CN115385847B - 多取代二芳基类化合物及其制备方法和应用 - Google Patents

多取代二芳基类化合物及其制备方法和应用 Download PDF

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CN115385847B
CN115385847B CN202211071077.9A CN202211071077A CN115385847B CN 115385847 B CN115385847 B CN 115385847B CN 202211071077 A CN202211071077 A CN 202211071077A CN 115385847 B CN115385847 B CN 115385847B
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CN115385847A (zh
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刘波
姚庆强
陈海蛟
杨新美
智英
李莹
汪海洋
崔正国
刘效祥
扈国栋
丁天地
张飞鹏
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Shandong First Medical University and Shandong Academy of Medical Sciences
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Abstract

本发明涉及药物化学领域，具体涉及一类多取代二芳基类化合物式(I)、其制备方法、并包含其药物制剂及其医药用途。药理试验结果表明，本发明的取代二芳基类化合物对人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞均具有良好的抑制作用。式(I)：

Description

多取代二芳基类化合物及其制备方法和应用
技术领域
本发明涉及药物化学领域，具体涉及一类多取代二芳基类化合物、其制备方法、并包含其药物制剂及其医药用途。
背景技术
1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇，CAS号2125657-10-3，分子式C28H42N2O5，结构式为：
目前公开的文献资料仅有该化合物的理化性质，未见其药理作用公开,更未见其具有抗肿瘤作用的文献报道。
发明内容
本发明解决的技术问题是提供一类取代二芳基类化合物及其药学上可接受的盐、其光学异构体、其制备方法、药物组合物以及其在制备治疗癌症药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供如通式(I)所示的化合物或其药学上可接受的盐、其光学异构体：
其中，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6为
优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述
R1为-H,-CH(CH3)2,-Br,-Cl
R2为-F,-Br,-Cl,-H,-CH(CH3)2，-CF3
R3为-H,-CH3,-Cl,-Br,-C14H29
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6为
更优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-C14H29；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-Cl；R4为-Br；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6为
更优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-H；R2为-H；R3为-C14H29；R4为-H；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6为
更优选的，上述的化合物或其药学上可接受的盐、其光学异构体，所述R1为-H；R2为-CF3；R3为-Br；R4为-H；R5为-H；
R6为
或
R1为-Br；R2为-H；R3为-Br；R4为-H；R5为-Br；
R6为
本发明上述任一化合物药学上可接受的盐为有机酸盐、无机酸盐、有机碱盐或无机碱盐，其中有机酸包括乙酸、三氟乙酸、甲磺酸、甲苯磺酸、马来酸、琥珀酸、酒石酸、柠檬酸、富马酸；无机酸包括盐酸、氢溴酸、硝酸、硫酸、磷酸；有机碱包括葡甲胺、氨基葡萄糖；无机碱包括钠、钾、钡、钙、镁、锌、锂的碱性化合物。
本发明上述任一化合物均为消旋体，其光学异构体为其左旋体或右旋体。
本发明技术方案的第二方面是提供第一方面所述化合物的制备方法，本发明的通式(I)化合物可用下述方法制备：
其中，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6为
通式(I)系列化合物的合成：将取代苯氧基甲基环氧乙烷(7)(1.0mmol)和化合物(5)(1.2mmol)溶于异丙醇(15mL)，于氮气保护下，加入催化量的吡啶，加热回流6h，TLC检测原料消失。反应液用乙酸乙酯稀释，有机相用依次用水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，粗品用硅胶柱层析分离纯化(流动相：二氯甲烷-甲醇＝20:1)得目标化合物(I)，产率80％—90％。
本发明技术方案的第三方面是提供包含第一方面所述化合物的药物组合物其药学上可接受的盐、其光学异构体与一种或多种药用载体和/或赋形剂的药物组合物，为临床上或药学上可接受的任一剂型，优选为口服制剂或注射剂
本发明技术方案的第四方面是提供包含第一方面所述化合物以及第三方面所述药物组合物在制备治疗癌症药物中的应用。所述癌症为肺癌或卵巢癌或黑色素瘤或结肠癌。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。本发明的化合物临床所用剂量为0.01-1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
有益技术效果：本发明提供了一系列结构全新的具有抗癌功效的化合物，该化合物对肺癌或卵巢癌或黑色素瘤或结肠癌有效。
具体实施方式
下面结合具体实施方式来对本发明作更进一步的说明，以便本领域的技术人员更了解本发明，但并不以此限制本发明。
本发明实施例目标化合物的合成，是将取代苯氧基甲基环氧乙烷(7)(1.0mmol)和化合物(5)(1.2mmol)溶于异丙醇(15mL)，于氮气保护下，加入催化量的吡啶，加热回流6h，TLC检测原料消失。反应液用乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，粗品用硅胶柱层析分离纯化(流动相：二氯甲烷-甲醇＝20:1)得目标化合物。
化合物(5)是由香草醛(1)为原料，经过4步反应合成的。
得到的4种化合物(5)如下表所示：
表1化合物(5)的具体结构
取代苯氧基甲基环氧乙烷(7)是由苯环上含有不同取代的苯酚与环氧溴丙烷发生亲核取代反应来合成，得到的该系列化合物如下表所示：
表2化合物(7)的具体结构
实施例1：1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(SAMS10)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-乙氧基苯氧基)甲基)环氧乙烷(7-1)。
将2-((2-乙氧基苯氧基)甲基)环氧乙烷(7-1)(194mg,1.0mmol)和1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)(354mg,1.2mmol)溶于异丙醇(15mL)，于氮气保护下，加入催化量的吡啶(8.0μL,0.1mmol)，加热回流6h，TLC检测(展开剂：二氯甲烷-甲醇＝10:1)原料消失。反应液用乙酸乙酯稀释，有机相依次用水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，粗品用硅胶柱层析分离纯化(流动相：二氯甲烷-甲醇＝20:1)，得无色油状物(437.9mg,90％)。1H NMR(CDCl3,600MHz)δ(ppm):6.89(m,7H),4.09(m,7H),3.84(s,3H),3.59(d,J＝19.80Hz,1H),3.47(d,J＝19.80Hz,1H),3.05(d,J＝17.40Hz,2H),2.90(t,J＝9.60Hz,2H),2.61(m,2H),2.28(s,3H),2.19(m,2H),1.66(d,J＝21.0Hz,2H),1.38(m,6H),0.94(d,J＝8.40Hz,3H).13C NMR(CDCl3,150MHz)δ(ppm):149.49,149.39,148.72,147.33,131.62,122.12,121.27,121.10,115.80,113.84,113.16,112.48,72.91,66.61(2C),64.51,62.45,59.60,57.25,55.94,54.37(2C),42.43,33.84(2C),30.39,21.76,14.93.IR(KBr,cm-1):2924,2871,2851,2794,2360,2340,1592,1512,1494,1460,1419,1368,1321,1272,1217,1138,1035,980,863,803,772,670.HRMS(ESI):m/z calcd for C28H43N2O5(M+H)+:487.3172.found:487.3199.
实施例2-58中化合物CHJ02029-CHJ05004的制备方法同实施例1，区别在于使用不同的化合物5和化合物7合成，具体每个实施例中使用的化合物5和化合物7原料在相应实施例中有记载。
实施例2：1-(2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02029)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,6-二氯苯氧基)甲基)环氧乙烷(7-2)。
无色油状物，产率88％，1H NMR(CD3OD,400MHz)δ(ppm):7.36(d,J＝8.0Hz,2H),7.08(t,J＝8.0Hz,1H),7.01(s,1H),6.87(m,2H),4.15(m,3H),3.99(m,2H),3.80(s,3H),3.59(m,2H),3.14(d,J＝11.20Hz,2H),2.92(t,J＝5.60Hz,2H),2.74(m,1H),2.59(dd,J＝12.80,7.60Hz,1H),2.32(m,5H),1.70(d,J＝12.80Hz,2H),1.45(s,1H),1.30(m,2H),0.95(d,J＝6.4Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):151.27,149.68,147.30,131.70,129.04,128.89(3C),125.31,121.62,113.84,113.09,75.76,67.86,66.25,62.02,59.27,56.86,55.00,53.81(2C),41.86,33.04(2C),29.92,20.60.IR(KBr,cm-1):2947,2926,2872,2841,2792,2360,2340,1651,1592,1511,1475,1455,1367,1286,1262,1230,1127,1036,979,937,863,807,670.HRMS(ESI):m/z calcd for C26H37Cl2N2O4(M+H)+:511.2130.found:511.2047.
实施例3：1-(4-溴-3-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02049)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴-3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-3)。
无色油状物，产率87％，1H NMR(CD3OD,400MHz)δ(ppm):7.64(d,J＝8.80Hz,1H),7.26(s,1H),7.02(d,J＝8.80Hz,1H),6.95(s,1H),6.83(q,J＝8.0Hz,2H),4.08(m,4H),3.91(m,1H),3.75(s,3H),3.50(q,J＝12.80Hz,2H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H),2.62(dd,J＝12.40,5.60Hz,1H),2.48(dd,J＝12.40,6.40Hz,1H),2.32(s,3H),2.17(t,J＝11.60Hz,2H),1.66(d,J＝12.40Hz,2H),1.39(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):158.33,149.62,147.45,135.7(2C),131.91,121.46(2C),118.91,114.35,114.29,113.48,113.06,70.99,67.29,66.69,62.29,58.70,57.12,54.94,54.00(2C),42.25,33.48(2C),33.25,20.75.IR(KBr,cm-1):2926,2872,2849,2793,2370,2323,1684,1651,1556,1512,1474,1455,1419,1367,1330,1313,1260,1235,1139,1035,980,936,879,809,753.HRMS(ESI):m/z calcd for C27H37BrF3N2O4(M+H)+:589.1889.found:589.2404.
实施例4：1-(2,5-双(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02050)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,5-双(三氟甲基)苯氧基)甲基)环氧乙烷(7-4)。
白色固体，产率85％，mp:70-72℃，1H NMR(CD3OD,400MHz)δ(ppm):7.77(d,J＝8.0Hz,1H),7.46(s,1H),7.38(d,J＝8.0Hz,1H),6.96(s,1H),6.83(q,J＝8.0Hz,2H),4.13(m,5H),3.76(s,3H),3.51(m,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.63(m,2H),2.30(s,3H),2.17(t,J＝11.60Hz,2H),1.66(d,J＝12.40Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):157.29,149.66,147.41,131.89,127.72,127.67,121.67,121.40,116.72,116.68,113.59,112.97,109.94,109.90,71.45,67.17,66.71,62.28,59.06,57.11,54.90,53.98(2C),41.93,33.46(2C),30.24,20.73.IR(KBr,cm-1):3562,3354,2945,2877,2831,2800,1624,1595,1517,1463,1435,1330,1259,1232,1174,1132,1087,1043,1022,962,910,866,833,804,750,673.HRMS(ESI):m/z calcd for C28H37F6N2O4(M+H)+:579.2658.found:579.2549.
