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CN107501169A - 一类反式二芳基乙烯类lsd1抑制剂、其制备方法及应用 - Google Patents

一类反式二芳基乙烯类lsd1抑制剂、其制备方法及应用 Download PDF

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CN107501169A
CN107501169A CN201710750071.7A CN201710750071A CN107501169A CN 107501169 A CN107501169 A CN 107501169A CN 201710750071 A CN201710750071 A CN 201710750071A CN 107501169 A CN107501169 A CN 107501169A
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段迎超
翟晓雨
关圆圆
谢智宇
秦文平
郑超
郑一超
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Xinxiang Medical University
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Abstract

本发明公开了一类具有反式二芳基乙烯结构的LSD1抑制剂、其制备方法及在制备抗肿瘤药物中的应用，属于药物化学技术领域。本发明所述的化合物具有如下通式：

Description

一类反式二芳基乙烯类LSD1抑制剂、其制备方法及应用
技术领域
本发明具体涉及一类具有反式二芳基乙烯结构的LSD1抑制剂、其制备方法及在制备抗肿瘤药物中的应用，属于药物化学技术领域。
背景技术
组蛋白赖氨酸特异性去甲基化酶1(Lysine specific histone demethylase 1，LSD1)是第一个被发现的组蛋白去甲基化酶。LSD1是一个黄素腺嘌呤二核苷酸依赖性的去甲基化酶，通过与不同的分子伴侣结合作用于不同的底物，产生不同的生物学功能。LSD1通过CoREST与靶基因结合，能够特异性的去除 H3K4(Histone 3,Lysine 4)的单或双甲基化，导致基因转录抑制。当LSD1和雄激素受体或者雌激素受体结合时，能特异性的去除H3K9(Histone 3,Lysine 9)的单或双甲基化，引起激素受体依赖的基因转录激活。LSD1通过调节组蛋白与其它蛋白的相互作用，影响基因转录的激活与抑制，染色体失活等重要生命过程。 LSD1与肿瘤、病毒性感染、代谢性疾病、炎症等疾病的发生均有紧密的关系，其中与肿瘤的发生发展尤为密切。
LSD1在乳腺癌、前列腺癌、白血病、胃癌等多种肿瘤中的表达量显著升高，与这些肿瘤的生长、转移和侵袭等过程高度相关。LSD1能与Snail1的 SNAG结构域结合，抑制E-cadherin基因的表达，促进肿瘤的转移和侵袭。用 RNA干扰技术降低LSD1的表达量或者用小分子抑制剂抑制LSD1的活性能够降低相关致癌基因的表达，抑制肿瘤的生长、转移和侵袭。因此，LSD1已经成为目前肿瘤表观遗传学治疗的热点靶蛋白之一，吸引了葛兰素史克、Oryzon、武田制药等众多国际医药公司的关注。目前已有多个LSD1抑制剂被报道，西班牙Oryzon公司报道的苯环丙胺类LSD1抑制剂目前正在进行II期临床试验，用于治疗白血病。
因此，发现新型、高活性的LSD1抑制剂，对于研究LSD1的生物学功能、开发新型的抗肿瘤、抗病毒等疾病治疗药物，具有十分重要意义。为了发现新型的LSD1小分子抑制剂，本发明合成了一类反式二芳基乙烯类化合物，该类化合物具有显著的LSD1抑制活性和体外抗肿瘤活性，目前尚未见有该类化合物的合成、LSD1抑制活性及抗肿瘤活性的报道。
发明内容
由上述可知，本发明的一个目的在于提供一类反式二芳基乙烯类化合物，为新药物筛选提供可能。
本发明的另一个目的在于提供此类反式二芳基乙烯类化合物的制备方法及其作为组蛋白赖氨酸特异性去甲基化酶1(LSD1)抑制剂的应用。
本发明的再一个目的在于提供所述化合物以LSD1为靶点在制备抗肿瘤药物中的应用。
为实现上述目的，本发明所涉及的反式二芳基乙烯类化合物的结构通式为：
通式I中，R1为单取代或多取代，取代基指：NH2、中的任意一个； R2为H、OH、F、Cl、Br、I、C2-C5饱和酯基、C1-5烷氧基中的任意一个；R3为H、OH、CN、F、Cl、Br、I中的任意一个；X为CH或N原子。
优选：通式I中，R1为单取代，取代基为：NH2、中的任意一个； R2为H、F、Cl、Br、I、乙酸甲酯酯基、乙氧基中的任意一个；R3为H、OH、 F、Cl、Br、I中的任意一个；X为CH或N原子。
更优选地，R1、R2、R3代表的取代基和取代位置，X所代表的原子如下表所示：
为实现上述第二个目的，本发明化合物的合成反应流程如下式所示：
R4为硝基或氰基，R1，R2，R3同上。
化合物1的制备方法:5-酰基-2-甲氧基苯硼酸和取代2-溴吡啶或取代2-溴嘧啶在甲苯中，碱性化合物和钯催化剂存在下，回流搅拌反应，得化合物1。其中，所述碱性化合物选自碳酸钾、碳酸钠、碳酸铯、磷酸钾中的一种，所述的钯催化剂选自四(三苯基膦)钯、醋酸钯、双(二亚苄基丙酮)钯、二氯化钯中的一种。
化合物2的制备方法:化合物1和取代苄基膦酸二乙酯，在DMF中，强碱性化合物存在下，室温搅拌反应，反应结束后，将反应体系倾入冰水中，抽滤，洗涤，收集固体，干燥，得化合物2。其中，所述强碱性化合物选自叔丁醇钾、甲醇钠、氢化钠、叔丁醇钠中的一种。
化合物3的制备方法:当化合物2中R4为硝基，则在有机溶剂中，SnCl2存在下，回流搅拌反应，反应结束后，反应体系真空浓缩，浓缩物加入乙酸乙酯、饱和碳酸氢钠水溶液搅拌，分取有机相，洗涤，干燥，柱层析分离，得化合物 3。其中，所述有机溶剂选自乙醇、乙酸乙酯、四氢呋喃中的一种。
化合物4的制备方法:当化合物2中R4为氰基，则在无水二氯甲烷中，三溴化硼存在下，-35℃-室温过夜反应，反应结束后，将反应体系倾入到饱和碳酸氢钠水溶液中，抽滤，收集固体，柱层析分离，得化合物4。
化合物I的制备方法:化合物4在甲醇中，强碱性化合物存在下，和盐酸羟胺回流搅拌反应，反应结束后，反应体系真空浓缩，浓缩物加入乙酸乙酯和水萃取，洗涤，有机相经柱层析分离，得化合物I。其中，所述强碱性化合物选自碳酸钾、碳酸铯、三乙胺、N,N-二异丙基乙胺中的一种。
或者将化合物3，在无水二氯甲烷中，三溴化硼存在下，-35℃-室温反应，反应结束后，反应体系倾入到饱和碳酸氢钠水溶液中，抽滤，收集固体，柱层析分离，得化合物I。
本发明优点：本发明合成的反式二芳基乙烯类化合物具有很强的LSD1抑制活性和体外抗肿瘤活性。大部分化合物的LSD1抑制IC50小于1μM，活性强于阳性对照药物苯环丙胺，多个化合物的体外抗肿瘤活性优于阳性对照5-氟尿嘧啶。本发明的化合物代表着一类具有全新结构的LSD1小分子抑制剂，为 LSD1抑制剂类药物的研发提供了基础，为LSD1的生物学功能研究提供了有效工具。可作为进一步开发的候选或者先导化合物用于开发抗肿瘤、抗病毒、抗艾滋病等疾病治疗药物，且合成方法简单，收率高，有利于推广应用。
具体实施方式
下面举实施例对本发明技术方案作详细说明。
实施例1 4-甲氧基-3-(吡啶-2-基)苯甲醛(1a)
在50毫升两口烧瓶中加入2-溴吡啶(456.5mg,2.89mmol)，甲苯(7mL)， K2CO3水溶液(2.76g碳酸钾溶于10mL水，2mL)，四(三苯基膦)钯(45.2mg, 0.04mmol)，氮气保护下室温搅拌反应15分钟，然后加入5-甲酰基-2-甲氧基苯硼酸(400mg,2.22mmol)的无水乙醇溶液(3mL)，92℃加热反应4个小时，将反应体系倾入水中，乙酸乙酯萃取，合并乙酸乙酯层，依次用水，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，浓缩物柱层析分离(石油醚：乙酸乙酯＝6:1)得白色固体414.6mg，收率87.5％，Mp:52-53℃。1H NMR(400MHz, CDCl3)δ9.98(s,1H),8.73(m,1H),8.31(d,1H,J＝2.4Hz),7.96(dd,1H,J1＝2.4 Hz,J2＝8.4Hz),7.78-7.87(m,1H),7.75(td,1H,J1＝1.6Hz,J2＝7.2Hz),7.25-7.28 (m,1H),7.13(d,1H,J＝8.4Hz),3.96(s,3H).13C NMR(101MHz,CDCl3)δ190.99, 161.71,154.63,149.58,135.94,134.21,131.15,130.02,129.55,125.03,122.33, 111.59,56.05.HRMS(ESI)calcd forC13H12NO2[M+H]+:214.0863,Found: 214.0870.
