CN107721975A - 具有抗肿瘤活性的brd4小分子抑制剂、合成方法及其应用 - Google Patents

具有抗肿瘤活性的brd4小分子抑制剂、合成方法及其应用 Download PDF

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CN107721975A
CN107721975A CN201711117562.4A CN201711117562A CN107721975A CN 107721975 A CN107721975 A CN 107721975A CN 201711117562 A CN201711117562 A CN 201711117562A CN 107721975 A CN107721975 A CN 107721975A
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brd4
dmso
nmr
micromolecular inhibitors
antitumor activity
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姚志艺
杨燕
夏晓明
舒启胜
薛楠楠
王庆宣
王东升
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Shanghai Institute of Technology
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Abstract

本发明属于药物化学技术领域，具体为一种具有抗肿瘤活性的BRD4小分子抑制剂、合成方法及其应用。本发明的BRD4小分子抑制剂的结构式用通式(Ⅰ)表示：

Description

具有抗肿瘤活性的BRD4小分子抑制剂、合成方法及其应用
技术领域
本发明涉及一类具有抗肿瘤活性的BRD4小分子抑制剂、合成方法及其应用，属于药物化学技术领域。
背景技术
随着医药学的不断发展，人们对于许多疾病的治疗取得了有目共睹的成就。癌症这些疾病，如今是困扰医学界的一大难题。对于抗肿瘤药物的研究在如火如荼地进行。近年来，临床上常用的抗肿瘤药物近七十种，而由于其可观的前景，处于临床试验阶段的抗肿瘤新药有三百多种。抗肿瘤药物数量繁多，但理想的抗肿瘤药物稀少。随着对抗肿瘤药物的不断研究和肿瘤生物学的飞速发展，人们逐渐认识到细胞的无限增生。研发焦点也从传统细胞毒药物专项针对肿瘤发生发展过程中众多靶向环节。这些靶点新药针对正常细胞与肿瘤细胞的差异，能够克服传统细胞毒药物的选择性差、毒副作用强、易产生耐药性等缺点，可达到高选择性和低毒性的治疗效果。
发明内容
为了克服现有技术的不足，本发明提供了一种具有靶向抗肿瘤活性的新型酰胺类药物结构，以及以溴结构域蛋白4为靶点进行筛选的有生物活性的化合物的合成方法及其应用。
本发明的技术方案具体介绍如下。
本发明提供具有抗肿瘤活性的BRD4小分子抑制剂，其具有通式(Ⅰ)所示的结构：
其中：
R1、R2、R3独立地选自卤素、氢、烷氧基、芳香基或杂环中任一种；
R4选自未取代或者取代的芳基、呋喃环基、噻唑基、三氮唑基、哌嗪基或者噻吩基，取代基为单取代、二取代或者三取代。
本发明中，R1、R2和R3独立地选自卤素、氢或C1～C14烷氧基中任意一种。
本发明中，R1、R2和R3独立地选自甲氧基或氢中任一种。
本发明中，R4取代基独立地选自卤素、硝基、氨基、甲氧基、烷基、甲氧酰基、乙氧酰基、乙酰胺基或对羟基苯中的一种。
本发明还提供一种上述具有抗肿瘤活性的BRD4小分子抑制剂的合成方法，具体步骤如下：
步骤一：3,4,5-三甲氧基苯甲酸衍生物和氯化亚砜反应生成3,4,5-三甲氧基苯甲酰氯衍生物2a-2c；
步骤二：3,4,5-三甲氧基苯甲酰氯衍生物2a-2c)杂环在碱性条件下反应生成目标化合物3a-3v；其合成的化学反应方程式如下：
本发明中，步骤一中，3,4,5-三甲氧基苯甲酸衍生物当量为1，氯化亚砜当量为4，溶剂为干燥的二氯甲烷，回流2～5小时；步骤二中，冰浴滴加酰氯，杂环当量为1，酰氯当量为1.5，溶剂为干燥的二氯甲烷，碱选自TEA或DIPEA的一种。
进一步的，本发明提供一种上述具有抗肿瘤活性的BRD4的抑制剂在制备治疗、预防肿瘤的抗肿瘤药物中的应用。优选的，抗肿瘤药物为治疗或预防乳腺癌、白血病或多发性骨髓瘤等疾病的药物。
和现有技术相比，本发明具有的有益效果如下：本发明合成方法简单，提供的BRD4小分子抑制剂结构新颖，部分化合物抑制活性好，抗肿瘤性能好。
具体实施方式
下面结合部分具体实施例子对本发明的BRD4小分子抑制剂做进一步说明，但本发明的保护范围并不仅限于此。
实施例1
