CN113264903A - 一种吩噻嗪类化合物及其制备方法和应用 - Google Patents

一种吩噻嗪类化合物及其制备方法和应用 Download PDF

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CN113264903A
CN113264903A CN202110586237.2A CN202110586237A CN113264903A CN 113264903 A CN113264903 A CN 113264903A CN 202110586237 A CN202110586237 A CN 202110586237A CN 113264903 A CN113264903 A CN 113264903A
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刘宏民
代兴杰
薛雷朋
郑一超
刘月娇
任红梅
熊小朋
周影
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Zhengzhou University
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Abstract

本发明公开了一种吩噻嗪类化合物，具有结构通式

Description

一种吩噻嗪类化合物及其制备方法和应用
技术领域
本发明属于药物化学领域，涉及一种吩噻嗪类化合物及其制备方法和应用。
背景技术
表观遗传学是指在不改变DNA序列的情况下，遗传基因发生的可遗传的变化，包括DNA修饰、组蛋白修饰、非编码RNA以及核小体的重塑。表观遗传调控异常会使基因错误表达，引起各种疾病，甚至发生肿瘤。组蛋白修饰是其中重要的研究方向，包括乙酰化、甲基化、磷酸化、羟基化和泛素化等，其中乙酰化和甲基化是最重要的内容。研究表明，它们对基因的转录具有调控作用。2004年，首个组蛋白赖氨酸去甲基化酶1(Lysine SpecificDemethylase l，LSD1)被发现，证实了组蛋白去甲基化是一个可逆的过程。机体内组蛋白赖氨酸残基上的甲基化水平通过2种特异性酶-组蛋白甲基转移酶和组蛋白去甲基化酶进行调节，LSD1是一种黄素腺嘌呤二核苷酸依赖的去甲基化酶，主要作用是作为转录激活剂或转录抑制剂，催化去除H3K4、H3K9的单甲基化和双甲基化。当H3K4上发生甲基化时，可引起基因转录的激活；当H3K9上发生甲基化时，可引起基因转录的抑制。
LSD1在多种肿瘤细胞中高表达，包括小细胞肺癌、膀胱癌、胃癌、前列腺癌乳腺癌和急性髓系白血病等，在肿瘤的分化、增殖、转移或侵袭方面起着重要作用。在一些癌细胞系中，通过RNAi敲除抑制LSD1可以激活肿瘤抑制基因(如p53)的表达，以及降低相关靶标基因的表达，因此，LSD1是一个很有潜力的抗肿瘤靶标。因此，研究开发高效低毒的LSD1抑制剂用于肿瘤的预防和治疗是重要的研究方向，已成为当前肿瘤药物研究的热点。
已有报道证实，吩噻嗪类化合物具有广泛的生物活性，可用作抗精神病类药物、抗菌药物、止吐药物和抗肿瘤药物等。但是目前尚无将吩噻嗪类化合物与基于LSD1靶点的抗肿瘤作用相联系起到抗肿瘤作用的报道，因此本研究具有非常重要的价值。
发明内容
为了克服现有技术的不足，本发明的目的之一在于提供一种吩噻嗪类化合物，该化合物对LSD1具有良好的抑制活性。
本发明的目的之二在于提供一种吩噻嗪类化合物的制备方法。
本发明的目的之三在于提供吩噻嗪类化合物在制备靶向LSD1的抗肿瘤药物中的应用。
本发明的目的之一采用如下技术方案实现：
一种吩噻嗪类化合物，具有结构通式Ⅰ：
Figure BDA0003087548470000021
其中R1自H或烷基、烷氧基、烷硫基、卤素中的一种；
n取0至6的整数；
R2选自R,
Figure BDA0003087548470000022
Figure BDA0003087548470000023
Figure BDA0003087548470000024
中的一种；
R选自C1-C4直链烷基、C1-C4支链烷基、环烷基、苯基、苄基、杂环、酰基、磺酰基、胺基、烷氧基、烷硫基中的一种。
进一步地，所述R1选自H或烷氧基、烷硫基、卤素中的一种；
n取0至4的整数；
R2选自R、
Figure BDA0003087548470000025
Figure BDA0003087548470000026
Figure BDA0003087548470000027
中的一种；
R选自C1-C4直链烷基、C1-C4支链烷基、环丙基、苯基、苄基、苄基并二氧戊环、嘧啶基、酰基、甲磺酰基中的一种。
进一步地，R1、R2选自下列基团的一种：
Figure BDA0003087548470000028
Figure BDA0003087548470000031
Figure BDA0003087548470000041
本发明的目的之二采用如下技术方案实现：
吩噻嗪类化合物的制备方法，其特征在于，包括以下步骤：
Figure BDA0003087548470000042
合成路线①：将化合物1和卤代烃加入到有机溶剂A中，在碱性物质A和催化剂A的作用下，反应制备得到化合物I；
合成路线②：将化合物1和二卤代烃或1-卤代-2,3-环氧丙烷在碱性物质B的作用下在有机溶剂B中进行反应，制备得到化合物2；将化合物2和亲核试剂R2H加入到有机溶剂C中，在碱性物质C和催化剂B的作用下反应制备得到化合物Ⅰ；
合成路线③：将化合物1和卤代酰卤在碱性物质D的作用下在有机溶剂D中进行反应，制备得到化合物3；将化合物3与BH3·Me2S在有机溶剂E中进行反应，制备得到化合物2；将化合物2和亲核试剂R2H加入到有机溶剂F中，在碱性物质E和催化剂C的作用下反应制备得到化合物Ⅰ；
所述X1为卤素、X2为卤素或环氧丙烷。
进一步地，所述合成路线①的反应温度为50℃-120℃；合成路线②中化合物1与二卤代烃反应温度为20℃-37℃，化合物1与1-卤代-2,3-环氧丙烷反应温度为50℃-120℃，化合物2与化合物4反应温度为50℃-120℃；合成路线③中化合物1和卤代酰卤反应温度为20℃-37℃，化合物3和BH3·Me2S反应温度为20℃-37℃，化合物2与亲核试剂R2H反应温度为50℃-120℃。
进一步地，所述有机溶剂A、B、C、E、F选自N,N-二甲基甲酰胺、四氢呋喃、乙腈、二氧六环中的一种，有机溶剂D选自二氯甲烷、氯仿、四氯化碳中的一种。。
进一步地，所述碱性物质A、C、E选自碳酸钾、三乙胺、吡啶、氢氧化钠、氢氧化钾中的一种，碱性物质B为氢化钠、氢氧化钠、氢氧化钾中的一种，碱性物质D选自三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶中的两种。
进一步地，所述催化剂A、B、C分别选自碘化钠、碘化钾中的一种，卤素选自Br、Cl中的一种或两种。
本发明的目的之三采用如下技术方案实现：
吩噻嗪类化合物在制备靶向LSD1的抗肿瘤药物中的应用。
相比现有技术，本发明的有益效果在于：
本发明提供了一种吩噻嗪类化合物，骨架新颖，高效低毒，对LSD1具有较好的抑制活性。本发明还提供了上述化合物的制备方法，具有反应条件温和、操作简单、反应收率高的特点。本发明以吩噻嗪为原料，在其母体上分别引入活性基团，合成得到新的吩噻嗪类药效团，并以哌嗪类、吗啉类、哌啶类等基团修饰，设计合成了一类吩噻嗪类化合物。该化合物保留了吩噻嗪的活性的同时，也兼具了修饰基团的特性，改善了原有分子的生物学活性，提高了目标分子的抗肿瘤活性。本发明还提供了上述化合物在制备靶向LSD1的抗肿瘤药物中的应用，表现出了对LSD1良好的抑制活性，显示出良好的开发潜力。
具体实施方式
下面，结合具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
化合物4至化合物21的制备过程如下：
Figure BDA0003087548470000051
实施例1
化合物4的制备：n＝2，
Figure BDA0003087548470000052
(1)将1a(1.99g，10mmol)溶于无水N,N-二甲基甲酰胺(20mL)中，然后在依次加入1-溴-3-氯丙烷(1.89g，12mmol)和氢化钠(0.48g，12mmol，60％纯度)，室温反应，TLC监测反应进度。反应完成后，旋蒸除去N,N-二甲基甲酰胺，将残余物溶于乙酸乙酯中，依次用水和饱和食盐水洗涤，有机相用无水硫酸镁干燥，过滤，旋蒸除去溶剂后，经柱层析分离得到化合物2b。收率为61.8％。
1H NMR(400MHz,CDCl3)δ7.17–7.15(m,4H),7.06(d,J＝7.5Hz,2H),6.94(d,J＝7.5Hz,2H),4.08(t,J＝6.5Hz,2H),3.67(t,J＝6.1Hz,2H),2.24–2.21(m,2H).13C NMR(100MHz,CDCl3)δ145.06,144.49,133.18,127.64,127.30,127.16,125.70,123.01,122.73,122.39,115.57,115.29,43.92,42.45,29.65.HRMS(ESI):m/z calcd forC15H15ClNS(M+H)+,276.0608；found,276.0608.
