CN108358894A - 一种抑制组蛋白乙酰转氨酶的化合物及其制备方法与应用 - Google Patents

一种抑制组蛋白乙酰转氨酶的化合物及其制备方法与应用 Download PDF

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CN108358894A
CN108358894A CN201810388196.4A CN201810388196A CN108358894A CN 108358894 A CN108358894 A CN 108358894A CN 201810388196 A CN201810388196 A CN 201810388196A CN 108358894 A CN108358894 A CN 108358894A
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杨胜勇
李琳丽
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Sichuan University
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Abstract

本发明属于有机合成医药领域，具体涉及抑制组蛋白乙酰转氨酶的化合物，其结构如下：。通过该化合物的一些实施方案证实，能够对组蛋白乙酰转氨酶p300产生较好的抑制作用，同时对肿瘤细胞具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明提供的新化合物结构较多，合成线路多样，其制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产，制备得到的化合物生物活性较高，对肿瘤细胞的选择性强，类药性显著，具有广阔的市场前景。

Description

一种抑制组蛋白乙酰转氨酶的化合物及其制备方法与应用
技术领域
本发明涉及有机合成药物技术领域，具体是指一种抑制组蛋白乙酰转氨酶的化合物及其制备方法与应用。
背景技术
由组蛋白乙酰转移酶(HATs)和组蛋白去乙酰化酶(HDACs)催化的蛋白质的动态和可逆的乙酰化是基因转录的表观遗传主要调控机制。研究表明，该过程参与到许多生物过程中，并与多种疾病有关。组蛋白去乙酰化酶抑制剂目前已经在临床上被批准用于治疗某些癌症，但是组蛋白乙酰转移酶抑制剂的发展的进展已经落后，目前为止，还没有可用于临床使用的药物。组蛋白乙酰转移酶旁系同源物p300和CREB-结合蛋白(CBP)是关键的转录共激活因子，其对于多种细胞过程是必不可少的，研究表明其参与到以下细胞信号通路中包括钙离子信号通路，对缺氧的应答信号通路，Notch信号通路和NFκB信号通路并且还涉及到多种人类病理状况(包括癌症)。p300/CBP是高等真核生物中的关键酶，其在许多主要的细胞信号传导途径中作为效应物，其响应于各种信号而调节蛋白质功能和基因表达。这些过程通过超过400个蛋白质配体与其各种蛋白质相互作用介导结构域的结合以及个蛋白质底物的乙酰化来实现。目前已经报道的p300和CBP组蛋白乙酰转移酶结构域的抑制剂，包括天然产物、双底物类似物和广泛使用的小分子C646，这些都缺乏活性或选择性。因此开发出高活性、选择性和类药性的P300小分子抑制剂是目前临床上急需要解决的难题。
发明内容
本发明的目的在于提供一种抑制组蛋白乙酰转氨酶的化合物，主要抑制p300。
本发明的另一个目的在于提供一种上述抑制组蛋白乙酰转氨酶的化合物的制备方法。
本发明还有一个目的在于提供一种活性较高，选择性强，类药性显著的组蛋白乙酰转氨酶P300抑制剂以及相应抗肿瘤的药物。
本发明提供一种丙烯酰胺类衍生物，其通式如下：
一种抑制组蛋白乙酰转氨酶的化合物，其通式如下：
具体分子结构如下所示：
其合成路线有三条，具体如下：
第一条合成线路：
第二条合成线路：
第三条合成线路：
根据其合成路线可知，本发明使用1H-吲哚-6-甲酸作为初始原料，通过合成中间体Ⅰ、中间体Ⅱ、中间体Ⅲ的依次合成，最后通过与相应的取代的硼酸频哪醇酯反应，得到目的化合物；
通过中间体Ⅰ，各种取代的胺反应，依次合成中间体IV、中间体V，最后通过与相应的取代的硼酸频哪醇酯反应，得到目的化合物。将该目的化合物加入相应氯化剂反应，即得终产物。
本发明与现有技术相比，具有以下优点及有益效果：
本发明合成了一种新的能够抑制组蛋白乙酰转氨酶p300的化合物，并证实了该化合物的一些实施方案中，能够对组蛋白乙酰转氨酶p300产生较好的抑制作用，同时对肿瘤细胞具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明提供的新化合物结构较多，合成线路多样，其制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产，制备得到的化合物生物活性较高，对肿瘤细胞的选择性强，类药性显著，具有广阔的市场前景。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其他特征、目的和优点将会变得更为明显：
图1为本发明中的化合物40对肿瘤细胞的抑制作用图；
图2为使用本发明中化合物40对小鼠体重的影响图。
具体实施方式
下面结合实施例对本发明作进一步地详细说明，但本发明的实施方式不限于此，在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段，做出各种替换和变更，均应包括在本发明的范围内。
为使本发明的目的、工艺条件及优点作用更加清楚明白，结合以下实施实例，对本发明作进一步详细说明，此处所描述的具体实施实例仅用以解释本发明，并不用于限定本发明。
实施例1：
本实施例公开通过第一条合成路线合成化合物的具体方法，合成路线如下：
具体合成步骤如下：
在100mL圆底烧瓶中，称取1H-吲哚-6-甲酸，加入20mL DMF溶解，然后移至常温磁力搅拌器上开始搅拌，称取相对当量的氢氧化钾加入到反应体系中，随后称取单质碘，在烧杯中加入20mL DMF溶解，转移到恒压滴液漏斗中，缓慢滴加到上述反应体系中，约30min滴加完毕，继续反应2h。TLC检测反应进程，反应完毕后停止反应。称取相对当量的硫代硫酸钠于1L的烧杯中，加入500mL冰水，然后，把反应液缓慢倒入到冰水中，随后，加入浓盐酸调节pH值至3左右，有大量固体析出，过滤，固体干燥的中间体Ⅰ。
在250mL圆底烧瓶中，称取中间体Ⅰ，加入100mL THF溶解，然后移至常温磁力搅拌器上开始搅拌，称取相对当量的HATU和DIEA加入到反应体系中，继续搅拌约30min。随后加入3-吗啉丙基-1-胺，移至40℃反应。TLC检测反应进程，反应完毕后停止反应。经减压蒸馏浓缩，加入水和二氯甲烷萃取3次，然后，有几层用饱和NaCl水溶液洗涤，随后，用无水MgSO4干燥，过滤，减压浓缩，经柱层析分离得到中间体Ⅱ。
在100mL圆底烧瓶中，称取中间体2，加入10mL Ac2O溶解，然后移至常温磁力搅拌器上开始搅拌，随后加入催化量的DMAP，继续反应1h。TLC检测反应进程，反应完毕后停止反应。经减压蒸馏浓缩，加入水和二氯甲烷萃取3次，然后，有机相用饱和NaCl水溶液洗涤，随后，用无水MgSO4干燥，过滤，减压浓缩得到中间体3，可直接用于下一步。
在100mL双口圆底烧瓶中，称取中间体3、相应的取代的硼酸频哪醇酯、Pd(dppf)2Cl2CH2Cl2和碳酸铯，用二氧六环和水溶解后，然后，置换氩气3次，移至90℃下反应，约4h。TLC检测反应进程，反应完毕后停止反应。反应液用硅藻土过滤，二氧六环洗涤后，经减压蒸馏浓缩，加入水和二氯甲烷萃取3次，然后，有机相用饱和NaCl水溶液洗涤，随后，用无水MgSO4干燥，过滤，减压浓缩，经柱层析分离纯化得到终产物。
实施例2：
本实施例公开通过第一条合成路线获得的具体化合物，包括：
1、3-(4-甲基-3-硝基苯基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.86(s,1H),8.48(s,1H),8.25(s,1H),7.98(dd,J＝42.2,15.4Hz,4H),7.61(dd,J＝37.2,6.5Hz,2H),3.58(s,4H),2.54(s,3H),2.36(s,6H),1.72(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.23,150.03,136.82,135.18,133.72,131.29,129.58,128.75,127.59,126.91,121.71,119.57,118.64,113.94,112.26,66.68,53.85,40.53,40.33,40.12,39.91,39.70,39.49,39.28,26.52.