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.22g的三乙胺和0.10g的2-氨基噻吩-3-羧酸甲酯，搅拌使溶解，在冰浴下滴加溶有0.19g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温磁力搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3a 0.11g(49％)。1H NMR(500MHz,DMSO)δ11.63(s,1H),7.27–7.21(m,3H),7.11(d,J＝5.7Hz,1H),3.89(s,9H),3.77(s,3H).13C NMR(125MHz,DMSO)δ165.58,163.05,153.57,148.49,141.94,127.52,124.21,117.84,113.59,105.28,60.69,56.58,52.46,40.35,40.19,40.02,39.85,39.69.HRMS(ESI):m/z calcd for C16H17NO6S[M+H]+352.0849；found 352.0848
实施例2
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.31g的三乙胺和0.10g的2-呋喃甲胺，搅拌使溶解，在冰浴下滴加溶有0.36g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温磁力搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3b 0.09g(30％)。1H NMR(500MHz,DMSO)δ8.93(t,J＝5.0Hz,1H),7.58(s,1H),7.23(s,2H),6.40(s,1H),6.28(s,1H),4.47(d,J＝5.4Hz,2H),3.82(s,6H),3.70(s,3H).13CNMR(125MHz,DMSO)δ165.88,153.04,152.91,142.50,129.69,110.95,107.42,105.33,60.51,56.43,40.31,40.14,39.98,39.81,39.64,36.54.HRMS(ESI):m/z calcd forC15H17NO5[M+H]+292.1179；found 292.1192
实施例3
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.18g的三乙胺和0.10g的2-氨基噻吩-3-羧酸乙酯，搅拌使溶解，在冰浴下滴加溶有0.20g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温磁力搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3c 0.10g(46％)。1H NMR(500MHz,DMSO)δ11.63(s,1H),7.24(d,J＝6.1Hz,3H),7.10(d,J＝5.7Hz,1H),4.35(q,J＝7.1Hz,2H),3.89(s,6H),3.77(s,3H),1.35–1.30(m,3H).13C NMR(125MHz,DMSO)δ161.21,158.55,148.69,144.47,137.30,122.63,119.21,111.38,108.58,100.18,72.56,72.31,72.05,56.21,56.04,51.62,9.62.HRMS(ESI):m/zcalcd for C17H19NO6S[M+H]+366.1006；found 366.1003
实施例4
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.19g的三乙胺和0.10g的2-氨基噻唑-4-甲酸甲酯，搅拌使溶解，在冰浴下滴加溶有0.22g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温磁力搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3d 0.04g(16％)。1H NMR(500MHz,DMSO)δ12.95(s,1H),8.11(s,1H),7.51(s,2H),3.86(d,J＝14.0Hz,6H),3.81(d,J＝15.4Hz,3H),3.74(d,J＝8.5Hz,3H).13CNMR(125MHz,DMSO)δ165.16,161.96,159.38,153.26,141.77,141.32,139.91,126.71,123.57,106.26,60.59,56.58,52.32,40.48,40.31,40.15,39.98,39.81,39.65,39.48.HRMS(ESI):m/z calcd for C15H16N2O6S[M+H]+353.0802；found 353.0800
实施例5
