CN115160310B - 作为CDK2/Topo I抑制剂的白叶藤碱衍生物及其制备方法和抗肿瘤的应用 - Google Patents

作为CDK2/Topo I抑制剂的白叶藤碱衍生物及其制备方法和抗肿瘤的应用 Download PDF

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CN115160310B
CN115160310B CN202210505333.4A CN202210505333A CN115160310B CN 115160310 B CN115160310 B CN 115160310B CN 202210505333 A CN202210505333 A CN 202210505333A CN 115160310 B CN115160310 B CN 115160310B
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chloride
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CN115160310A (zh
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赵庆春
黄耀广
许子华
刘文武
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General Hospital of Shenyang Military Region
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Abstract

本发明提出一种作为CDK2/Topo I抑制剂的白叶藤碱衍生物及其制备方法和抗肿瘤的应用，本发明合成方法简单，温和；部分衍生物能够同时抑制CDK2和Topo I；3、衍生物的抗肿瘤细胞增值活性显著增强。本发明化合物作为先导化合物在肿瘤治疗中具有重要作用。

Description

作为CDK2/Topo I抑制剂的白叶藤碱衍生物及其制备方法和 抗肿瘤的应用
技术领域
本发明涉及有机化合物合成与医药应用技术领域，特别是制备抗癌药物技术领域，具体是一类作为CDK2/Topo I抑制剂的白叶藤碱衍生物及其制备方法和靶向CDK2及Topo I抗肿瘤的应用。
背景技术
近年来，分子靶点的发现和对细胞功能的不断了解有助于改善小分子化疗药物作为癌症治疗的主要治疗类别。来自天然产物的启示为小分子化疗药物的发展注入了新的能量。
天然产物因其高生物利用度和低毒性而成为研究热点。吲哚喹啉类生物碱的特征结构是由吲哚和喹啉融合而成的四元环核，代表性的天然产物是从西非灌木sanguinolenta的根中提取到的白叶藤碱。白叶藤碱的大部分研究靶向DNA，即通过与DNA本身或DNA-酶复合物结合形成稳定的靶点抑制剂复合物，影响DNA复制、转录和翻译，最终导致肿瘤细胞死亡。
细胞***周期控制细胞增殖，其检查点确保基因组的稳定性。细胞周期中不受监管的进展是癌症的标志。细胞周期蛋白依赖性蛋白激酶(CDK)家族的成员被鉴定为丝氨酸/苏氨酸特异性蛋白激酶，在细胞周期蛋白伴侣激活表达后驱动细胞周期。其中关于CDK2的研究最多，其失调导致细胞增殖失控是癌症的预兆。在G1晚期，CDK2/cyclin E充分磷酸化视网膜母细胞瘤(Rb)蛋白，启动细胞周期的S期，然后CDK2/cyclin A维持Rb蛋白的磷酸化，确保细胞周期进程并促进S/G2转变。CDK2除控制细胞周期外，还是凋亡通路的核心调控因子和功能成分。
研究表明CDK2和Topo I互为上下游靶点，Topo I通过结合和催化细胞核中DNA链的断裂来控制DNA的拓扑状态，从而调节超螺旋结构模板。Topo I抑制剂通过稳定Topo I-DNA复合物以抑制Topo I活性或作为DNA破坏剂直接破坏DNA发挥作用。众所周知，DNA损伤反应会触发检查点激酶ATM的磷酸化。ATM通过抑制CDC25磷酸酶和下游CDK2激活CHK2以阻止细胞周期。有趣的是，CDK2的失活直接导致DNA损伤并刺激DDR。CDK2似乎根据细胞状态发挥不同的作用。因此，Topo I和CDK2之间的联系是复杂而密切的。目前并没有关于CDK2/Topo I双靶点抑制剂的相关报道，研究二者的双靶点药物是有意义的尝试。