(2)将步骤(1)制备得到的化合物2b(275mg，1mmol)溶于乙腈(10mL)中，然后依次加碳酸钾(152mg，1.1mmol)、碘化钠(30mg，0.2mmol)和哌嗪(344mg，4mmol)，回流反应，TLC监测反应进度。反应完成后，旋蒸除去乙腈，将残余物溶于乙酸乙酯中，依次用水和饱和食盐水洗涤，有机相用无水硫酸镁干燥，过滤，旋蒸除去溶剂后，经柱层析分离得到化合物4。收率为72.8％。
1H NMR(400MHz,DMSO-d6)δ7.19(t,J＝7.7Hz,2H),7.13(d,J＝7.5Hz,2H),7.03(d,J＝8.0Hz,2H),6.93(t,J＝7.3Hz,2H),3.90(t,J＝6.7Hz,2H),2.76–2.61(m,4H),2.33(t,J＝6.8Hz,2H),2.22(s,4H),1.82–1.75(m,2H).13C NMR(100MHz,DMSO-d6)δ144.68,127.52,127.02,123.39,122.35,115.76,55.58,54.35,45.61,44.51,23.51.HRMS(ESI)calcd forC19H24N3S[M+H]+,326.1685；found,326.1632.
实施例2
化合物5的制备：n＝2，
Figure BDA0003087548470000062
实施例2与实施例1的区别在于将步骤(2)中的哌嗪替换为N-甲基哌嗪，步骤(4)中的碱性物质为吡啶、氢氧化钠，其余与实施例1相同。制备得到化合物5，收率为81.4％。
1H NMR(400MHz,CDCl3)δ7.15–7.12(m,4H),6.92–6.87(m,4H),3.92(t,J＝6.9Hz,2H),2.50–2.47(m,10H),2.28(s,3H),1.99–1.92(m,2H).13C NMR(100MHz,CDCl3)δ145.21,127.44,127.21,125.07,122.42,115.51,55.59,54.99,53.06,45.87,45.28,24.38.HRMS(ESI)calcd for C20H26N3S[M+H]+,340.1842；found,340.1833.
实施例3
化合物6的制备：n＝2，
Figure BDA0003087548470000061
实施例3与实施例1的区别在于将步骤(2)中的哌嗪替换为N-乙基哌嗪，其余与实施例1相同。制备得到化合物6，收率为78.1％。
1H NMR(400MHz,CDCl3)δ7.18–7.14(m,4H),6.95–6.91(m,2H),6.87(d,J＝8.0Hz,2H),3.97(t,J＝6.3Hz,2H),2.92–2.86(m,10H),2.69(t,J＝6.9Hz,2H),2.08–1.96(m,2H),1.37(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ145.07,127.62,127.35,125.52,122.73,115.77,54.22,52.05,50.93,49.73,44.50,23.47,9.68.HRMS(ESI)calcd for C21H28N3S[M+H]+,354.1998；found,354.1999.
实施例4
化合物7的制备：n＝2，
Figure BDA0003087548470000071
实施例4与实施例1的区别在于将步骤(2)中的哌嗪替换为N-苯基哌嗪，其余与实施例1相同。制备得到化合物7，收率为92.9％。
1H NMR(400MHz,CDCl3)δ7.25(t,J＝7.7Hz,3H),7.15(t,J＝7.4Hz,4H),6.91(t,J＝7.6Hz,6H),3.97(t,J＝6.6Hz,2H),3.19(s,4H),2.63–2.58(m,6H),2.10–2.05(m,2H).13CNMR(100MHz,CDCl3)δ145.72,139.87,123.90,122.28,122.07,120.06,117.35,114.80,110.99,110.41,89.29,75.11,72.11,71.79,50.28,47.81,43.43,39.82,24.48.HRMS(ESI)calcd for C24H32N3O2S[M+H]+,333.1420；found,333.1414.
实施例5
化合物8的制备：n＝2，
Figure BDA0003087548470000072
实施例5与实施例1的区别在于将步骤(2)中的哌嗪替换为N-甲基哌嗪，其余与实施例1相同。制备得到化合物8，收率为84.9％。
1H NMR(400MHz,DMSO-d6)δ7.32–7.23(m,5H),7.18(t,J＝7.6Hz,2H),7.13(d,J＝7.4Hz,2H),7.03(d,J＝8.1Hz,2H),6.92(t,J＝7.4Hz,2H),3.89(t,J＝6.5Hz,2H),3.41(s,2H),2.36–1.31(m,10H),1.81–1.75(m,2H).13C NMR(100MHz,DMSO-d6)δ144.67,138.20,128.74,128.08,127.52,127.02,126.81,123.42,122.36,115.76,62.02,54.81,52.86,52.61,44.50,23.73.HRMS(ESI)calcd for C26H30N3S[M+H]+,416.2155；found,416.2148.
实施例6
化合物9的制备：n＝2，
Figure BDA0003087548470000073
实施例6与实施例1的区别在于将步骤(2)中的哌嗪替换为N-胡椒基哌嗪，其余与实施例1相同。制备得到化合物9，收率为55.6％。
1H NMR(400MHz,CDCl3)δ7.15–7.11(m,4H),6.91–6.87(m,4H),6.83(s,1H),6.73(s,2H),5.92(s,2H),3.90(t,J＝6.9Hz,2H),3.39(s,2H),2.48–2.42(m,10H),1.99–1.91(m,2H).13C NMR(100MHz,CDCl3)δ147.58,146.54,145.22,132.08,127.41,127.18,125.02,122.37,122.22,115.48,109.52,107.82,100.84,62.76,55.75,53.31,52.96,45.37,24.45.HRMS(ESI)calcd for C27H30N2S[M+H]+,460.2053；found,460.2063.