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.18g的三乙胺和0.10g的2-氨基噻唑-4-甲酸乙酯，搅拌使溶解，在冰浴下滴加溶有0.20g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温磁力搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3e 0.06g(28％)。1H NMR(500MHz,DMSO)δ12.94(s,1H),8.11(s,1H),7.52(s,2H),4.30(q,J＝7.1Hz,2H),3.88(s,6H),3.75(s,3H),1.31(t,J＝7.1Hz,3H).13CNMR(125MHz,DMSO)δ165.22,161.57,159.37,153.27,126.74,123.55,106.31,61.10,60.61,56.60,40.52,40.36,40.19,40.02,39.86,39.69,39.53,14.68.HRMS(ESI):m/zcalcd forC16H18N2O6S[M+H]+367.0958；found 367.0955
实施例6
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.20g的三乙胺和0.10g的间氨基乙酰苯胺，搅拌使溶解，在冰浴下滴加溶有0.23g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温磁力搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3f 0.05g(21％)。1H NMR(500MHz,DMSO)δ12.77(s,1H),8.11(s,1H),7.79(d,J＝4.7Hz,1H),7.78(d,J＝3.3Hz,1H),7.77(s,1H),7.11(d,J＝5.9Hz,1H),7.10(s,1H),6.89(d,J＝8.6Hz,1H),3.85(d,J＝3.3Hz,3H),3.84(s,3H),3.83(s,3H),3.80–3.75(m,3H).13C NMR(125MHz,CDCl3)δ169.22,166.09,153.11,141.11,138.57,130.05,129.31,116.61,116.14,112.60,104.81,77.31,77.06,76.80,60.90,56.27,24.29.HRMS(ESI):m/zcalcd forC18H20N2O5[M+H]+345.1444；found 345.1440
实施例7
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.17g的三乙胺和0.1g的4-(1-哌嗪基)苯酚，搅拌使溶解，在冰浴下滴加溶有0.19g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3g 0.07g(34％)。1H NMR(500MHz,DMSO)δ8.89(s,1H),6.81(d,J＝8.8Hz,2H),6.70(s,2H),6.66(d,J＝8.8Hz,2H),3.79(s,6H),3.69(s,4H),3.34(s,3H),2.97(s,4H).13CNMR(125MHz,DMSO)δ169.13,153.29,151.87,144.38,138.83,131.75,118.97,115.97,105.00,60.53,56.54,50.92,40.51,40.34,40.18,40.01,39.84,39.67,39.51.HRMS(ESI):m/zcalcd for C20H24N2O5[M+H]+373.1758；found 373.1797
实施例8
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.27g的三乙胺和0.1g的2-氟-5-氨基吡啶，搅拌使溶解，在冰浴下滴加溶有0.31g 3,4,5-三甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3h 0.14g(51％)。1H NMR(500MHz,DMSO)δ10.42(s,1H),8.55(s,1H),8.34–8.21(m,1H),7.29(s,2H),7.25–7.20(m,1H),3.87(s,6H),3.73(d,J＝8.0Hz,3H).13C NMR(125MHz,DMSO)δ165.62,160.29,158.44,153.16,139.72,139.60,134.71,134.65,134.48,129.66,109.86,109.54,105.88,60.61,56.61,40.48,40.31,40.15,39.98,39.81,39.65,39.48.HRMS(ESI):m/z calcd for C15H15FN2O4[M+H]+307.1088；found 307.1100
实施例9
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.31g的三乙胺和0.1g的2-呋喃甲胺，搅拌使溶解，在冰浴下滴加溶有0.31g 3,5-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3i 0.03g(23％)。1H NMR(500MHz,CDCl3)δ7.38(s,1H),6.91(d,J＝2.1Hz,2H),6.58(d,J＝2.1Hz,1H),6.47(s,1H),6.37–6.32(m,1H),6.30(d,J＝2.9Hz,1H),4.62(d,J＝5.4Hz,2H),3.81(s,6H).13C NMR(125MHz,CDCl3)δ167.18,160.83,151.26,142.21,136.37,110.48,107.61,105.01,103.73,77.38,77.12,76.87,55.50,37.01.HRMS(ESI):m/z calcdforC14H15NO4[M+H]+262.1074；found 262.1083