实施例5：1-(3-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03001)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴苯氧基)甲基)环氧乙烷(7-5)。
无色油状物，产率86％，1H NMR(CDCl3,400MHz)δ(ppm):7.10(m,3H),6.82(m,4H),4.14(m,3H),3.94(d,J＝4.80Hz,2H),3.85(s,3H),3.62(d,J＝13.60Hz,1H),3.45(d,J＝13.20Hz,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.0Hz,2H),2.62(m,1H),2.49(dd,J＝12.40,3.60Hz,1H),2.29(s,3H),2.11(t,J＝11.60Hz,2H),1.64(d,J＝12.40Hz,2H),1.30(m,3H),0.93(d,J＝4.0Hz,3H).13CNMR(CDCl3,100MHz)δ(ppm):159.54,149.44,147.60,131.18,130.53,124.07,122.76,121.30,117.86,113.58,112.97,112.49,70.63,66.81,66.04,62.37,59.25,57.40,55.97,54.49(2C),42.26,34.19(2C),30.57,21.87.IR(KBr,cm-1):2947,2924,2871,2846,2792,2360,2340,1651,1591,1572,1512,1476,1463,1459,1368,1324,1283,1261,1229,1157,1138,1090,1035,991,936,861,804,800,674.HRMS(ESI):m/z calcd for C26H38BrN2O4(M+H)+:521.2015.found:521.1945.
实施例6：1-(2-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03003)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-溴苯氧基)甲基)环氧乙烷(7-6)。
无色油状物，产率90％，1H NMR(CDCl3,400MHz)δ(ppm):7.52(d,J＝7.60Hz,1H),7.23(d,J＝8.0Hz,1H),6.85(m,5H),4.14(t,J＝6.0Hz,3H),4.03(d,J＝4.40Hz,2H),3.84(s,3H),3.72(q,J＝7.20Hz,1H),3.63(d,J＝12.80Hz,1H),3.47(d,J＝12.80Hz,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.40Hz,2H),2.72(m,1H),2.59(dd,J＝12.0,3.60Hz,1H),2.31(s,3H),2.11(t,J＝11.20Hz,2H),1.64(d,J＝12.40Hz,2H),1.27(m,3H),0.93(d,J＝6.0Hz,3H).13CNMR(CDCl3,100MHz)δ(ppm):155.10,149.41,147.54,133.30,131.32,128.46,122.19,121.33,113.54,112.94,112.52,112.41,71.39,66.74,66.25,62.47,59.35,58.43,57.39,55.96,54.47,42.43,34.17,30.57,21.86,18.45.IR(KBr,cm-1):2947,2924,2871,2844,2792,2361,2340,1589,1513,1480,1462,1417,1368,1323,1276,1261,1232,1158,1138,1084,1053,1030,979,939,872,806,749.HRMS(ESI):m/zcalcd forC26H38BrN2O4(M+H)+:521.2015.found:521.1943.
实施例7：1-(2-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03004)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-异丙基苯氧基)甲基)环氧乙烷(7-7)。
无色油状物，产率87％，1H NMR(CDCl3,400MHz)δ(ppm):7.2(d,J＝7.60Hz,1H),7.13(t,J＝7.60Hz,1H),6.92(t,J＝7.20Hz,1H),6.82(m,4H),4.14(m,3H),3.99(m,2H),3.84(s,3H),3.65(d,J＝13.20Hz,1H),3.45(d,J＝12.80Hz,1H),3.26(m,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.40Hz,2H),2.69(m,1H),2.53(dd,J＝12.0,3.20Hz,1H),2.31(s,3H),2.11(t,J＝11.2Hz,2H),1.64(d,J＝12.0Hz,2H),1.30(m,3H),1.19(d,J＝6.80Hz,6H),0.96(d,J＝6.0Hz,3H).13CNMR(CDCl3,100MHz)δ(ppm):155.82,149.43,147.56,137.05,131.31,126.55,126.07,121.26,120.89,112.93,112.45,111.30,70.34,66.78,66.35,62.47,59.67,57.40,55.94,54.48(2C),42.36,34.19(2C),30.57,26.90,22.64(2C),21.88.IR(KBr,cm-1):2950,2925,2870,2792,2360,2340,1597,1513,1491,1452,1418,1365,1323,1261,1238,1193,1138,1088,1033,1030,980,937,878,822,805,751.HRMS(ESI):m/z calcd for C29H45N2O4(M+H)+:485.3379.found:485.3330.
实施例8：1-(4-溴-2-甲氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03005)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴-2-甲氧基苯氧基)甲基)环氧乙烷(7-8)。
无色油状物，产率90％，1H NMR(CD3OD,400MHz)δ(ppm):7.06(s,1H),7.00(d,J＝8.40Hz,1H),6.95(s,1H),6.83(m,3H),4.10(m,3H),3.96(dd,J＝9.60,5.60Hz,1H),3.85(dd,J＝9.60,5.60Hz,1H),3.77(d,J＝12.0Hz,6H),3.53(m,2H),3.06(d,J＝11.60Hz,2H),2.83(t,J＝5.88Hz,2H),2.63(dd,J＝13.44,5.60Hz,1H),2.49(dd,J＝13.44,6.80Hz,1H),2.31(s,3H),2.20(t,J＝11.60Hz,2H),1.67(d,J＝12.80Hz,2H),1.40(s,1H),1.28(m,2H),0.94(d,J＝6.40Hz,3H).13C NMR(CD3OD,100MHz)δ(ppm):150.42,149.62,147.91,147.36,131.88,123.29,121.47,115.25,114.88,113.54,113.05,112.79,71.91,67.50,66.61,62.22,58.89,57.07,55.34,54.94,53.96(2C),42.13,33.39(2C),30.18,20.71.IR(KBr,cm-1):2946,2924,2843,2792,2360,2340,1589,1556,1539,1506,1459,1418,1398,1364,1324,1255,1225,1183,1136,1084,1029,936,857,797,670.HRMS(ESI):m/z calcd forC27H40BrN2O5(M+H)+:551.2101.found:551.2094.
实施例9：1-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基-4-丙基苯氧基)丙-2-醇(CHJ03011)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-甲氧基-4-丙基苯氧基)甲基)环氧乙烷(7-9)。
白色固体，产率83％，mp:45-47℃，1H NMR(CD3OD,400MHz)δ(ppm):6.97(s,1H),6.87(d,J＝8.0Hz,1H),6.80(m,3H),6.69(d,J＝8.0Hz,1H),4.10(m,3H),3.96(dd,J＝9.60,3.60Hz,1H),3.84(dd,J＝9.60,6.40Hz,1H),3.78(d,J＝13.60Hz,6H),3.54(m,2H),3.05(d,J＝11.60Hz,2H),2.82(t,J＝5.60Hz,2H),2.61(dd,J＝12.80,5.20Hz,1H),2.51(q,J＝7.20Hz,3H),2.30(s,3H),2.19(t,J＝11.60Hz,2H),1.63(m,4H),1.40(s,1H),1.28(m,2H),0.94(d,J＝7.20Hz,6H).13C NMR(CD3OD,100MHz)δ(ppm):149.66,149.33,147.40,146.45,136.10,131.85,121.50,120.41,113.95,113.60,113.07,112.54,72.26,67.62,66.67,62.16,59.08,57.08,55.14,54.96,53.97(2C),42.01,37.26,33.41(2C),30.19,24.48,20.71,12.68.IR(KBr,cm-1):2922,2868,2791,2360,2340,1597,1516,1458,1419,1371,1330,1261,1230,1138,1091,1031,970,850,804,750,646,553,489.HRMS(ESI):m/zcalcd for C30H47N2O5(M+H)+:515.3485.found:515.3423.
实施例10：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(4-十五烷基苯氧基)丙-2-醇(CHJ03012)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-十五烷基苯氧基)甲基)环氧乙烷(7-10)。
白色固体，产率85％，mp:40-42℃，1H NMR(CD3OD,400MHz)δ(ppm):7.13(t,J＝7.60Hz,1H),6.97(s,1H),6.84(m,2H),6.72(m,3H),4.11(m,3H),3.98(m,1H),3.86(m,1H),3.76(s,3H),3.55(m,2H),3.05(d,J＝11.60Hz,2H),2.81(t,J＝5.60Hz,2H),2.59(m,4H),2.30(m,3H),2.18(t,J＝11.60Hz,2H),1.64(m,4H),1.28(s,27H),0.94(d,J＝6.40Hz,3H),0.89(t,J＝6.0Hz,3H).13C NMR(CD3OD,100MHz)δ(ppm):159.02,149.69,147.42,144.23,131.93,128.79,121.47,120.62,114.35,113.65,113.08,111.38,70.34,67.53,66.71,62.22,59.19,57.11,54.98,53.98(2C),53.38,42.07,35.56,33.43(2C),31.67,31.21,30.21,29.35(6C),29.20,29.07,28.91,22.33,20.72,13.04.IR(KBr,cm-1):2924,2852,2794,2360,2340,1591,1514,1458,1367,1325,1263,1151,1085,1035,937,869,806,775,694.HRMS(ESI):m/z calcd for C41H69N2O4(M+H)+:653.5257.found:653.5163.
实施例11：1-(2,3-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03013)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,3-二氯苯氧基)甲基)环氧乙烷(7-11)。
无色油状物，产率88％，1H NMR(CD3OD,400MHz)δ(ppm):7.20(t,J＝8.11Hz,1H),7.08(t,J＝8.08Hz,1H),6.96(m,2H),6.82(q,J＝8.05Hz,2H),4.05(m,5H),3.75(s,3H),3.52(s,2H),3.03(d,J＝11.43Hz,2H),2.80(t,J＝5.65Hz,2H),2.69(dd,J＝12.82,5.4Hz,1H),2.56(dd,J＝12.73,7.02Hz,1H),2.32(s,3H),2.17(t,J＝11.7Hz,2H),1.65(d,J＝12.71Hz,2H),1.38(s,1H),1.27(m,2H),0.93(d,J＝6.28Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):155.92,149.65,147.41,133.15,131.90,127.52,121.91,121.45,121.32,113.56,113.03,111.43,71.63,67.36,66.65,62.35,58.90,57.11,54.97,53.97(2C),42.20,33.46(2C),30.22,20.76.IR(KBr,cm-1):2947,2926,2872,2841,2792,2360,2340,1651,1592,1511,1475,1455,1367,1286,1262,1230,1127,1036,979,937,863,807,670.HRMS(ESI):m/z calcd for C26H37Cl2N2O4(M+H)+:511.2130.found:511.2095.
实施例12：1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03014)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴苯氧基)甲基)环氧乙烷(7-12)。
无色油状物，产率81％，1H NMR(CD3OD,400MHz)δ(ppm):7.35(d,J＝8.0Hz,2H),6.95(s,1H),6.82(m,4H),4.10(t,J＝5.60Hz,2H),4.05(m,1H),3.95(dd,J＝9.60,3.20Hz,1H),3.84(dd,J＝9.60,6.0Hz,1H),3.77(s,3H),3.50(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.61(dd,J＝12.83,6.0Hz,1H),2.48(dd,J＝12.80,7.20Hz,1H),2.30(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.28(m,2H),0.93(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):158.28,149.64,147.44,131.89(2C),131.89,121.49,116.19(2C),113.56,113.10,112.35,70.66,67.42,66.70,62.27,58.96,57.12,54.88,53.99(2C),42.21,33.47(2C),30.23,20.76.IR(KBr,cm-1):2947,2925,2871,2844,2792,2360,2331,1591,1556,1512,1489,1458,1418,1368,1322,1285,1245,1157,1074,1034,980,937,879,863,821,756,647.HRMS(ESI):m/z calcdfor C26H38BrN2O4(M+H)+:521.2015.found:521.1975.