H RMS m/z(ESI)calcd for C23H26N4O4[M+H]+422.1954found:422.1950.
其产率为76％。
2、N-(3-吗啉基丙基)-3-(3,4,5-三甲氧基苯基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.65(s,1H),8.48(s,1H),7.98(s,1H),7.91(d,J＝8.4Hz,1H),7.85(d,J＝2.2Hz,1H),7.62(d,J＝8.3Hz,1H),6.93(s,2H),3.87(s,6H),3.70(s,3H),3.64(s,4H),2.58(s,5H),1.84–1.69(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.55,153.68,136.66,126.54,119.18,118.96,112.06,104.47,65.95,60.57,56.25,53.27,40.54,40.33,40.12,39.92,39.71,39.53,39.39,37.95,25.96.
H RMS m/z(ESI)calcd for C25H31N3O5[M+H]+453.2264found:453.2260.
其产率：81％。
3、3-(3,5-二甲基异恶唑-4-基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.71(s,1H),8.43(s,1H),7.99(s,1H),7.63(s,1H),7.56(d,J＝8.2Hz,1H),7.40(d,J＝8.2Hz,1H),3.58(s,4H),2.35(s,8H),2.17(s,2H),1.71(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.41,165.50,159.75,136.03,128.64,127.97,118.75,112.07,110.89,109.42,104.46,102.81,66.68,53.85,40.55,40.34,40.13,39.92,39.71,39.50,39.29,38.33,26.52,25.41,11.96,10.89.
H RMS m/z(ESI)calcd for C21H26N4O3[M+H]+382.2005found:382.2002.
其产率：71％。
4、3-(5-乙酰基噻吩-2-基)-N-(3-吗啉丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ12.03(s,1H),8.51(s,1H),8.18(s,1H),8.00(s,1H),7.95(t,J＝5.6Hz,2H),7.70(d,J＝8.4Hz,1H),7.54(d,J＝4.0Hz,1H),3.62–3.54(m,4H),2.54(s,3H),2.35(t,J＝6.9Hz,6H),1.77–1.67(m,2H),1.24(s,2H).
H RMS m/z(ESI)calcd for C22H25N3O3S[M+H]+411.1617found:411.1618.
其产率：86％。
5、3-(4-甲酰胺基苯基)-N-(3-吗啉代丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.81(s,1H),8.79(s,1H),8.48(s,1H),8.00(s,2H),7.96(d,J＝8.1Hz,4H),7.81(d,J＝8.4Hz,3H),7.64(d,J＝8.3Hz,1H),7.32(d,J＝11.8Hz,1H),3.58(s,4H),2.51(s,4H),2.36(d,J＝5.7Hz,6H),1.79–1.60(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ168.26,167.28,138.92,136.91,134.31,131.37,128.65,127.47,127.15,126.79,126.26,119.44,119.04,115.49,112.19,66.69,56.72,53.86,40.56,40.35,40.15,39.94,39.73,39.52,39.31,38.37,26.53.
H RMS m/z(ESI)calcd for C23H26N4O3[M+H]+406.2005found:406.2009.
其产率：73％。
6、3-(苯并[d]噻唑-5-基)-N-(3-吗啉代苯基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.76(s,1H),9.42(s,1H),8.48(s,1H),8.38(s,1H),8.22(d,J＝7.5Hz,1H),8.14–7.92(m,3H),7.87(d,J＝7.4Hz,1H),7.66(d,J＝7.5Hz,1H),3.58(s,4H),2.36(s,6H),1.72(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.32,156.91,154.45,136.86,134.30,131.03,128.59,127.30,127.05,125.27,123.19,120.57,119.34,118.76,115.80,112.19,66.71,56.74,53.87,40.60,40.39,40.19,39.98,39.77,39.56,39.35,38.39,26.55.
H RMS m/z(ESI)calcd for C23H24N4O2S[M+H]+420.1620found:420.1616.
其产率：86％。
7、N-(3-吗啉代苯基)-3-(1H-吡唑并[2,3-b]吡啶-4-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.97(s,1H),11.68(s,1H),8.49(s,1H),8.26(d,J＝4.8Hz,1H),8.05(d,J＝3.9Hz,2H),7.89(d,J＝8.4Hz,1H),7.65(d,J＝8.5Hz,1H),7.49(s,1H),7.35(d,J＝4.8Hz,1H),6.66(s,1H),3.58(s,4H),2.36(s,6H),1.71(dd,J＝14.5,7.6Hz,2H),1.24(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.30,149.57,143.35,136.69,135.58,128.81,127.71,125.89,119.31,117.49,114.15,113.80,112.25,100.39,66.70,56.72,53.86,40.57,40.36,40.15,39.95,39.74,39.53,39.32,38.37,26.54.
其产率：91％。
8、3-(苯并[d]噁唑-5-基)-N-(3-吗啉代苯基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.76(s,1H),9.42(s,1H),8.48(s,1H),8.38(s,1H),8.22(d,J＝7.5Hz,1H),8.14–7.92(m,3H),7.87(d,J＝7.4Hz,1H),7.66(d,J＝7.5Hz,1H),3.58(s,4H),2.36(s,6H),1.72(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.32,156.91,154.45,136.86,134.30,131.03,128.59,127.30,127.05,125.27,123.19,120.57,119.34,118.76,115.80,112.19,66.71,56.74,53.87,40.60,40.39,40.19,39.98,39.77,39.56,39.35,38.39,26.55.
H RMS m/z(ESI)calcd for C23H24N4O3[M+H]+404.1848found:404.1852.
其产率：78％。
9、3-(苯并呋喃-2-基)-N-(3-吗啉代苯基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.96(s,1H),8.51(s,1H),8.08(dd,J＝25.3,17.0Hz,3H),7.71(d,J＝7.6Hz,1H),7.60(s,2H),7.22(d,J＝15.6Hz,3H),3.58(s,4H),2.36(s,6H),1.72(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.19,153.69,153.19,136.54,129.93,129.19,127.42,126.18,123.68,123.39,120.61,119.78,119.61,112.29,110.99,106.91,99.43,66.70,56.72,53.86,40.56,40.35,40.14,39.93,39.73,39.52,39.31,38.40,26.51.
H RMS m/z(ESI)calcd for C24H25N3O3[M+H]+403.1896found:403.1892.
其产率：69％.