实施例10
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.19g的三乙胺和0.10g的2-氨基噻唑-4-甲酸甲酯，搅拌使溶解，在冰浴下滴加溶有0.19g 3,5-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3j 0.03g(15％)。1H NMR(500MHz,DMSO)δ8.93(t,J＝5.0Hz,1H),7.58(s,1H),7.23(s,2H),6.40(s,1H),6.28(s,1H),4.47(d,J＝5.4Hz,2H),3.82(s,6H),3.70(s,3H).13C NMR(125MHz,DMSO)δ165.42,161.94,160.97,159.21,141.34,133.81,123.64,106.29,105.78,56.01,52.31,40.48,40.31,40.14,39.98,39.81,39.64,39.47.HRMS(ESI):m/z calcdfor C14H14N2O5S[M+H]+323.0696；found 323.0707
实施例11
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.17g的三乙胺和0.10g的2-氨基噻唑-4-甲酸乙酯，搅拌使溶解，在冰浴下滴加溶有0.17g 3,5-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3k 0.04g(23％)。1H NMR(500MHz,DMSO)δ13.06(s,1H),8.17(s,1H),7.37(d,J＝2.2Hz,2H),6.79(t,J＝2.1Hz,1H),4.34(q,J＝7.1Hz,2H),3.86(s,6H),1.37–1.29(m,3H).13C NMR(125MHz,DMSO)δ165.46,161.55,160.95,159.20,141.66,133.82,123.60,106.29,105.76,61.11,56.01,40.43,40.26,40.09,39.93,39.76,39.59,39.43,14.65.HRMS(ESI):m/z calcd for C15H16N2O5S[M+H]+337.0853；found 337.0854
实施例12
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.20g的三乙胺和0.10g的3-氨基乙酰苯胺，搅拌使溶解，在冰浴下滴加溶有0.20g 3,5-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3l 0.1g(50％)。1H NMR(500MHz,DMSO)δ10.20(s,1H),9.98(s,1H),8.07(s,1H),7.41(d,J＝8.0Hz,1H),7.34(d,J＝8.1Hz,1H),7.24(dd,J＝15.8,7.8Hz,1H),7.08(dd,J＝19.5,2.2Hz,2H),6.71(s,1H),3.82(s,6H),2.05(s,3H).13C NMR(125MHz,DMSO)δ168.74,165.50,160.81,139.96,139.69,129.06,116.03,115.19,112.11,106.15,103.77,55.95,40.32,40.16,39.99,39.82,39.66,24.46.HRMS(ESI):m/z calcd for C17H18N2O4[M+H]+315.1339；found 315.1336
实施例13
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.17g的三乙胺和0.1g的对羟基苯基哌嗪，搅拌使溶解，在冰浴下滴加溶有0.16g 3,5-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3m 0.07g(36％)。1H NMR(500MHz,DMSO)δ8.89(s,1H),6.80(d,J＝8.8Hz,2H),6.66(d,J＝8.8Hz,2H),6.54(dd,J＝20.0,2.1Hz,3H),3.86–3.61(m,8H),3.39(d,J＝32.6Hz,2H),2.96(d,J＝46.5Hz,4H).13C NMR(125MHz,DMSO)δ168.93,160.91,151.89,144.36,138.50,119.00,115.97,105.15,101.63,55.88,50.81,40.37,40.20,40.03,39.87,39.70.HRMS(ESI):m/z calcd for C19H22N2O4[M+H]+343.1652；found 343.1657