实施例13：1-(3-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03015)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-异丙基苯氧基)甲基)环氧乙烷(7-13)。
无色油状物，产率89％，1H NMR(CD3OD,400MHz)δ(ppm):7.15(t,J＝7.60Hz,1H),6.97(s,1H),6.82(m,4H),6.69(d,J＝8.0Hz,1H),4.10(m,3H),3.97(m,1H),3.86(m,1H),3.76(s,3H),3.54(m,2H),3.03(d,J＝11.20Hz,2H),2.82(m,3H),2.63(dd,J＝12.80,5.60Hz,1H),2.51(dd,J＝12.40,6.8Hz,1H),2.30(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.40(s,1H),1.24(m,8H),0.94(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):159.09,150.37,149.68,147.44,131.90,128.90,121.47,118.55,113.62,113.09,112.54,111.36,70.39,67.54,66.74,62.21,59.25,57.12,54.99(3C),42.05,34.05,33.46(2C),30.23,23.03(2C),20.75.IR(KBr,cm-1):2952,2925,2871,2844,2792,2360,2340,1606,1588,1513,1486,1460,1418,1366,1320,1262,1233,1286,1138,1088,1037,1003,980,940,870,804,789,754,700.HRMS(ESI):m/zcalcd for C29H45N2O4(M+H)+:485.3379.found:485.3296.
实施例14：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇(CHJ03017)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-甲氧基苯氧基)甲基)环氧乙烷(7-14)。
无色油状物，产率83％，1H NMR(CD3OD,400MHz)δ(ppm):7.13(t,J＝8.0Hz,1H),6.96(s,1H),6.83(m,2H),6.48(m,3H),4.09(m,3H),3.96(dd,J＝9.60,6.80Hz,1H),3.85(dd,J＝9.20,6.0Hz,1H),3.75(d,J＝7.60Hz,6H),3.52(m,2H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H),2.61(dd,J＝12.80,5.60Hz,1H),2.49(dd,J＝12.80,7.20Hz,2H),2.30(s,3H),2.16(t,J＝11.60Hz,2H),1.65(dd,J＝12.40Hz,2H),1.40(s,1H),1.27(m,2H),0.93(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):160.97,160.23,149.65,147.42,131.90,129.48,121.46,113.58,113.05,106.35,106.02,100.65,70.42,67.48,66.69,62.23,59.13,57.12,54.98,54.28,53.99(2C),42.10,33.46(2C),30.23,20.76.IR(KBr,cm-1):2947,2925,2872,2837,2792,2360,2340,1593,1559,1513,1492,1455,1418,1368,1334,1287,1264,1231,1201,1154,1083,1036,980,940,834,807,762,687.HRMS(ESI):m/z calcd for C27H41N2O5(M+H)+:473.3015.found:473.2947.
实施例15：1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03018)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((5-溴-2-氟苯氧基)甲基)环氧乙烷(7-15)。
无色油状物，产率85％，1H NMR(CD3OD,400MHz)δ(ppm):7.23(d,J＝7.20Hz,1H),7.02(m,3H),6.85(dd,J＝22.0,8.0Hz,2H),4.09(m,4H),3.94(dd,J＝10.0,5.60Hz,1H),3.78(s,3H),3.50(m,2H),3.05(d,J＝11.60Hz,2H),2.81(t,J＝5.60Hz,2H),2.63(dd,J＝12.80,5.60Hz,1H),2.50(dd,J＝12.85,6.51Hz,1H),2.31(s,3H),2.18(t,J＝12.0Hz,2H),1.66(d,J＝13.20Hz,2H),1.41(s,1H),1.28(m,2H),0.94(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):150.62,149.66,147.40,131.94,123.66,123.59,121.44,118.06,117.16,116.96,115.94,113.59,112.97,72.04,67.36,66.68,62.24,58.85,57.10,54.98,53.98(2C),42.10,33.44(2C),30.22,20.72.IR(KBr,cm-1):2947,2925,2872,2845,2794,2360,2340,1607,1511,1459,1417,1404,1369,1323,1303,1262,1231,1138,1117,1090,1020,962,935,877,837,803,755,627.HRMS(ESI):m/zcalcd for C26H37BrFN2O4(M+H)+:539.1921.found:539.1911.
实施例16：1-(3,4-二甲氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03019)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3,4-二甲氧基苯氧基)甲基)环氧乙烷(7-16)。
无色油状物，产率87％，1H NMR(CD3OD,400MHz)δ(ppm):6.97(s,1H),6.84(m,3H),6.54(s,1H),6.40(d,J＝8.55Hz,1H),4.08(m,3H),3.93(dd,J＝9.57,3.33Hz,1H),3.83(m,1H),3.77(d,J＝8.88Hz,9H),3.52(q,J＝12.85Hz,2H),3.05(d,J＝11.47Hz,2H),2.82(t,J＝5.55Hz,2H),2.62(dd,J＝12.84,5.5Hz,1H),2.49(dd,J＝12.77,7.05Hz,1H),2.31(s,3H),2.19(t,J＝11.69Hz,2H),1.66(d,J＝12.59Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.29Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):153.95,150.09,149.63,147.39,143.54,131.88,121.48,113.57,113.07,112.86,104.22,100.91,70.91,67.53,66.61,62.22,59.10,57.08,55.91,54.97(2C),53.97(2C),42.12,33.39(2C),30.18,20.72.IR(KBr,cm-1):2926,2871,2850,2794,2360,2340,1700,1651,1611,1596,1513,1418,1368,1320,1261,1229,1199,1162,1138,1029,981,943,875,804,764.HRMS(ESI):m/zcalcd forC28H43N2O6(M+H)+:503.3121.found:503.2817.
实施例17：1-(3-溴-4-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03043)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-4-氯苯氧基)甲基)环氧乙烷(7-17)。
无色油状物，产率89％，1H NMR(CDCl3,400MHz)δ(ppm):7.30(m,1H),7.17(s,1H),6.81(m,4H),4.11(m,3H),3.91(m,2H),3.84(s,3H),3.61(d,J＝12.0Hz,1H),3.45(d,J＝12.80Hz,1H),2.98(d,J＝11.20Hz,2H),2.84(t,J＝6.40Hz,2H),2.61(m,1H),2.47(dd,J＝12.40,3.60Hz,1H),2.29(s,3H),2.11(t,J＝11.20Hz,2H),1.63(d,J＝12.40Hz,2H),1.29(m,3H),0.93(d,J＝6.0Hz,3H).13CNMR(CDCl3,100MHz)δ(ppm):157.74,149.48,147.66,131.13,130.47,126.18,122.53,121.31,119.57,115.31,113.07,112.55,71.00,66.93,65.99,62.37,59.10,57.39,55.99,54.50(2C),42.29,34.21(2C),30.56,21.87.IR(KBr,cm-1):2923,2846,2360,2340,1700,1651,1613,1590,1559,1539,1511,1470,1460,1418,1373,1337,1288,1262,1229,1157,1138,1083,1035,931,859,805,669.HRMS(ESI):m/zcalcd for C26H37BrClN2O4(M+H)+:555.1625.found:555.1610.
实施例18：1-(3-溴-4-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04010)的合成
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所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-4-甲基苯氧基)甲基)环氧乙烷(7-18)。
无色油状物，产率82％，1H NMR(CD3OD,400MHz)δ(ppm):7.15(d,J＝8.40Hz,1H),7.09(s,1H),6.96(s,1H),6.82(m,3H),4.11(t,J＝5.60Hz,2H),4.04(m,1H),3.95(m,1H),3.83(m,1H),3.77(s,3H),3.51(q,J＝12.80Hz,2H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H),2.60(dd,J＝12.40,5.60Hz,1H),2.48(dd,J＝13.20,6.80Hz,1H),2.30(d,J＝2.40Hz,6H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):157.77,149.67,147.44,131.94,130.79,129.42,124.18,121.46,117.97,113.65,113.61,113.06,70.79,67.42,66.75,62.25,59.98,57.13,55.00,53.99(2C),42.14,33.47(2C),30.24,20.74,20.50.IR(KBr,cm-1):2946,2923,2871,2792,2360,2340,1651,1604,1579,1539,1511,1492,1458,1418,1368,1323,1289,1262,1236,1158,1138,1086,1030,1003,932,866,838,806,757,671.HRMS(ESI):m/zcalcd for C27H40BrN2O4(M+H)+:535.2171.found:535.2149.
实施例19：1-(2-溴-5-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04011)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
无色油状物，产率85％，1H NMR(CD3OD,400MHz)δ(ppm):7.71(d,J＝8.0Hz,1H),7.27(s,1H),7.16(d,J＝8.40Hz,1H),6.95(s,1H),6.82(q,J＝8.0Hz,3H),4.09(m,5H),3.74(s,3H),3.53(s,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.72(dd,J＝12.40,4.80Hz,1H),2.58(dd,J＝12.80,6.40Hz,1H),2.33(s,3H),2.18(t,J＝12.0Hz,2H),1.66(d,J＝12.80Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):155.81,149.65,147.39,133.69,131.95,121.42,118.16,118.12,116.09,113.57,112.96,109.59,109.55,71.58,67.30,66.67,62.39,58.82,57.10,54.91,53.97(2C),42.13,33.45(2C),30.22,20.73.IR(KBr,cm-1):3560,3354,2927,2868,2818,1591,1516,1462,1421,1371,1332,1255,1226,1165,1130,1080,1041,1020,935,904,862,802,752.HRMS(ESI):m/z calcd for C27H37BrF3N2O4(M+H)+:589.1889.found:589.1827.
实施例20：1-(3,5-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04012)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3,5-二氯苯氧基)甲基)环氧乙烷(7-20)。
无色油状物，产率88％，1H NMR(CD3OD,400MHz)δ(ppm):6.96(d,J＝9.60Hz,2H),6.84(m,4H),4.10(t,J＝5.60Hz,2H),4.02(m,2H),3.87(m,1H),3.78(s,3H),3.48(m,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝6.40Hz,2H),2.60(dd,J＝12.80,6.0Hz,1H),2.46(dd,J＝12.80,6.40Hz,1H),2.31(s,3H),2.17(t,J＝12.0Hz,2H),1.65(d,J＝12.75Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):160.34,149.66,147.46,135.12,131.94,121.46,120.38,113.52,113.42(3C),113.04,70.04,67.26,66.70,62.29,58.68,57.13,54.99,54.00(2C),42.25,33.47(2C),30.24,20.75.IR(KBr,cm-1):2948,2925,2872,2843,2793,2360,2340,1590,1571,1513,1442,1424,1368,1323,1303,1262,1192,1157,1138,1039,980,938,853,831,800,756,670.HRMS(ESI):m/z calcd for C26H37Cl2N2O4(M+H)+:511.2130.found:511.2075.