10、3-(4-吗啉基苯基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.50(s,1H),8.42(s,1H),7.95(s,1H),7.83(d,J＝8.3Hz,1H),7.72(s,1H),7.57(d,J＝7.9Hz,3H),7.03(d,J＝8.3Hz,2H),3.77(s,4H),3.58(s,4H),3.13(s,4H),2.35(s,6H),1.81–1.62(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.39,149.59,136.66,128.23,127.73,127.42,126.97,125.33,118.81,116.41,116.13,111.97,66.62,56.72,53.83,49.15,40.63,40.42,40.21,40.00,39.80,39.59,39.38,38.35,26.52.
H RMS m/z(ESI)calcd for C26H32N4O3[M+H]+448.2474found:448.2470.
其产率：79％.
11、3-(4-(4-甲基哌嗪-1-基)苯基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.49(s,1H),8.42(s,1H),7.95(s,1H),7.82(d,J＝8.2Hz,1H),7.66(dd,J＝18.8,10.4Hz,2H),7.61–7.51(m,2H),7.02(d,J＝8.2Hz,1H),6.98–6.81(m,1H),3.58(s,4H),3.16(s,4H),2.43(s,2H),2.35(s,4H),2.24(s,2H),2.22(s,2H),1.86–1.60(m,2H),1.25(d,J＝9.0Hz,3H).
其碳谱：13C NMR(101MHz,DMSO)δ167.39,149.52,136.65,136.21,135.83,128.22,127.71,127.43,126.58,125.26,118.85,116.47,116.36,114.17,111.96,66.70,56.74,55.09,53.86,48.72,47.80,46.20,40.63,40.42,40.21,40.01,39.80,39.59,39.38,38.36,26.54,25.16.
H RMS m/z(ESI)calcd for C27H35N5O2[M+H]+461.2791found:461.2788.
其产率：83％。
12、3-(4-(吗啉甲基)苯基)-N-(3-吗啉丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.63(s,1H),8.44(s,1H),7.98(s,1H),7.88(d,J＝7.9Hz,1H),7.83(s,1H),7.66(d,J＝7.2Hz,2H),7.60(d,J＝7.8Hz,1H),7.44–7.31(m,2H),3.58(s,8H),3.48(s,2H),2.37(s,10H),1.71(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.33,136.77,135.39,134.62,129.98,128.43,127.30,126.79,126.32,119.08,118.90,116.21,112.07,66.70,62.77,56.72,53.85,53.68,40.63,40.42,40.21,40.00,39.79,39.59,39.38,38.36,26.53.
H RMS m/z(ESI)calcd for C27H34N4O3[M+H]+462.2631found:462.2624.
其产率：68％。
13、3-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.68(s,1H),8.46(s,1H),7.98(s,1H),7.88(d,J＝8.4Hz,1H),7.83(s,1H),7.65(d,J＝7.8Hz,2H),7.63–7.57(m,2H),7.39–7.34(m,3H),3.58(s,4H),3.47(s,4H),2.50(s,4H),2.16(d,J＝2.4Hz,6H),1.77–1.65(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.33,139.10,137.88,136.77,135.86,134.54,129.85,128.41,127.30,126.81,126.76,126.29,119.07,118.89,116.21,112.09,66.70,62.37,62.15,56.74,55.16,53.87,52.96,46.13,40.63,40.42,40.21,40.01,39.80,39.59,39.38,38.36,26.56.
H RMS m/z(ESI)calcd for C28H37N5O2[M+H]+475.2947found:475.2943.
其产率：74％。
14、3-(4-((2-(二甲基氨基)乙基)胺甲酰基)苯基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.80(s,1H),8.47(s,1H),8.39(s,1H),8.00(s,2H),7.94(dd,J＝11.9,8.6Hz,3H),7.81(d,J＝8.1Hz,2H),7.70(d,J＝8.4Hz,1H),7.64(d,J＝8.3Hz,1H),6.79(d,J＝8.3Hz,1H),3.58(s,4H),2.36(s,6H),2.23(d,J＝9.6Hz,7H),1.77–1.65(m,2H),1.23(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.24,166.42,138.79,136.92,129.49,128.28,127.14,126.30,119.45,115.47,66.70,58.60,56.72,53.86,50.37,45.56,40.62,40.41,40.20,40.00,39.79,39.58,39.37,38.37,37.68,26.55.
H RMS m/z(ESI)calcd for C27H35N5O3[M+H]+477.2740found:477.2735.
其产率：85％。
15、3-(6-氨基吡啶-3-基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.51(s,1H),8.43(s,1H),8.25(s,1H),7.95(s,1H),7.72(d,J＝24.6Hz,3H),7.58(s,1H),6.57(s,1H),5.85(s,2H),3.58(s,4H),2.43(d,J＝55.8Hz,6H),1.71(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.42,158.41,145.81,136.55,136.32,128.25,127.43,124.90,120.02,118.77,114.11,111.95,108.63,66.58,56.65,53.77,40.62,40.42,40.21,40.00,39.79,39.58,39.37,38.30,26.46.
H RMS m/z(ESI)calcd for C21H25N5O2[M+H]+379.2008found:379.2012.
其产率：79％。
16、3-(6-乙酰氨基吡啶-3-基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.74(s,1H),10.49(s,1H),8.59(d,J＝63.6Hz,2H),8.14(d,J＝14.0Hz,2H),8.03–7.80(m,3H),7.65(s,1H),3.64(s,5H),2.51(s,8H),2.13(s,3H),1.77(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ169.60,167.45,150.21,145.70,136.69,136.10,128.44,127.31,127.22,126.55,119.28,118.85,113.98,112.81,112.15,66.01,56.22,53.32,40.54,40.33,40.12,39.91,39.70,39.49,39.28,38.02,25.99,24.36.
H RMS m/z(ESI)calcd for C23H27N5O3[M+H]+421.2114found:421.2110.
其产率：84％。
17、3-(6-(二甲基氨基)吡啶-3-基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.55(s,1H),8.45(s,2H),7.96(s,1H),7.88–7.77(m,2H),7.72(d,J＝2.3Hz,1H),7.58(d,J＝8.5Hz,1H),6.75(d,J＝8.8Hz,1H),3.58(d,J＝3.9Hz,4H),3.06(s,6H),2.36(d,J＝6.0Hz,6H),1.82–1.62(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.36,157.95,145.72,136.60,136.29,128.30,127.43,125.08,119.60,118.84,118.78,113.82,111.98,106.46,66.66,56.71,53.83,40.63,40.42,40.21,40.01,39.80,39.59,39.38,38.30,26.51.
H RMS m/z(ESI)calcd for C23H29N5O2[M+H]+407.2321found:407.2325.
其产率：91％。
18、N-(3-吗啉基丙基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.60(s,1H),8.63–8.41(m,2H),7.98(s,1H),7.89(dd,J＝8.7,2.3Hz,1H),7.80(dd,J＝10.8,5.5Hz,2H),7.60(d,J＝8.4Hz,1H),6.94(d,J＝8.8Hz,1H),3.83–3.70(m,4H),3.64(s,4H),3.52–3.43(m,4H),2.58(s,4H),1.78(d,J＝6.3Hz,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.54,157.97,145.58,136.60,136.48,128.17,127.41,125.59,121.73,118.97,118.81,113.46,112.07,107.80,66.47,45.88,40.55,40.34,40.13,39.92,39.71,39.50,39.30.
其产率：68％。
19、N-(3-吗啉基丙基)-3-(6-(吡咯-1-基)吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.52(s,1H),8.42(s,2H),7.95(s,1H),7.78(d,J＝7.4Hz,2H),7.70(s,1H),7.58(d,J＝7.7Hz,1H),6.54(d,J＝8.5Hz,1H),3.58(s,4H),3.42(s,4H),2.35(s,6H),1.97(s,4H),1.71(s,2H).