实施例14
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.19g的三乙胺和0.1g的2-氨基噻吩-3-羧酸甲酯，搅拌使溶解，在冰浴下滴加溶有0.19g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3n 0.03g(15％)。1H NMR(500MHz,CDCl3)δ11.96(s,1H),7.65(d,J＝1.6Hz,1H),7.60(d,J＝8.3Hz,1H),7.26(d,J＝5.8Hz,1H),6.97(d,J＝8.4Hz,1H),6.78(d,J＝5.7Hz,1H),3.99(d,J＝4.4Hz,3H),3.97(s,3H),3.94(s,3H).13C NMR(125MHz,CDCl3)δ166.43,163.26,152.87,149.71,149.37,124.71,123.78,120.27,116.08,112.62,110.94,110.66,77.31,77.06,76.80,56.09,56.06,51.76.HRMS(ESI):m/z calcd for C15H15NO5S[M+H]+322.0743；found 322.0754
实施例15
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.31g的三乙胺和0.1g的2-呋喃甲胺，搅拌使溶解，在冰浴下滴加溶有0.31g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3o 0.13g(50％)。1H NMR(500MHz,DMSO)δ8.84(s,1H),7.51(dd,J＝30.6,22.2Hz,3H),7.01(d,J＝8.3Hz,1H),6.39(s,1H),6.26(s,1H),4.45(d,J＝5.3Hz,2H),3.79(s,6H).13CNMR(125MHz,CDCl3)δ166.83,151.88,151.39,149.03,142.26,126.82,119.44,110.74,110.52,110.28,107.65,77.30,77.05,76.79,56.03,56.01,37.03.HRMS(ESI):m/z calcdforC14H15NO4[M+H]+262.1074；found 262.1082
实施例16
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.17g的三乙胺和0.1g的2-氨基噻吩-3-甲酸乙酯，搅拌使溶解，在冰浴下滴加溶有0.17g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3p 0.07g(36％)。1H NMR(500MHz,DMSO)δ11.71(s,1H),7.51(dd,J＝11.2,2.6Hz,2H),7.21(dd,J＝15.5,7.0Hz,2H),7.07(d,J＝5.7Hz,1H),4.36(q,J＝7.1Hz,2H),3.86(d,J＝3.1Hz,6H),1.33(dd,J＝18.4,11.4Hz,3H).13C NMR(125MHz,CDCl3)δ166.07,163.31,152.85,149.56,149.39,123.91,120.26,115.97,113.02,111.00,110.66,77.27,77.02,76.77,60.78,56.11,56.08,14.38.HRMS(ESI):m/z calcd for C16H17NO5S[M+H]+336.0900；found 336.0903
实施例17
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.19g的三乙胺和0.1g的2-氨基噻唑-4-甲酸甲酯，搅拌使溶解，在冰浴下滴加溶有0.19g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3q 0.05(25％)。1H NMR(500MHz,DMSO)δ12.84(s,1H),8.09(s,1H),7.88–7.67(m,2H),7.10(d,J＝8.4Hz,1H),3.91–3.76(m,9H).13C NMR(125MHz,DMSO)δ165.27,161.99,159.48,153.11,148.91,141.27,123.91,123.45,122.68,111.68,111.53,56.18,56.14,52.30,40.49,40.33,40.16,39.99,39.83,39.66,39.49.HRMS(ESI):m/z calcdforC14H14N2O5S[M+H]+323.0696；found 323.0694
实施例18