实施例21：1-(3-溴-4-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04020)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-4-氟苯氧基)甲基)环氧乙烷(7-21)。
无色油状物，产率90％，1H NMR(CD3OD,400MHz)δ(ppm):7.10(m,2H),6.95(s,1H),6.84(m,3H),4.10(m,3H),3.96(m,1H),3.84(m,1H),3.77(s,3H),3.50(q,J＝12.0Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.20Hz,2H),2.60(dd,J＝12.80,6.0Hz,1H),2.47(dd,J＝11.20,6.80Hz,1H),2.31(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.41(s,1H),1.28(m,2H),0.93(d,J＝6.0Hz,3H).13C NMR(CD3OD,100MHz)δ(ppm):155.71,149.65,147.44,131.92,121.47,118.73,116.32,116.08,114.95,114.88,113.55,113.07,71.29,67.38,66.71,62.27,58.86,57.12,55.01,54.00(2C),42.21,33.47(2C),30.23,20.76.IR(KBr,cm-1):2947,2925,2872,2843,2793,2360,2340,1591,1513,1493,1458,1418,1368,1322,1262,1220,1203,1157,1138,1088,1035,979,938,862,840,806,774.HRMS(ESI):m/z calcd for C26H37BrFN2O4(M+H)+:539.1921.found:539.1888.
实施例22：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,4,6-三溴苯氧基)甲基)环氧乙烷(7-22)。
无色油状物，产率90％，1H NMR(CD3OD,400MHz)δ(ppm):7.75(s,2H),6.98(s,1H),6.85(m,2H),4.10(t,J＝5.69Hz,2H),4.22(m,1H),4.12(t,J＝5.61Hz,2H),3.79(s,3H),3.54(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.72(dd,J＝13.20,5.20Hz,1H),2.54(dd,J＝12.80,7.20Hz,1H),2.32(s,3H),2.16(t,J＝11.60Hz,2H),1.65(d,J＝12.40Hz,2H),1.39(s,1H),1.30(m,2H),0.93(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):152.75,149.67,147.45,134.96(3C),131.75,121.55,118.54,117.13,113.66,113.14,75.83,67.96,66.75,62.14,59.34,57.11,55.06,53.99(2C),42.08,33.48(2C),30.24,20.77.IR(KBr,cm-1):2923,2846,2360,2340,1700,1651,1613,1590,1559,1539,1511,1470,1460,1418,1373,1337,1288,1262,1229,1157,1138,1083,1035,931,859,805.HRMS(ESI):m/z calcd for C26H36Br3N2O4(M+H)+:677.0225.found:677.0256.
实施例23：1-(3-溴-5-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04023)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-5-氟苯氧基)甲基)环氧乙烷(7-23)。
无色油状物，产率85％，1H NMR(CD3OD,400MHz)δ(ppm):6.95(s,1H),6.85(m,4H),6.65(d,J＝10.80Hz,1H),4.11(t,J＝5.60Hz,2H),4.02(m,2H),3.87(m,1H),3.78(s,3H),3.50(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.60(dd,J＝12.40,5.60Hz,1H),2.46(dd,J＝12.80,6.40Hz,1H),2.31(s,3H),2.17(t,J＝12.0Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.29(m,2H),0.93(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):164.64,162.18,161.02,149.65,147.45,131.93,122.34,121.46,113.83,113.29,110.85,101.17,71.09,67.25,66.68,62.28,58.72,57.12,55.00,53.99(2C),42.23,33.46(2C),30.23,20.76.IR(KBr,cm-1):2947,2925,2872,2841,2792,2360,2340,1605,1583,1512,1454,1418,1367,1318,1280,1263,1231,1280,1263,1231,1146,1084,1039,980,941,833.HRMS(ESI):m/z calcd for C26H37BrFN2O4(M+H)+:539.1921.found:539.1879.
实施例24：1-(3-氯苯氧基)-3-((3-甲氧基-4-(2-(4(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04024)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-氯苯氧基)甲基)环氧乙烷(7-24)。
无色油状物，产率83％，1H NMR(CD3OD,400MHz)δ(ppm):7.21(t,J＝8.40Hz,1H),6.88(m,6H),4.09(m,3H),3.98(m,1H),3.86(m,1H),3.77(s,3H),3.51(q,J＝12.80Hz,1H),3.03(d,J＝11.20Hz,1H),2.80(t,J＝5.60Hz,2H),2.61(dd,J＝12.80,6.80Hz,2H),2.49(dd,J＝12.80,6.80Hz,2H),2.30(s,3H),2.16(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.39(s,1H),1.28(m,2H),0.93(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):159.91,149.66,147.45,134.44,131.93,130.12,121.47,120.46,114.57,113.58,113.06,112.81,70.71,67.38,66.72,62.26,58.98,57.13,55.00,53.99(2C),42.16,33.48(2C),30.24,20.76.IR(KBr,cm-1):2947,2925,2872,2843,2792,2360,2340,1651,1595,1580,1539,1511,1470,1459,1419,1367,1326,1283,1260,1231,1192,1157,1138,1091,1036,979,935,870,807,770,681.HRMS(ESI):m/z calcd for C26H38ClN2O4(M+H)+:477.2520.found:477.2476.
实施例25：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-(三氟甲基)苯氧基)丙-2-醇(CHJ04025)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-25)。
无色油状物，产率83％，1H NMR(CD3OD,400MHz)δ(ppm):7.44(t,J＝8.0Hz,1H),7.17(m,3H),6.97(s,1H),6.85(m,2H),4.09(m,4H),3.93(m,1H),3.76(s,3H),3.53(m,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.63(dd,J＝12.40,5.20Hz,1H),2.51(dd,J＝12.80,6.80Hz,1H),2.31(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.28(m,2H),0.93(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):159.32,149.66,147.45,131.92,131.39,131.55,130.01,121.46,117.96,116.91,113.57,113.06,110.96,70.71,67.38,66.72,62.26,58.98,57.13,55.00,53.99(2C),42.16,33.48(2C),30.24,20.76.IR(KBr,cm-1):2947,2926,2873,2845,2794,2360,2340,1651,1593,1557,1539,1513,1493,1453,1419,1367,1330,1289,1262,1234,1165,1096,1065,1037,979,934,880,794,753,698.HRMS(ESI):m/z calcd for C27H38F3N2O4(M+H)+:511.2784.found:511.2765.
实施例26：1-(3,4-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04026)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3,4-二氯苯氧基)甲基)环氧乙烷(7-26)。
无色油状物，产率81％，1H NMR(CD3OD,400MHz)δ(ppm):7.36(d,J＝9.20Hz,1H),7.05(s,1H),6.95(s,1H),6.84(m,3H),4.10(t,J＝5.60Hz,2H),4.04(m,1H),3.97(m,1H),3.86(m,1H),3.77(s,3H),3.50(q,J＝12.80Hz,1H),3.03(d,J＝11.60Hz,2H),2.80(t,J＝5.60Hz,2H),2.61(dd,J＝12.80,6.0Hz,1H),2.47(dd,J＝12.80,6.80Hz,1H),2.31(s,3H),2.16(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.40Hz,3H).13C NMR(CD3OD,100MHz)δ(ppm):158.36,149.64,147.45,132.25,131.93,130.48,123.33,121.47,116.16,114.57,113.52,113.07,70.99,67.33,66.70,62.29,58.76,57.13,54.98,54.00(2C),42.26,33.48(2C),30.24,20.76.IR(KBr,cm-1):2947,2926,2872,2841,2792,2360,2340,1651,1592,1570,1539,1511,1475,1455,1419,1367,1286,1262,1230,1191,1156,1127,1092,1036,979,937,861,807,757,670.HRMS(ESI):m/zcalcd for C26H37Cl2N2O4(M+H)+:511.2130.found:511.2115.
实施例27：1-(2-碘苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04027)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-碘苯氧基)甲基)环氧乙烷(7-27)。
无色油状物，产率90％，1H NMR(CD3OD,400MHz)δ(ppm):7.72(d,J＝7.60Hz,1H),7.30(t,J＝8.0Hz,1H),6.96(s,1H),6.90(d,J＝8.40Hz,1H),6.83(q,J＝8.0Hz,2H),6.70(t,J＝7.60Hz,1H),4.09(m,3H),3.98(m,2H),3.74(s,3H),3.55(q,J＝12.80Hz,2H),3.03(d,J＝11.20Hz,2H),2.80(t,J＝5.60Hz,2H),2.74(d,J＝5.20Hz,1H),2.64(dd,J＝12.80,7.60Hz,1H),2.32(s,3H),2.17(t,J＝11.60Hz,2H),1.65(d,J＝12.80Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):157.53,149.66,147.40,139.11,131.94,129.30,122.32,121.47,113.60,113.07,112.12,85.66,71.22,67.40,62.42,59.28,57.11,55.00,53.97(3C),42.07,33.47(2C),30.23,20.75.IR(KBr,cm-1):2946,2923,2871,2844,2792,2360,2340,1584,1513,1471,1441,1418,1368,1323,1261,1231,1192,1158,1138,1084,1050,1030,1019,979,962,938,873,822,806,749.HRMS(ESI):m/z calcd for C26H38IN2O4(M+H)+:569.1876.found:569.1842.
实施例28：1-(4-溴-2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04033)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-溴-2,6-二氯苯氧基)甲基)环氧乙烷(7-28)。
无色油状物，产率84％，1H NMR(CD3OD,400MHz)δ(ppm):7.56(s,2H),6.97(s,1H),6.85(m,2H),4.16(m,1H),4.12(t,J＝5.60Hz,2H),3.99(m,2H),3.79(s,3H),3.52(m,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.67(dd,J＝13.20,4.80Hz,1H),2.55(dd,J＝13.20,7.60Hz,1H),2.30(s,3H),2.17(t,J＝12.0Hz,2H),1.65(d,J＝12.40Hz,2H),1.40(s,1H),1.29(m,2H),0.94(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):150.93,149.67,147.43,131.79,131.46(3C),129.99,121.50,116.13,113.67,113.08,76.07,67.97,66.71,62.14,59.26,57.09,55.02,53.97(2C),42.01,33.44(2C),30.21,20.76.IR(KBr,cm-1):2947,2924,2872,2840,2794,2360,2340,1544,1511,1459,1419,1375,1320,1259,1231,1193,1158,1138,1084,1031,994,933,856,803.HRMS(ESI):m/zcalcd for C26H36BrCl2N2O4(M+H)+:589.1236.found:589.1220.
实施例29：1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04034)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((3-溴-5-氯苯氧基)甲基)环氧乙烷(7-29)。
无色油状物，产率85％，1H NMR(CD3OD,400MHz)δ(ppm):7.12(s,1H),7.02(s,1H),6.95(s,1H),6.91(s,1H),6.83(m,2H),4.10(t,J＝5.60Hz,2H),4.02(m,2H),3.87(m,1H),3.78(s,3H),3.48(m,2H),3.04(d,J＝11.60Hz,2H),2.81(t,J＝5.60Hz,2H),2.60(dd,J＝12.40,6.0Hz,1H),2.46(dd,J＝12.40,6.0Hz,1H),2.31(s,3H),2.18(t,J＝12.0Hz,2H),1.66(d,J＝12.80Hz,2H),1.40(s,1H),1.27(m,2H),0.94(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):160.39,149.66,147.44,135.27,131.85,123.18,122.49,121.46,116.33,113.87,113.54,113.04,71.04,67.26,66.67,62.29,58.67,57.11,55.01,53.99(2C),42.26,33.45(2C),30.22,20.74.IR(KBr,cm-1):2947,2926,2870,2840,2793,2360,2331,1588,1563,1539,1512,1459,1437,1420,1367,1335,1319,1301,1230,1259,1190,1156,1138,1091,1038,978,930,912,864,831,770,670.HRMS(ESI):m/z calcd forC26H37BrClN2O4(M+H)+:555.1625.found:555.1600.
