₇H₂₁N₃O₃S[M+H]⁺348.13764,found 348.13747.鉴定数据表明化合物2制备成功。

(3)化合物3的制备

将0.25mmol化合物3-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到26.4mg化合物3，产率为28.2％。对化合物3的进行分析，图谱表征：

IR(KBr,cm^-1)2967.95,2800.00,1720.33,1639.22,1593.52,1315.51,1191.92,1028.45,762.48,696.10,470.69；¹H NMR(400MHz,CDCl₃)δ＝7.37–7.32(m,2H),7.18–7.13(m,1H),6.99–6.94(m,2H),6.88(s,1H),4.26–4.20(m,2H),4.07–4.02(m,2H),2.83–2.78(m,2H),2.58(q,J＝7.1Hz,4H),1.31–1.27(m,3H),1.04–0.99(m,6H).¹³C NMR(100MHz,CDCl₃)δ＝166.0(s),164.9(s),151.0(s),147.4(s),141.6(s),129.3(s),125.1(s),121.0(s),116.2(s),61.6(s),49.0(s),47.3(s),40.9(s),14.1(s),12.2(s).HRMS(ESI):calcd.for C₁₉H₂₅N₃O₃S[M+H]⁺376.16894,found 376.17009.鉴定数据表明化合物3制备成功。

将0.25mmol化合物4-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到28.1mg化合物4，产率为31.1％。对化合物4的进行分析，图谱表征：

IR(KBr,cm^-1)2934.58,2822.43,1728.97,1644.86,1591.59,1384.11,1314.02,1201.87,1025.23,862.62,758.88,702.80；¹H NMR(400MHz,CDCl₃)δ＝7.37–7.32(m,2H),7.19–7.14(m,1H),6.99–6.94(m,2H),6.89(s,1H),4.24(q,J＝7.1Hz,2H),4.06–4.00(m,2H),2.39(t,J＝7.2Hz,2H),2.24(s,6H),1.94(dt,J＝14.4,7.2Hz,2H),1.29(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝166.0(s),165.0(s),151.0(s),147.4(s),141.5(s),129.3(s),125.1(s),121.0(s),116.3(s),61.6(s),56.9(s),45.3(s),41.5(s),29.7(s),29.3(s),25.4(s),14.1(s).HRMS(ESI):calcd.for C₁₈H₂₃N₃O₃S[M+H]⁺362.15329,found362.15312。鉴定数据表明化合物4制备成功。

(5)化合物5的制备

将0.25mmol化合物5-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到32.3mg化合物5，产率为32.1％。对化合物5的进行分析，图谱表征：

IR(KBr,cm^-1)2956.02,2853.75,1720.01,1640.64,1593.11,1315.78,1193.18,1117.64,1027.53,862.33,762.45,696.74；¹H NMR(400MHz,CDCl₃)δ＝7.37–7.31(m,2H),7.18–7.13(m,1H),6.94(dt,J＝8.5,1.7Hz,2H),6.87(s,1H),4.28–4.18(m,2H),4.09–4.00(m,2H),3.69–3.62(m,4H),2.47–2.40(m,6H),1.95(p,J＝6.9Hz,2H),1.28(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.9(s),165.0(s),151.1(s),147.3(s),141.6(s),129.3(s),125.1(s),120.9(s),116.2(s),66.9(s),61.6(s),56.3(s),53.6(s),41.6(s),23.8(s),14.1(s).HRMS(ESI):calcd.for C₂₀H₂₅N₃O₄S[M+H]⁺404.16385,found 404.16444.鉴定数据表明化合物5制备成功。

将0.25mmol化合物6-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到24.5mg化合物6，产率为25.2％。对化合物6的进行分析，图谱表征：

IR(KBr,cm^-1)2957.62,2853.52,2809.39,1720.56,1641.54,1593.13,1444.62,1383.60,1315.97,1117.13,1028.22,858.42,763.9,697.31；¹H NMR(400MHz,CDCl₃)δ＝7.35(t,J＝7.9Hz,2H),7.17(t,J＝8.5Hz,1H),6.95(d,J＝7.3Hz,2H),6.89(s,1H),4.25(q,J＝7.1Hz,2H),4.11(t,J＝6.4Hz,2H),3.68–3.64(m,4H),2.74(t,J＝6.4Hz,2H),2.56(s,4H),1.30(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl3)δ＝166.0(s),165.0(s),151.1(s),147.3(s),141.5(s),129.4(s),125.2(s),121.0(s),116.4(s),77.3(s),77.0(s),76.7(s),67.0(s),61.7(s),55.2(s),53.6(s),39.8(s),29.8(s),14.1(s).HRMS(ESI):calcd.for C₁₉H₂₃N₃O₄S[M+H]⁺390.14820,found 390.14796.鉴定数据表明化合物6制备成功。