实施例7
化合物10的制备：n＝2，
Figure BDA0003087548470000081
实施例7与实施例1的区别在于将步骤(2)中的哌嗪替换为N-甲酰基哌嗪，其余与实施例1相同。制备得到化合物10，收率为84.6％。
1H NMR(400MHz,CDCl3)δ7.19–7.15(m,4H),6.96–6.89(m,4H),4.00(t,J＝6.4Hz,2H),3.70(s,2H),3.55(s,2H),2.69(t,J＝7.0Hz,2H),2.59–2.55(m,4H),2.15–2.09(m,2H),2.06(s,3H).13C NMR(100MHz,CDCl3)δ168.87,144.98,127.63,127.40,125.56,122.80,115.78,55.30,52.97,52.39,44.72,23.24,21.19.HRMS(ESI)calcd for C21H26N3OS[M+H]+,368.1791；found,368.1783.
实施例8
化合物11的制备：n＝2，
Figure BDA0003087548470000082
实施例8与实施例1的区别在于将步骤(2)中的哌嗪替换为N-甲基吡啶，其余与实施例1相同。制备得到化合物11，收率为91.2％。
1H NMR(400MHz,CDCl3)δ7.13(dd,J＝12.1,4.7Hz,4H),6.90(dd,J＝11.1,4.2Hz,4H),3.89(t,J＝7.0Hz,2H),2.84(d,J＝11.6Hz,2H),2.44(t,J＝7.1Hz,2H),2.01–1.92(m,2H),1.89(td,J＝11.7,2.2Hz,2H),1.58(d,J＝13.9Hz,2H),1.38–1.27(m,1H),1.26–1.14(m,2H),0.90(d,J＝6.4Hz,3H).13C NMR(100MHz,CDCl3)δ145.23,127.38,127.18,124.93,122.34,115.46,56.19,54.12,45.57,34.29,30.77,24.60,21.87.HRMS(ESI)calcd forC21H27N2S[M+H]+,339.1889；found,339.1880.
实施例9
化合物12的制备：n＝2，
Figure BDA0003087548470000083
实施例9与实施例1的区别在于将步骤(2)中的哌嗪替换为吗啉，其余与实施例1相同。制备得到化合物12，收率为75.2％。
1H NMR(400MHz,DMSO-d6)δ7.21–7.17(m,2H),7.14(d,J＝7.6Hz,2H),7.04(d,J＝8.1Hz,2H),6.93(t,J＝7.4Hz,2H),3.92(t,J＝6.7Hz,2H),3.51–3.49(m,4H),2.37(t,J＝6.9Hz,2H),2.29(s,4H),1.82–1.76(m,2H).13C NMR(100MHz,DMSO-d6)δ144.69,127.54,127.04,123.48,122.38,115.81,66.18,55.23,53.39,44.41,23.40.HRMS(ESI)calcd forC19H23N2OS[M+H]+,327.1526；found,327.1527.
实施例10
化合物13的制备：n＝2，
Figure BDA0003087548470000091
实施例10与实施例1的区别在于将步骤(2)中的哌嗪替换为硫代吗啉，其余与实施例1相同。制备得到化合物13，收率为61.4％。
1H NMR(400MHz,CDCl3)δ7.17–7.13(m,4H),6.94–6.88(m,4H),3.95(t,J＝6.6Hz,2H),2.75–2.73(m,4H),2.68–2.65(m,4H),2.57(t,J＝7.1Hz,2H),2.04–1.96(m,2H).13CNMR(100MHz,CDCl3)δ145.11,127.51,127.28,125.27,122.57,115.64,56.03,54.95,44.85,27.45,23.61.HRMS(ESI)calcd for C19H23N2S2[M+H]+,343.1297；found,343.1293.
实施例11
化合物14的制备：n＝2，
Figure BDA0003087548470000092
实施例11与实施例1的区别在于将步骤(2)中的哌嗪替换为N,N-二甲基乙二胺，其余与实施例1相同。制备得到化合物14，收率为81.4％。
1H NMR(400MHz,CDCl3)δ7.16–7.12(m,4H),6.90(td,J＝8.5,1.5Hz,4H),3.95(t,J＝6.8Hz,2H),2.75(t,J＝6.9Hz,2H),2.64(t,J＝6.1Hz,2H),2.36(t,J＝6.1Hz,2H),2.16(s,6H),2.02–1.96(m,2H).13C NMR(100MHz,CDCl3)δ145.27,127.47,127.23,125.26,122.45,115.58,58.90,47.41,47.33,45.46,45.24,27.22.HRMS(ESI)calcd for C19H26N3S[M+H]+,328.1842；found,328.1831.
实施例12
化合物15的制备：n＝2，
Figure BDA0003087548470000093
实施例12与实施例1的区别在于将步骤(2)中的哌嗪替换为N-(2-氨基乙基)，其余与实施例1相同。制备得到化合物15，收率为46.7％。
1H NMR(400MHz,CDCl3)δ7.18–7.14(m,4H),δ6.95–6.89(m,4H),3.97(t,J＝6.6Hz,2H),3.62–3.59(m,4H),2.76(t,J＝6.8Hz,2H),2.68(t,J＝6.1Hz,2H),2.44(t,J＝6.1Hz,2H),2.38–2.36(m,4H),2.04(dd,J＝13.5,6.7Hz,2H).13C NMR(100MHz,CDCl3)δ145.28,127.57,127.29,125.45,122.60,115.66,66.95,57.83,47.11,46.05,44.96,26.89.HRMS(ESI)calcd for C22H30N3OS[M+H]+,384.2104；found,384.2097.
实施例13
化合物16的制备：n＝2，
Figure BDA0003087548470000101
实施例13与实施例1的区别在于将步骤(2)中的哌嗪替换为1-(2-氨乙基)哌啶，其余与实施例1相同。制备得到化合物16，收率为85.7％。
1H NMR(400MHz,CDCl3)δ7.34–7.17(m,4H),6.97–6.95(m,4H),4.08(t,J＝6.2Hz,1H),3.07(dd,J＝12.2,4.4Hz,4H),2.94(t,J＝6.6Hz,2H),2.83(s,4H),2.24–2.20(m,2H),1.74–1.68(m,4H),1.51(d,J＝4.7Hz,2H).13C NMR(100MHz,CDCl3)δ145.03,127.72,125.67,123.00,116.23,53.97,53.80,45.81,44.20,43.59,24.70,23.54,22.32.HRMS(ESI)calcd for C22H30N3S[M+H]+,368.2155；found,368.2149.
实施例14
化合物17的制备：n＝2，
Figure BDA0003087548470000102
实施例14与实施例1的区别在于将步骤(2)中的哌嗪替换为N-(3-氨丙基)吗啉，其余与实施例1相同。制备得到化合物17，收率为55.6％。
1H NMR(400MHz,DMSO-d6)δ7.24–7.17(m,4H),7.10(d,J＝8.0Hz,2H),6.97(t,J＝7.3Hz,2H),4.00(t,J＝6.6Hz,2H),3.55–3.53(m,4H),2.99–2.95(m,2H),2.86–2.82(m,2H),2.33–2.30(m,4H),2.08–2.05(m,2H),1.89(s,2H),1.79–1.75(m,2H).13C NMR(100MHz,DMSO-d6)δ144.53,127.64,127.18,123.81,122.68,115.99,66.10,55.04,53.00,45.34,44.42,43.96,23.34,22.24.HRMS(ESI)calcd for C21H28N3OS[M+H]+,370.1948；found,370.1943.