实施例2 4-甲氧基-3-(4-氟吡啶-2-基)苯甲醛(1b)
按照实施例1的方法，用2-溴-4-氟吡啶(508.6mg,2.89mmol)替换2-溴吡啶，得白色固体395.8mg，收率77.1％，Mp:73-74℃。1H NMR(400MHz,CDCl3)δ 10.00(s,1H),8.72(dd,1H,J1＝5.6Hz,J2＝8.8Hz),8.40(t,1H,J＝2.0Hz),8.00(dd, 1H,J1＝1.2Hz,J2＝8.8Hz),7.65(d,1H,J＝10.4Hz),7.16(d,1H,J＝8.4Hz),7.05 (m,1H),4.01(s,3H).13C NMR(101MHz,CDCl3)δ190.88,175.95,169.87,167.27, 161.69,157.37,157.29,151.61,151.54,134.23,131.67,130.04,128.13,128.10, 113.06,112.87,111.74,110.42,110.25,56.11.HRMS(ESI)calcd for C13H10FNNaO2 [M+Na]+:254.0588,Found:254.0582.
实施例3 4-甲氧基-3-(嘧啶-2-基)苯甲醛(1c)
按照实施例1的方法，用2-溴嘧啶(445.1mg,2.80mmol)替换2-溴吡啶，得白色固体414.2mg，收率87.1％，Mp:80-81℃。1H NMR(400MHz,CDCl3)δ 9.96(s,1H),8.88(d,2H,J＝4.8Hz),8.26(d,1H,J＝2.4Hz),8.00(dd,1H,J1＝2.4 Hz,J2＝8.8Hz),7.29(t,1H,J＝4.8Hz),7.16(d,1H,J＝8.8Hz),3.96(s,3H).13C NMR(101MHz,CDCl3)δ190.61,164.71,162.41,157.17,134.47,132.52,129.64, 128.77,119.23,112.05,56.44.HRMS(ESI)calcdfor C12H10N2NaO2[M+Na]+: 237.0634,Found:237.0639.
实施例4 4-甲氧基-3-(4-甲氧酰基吡啶-2-基)苯甲醛(1d)
按照实施例1的方法，用2-溴异烟酸甲酯(604.9mg,2.80mmol)替换2-溴吡啶，得白色固体422.2mg，收率70.1％，Mp:117-118℃。1H NMR(400MHz, CDCl3)δ9.99(s,1H),8.87(d,1H,J＝4.8Hz),8.39(s,1H),8.34(d,1H,J＝2.0Hz), 7.98(dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.81(dd,1H,J1＝1.2Hz,J2＝4.8Hz),7.16 (d,1H,J＝8.4Hz),3.99(s,6H).13C NMR(101MHz,CDCl3)δ190.86,165.84, 161.79,155.77,150.30,137.39,134.10,131.69,130.08,128.78,124.33,121.41, 111.68,56.18,52.79.HRMS(ESI)calcd for C15H13NNaO4[M+Na]+:294.0742, Found:294.0741.
实施例5 4-甲氧基-3-(5-甲氧基吡啶-2-基)苯甲醛(1e)
按照实施例1的方法，用2-溴-5-甲氧基吡啶(565.7mg,2.80mmol)替换2-溴吡啶，得白色固体395.8mg，收率69.3％，Mp:91-92℃。1H NMR(400MHz, CDCl3)δ9.98(s,1H),8.43(d,1H,J＝2.8Hz),8.31(d,1H,J＝2.0Hz),7.93(dd, 1H,J1＝2.0Hz,J2＝8.4Hz),7.79(d,1H,J＝8.8Hz),7.26-7.29(m,1H),7.12(d,1H, J＝8.8Hz),3.97(s,3H),3.92(s,3H).13CNMR(101MHz,CDCl3)δ191.12,161.54, 154.73,146.94,137.17,133.93,130.57,130.06,129.29,125.22,120.36,111.53, 56.03,55.68.HRMS(ESI)calcd for C14H13NNaO3[M+Na]+:266.0788, Found:266.0790.
实施例6(E)-2-(2-甲氧基-5-(3-硝基苯乙烯基)苯基)吡啶(2a)
将化合物1a(319.9mg,1.50mmol)和3-硝基苄基膦酸二乙酯(430.3mg,1.575mmol)溶于无水DMF(6mL)，冰浴下慢慢加入叔丁醇钾(336.6mg,3.0mmol)，加毕室温搅拌反应3小时，将反应体系慢慢倾入冰水中，析出固体，抽滤，收集固体，用乙酸乙酯重结晶得黄色固体336.5mg，收率67.5％，Mp:108-109℃。1H NMR(400MHz,CDCl3)δ8.74(ddd,1H,J1＝0.8Hz,J2＝1.6Hz,J3＝2.8Hz), 8.34(t,1H,J＝2.0Hz),8.07(ddd,1H,J1＝0.8Hz,J2＝2.0Hz,J3＝2.8Hz),8.02(d, 1H,J＝2.0Hz),7.85(dt,1H,J1＝0.8Hz,J2＝8.0Hz),7.72-7.78(m,2H),7.54(dd, 1H,J1＝2.4Hz,J2＝8.4Hz),7.50(t,1H,J＝8.0Hz),7.23-7.27(m,2H),7.10(d,1H, J＝16.4Hz),7.03(d,1H,J＝8.4Hz),3.91(s,3H).13C NMR(101MHz,CDCl3)δ 157.29,155.55,149.53,148.75,139.54,135.76,132.02,131.07,129.52,129.49,129.46,129.38,128.72,125.19,124.50,121.99,121.63,120.66,111.71,55.81.HRMS(ESI)calcd for C20H17N2O3[M+H]+:333.1234,Found:333.1242.