将0.25mmol化合物7-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到29.9mg化合物7，产率为31％。对化合物7的进行分析，图谱表征：

IR(KBr,cm^-1)2928.12,2787.11,1721.58,1642.04,1315.85,1193.5,1028.2,763.66,697.11；¹H NMR(400MHz,CDCl₃)δ＝7.37–7.32(m,2H),7.16(t,J＝7.5Hz,1H),6.96(d,J＝7.3Hz,2H),6.88(s,1H),4.24(q,J＝7.1Hz,2H),4.05(t,J＝7.1Hz,2H),2.61(dd,J＝15.9,8.3Hz,6H),2.04–1.99(m,2H),1.81–1.75(m,4H),1.28(d,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.9(s),165.0(s),151.1(s),147.3(s),141.5(s),129.3(s),125.2(s),121.0(s),116.3(s),54.1(s),53.7(s),41.6(s),29.7(s),26.4(s),23.4(s),14.1(s).HRMS(ESI):calcd.for C₂₀H₂₅N₃O₃S[M+CH₃OH H]⁺420.19515,found 420.19438.鉴定数据表明化合物7制备成功。

将0.25mmol化合物8-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到27mg化合物8，产率为29％。对化合物8的进行分析，图谱表征：

IR(KBr,cm^-1)2961.34,2792.04,1722.32,1643.16,1593.46,1383.87,1315.7,1193.43,1027.88,763.12,696.59；¹H NMR(400MHz,CDCl₃)δ＝7.35(t,J＝7.9Hz,2H),7.16(t,J＝7.5Hz,1H),6.96(d,J＝7.3Hz,2H),6.89(s,1H),4.27–4.22(m,2H),4.13(t,J＝6.8Hz,2H),2.86(t,J＝6.8Hz,2H),2.63(t,J＝6.6Hz,4H),1.80–1.76(m,4H),1.30(d,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝166.0(s),165.0(s),151.0(s),147.4(s),141.6(s),129.3(s),125.1(s),121.0(s),116.3(s),61.6(s),54.3(s),52.8(s),41.9(s),23.6(s),14.1(s).HRMS(ESI):calcd.for C₁₉H₂₃N₃O₃S[M+CH₃OH H]⁺406.17950,found406.17862.鉴定数据表明化合物8制备成功。

(9)化合物9的制备

将0.25mmol化合物9-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到22mg化合物9，产率为22.7％。对化合物9的进行分析，图谱表征：

IR(KBr,cm^-1)2934.27,2852.60,2799.31,1721.27,1641.61,1593.59,1443.34,1315.62,1193.19,1123.81,1028.27,859.61,763.34,696.40；¹H NMR(400MHz,CDCl₃)δ＝7.36–7.31(m,2H),7.15(t,J＝7.5Hz,1H),6.95(d,J＝7.3Hz,2H),6.88(s,1H),4.23(q,J＝7.1Hz,2H),4.10(t,J＝6.8Hz,2H),2.68(t,J＝6.8Hz,2H),2.48(s,4H),1.53(dt,J＝10.9,5.6Hz,4H),1.40(dd,J＝11.2,5.9Hz,2H),1.28(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.9(s),164.9(s),151.0(s),147.4(s),141.6(s),129.3(s),125.0(s),121.0(s),116.1(s),61.5(s),55.3(s),54.6(s),40.3(s),26.0(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₀H₂₅N₃O₃S[M+H]⁺388.16894,found 388.17091.鉴定数据表明化合物9制备成功。

将0.25mmol化合物10-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到36.6mg化合物10，产率为40％。对化合物10的进行分析，图谱表征：