实施例15
化合物18的制备：n＝2，
Figure BDA0003087548470000103
实施例18与实施例1的区别在于将步骤(2)中的哌嗪替换为2-疏基嘧啶，其余与实施例1相同。制备得到化合物18，收率为68.1％。
1H NMR(400MHz,CDCl3)δ8.43(d,J＝4.8Hz,2H),7.16–7.11(m,4H),6.90–6.88(m,5H),4.04(t,J＝6.7Hz,2H),3.27(t,J＝7.1Hz,2H),2.29–2.22(m,2H).13C NMR(100MHz,CDCl3)δ172.24,157.19,145.18,127.50,127.21,125.41,122.52,116.40,115.55,45.83,28.16,26.53.HRMS(ESI)calcd for C19H18N3S2[M+H]+,352.0937；found,352.0933.
实施例16
化合物19的制备：n＝2，
Figure BDA0003087548470000104
实施例16与实施例1的区别在于将步骤(2)中的哌嗪替换为疏基乙酸乙酯，其余与实施例1相同。制备得到化合物19，收率为47.9％。
1H NMR(400MHz,CDCl3)δ7.18–7.14(m,4H),6.94–6.87(m,4H),4.00(t,J＝6.7Hz,2H),3.69(s,3H),3.17(s,2H),2.75(t,J＝7.0Hz,2H),2.10–2.05(m,2H).13C NMR(100MHz,CDCl3)δ170.83,145.11,127.58,127.26,125.57,122.64,115.60,52.38,45.59,33.63,30.05,26.18.HRMS(ESI)calcd for C18H20NOS2[M+H]+,346.0930；found,346.0926.
实施例17
化合物20的制备：n＝3，
Figure BDA0003087548470000111
实施例17与实施例1的区别在于将步骤(1)中的1-溴-3-氯丙烷替换为1-溴-4-氯丁烷，步骤(2)中的哌嗪替换为吗啉，其余与实施例1相同。制备得到化合物20，收率为78.7％。
1H NMR(400MHz,CDCl3)δ7.16–7.12(m,4H),6.92–6.86(m,4H),3.89(t,J＝6.9Hz,2H),3.65(t,J＝4.6Hz,4H),2.37–2.32(m,3H),1.88–1.81(m,2H),1.66–1.58(m,2H).13CNMR(100MHz,CDCl3)δ145.26,127.45,127.16,125.15,115.51,66.97,58.22,53.62,46.98,24.49,23.54.HRMS(ESI)calcd for C20H25N2OS[M+H]+,341.1682；found,341.1682.
实施例18
化合物21的制备：n＝4，
Figure BDA0003087548470000112
实施例18与实施例1的区别在于将步骤(1)中的1-溴-3-氯丙烷替换为1-溴-5-氯戊烷，步骤(2)中的哌嗪替换为吗啉，其余与实施例1相同。制备得到化合物21，收率为74.9％。
1H NMR(400MHz,CDCl3)δ7.16–7.12(m,4H),6.92–6.84(m,4H),3.86(t,J＝7.0Hz,2H),3.69(t,J＝4.6Hz,4H),2.38(s,4H),2.30(t,J＝6.8Hz,2H),1.85–1.78(m,2H),1.54–1.41(m,4H).13C NMR(100MHz,CDCl3)δ145.28,127.46,127.16,125.11,122.38,115.44,66.91,58.85,53.68,47.08,26.71,26.06,24.73.HRMS(ESI)calcd for C21H27N2OS[M+H]+,355.1839；found,355.1839.
化合物22至化合物43的制备过程如下：
Figure BDA0003087548470000113
实施例19
化合物22的制备：
Figure BDA0003087548470000114
(1)将化合物1a(1.99g，10mmol)溶于二氯甲烷(30mL)中，向体系中依次加入三乙胺(1.21g，12mmol)和4-二甲氨基吡啶(122mg，1mmol)。然后在0℃下，将溶解于二氯甲烷(10mL)中的溴乙酰溴(6.06g，30mmol)缓慢滴加进体系中，室温反应，TLC监测反应进度。反应完全后，体系用饱和食盐水洗涤，并用二氯甲烷萃取，有机相用无水硫酸镁干燥，过滤后旋蒸除去溶剂，经柱层析分离得到相应的化合物3a，收率为85.2％。
(2)将步骤(1)制备得到的化合物3a(1.6g，5mmol)溶解于无水N,N-二甲基甲酰胺(10mL)中，然后在0℃下滴加BH3·Me2S(5mL，2M)，在室温下反应并用TLC监测反应进度。反应完全后，旋蒸除去N,N-二甲基甲酰胺，将残渣溶于乙酸乙酯中，然后依次用水和饱和食盐水洗涤。有机相用无水硫酸镁干燥，过滤后旋蒸除去溶剂，经柱层析分离得到化合物2，产率：75.2％。
(3)将步骤(2)制备得到的化合物2a(306mg，1mmol)溶于MeCN(10mL)中，然后依次加碳酸钾(152mg，1.1mmol)、碘化钠(30mg，0.2mmol)和吗啉(348mg，4mmol)，回流反应，TLC监测反应进度。反应完成后，旋蒸除去乙腈，将残余物溶于乙酸乙酯中，依次用水和饱和食盐水洗涤，有机相用无水硫酸镁干燥，过滤后旋蒸除去溶剂后，经柱层析分离得到化合物22。收率54.9％。
1H NMR(400MHz,CDCl3)δ7.17–7.12(m,4H),6.93–6.90(m,4H),4.03(t,J＝6.8Hz,2H),3.72(t,J＝4.4Hz,4H),2.77(t,J＝6.9Hz,2H),2.54(t,J＝4.6Hz,4H).13C NMR(100MHz,CDCl3)δ145.02,127.50,127.29,124.95,122.61,115.38,66.92,55.94,53.94,45.61.HRMS(ESI)calcd for C18H21N2OS[M+H]+,313.1369；found,313.1370.
实施例20
化合物23的制备：
Figure BDA0003087548470000121
实施例20与实施例19的区别在于：将步骤(1)中的碱性物质替换为二异丙基乙胺、吡啶，步骤(3)中的吗啉替换为哌嗪，其余与实施例19相同，制备得到化合物23。收率为77.6％。
1H NMR(400MHz,DMSO-d6)δ7.23–7.15(m,4H),7.07(d,J＝8.0Hz,2H),6.96(t,J＝7.2Hz,2H),4.00(t,J＝6.2Hz,2H),2.96(s,4H),2.69(t,J＝6.1Hz,2H),2.59(s,4H).13CNMR(100MHz,DMSO-d6)δ144.58,127.65,127.12,123.51,122.61,115.84,54.73,50.69,45.16,43.62.HRMS(ESI)calcd for C18H22N3S[M+H]+,312.1529；found,271.1530.
实施例21
化合物24的制备：
Figure BDA0003087548470000122
实施例21与实施例19的区别在于：将步骤(3)中的吗啉替换为N-甲基哌嗪，其余与实施例19相同，制备得到化合物24。收率为80.1％。
1H NMR(400MHz,CDCl3)δ7.16–7.12(m,4H),6.93–6.89(m,4H),4.02(t,J＝6.9Hz,2H),2.79(t,J＝7.0Hz,2H),2.54(d,J＝45.2Hz,8H),2.30(s,3H).13C NMR(100MHz,CDCl3)δ145.08,127.46,127.29,124.87,122.55,115.40,55.53,55.06,53.44,46.00,45.80.HRMS(ESI)calcd for C19H24N3S[M+H]+,326.1686；found,326.1686.