实施例30：1-(2-溴-5-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04036)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-溴-5-氟苯氧基)甲基)环氧乙烷(7-30)。
无色油状物，产率82％，1H NMR(CD3OD,400MHz)δ(ppm):7.48(m,1H),6.95(s,1H),6.82(m,3H),6.63(t,J＝8.40Hz,1H),4.11(t,J＝5.6Hz,3H),4.01(m,2H),3.76(s,3H),3.53(s,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.60Hz,2H),2.71(dd,J＝12.80,5.20Hz,1H),2.58(dd,J＝12.80,7.20Hz,1H),2.32(s,3H),2.18(t,J＝11.60Hz,2H),1.66(d,J＝12.80Hz,2H),1.41(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):164.01,161.58,156.35,149.65,147.40,133.34,131.93,121.47,113.59,107.89,106.05,101.44,71.52,67.28,66.65,62.36,58.95,57.09,54.96,53.96(2C),42.01,33.43(2C),30.21,20.73.IR(KBr,cm-1):3529,3277,3088,2929,2852,2796,2769,2428,1681,1604,1514,1477,1452,1417,1371,1286,1259,1224,1151,1101,1037,960,871,833,790,748,609,451.HRMS(ESI):m/z calcd for C26H37BrFN2O4(M+H)+:539.1921.found:539.1914.
实施例31：N-(3-(2-羟基-3-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04058)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为N-(3-(环氧乙烷-2-基甲氧基)苯基)乙酰胺(7-31)。
白色固体，产率90％，mp:60-62℃，1H NMR(CD3OD,400MHz)δ(ppm):7.27(s,1H),7.17(t,J＝8.0Hz,1H),7.05(m,2H),6.86(m,2H),6.63(d,J＝8.0Hz,1H),4.11(m,3H),3.97(m,1H),3.87(m,1H),3.78(s,3H),3.55(s,2H),3.13(d,J＝11.20Hz,2H),2.91(t,J＝5.20Hz,1H),2.65(dd,J＝12.40,6.80Hz,1H),2.53(dd,J＝12.40,6.80Hz,1H),2.32(m,5H),2.11(s,3H),1.70(d,J＝13.20Hz,2H),1.46(s,1H),1.32(m,3H),0.94(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):170.23,159.35,149.61,147.25,139.66,131.87,129.11,121.58,113.73,113.06,112.11,109.83,106.29,70.42,67.37,66.13,62.12,59.09,56.86,55.00,53.79(2C),42.01,33.02(2C),29.92,22.53,20.59.IR(KBr,cm-1):2924,2852,2360,2340,1699,1670,1651,1616,1556,1540,1510,1491,1458,1419,1373,1286,1265,1230,1198,1156,1083,1034,980,871,768,686,669.HRMS(ESI):m/z calcdfor C28H42N3O5(M+H)+:500.3124.found:500.3071.
实施例32：1-(2,4-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04059)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2,4-二氯苯氧基)甲基)环氧乙烷(7-32)。
无色油状物，产率81％，1H NMR(CD3OD,400MHz)δ(ppm):7.37(s,1H),7.23(d,J＝8.40Hz,1H),7.00(d,J＝8.80Hz,1H),6.94(s,1H),6.82(q,J＝8.0Hz,2H),4.11(t,J＝5.60Hz,3H),4.00(m,2H),3.75(s,3H),3.52(s,2H),3.06(d,J＝11.60Hz,2H),2.82(t,J＝5.60Hz,2H),2.69(dd,J＝12.80,5.60Hz,1H),2.54(dd,J＝12.80,6.80Hz,1H),2.32(s,3H),2.19(t,J＝12.0Hz,2H),1.67(d,J＝12.80Hz,2H),1.41(s,1H),1.29(m,2H),0.94(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):153.47,149.61,147.37,131.88,129.29,127.46,125.32,123.37,121.45,114.33,113.50,112.98,71.53,67.36,66.58,62.33,58.86,57.07,54.92,53.96(2C),42.19,33.41(2C),30.20,20.73.IR(KBr,cm-1):2947,2924,2872,2845,2360,2339,1590,1513,1484,1458,1419,1389,1368,1323,1290,1263,1232,1156,1060,1028,1007,938,867,846,804,745,653.HRMS(ESI):m/z calcd forC26H37Cl2N2O4(M+H)+:511.2130.found:511.2120.
实施例33：1-(5-溴-2-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04060)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((5-溴-2-甲基苯氧基)甲基)环氧乙烷(7-33)。
无色油状物，产率82％，1H NMR(CD3OD,400MHz)δ(ppm):6.97(m,4H),6.82(q,J＝8.0Hz,2H),4.10(t,J＝5.20Hz,3H),3.97(dd,J＝9.60,2.80Hz,1H),3.89(dd,J＝9.20,5.2Hz,1H),3.74(s,3H),3.51(q,J＝12.8Hz,2H),3.04(d,J＝11.20Hz,2H),2.81(t,J＝5.20Hz,2H),2.66(dd,J＝12.80,6.0Hz,1H),2.49(dd,J＝12.80,6.0Hz,1H),2.33(s,3H),2.18(t,J＝11.60Hz,2H),2.05(s,3H),1.66(d,J＝12.80Hz,2H),1.41(s,1H),1.27(m,2H),0.94(d,J＝6.0Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):157.70,149.65,147.37,131.99,131.30,125.78,122.88,121.36,119.06,113.96,113.48,112.83,70.39,67.47,66.64,62.41,58.80,57.10,54.91,53.98(2C),42.28,33.45(2C),30.23,20.72,14.59.IR(KBr,cm-1):2947,2923,2871,2844,2360,2340,1592,1555,1513,1491,1458,1417,1398,1373,1260,1239,1191,1129,1084,1034,984,939,870,836,800,756.HRMS(ESI):m/z calcd forC27H40BrN2O4(M+H)+:535.2171.found:535.2170.
实施例34：N-(4-(2-羟基-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04061)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为N-(4-(环氧乙烷-2-基甲氧基)苯基)乙酰胺(7-34)。
白色固体，产率90％，mp:60-62℃,1H NMR(CD3OD,400MHz)δ(ppm):7.41(d,J＝8.0Hz,2H),6.98(s,1H),6.86(m,4H),4.14(m,3H),3.96(m,1H),3.85(m,1H),3.78(s,3H),3.54(d,J＝5.60Hz,2H),3.14(d,J＝11.20Hz,2H),2.92(t,J＝5.20Hz,1H),2.64(dd,J＝12.80,7.20Hz,1H),2.52(dd,J＝12.80,7.20Hz,1H),2.32(m,5H),2.09(s,3H),1.70(d,J＝13.20Hz,2H),1.46(s,1H),1.32(m,3H),0.95(d,J＝6.40Hz,3H).13CNMR(CD3OD,100MHz)δ(ppm):170.23,159.35,149.61,147.25,139.66,131.87,129.11,121.58,113.73,113.06,112.11,109.83,106.29,70.42,67.37,66.13,62.12,59.09,56.86,55.00,53.79(2C),42.01,33.02(2C),29.92,22.53,20.59.IR(KBr,cm-1):2922,2848,2362,2340,2044,1681,1602,1548,1512,1460,1417,1369,1325,1259,1240,1136,1031,931,819,750,686,669.HRMS(ESI):m/z calcd for C28H42N3O5(M+H)+:500.3124.found:500.3074.
实施例35：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-(三氟甲基)苯氧基)丙-2-醇(CHJ04082)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-(三氟甲基)苯氧基)甲基)环氧乙烷(7-35)。
无色油状物，产率83％，1H NMR(CDCl3,400MHz)δ(ppm):7.55(d,J＝7.60Hz,1H),7.47(t,J＝8.0Hz,1H),7.00(t,J＝8.40Hz,2H),6.81(m,3H),4.10(m,5H),3.84(s,3H),3.62(d,J＝12.80Hz,1H),3.47(d,J＝12.80Hz,1H),3.00(d,J＝10.80Hz,2H),2.86(t,J＝6.0Hz,2H),2.68(m,1H),2.59(m,1H),2.30(s,3H),2.15(t,J＝10.80Hz,2H),1.64(d,J＝12.0Hz,2H),1.31(m,3H),0.93(d,J＝5.60Hz,3H).13C NMR(CDCl3,100MHz)δ(ppm):156.61,149.49,147.54,133.28,131.37,127.08,121.34(2C),120.33(2C),113.18,112.96,112.61,70.86,66.82,66.17,62.45,59.40,57.34,55.95,54.43(2C),42.43,34.08(2C),30.50,21.81.IR(KBr,cm-1):2939,2873,2841,2794,2362,1602,1510,1460,1363,1323,1269,1132,1033,974,948,879,808,758,650.HRMS(ESI):m/z calcd for C27H38F3N2O4(M+H)+:511.2784.found:511.2741.
实施例36：1-(4-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04083)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-氯苯氧基)甲基)环氧乙烷(7-36)。
无色油状物，产率90％，1H NMR(CDCl3,400MHz)δ(ppm):7.22(d,J＝15.2Hz,2H),6.81(m,5H),4.16(t,J＝6.0Hz,2H),4.09(m,1H),3.92(d,J＝4.40Hz,2H),3.84(s,3H),3.62(d,J＝13.20Hz,1H),3.45(d,J＝13.20Hz,1H),2.99(d,J＝10.8Hz,2H),2.85(t,J＝6.0Hz,2H),2.63(t,J＝11.60Hz,1H),2.50(m,1H),2.29(s,3H),2.14(t,J＝10.80Hz,2H),1.64(d,J＝12.40Hz,2H),1.32(m,3H),0.93(d,J＝5.60Hz,3H).13CNMR(CDCl3,100MHz)δ(ppm):157.41,149.51,147.62,131.25,129.30(2C),125.84,121.32,115.88(2C),113.16,112.59,70.74,66.91,66.11,62.37,59.29,57.36,55.99,54.47(2C),42.28,34.12(2C),30.52,21.83.IR(KBr,cm-1):2947,2925,2872,2843,2792,2360,2325,1651,1595,1539,1511,1492,1458,1418,1367,1322,1283,1246,1157,1138,1092,1035,1008,824,672.HRMS(ESI):m/z calcd for C26H38ClN2O4(M+H)+:477.2520.found:477.2471.
实施例37：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(4-甲氧基苯氧基)丙-2-醇(CHJ04084)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((4-甲氧基苯氧基)甲基)环氧乙烷(7-37)。
无色油状物，产率90％，1HNMR(CDCl3,400MHz)δ(ppm):6.82(m,7H),4.17(t,J＝6.0Hz,2H),4.09(m,1H),3.91(d,J＝4.40Hz,2H),3.84(s,3H),3.76(s,3H),3.62(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),3.01(d,J＝12.40Hz,2H),2.86(t,J＝6.0Hz,2H),2.63(t,J＝11.20Hz,1H),2.51(m,1H),2.28(s,3H),2.16(t,J＝11.20Hz,2H),1.65(d,J＝12.0Hz,2H),1.31(m,3H),0.93(d,J＝5.48Hz,3H).13C NMR(CDCl3,100MHz)δ(ppm):154.01,152.97,149.49,147.52,131.40,121.31,115.55(2C),114.64(2C),113.17,112.57,71.16,66.78,66.29,62.37,59.53,57.34,55.98,55.73,54.43(2C),42.25,34.04(2C),30.48,21.80.IR(KBr,cm-1):2947,2925,2871,2834,2792,2360,2325,1595,1510,1459,1418,1368,1322,1262,1231,1156,1138,1036,980,937,878,824,748.HRMS(ESI):m/z calcdfor C27H41N2O5(M+H)+:473.3015.found:473.2975.