IR(KBr,cm^-1)3418.16,2980.4,1770.2,1642.58,1383.8,1316.36,1194.65,1028.7,760.11,697.09,532.42；¹H NMR(400MHz,CDCl₃,ppm)δ＝7.53-7.51(d,J＝8Hz,2H),7.37-7.28(m,5H),7.18-7.15(t,J＝8Hz,1H),6.97-6.95(d,J＝8Hz,2H),6.90(s,1H),5.14(s,2H),4.26-4.21(q,J＝8Hz,2H),1.30-1.27(t,J＝8Hz,3H)；¹³C NMR(100MHz,CDCl₃,ppm)δ＝165.9(s),164.9(s),150.8(s),147.2(s),141.4(s),135.6(s),129.4(s),129.1(s),128.6(s),128.1(s),125.2(s),121.1(s),116.6(s),61.7(s),46.2(s),14.2(s).HRMS(ESI):calcd.for C₂₀H₁₈N₂O₃S[M+H]⁺367.11109,found 367.11072.鉴定数据表明化合物10制备成功。

(11)化合物11的制备

将0.25mmol化合物11-1、0.25mmol异硫氰酸苯酯、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到31.2mg化合物11，产率为26.2％。对化合物11的进行分析，图谱表征：

IR(KBr,cm^-1)3063.55,2924.28,2853.30,1719.51,1641.24,1593.17,1391.5,1315.50,1192.88,1028.05,857.01,763.55,696.78；¹H NMR(400MHz,CDCl₃)δ＝7.35(t,J＝7.9Hz,2H),7.31(d,J＝4.4Hz,4H),7.24(d,J＝4.3Hz,1H),7.17(t,J＝6.9Hz,1H),6.95(d,J＝7.3Hz,2H),6.89(s,1H),4.24(q,J＝7.1Hz,2H),4.05–3.96(m,2H),3.50(s,2H),2.89(d,J＝11.3Hz,2H),1.96(t,J＝10.9Hz,2H),1.78(d,J＝9.1Hz,2H),1.71(dd,J＝13.4,6.6Hz,2H),1.30(t,J＝7.1Hz,6H).¹³C NMR(100MHz,CDCl₃)δ＝165.9(s),164.9(s),150.9(s),147.3(s),141.5(s),138.3(s),129.3(s),129.2(s),128.1(s),126.9(s),125.1(s),121.0(s),116.3(s),63.3(s),61.6(s),53.6(s),41.0(s),34.0(s),33.5(s),32.0(s),29.7(s),14.1(s).HRMS(ESI):calcd.for C₂₇H₃₁N₃O₃S[M+H]⁺478.21589,found 478.21621.鉴定数据表明化合物11制备成功。

将0.25mmol化合物1-1、0.25mmol 12-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到17.9mg化合物12，产率为16.1％。对化合物12的进行分析，图谱表征：

IR(KBr,cm^-1)2934.93,2794.48,1720.54,1640.77,1507.48,1388.91,1314.89,1192.25,1029.56,859.81,756.07；¹HNMR(400MHz,CDCl₃)δ＝7.17(d,J＝8.4Hz,2H),6.90–6.85(m,3H),4.24(q,J＝7.1Hz,2H),4.03(t,J＝7.1Hz,2H),2.64(q,J＝7.6Hz,2H),2.46(t,J＝7.0Hz,10H),2.24(s,3H),1.95(p,J＝7.0Hz,2H),1.31–1.24(m,6H).¹³C NMR(100MHz,CDCl₃)δ＝166.0(s),165.1(s),150.7(s),145.0(s),141.9(s),141.2(s),128.7(s),120.9(s),116.0(s),61.6(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),28.3(s),24.3(s),15.5(s),14.1(s).HRMS(ESI):calcd.for C₂₃H₃₃N₄O₃S[M+H]⁺445.22679,found 445.22643.鉴定数据表明化合物12制备成功。

将0.25mmol化合物1-1、0.25mmol 13-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到20mg化合物13，产率为18％。对化合物13的进行分析，图谱表征：

IR(KBr,cm^-1)2936.57,2794.57,1718.56,1637.13,1505.44,1390.13,1244.47,1193.11,1031.94,834.00,761.03,556.79；¹H NMR(400MHz,CDCl₃)δ＝6.95–6.82(m,5H),4.24(q,J＝7.1Hz,2H),4.02(t,J＝7.1Hz,2H),3.80(s,3H),2.45(t,J＝7.0Hz,10H),2.23(s,3H),1.99–1.89(m,2H),1.29(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝166.0(s),165.0(s),157.2(s),150.7(s),141.8(s),140.5(s),122.2(s),1156.0(s),114.6(s),61.6(s),55.8(s),55.5(s),55.1(s),53.1(s),46.0(s),41.7(s),24.3(s),14.1(s).HRMS(ESI):calcd.for C₂₂H₃₀N₄O₄S[M+H]⁺447.20605,found447.20567.鉴定数据表明化合物13制备成功。