发明内容
本发明提出一种作为CDK2/Topo I抑制剂的白叶藤碱衍生物及其制备方法和抗肿瘤的应用，其目的是提供具有CDK2/Topo I双靶点抑制活性的新型白叶藤碱衍生物，并指出其在抗肿瘤中的应用。
技术方案：一种白叶藤碱抗肿瘤衍生物或其药学上可接受的盐，该化合物的结构如通式I所示：
Figure BDA0003635730810000021
其中，R1为脂肪胺，如吗啉，哌嗪，哌啶，吡咯，高哌嗪或者乙，丙，丁二胺以及氨基被boc取代的产物；R2为被取代基取代的芳香基团如吡啶，苯，吡唑环，所述取代基为酰胺基、烷氧基或者卤素；X为N或O以及延伸的S。
下列化合物或其在药学上可用的盐，选自：
Figure BDA0003635730810000022
Figure BDA0003635730810000031
一种化合物的制备方法，制备方法包括以下步骤：
(1)将苯氧乙酸经氯化亚砜氯化得到酰氯化合物2；再将化合物2与2-氨基-5-溴苯甲酸进行酰胺缩合得化合物5-1；随后用多聚磷酸作为脱水剂，130℃下反应2小时，得化合物6-1；再经由三氯氧磷回流氯化得中间体化合物7-1；
或者将2-氨基-5-溴苯甲酸，经氯乙酰氯进行酰胺缩合得化合物4；再同5-10倍量苯胺亲核取代得化合物5-2；随后用多聚磷酸作为脱水剂，130℃下反应2小时，得化合物6-2；再经由三氯氧磷回流氯化得中间体化合物7-2；
(2)使用脂肪胺，在两个中间体化合物7-1或中间体化合物7-2的11位点进行亲核取代，粗处理后再同硼酸酯或硼酸进行Suzuki偶联，得到化合物ZLHQ-1b、化合物ZLHQ-1d、化合物ZLHQ-1f、化合物ZLHQ-5j、化合物ZLHQ-5k、化合物ZLHQ-5l、化合物ZLHQ-5m、化合物ZLHQ-5n、化合物ZLHQ-1a、化合物ZLHQ-1c、化合物ZLHQ-2a、化合物ZLHQ-2b、化合物ZLHQ-2c、化合物ZLHQ-2d、化合物ZLHQ-3a、化合物ZLHQ-3b、化合物ZLHQ-3c、化合物ZLHQ-3d、化合物ZLHQ-3e、化合物ZLHQ-4a、化合物ZLHQ-4b、化合物ZLHQ-4c、化合物ZLHQ-4d、化合物ZLHQ-4f或者带有boc保护基的产物化合物；
(3)化合物ZLHQ-5l、化合物ZLHQ-5n、带有boc保护基的产物化合物，再在酸性溶剂中脱Boc得到化合物ZLHQ-5c、化合物ZLHQ-5h、化合物ZLHQ-5a、化合物ZLHQ-5b、化合物ZLHQ-5d、化合物ZLHQ-5e、化合物ZLHQ-5f、化合物ZLHQ-5g、化合物ZLHQ-5i或者化合物ZLHQ-1e。
优选的，步骤(2)中硼酸酯或硼酸为中间体化合物10、4-吡啶硼酸、3-吡啶硼酸、2-氟吡啶-5-硼酸、1-甲基-4-吡唑硼酸频哪醇酯、(1H-吡唑-4-基)硼酸、3-甲氧基苯硼酸、4-羟甲基苯硼酸、苯并-1,4-二氧六环-6-硼酸、苯并[d][1,3]二氧杂环戊烯-5-基硼酸或者2-羟甲基苯硼酸。
优选的，所述中间体化合物10的制备过程为，2-氨基4-溴吡啶5g与酰氯在THF溶剂中酰胺缩合，得到产物9，然后进行宫浦反应，110℃氮气保护12h得到中间体化合物10。
优选的，酰氯为环丙酰氯，环丁酰氯，环戊酰氯，环己酰氯或者苯丙酰氯。
优选的，步骤(2)中脂肪胺为3-(4-吗啉基)-1-丙胺、吗啉、N，N-二甲基乙烷-1,2-二胺、(S)-吡咯烷-3-醇、四氢吡咯、4-叔丁氧羰基氨基哌啶、丙醇胺、N-Boc-1,3-丙二胺、N-Boc-哌嗪、N-Boc-高哌嗪、3-叔丁氧羰基氨基哌啶、(R)-3-叔丁氧羰基氨基吡咯烷、(S)-3-叔丁氧羰基氨基吡咯烷、N-Boc-乙二胺或者N-Boc-1,4-丁二胺。
优选的，步骤(3)中酸性溶剂为二氯甲烷与三氟乙酸等体积比的混合物或者盐酸乙酸乙酯。
本发明化合物或其药学上可用的盐在制备抗肿瘤药物中的应用。
本发明化合物或其药学上可用的盐在制备CDKs抑制剂或TopoI抑制剂中的应用。
与现有的技术相比，本发明具有如下显著的特点：1、合成方法简单，温和；2、部分衍生物能够同时抑制CDK2和Topo I；3、衍生物的抗肿瘤细胞增值活性显著增强。因此，该类化合物作为先导化合物在肿瘤治疗中具有重要作用。