实施例7(E)-2-(2-甲氧基-5-(4-硝基苯乙烯基)苯基)吡啶(2b)
按照实施例6的方法，用4-硝基苄基膦酸二乙酯替换3-硝基苄基膦酸二乙酯，得黄色固体465.1mg，收率93.3％，Mp:82-83℃.1H NMR(400MHz,CDCl3) δ8.72-8.79(m,1H),8.22(d,2H,J＝8.8Hz),8.05(d,1H,J＝2.0Hz),7.88(d,1H,J ＝8.0Hz),7.76(td,1H,J1＝2.0Hz,J2＝8.0Hz),7.62(d,2H,J＝8.8Hz),7.57(dd, 1H,J1＝2.4Hz,J2＝8.8Hz),7.24-7.34(m,2H),7.13(d,1H,J＝16.4Hz),7.05(d, 1H,J＝8.4Hz),3.93(s,3H).13C NMR(101MHz,CDCl3)δ157.53,155.42,149.51, 146.43,144.29,135.79,132.70,129.75,129.48,129.28,128.94,126.55,125.21, 124.66,124.17,122.05,111.71.HRMS(ESI)calcd for C20H17N2O3[M+H]+: 333.1234,Found:333.1238.
实施例8(E)-4-氟-2-(2-甲氧基-5-(3-硝基苯乙烯基)苯基)吡啶(2c)
按照实施例6的方法，用1b(346.8mg,1.50mmol)替换1a，得黄色固体 435.2mg，收率82.8％，Mp:97-98℃。HRMS(ESI)calcd forC20H15FN2NaO3[M+ Na]+:373.0959,Found:373.0962.
实施例9(E)-2-(2-甲氧基-5-(4-硝基苯乙烯基)苯基)异烟酸甲酯(2d)
将化合物1d(406.9mg,1.50mmol)和4-硝基苄基膦酸二乙酯(430.3mg,1.575mmol)溶于无水DMF(6mL)，冰浴下慢慢加入叔丁醇钾(336.6mg,3.0mmol)，加毕室温搅拌反应3小时，将反应体系慢慢倾入冰水中，析出固体，抽滤，收集固体，用乙酸乙酯重结晶得黄色固体245.9mg，产率42.0％，Mp:193-194℃. 1H NMR(400MHz,CDCl3)δ8.88(d,1H,J＝4.8Hz),8.42(s,1H),8.21(d,2H,J＝ 8.8Hz),8.04(d,1H,J＝2.0Hz),7.80(dd,1H,J1＝1.2Hz,J2＝4.8Hz),7.56-7.62 (m,3H),7.27-7.30(m,1H),7.04-7.13(m,2H),3.99(s,3H),3.94(s,3H).HRMS(ESI) calcd for C22H18N2NaO5[M+Na]+:413.1108,Found:413.1111.
实施例10(E)-5-甲氧基-2-(2-甲氧基-5-(3-硝基苯乙烯基)苯基)吡啶(2e)
按照实施例6的方法，用1e(385.9mg,1.50mmol)替换1a，得黄色固体 329.7mg，产率58.4％，Mp:142-143℃。1H NMR(400MHz,CDCl3)δ8.44(d,1H, J＝2.8Hz),8.33(t,1H,J＝1.6Hz),8.06(dd,1H,J1＝1.6Hz,J2＝7.6Hz),8.00(d, 1H,J＝2.0Hz),7.82(d,1H,J＝8.8Hz),7.76(d,1H,J＝8.0Hz),7.47-7.51(m, 2H),7.22-7.27(m,2H),7.08(d,1H,J＝16.4Hz),7.01(d,1H,J＝8.4Hz),3.92(s, 3H),3.90(s,3H).13C NMR(101MHz,CDCl3)δ157.12,154.54,148.74,147.89, 139.58,137.01,132.01,131.19,129.50,129.34,129.19,129.12,128.14,125.36, 124.36,121.58,120.64,120.35,111.66,55.80,55.68.HRMS(ESI)calcd for C21H19N2O4[M+H]+:363.1339,Found:363.1339.
实施例11(E)-2-(2-甲氧基-5-(4-硝基苯乙烯基)苯基)嘧啶(2f)
按照实施例9的方法，用1c(321.3mg,1.50mmol)替换1d，得黄色固体 435mg，产率87.1％，Mp:174-175℃。1H NMR(400MHz,CDCl3)δ8.92(d,2H,J ＝4.8Hz),8.22(d,2H,J＝8.8Hz),7.98(d,1H,J＝2.0Hz),7.60-7.64(m,3H),7.28- 7.30(m,2H),7.10(d,1H,J＝16.8Hz),7.09(d,1H,J＝8.4Hz),3.95(s,3H).13C NMR(101MHz,CDCl3)δ165.47,158.21,157.13,146.50,144.18,132.43,130.38, 130.02,128.98,128.73,126.59,124.82,124.18,118.97,112.26,56.27.HRMS(ESI) calcd for C19H16N3O3[M+H]+:334.1186,Found:334.1188.
实施例12(E)-2-(2-甲氧基-5-(3-硝基苯乙烯基)苯基)嘧啶(2g)
按照实施例6的方法，用1c(321.3mg,1.50mmol)替换1a，得黄色固体 261mg，产率52.2％，Mp:130-131℃。1H NMR(400MHz,CDCl3)δ8.90(d,2H,J ＝4.8Hz),8.34(t,1H,J＝2.0Hz),8.07(ddd,1H,J1＝1.2Hz,J2＝2.4Hz,J3＝3.2 Hz),7.96(d,1H,J＝2.4Hz),7.76(d,1H,J＝7.6Hz),7.60(dd,1H,J1＝2.4Hz,J2＝ 8.8Hz),7.50(t,1H,J＝8.0Hz),7.24(t,1H,J＝4.8Hz),7.24(d,1H,J＝16.4Hz), 7.09(d,1H,J＝6.4Hz),7.06(s,1H),3.93(s,3H).13CNMR(101MHz,CDCl3)δ 165.55,157.95,157.11,148.75,139.43,132.01,130.82,130.13,129.80,129.53, 129.07,128.68,124.65,121.70,120.69,118.93,112.26,56.27.HRMS(ESI)calcd for C19H15N3NaO3[M+Na]+:356.1006,Found:356.1004.
实施例13(E)-4-(4-甲氧基-3-(吡啶-2-基)苯乙烯基)苯甲腈(2h)
按照实施例6的方法，用3-氰基苄基膦酸二乙酯(398.8mg,1.575mmol)替换 3-硝基苄基膦酸二乙酯，得无色油状物270.8mg，收率57.8％。1H NMR(400 MHz,CDCl3)δ8.76(ddd,1H,J1＝1.2Hz,J2＝2.0Hz,J3＝3.2Hz),8.03(d,1H,J＝ 2.4Hz),7.87(dt,1H,J1＝1.2Hz,J2＝8.0Hz),7.75(td,1H,J1＝2.0Hz,J2＝8.0 Hz),7.63(d,2H,J＝8.4Hz),7.52-7.59(m,3H),7.20-7.30(m,2H),7.06(d,1H,J＝ 16.4Hz),7.04(d,1H,J＝8.4Hz),3.92(s,3H).13C NMR(101MHz,CDCl3)δ157.36, 155.48,149.52,142.22,135.77,132.47,131.74,129.62,129.44,129.38,128.77, 126.60,125.21,125.08,122.02,119.20,111.68,110.05,55.81.HRMS(ESI)calcd for C21H16N2NaO[M+Na]+:335.1155,Found:335.1151.