H RMS m/z(ESI)calcd for C25H31N5O2[M+H]+433.2478found:433.2480.
其产率：72％
20、3-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.82(s,1H),8.50(s,1H),8.25(s,1H),7.93(d,J＝60.1Hz,4H),7.64(s,2H),3.61(s,4H),2.67(s,3H),2.47(d,J＝28.0Hz,6H),1.74(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.37,157.85,145.62,136.61,136.44,128.36,127.37,125.39,121.23,118.92,118.78,113.53,112.01,107.80,66.69,56.75,53.86,40.63,40.42,40.21,40.00,39.79,39.58,39.37,38.36,26.55.
H RMS m/z(ESI)calcd for C26H34N6O2[M+H]+462.2743found:462.2740.
其产率：69％。
21、3-(2-甲氧基嘧啶-5-基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.80(s,1H),8.95(s,2H),8.47(s,1H),8.10–7.94(m,2H),7.88(d,J＝8.4Hz,1H),7.63(d,J＝8.5Hz,1H),3.97(s,3H),3.70–3.51(m,4H),2.35(t,J＝6.9Hz,6H),1.83–1.63(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.17,163.83,157.03,136.65,128.78,127.04,126.69,123.86,119.42,118.75,112.14,109.35,66.68,56.71,55.00,53.85,40.63,40.42,40.21,40.00,39.80,39.59,39.38,38.36,26.51.
H RMS m/z(ESI)calcd for C21H25N5O3[M+H]+395.1957found:395.1953.
其产率：73％。
22、3-(2-氨基吡啶-5-基)-N-(3-吗啉基丙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.62(s,1H),8.57(s,2H),8.44(s,1H),7.97(s,1H),7.86(s,1H),7.77(d,J＝10.3Hz,2H),7.59(d,J＝8.3Hz,1H),6.58(s,2H),5.91(s,1H),3.68–3.51(m,4H),2.48–2.14(m,6H),1.82–1.61(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.31,162.45,156.17,145.84,136.51,128.48,127.25,125.27,119.00,118.71,118.48,111.99,110.86,66.70,56.72,53.86,40.63,40.42,40.21,40.00,39.79,39.58,39.37,38.36,26.55.
H RMS m/z(ESI)calcd for C20H24N6O2[M+H]+380.1961found:380.1963.
其产率：84％。
23、N-(3-吗啉基丙基)-3-(2-吗啉基嘧啶-5-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.67(s,1H),8.75(s,2H),8.44(t,J＝5.1Hz,1H),7.98(s,1H),7.82(dd,J＝10.3,5.4Hz,2H),7.60(d,J＝8.3Hz,1H),3.83–3.64(m,8H),3.64–3.49(m,4H),2.44–2.26(m,6H),1.80–1.61(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.26,160.35,155.92,136.56,128.56,127.22,125.66,119.12,118.96,118.74,112.05,110.40,66.69,66.47,56.73,53.86,44.61,40.62,40.41,40.20,39.99,39.79,39.58,39.37,38.37,26.52.
H RMS m/z(ESI)calcd for C24H30N6O3[M+H]+450.2379found:450.2380.
其产率：87％。
实施例3：
本实施例公开通过第二条合成路线合成化合物的具体方法，合成路线如下：
在250mL圆底烧瓶中，称取中间体I，加入100mL THF溶解，然后移至常温磁力搅拌器上开始搅拌，称取相对当量的HATU和DIEA加入到反应体系中，继续搅拌约30min。随后加入各种取代的胺，移至40℃反应，。TLC检测反应进程，反应完毕后停止反应。经减压蒸馏浓缩，加入水和二氯甲烷萃取3次，然后，有几层用饱和NaCl水溶液洗涤，随后，用无水MgSO4干燥，过滤，减压浓缩，经柱层析分离得到中间体IV。
在100mL圆底烧瓶中，称取中间体IV，加入10mL Ac2O溶解，然后移至常温磁力搅拌器上开始搅拌，随后加入催化量的DMAP，继续反应1h。TLC检测反应进程，反应完毕后停止反应。经减压蒸馏浓缩，加入水和二氯甲烷萃取3次，然后，有机相用饱和NaCl水溶液洗涤，随后，用无水MgSO4干燥，过滤，减压浓缩得到中间体V，可直接用于下一步。
在100mL双口圆底烧瓶中，称取中间体V、相应的取代的硼酸频哪醇酯、Pd(dppf)2Cl2CH2Cl2和碳酸铯，用二氧六环和水溶解后，然后，置换氩气3次，移至90℃下反应，约4h。TLC检测反应进程，反应完毕后停止反应。反应液用硅藻土过滤，二氧六环洗涤后，经减压蒸馏浓缩，加入水和二氯甲烷萃取3次，然后，有机相用饱和NaCl水溶液洗涤，随后，用无水MgSO4干燥，过滤，减压浓缩，经柱层析分离纯化得到终产物。
实施例4：
本实施例公开通过第二条合成路线获得的具体化合物，包括：
1、3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酸
其氢谱：1H NMR(400MHz,DMSO)δ12.25(s,1H),11.74(s,1H),8.50(s,1H),8.10(s,1H),7.88(t,J＝8.2Hz,3H),7.69(d,J＝8.4Hz,1H),7.04–6.90(m,1H),3.72(dd,J＝11.0,6.6Hz,4H),3.47(s,4H).
其碳谱：13C NMR(101MHz,DMSO)δ167.59,158.07,145.74,136.56,136.47,128.88,126.91,122.83,121.36,120.56,119.26,114.31,113.83,107.75,66.47,45.86,40.62,40.41,40.20,39.99,39.78,39.57,39.37.
H RMS m/z(ESI)calcd for C18H17N3O3[M+H]+323.1270found:323.1268.
其产率：68％。
2、3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酸甲酯
其氢谱：1H NMR(400MHz,DMSO)δ11.74(s,1H),8.50(s,1H),8.10(s,1H),7.88(t,J＝8.2Hz,3H),7.69(d,J＝8.4Hz,1H),7.04–6.90(m,1H),3.87(s,3H),3.72(dd,J＝11.0,6.6Hz,4H),3.47(s,4H).
其碳谱：13C NMR(101MHz,DMSO)δ167.59,158.07,145.74,136.56,136.47,128.88,126.91,122.83,121.36,120.56,119.26,114.31,113.83,107.75,66.47,52.31,45.86,40.62,40.41,40.20,39.99,39.78,39.57,39.37.
H RMS m/z(ESI)calcd for C19H19N3O3[M+H]+337.1426found:337.1428.
其产率：69％。
3、3-(6-吗啉基吡啶-3-基)-N-(四氢-2H-吡喃-4-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.57(s,1H),8.51(s,1H),8.26(d,J＝7.6Hz,1H),7.99(s,1H),7.89(d,J＝8.7Hz,1H),7.84–7.73(m,2H),7.62(d,J＝8.4Hz,1H),6.94(d,J＝8.8Hz,1H),4.04(d,J＝7.0Hz,1H),3.89(d,J＝10.3Hz,2H),3.80–3.65(m,4H),3.58–3.44(m,4H),3.40(t,J＝11.1Hz,2H),1.78(d,J＝11.0Hz,2H),1.62(dt,J＝11.9,8.1Hz,2H).