实施例22
化合物25的制备：
Figure BDA0003087548470000131
实施例22与实施例19的区别在于：将步骤(3)中的吗啉替换为N-乙基哌嗪，其余与实施例19相同，制备得到化合物25。收率为87.1％。
1H NMR(400MHz,Acetone-d6)δ7.20–7.17(m,2H),7.13–7.08(m,4H),6.93(td,J＝7.5,1.2Hz,2H),4.05(t,J＝6.6Hz,2H),2.72(t,J＝6.6Hz,2H),2.47(d,J＝48.7Hz,8H),2.32(q,J＝7.2Hz,2H),1.01(t,J＝7.2Hz,3H).13C NMR(100MHz,Acetone-d6)δ146.08,128.36,127.93,125.12,123.36,116.64,56.42,54.41,53.76,52.86,47.03,12.58.HRMS(ESI)calcd for C20H26N3S[M+H]+,340.1842；found,340.1843.
实施例23
化合物26的制备：
Figure BDA0003087548470000132
实施例23与实施例19的区别在于：将步骤(3)中的吗啉替换为N-异丙基哌嗪，其余与实施例19相同，制备得到化合物26。收率为78.4％。
1H NMR(400MHz,CDCl3)δ7.18–7.13(m,4H),6.96–6.87(m,4H),4.05(t,J＝6.1Hz,2H),3.28–3.25(m,1H),3.00(s,8H),2.88(t,J＝6.2Hz,2H),1.34(d,J＝6.6Hz,6H).13C NMR(100MHz,CDCl3)δ145.10,127.46,127.29,124.85,122.55,115.41,55.56,54.46,53.86,48.59,45.68,18.61.HRMS(ESI)calcd for C21H28N3S[M+H]+,354.1999；found,354.1999.
实施例24
化合物27的制备：
Figure BDA0003087548470000133
实施例24与实施例19的区别在于：将步骤(3)中的吗啉替换为N-正丁基哌嗪，其余与实施例19相同，制备得到化合物27。收率为92.8％。
1H NMR(400MHz,CDCl3)δ7.16–7.11(m,4H),6.93–6.89(m,4H),4.02(t,J＝6.9Hz,2H),2.78(t,J＝7.1Hz,2H),2.61–2.50(m,8H),2.34(t,J＝7.6Hz,2H),1.49–1.44(m,2H),1.35–1.29(m,2H),0.91(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ145.10,127.44,127.28,124.83,122.53,115.40,58.50,55.61,53.59,53.23,45.78,29.05,20.79,14.05.HRMS(ESI)calcd for C22H30N3S[M+H]+,368.2155；found,368.2156.
实施例25
化合物28的制备：
Figure BDA0003087548470000141
实施例25与实施例19的区别在于：将步骤(3)中的吗啉替换为N-环丙基哌嗪，其余与实施例19相同，制备得到化合物28。收率为67.0％。
1H NMR(400MHz,CDCl3)δ7.16–7.10(m,4H),6.94–6.89(m,4H),4.03(t,J＝6.9Hz,2H),2.78(t,J＝7.1Hz,2H),2.67(s,4H),2.55(s,4H),1.64–1.61(m,1H),0.47–0.37(m,4H).13C NMR(100MHz,CDCl3)δ145.11,127.47,127.29,124.85,122.55,115.41,55.60,53.50,53.24,45.73,38.43,5.72.HRMS(ESI)calcd for C21H26N3S[M+H]+,352.1842；found,352.1842.
实施例26
化合物29的制备：
Figure BDA0003087548470000142
实施例26与实施例19的区别在于：将步骤(3)中的吗啉替换为N-苄基哌嗪，其余与实施例19相同，制备得到化合物29。收率为64.7％。
1H NMR(400MHz,CDCl3)δ7.30(d,J＝4.4Hz,4H),7.25–7.24(m,1H),7.15–7.11(m,4H),6.92–6.88(m,4H),4.01(d,J＝6.9Hz,2H),3.51(s,2H),2.77(d,J＝7.1Hz,2H),2.59–2.50(m,8H).13C NMR(100MHz,CDCl3)δ145.07,138.06,129.18,128.20,127.43,127.26,127.04,124.81,122.51,115.38,63.03,55.53,53.58,53.02,45.80.HRMS(ESI)calcd forC25H28N3S[M+H]+,402.1999；found,402.1999.
实施例27
化合物30的制备：
Figure BDA0003087548470000143
实施例27与实施例19的区别在于：将步骤(3)中的吗啉替换为1-(2-嘧啶基)哌嗪，其余与实施例19相同，制备得到化合物30。收率为90.4％。
1H NMR(400MHz,CDCl3)δ8.30(d,J＝4.7Hz,2H),7.17–7.12(m,4H),6.93(dd,J＝14.1,7.6Hz,4H),6.47(t,J＝4.7Hz,1H),4.07(t,J＝4.7Hz,2H),3.85(t,J＝4.9Hz,4H),2.82(t,J＝7.0Hz,2H),2.60(t,J＝5.1Hz,4H).13C NMR(100MHz,CDCl3)δ161.62,157.70,145.06,127.49,127.29,124.97,122.59,115.43,109.88,55.66,53.44,45.89,43.67.HRMS(ESI)calcd for C22H24N5S[M+H]+,390.1747；found,390.1747.
实施例28
化合物31的制备：
Figure BDA0003087548470000151
实施例28与实施例19的区别在于：将步骤(3)中的吗啉替换为N-甲酰基哌嗪，其余与实施例19相同，制备得到化合物31。收率为63.4％。
1H NMR(400MHz,CDCl3)δ7.18–7.13(m,4H),6.95–6.90(m,4H),4.04(t,J＝6.6Hz,2H),3.62(t,J＝5.0Hz,2H),3.46(t,J＝5.0Hz,2H),2.80(t,J＝6.8Hz,2H),2.55–2.49(m,4H),2.07(s,3H).13C NMR(100MHz,CDCl3)δ168.95,145.01,127.54,127.30,125.11,122.67,115.45,55.32,53.53,53.05,46.27,45.84,41.38,21.30.HRMS(ESI)calcd forC20H23N3OS[M+Na]+,376.1566；found,376.1455.
实施例29
化合物32的制备：
Figure BDA0003087548470000152
实施例29与实施例19的区别在于：将步骤(3)中的吗啉替换为1-(2-呋喃甲酰基)哌嗪，其余与实施例19相同，制备得到化合物32。收率为70.5％。
1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.15(t,J＝8.3Hz,4H),6.98(d,J＝3.3Hz,1H),6.92(t,J＝7.3Hz,4H),6.47(dd,J＝3.3,1.7Hz,1H),4.05(t,J＝6.7Hz,2H),3.81(s,4H),2.81(t,J＝6.8Hz,2H),2.59(t,J＝4.9Hz,4H).13C NMR(100MHz,CDCl3)δ159.06,147.91,145.03,143.66,127.56,127.31,125.11,122.68,116.39,115.44,111.27,55.36,53.57,45.88.HRMS(ESI)calcd for C23H23N3O2S[M+Na]+,428.1403；found,428.1404.