实施例14(E)-3-(4-甲氧基-3-(嘧啶-2-基)苯乙烯基)苯甲腈(2i)
按照实施例6的方法，用1c(321.3mg,1.50mmol)替换1a，用3-氰基苄基膦酸二乙酯(398.8mg,1.575mmol)替换3-硝基苄基膦酸二乙酯，得无色油状物 275.4mg，收率58.6％。1H NMR(400MHz,CDCl3)δ8.91(d,2H,J＝4.8Hz),7.95 (d,1H,J＝2.4Hz),7.76(s,1H),7.70(d,1H,J＝8.0Hz),7.59(dd,1H,J1＝2.4Hz,J2＝8.4Hz),7.52(dt,1H,J1＝1.6Hz,J2＝7.6Hz),7.45(t,1H,J＝7.6Hz),7.28(t,1H, J＝4.8Hz),7.17(d,1H,J＝16.4Hz),7.08(d,1H,J＝8.8Hz),7.02(d,1H,J＝16.4 Hz),3.93(s,3H).13C NMR(101MHz,CDCl3)δ165.54,157.86,157.09,138.84, 130.38,130.36,130.29,130.06,129.71,129.67,129.44,129.14,128.64,124.73, 118.92,118.88,112.87,112.22,56.26.HRMS(ESI)calcdforC20H15N3NaO[M+Na]+:336.1107,Found:336.1108.
实施例15(E)-4-(4-甲氧基-3-(嘧啶-2-基)苯乙烯基)苯甲腈(2j)
按照实施例6的方法，用1c(321.3mg,1.50mmol)替换1a，用4-氰基苄基膦酸二乙酯(398.8mg,1.575mmol)替换3-硝基苄基膦酸二乙酯，得白色固体 283.7mg，收率60.3％，Mp:142-143℃。1H NMR(400MHz,CDCl3)δ8.91(d, 2H,J＝4.8Hz),7.96(t,1H,J＝2.0Hz),7.66-7.50(m,5H),7.32-7.17(m,2H),7.11- 7.00(m,2H),3.94(s,3H).13C NMR(101MHz,CDCl3)δ165.52,158.04,157.11, 142.13,132.49,131.50,130.25,129.85,129.09,128.70,126.63,125.27,119.15, 118.94,112.25,110.17,56.26.HRMS(ESI)calcd forC20H15N3NaO[M+Na]+:336.1107,Found:336.1108.
实施例16(E)-3-(4-甲氧基-3-(吡啶-2-基)苯乙烯基)苯胺(3a)
在25毫升圆底烧瓶中，加入化合物2a(249mg,0.75mmol)和无水氯化亚锡(713.1mg,3.75mmol)，用无水乙醇10mL溶解，100℃回流反应2个小时。反应结束后，将反应体系真空浓缩，浓缩物加乙酸乙酯超声分散，加饱和碳酸氢钠水溶液搅拌30分钟，抽滤，将滤液分取乙酸乙酯层，依次用水，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液真空浓缩，浓缩物柱层析分离纯化(石油醚：丙酮＝5:1)，得黄色固体114mg，收率50.3％，Mp:133-134℃。1H NMR(400 MHz,DMSO-d6)δ8.69(dt,1H,J1＝2.0Hz,J2＝4.8Hz),7.90(d,1H,J＝2.4Hz), 7.82-7.84(m,2H),7.62(dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.34(ddd,1H,J1＝2.8Hz,J2＝4.8Hz,J3＝6.0Hz),7.16(d,1H,J＝8.4Hz),7.10(d,1H,J＝16.4Hz),7.00(t, 1H,J＝8.0Hz),6.98(d,1H,J＝16.4Hz),6.74-6.76(m,2H),6.46-6.48(m,1H),5.06 (s,2H),3.85(s,3H).13CNMR(101MHz,DMSO-d6)δ156.73,155.48,149.81, 149.28,138.17,136.40,130.31,129.57,129.09,129.03,128.52,127.93,127.24, 125.31,122.58,114.90,113.92,112.74,112.02,56.25.HRMS(ESI)calcd for C20H18N2NaO[M+Na]+:325.1311,Found:325.1318.
实施例17(E)-4-(4-甲氧基-3-(吡啶-2-基)苯乙烯基)苯胺(3b)
按照实施例16的方法，用2b替换2a，得黄色固体97mg，收率42.3％， Mp:148-149℃。1H NMR(400MHz,CDCl3)δ8.75-8.77(m,1H),7.92(d,1H,J＝ 2.4Hz),7.85(d,1H,J＝8.0Hz),7.75(td,1H,J1＝2.0Hz,J2＝7.6Hz),7.50(dd,1H, J1＝2.4Hz,J2＝8.8Hz),7.34(d,2H,J＝8.4Hz),7.26(m,1H),6.99-7.03(m,2H), 6.95(d,1H,J＝16.4Hz),6.69(d,2H,J＝8.4Hz).13C NMR(101MHz,CDCl3)δ 156.10,155.95,149.28,145.82,135.83,131.13,129.02,128.81,128.39,127.69, 127.50,127.21,125.23,124.45,121.80,115.24,111.66,55.81.HRMS(ESI)calcd for C20H19N2O[M+H]+:303.1492,Found:303.1494.
实施例18(E)-3-(4-氟吡啶-2-基)-4-甲氧基苯乙烯基)苯胺(3c)
在25毫升圆底烧瓶中，加入化合物2c(262.8mg,0.75mmol)和无水氯化亚锡(713.1mg,3.75mmol)，加入乙酸乙酯20mL，100℃回流反应2个小时。反应结束后，向反应体系加入饱和碳酸氢钠水溶液30mL搅拌30分钟，抽滤，滤液分取乙酸乙酯层，依次用水，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液真空浓缩，浓缩物柱层析分离纯化(石油醚:丙酮＝5:1)，得黄色固体167mg，收率69.4％，Mp:173-174℃。1H NMR(400MHz,DMSO-d6)δ8.72(dd,1H,J1＝5.6 Hz,J2＝9.2Hz),7.99(d,1H,J＝2.4Hz),7.74(dd,1H,J1＝2.4Hz,J2＝11.2Hz),7.66(dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.28-7.33(m,1H),7.19(d,1H,J＝8.8 Hz),7.10(d,1H,J＝16.4Hz),6.96-7.03(m,2H),6.75-6.77(m,2H),6.46-6.50(m, 1H),5.06(s,2H),3.88(s,3H).13C NMR(101MHz,DMSO-d6)δ169.56,167.00, 158.43,158.35,156.81,152.42,152.34,149.29,138.12,130.35,129.58,129.14, 129.02,128.14,127.64,127.60,127.08,114.91,113.97,112.87,112.72,112.54, 112.06,110.51,110.35,56.34.HRMS(ESI)calcd for C20H17FN2NaO[M+Na]+:343.1217,Found:343.1218.