附图说明
图1为关键中间体化合物7的制备方法示意图；
图2为关键中间体化合物10的制备方法示意图；
图3为化合物ZLHQ-5f对Topo I活性的评价。
具体实施方式
以下结合说明书附图更详细的说明本发明。本发明所用溶剂均为市售化学纯或分析纯。通过核磁共振(NMR)确定化合物的结构。NMR的测定是使用Bruker AVANCE-300/500核磁共振仪，测定的溶剂是CDCl3、DMSO-d6或重水，内标为TMS。
实施例1中间体化合物7
如图1所示，图1中(a)氯化亚砜，三氯甲烷，回流4小时；(b)2-氨基-5-溴苯甲酸，乙腈，室温2小时；(c)氯乙酰氯，1，4-二氧六环，DMF，室温，6小时；(d)苯胺，乙腈，回流，24小时；(e)多聚磷酸，130℃，2小时；(f)三氯氧磷，回流，2小时。(g)各种酰氯，吡啶，THF，2h；(h)(BPIN)2，Pd(dppf)Cl2，乙酸钾，1，4-二氧六环，N2，12h。具体为，将市售的苯氧乙酸5g溶于三氯甲烷30ml，加入氯化亚砜5ml，回流4小时后减压除去溶剂得化合物2；乙腈为溶剂，与2-氨基-5-溴苯甲酸8g反应得化合物5-1；随后溶于150g多聚磷酸，130℃反应2小时，冷缩后倒入冰水，NaOH调PH至碱性，抽滤，干燥得化合物6-1；三氯氧磷回流氯化得化合物7-1。
市售的2-氨基-5-溴苯甲酸8g溶于10mlDMF与10ml1，4-二氧六环中，冰浴下缓慢滴加氯乙酰氯7ml，室温过夜，加入大量水，析出黄色固体，抽滤得化合物4；以乙腈为溶剂，加入多倍量苯胺回流24小时得化合物5-2；再经PPA合环、三氯氧磷氯化得化合物7-2。
实施例2中间体化合物10
如图2所示，图中(a)各种酰氯，吡啶，THF，2h；(b)(BPIN)2，Pd(dppf)Cl2，乙酸钾，1，4-二氧六环，110℃，N2，12h。具体为，2-氨基4-溴吡啶5g与各种酰氯(1.1eq)在THF溶剂中酰胺缩合，得到产物化合物9，然后进行宫浦反应(3eq醋酸钾，1.5eq(BPIN)2，0.5％eqPd(dppf)Cl2)，110℃氮气保护12h得到中间体化合物10。酰氯为环丙酰氯，环丁酰氯，环戊酰氯，环己酰氯或者苯丙酰氯。酰氯为环丙酰氯时产物为中间体化合物10-1，环丁酰氯时产物为中间体化合物10-2，环戊酰氯时产物为中间体化合物10-3，环己酰氯时产物为中间体化合物10-4，苯丙酰氯时产物为中间体化合物10-5。
实施例3 N-(4-(11-((3-吗啉丙基)氨基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-1b)
Figure BDA0003635730810000061
将3-(4-吗啉基)-1-丙胺(5-10eq)和催化量的NaI放入茄形瓶中。当它在170℃熔化时，加入中间体化合物7-1反应2小时，及时检测反应。反应完成后冷却***。用甲醇打浆，抽滤，洗涤两次，干燥后直接进行SUZUKI偶联。新获得的中间体(1eq)、中间体化合物10-1(1.2eq)、Pd(dppf)Cl2(0.5％eq)、Cs2CO3(3eq)的混合物溶于1,4-二氧六环：水＝4:1的溶剂中，N2交换3次。将反应混合物加热至95℃并在N2保护下搅拌12小时。减压蒸馏除去溶剂后，混合物通过硅胶柱色谱(PE/EA)纯化得终产物化合物ZLHQ-1b。收率57％，淡黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.91(s,1H),8.73(d,J＝2.0Hz,1H),8.55(d,J＝1.7Hz,1H),8.44(d,J＝5.2Hz,1H),8.21(dd,J＝7.6,1.2Hz,1H),8.09(d,J＝8.9Hz,1H),7.93(dd,J＝8.9,1.9Hz,1H),7.74–7.59(m,4H),7.48(ddd,J＝7.9,6.6,1.6Hz,1H),4.00(q,J＝6.7Hz,2H),3.52(t,J＝4.6Hz,4H),2.48(t,J＝6.9Hz,2H),2.36(d,J＝4.6Hz,4H),2.08(tt,J＝7.5,4.9Hz,1H),1.93(p,J＝7.0Hz,2H),0.92–0.80(m,4H)；13CNM