其碳谱：13C NMR(101MHz,DMSO)δ166.79,157.97,145.60,136.46,128.37,127.39,125.54,121.77,119.19,118.69,113.44,112.22,107.78,66.77,66.48,46.23,45.90,40.63,40.42,40.21,40.00,39.79,39.59,39.38,33.05.
H RMS m/z(ESI)calcd for C23H26N4O3[M+H]+406.2005found:406.2002.
其产率：71％。
4、3-(6-吗啉基吡啶-3-基)-N-(四氢-2H-吡喃-4-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.57(s,1H),8.50(d,J＝2.2Hz,1H),8.43(t,J＝5.7Hz,1H),7.98(s,1H),7.89(dd,J＝8.7,2.4Hz,1H),7.79(dd,J＝10.6,5.5Hz,2H),7.60(dd,J＝8.5,1.2Hz,1H),6.94(d,J＝8.8Hz,1H),3.85(dd,J＝11.3,2.4Hz,2H),3.78–3.69(m,4H),3.53–3.42(m,4H),3.27(t,J＝11.7Hz,2H),3.19(t,J＝6.3Hz,2H),1.91–1.76(m,1H),1.61(d,J＝12.6Hz,2H),1.30–1.15(m,3H).
其碳谱：13C NMR(101MHz,DMSO)δ167.57,157.97,145.60,136.61,136.46,128.39,127.36,125.49,121.78,119.05,118.76,113.44,112.08,107.77,67.29,66.48,45.90,45.45,40.63,40.42,40.21,40.00,39.79,39.58,39.37,35.42,31.11.
H RMS m/z(ESI)calcd for C24H28N4O3[M+H]+420.2161found:420.2164.
其产率：54％。
5、N-(2-吗啉基乙基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.59(s,1H),8.50(s,1H),8.34(s,1H),7.97(s,1H),7.89(d,J＝8.1Hz,1H),7.84–7.73(m,2H),7.59(d,J＝8.2Hz,1H),6.93(d,J＝8.6Hz,1H),3.73(s,5H),3.58(s,4H),3.46(s,4H),3.42(d,J＝5.6Hz,2H),2.43(s,4H),1.23(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.34,157.97,145.61,136.62,136.46,128.27,127.39,125.54,121.76,118.98,118.81,113.46,112.04,107.76,66.70,66.48,58.00,53.81,45.90,40.62,40.41,40.21,40.00,39.79,39.58,39.37,37.06.
H RMS m/z(ESI)calcd for C24H29N5O3[M+H]+435.2270found:435.2268.
其产率：61％。
6、3-(6-吗啉基吡啶-3-基)-N-(2-(噻吩-2-基)乙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.61(s,1H),8.72–8.44(m,2H),7.99(s,1H),7.90(dd,J＝8.7,1.9Hz,1H),7.80(dd,J＝12.7,5.2Hz,2H),7.61(d,J＝8.4Hz,1H),7.34(d,J＝4.8Hz,1H),7.03–6.86(m,3H),3.85–3.70(m,4H),3.62–3.50(m,3H),3.50–3.40(m,4H),3.10(t,J＝7.0Hz,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.46,157.97,145.62,142.22,136.61,136.47,128.21,127.45,127.39,125.57,124.46,121.75,119.01,118.82,113.48,112.07,107.76,66.48,45.90,41.54,40.62,40.41,40.20,39.99,39.78,39.58,39.37,29.83,25.42.
H RMS m/z(ESI)calcd for C24H24N4O2S[M+H]+432.1620found:432.1616.
其产率：69％.
7、N-(3,4-二氯苯乙基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.60(s,1H),8.49(dd,J＝7.6,3.7Hz,2H),7.95(s,1H),7.89(dd,J＝8.7,2.3Hz,1H),7.79(dd,J＝9.1,5.5Hz,2H),7.65–7.50(m,4H),7.32–7.19(m,1H),6.90(t,J＝22.3Hz,1H),3.81–3.68(m,4H),3.53(dd,J＝12.3,6.4Hz,2H),3.50–3.42(m,4H),2.99–2.75(m,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.48,157.97,145.62,141.58,136.59,136.46,131.25,130.78,129.74,129.10,128.19,127.43,125.56,121.75,118.95,118.80,113.47,112.03,107.76,66.48,45.90,40.78,40.63,40.42,40.21,40.00,39.79,39.58,39.37,34.55,25.43.
H RMS m/z(ESI)calcd for C26H24Cl2N4O2[M+H]+494.1276found:494.1279.
其产率：73％。
8、3-(6-吗啉基吡啶-3-基)-N-(2-(吡啶-2-基)乙基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.59(s,1H),8.51(d,J＝6.0Hz,3H),7.96(s,1H),7.92–7.86(m,1H),7.79(dd,J＝9.7,5.3Hz,2H),7.71(t,J＝7.0Hz,1H),7.58(d,J＝8.2Hz,1H),7.29(d,J＝7.7Hz,1H),7.26–7.13(m,1H),6.94(d,J＝8.8Hz,1H),3.84–3.69(m,4H),3.64(dd,J＝13.1,6.8Hz,2H),3.47(d,J＝4.5Hz,4H),3.03(t,J＝7.3Hz,2H).
其碳谱：13C NMR(101MHz,DMSO)δ167.37,159.86,157.97,149.56,145.62,136.92,136.61,136.46,128.30,127.39,125.52,123.59,121.94,121.76,118.79,113.46,112.03,107.76,66.48,45.90,40.64,40.43,40.22,40.01,39.81,39.60,39.39,37.98.
H RMS m/z(ESI)calcd for C25H25N5O2[M+H]+427.2008found:427.2007.
其产率：58％。
9、3-(6-吗啉基吡啶-3-基)-N-(吡啶-3-基甲基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.66(s,1H),9.07(s,1H),8.58(s,1H),8.51(d,J＝2.0Hz,1H),8.46(d,J＝3.5Hz,1H),8.04(s,1H),7.90(dd,J＝8.7,2.3Hz,1H),7.85–7.78(m,2H),7.75(d,J＝7.8Hz,1H),7.66(d,J＝8.4Hz,1H),7.36(dd,J＝7.6,4.8Hz,1H),6.93(d,J＝8.8Hz,1H),4.53(d,J＝5.6Hz,2H),3.89–3.65(m,4H),3.63–3.42(m,4H).
其碳谱：13C NMR(101MHz,DMSO)δ167.58,157.98,149.32,148.46,145.63,136.62,136.47,135.96,135.58,127.77,127.59,125.72,123.93,121.72,119.05,118.91,113.51,112.22,107.76,66.47,45.90,40.94,40.63,40.43,40.22,40.01,39.80,39.59,39.38.
H RMS m/z(ESI)calcd for C24H23N5O2[M+H]+413.1852found:413.1850.
其产率：59％。
10、3-(6-吗啉基吡啶-3-基)-N-(噻吩-2-基甲基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.61(s,1H),9.08(t,J＝5.9Hz,1H),8.50(d,J＝2.2Hz,1H),8.02(s,1H),7.89(dd,J＝8.7,2.4Hz,1H),7.81(dd,J＝11.5,5.5Hz,2H),7.67–7.60(m,1H),7.38(dd,J＝5.0,1.0Hz,1H),7.03(d,J＝2.7Hz,1H),6.99–6.91(m,2H),4.65(d,J＝5.8Hz,2H),3.83–3.65(m,4H),3.53–3.40(m,4H).