实施例19(E)-2-(5-(4-氨基苯乙烯基)-2-甲氧基苯基)异烟酸乙酯(3d)
按照实施例16的方法，用2d(303.3mg,0.75mmol)替换2a，得黄色固体 113mg，收率40.3％，Mp:123-124℃。1H NMR(400MHz,DMSO-d6)δ8.88(d, 1H,J＝4.8Hz),8.30(s,1H),7.88(d,1H,J＝2.4Hz),7.76(dd,1H,J1＝1.6Hz,J2＝ 5.2Hz),7.58(dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.26(d,2H,J＝8.4Hz),7.16(d,1H, J＝8.4Hz),6.96(d,1H,J＝16.4Hz),6.91(d,1H,J＝16.4Hz),6.54(d,2H,J＝8.4 Hz),5.26(s,2H),4.37(q,2H,J＝7.2Hz),3.85(s,3H),1.38(t,3H,J＝7.2Hz).13C NMR(101MHz,DMSO-d6)δ165.29,156.73,156.12,150.95,148.97,137.48, 131.31,128.43,128.38,128.04,127.88,125.40,123.89,122.57,121.13,114.36, 112.91,62.08,56.35,31.17,14.49.HRMS(ESI)calcd for C22H20N2NaO3[M+Na]+: 397.1523,Found:397.1528.
实施例20(E)-3-(4-甲氧基-3-(5-甲氧基吡啶-2-基)-苯乙烯基)苯胺(3e)
按照实施例16的方法，用2e(272mg,0.75mmol)替换2a，得淡黄色固体 160mg，收率64.2％，Mp:110-111℃。1H NMR(400MHz,DMSO-d6)δ8.40(d, 1H,J＝2.8Hz),7.90(d,1H,J＝2.4Hz),7.83(d,1H,J＝8.8Hz),7.57(dd,1H,J1＝ 2.0Hz,J2＝8.4Hz),7.44(dd,1H,J1＝2.8Hz,J2＝8.4Hz),7.13(d,1H,J＝8.4Hz), 7.09(d,1H,J＝16.4Hz),6.98(t,1H,J＝8.4Hz),6.96(d,1H,J＝16.4Hz),6.76(s, 1H),6.74(d,1H,J＝7.2Hz),6.48(d,1H,J＝7.2Hz),5.05(s,2H),3.88(s,3H), 3.85(s,3H).13C NMR(101MHz,DMSO-d6)δ156.53,154.70,149.29,147.64, 138.19,137.38,130.25,129.57,128.78,128.68,127.88,127.79,127.36,125.59, 120.75,114.88,113.89,112.68,112.02,56.22,56.07.HRMS(ESI)calcd for C21H20N2NaO2[M+Na]+:355.1417,Found:355.1416.
实施例21(E)-4-(4-甲氧基-3-(嘧啶-2-基)苯乙烯基)苯胺(3f)
按照实施例16的方法，用2f(250mg,0.75mmol)替换2a,得淡黄色固体 158.4mg，收率69.6％，Mp:199-200℃。1H NMR(400MHz,DMSO-d6)δ8.90(d, 2H,J＝4.8Hz),7.68(d,1H,J＝2.0Hz),7.58(dd,1H,J1＝2.0Hz,J2＝8.4Hz), 7.46(t,1H,J＝4.8Hz),7.26(d,2H,J＝8.4Hz),7.13(d,1H,J＝8.4Hz),6.94(d, 1H,J1＝16.4Hz),6.90(d,1H,J1＝16.4Hz),6.55(d,2H,J＝8.4Hz),5.26(s,2H), 3.77(s,3H).13C NMR(101MHz,DMSO-d6)δ165.65,157.65,156.54,148.93, 130.77,129.22,128.71,128.49,127.95,127.85,125.44,122.48,119.86,114.37, 112.97,56.26.HRMS(ESI)calcd for C19H17N3NaO[M+Na]+:326.1264,Found:326.1269.
实施例22(E)-3-(4-甲氧基-3-(嘧啶-2-基)苯乙烯基)苯胺(3g)
按照实施例16的方法，用2g(250mg,0.75mmol)替换2a,得淡黄色固体 112.5mg，收率49.4％，Mp:160-161℃。1H NMR(400MHz,DMSO-d6)δ8.91(d, 2H,J＝4.8Hz),7.75(d,1H,J＝6.4Hz),7.66(dd,1H,J1＝3.0Hz,J2＝8.8Hz),7.47 (t,1H,J＝4.8Hz),7.16(d,1H,J＝8.8Hz),7.08(d,1H,J＝16.4Hz),7.02(t,1H,J ＝7.2Hz),6.75(s,1H),6.74(d,1H,J＝7.2Hz),6.47(m,1H),5.05(s,2H),3.78(s, 3H).13C NMR(101MHz,DMSO-d6)δ165.53,157.67,157.18,149.28,138.15, 129.95,129.57,129.34,129.27,129.23,128.08,126.98,119.91,114.89,113.94, 112.95,112.01,56.27.HRMS(ESI)calcd forC19H17N3NaO[M+Na]+:326.1264, Found:326.1266.
实施例23(E)-3-(3-(4-乙氧基吡啶-2-基)-4-甲氧基苯乙烯基)苯胺(3h)
按照实施例16的方法，用2c(262.8mg,0.75mmol)替换2a，得棕黄色固体 139.3mg，产率53.6％，Mp:88-89℃。1H NMR(400MHz,DMSO-d6)δ8.48(d, 1H,J＝5.6Hz),7.93(d,1H,J＝2.4Hz),7.61(dd,1H,J1＝2.0Hz,J2＝8.4Hz), 7.37(d,1H,J＝2.8Hz),7.15(d,1H,J＝8.4Hz),7.09(d,1H,J＝16.4Hz),7.00(t, 1H,J＝7.6Hz),6.97(d,1H,J＝16.4Hz),6.93(dd,1H,J1＝2.8Hz,J2＝6.0Hz), 6.74-6.76(m,2H),6.46-6.49(m,1H),5.06(s,2H),4.15(q,2H,J＝6.8Hz),3.86(s, 3H),1.37(t,3H,J＝6.8Hz).13CNMR(101MHz,DMSO-d6)δ164.67,156.81, 156.71,150.95,149.29,138.17,130.18,129.57,129.05,128.94,128.47,127.89, 127.25,114.88,113.91,112.74,112.02,111.83,108.99,63.80,56.26,14.79.HRMS (ESI)calcd for C22H22N2NaO2[M+Na]+:369.1579,Found:369.1575.
实施例24(E)-3-(4-羟基-3-(吡啶-2-基)苯乙烯基)苯甲腈(4a)
在25毫升圆底烧瓶中加入化合物2h(468.5mg,1.5mmol)，用无水二氯甲烷 (5mL)溶解，氮气保护，-35℃搅拌下，慢慢加入三溴化硼的二氯甲烷溶液(1.13g, 4.5mmol,5mL)，加毕，将反应体系缓慢升至室温，室温搅拌过夜。将反应体系慢慢加入饱和碳酸氢钠水溶液中，析出黄色固体，抽滤，水洗，收集黄色固体，柱层析分离纯化(石油醚：丙酮＝6:1)得黄色固体252.8mg，产率56.5％， Mp:116-117℃。1H NMR(400MHz,DMSO-d6)δ14.36(s,1H),8.65-8.67(m,1H), 8.34(d,1H,J＝8.4Hz),8.30(d,1H,J＝2.0Hz),8.10(td,1H,J1＝2.0Hz,J2＝8.0 Hz),8.04(s,1H),7.89(d,1H,J＝8.0Hz),7.70(d,1H,J＝7.6Hz),7.57-7.62(m,2H),7.46-7.50(m,1H),7.44(d,1H,J＝16.4Hz),7.28(d,1H,J＝16.4Hz),6.99(d,1H,J ＝8.4Hz).13C NMR(101MHz,DMSO-d6)δ159.92,156.95,146.79,139.43,139.17, 131.19,131.12,130.74,130.42,130.22,129.76,128.07,126.25,124.24,123.03, 120.46,119.43,119.34,118.92,112.35.HRMS(ESI)calcd for C20H15N2O[M+H]+: 299.1179,Found:299.1179.