实施例30
化合物33的制备：
Figure BDA0003087548470000153
实施例30与实施例19的区别在于：将步骤(3)中的吗啉替换为N-Boc哌嗪，其余与实施例19相同，制备得到化合物33。收率为61.7％。
1H NMR(400MHz,CDCl3)δ7.17–7.12(m,4H),6.93–6.90(m,4H),4.03(t,J＝6.7Hz,2H),3.44(t,J＝4.8Hz,4H),2.78(t,J＝6.9Hz,2H),2.48(t,J＝4.7Hz,4H),1.45(s,9H).13CNMR(100MHz,CDCl3)δ154.72,145.05,127.51,127.29,125.00,122.62,115.41,79.68,77.34,77.02,76.70,55.59,53.33,45.88,28.43.HRMS(ESI)calcd for C23H29N3O2S[M+Na]+,434.1872；found,434.1873.
实施例31
化合物34的制备：
Figure BDA0003087548470000154
实施例31与实施例19的区别在于：将步骤(3)中的吗啉替换为N-甲烷磺酰基哌嗪，其余与实施例19相同，制备得到化合物34。收率为63.7％。
1H NMR(400MHz,CDCl3)δ7.25–7.11(m,4H),6.96–6.87(m,4H),4.03(t,J＝6.5Hz,2H),3.23(t,J＝6.5Hz,4H),2.82(dd,J＝13.2,6.7Hz,2H),2.77(s,3H),2.65–2.61(m,4H).13C NMR(100MHz,CDCl3)δ144.99,127.59,127.31,125.25,122.72,115.48,55.02,54.90,52.64,45.87,34.25.HRMS(ESI)calcd for C19H23N3O2S2[M+Na]+,412.1124；found,412.1125.
实施例32
化合物35的制备：
Figure BDA0003087548470000161
实施例32与实施例19的区别在于：将步骤(3)中的吗啉替换为4-甲基哌啶，其余与实施例19相同，制备得到化合物35。收率为88.2％。
1H NMR(400MHz,CDCl3)δ7.17–7.09(m,4H),6.94–6.88(m,4H),2.96–2.91(m,2H),2.75(t,J＝7.2Hz,2H),2.18–2.03(m,4H),1.65(s,1H),1.36–1.21(m,4H),0.93(d,J＝6.2Hz,1H).13C NMR(100MHz,CDCl3)δ145.14,127.42,127.29,124.72,122.49,115.41,55.91,54.44,45.88,34.25,30.61,21.87.HRMS(ESI)calcd for C20H24N2S[M+Na]+,347.1552；found,347.1553.
实施例33
化合物36的制备：
Figure BDA0003087548470000162
实施例33与实施例19的区别在于：将步骤(3)中的吗啉替换为4-哌啶基哌啶，其余与实施例19相同，制备得到化合物36。收率为67.0％。
1H NMR(400MHz,CDCl3)δ7.18–7.13(m,4H),6.95–6.87(m,4H),4.02(t,J＝6.4Hz,2H),3.17–3.08(m,5H),2.79(t,J＝6.4Hz,2H),2.29–2.18(m,8H),2.04–1.82(m,4H),1.25(s,2H).13C NMR(100MHz,CDCl3)δ144.96,127.58,127.39,125.26,122.75,115.57,64.28,52.17,49.86,45.88,29.69,25.88,22.51,22.34.HRMS(ESI)calcd for C24H32N3S[M+H]+,394.2312；found,394.2315.
实施例34
化合物37的制备：
Figure BDA0003087548470000163
实施例34与实施例19的区别在于：将步骤(3)中的吗啉替换为硫代吗啉，其余与实施例19相同，制备得到化合物37。收率为77.6％。
1H NMR(400MHz,CDCl3)δ7.16–7.12(m,4H),6.91(t,J＝7.5Hz,4H),4.00(t,J＝7.3Hz,2H),2.82–2.77(m,6H),2.69–2.66(m,4H).13C NMR(100MHz,CDCl3)δ145.03,127.49,127.27,124.94,122.58,115.41,56.26,55.28,45.83,27.95.HRMS(ESI)calcd forC18H21N2S2[M+H]+,329.1141；found,329.1141.
实施例35
化合物38的制备：
Figure BDA0003087548470000171
实施例35与实施例19的区别在于：将步骤(3)中的吗啉替换为二甲胺，其余与实施例19相同，制备得到化合物38。收率为63.5％。
1H NMR(400MHz,CDCl3)δ7.18–7.13(m,4H),6.94–6.90(m,4H),4.04(t,J＝6.8Hz,2H),2.78(m,t,J＝7.0Hz,2H),2.36(s,6H).13C NMR(100MHz,CDCl3)δ145.00,127.51,127.37,124.92,122.63,115.33,56.22,45.77,45.43.HRMS(ESI)calcd for C16H19N2S[M+H]+,271.1264；found,271.1264.
实施例36
化合物39的制备：
Figure BDA0003087548470000172
实施例36与实施例19的区别在于：将步骤(3)中的吗啉替换为4-甲基-1-哌嗪乙胺，其余与实施例19相同，制备得到化合物39。收率为86.4％。
1H NMR(400MHz,CDCl3)δ7.17–7.13(m,4H),6.96–6.90(m,4H),4.06–3.98(m,2H),3.01–2.97(m,2H),2.66(t,J＝6.1Hz,2H),2.43–2.29(m,8H),2.26(s,3H),2.10–1.99(m,2H).13C NMR(100MHz,CDCl3)δ145.17,127.58,127.25,125.67,122.67,115.67,57.66,55.07,53.13,47.01,46.34,46.09,46.07.HRMS(ESI)calcd for C21H29N4S[M+H]+,369.2108；found,369.2109.
实施例37
化合物40的制备：
Figure BDA0003087548470000173
实施例37与实施例19的区别在于：将步骤(3)中的吗啉替换为N-(2-氨基乙基)吗啉，其余与实施例19相同，制备得到化合物40。收率为67.4％。
1H NMR(400MHz,CDCl3)δ7.28(d,J＝2.2Hz,1H),7.19–7.15(m,3H),6.97–6.91(m,3H),6.77(d,J＝8.6Hz,1H),4.05(t,J＝5.9Hz,2H),3.61(t,J＝4.5Hz,4H),3.02(t,J＝5.9Hz,1H),2.72–2.66(m,2H),2.42(t,J＝5.9Hz,2H),2.31(t,J＝4.4Hz,4H).13C NMR(100MHz,CDCl3)δ144.70,144.32,130.00,129.88,127.73,127.59,125.07,123.15,116.85,115.85,66.90,57.72,53.59,46.79,45.95,45.46.HRMS(ESI)calcd for C20H26N3OS[M+H]+,356.1791；found,356.1792.
实施例38
化合物41的制备：
Figure BDA0003087548470000181
实施例38与实施例19的区别在于：将步骤(3)中的吗啉替换为2-巯基嘧啶，其余与实施例19相同，制备得到化合物41。收率为61.5％。
1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.8Hz,2H),7.23–7.07(m,6H),7.02–7.00(m,1H),6.95–6.90(m,2H),4.23(t,J＝7.6Hz,2H),3.53(t,J＝7.8Hz,2H).13C NMR(100MHz,CDCl3)δ172.00,157.40,144.61,127.42,127.34,124.40,122.65,116.74,115.32,47.39,27.61.HRMS(ESI)calcd for C18H15N3S2[M+Na]+,360.0600；found,360.3237.