将0.25mmol化合物1-1、0.25mmol 14-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到17.2mg化合物14，产率为15％。对化合物14的进行分析，图谱表征：IR(KBr,cm^-1)2934.07,2794.63,1725.57,1642.33,1584.15,1458.37,1315.67,1193.50,1030.17,758.62；¹H NMR(400MHz,CDCl₃)δ＝7.42(dd,J＝8.0,1.3Hz,1H),7.23(td,J＝7.7,1.4Hz,1H),7.10(td,J＝7.8,1.6Hz,1H),6.94(dd,J＝7.8,1.5Hz,1H),6.91(s,1H),4.24(q,J＝7.1Hz,2H),4.06(t,J＝7.0Hz,2H),2.48(t,J＝6.9Hz,10H),2.24(s,3H),2.00(dd,J＝14.1,7.0Hz,2H),1.29(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl3)δ＝165.9(s),165.0(s),153.0(s),144.5(s),141.3(s),130.2(s),127.6(s),126.5(s),126.1(s),121.7(s),116.7(s),61.7(s),55.8(s),55.0(s),52.9(s),45.9(s),41.8(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₇N₄O₃SCl[M+H]⁺451.15652,found451.15629鉴定数据表明化合物14制备成功。

将0.25mmol化合物1-1、0.25mmol 15-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到16.3mg化合物15，产率为13％。对化合物15的进行分析，图谱表征：

IR(KBr,cm^-1)2936.43,2793.81,1723.87,1696.71,1641.46,1579.92,1465.83,1315.63,1193.23,1027.82,758.99；¹H NMR(400MHz,CDCl₃)δ＝7.58(dd,J＝8.0,1.3Hz,1H),7.29–7.24(m,1H),7.01(td,J＝7.8,1.5Hz,1H),6.94–6.87(m,2H),4.22(q,J＝7.1Hz,2H),4.04(t,J＝7.1Hz,2H),2.61–2.29(m,10H),2.22(s,3H),1.98(dd,J＝14.0,7.0Hz,2H),1.27(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.8(s),164.9(s),152.9(s),145.9(s),141.3(s),133.2(s),128.2(s),126.3(s),121.4(s),116.6(d,J＝11.1Hz),61.7(s),55.8(s),55.0(s),52.9(s),45.9(s),41.8(s),24.3(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₇N₄O₃SBr[M+H]⁺495.10600,found 495.10582.鉴定数据表明化合物15制备成功。

将0.25mmol化合物1-1、0.25mmol 16-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到16.5mg化合物16，产率为13.6％。对化合物16的进行分析，图谱表征：

IR(KBr,cm^-1)2937.53,2795.521726.68,1644.29,1579.07,1371.70,1264.02,1194.74,1130.11,1033.22,859.82,761.80；¹H NMR(400MHz,CDCl₃)δ7.36–7.31(m,2H),7.15(t,J＝7.5Hz,1H),6.95(d,J＝7.3Hz,2H),6.88(s,1H),4.23(q,J＝7.1Hz,2H),4.10(t,J＝6.8Hz,2H),2.68(t,J＝6.8Hz,2H),2.48(s,4H),1.53(dt,J＝10.9,5.6Hz,4H),1.40(dd,J＝11.2,5.9Hz,2H),1.28(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ165.3(d,J＝107.3Hz),164.8(s),152.6(s),145.5(s),141.0(s),132.8(s),126.8(dd,J＝10.5,5.3Hz),124.8(d,J＝18.6Hz),122.2(t,J＝30.2Hz),121.6(d,J＝61.7Hz),116.9(s),61.7(s),55.7(s),55.0(s),52.8(s),45.9(s),41.8(s),24.1(s),14.0(s).HRMS(ESI):calcd.for C₂₂H₂₇N₄O₃F₃S[M+H]⁺485.18287，found 485.18233.鉴定数据表明化合物16制备成功。