实施例38：1-(2-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04085)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-氯苯氧基)甲基)环氧乙烷(7-38)。
无色油状物，产率83％，1H NMR(CDCl3,400MHz)δ(ppm):7.34(d,J＝8.0Hz,1H),7.19(t,J＝7.60Hz,1H),6.86(m,5H),4.15(t,J＝6.0Hz,3H),4.03(d,J＝4.40Hz,2H),3.84(s,3H),3.63(d,J＝13.2Hz,1H),3.47(d,J＝13.2Hz,1H),3.00(d,J＝13.14Hz,2H),2.85(t,J＝6.40Hz,2H),2.70(m,1H),2.58(m,1H),2.30(s,3H),2.13(t,J＝11.22Hz,2H),1.64(d,J＝12.06Hz,2H),1.30(m,3H),0.93(d,J＝5.80Hz,3H).13CNMR(CDCl3,100MHz)δ(ppm):154.31,149.41,147.52,131.30,130.25,127.69,123.15,121.72,121.34,113.80,112.97,112.53,71.46,66.64,66.24,62.42,59.34,57.36,55.95,54.41(2C),42.40,34.08(2C),30.58,21.83.IR(KBr,cm-1):2925,2872,2845,2792,2360,2325,1591,1512,1486,1455,1418,1368,1322,1276,1258,1232,1158,1137,1084,1061,980,937,877,807,749,693.HRMS(ESI):m/z calcd for C26H38ClN2O4(M+H)+:477.2520.found:477.2506.
实施例39：1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基苯氧基)丙-2-醇(CHJ04086)的合成
所用化合物5为1-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苯基)-N-甲基甲胺(5-1)。
所用化合物7为2-((2-甲氧基苯氧基)甲基)环氧乙烷(7-39)。
无色油状物，产率85％，1H NMR(CDCl3,400MHz)δ(ppm):6.86(m,7H),4.16(t,J＝6.0Hz,3H),4.02(m,2H),3.84(s,6H),3.60(d,J＝13.20Hz,1H),3.47(d,J＝13.20Hz,1H),3.03(d,J＝11.20Hz,2H),2.87(t,J＝6.0Hz,2H),2.63(m,1H),2.54(m,1H),2.28(s,3H),2.16(t,J＝10.8Hz,2H),1.65(d,J＝12.0Hz,2H),1.33(m,3H),0.94(d,J＝5.60Hz,3H).13CNMR(CDCl3,100MHz)δ(ppm):149.80,149.37,148.39,147.38,131.50,121.78,121.30,120.93,114.58,112.97,112.50,112.04,72.39,66.46,66.41,62.38,59.50,57.31,55.88(2C),54.33(2C),42.35,33.89(2C),30.45,21.77.IR(KBr,cm-1):2925,2872,2838,2792,2360,2340,1593,1556,1510,1458,1418,1368,1328,1250,1226,1258,1157,1125,1090,1030,980,939,876,807,744.HRMS(ESI):m/z calcd for C27H41N2O5(M+H)+:473.3015.found:473.2972.
实施例40：1-(3-溴-4-甲基苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04064)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3-溴-4-甲基苯氧基)甲基)环氧乙烷(7-18)。
无色油状物，产率80％，1H NMR(CD3OD,400MHz)δ(ppm):7.15(d,J＝8.40Hz,1H),7.09(s,1H),6.98(s,1H),6.83(m,3H),4.13(t,J＝5.20Hz,2H),4.05(m,1H),3.96(m,1H),3.82(m,4H),3.54(m,2H),3.04(t,J＝5.20Hz,2H),2.83(s,4H),2.61(dd,J＝12.40,5.6Hz,1H),2.49(dd,J＝12.80,6.80Hz,1H),2.30(d,J＝6.80Hz,6H),1.87(s,4H).13CNMR(CD3OD,100MHz)δ(ppm):157.76,149.69,147.25,132.08,130.80,129.43,124.18,121.47,117.94,113.75,113.64,112.98,70.76,67.36,67.27,62.21,58.95,54.94,54.50,54.23(2C),42.08,22.77(2C),20.50.IR(KBr,cm-1):2924,2873,2850,2793,2360,2339,1604,1513,1492,1459,1418,1369,1325,1263,1235,1139,1031,976,928,863,805,750,669.HRMS(ESI):m/z calcd for C25H36BrN2O4(M+H)+:507.1858.found:507.1858.
实施例41：1-(2-溴-5)-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04065)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
无色油状物，产率82％，1H NMR(CD3OD,400MHz)δ(ppm):7.71(d,J＝8.0Hz,1H),7.27(s,1H),7.16(d,J＝8.0Hz,1H),6.97(s,1H),6.84(m,2H),4.10(m,5H),3.75(s,3H),3.55(s,2H),3.07(t,J＝5.20Hz,2H),2.87(s,4H),2.73(dd,J＝12.80,4.80Hz,1H),2.60(dd,J＝12.40,6.40Hz,1H),2.34(s,3H),1.89(s,4H).13CNMR(CD3OD,100MHz)δ(ppm):155.80,149.68,147.16,133.70,132.16,130.42,121.44,118.14,116.09,113.78,112.88,109.57,71.55,67.09,62.34,58.80,54.86,54.45,54.22(2C),42.08,23.39,22.76(2C),12.54.IR(KBr,cm-1):2968,2938,2879,2793,2361,2323,1734,1700,1518,1492,1459,1419,1398,1328,1268,1252,1167,1137,1080,1035,977,935,906,861,748,670.HRMS(ESI):m/z calcd for C25H33BrF3N2O4(M+H)+:561.1576.found:561.1569.
实施例42：1-(3，5-二氯苯氧基)-3-((3-甲氧基-4-(2(吡咯烷基-1-乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04066)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3,5-二氯苯氧基)甲基)环氧乙烷(7-20)。
无色油状物，产率84％，1H NMR(CD3OD,400MHz)δ(ppm):6.98(d,J＝3.60Hz,2H),6.87(m,3H),6.82(d,J＝8.40Hz,1H),4.13(t,J＝4.80Hz,2H),4.03(m,2H),3.88(m,1H),3.79(s,3H),3.52(q,J＝12.80Hz,2H),3.06(t,J＝5.20Hz,2H),2.85(s,4H),2.62(dd,J＝12.40,6.0Hz,1H),2.47(dd,J＝12.40,6.40Hz,1H),2.32(s,3H),1.88(s,4H).13CNMR(CD3OD,100MHz)δ(ppm):160.34,149.67,147.23,135.12,132.16,121.46,120.37,113.68,113.40(3C),112.94,71.00,67.21,67.17,62.25,58.63,54.92,54.48,54.24(2C),42.20,22.76(2C).IR(KBr,cm-1):2933,2877,2843,2787,2361,2340,1591,1514,1454,1421,1330,1290,1261,1230,1165,1130,1089,1028,964,908,875,808,752,692,661,617.HRMS(ESI):m/z calcd for C24H33Cl2N2O4(M+H)+:483.1817.found:483.1801.
实施例43：1-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)-3-(2，4，6-三溴苯氧基)丙-2-醇(CHJ04068)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((2,4,6-三溴苯氧基)甲基)环氧乙烷(7-22)。
白色固体，产率84％，mp:60-70℃，1H NMR(CD3OD,400MHz)δ(ppm):7.76(s,2H),6.99(s,1H),6.86(m,2H),4.23(m,1H),4.11(t,J＝5.20Hz,2H),3.97(s,2H),3.79(s,3H),3.54(q,J＝12.80Hz,2H),2.94(t,J＝5.60Hz,2H),2.72(s,5H),2.55(dd,J＝12.80,7.60Hz,1H),2.32(s,3H),1.83(s,4H).13CNMR(CD3OD,100MHz)δ(ppm):152.74,149.66,147.42,134.96(2C),134.96,131.75,121.53,118.54,117.14,113.56,113.07,75.82,67.94,67.68,62.12,59.35,55.01,54.58,54.23(2C),42.05,22.83(2C).IR(KBr,cm-1):3103,2924,2873,2808,1695,1597,1514,1435,1371,1334,1253,1138,1031,989,852,798,734,684,570.HRMS(ESI):m/z calcd for C24H32Br3N2O4(M+H)+:648.9912.found:648.9938.
实施例44：1-(3，4-二氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04072)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3,4-二氯苯氧基)甲基)环氧乙烷(7-26)。
无色油状物，产率85％，1H NMR(CD3OD,400MHz)δ(ppm):7.37(d,J＝8.80Hz,1H),7.06(s,1H),6.96(s,1H),6.85(m,3H),4.11(t,J＝5.20Hz,2H),4.04(m,1H),3.98(m,1H),3.86(m,1H),3.77(s,3H),3.51(q,J＝12.80Hz,2H),2.97(t,J＝5.20Hz,2H),2.76(s,4H),2.61(dd,J＝12.80,6.0Hz,1H),2.47(dd,J＝12.80,6.80Hz,1H),2.32(s,3H),1.85(s,4H).13CNMR(CD3OD,100MHz)δ(ppm):158.36,149.64,147.37,132.25,131.99,130.48,123.32,121.45,116.13,114.57,113.50,112.99,70.96,67.30,62.27,58.73,54.92,54.56,54.24(2C),53.40,42.22,22.81(2C).IR(KBr,cm-1):2926,2875,2851,2802,2361,2340,1736,1651,1593,1563,1512,1475,1462,1418,1368,1328,1284,1262,1230,1127,1035,976,932,902,860,805,752,671.HRMS(ESI):m/z calcd for C24H33Cl2N2O4(M+H)+:483.1817.found:483.1790.
实施例45：1-(4-溴-2，6-二氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04074)的合成
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所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((4-溴-2,6-二氯苯氧基)甲基)环氧乙烷(7-28)。
无色油状物，产率85％，1H NMR(CD3OD,400MHz)δ(ppm):7.59(s,2H),7.00(s,1H),6.91(d,J＝8.04Hz,1H),6.85(d,J＝8.09Hz,1H),4.16(m,3H),4.00(m,2H),3.81(s,3H),3.56(d,J＝6.47Hz,2H),3.09(t,J＝5.24Hz,2H),2.89(s,4H),2.69(dd,J＝5.54,4.71Hz,1H),2.57(dd,J＝12.76,7.5Hz,1H),2.32(s,3H),1.90(s,4H).13CNMR(CD3OD,100MHz)δ(ppm):150.90,149.71,147.19,131.98,131.46(3C),129.99,121.53,116.16,113.92,113.01,76.00,67.88,67.09,62.06,59.18,54.95,54.44,54.23(2C),41.93,22.75(2C).IR(KBr,cm-1):2953,2920,2866,2765,1726,1651,1593,1516,1458,1419,1373,1327,1261,1230,1136,1085,1028,964,875,842,800,752,557.HRMS(ESI):m/z calcd forC24H32BrCl2N2O4(M+H)+:561.0923.found:561.0882.