R(100MHz,DMSO-d6):δ173.29,157.90,153.39,149.63,148.85,147.54,147.07,136.31,133.26,132.81,130.81,130.38,126.83,123.81,123.55,122.07,121.43,118.64,117.89,112.59,111.63,66.60(2C),55.37,53.83(2C),43.56,28.09,14.72,8.13(2C).HR-ESI-MS:522.2481[M+H]+,(calcdforC31H31N5O3,522.2500).
实施例4 N-(4-(11-(4-氨基哌啶-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-1d)
Figure BDA0003635730810000071
吗啉代替3-(4-吗啉基)-1-丙胺，按照实施例3程序合成化合物ZLHQ-1d。产率48％，黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.94(s,1H),8.64(d,J＝1.6Hz,1H),8.52–8.43(m,2H),8.35–8.21(m,2H),8.05(dd,J＝8.8,2.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.74(t,J＝7.5Hz,1H),7.60–7.48(m,2H),3.82(dt,J＝12.6,3.9Hz,2H),3.53–3.42(m,2H),2.93(dq,J＝9.5,4.7,4.0Hz,1H),2.08(td,J＝7.8,3.8Hz,1H),2.01(dd,J＝13.1,3.7Hz,2H),1.75–1.61(m,2H),0.87(dtd,J＝10.2,8.0,4.9Hz,4H)；13CNMR(100MHz,DMSO-d6):δ173.40,158.73,153.51,149.26,148.91,148.44,147.76,140.82,137.85,134.19,131.83,130.73,126.88,124.39,123.45,122.82,122.72,122.34,117.37,112.95,111.32,67.16(2C),52.78(2C),14.79,8.24(2C).HR-ESI-MS:469.1514[M+H]+,(calcdforC28H24N4O3,469.1521).
实施例5 N-(4-(11-((2-(二甲基氨基)乙基)氨基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-1f)
Figure BDA0003635730810000072
N，N-二甲基乙烷-1,2-二胺代替3-(4-吗啉基)-1-丙胺，按照实施例3程序合成化合物ZLHQ-1f。产率61％，黄色固体。
1HNMR(600MHz,DMSO-d6):δ10.93(s,1H),8.72(s,1H),8.54(d,J＝1.7Hz,1H),8.46(d,J＝5.3Hz,1H),8.25(d,J＝7.6Hz,1H),8.14(d,J＝8.8Hz,1H),7.97(d,J＝8.9Hz,1H),7.81–7.69(m,2H),7.64(d,J＝5.1Hz,1H),7.51(t,J＝7.4Hz,1H),4.28(s,2H),3.49(s,2H),2.90(s,6H),2.07(t,J＝5.9Hz,1H),0.91–0.80(m,4H)；13CNMR(150MHz,DMSO-d6):δ173.36,158.13,153.41,149.50,148.94,147.23,135.41,133.27,133.17,131.04,130.32,127.09,124.06,123.26,122.15,121.62,118.64,117.97,112.99,111.60,57.46,43.30(2C),40.51,14.73,8.18(2C).HR-ESI-MS:466.2228[M+H]+,(calcdforC28H27N5O2,466.2238).