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.18g的三乙胺和0.1g的2-氨基噻唑-4-甲酸乙酯，搅拌使溶解，在冰浴下滴加溶有0.17g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3r 0.04g(20％)。1H NMR(500MHz,DMSO)δ12.75(s,1H),8.09(s,1H),7.79(dd,J＝11.1,2.6Hz,2H),7.10(d,J＝8.4Hz,1H),4.29(q,J＝7.1Hz,2H),3.85(s,3H),3.84(s,3H),1.30(t,J＝7.1Hz,3H).13C NMR(125MHz,DMSO)δ165.31,161.60,159.45,153.09,148.88,141.59,123.91,123.40,122.69,111.69,111.54,61.08,56.19,56.14,40.47,40.30,40.14,39.97,39.80,39.64,39.47,14.67.HRMS(ESI):m/z calcd for C15H16N2O5S[M+H]+337.0853；found 337.0854
实施例19
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.20g的三乙胺和0.1g的3-氨基乙酰苯胺，搅拌使溶解，在冰浴下滴加溶有0.20g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3s 0.11g(52％)。1H NMR(500MHz,DMSO)δ10.11(s,1H),10.00(s,1H),8.07(s,1H),7.63(d,J＝7.3Hz,1H),7.54(s,1H),7.42(d,J＝7.8Hz,1H),7.32(d,J＝7.9Hz,1H),7.24(t,J＝8.0Hz,1H),7.07(d,J＝8.4Hz,1H),3.84(d,J＝7.6Hz,6H),2.05(s,3H).13C NMR(125MHz,DMSO)δ168.77,165.39,152.12,148.76,139.94,129.02,127.51,116.08,115.01,112.18,111.66,111.42,56.15,40.32,40.15,39.99,39.82,39.65,24.46.HRMS(ESI):m/zcalcd forC17H18N2O4[M+H]+315.1339；found 315.1335
实施例20
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.17g的三乙胺和0.1g的对羟基苯基哌嗪，搅拌使溶解，在冰浴下滴加溶有0.17g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3t 0.04g(20％)。1H NMR(500MHz,DMSO)δ8.92(s,1H),6.98(d,J＝9.3Hz,3H),6.81(d,J＝8.9Hz,2H),6.66(d,J＝8.8Hz,2H),3.78(d,J＝4.5Hz,3H),3.77(s,3H),3.62(d,J＝5.9Hz,4H),3.06–2.73(m,4H).13C NMR(125MHz,DMSO)δ169.43,151.84,150.34,148.93,144.39,128.40,120.48,118.96,115.97,111.67,111.54,56.06,50.92,40.29,40.12,39.95,39.79,39.62.HRMS(ESI):m/z calcd for C19H22N2O4[M+H]+343.1652；found343.1659
实施例21
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.31g的三乙胺和0.1g的3-氨基-5-甲基异恶唑，搅拌使溶解，在冰浴下滴加溶有0.31g 3,4-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3u 0.06g(23％)。1H NMR(500MHz,DMSO)δ11.15(s,1H),7.73–7.61(m,2H),7.06(d,J＝8.4Hz,1H),6.75(s,1H),3.83(d,J＝4.7Hz,6H),2.41(s,3H).13C NMR(125MHz,DMSO)δ169.69,165.03,159.33,148.76,122.31,111.61,111.47,97.47,56.11,40.51,40.34,40.17,40.01,39.84,39.67,39.51,12.58.HRMS(ESI):m/z calcd for C13H14N2O4[M+H]+263.1026；found 263.1035
实施例22