其碳谱：13C NMR(101MHz,DMSO)δ167.24,157.98,145.63,143.70,136.60,136.47,127.80,127.56,127.07,125.65,125.28,121.72,119.07,118.88,113.50,112.21,107.76,66.48,45.90,40.64,40.43,40.23,40.02,39.81,39.60,39.39.
H RMS m/z(ESI)calcd for C23H22N4O2S[M+H]+418.1463found:418.1461.
其产率：79％。
11、N-(4-吗啉基苯基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.67(s,1H),10.05(s,1H),8.53(s,1H),8.10(s,1H),7.91(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,1H),7.82(s,1H),7.73(d,J＝8.6Hz,1H),7.68(d,J＝8.7Hz,2H),7.56(dd,J＝11.4,7.3Hz,3H),7.49(d,J＝6.3Hz,2H),3.74(d,J＝4.0Hz,9H),3.48(d,J＝4.2Hz,4H),3.07(s,4H).
其碳谱：13C NMR(101MHz,DMSO)δ166.17,157.99,147.79,145.64,136.59,136.49,132.29,128.61,127.59,125.85,121.96,121.71,119.40,118.89,115.75,113.55,112.48,107.79,66.62,66.48,49.45,45.90,40.62,40.42,40.21,40.00,39.79,39.58,39.37.
H RMS m/z(ESI)calcd for C28H29N5O3[M+H]+483.2270found:483.2268.
其产率：68％。
12、N-(4-(4-甲基哌嗪-1-基)苯基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ11.68(s,1H),10.02(s,1H),8.52(d,J＝1.9Hz,1H),8.09(s,1H),7.88(ddd,J＝22.9,11.6,2.1Hz,3H),7.72(d,J＝8.9Hz,1H),7.65(t,J＝7.7Hz,2H),6.94(t,J＝8.8Hz,3H),3.83–3.67(m,4H),3.55–3.43(m,4H),3.10(s,4H),2.46(d,J＝4.2Hz,4H),2.22(s,3H).
其碳谱：13C NMR(101MHz,DMSO)δ166.12,157.99,147.78,145.63,136.59,136.48,131.96,128.64,127.58,125.83,121.93,121.72,119.40,118.87,115.97,113.54,107.78,66.48,55.14,49.06,46.26,45.90,40.64,40.43,40.22,40.01,39.80,39.59,39.39.
H RMS m/z(ESI)calcd for C29H32N6O2[M+H]+496.2587found:496.2585.
其产率：78％。
13、(3,4-二氢异喹啉-2(1H)-基)(3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-基)甲酮
其氢谱：1H NMR(400MHz,DMSO)δ11.52(s,1H),8.50(s,1H),7.86(d,J＝21.2Hz,2H),7.75(s,1H),7.54(s,1H),7.18(s,5H),6.94(s,1H),4.74(s,2H),3.73(s,6H),3.47(s,4H),2.88(s,2H).
H RMS m/z(ESI)calcd for C27H26N4O2[M+H]+438.2056found:438.2056.
其产率：64％。
14、(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)(3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-基)甲酮
其氢谱：1H NMR(400MHz,DMSO)δ11.52(s,1H),8.50(s,1H),7.88(s,1H),7.83(d,J＝6.5Hz,1H),7.75(s,1H),7.53(s,1H),7.17(s,1H),6.94(d,J＝7.7Hz,1H),6.75(s,2H),4.65(s,2H),3.72(s,11H),3.47(s,4H),2.79(s,2H),1.25(d,J＝12.7Hz,2H).
其碳谱：13C NMR(101MHz,DMSO)δ157.99,147.89,145.65,136.48,129.55,126.39,125.52,124.88,121.73,119.23,113.53,112.52,111.59,107.75,77.86,66.48,56.00,45.89,40.63,40.42,40.21,40.00,39.79,39.58,39.37.
H RMS m/z(ESI)calcd for C29H30N4O4[M+H]+498.2267found:498.2269.
其产率：73％。
15、(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)(3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-基)甲酮
其氢谱：1H NMR(400MHz,DMSO)δ11.54(s,1H),8.50(d,J＝1.7Hz,1H),7.89(dd,J＝8.7,2.0Hz,1H),7.83(d,J＝8.3Hz,1H),7.76(s,1H),7.54(s,2H),7.35(s,1H),7.17(d,J＝8.2Hz,1H),6.94(d,J＝8.8Hz,1H),4.65(s,2H),3.77–3.69(m,5H),3.47(dd,J＝10.3,5.7Hz,4H),2.90(s,2H),1.27(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ158.00,145.66,136.49,132.84,129.39,126.47,124.97,124.20,121.72,119.26,113.54,107.75,66.48,45.89,40.63,40.42,40.22,40.01,39.80,39.59,39.38,25.43.
H RMS m/z(ESI)calcd for C25H24N4O2S[M+H]+444.1620found:444.1619.
其产率：64％。
实施例5：
本实施例公开通过第二条合成路线合成化合物的具体方法，合成路线如下：
在100mL圆底烧瓶中，称取化合物9，加入10mL干燥的THF溶解，然后移至低温反应器开始搅拌，维持温度在0℃，加入NaH，继续反应1h。加入相应的氯化试剂，移至室温继续反应。TLC检测反应进程，反应完毕后停止反应。经减压蒸馏浓缩，加入水和二氯甲烷萃取3次，然后，有机相用饱和NaCl水溶液洗涤，随后，用无水MgSO4干燥，过滤，减压浓缩，经柱层析分离纯化得到终产物。
实施例6：
本实施例公开通过第二条合成路线获得的具体化合物，包括：
1、1-乙酰基-N-(3-吗啉基丙基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ8.91(s,1H),8.56(s,2H),8.21(s,1H),7.96(d,J＝8.1Hz,1H),7.84(dd,J＝18.5,7.8Hz,2H),7.00(d,J＝8.3Hz,1H),3.74(s,4H),3.57(s,4H),3.52(s,4H),2.73(s,3H),2.36(s,6H),1.72(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ170.03,166.85,158.81,146.58,137.24,135.70,132.03,130.81,125.96,123.11,119.62,119.20,118.79,116.17,107.62,66.63,66.44,56.65,55.38,53.80,45.63,40.64,40.43,40.22,40.01,39.81,39.60,39.39,38.45,26.39,24.45.
H RMS m/z(ESI)calcd for C27H33N5O4[M+H]+491.2533found:491.2533.
其产率：45％。
2、1-丙烯酰基-N-(3-吗啉基丙基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺
其氢谱：1H NMR(400MHz,DMSO)δ8.81(s,1H),8.56(s,2H),7.96(s,2H),7.64(s,1H),7.49(s,1H),7.01(s,1H),6.65(d,J＝15.6Hz,1H),6.31(s,1H),6.17(d,J＝31.7Hz,2H),5.60(s,1H),3.85(s,2H),3.74(s,4H),3.53(s,4H),3.45(s,4H),2.26(s,6H),1.77(s,2H).
其碳谱：13C NMR(101MHz,DMSO)δ170.03,166.85,158.81,146.58,137.24,135.70,132.03,131.89,130.81,125.96,123.11,119.62,119.20,118.79,116.17,107.62,66.63,66.44,56.65,55.38,53.80,45.63,40.64,40.43,40.22,40.01,39.81,39.60,39.39,38.45,26.39,24.45
H RMS m/z(ESI)calcd for C28H33N5O4[M+H]+503.2533found:503.2532.