实施例39
化合物42的制备：
Figure BDA0003087548470000182
实施例39与实施例19的区别在于：将步骤(3)中的吗啉替换为N-氨基吗啉，其余与实施例19相同，制备得到化合物42。收率为74.1％。
1H NMR(400MHz,CDCl3)δ7.07(t,J＝8.2Hz,4H),6.86–6.83(m,4H),3.96(t,J＝6.7Hz,2H),3.65(t,J＝4.3Hz,4H),2.70(t,J＝6.6Hz,2H),2.47(s,4H).13C NMR(100MHz,CDCl3)δ144.01,126.49,126.27,123.95,121.59,114.37,65.89,54.93,52.92,44.57.HRMS(ESI)calcd for C18H22N3OS[M+H]+,328.1478；found,328.1475.
实施例40
化合物43的制备：
Figure BDA0003087548470000183
实施例40与实施例19的区别在于：将步骤(3)中的吗啉替换为2-甲基吗啉，其余与实施例19相同，制备得到化合物43。收率为77.6％。
1H NMR(400MHz,CDCl3)δ7.17–7.10(m,4H),6.95–6.89(m,4H),4.03(t,J＝6.8Hz,2H),3.86–3.83(m,1H),3.66(t,J＝7.7Hz,2H),2.23(t,J＝8.0Hz,2H),1.93(t,J＝10.0Hz,2H),1.14(d,J＝6.3Hz,1H).13C NMR(100MHz,CDCl3)δ145.05,127.49,127.28,124.95,122.59,115.40,71.79,66.74,60.44,55.76,53.24,45.70,19.11.HRMS(ESI)calcd forC19H23N2OS[M+H]+,327.1526；found,327.1526.
化合物44至化合物48的制备过程如下：
Figure BDA0003087548470000184
实施例41
化合物44的制备：R1＝Cl
Figure BDA0003087548470000191
将2-氯吩噻嗪(199mg，1mmol)溶于乙腈(10mL)中，然后依次加碳酸钾(152mg，1.1mmol)、碘化钠(30mg，0.2mmol)和2-(4-吗啉)乙基溴(776mg，4mmol)，回流反应，TLC监测反应进度。反应完成后，旋蒸除去乙腈，将残余物溶于乙酸乙酯中，依次用水和饱和食盐水洗涤，有机相用无水硫酸镁干燥，过滤后旋蒸除去溶剂后，经柱层析分离得到化合物44。收率56.7％。
1H NMR(400MHz,CDCl3)δ7.18–7.11(m,2H),7.03–6.94(m,3H),6.92–6.88(m,2H),3.99(t,J＝6.5Hz,2H),3.73(t,J＝3.6Hz,4H),2.76(t,J＝6.6Hz,2H),2.54(m,t,J＝4.6Hz,4H).13C NMR(100MHz,CDCl3)δ146.29,144.32,133.31,127.89,127.55,127.49,124.56,123.27,123.05,122.40,115.95,115.62,66.97,55.99,53.93,46.04.HRMS(ESI)calcd for C18H20ClN2OS[M+H]+,347.0980；found,347.0980.
实施例42
化合物45的制备：R1＝CF3
Figure BDA0003087548470000192
实施例42与实施例41的区别在于：将2-氯吩噻嗪替换为2-三氟甲基吩噻嗪，制备得到化合物45。收率为45.8％。
1H NMR(400MHz,Acetone)δ7.53(s,1H),7.31(d,J＝7.9Hz,1H),7.23(dd,J＝12.1,4.9Hz,2H),7.14(dd,J＝7.6,1.4Hz,1H),7.09(d,J＝7.7Hz,1H),6.99(td,J＝7.5,1.1Hz,1H),4.14(t,J＝6.1Hz,2H),3.63(t,J＝4.6Hz,4H),2.76(t,J＝6.1Hz,2H),2.51(s,4H).13C NMR(100MHz,Acetone)δ146.55,145.12,130.29,130.12(2J＝29.6Hz),128.84,128.24,128.05,125.39(1J＝269.9Hz),124.09,123.82,119.84(3J＝4.0Hz),117.01,113.31(3J＝3.7Hz),67.45,56.89,54.73,47.39.HRMS(ESI)calcd for C19H20F3N2OS[M+H]+,381.1243；found,381.1244.
实施例43
化合物46的制备：R1＝OMe
Figure BDA0003087548470000201
实施例43与实施例41的区别在于：将2-氯吩噻嗪替换为2-甲氧基吩噻嗪，制备得到化合物46。收率64.1％。
1H NMR(400MHz,CDCl3)δ7.13(d,J＝9.1Hz,2H),7.02(d,J＝8.4Hz,1H),6.93–6.89(m,2H),6.56(d,J＝2.4Hz,1H),6.49(dd,J＝8.4,2.4Hz,1H),4.02(t,J＝6.7Hz,2H),3.78(s,3H),3.73(t,J＝4.6Hz,4H),2.80(t,J＝6.8Hz,2H),2.56(t,J＝4.3Hz,4H).13C NMR(100MHz,CDCl3)δ159.85,146.44,144.81,127.73,127.47,127.16,125.48,122.65,115.78,115.43,107.09,103.28,66.88,56.04,55.53,53.92,45.73.HRMS(ESI)calcd forC19H23N2O2S[M+H]+,343.1475；found,343.1475.
实施例44
化合物47的制备：R1＝SMe
Figure BDA0003087548470000202
实施例44与实施例41的区别在于：将2-氯吩噻嗪替换为2-甲巯基吩噻嗪，得到化合物47。收率为47.8％。
1H NMR(400MHz,acetone)δ7.20–7.16(m,1H),7.11(dd,J＝7.6,1.4Hz,1H),7.04(dd,J＝9.0,7.7Hz,3H),6.93(td,J＝7.5,1.0Hz,1H),6.85(dd,J＝8.0,1.8Hz,1H),4.07(t,J＝6.4Hz,2H),3.63(t,J＝4.6Hz,4H),2.72(t,J＝6.4Hz,2H),2.50(s,7H).13C NMR(100MHz,acetone)δ146.46,145.74,139.22,128.38,128.04,127.93,125.12,123.52,121.49,121.31,116.75,114.89,67.50,56.93,54.82,47.07.HRMS(ESI)calcd forC19H22N2OS2[M+Na]+,381.1066；found,381.1066.
实施例45
化合物48的制备：n＝0，R1＝H，
Figure BDA0003087548470000211
制备过程如下：
Figure BDA0003087548470000212
将化合物1(199mg，1mmol)溶于乙腈(10mL)中，然后依次加碳酸钾(235mg，1.1mmol)、碘化钠(30mg，0.2mmol)和2-氯-N-[(2-吡啶氨基)羰基]乙酰胺(854mg，1.1mmol)，回流反应，TLC监测反应进度。反应完成后，旋蒸除去乙腈，将残余物溶于乙酸乙酯中，依次用水和饱和食盐水洗涤，有机相用无水硫酸镁干燥，过滤，旋蒸除去溶剂后，经柱层析分离得到化合物48。收率80.8％。
1H NMR(400MHz,DMSO-d6)δ11.12(s,2H),10.67(s,2H),8.32(dd,J＝4.8,1.0Hz,2H),7.96(d,J＝8.3Hz,2H),7.85–7.80(m,2H),7.17–7.13(m,2H),3.91(s,2H).13C NMR(100MHz,DMSO-d6)δ171.96,151.05,150.66,148.58,139.01,120.17,113.52.HRMS(ESI)calcd for C20H17N4O2SNa+,377.1067；found,377.0931.