实施例6(S)-N-(4-(11-(3-羟基吡咯烷-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-5j)
Figure BDA0003635730810000081
(S)-吡咯烷-3-醇代替3-(4-吗啉基)-1-丙胺，按照实施例3程序合成化合物ZLHQ-5j。收率55％，淡黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.91(s,1H),8.63(d,J＝2.0Hz,1H),8.54(d,J＝1.7Hz,1H),8.41(d,J＝5.2Hz,1H),8.26–8.19(m,1H),8.11(d,J＝8.8Hz,1H),7.94(dd,J＝8.8,1.9Hz,1H),7.75(d,J＝8.3Hz,1H),7.72–7.65(m,1H),7.53(dd,J＝5.2,1.7Hz,1H),7.48(t,J＝7.4Hz,1H),5.16(s,1H),4.55–4.45(m,2H),4.41(dd,J＝10.7,4.4Hz,1H),4.11(s,1H),3.87(d,J＝10.6Hz,1H),2.15(tq,J＝8.3,4.2Hz,1H),2.06(pt,J＝7.6,3.2Hz,2H),0.93–0.80(m,4H)；13CNMR(100MHz,DMSO-d6):δ173.37,157.62,153.45,150.68,149.35,149.12,146.80,138.89,137.02,131.87,131.01,129.84,126.78,124.67,123.98,122.88,122.15,121.21,117.38,112.70,111.23,69.67,62.38,51.91,34.52,14.78,8.19(2C).HR-ESI-MS:465.1918[M+H]+,(calcd forC28H24N4O3,465.1921).
实施例7 N-(4-(11-(吡咯烷-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-5k)
Figure BDA0003635730810000082
四氢吡咯代替3-(4-吗啉基)-1-丙胺，按照实施例3程序合成化合物ZLHQ-5k，收率37％，淡黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.90(s,1H),8.65(d,J＝2.0Hz,1H),8.55(d,J＝1.7Hz,1H),8.41(d,J＝5.2Hz,1H),8.23(d,J＝7.6Hz,1H),8.12(d,J＝8.9Hz,1H),7.94(dd,J＝8.8,2.0Hz,1H),7.75(d,J＝8.2Hz,1H),7.72–7.64(m,1H),7.57–7.44(m,2H),4.13(q,J＝7.5,7.0Hz,4H),2.06(m,5H),0.86(ddt,J＝10.9,5.3,3.1Hz,4H)；13CNMR(100MHz,DMSO-d6):δ173.38,157.72,153.45,149.43,149.15,148.52,138.56,137.39,132.90,131.91,130.97,130.29,126.59,124.66,123.98,123.22,122.12,121.75,117.42,112.70,111.23,54.07(2C),26.25(2C),14.77,8.19(2C).HR-ESI-MS:449.1956[M+H]+,(calcdforC28H24N4O2,449.1972).
实施例8 1-(2-(2-(环丙烷甲酰胺)吡啶-4-基)苯并呋喃[3,2-b]喹啉-11-基)哌啶-4-基)氨基甲酸叔丁酯(ZLHQ-5l)
Figure BDA0003635730810000091
4-叔丁氧羰基氨基哌啶代替3-(4-吗啉基)-1-丙胺，按照实施例3程序合成化合物ZLHQ-5l，产率49％，白色粉末。
1HNMR(400MHz,CDCl3):δ8.69(s,1H),8.51(s,1H),8.31(t,J＝7.3Hz,2H),8.24(d,J＝8.9Hz,1H),7.95(d,J＝8.8Hz,1H),7.55(dt,J＝12.8,8.0Hz,2H),7.38(t,J＝7.5Hz,2H),3.79(d,J＝12.8Hz,2H),3.52(t,J＝12.3Hz,2H),2.18(d,J＝12.3Hz,2H),1.96(s,1H),1.93–1.82(m,2H),1.58(m,1H),1.44(s,9H),0.87(d,J＝7.2Hz,2H),0.85(m,4H)；13CNMR(150MHz,CDCl3):δ172.65,158.81(2C),155.37,152.35,149.90,148.35,147.56,140.79,138.94,133.43,130.95,129.87,126.46,123.63(2C),123.10,122.81,122.55,117.29,112.16,111.44,79.40,51.56(2C),33.42,29.57(2C),28.51(3C),16.12,8.65(2C).HR-ESI-MS:578.2738[M+H]+,(calcdforC34H35N5O4,578.2762).