实施例25(E)-3-(4-羟基-3-(嘧啶-2-基)苯乙烯基)苯甲腈(4b)
按照实施例24的方法，用化合物2i(470mg,1.5mmol)替换2h，得黄色固体227.2mg，产率50.6％，Mp:141-142℃。1H NMR(400MHz,DMSO-d6)δ13.42(s,1H),9.02(d,2H,J＝5.2Hz),8.64(d,1H,J＝2.4Hz),8.11(s,1H),7.94(dt, 1H,J1＝1.6Hz,J2＝8.0Hz),7.75(dd,1H,J1＝2.4Hz,J2＝8.8Hz),7.68(dt,1H,J1＝1.2Hz,J2＝7.6Hz),7.54-7.62(m,2H),7.51(d,1H,J＝16.4Hz),7.18(d,1H,J＝ 16.4Hz),7.04(d,1H,J＝8.4Hz).13C NMR(101MHz,DMSO-d6)δ163.90,160.66, 157.50,139.26,131.64,131.28,131.02,130.80,130.31,129.98,128.24,128.03, 124.43,120.15,119.34,118.90,118.83,112.29.HRMS(ESI)calcd forC19H13N3NaO[M+Na]+:322.0951,Found:322.0952.
实施例26(E)-4-(4-羟基-3-(嘧啶-2-基)苯乙烯基)苯甲腈(4c)
按照实施例24的方法，用化合物2j(470mg,1.5mmol)替换2h，得黄色固体227.2mg，产率66.3％，Mp:199-200℃。1H NMR(400MHz,DMSO-d6)δ 13.28(s,1H),8.85(d,2H,J＝4.8Hz),8.69(d,1H,J＝2.0Hz),7.57-7.65(m,5H), 7.24-7.31(m,3H),7.08(d,1H,J＝8.4Hz),7.07(d,1H,J＝16.4Hz).13C NMR(101 MHz,DMSO-d6)δ164.79,161.21,156.24,142.29,132.49,131.96,131.53,128.17, 127.69,126.57,124.54,119.21,118.78,118.76,118.69,110.02.HRMS(ESI)calcd forC19H13N3NaO[M+Na]+:322.0951,Found:322.0946.
实施例27(E)-4-(3-氨基苯乙烯基)-2-(吡啶-2-基)苯酚(I-1)
在25毫升圆底烧瓶中加入将化合物3a(302.37mg 1.0mmol)用无水二氯甲烷(5mL)溶解，氮气保护，-35℃搅拌下，慢慢加入三溴化硼的二氯甲烷溶液 (0.75g,3.0mmol,5mL)，加毕，将反应体系慢慢升至室温，室温搅拌过夜反应。将反应体系慢慢加入饱和碳酸氢钠水溶液中，析出黄色固体，抽滤，收集固体，柱层析分离纯化(石油醚：丙酮＝4:1)得黄色固体113.3mg，收39.3％，Mp:133- 134℃。1H NMR(400MHz,DMSO-d6)δ14.31(s,1H),8.65(d,1H,J＝4.0 Hz),8.38(d,1H,J＝8.4Hz),8.23(d,1H,J＝1.6Hz),8.07(td,1H,J1＝2.0Hz,J2＝7.6Hz),7.58(dd,1H,J1＝1.6Hz,J2＝8.4Hz),7.47(dd,1H,J1＝5.2Hz,J2＝7.6 Hz),7.08(s,2H),7.03(t,1H,J＝7.6Hz),6.94(d,1H,J＝8.4Hz),6.77-6.74(m, 2H),6.48(dd,1H,J1＝2.4Hz,J2＝8.8Hz),5.12(s,2H).13C NMR(101MHz, DMSO-d6)δ159.30,157.15,149.22,146.70,139.13,138.40,129.75,129.59,128.78, 127.50,127.37,125.70,122.91,120.56,119.27,118.80,114.83,113.85, 111.95.HRMS(ESI)calcd for C19H16N2NaO[M+Na]+:311.1160,Found:311.1158.
实施例28(E)-4-(4-氨基苯乙烯基)-2-(吡啶-2-基)苯酚(I-2)
按照实施例27的方法，用化合物3b替换3a，得棕黄色固体144.7mg，产率50.2％，Mp:167-168℃。1H NMR(400MHz,DMSO-d6)δ14.16(s,1H),8.63- 8.65(m,1H),8.34(d,1H,J＝8.4Hz),8.14(d,1H,J＝2.4Hz),8.04-8.06(m,1H), 7.50(dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.46(ddd,1H,J1＝0.8Hz,J2＝5.2Hz,J3＝ 6.0Hz),7.26(d,2H,J＝8.4Hz),7.04(d,1H,J＝16.4Hz),6.88-6.93(m,2H),6.57(d, 2H,J＝8.4Hz),5.26(s,2H).13C NMR(101MHz,DMSO-d6)δ158.57,157.25, 148.77,146.71,139.07,129.56,129.17,127.65,127.28,125.67,124.88,123.06, 122.81,120.45,119.22,118.70,114.43.HRMS(ESI)calcd for C19H17N2O[M+H]+: 289.1335,Found:289.1332.
实施例29(E)-4-(3-氨基苯乙烯基)-2-(4-氟吡啶-2-基)苯酚(I-3)
按照实施例27的方法，用化合物3c(320.36mg,1mmol)替换3a，得黄色固体189mg，产率61.7％，Mp:173-174℃。1H NMR(400MHz,DMSO-d6)δ13.93 (s,1H),7.14(dd,1H,J1＝5.6Hz,J2＝8.8Hz),8.34(dd,1H,J1＝2.0Hz,J2＝11.2 Hz),8.27(d,1H,J＝2.0Hz),7.59(dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.42(m,1H), 7.01-7.14(m,3H),6.96(d,1H,J＝8.8Hz),6.76-6.73(m,2H),6.48(dd,1H,J1＝2.4 Hz,J2＝8.0Hz),5.10(s,2H).13C NMR(101MHz,DMSO-d6)δ171.12,168.54, 160.68,160.59,159.07,150.31,150.23,149.31,138.38,130.53,129.60,129.00, 127.65,127.26,126.00,118.93,118.89,118.83,114.76,113.86,111.89,111.14, 110.96,108.29,108.10.HRMS(ESI)calcd for C19H15FNaN2O[M+Na]+:329.1066, Found:329.1065.