实施例46
化合物49的制备：n＝0，R1＝H，
Figure BDA0003087548470000213
制备过程如下：
Figure BDA0003087548470000214
(1)将化合物1a(1.99g，10mmol)溶于四氢呋喃(20mL)中，然后分批加入NaH(0.48g，12mmol，60％纯度)。室温反应1h后，加入1-溴-2,3-环氧丙烷(1.64g,12mmol)，在室温下进行反应并用TLC监测反应进度。反应完成后，加冰水淬灭，用乙酸乙酯萃取、有机相用无水硫酸镁干燥，过滤后旋蒸除去溶剂后，经柱层析分离得到化合物2e。收率60.2％。
(2)将步骤(1)制备得到的化合物2e(255mg，1mmol)溶于乙醇(15mL)中，然后加入吗啉(87mg，1mmol)，100℃下回流反应并用TLC监测反应进度。反应完成后，加入乙酸乙酯，再用水洗涤，有机相用无水硫酸镁干燥，过滤后旋蒸除去溶剂后，经柱层析分离得到化合物49。收率41.4％。
1H NMR(400MHz,CDCl3)δ7.18–7.14(m,4H),6.98–6.92(m,4H),4.16–4.10(m,1H),4.09–4.04(m,1H),3.95(dd,J＝13.5,6.0Hz,1H),3.66(t,J＝4.5Hz,1H),2.60(dd,J＝12.7,3.7Hz,0H),2.56–2.51(m,1H),2.43–2.37(m,1H).13C NMR(100MHz,CDCl3)δ145.42,127.74,127.34,126.15,122.96,115.98,66.97,64.00,62.54,53.93,51.73.HRMS(ESI)calcd for C19H23N2O2S[M+H]+,343.1475；found,343.1486.
实验例1
LSD1抑制活性测定：
LSD1抑制活性的检测样品为实施例1至46所制备得到的化合物经纯化得到。样品储备液的配制过程为：称取1～2mg样品置于1.5mL EP管中，用DMSO配制成浓度为20mM的溶液，于4℃环境下保存备用，实验时根据所需浓度用DMSO稀释。将待测样品与LSD1蛋白在室温孵育后，加入LSD1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检测荧光数值数值。实验结果采用SPSS软件计算IC50值，结果如表1所示。抑制率的计算公式如下所示：
Figure BDA0003087548470000221
表1
Figure BDA0003087548470000222
Figure BDA0003087548470000231
Figure BDA0003087548470000241
由表1可知，本发明提供的一种吩噻嗪类化合物对LSD1有一定的抑制活性。当化合物浓度为10μM时，如化合物4-6、化合物9-10、化合物12-17、化合物20-22、化合物25-28、化合物31-32、化合物34、化合物36-39、化合物41-43、化合物46-49等抑制活性较好，对LSD1的抑制活性较高，均达80％以上。化合物5、10、11、12、14、20、22、24、42、47、48等发挥作用时，其IC50值较低，具有较小的生物毒性。
综上，本发明提供的吩噻嗪类化合物对LSD1具有良好的抑制活性，显示出良好的开发潜力，为开发新型抗肿瘤药物、药物的联合用药以及新型LSD1抑制剂药物的开发开辟了一条有效途径，具有良好的市场应用前景。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。

Claims (9)

1.一种吩噻嗪类化合物，其特征在于，具有结构通式Ⅰ：
Figure FDA0003087548460000011
其中R1选自H或烷基、烷氧基、烷硫基、卤素中的一种；
n取0至6的整数；
R2选自R,
Figure FDA0003087548460000012
Figure FDA0003087548460000013
Figure FDA0003087548460000014
中的一种；
R选自C1-C4直链烷基、C1-C4支链烷基、环烷基、苯基、苄基、杂环、酰基、磺酰基、胺基、烷氧基、烷硫基中的一种。
2.如权利要求1所述的吩噻嗪类化合物，其特征在于，所述R1选自H或烷氧基、烷硫基、卤素中的一种；
n取0至4的整数；
R2选自R、
Figure FDA0003087548460000015
Figure FDA0003087548460000016
Figure FDA0003087548460000017
中的一种；
R选自C1-C4直链烷基、C1-C4支链烷基、环丙基、苯基、苄基、苄基并二氧戊环、嘧啶基、酰基、甲磺酰基中的一种。
3.如权利要求2所述的吩噻嗪类化合物，其特征在于，R1、R2选自下列基团的一种：
Figure FDA0003087548460000018
Figure FDA0003087548460000021
Figure FDA0003087548460000031
。
4.如权利要求1至3任一项所述的吩噻嗪类化合物的制备方法，其特征在于，包括以下步骤：
Figure FDA0003087548460000032
合成路线①：将化合物1和含有卤素取代的杂烷烃加入到有机溶剂A中，在碱性物质A和催化剂A的作用下，反应制备得到化合物I；
合成路线②：将化合物1和二卤代烃或1-卤代-2,3-环氧丙烷在碱性物质B的作用下在有机溶剂B中进行反应，制备得到化合物2；将化合物2和亲核试剂R2H加入到有机溶剂C中，在碱性物质C和催化剂B的作用下反应制备得到化合物Ⅰ；其中X2为卤素或环氧丙烷；
合成路线③：将化合物1和卤代酰卤在碱性物质D的作用下在有机溶剂D中进行反应，制备得到化合物3；将化合物3与BH3·Me2S在有机溶剂E中进行反应，制备得到化合物2；将化合物2和亲核试剂R2H加入到有机溶剂F中，在碱性物质E和催化剂C的作用下反应制备得到化合物Ⅰ；其中X2为卤素；
所述X1为卤素、X2为卤素或环氧丙烷。
5.如权利要求4所述的吩噻嗪类化合物的制备方法，其特征在于，所述合成路线①的反应温度为50℃-120℃；合成路线②中化合物1与二卤代烃反应温度为20℃-37℃，化合物1与1-卤代-2,3-环氧丙烷反应温度为50℃-120℃，化合物2与亲核试剂R2H反应温度为50℃-120℃；合成路线③中化合物1和卤代酰卤反应温度为20℃-37℃，化合物3和BH3·Me2S反应温度为20℃-37℃，化合物2与亲核试剂R2H反应温度为50℃-120℃。
6.如权利要求4所述的吩噻嗪类化合物的制备方法，其特征在于，所述有机溶剂A、B、C、E、F选自N,N-二甲基甲酰胺、四氢呋喃、乙腈、二氧六环中的一种，有机溶剂D选自二氯甲烷、氯仿、四氯化碳中的一种。
7.如权利要求4所述的吩噻嗪类化合物的制备方法，其特征在于，所述碱性物质A、C、E选自碳酸钾、三乙胺、吡啶、氢氧化钠、氢氧化钾中的一种，碱性物质B为氢化钠、氢氧化钠、氢氧化钾中的一种，碱性物质D选自三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶中的两种。
8.如权利要求4所述的吩噻嗪类化合物的制备方法，其特征在于，所述催化剂A、B、C分别选自碘化钠、碘化钾中的一种，卤素选自Br、Cl中的一种或两种。
9.如权利要求1至3任一项所述的吩噻嗪类化合物在制备靶向LSD1的抗肿瘤药物中的应用。
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