取100ml单口瓶，依次加入10ml无水二氯甲烷、0.27g的三乙胺和0.10g的2-氟-5-氨基吡啶，搅拌使溶解，在冰浴下滴加溶有0.27g 3,5-二甲氧基苯甲酰氯的二氯甲烷溶液，室温搅拌过夜。反应结束后，加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩。柱层析得目标化合物3v 0.10g(41％)。1H NMR(500MHz,DMSO)δ8.89(s,1H),6.80(d,J＝8.8Hz,2H),6.66(d,J＝8.8Hz,2H),6.54(dd,J＝20.0,2.1Hz,3H),3.86–3.61(m,8H),3.39(d,J＝32.6Hz,2H),2.96(d,J＝46.5Hz,4H).13C NMR(125MHz,CDCl3)δ166.01,161.13,139.16,139.04,136.11,133.76,133.70,133.03,132.91,132.73,109.62,109.31,105.17,104.21,77.28,77.03,76.78,55.63.HRMS(ESI):m/z calcd for C14H13FN2O3[M+H]+277.0983；found277.0993
细胞活性生物测试实验
测定原理：化合物抑制癌细胞生长具体细节可以用经MTT方法来测得。MTT法的原理是：黄色噻唑兰可穿过细胞膜进入细胞内，活细胞线粒体中的琥珀酸脱氢酶能够让外源性MTT还原成沉积于细胞中的蓝紫结晶甲瓒，然而死细胞却没有这种功能。再用二甲基亚砜溶解甲瓒。在570nm波长处，用酶联免疫检测仪测定其吸光值，来间接得到活细胞数量。
实验材料：MCF-7(人乳腺癌细胞)，K562(人慢性粒细胞白血病细胞)KMS-1(人多发性骨髓瘤细胞)，分别用DMEM+10％FBS培养基培养或者使用1640+10％FBS培养。
试验方法与结果分析：
实验组：190μl细胞悬液+10μl不同浓度的药物(终浓度为10-5-10-10)
空白对照组：200μl PBS
阴性对照组：190μl细胞悬液+10μl 2％DMSO(DMSO终浓度为0.1％)
阳性对照组：190μl细胞悬液+10μl不同浓度的化合物
MTT细胞活力检测步骤
a)接种细胞
在37℃、5％CO2条件下，用含有10％的胎牛血清、1％的青霉素和链霉素的DMEM培养基中传代培养细胞。弃去培养皿中的上层培养基，用PBS洗细胞2次，再加入胰酶，放入培养基中消化1-2min，待细胞脱壁后，再加入新的培养基，轻轻吹打，使细胞完全脱落，待细胞入5ml新的培养基，轻轻吹打，用细胞计数法计算细胞浓度，然后接种于96孔板中。
b)细胞培养
将接种完的96孔板放置于37℃、5％的CO2培养箱中孵育过夜，次日细胞即可贴壁。
c)加药
按照不同的实验设计加入不同浓度的药物，每组设3～4个复孔，每孔加入10μl相应浓度的药物，再将96孔板放入培养箱继续培养。
d)MTT活力检测
给药后培养24小时、48小时、72小时后，每孔加入10μl 5mg/ml的MTT，后将96孔板放置于培养箱中，继续培养4小时后取出，小心吸取每孔的上清液，每孔再加入100μl的二甲基亚砜(DMSO)溶液，放置培养箱中孵育10min后，震荡40s左右，使甲瓒晶体完全溶解。
e)测吸光度并计算IC50值
将96孔板置于酶标仪中，检测波长为570nm处的吸光值。以每3～4个复孔吸光度的平均值计算其相对抑制率。根据不同药物浓度下对白血病细胞的抑制率，计算半数有效抑制浓度(IC50)。每组样品要做3次平行实验。
570nm读数，计算细胞存活率，根据结果计算IC50，结果如下表1。
表1.BRD4小分子抑制剂的结构和活性数据(μmol)

Claims (8)

1.具有抗肿瘤活性的BRD4小分子抑制剂，其特征在于，其具有通式(Ⅰ)所示的结构：
其中：
R1、R2和R3独立地选自卤素、氢、烷氧基、芳香基或杂环中任一种；
R4选自未取代或者取代的芳基、呋喃环基、噻唑基、三氮唑基、哌嗪基或者噻吩基，取代基为单取代、二取代或者三取代。
2.如权利要求1所述的BRD4小分子抑制剂，其特征在于，R1、R2和R3独立地选自卤素、氢或C1～C14烷氧基中任意一种。
3.如权利要求1所述的BRD4小分子抑制剂，其特征在于，R1、R2和R3独立地选自甲氧基或氢中任一种。
4.如权利要求1所述的BRD4小分子抑制剂，其特征在于，R4取代基独立地选自卤素、硝基、氨基、甲氧基、烷基、甲氧酰基、乙氧酰基、乙酰胺基或对羟基苯中的一种。
5.一种如权利要求1所述的具有抗肿瘤活性的BRD4小分子抑制剂的合成方法，其特征在于，具体步骤如下：
步骤一：3,4,5-三甲氧基苯甲酸衍生物和氯化亚砜反应生成3,4,5-三甲氧基苯甲酰氯衍生物2a-2c；
步骤二：3,4,5-三甲氧基苯甲酰氯衍生物2a-2c)杂环在碱性条件下反应生成目标化合物3a-3v；其合成的化学反应方程式如下：
6.如权利要求5所述的合成方法，其特征在于：步骤一中，3,4,5-三甲氧基苯甲酸衍生物当量为1，氯化亚砜当量为4，溶剂为干燥的二氯甲烷，回流2～5小时；步骤二中，冰浴滴加酰氯，杂环当量为1，酰氯当量为1.5～1.8，溶剂为干燥的二氯甲烷，碱选自TEA或DIPEA的一种。
7.一种如权利要求1-4之一所述的具有抗肿瘤活性的BRD4的抑制剂在制备治疗、预防肿瘤的抗肿瘤药物中的应用。
8.如权利要求7所述的应用，其特征在于，抗肿瘤药物为治疗或预防乳腺癌、白血病或多发性骨髓瘤等疾病的药物。
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