其产率：59％。
实施例27：
本实施例以上述实施例提供的40化合物为基础，对其分别进行体外P300蛋白活性的抑制效果的测试实验。
测试方法如下：
(1)实验材料：
购买于美国BPS Bioscience公司的P300酶(产品编号：50071)；美国Perkin Elmer公司的384孔板(产品编号：SMP410A001PK)；Calbiochem公司的阳性对照产品C646(产品编号：382113)；Sigma公司的底物Ac-CoA(产品编号：A2056)；PerkinElmer公司的底物类似物产品[3H]-Ac-CoA(产品编号：NET290)。。
(2)实验方法的具体步骤：
1)准备1x测定缓冲液(改良的Tris缓冲液)；
2)化合物系列稀释：将化合物通过Echo在100％DMSO中转移至测定板；
3)准备酶溶液：在1x测定缓冲液中准备酶溶液；
4)准备底物溶液：在1x测定缓冲液中加入肽和[3H]-Ac-CoA以制备底物溶液；
5)将10μL酶溶液转移至测定板或用于低对照转移10μL1x测定缓冲；
6)在室温下孵育15分钟；
7)加入10μL的底物溶液到每个孔开始反应；
8)在室温下孵育60分钟；
9)在1x测定缓冲液中加入冷的Ac-CoA以制成终止混合物；
10)停止反应，每孔加入10μL停止溶液；
11)将每孔25μL的体积转移到测定板上的闪光板上；
12)在室温下至少孵育1小时；
13)用ddH2O+0.1％Tween-20洗涤闪光板三次；
14)数据读取及进一步处理；
为了使用下列公式在Excel中获得抑制值：
公式：Inh％＝(Max-Signal)/(Max-Min)*100。
(3)实验结果：
通过以上实验方法，测试了本发明化合物针对P300的抑制活性，具体的化合物在10μM、1μM浓度下的抑制活性及部分化合物对P300的半数抑制有效浓度(IC50)见表1，其中“-”表示未测。
表一本发明化合物对P300的抑制活性(Inh％)
由表一可知，本发明提供的40种具体的化合物均能对p300有一定的抑制作用，其中，化合物2、4、9、10、14、16、18、19、32、40对p300抑制效果非常显著，无论是10μM、1μM，均明显优于阳性对照组C646的抑制活性，其他组别化合物p300的也有较好的抑制效果，与阳性对照组C646的抑制活性相近，由此可证明本发明提供的丙烯酰胺类衍生物对p300酶具有明显抑制效果，部分化学结构远远优于现有C646的抑制活性，因此本发明中合成的丙烯酰胺类衍生物在p300酶抑制领域具有显著的进步。
实施例28：
本实施例以上述实施例提供的对p300抑制效果最优的化合物为基础，即1-丙烯酰基-N-(3-吗啉基丙基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺，对其分别对多种肿瘤细胞株增殖进行抑制实验，验证其对肿瘤细胞的抑制效果。
(1)实验材料：
主要试剂：RPMI-1640、胎牛血清、胰酶等购自Gibco BRL公司(InvitrogenCorporation，USA)，IMDM培养基购自ATCC(American Type Culture Collection)。四甲基偶氮唑盐(MTT)、二甲基亚砜(DMSO)为Sigma公司(USA)产品。人前列腺癌细胞系(PC-3),人宫颈癌细胞系(Hela)，人肺癌细胞系(H2228),人肺癌细胞系(NCI-H1975)，人肺癌细胞系(PC-9)，人肺癌细胞系(NCI-H358),人肺癌细胞系(Calu-1),人胰腺癌细胞系(AsPC-1)，人胰腺癌细胞系(BxPC-3)，淋巴瘤细胞系(Jeko-1)，淋巴瘤细胞系(Molt-4)，人三阴性乳腺癌细胞系(MDA-MB-231),人三阴性乳腺癌细胞系(MDA-MB-435),人卵巢癌细胞系(SK-OV-3),人卵巢癌细胞系(OVCAR-3),人卵巢癌细胞系(HO8910),人卵巢癌细胞系(A2780S),人卵巢癌细胞系(A2780/T),人纤维肉瘤细胞(HT1080)等均购于美国ATCC(American typeculture collection)，由本实验室保存。
(2)实验方法：
用完全细胞培养液调整细胞浓度为1～2×104个/mL的细胞悬液，接种于96孔板，每孔200μl细胞悬液，培养过夜。次日，吸弃上清(悬浮细胞离心后吸取上清)，然后分别用梯度浓度的受试化合物处理细胞。同时设不含药物的阴性对照组和等体积的溶剂对照组，DMSO浓度为0.1％，每个剂量组设3个复孔，在37℃，5％CO2条件下培养。72小时后，每孔加入浓度为5mg/mL的MTT试剂20μl，再培养2-4h后，弃上清，每孔再加入DMSO 150μL，振荡混匀15min，用酶标仪(λ＝570nm)测定吸光度(A)值(A值与活细胞数成正比)，取其平均值。相对细胞增殖抑制率＝(阴性对照组A570-实验组A570)/阴性对照组A 570×100％。实验至少重复3次。实验数据用均数表示，数据统计资料采用t检验，P<0.05为差异有统计学意义。以下各化合物对细胞增殖抑制作用均用IC50表示。
(3)实验结果：
采用以上方法，选取对p300酶抑制效果相对显著的化合物6作为测试对象，对其分别进行了人前列腺癌细胞系(PC-3),人宫颈癌细胞系(Hela)，人肺癌细胞系(H2228),人肺癌细胞系(NCI-H1975)，人肺癌细胞系(PC-9)，人肺癌细胞系(NCI-H358),人肺癌细胞系(Calu-1),人胰腺癌细胞系(AsPC-1)，人胰腺癌细胞系(BxPC-3)，淋巴瘤细胞系(Jeko-1)，淋巴瘤细胞系(Molt-4)，人三阴性乳腺癌细胞系(MDA-MB-231),人三阴性乳腺癌细胞系(MDA-MB-435),人卵巢癌细胞系(SK-OV-3),人卵巢癌细胞系(OVCAR-3),人卵巢癌细胞系(HO8910),人卵巢癌细胞系(A2780S),人卵巢癌细胞系(A2780/T),人纤维肉瘤细胞(HT1080)等增殖抑制活性测试，具体抑制效果见表二：
表二本发明化合物对不同肿瘤细胞株的增殖抑制活性(IC50)
由表二内容可知，化合物1-丙烯酰基-N-(3-吗啉基丙基)-3-(6-吗啉基吡啶-3-基)-1H-吲哚-6-甲酰胺对各肿瘤细胞的IC50(μM)数量均小于10，其抑制效果显著，针对的肿瘤细胞较多元，未发生额外异变，具有很好的药用潜力。可以用于制备治疗和/或预防肿瘤的药物。
实施例29：
本实施例为了对筛选得到的1个候选化合物进行体内药效评价，我们使用PC-3细胞构建NOD-SCID鼠皮下的异种移植肿瘤模型。具体过程如下：