实施例9 N-(4-(11-(4-氨基哌啶-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-5c)
Figure BDA0003635730810000092
将化合物ZLHQ-5l溶于二氯甲烷：三氟乙酸＝1：1混合物中，室温1小时，加入饱和碳酸氢钠析出，减压抽滤得化合物ZLHQ-5c，产量83％，淡黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.94(s,1H),8.64(d,J＝1.6Hz,1H),8.52–8.43(m,2H),8.35–8.21(m,2H),8.05(dd,J＝8.8,2.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.74(t,J＝7.5Hz,1H),7.60–7.48(m,2H),3.82(dt,J＝12.6,3.9Hz,2H),3.53–3.42(m,2H),2.93(dq,J＝9.5,4.7,4.0Hz,1H),2.08(td,J＝7.8,3.8Hz,1H),2.01(dd,J＝13.1,3.7Hz,2H),1.75–1.61(m,2H),0.87(dtd,J＝10.2,8.0,4.9Hz,4H)；13CNMR(100MHz,DMSO-d6):δ178.16,163.39,158.32,154.05,153.95,153.01,152.64,145.40,143.75,138.74,136.47,135.50,131.60,129.07,128.40,127.77(2C),127.10,122.09,117.65,116.16,84.39,56.29(2C),53.23,40.78(2C),19.51,13.01(2C).HR-ESI-MS:478.2235[M+H]+,(calcdforC29H27N5O2,478.2238).
实施例10 N-(4-(11-((3-羟基丙基)氨基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-5m)
Figure BDA0003635730810000101
丙醇胺代替3-(4-吗啉基)-1-丙胺，按照实施例3程序合成化合物ZLHQ-5m，产量33％，淡黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.91(s,1H),8.76(d,J＝1.9Hz,1H),8.54(d,J＝1.7Hz,1H),8.45(dd,J＝5.3,3.5Hz,1H),8.22(dd,J＝7.6,1.2Hz,1H),8.10(d,J＝8.9Hz,1H),7.94(dd,J＝8.9,1.8Hz,1H),7.76(d,J＝8.2Hz,1H),7.72–7.61(m,3H),7.48(td,J＝7.5,1.0Hz,1H),4.59(t,J＝5.1Hz,1H),4.15–4.06(m,1H),3.64(q,J＝6.0Hz,2H),3.18(d,J＝5.2Hz,2H),2.07(td,J＝7.4,3.8Hz,1H),1.95(p,J＝6.5Hz,2H),0.86(dtd,J＝10.4,8.3,5.2Hz,4H)；13CNMR(100MHz,DMSO-d6):δ173.30,157.96,153.39,149.61,148.86,147.56,147.12,136.36,133.28,132.77,130.78,130.39,126.81,123.81,123.53,122.05,121.46,118.64,117.90,112.73,111.62,59.00,49.06,42.46,34.51,14.72,8.14(2C).HR-ESI-MS:453.1913[M+H]+,(calcdforC27H24N4O3,453.1921).
实施例11 3-((2-(2-(环丙甲酰氨基)吡啶-4-基)苯并呋喃[3,2-b]喹啉-11-基)氨基)丙基)氨基甲酸叔丁酯(ZLHQ-5n)
Figure BDA0003635730810000111
N-Boc-1,3-丙二胺代替3-(4-吗啉基)-1-丙胺，按照实施例3程序合成化合物ZLHQ-5n，产量61％，白色粉末。
1HNMR(400MHz,CDCl3):δ8.85(s,1H),8.78(d,J＝5.3Hz,1H),8.62(q,J＝5.6,5.1Hz,2H),8.42(d,J＝9.1Hz,1H),8.25(d,J＝9.1Hz,1H),7.91–7.80(m,3H),7.74–7.61(m,2H),4.48(d,J＝6.3Hz,2H),4.11(s,9H),3.90(t,J＝5.8Hz,2H),3.74–3.58(m,2H),2.11(td,J＝8.1,4.0Hz,1H),1.49–1.15(m,4H)；13CNMR(100MHz,CDCl3):δ177.79,161.95,161.39,155.90,154.25,151.85,150.73,150.40,140.50,137.34,136.43,134.26,132.57,130.73,132.57,127.24,126.38,126.02,124.36,121.72,121.65,115.88,83.62,50.10,45.05,33.53,32.05,19.24,12.39(2C).HR-ESI-MS:552.2613[M+H]+,(calcdforC32H33N5O4,552.2605).