将0.25mmol化合物1-1、0.25mmol 17-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到18mg化合物17，产率为15.9％。对化合物17的进行分析，图谱表征：

IR(KBr,cm^-1)2937.53,2795.07,1723.72,1642.36,1460.29,1316.24,1194.28,1028.99,865.13,694.65；¹H NMR(400MHz,CDCl₃)δ＝7.25(dd,J＝9.5,6.4Hz,1H),7.14–7.10(m,1H),6.93(t,J＝2.0Hz,1H),6.88(s,1H),6.81(ddd,J＝7.9,2.0,1.0Hz,1H),4.23(q,J＝7.1Hz,2H),3.99(t,J＝7.1Hz,2H),2.43(t,J＝6.9Hz,10H),2.22(s,3H),1.96–1.87(m,2H),1.27(d,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.8(s),164.9(s),152.2(s),148.5(s),141.1(s),134.8(s),130.3(s),125.1(s),121.4(s),119.1(s),116.7(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₇N₄O₃SCl[M+H]⁺451.15652,found 451.15644.鉴定数据表明化合物17制备成功。

将0.25mmol化合物1-1、0.25mmol 18-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到17.3mg化合物18，产率为14％。对化合物18的进行分析，图谱表征：

IR(KBr,cm^-1)2936.52,2795.27,1721.28,1641.73,1581.67,1467.78,1370.53,1194.51,1021.65,864.15,784.15,695.01；¹H NMR(400MHz,CDCl₃)δ＝7.31–7.27(m,1H),7.20(t,J＝7.9Hz,1H),7.10(t,J＝1.9Hz,1H),6.90(s,1H),6.89–6.85(m,1H),4.24(t,J＝7.1Hz,2H),4.00(t,J＝7.1Hz,2H),2.44(t,J＝6.9Hz,10H),2.25(s,3H),1.97–1.88(m,2H),1.29(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.8(s),164.9(s),152.3(s),148.7(s),141.1(s),130.6(s),128.0(s),124.2(s),122.9(s),119.6(s),116.7(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₇N₄O₃SBr[M+H]⁺495.10600,found495.10574.鉴定数据表明化合物18制备成功。

将0.25mmol化合物1-1、0.25mmol 19-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到16.4mg化合物19，产率为13.3％。对化合物19的进行分析，图谱表征：

IR(KBr,cm^-1)2936.17,2794.92,1721.70,1638.95,1483.26,1315.47,1193.55,1009.94,828.97,761.68；¹H NMR(400MHz,CDCl₃)δ＝7.49–7.44(m,2H),6.89(s,1H),6.86–6.81(m,2H),4.25(q,J＝7.1Hz,2H),4.01(t,J＝7.1Hz,2H),2.45(t,J＝7.0Hz,10H),2.25(s,3H),1.94(dd,J＝14.1,7.0Hz,2H),1.31(d,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.9(s),164.9(s),151.9(s),146.4(s),141.1(s),132.4(s),122.8(s),118.3(s),116.7(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₇N₄O₃SBr[M+H]⁺495.10600,found495.10655.鉴定数据表明化合物19制备成功。

将0.25mmol化合物1-1、0.25mmol 20-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到19.2mg化合物20，产率为17％。对化合物20的进行分析，图谱表征：

IR(KBr,cm^-1)2937.00,2795.57,1721.91,1638.59,1588.12,1486.44,1316.10,1194.18,1012.66,834.77,760.89,525.38；¹HNMR(400MHz,CDCl₃)δ＝7.34–7.28(m,2H),6.91–6.85(m,3H),4.24(q,J＝7.1Hz,2H),4.01(t,J＝7.1Hz,2H),2.44(t,J＝7.0Hz,10H),2.24(s,3H),1.97–1.89(m,2H),1.29(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl₃)δ＝165.8(s),164.9(s),151.9(s),145.9(s),141.1(s),130.6(s),129.4(s),122.4(s),116.6(s),61.7(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₇N₄O₃SCl[M+H]⁺451.15652,found 451.15633.鉴定数据表明化合物20制备成功。

将0.25mmol化合物1-1、0.25mmol 21-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到19.3mg化合物21，产率为15.9％。对化合物21的进行分析，图谱表征：