实施例30(E)-2-(5-(4-氨基苯乙烯基)-2-羟基苯基)异烟酸乙酯(I-4)
按照实施例27的方法，用化合物3d(375mg,1mmol)替换3a，得黄色固体 175mg，产率48.6％，Mp:111-112℃。1H NMR(400MHz,DMSO-d6)δ13.04(s, 1H),8.83(dd,1H,J1＝0.8Hz,J2＝5.2Hz),8.60(s,1H),8.10(d,1H,J＝2.0Hz), 7.82(dd,1H,J1＝1.2Hz,J2＝5.2Hz),7.56(dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.26 (d,2H,J＝8.4Hz),6.93-6.97(m,3H),6.55(d,2H,J＝8.4Hz),5.25(s,2H),4.42(q, 2H,J＝7.2Hz),1.38(t,3H,J＝7.2Hz).13CNMR(101MHz,DMSO-d6)δ164.70, 157.73,157.45,148.52,148.37,139.06,129.67,128.64,127.44,127.07,125.90, 125.32,122.72,120.90,119.79,119.71,118.37,114.08,62.06,14.23.HRMS(ESI) calcd for C22H20N2NaO3[M+Na]+:383.1372,Found:383.1370.
实施例31(E)-6-(5-(3-氨基苯乙烯基)-2-羟基苯基)吡啶-3-酚(I-5)
按照实施例27的方法，用化合物3e(332.4mg,1mmol)替换3a，得黄色固体194.5mg，产率63.9％，Mp:233-234℃。1H NMR(400MHz,DMSO-d6)δ 13.98(s,1H),10.39(s,1H),8.22(d,1H,J＝8.8Hz),8.19(d,1H,J＝3.2Hz),8.09 (d,1H,J＝2.0Hz),7.47(td,2H,J1＝2.0Hz,J2＝8.0Hz),7.00-7.03(m,3H),6.89(d, 1H,J＝8.4Hz),6.71-6.78(m,2H),6.48(dd,1H,J1＝2.4Hz,J2＝8.0Hz),5.07(s, 2H).HRMS(ESI)calcd for C19H15N2O2[M-H]-:303.1139,Found:303.1129.
实施例32(E)-4-(3-氨基苯乙烯基)-2-(嘧啶-2-基)苯胺(I-6)
按照实施例27的方法，用化合物3g(303mg,1mmol)替换3a,得黄色固体 180mg，产率62.3％，Mp:207-208℃。1H NMR(400MHz,DMSO-d6)δ13.32(s, 1H),9.01(d,2H,J＝4.8Hz),8.56(d,1H,J＝2.0Hz),7.72(dd,1H,J1＝2.0Hz,J2＝ 8.8Hz),7.57(t,1H,J＝4.8Hz),7.12(d,1H,J＝16.4Hz),7.02(t,2H,J＝8.8Hz), 6.97(d,1H,J＝16.4Hz),6.77-6.79(m,2H),6.49(d,1H,J＝8.4Hz),5.06(s, 2H).13C NMR(101MHz,DMSO-d6)δ164.03,160.06,157.52,149.27,138.16, 131.42,129.58,128.92,127.62,127.29,127.23,120.06,118.75,114.83,113.89, 112.12.HRMS(ESI)calcd for C18H15N3NaO[M+Na]+:312.1107,Found:312.1108.
实施例33(E)-4-(4-氨基苯乙烯基)-2-(嘧啶-2-基)苯酚(I-7)
按照实施例27的方法，用化合物3f(303mg,1mmol)替换3a,得黄色固体 169.9mg，产率58.8％，Mp:194-195℃。1H NMR(400MHz,DMSO-d6)δ13.22(s, 1H),9.00(d,2H,J＝4.8Hz),8.50(d,1H,J＝2.0Hz),7.64(dd,1H,J1＝2.4Hz,J2＝8.8Hz),7.56(t,1H,J＝4.8Hz),7.29(d,2H,J＝8.4Hz),6.97(d,1H,J＝8.8 Hz),6.94-6.99(m,2H),6.56(d,2H,J＝8.4Hz),5.26(s,2H).HRMS(ESI)calcd for C18H16N3O[M+H]+:290.1288,Found:290.1288.
实施例34(E)-4-(3-氨基苯乙烯基)-2-(4-乙氧基吡啶-2-基)苯酚(I-8)
按照实施例27的方法，用化合物3h(346.4mg,1mmol)替换3a，得黄色固体 217mg，产率65.4％，Mp:103-104℃。1H NMR(400MHz,DMSO-d6)δ14.80(s, 1H),8.45(d,1H,J＝6.0Hz),8.24(d,1H,J＝2.0Hz),7.83(d,1H,J＝2.4Hz),7.57 (dd,1H,J1＝1.6Hz,J2＝8.4Hz),7.00-7.08(m,4H),6.90(d,1H,J＝8.4Hz),6.73- 6.76(m,2H),6.47(dd,1H,J1＝0.8Hz,J2＝8.0Hz),5.07(s,2H),4.30(q,2H,J＝6.8 Hz),1.42(t,3H,J＝6.8Hz).13C NMR(101MHz,DMSO-d6)δ166.73,159.72, 158.97,149.32,147.97,138.47,129.56,128.58,127.59,127.24,125.92,118.92, 118.82,114.67,113.73,111.93,110.03,105.86,64.53,55.40,14.79.HRMS(ESI) calcd for C21H20N2NaO2[M+Na]+:355.1422,Found:355.1421.
实施例35N'-羟基-3-((E)-4-羟基-3-(吡啶-2-基)乙烯基)苯甲酰胺(I-9)
在25毫升圆底烧瓶中，加入化合物4a(345mg,1mmol)、盐酸羟胺(208.5mg,3mmol)，用甲醇10mL溶解，室温搅拌下加入三乙胺(313mg,3.1mmol)，加毕，回流反应6个小时。反应结束后，将体系真空浓缩，浓缩物加入乙酸乙酯和水萃取，洗涤，有机相柱层析分离纯化(石油醚：丙酮＝3:1)得白色固体192mg，收率57.9％，Mp:195-196℃。1H NMR(400MHz,DMSO-d6)δ14.34(s,1H),9.65 (s,1H),8.66(d,1H,J＝4.4Hz),8.38(d,1H,J＝8.0Hz),8.29(s,1H),8.08(t,1H,J ＝7.2Hz),7.91(s,1H),7.54-7.63(m,3H),7.46-7.49(m,1H),7.38(t,1H,J＝7.6Hz), 7.31(d,1H,J＝16.4Hz),7.26(d,1H,J＝16.4Hz),6.97(d,1H,J＝8.8Hz),5.87(s, 2H).13C NMR(101MHz,DMSO-d6)δ159.55,157.09,151.35,146.73,139.14,137.82,134.29,129.95,128.96,128.54,127.16,126.27,125.90,124.72,123.51,122.96,120.54,119.36,118.87.HRMS(ESI)calcd for C20H18N3O2[M+H]+:332.1394,Found:332.1389.
实施例36N'-羟基-3-((E)-4-羟基-3-(吡啶-2-基)乙烯基)苯甲酰胺(I-10)
按照实施例35的方法，用化合物4b(346mg,1mmol)替换4a，得白色固体 142mg，产率42.8％，Mp:221-222℃。1H NMR(400MHz,DMSO-d6)δ13.36(s, 1H),9.65(s,1H),9.02(d,2H,J＝4.8Hz),8.62(d,1H,J＝2.0Hz),7.92(s,1H),7.76 (dd,1H,J1＝2.0Hz,J2＝8.4Hz),7.67-7.53(m,3H),7.35-7.39(m,2H),7.16(d, 1H,J＝16.4Hz),7.04(d,1H,J＝8.8Hz),5.88(s,2H).13C NMR(101MHz,DMSO-d6) δ164.11,160.31,157.47,151.28,137.73,134.25,131.49,128.93,128.88,128.77, 127.62,127.28,126.56,124.78,123.59,120.03,118.93,118.81.HRMS(ESI)calcd forC19H16N4NaO2[M+Na]+:355.1165,Found:355.1169.