实施例12 N-(4-(11-((3-氨基丙基)氨基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-5h)
Figure BDA0003635730810000112
将化合物ZLHQ-5n加入盐酸乙酸乙酯，室温反应1小时，减压抽滤得化合物ZLHQ-5h，产量93％，淡黄色固体。
1HNMR(400MHz,DeuteriumOxide):δ7.76(d,J＝5.8Hz,1H),7.58(s,1H),7.43–7.24(m,6H),7.07(t,J＝7.3Hz,1H),6.83(s,1H),3.90(t,J＝7.9Hz,2H),3.16(t,J＝7.7Hz,2H),2.14(p,J＝7.9Hz,2H),1.60(s,1H),1.07–1.01(m,2H),0.94(s,2H)；13CNMR(150MHz,DeuteriumOxide):δ177.32,165.70,157.26,156.50,147.82,141.83,137.56,136.94,134.08,130.84,129.58,125.13,121.92,120.51,116.30,114.80,114.64,112.87,109.78,86.00,69.73,42.55,39.47,29.57,14.96,10.06(2C).HR-ESI-MS:452.2074[M+H]+,(calcdforC27H25N5O2,452.2081).
实施例13N-(4-(11-(哌嗪-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-5a)
Figure BDA0003635730810000121
N-Boc-哌嗪代替4-叔丁氧羰基氨基哌啶，N-Boc-哌嗪，在170℃熔化时，加入中间体7-1反应2小时。反应完成后冷却***。甲醇打浆，抽滤，洗涤两次，干燥后直接进行SUZUKI偶联。新获得的中间体(1eq)、中间体10-1(1.2eq)、Pd(dppf)Cl2(0.5％eq)、Cs2CO3(3eq)的混合物溶于1,4-二氧六环：水＝4:1的溶剂中，N2交换3次。将反应混合物加热至95℃并在N2保护下搅拌12小时。减压蒸馏除去溶剂后，混合物通过硅胶柱色谱(PE/EA)纯化得中间体。经V二氯甲烷：V三氟乙酸＝1：1混合溶液，室温1小时脱Boc，加入饱和碳酸氢钠析出，减压抽滤得化合物ZLHQ-5a，产量64％，淡黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.94(s,1H),8.62(d,J＝1.6Hz,1H),8.48(d,J＝2.1Hz,1H),8.45(d,J＝5.2Hz,1H),8.27(dd,J＝8.5,7.1Hz,2H),8.05(dd,J＝8.9,2.1Hz,1H),7.84–7.78(m,1H),7.74(ddd,J＝8.4,7.1,1.4Hz,1H),7.53(td,J＝7.4,1.1Hz,1H),3.80(t,J＝5.0Hz,4H),3.41(t,J＝5.0Hz,4H),2.06(m,1H),0.95–0.81(m,4H)；13CNMR(100MHz,DMSO-d6):δ173.48,158.76,153.48,149.22,148.98,148.51,147.69,140.92,137.24,134.60,131.96,130.78,127.03,124.51,123.42,122.79,122.63,122.40,117.60,112.92,111.58,50.06(2C),44.31(2C),14.81,8.26(2C).HR-ESI-MS:464.2067[M+H]+,(calcdforC28H25N5O2,464.2081).