实施例46：1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04075)的合成
所用化合物5为1-(3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苯基)-N-甲基甲胺(5-2)。
所用化合物7为2-((3-溴-5-氯苯氧基)甲基)环氧乙烷(7-29)。
无色油状物，产率87％，1H NMR(CD3OD,400MHz)δ(ppm):7.13(s,1H),7.03(s,1H),6.98(s,1H),6.90(m,2H),6.82(d,J＝8.08Hz,1H),4.15(t,J＝5.54Hz,2H),4.03(m,2H),3.88(m,1H),3.80(s,3H),3.52(q,J＝12.86Hz,2H),3.12(t,J＝5.24Hz,2H),2.92(s,4H),2.62(dd,J＝12.72,6.12Hz,1H),2.48(dd,J＝12.71,6.44Hz,1H),2.33(s,3H),1.91(s,4H).13CNMR(CD3OD,100MHz)δ(ppm):160.38,149.69,147.13,135.27,132.25,123.18,122.49,121.48,116.32,113.84(2C),112.93,70.99,67.18,62.23,58.61,54.94,54.42,54.25(2C),42.19,22.74(2C),12.54.IR(KBr,cm-1):2974,2934,2379,2309,1716,1651,1593,1557,1539,1510,1475,1419,1393,1339,1231,1124,1038,854,670,520.HRMS(ESI):m/z calcd for C24H33BrClN2O4(M+H)+:527.1312.found:527.1275.
实施例47：1-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基)(甲基)氨基)-3-(2-异丙基苯氧基)丙-2-醇(CHJ04089)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((2-异丙基苯氧基)甲基)环氧乙烷(7-7)。
无色油状物，产率82％，1H NMR(CDCl3,400MHz)δ(ppm):7.20(d,J＝7.60Hz,1H),7.13(t,J＝8.0Hz,1H),6.93(t,J＝7.20Hz,1H),6.82(m,4H),4.11(m,3H),3.98(m,2H),3.84(s,3H),3.65(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),3.26(m,1H),2.94(t,J＝6.80Hz,2H),2.66(m,5H),2.54(m,1H),2.31(s,3H),1.20(d,J＝7.20Hz,6H),1.08(t,J＝7.20Hz,6H).13CNMR(CDCl3,100MHz)δ(ppm):155.82,149.38,147.59,137.05,131.20,126.55,126.07,121.26,120.89,112.69,112.41,111.30,70.35,67.24,66.34,62.47,59.66,55.94,51.66,47.85(2C),42.36,26.89,22.63(2C),11.78(2C).IR(KBr,cm-1):3035,2965,2933,2871,2360,1598,1513,1491,1451,1417,1368,1286,1261,1239,1197,1139,1088,1034,983,938,881,823,751.HRMS(ESI):m/z calcd for C27H43N2O4(M+H)+:459.3223.found:459.3166.
实施例48：1-(2-溴-5-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04090)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
无色油状物，产率81％，1H NMR(CDCl3,400MHz)δ(ppm):7.63(d,J＝8.40Hz,1H),7.10(m,2H),6.81(m,3H),4.11(m,5H),3.84(s,3H),3.65(d,J＝12.80Hz,1H),3.47(d,J＝13.20Hz,1H),2.94(t,J＝6.80Hz,2H),2.67(m,5H),2.55(m,1H),2.32(s,3H),1.08(t,J＝7.20Hz,6H).13CNMR(CDCl3,100MHz)δ(ppm):155.44,149.39,147.63,133.70(2C),131.09,121.31(2C),118.73,116.43,112.73,112.45,109.89,71.63,67.28,66.10,62.48,58.95,55.94,51.65,47.85(2C),42.42,11.77(2C).IR(KBr,cm-1):2969,2936,2876,2837,2360,2340,1651,1597,1539,1512,1488,1461,1420,1329,1296,1263,1231,1169,1128,1081,1036,979,934,857,814,751,656,565.HRMS(ESI):m/z calcd for C25H35BrF3N2O4(M+H)+:563.1732.found:563.1676.
实施例49：1-(3,4-二氯苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04091)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((3,4-二氯苯氧基)甲基)环氧乙烷(7-26)。
无色油状物，产率85％，1H NMR(CDCl3,400MHz)δ(ppm):7.31(d,J＝8.8Hz,1H),7.00(s,1H),6.80(m,4H),4.09(m,3H),3.91(m,2H),3.85(s,3H),3.62(d,J＝12.80Hz,1H),3.45(d,J＝12.80Hz,1H),2.95(t,J＝6.40Hz,2H),2.67(m,5H),2.47(m,1H),2.29(s,3H),1.08(t,J＝7.20Hz,6H).13CNMR(CDCl3,100MHz)δ(ppm):157.83,149.37,147.63,132.81,131.03,130.65,124.20,121.31,116.45,114.63,112.73,112.46,70.97,67.20,65.97,62.37,59.08,55.96,51.65,47.80(2C),42.28,11.70(2C).IR(KBr,cm-1):2970,2936,2874,2832,2360,2326,1700,1651,1593,1559,1539,1511,1475,1459,1418,1337,1285,1263,1230,1158,1126,1090,1126,1035,930,865,806,671.HRMS(ESI):m/z calcd forC24H35Cl2N2O4(M+H)+:485.1974.found:485.1904.
实施例50：1-(3-溴-4-氟苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基(甲基)氨基)丙-2-醇(CHJ04092)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((3-溴-4-氟苯氧基)甲基)环氧乙烷(7-21)。
无色油状物，产率82％，1H NMR(CDCl3,400MHz)δ(ppm):7.09(m,1H),7.02(t,J＝8.80Hz,1H),6.81(m,4H),4.09(m,3H),3.90(m,2H),3.85(s,3H),3.62(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),2.95(t,J＝6.40Hz,2H),2.67(m,5H),2.47(m,1H),2.29(s,3H),1.09(t,J＝7.20Hz,6H).13CNMR(CDCl3,100MHz)δ(ppm):155.25,149.38,147.62,131.06,121.3(2C),119.02(2C),116.52,114.98,112.58,109.01,71.29,67.19,66.04,62.37,59.14,55.96,51.64,47.80(2C),42.27,11.69(2C).IR(KBr,cm-1):2969,2936,2875,2832,2360,2340,1651,1592,1556,1539,1511,1493,1459,1418,1373,1333,1262,1220,1203,1158,1139,1092,1036,929,864,805,752.HRMS(ESI):m/z calcd for C24H35BrFN2O4(M+H)+:513.1764.found:513.1710.
实施例51：1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04093)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((4-溴-3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-3)。
无色油状物，产率83％，1H NMR(CDCl3,400MHz)δ(ppm):7.57(d,J＝8.80Hz,1H),7.24(s,1H),6.92(d,J＝8.80Hz,1H),6.82(m,3H),4.11(t,J＝6.40Hz,3H),3.96(m,2H),3.84(s,3H),3.63(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),2.97(t,J＝6.4Hz,2H),2.67(m,5H),2.48(m,1H),2.30(s,3H),1.10(t,J＝7.20Hz,6H).13CNMR(CDCl3,100MHz)δ(ppm):157.82,149.40,147.62,135.72(2C),131.02,121.32(2C),118.88(2C),114.64,112.77,110.18,71.29,67.19,66.04,62.37,59.14,55.96,51.64,47.80(2C),42.27,11.69(2C).IR(KBr,cm-1):2969,2936,2875,2800,2360,2340,1603,1512,1475,1462,1419,1373,1330,1313,1260,1233,1171,1139,1097,1036,1017,980,932,880,810,752,702.HRMS(ESI):m/z calcd for C25H35BrF3N2O4(M+H)+:563.1732.found:563.1695.
实施例:52：1-(4-溴-2,6-二氯苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基(甲基)氨基)丙-2-醇(CHJ04094)的合成
所用化合物5为N,N-二乙基-2-(2-甲氧基-4-((甲氨基)甲基)苯氧基)乙烷-1-胺(5-3)。
所用化合物7为2-((4-溴-2,6-二氯苯氧基)甲基)环氧乙烷(7-28)。
无色油状物，产率87％，1H NMR(CDCl3,400MHz)δ(ppm):7.44(s,2H),6.81(m,3H),4.06(m,5H),3.84(s,3H),3.61(d,J＝12.80Hz,1H),3.49(d,J＝12.80Hz,1H),2.96(t,J＝6.80Hz,2H),2.69(m,5H),2.59(m,1H),2.28(s,3H),1.09(t,J＝7.20Hz,6H).13CNMR(CDCl3,100MHz)δ(ppm):150.74,149.36,147.52,131.62(3C),131.24,130.16,121.30,116.51,112.76,112.45,71.29,67.19,66.04,62.37,59.14,55.96,51.64,47.80(2C),42.27,11.69(2C).IR(KBr,cm-1):2966,2935,2875,2800,2362,2340,1597,1548,1514,1456,1375,1328,1261,1134,1031,995,929,854,802,748,702,569.HRMS(ESI):m/z calcd forC24H34BrCl2N2O4(M+H)+:563.1079.found:563.1039.
实施例53：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴-3-三氟甲基)苯氧基)丙-2-醇(CHJ04097)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((4-溴-3-(三氟甲基)苯氧基)甲基)环氧乙烷(7-3)。
白色固体，产率85％，1H NMR(CDCl3,400MHz)δ(ppm):7.64(s,1H),7.56(d,J＝8.80Hz,1H),7.23(s,1H),7.10(s,1H),7.05(s,1H),6.92(d,J＝8.8Hz,1H),6.84(s,1H),6.74(m,2H),4.34(m,2H),4.24(m,2H),4.10(m,1H),3.96(m,2H),3.84(s,3H),3.62(d,J＝12.80Hz,1H),3.46(d,J＝12.80Hz,1H),2.62(t,J＝11.20Hz,1H),2.49(m,1H),2.30(s,3H).13CNMR(CDCl3,100MHz)δ(ppm):157.80,149.88,146.88,137.64,135.73,132.45,130.69,129.26,121.25,119.59,118.87,114.63,114.58,114.18,112.82,110.21,70.88,68.92,66.00,62.35,59.07,55.95,46.69,42.35.IR(KBr,cm-1):3111,2929,2877,2787,2362,2340,1600,1514,1473,1419,1321,1261,1230,1170,1138,1093,1026,962,908,871,810,759,663.HRMS(ESI):m/z calcd for C24H28BrF3N3O4(M+H)+:558.1215.found:558.1172.
实施例54：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(2-溴-5-三氟甲基)苯氧基)丙-2-醇(CHJ04099)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((2-溴-5-(三氟甲基)苯氧基)甲基)环氧乙烷(7-19)。
白色固体，产率90％，1H NMR(CDCl3,400MHz)δ(ppm):7.62(d,J＝12.40Hz,2H),7.08(m,4H),6.85(s,1H),6.78(d,J＝8.0Hz,1H),6.71(d,J＝8.0Hz,1H),4.34(m,2H),4.23(m,2H),4.09(m,3H),3.83(s,3H),3.64(d,J＝12.80Hz,1H),3.47(d,J＝13.20Hz,1H),2.73(t,J＝11.60Hz,1H),2.55(m,1H),2.32(s,3H).13CNMR(CDCl3,100MHz)δ(ppm):155.41,149.90,146.85,137.67,133.71,132.57,130.71,129.39,122.28,121.25,119.58,118.81,116.41,114.19,112.80,109.89,71.55,68.94,66.15,62.45,58.93,55.94,46.65,42.52.IR(KBr,cm-1):3118,2879,2845,2787,2362,2340,1676,1595,1516,1460,1421,1388,1332,1290,1259,1138,1114,1085,1029,964,906,819,752.HRMS(ESI):m/z calcdfor C24H28BrF3N3O4(M+H)+:558.1215.found:558.1160.