实施例37N'-羟基-4-((E)-4-羟基-3-(吡啶-2-基)乙烯基)苯甲酰胺(I-11)
按照实施例35的方法，用化合物4c(346mg,1mmol)替换4a，得白色固体 144mg，产率44.3％，Mp:237-238℃。1H NMR(400MHz,DMSO-d6)δ13.38(s, 1H),9.66(s,1H),9.02(d,2H,J＝4.8Hz),8.62(s,1H),7.65(m,6H),7.37(d,1H,J＝ 16.4Hz),7.15(d,1H,J＝16.4Hz),7.03(d,1H,J＝8.5Hz),5.82(s,2H).13C NMR (101MHz,DMSO-d6)δ164.00,160.32,157.53,151.05,138.33,132.40,131.52, 128.89,128.75,127.61,126.41,126.17,126.06,120.11,118.84,118.8.HRMS(ESI) calcd forC19H17N4O2[M+H]+:333.1346,Found:333.1342.
实施例38本发明所合成的反式二苯乙烯类化合物的LSD1抑制活性评价
(一)酶水平LSD1抑制活性评价：
1、实验方法
样品为实施例所合成的上述化合物、纯化而得；样品储备液：称取3-5mg 样品置于1.5mL EP管中，然后用DMSO配制成浓度是20mM的溶液，4℃保存放置，实验时根据所需浓度用DMSO稀释。将待测样品与LSD1蛋白于室温孵育后，加入LSD1反应底物H3K4me2并孵育反应，最后加入荧光染料Amplex 和辣根过氧化酶HRP室温孵育，在酶标仪上激发光530nm，发射光590nm检测荧光数值:
试验结果采用SPSS软件计算IC50值。
2、实验结果
表1LSD1抑制活性测定结果
an.t.:未测定
从上表实验结果可以看出，本发明大部分的化合物具有较好的LSD1抑制活性，多个化合物的IC50小于1μM，活性强于阳性对照药物2-PCPA。其中活性最强的化合物I-2和I-7，其LSD1抑制活性是2-PCPA的100多倍。本发明的化合物代表着一类结构全新的LSD1抑制剂，为LSD1抑制剂类药物的研发提供了基础，为LSD1的生物学功能研究提供了有效工具。
(二)体外抗肿瘤活性测定
1、实验方法
样品为实施例所合成的化合物I-2，I-5，I-7，I-9，I-10和I-11；样品储备液: 称取3-5mg样品置于1.5mL EP管中，然后用DMSO配制成浓度为128μmol/L溶液， 4℃保存放置，实验时根据所需浓度利用培养基稀释。
取对数生长期的细胞，消化计数后，用培养基调整细胞密度，以4000-5000 个细胞/孔接种至96孔板中，每孔150μL，培养24h后，弃去培养基，加入用培养基稀释好的不同浓度的药物(128μM、64μM、32μM、16μM、8μM、4μM、2μM、 1μM、0.5μM)，每个浓度设6个复孔，另设空白对照组及阳性对照组。药物作用 72h后，每孔加入20μLMTT，继续培养4h后，吸去液体，加入150μL的DMSO，振荡均匀，酶标仪490nm处检测吸光度值，计算抑制率，计算公式如下:
抑制率％＝(1-给药组吸光度值/空白组吸光度值)×100％
2、实验结果
表2体外抗肿瘤活性评价结果
a人类结肠癌细胞，b人类乳腺癌细胞，c人类食管癌细胞
实验结果表明:所测试化合物对人类结肠癌SW-620细胞均表现出较好的抗肿瘤活性，多个化合物的抑制活性强于阳性对照药物5-Fu，其中化合物I-2对所测试的三种癌细胞的抑制活性均优于5-Fu，可作为进一步开发的候选或者先导化合物，应用于制备抗癌药物。

Claims (6)

1.一类反式二芳基乙烯化合物，其特征在于，具有通式I所示结构：
通式I中，R1为单取代或多取代，取代基选：NH2、中的任意一个；R2为H、OH、F、Cl、Br、I、C2-C5饱和酯基、C1-5烷氧基中的任意一个；R3为H、OH、CN、F、Cl、Br、I中的任意一个；X为C或者N原子。
2.如权利要求1所述的一类反式二芳基乙烯化合物，其特征在于，
通式I中，R1为单取代，取代基为：NH2、中的任意一个；R2为H、F、Cl、Br、I、乙酸甲酯酯基、乙氧基中的任意一个；R3为H、OH、F、Cl、Br、I中的任意一个；X为CH或N原子。
3.如权利要求1或2所述的一类反式二芳基乙烯类化合物，其特征在于，选以下化合物:
。
4.如权利要求3所述的一类反式二芳基乙烯类化合物，其特征在于，优选化合物I-2。
5.如权利要求1-4其中之一所述的一类反式二芳基乙烯类化合物在药物制备中的应用，其特征在于，将其作为活性成分用于LSD1抑制剂类药物的制备。
6.制备权利要求1或2所述的一类反式二芳基乙烯类化合物的方法，其特征在于，通过如下步骤实现：
R4为硝基或氰基，R1,R2，R3同权利要求1或2所述；
化合物1的制备方法:5-酰基-2-甲氧基苯硼酸和取代2-溴吡啶或取代2-溴嘧啶在甲苯中，碱性化合物和钯催化剂存在下，回流搅拌反应，得化合物1，其中，所述强碱性化合物选自碳酸钾、碳酸钠、碳酸铯、磷酸钾中的一种，所述的钯催化剂选在四(三苯基膦)钯、醋酸钯、双(二亚苄基丙酮)钯、二氯化钯中的一种；
化合物2的制备方法：化合物1和取代苄基膦酸二乙酯在DMF中，强碱性化合物存在下，室温搅拌反应，反应结束后，将反应体系倾入冰水中，抽滤，洗涤，收集固体，干燥，分别得化合物2；其中，所述强碱性化合物选自叔丁醇钾、甲醇钠、氢化钠、叔丁醇钠中的一种；
化合物3的制备方法：当化合物2中R’为硝基，则在有机溶剂中，SnCl2存在下，回流搅拌反应，反应结束后，反应体系真空浓缩，浓缩物加入乙酸乙酯、饱和碳酸氢钠水溶液搅拌，分取有机相，洗涤，干燥，柱层析分离分别得化合物3；其中，所述有机溶剂选自乙醇、乙酸乙酯、四氢呋喃中的一种；
化合物4的制备方法：当化合物2中R’为氰基，在无水二氯甲烷中，三溴化硼存在下，-35℃-室温过夜反应，反应结束后，将反应体系倾入到饱和碳酸氢钠水溶液中，抽滤，收集固体，柱层析分离得化合物4；
化合物I的制备方法：化合物4在甲醇中，强碱性化合物存在下，和盐酸羟胺回流搅拌反应，反应结束后，反应体系真空浓缩，浓缩物加入乙酸乙酯和水萃取，洗涤，有机相经柱层析分离，分别得化合物I；其中，所述强碱性化合物选自碳酸钾、碳酸铯、三乙胺、N,N-二异丙基乙胺中的一种；
或者将化合物3在无水二氯甲烷中，三溴化硼存在下，-35℃-室温反应，反应结束后，反应体系倾入到饱和碳酸氢钠水溶液中，抽滤，收集固体，经柱层析分离，得化合物I。
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