IR(KBr,cm^-1)2933.34,2796.34,1725.74,1643.23,1459.60,1322.66,1194.69,1065.69,848.81,758.88,615.89,514.95；¹H NMR(400MHz,CDCl₃)δ＝7.60(d,J＝8.3Hz,2H),7.03(d,J＝8.2Hz,2H),6.90(s,1H),4.23(t,J＝7.1Hz,2H),4.02(t,J＝7.1Hz,2H),2.46(t,J＝6.9Hz,10H),2.24(s,3H),1.93(dd,J＝14.1,7.0Hz,2H),1.28(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ165.8(s),164.9(s),151.4(d,J＝196.1Hz),140.9(s),127.1(d,J＝32.8Hz),126.8–126.4(m),121.3(s),116.9(s),61.8(s),55.8(s),55.0(s),52.9(s),45.9(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₂H₂₇N₄O₃F₃S[M+H]⁺485.18287,found 485.18292.鉴定数据表明化合物21制备成功。

(22)化合物22的制备

将0.25mmol化合物1-1、0.25mmol 22-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到18.2mg化合物22，产率为16.8％。对化合物22的进行分析，图谱表征：

IR(KBr,cm^-1)2937.45,2795.83,1721.72,1640.48,1503.27,1389.46,1316.09,1193.21,1029.18,841.07,761.20；¹H NMR(400MHz,CDCl₃)δ＝7.03(t,J＝8.6Hz,2H),6.94–6.86(m,3H),4.24(q,J＝7.1Hz,2H),4.01(t,J＝7.1Hz,2H),2.45(t,J＝7.0Hz,10H),2.25(s,3H),1.97–1.89(m,2H),1.28(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ165.9(s),164.9(s),160.3(d,J＝244.1Hz),151.7(s),143.4(d,J＝2.9Hz),141.3(s),122.4(d,J＝8.2Hz),116.3(d,J＝22.8Hz),116.0(s),61.7(s),55.8(s),55.0(s),52.9(s),45.8(s),41.7(s),24.2(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₇N₄O₃FS[M+H]⁺435.18607,found435.18588.鉴定数据表明化合物22制备成功。

将0.25mmol化合物1-1、0.25mmol 23-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到14.9mg化合物23，产率为13.2％。对化合物23的进行分析，图谱表征：

IR(KBr,cm^-1)2934.58,2795.10,1728.57,1643.85,1613.50,1496.18,1386.03,1316.22,1194.58,1027.99,861.51,761.53；¹H NMR(400MHz,CDCl₃)δ＝7.03(td,J＝9.3,4.9Hz,1H),6.89(s,1H),6.82–6.75(m,1H),6.66(ddd,J＝9.2,6.3,3.1Hz,1H),4.22(q,J＝7.1Hz,2H),4.01(t,J＝6.9Hz,2H),2.42(t,J＝6.8Hz,10H),2.19(s,3H),1.92(dd,J＝13.7,6.9Hz,2H),1.27(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ165.7(s),164.8(s),158.5(dd,J＝243.9,2.5Hz),154.4(s),149.8(dd,J＝242.7,2.9Hz),140.8(s),136.0(dd,J＝14.8,9.9Hz),117.1(d,J＝9.6Hz),117.0–116.8(m),112.1(dd,J＝23.9,7.5Hz),109.7(d,J＝25.4Hz),61.7(s),55.8(s),55.0(s),53.4(d,J＝96.3Hz),45.9(s),41.8(s),23.9(s),14.0(s).HRMS(ESI):calcd.for C₂₁H₂₆N₄O₃F₂S[M+Na]⁺475.15859,found 475.15750.鉴定数据表明化合物23制备成功。

(24)化合物24的制备

将0.25mmol化合物1-1、0.25mmol 24-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到19.7mg化合物24，产率为16.2％。对化合物24的进行分析，图谱表征：