将处于对数生长期的细胞消化后用双无的培养基洗3遍，接种于NOD-SCID鼠皮下，待肿瘤长至100-150mm3时开始给药，按照剂量50mg/kg做预实验。根据实施例27中各化合物对P300的抑制活性，选择使用化合物40进行试验。继续使用PC-3细胞构建NOD-SCID鼠皮下的异种移植肿瘤模型做正式实验。
建模过程同上，待肿瘤长到100-150mm3时随机分为3个组，每组6只小鼠。
实验组1，使用化合物40给药，其给药剂量为50mg/kg/d；
实验组2，使用化合物40给药，其给药剂量为100mg/kg/d；
对照组，不添加化合物40，使用不普通的赋形剂给药，。
给药时间为27天，每三天测试一次肿瘤体积并称量小鼠体重。另外，在给药时观察动物的健康状况，如精神状态、进食情况、皮肤光泽及颜色、有无腹泻状况。
实验结论：
结论1：使用化合物40给药，能够明显抑制肿瘤细胞体积增长，如图1所示，且随着化合物40剂量的增加，能够进一步提升对肿瘤的抑制效果；
结论2：使用化合物40给药，其剂量在50～100mg/kg/d的正常使用区间内，对小鼠体重无明显影响，如图2所示，因此其明显没有毒副作用，具有药用潜力。
尽管已经示出和描述了本发明的实施例，本领域的普通技术人员可以理解：在不脱离本发明的原理和宗旨下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。

Claims (12)

1.一种抑制组蛋白乙酰转氨酶的化合物，其通式如下：
其中，
R为独立的H、-Me、
X为独立的O或N；
Y为独立的H、-OMe、
Z为独立的
2.根据权利要求1所述的抑制组蛋白乙酰转氨酶的化合物，其特征在于，当X为氧原子时，其结构通式为：
其中，R和Y均为H，Z为
3.根据权利要求1所述的抑制组蛋白乙酰转氨酶的化合物，其特征在于，当X为氮原子时，其结构通式为：
Y为Z为时，R为以下结构中的一种：-Me、
4.根据权利要求1所述的抑制组蛋白乙酰转氨酶的化合物，其特征在于，当R为H，X为氮原子时，其结构通式为：
其中：Y为Z为以下结构中的一种：
5.根据权利要求1所述的抑制组蛋白乙酰转氨酶的化合物，其特征在于，当R为H，X为氮原子，Z为时，其结构通式为：
其中，R为H，Y为以下结构中的一种：
H、-OMe、
6.一种抑制组蛋白乙酰转氨酶的化合物，其特征在于，具体结构式为：
7.根据权利要求1所述的一种抑制组蛋白乙酰转氨酶的化合物的制备方法，其特征在于，包括以下步骤：
(7.1)称取1H-吲哚-6-甲酸，使用DMF溶解，常温搅拌，称取相对当量的氢氧化钾加入到反应体系中；
(7.2)随后称取单质碘，将其通过DMF溶解后，转移到恒压滴液漏斗中，缓慢滴加到上述反应体系中，滴加完后，检测反应进程，待反应结束；
(7.3)称取相对当量的硫代硫酸钠，并加入冰水，然后将反应液缓慢倒入到冰水中，调节pH值至3左右，析出固体，过滤干燥得中间体Ⅰ；
(7.4)称取中间体Ⅰ，使用THF溶解，常温搅拌，称取相对当量的HATU和DIEA加入到反应体系中，继续搅拌，接着加入3-吗啉丙基-1-胺，在40℃环境下反应，检测反应进程，待反应结束，经减压蒸馏浓缩，萃取，洗涤，干燥，过滤，减压浓缩，经柱层析分离得到中间体Ⅱ；
(7.5)称取中间体Ⅱ，通过Ac2O溶解，常温搅拌，随后加入催化量的DMAP，继续反应，检测反应进程，待反应结束，经减压蒸馏浓缩，萃取，洗涤，干燥，过滤，减压浓缩得到中间体Ⅲ。
(7.6)称取中间体Ⅲ、取代的硼酸频哪醇酯Pd(dppf)2Cl2CH2Cl2和碳酸铯，用二氧六环和水溶解后，然后，置换氩气3次，移至90℃下反应，检测反应进程，待反应结束，反应液用硅藻土过滤，二氧六环洗涤后，经减压蒸馏浓缩，萃取3次，洗涤，干燥，过滤，减压浓缩，经柱层析分离纯化得到终产物。
8.根据权利要求1所述的一种抑制组蛋白乙酰转氨酶的化合物的制备方法，其特征在于，包括以下步骤：
(8.1)称取1H-吲哚-6-甲酸，使用DMF溶解，常温搅拌，称取相对当量的氢氧化钾加入到反应体系中；
(8.2)随后称取单质碘，将其通过DMF溶解后，转移到恒压滴液漏斗中，缓慢滴加到上述反应体系中，滴加完后，检测反应进程，待反应结束；
(8.3)称取相对当量的硫代硫酸钠，并加入冰水，然后将反应液缓慢倒入到冰水中，调节pH值至3左右，析出固体，过滤干燥得中间体Ⅰ；
(8.4)称取中间体Ⅰ，使用THF溶解，常温搅拌，称取相对当量的HATU和DIEA加入到反应体系中，继续搅拌，随后加入取代的胺Y-NH2，移至40℃反应，检测反应进程，待反应结束，经减压蒸馏浓缩，萃取，洗涤，干燥，过滤，减压浓缩，经柱层析分离得到中间体IV；
(8.5)使用Ac2O溶解中间体IV，常温搅拌，随后加入催化量的DMAP，继续反应，检测反应进程，待反应结束，经减压蒸馏浓缩，萃取，洗涤，随后，干燥，过滤，减压浓缩得到中间体V；
(8.6)称取中间体V、相应的取代的硼酸频哪醇酯、Pd(dppf)2Cl2CH2Cl2和碳酸铯，用二氧六环和水溶解后，然后，置换氩气3次，移至90℃下反应，检测反应进程，待反应结束，反应液用硅藻土过滤，二氧六环洗涤后，经减压蒸馏浓缩，萃取，洗涤，干燥，过滤，减压浓缩，经柱层析分离纯化得到终产物。
9.根据权利要求8所述的一种抑制组蛋白乙酰转氨酶的化合物的制备方法，其特征在于，称取步骤(8.6)最后得到的终产物，使用THF溶解，低温搅拌，加入NaH，继续反应，加入氯化试剂，移至室温继续反应，检测反应进程，待反应结束，经减压蒸馏浓缩，萃取，洗涤，干燥，过滤，减压浓缩，经柱层析分离纯化得到终产物。
10.一种组蛋白乙酰转氨酶P300抑制剂，其特征在于，以权利要求1-6所述化合物为主要活性成分的生物药学上可接受的盐、晶型、溶剂合物。
11.一种治疗癌症的药物，其特征在于，以权利要求9所述的组蛋白乙酰转氨酶P300抑制剂为主要成分，添加生物药学上能够接受的辅助性成分制备而成。
12.根据权利要求9所述治疗癌症的药物，其特征在于，治疗的癌症包括前列腺癌、宫颈癌、肺癌、胰腺癌、淋巴瘤、三阴性乳腺癌、卵巢癌、纤维肉瘤。
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CN109748884A (zh) * 2019-02-19 2019-05-14 四川大学 一种铁死亡抑制剂及其制备方法与应用
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CN113924146A (zh) * 2019-05-29 2022-01-11 加拉帕戈斯股份有限公司 用于治疗疾病的新化合物及其药物组合物

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