实施例55：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴苯氧基)丙-2-醇(CHJ05001)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((4-溴苯氧基)甲基)环氧乙烷(7-12)。
白色固体，产率85％，1H NMR(CDCl3,400MHz)δ(ppm):7.63(s,1H),7.35(d,J＝8.40Hz,2H),7.08(d,J＝14.80Hz,2H),6.78(m,5H),4.34(m,2H),4.23(m,2H),4.09(m,1H),3.92(d,J＝4.40Hz,2H),3.83(s,3H),3.61(d,J＝13.20Hz,1H),3.45(d,J＝12.80Hz,1H),2.62(t,J＝11.60Hz,1H),2.49(m,1H),2.29(s,3H).13CNMR(CDCl3,100MHz)δ(ppm):157.89,149.88,146.84,137.67,132.56,132.24(2C),129.38,121.23,119.58,116.36(2C),114.19,113.12,112.81,70.60,68.95,66.12,62.34,59.31,55.96,46.65,42.34.IR(KBr,cm-1):3111,2931,2879,2843,2771,2362,2340,1712,1587,1514,1487,1456,1419,1355,1325,1242,1139,1099,1064,1028,999,960,910,883,858,819,754,692,663,615.HRMS(ESI):m/z calcd for C23H29BrN3O4(M+H)+:490.1341.found:490.1341.
实施例56：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-氯苯氧基)丙-2-醇(CHJ05002)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((3-溴-4-氯苯氧基)甲基)环氧乙烷(7-17)。
白色固体，产率90％，1H NMR(CDCl3,400MHz)δ(ppm):7.63(s,1H),7.30(d,J＝8.80Hz,1H),7.16(s,1H),7.08(d,J＝16.0Hz,2H),6.78(m,4H),4.34(m,2H),4.23(m,2H),4.09(m,1H),3.92(m,2H),3.84(s,3H),3.61(d,J＝13.2Hz,1H),3.45(d,J＝13.2Hz,1H),2.61(t,J＝11.60Hz,1H),2.48(m,1H),2.29(s,3H).13CNMR(CDCl3,100MHz)δ(ppm):157.73,149.89,146.87,137.67,132.50,130.48,129.37,126.16,122.52,121.24,119.55(2C),115.30,114.19,112.81,70.74,68.95,66.04,62.35,59.12,55.97,46.66,42.37.IR(KBr,cm-1):3113,2927,2877,2845,2785,2362,2340,1589,1564,1512,1467,1419,1384,1323,1261,1239,1141,1089,1029,960,906,858,808,754,666.HRMS(ESI):m/z calcd forC23H28BrClN3O4(M+H)+:524.0952.found:524.0916.
实施例57：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-甲基苯氧基)丙-2-醇(CHJ05003)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((3-溴-4-甲基苯氧基)甲基)环氧乙烷(7-18)。
白色固体，产率90％,1H NMR(CDCl3,400MHz)δ(ppm):7.64(s,1H),7.10(s,3H),7.06(s,1H),6.86(s,1H),6.73(m,3H),4.34(m,2H),4.24(m,2H),4.09(m,1H),3.92(m,2H),3.84(s,3H),3.61(d,J＝12.80Hz,1H),3.46(d,J＝13.20Hz,1H),2.62(t,J＝12.0Hz,1H),2.48(m,1H),2.30(d,J＝10.40Hz,6H).13CNMR(CDCl3,100MHz)δ(ppm):157.34,149.86,146.83,137.67,132.49,130.99,130.04,129.37,124.80,121.24,119.60,118.30,114.15,113.90,112.77,70.68,68.93,66.11,62.33,59.30,55.96,46.64,42.30,21.84.IR(KBr,cm-1):3112,2924,2877,2844,2777,2361,2340,1605,1564,1511,1492,1454,1418,1264,1239,1226,1158,1141,1091,1029,962,896,866,815,800,764,739,658,614.HRMS(ESI):m/z calcd for C24H31BrN3O4(M+H)+:504.1498.found:504.1460.
实施例58：1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-5-氯苯氧基)丙-2-醇(CHJ05004)的合成
所用化合物5为1-(4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯基)-N-甲基甲胺(5-4)。
所用化合物7为2-((3-溴-5-氯苯氧基)甲基)环氧乙烷(7-29)。
白色固体，产率88％，1H NMR(CDCl3,400MHz)δ(ppm):7.63(s,1H),7.10(s,2H),7.06(s,1H),6.96(s,1H),6.84(s,2H),6.73(m,2H),4.35(m,2H),4.24(m,2H),4.07(m,1H),3.93(m,2H),3.84(s,3H),3.61(d,J＝12.94Hz,1H),3.45(d,J＝13.35Hz,1H),2.60(t,J＝11.55Hz,1H),2.47(m,1H),2.29(s,3H).13CNMR(CDCl3,100MHz)δ(ppm):159.85,149.91,146.89,137.67,135.53,132.46,129.39 124.03,122.83,121.24,119.58,116.57,114.21(2C),112.79,70.90,68.95,65.96,62.35,59.05,55.97,46.66,42.37.HRMS(ESI):m/zcalcd for C23H28BrClN3O4(M+H)+:524.0952.found:524.0913.
本发明化合物对肿瘤细胞生长抑制活性实验
1、实验材料
将CHJ系列化合物用二甲基亚砜(DMSO，终浓度0.4％)溶解，用含15％胎牛血清RPMI-1640培养基配制成1mg/mL备用，在进行分组给药时，用该培养基进行倍数稀释至所需浓度。
实验试剂
细胞株：人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞系，均购买于中国科学院细胞库，使用含15％胎牛血清的DMEM(High Glucose)培养基，置于37℃，5％的CO2培养箱内培养。
2、实验方法
2.1 MTT实验原理及配制方法
MTT是一种具有氧化性的黄色染料，化学名为3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazoliumbromide[3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐。MTT法又叫MTT比色法，可检测细胞的存活和生长，方法简单，易于操作，常用于筛选具有细胞毒活性的物质。其检测基本原理为琥珀酸脱氢酶能够还原外源性MTT，使MTT被还原为不溶于水的蓝紫色结晶甲瓒(Formazan)，该结晶沉积于细胞中。琥珀酸脱氢酶存在于活细胞的线粒体中，死细胞中则无此酶。因而，该显色反应只能在活细胞中发生[56]。然后将细胞中的蓝紫色结晶甲瓒用二甲基亚砜(DMSO)溶解，用酶标仪测定其吸光度，从而间接地反映活细胞的数量。在一定的细胞数范围内，形成的蓝紫色结晶甲瓒的量与活细胞数量成正相关。
MTT法具有高效、准确、简便、经济、重复性好等优点，已被广泛应用于抗肿瘤药物筛选、医学生物活性因子活性检测、细胞毒活性试验测定以及肿瘤放射敏感性的测定。
5mg/mL的MTT溶液配制：称取MTT粉末500.0mg，溶于温的100mL PBS中，用0.22μm孔径的微孔滤膜过滤除去细菌得滤液，小剂量分装于高压灭菌后的离心管中，置于-20℃下冷冻避光保存。
2.2细胞培养及实验方法
将保存有肿瘤细胞的冻存管从液氮中取出，迅速放入37℃恒温箱中，不停摇动，直到融化。用75％酒精擦拭冻存管盖边缘后，吸取细胞悬液转入10mL离心管中，补加5mL培养基。低速离心(25℃，3000r/min，5min)，弃上清，加培养基再重复离心清洗一次。加适量培养基稀释后，用吸管将细胞吹散制成悬液，转入培养瓶中，置于37℃、5％的CO2细胞培养箱中培养。次日更换培养液，置于37℃、5％的CO2细胞培养箱中继续培养。
人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞均为贴壁细胞，根据肿瘤细胞生长速率，将处于对数生长期的贴壁肿瘤细胞洗涤，经0.25％的EDTA胰酶消化，调整细胞数为1×105/mL接种于96孔板内，每孔100μL，37℃下于CO2孵箱内培养，24h后给药。给药组加入不同浓度药物(CHJ系列化合物)，每个药物设置5个剂量组，分别为100、10、1、0.1、0.01μmol/L，每个浓度设三个复孔。设置空白对照、DMSO(0.8％)溶剂对照和顺铂阳性对照。于37℃，5％的CO2培养箱内培养48h后，用MTT法测定OD值，计算细胞抑制率。
2.3 IC50值的计算
人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞培养48h后，终止，然后每个孔中加入10μL 0.5％MTT溶液放置于CO2培养箱中，4h后，除去每个孔中的液体，再分别加入0.2mL的DMSO溶液，在摇床上低频充分振荡，使蓝紫色结晶的甲瓒充分溶解，置于酶标仪中，于490nm波长处记录OD值，计算不同浓度的三个平行孔的平均OD值，根据平均值计算不同浓度下的每一种受试药物的细胞抑制率以及IC50值。
抑制率(％)＝[1-供试品OD值/阴性对照组OD值]×100％
3、实验结果
目标化合物抗癌细胞增殖的IC50值
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通过观察上述实验数据发现，目标化合物中绝大多数对人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞均具有良好的抑制作用。并且从数据中可以看出，化合物右侧为四甲基哌啶时的化合物在抗癌方面普遍要比右侧为四氢吡咯、二乙胺基和吡咯的化合物活性要好。化合物左侧增加疏水侧链长度时(CHJ03011和CHJ03012)仍然具有很好的抗癌效果，但在左侧芳环引入大极性化合物时(CHJ04068和CHJ04061)，可以明显的降低化合物的抗癌活性。值得注意的是左侧芳环有3个Br原子取代的化合物(CHJ04022和CHJ04068)活性最好，其活性与对照品顺铂相当。

Claims (6)

1.通式(I)所示化合物或其药学上可接受的盐、其光学异构体,
其中，
其中，R1为-H,
R2为-F,-CF3,-Br,-Cl,-H,-OCH3,-CH(CH3)2，
R3为-H，
R4为-H,-Br,-CF3,-Cl，
R5为-H,-Cl,-I,-Br，
R6为所述化合物的结构式如下：
2.如权利要求1所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述化合物结构式如下：
3.如权利要求2所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述化合物结构式如下：
4.如权利要求3所述的化合物或其药学上可接受的盐、其光学异构体，其特征在于，所述化合物结构式如下：
5.一种药物组合物，其特征在于，含有权利要求1-4任一项所述的化合物或其药学上可接受的盐、其光学异构体和药学上可接受的载体或赋形剂。
6.权利要求1-4任一项所述的化合物或其药学上可接受的盐、其光学异构体或权利要求5的药物组合物在制备治疗癌症药物中的应用，所述癌症为肺癌或卵巢癌或黑色素瘤或结肠癌。
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