IR(KBr,cm^-1)2936.41,2795.27,1724.46,1639.69,1583.51,1467.67,1371.06,1315.87,1194.32,1027.22,871.03,758.88；¹H NMR(400MHz,CDCl₃)δ＝7.40(d,J＝8.5Hz,1H),7.05(d,J＝2.4Hz,1H),6.90(s,1H),6.80(dd,J＝8.5,2.5Hz,1H),4.25(q,J＝7.1Hz,2H),3.99(t,J＝7.1Hz,2H),2.43(t,J＝6.9Hz,10H),2.23(s,3H),1.91(p,J＝7.0Hz,2H),1.29(t,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ＝165.8(s),164.8(s),152.8(s),146.8(s),140.7(s),133.1(s),131.0(s),128.7(s),123.1(s),120.5(s),117.0(s),61.8(s),55.8(s),55.0(s),53.0(s),45.9(s),41.7(s),24.2(s),21.0(s),14.1(s).HRMS(ESI):calcd.for C₂₁H₂₆N₄O₃SCl₂[M+H]⁺485.11754,found 485.11710.鉴定数据表明化合物24制备成功。

(25)化合物25的制备

将0.25mmol化合物1-1、0.25mmol 25-1、0.25mmol乙炔二羧酸二乙酯和2mL乙醇混合，在白光下室温反应12h，经TLC分离法分离得到20.2mg化合物25，产率为14.6％。对化合物25的进行分析，图谱表征：

IR(KBr,cm^-1)2938.16,2796.82,1729.72,1641.45,1458.92,1317.12,1279.33,1137.41,1028.83,890.04,761.68,703.57,613.08；¹H NMR(400MHz,CDCl₃)δ＝7.67(s,1H),7.37(s,2H),6.94(s,1H),4.25(q,J＝7.1Hz,2H),4.02(t,J＝7.1Hz,2H),2.61–2.35(m,10H),2.25(s,3H),1.98–1.90(m,2H),1.28(d,J＝7.1Hz,3H).¹³C NMR(100MHz,CDCl₃)δ165.6(s),164.7(s),154.0(s),148.8(s),140.1(s),132.8(q,J＝33.6Hz),127.1(s),124.3(s),121.6(s),121.4(s),118.7–118.3(m),117.8(s),62.0(s),55.7(s),54.9(s),52.9(s),45.8(s),41.8(s),29.5(d,J＝38.3Hz),24.1(s),14.0(s).HRMS(ESI):calcd.forC₂₃H₂₆N₄O₃F₆S[M+H]⁺553.17026,found 553.17020.鉴定数据表明化合物25制备成功。

实施例2：体外杀成虫的活性试验

(1)体外杀成虫的活性试验

采集活的45天日本血吸虫成虫置于RPMI-1640培养液(10条/3mL/皿)中，每皿分别加入化合物1～25各3μL，每个化合物的终浓度为0.5mmol/L、0.1mmol/L、0.05mmol/L，对照组加3μL DMSO，加药后充分摇匀，放入37℃、5％CO2培养箱中，培养16h后用生理盐水洗涤虫体3次，加入新鲜培养液，在体视显微镜下观察培养24～72h后的血吸虫活力状态，吡喹酮为阳性对照，即向3mL培养液中加3μL 50μmol/mL的吡喹酮溶液，即得到50μmol/L的吡喹酮药液；阴性对照为在培养液中加3μL溶剂DMSO；空白对照不往培养液中加任何试剂。结果见表1。

表1化合物1～25对45天日本血吸虫成虫的灭杀效果

表1中死亡等级∶A为药物浓度为0.05mmol/L时，成虫在72h内的死亡率为100％；B为药物浓度为0.1mmol/L时，成虫在72h内的死亡率为100％；C为药物浓度为0.5mmol/L时，成虫在72h内的死亡率为100％；D为药物浓度为0.5mmol/L时，成虫在72h内的死亡率为0％。

实施例3：体内抗血吸虫成虫的作用

将12只感染50条尾蚴的小鼠培养至35天，分为A、B、C、D四组，每组3只，并称取体重，分别称取化合物1、化合物2、化合物3各120mg，用5mL食用油超声溶解，分别得到24mg/mL的化合物1、化合物2和化合物3溶液。

A组小鼠以400mg/kg的剂量灌服化合物1，B组小鼠以400mg/kg的剂量灌服化合物2，C组小鼠以400mg/kg的剂量灌服化合物3，D组小鼠灌服相应体积的食用油作为对照组，连续灌服3天，在感染后的第45天处死小鼠解剖观察减虫效果和小鼠肝脏、脾脏的病理特征，结果见表3。

表3化合物1～3体内抗血吸虫成虫的效果

由表3可知，化合物1～3的减虫率分别为67.6％、29％、61.7％，表现出了较高的体内杀灭成虫的活性。

以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。