实施例14 N-(4-(11-(4-氨基氮杂环庚烷-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-5b)
Figure BDA0003635730810000122
N-Boc-高哌嗪代替4-叔丁氧羰基氨基哌啶，按照实施例13程序合成化合物ZLHQ-5b，收率69％，黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.92(d,J＝13.3Hz,1H),8.67(d,J＝2.1Hz,1H),8.61(d,J＝1.6Hz,1H),8.42(d,J＝5.2Hz,1H),8.22(dd,J＝17.7,8.2Hz,2H),8.00(dd,J＝8.9,2.1Hz,1H),7.77(d,J＝8.2Hz,1H),7.70(t,J＝7.7Hz,1H),7.56–7.44(m,2H),3.77(ddd,J＝12.3,8.9,5.5Hz,4H),3.06(q,J＝6.2Hz,4H),2.49(p,J＝1.8Hz,2H),2.05(td,J＝7.6,3.8Hz,1H),1.98(m,1H),1.28–1.12(m,2H),0.93–0.78(m,4H)；13CNMR(100MHz,DMSO-d6):δ173.36,158.38,153.54,149.23,149.21148.11,148.05,140.77,140.60,133.69,131.57,130.60,126.72,124.36,124.26,123.58,123.15,122.27,117.39,112.84,111.30,79.64,58.85,54.90,50.56,48.38,45.78,32.04,29.48,14.76,8.24(2C).HR-ESI-MS:478.2238[M+H]+,(calcdforC29H27N5O2,478.2238).
实施例15 N-(4-(11-(3-氨基哌啶-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-5d)
Figure BDA0003635730810000131
3-叔丁氧羰基氨基哌啶代替4-叔丁氧羰基氨基哌啶，按照实施例13程序合成化合物ZLHQ-5d，收率70％，黄色固体。
1HNMR(400MHz,DMSO-d6):δ12.06(d,J＝13.4Hz,1H),8.76(d,J＝7.8Hz,4H),8.63(s,1H),8.58–8.48(m,3H),8.33(d,J＝8.9Hz,1H),8.04(d,J＝8.4Hz,1H),7.90(d,J＝6.3Hz,2H),7.66(t,J＝7.8Hz,1H),4.63(d,J＝12.6Hz,1H),4.17(s,1H),4.06(t,J＝11.0Hz,1H),3.92(t,J＝11.0Hz,1H),3.79(s,1H),2.20(dt,J＝12.5,6.1Hz,2H),2.09–1.93(m,1H),1.02(d,J＝6.0Hz,4H)；13CNMR(100MHz,DMSO-d6):δ174.50,158.18,151.40,150.63,145.66,145.41,140.16(d,J＝31.1Hz),138.69,133.99,133.29,130.67,125.85,125.23,124.58,122.86,120.36,118.05,117.72,113.62,112.33,54.88,53.75,47.24,28.01,23.58,15.03,9.02(2C).HR-ESI-MS:478.2228[M+H]+,(calcdforC29H27N5O2,478.2238).
实施例16(R)-N-(4-(11-(3-氨基吡咯烷-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-5e)
Figure BDA0003635730810000141
(R)-3-叔丁氧羰基氨基吡咯烷代替N-Boc-1,3-丙二胺，(R)-3-叔丁氧羰基氨基吡咯烷，在170℃熔化时，加入中间体化合物7-1反应2小时。反应完成后冷却***。甲醇打浆，抽滤，洗涤两次，干燥后直接进行SUZUKI偶联。新获得的中间体(1eq)、中间体化合物10-1(1.2eq)、Pd(dppf)Cl2(0.5％eq)、Cs2CO3(3eq)的混合物溶于1,4-二氧六环：水＝4:1的溶剂中，N2交换3次。将反应混合物加热至95℃并在N2保护下搅拌12小时。减压蒸馏除去溶剂后，混合物通过硅胶柱色谱(PE/EA)纯化得中间体。经盐酸乙酸乙酯溶液，室温1小时脱Boc，加入饱和碳酸氢钠析出，减压抽滤得化合物ZLHQ-5e，产量55％，淡黄色固体。
1HNMR(400MHz,DeuteriumOxide):δ7.98(d,J＝1.9Hz,1H),7.87(d,J＝6.4Hz,1H),7.50–7.42(m,2H),7.36(d,J＝8.9Hz,1H),7.31(dd,J＝6.5,1.9Hz,1H),7.28–7.20(m,2H),6.96(ddd,J＝8.0,5.6,2.4Hz,1H),6.89(d,J＝1.8Hz,1H),4.58(dd,J＝12.7,6.3Hz,1H),4.31(ddd,J＝27.5,12.1,5.8Hz,1H),4.19(p,J＝6.8Hz,1H),4.06(p,J＝5.8Hz,1H),2.41(dq,J＝13.5,7.1Hz,1H),2.16(dq,J＝13.0,6.5Hz,1H),1.52(td,J＝7.7,3.9Hz,1H),0.92–0.78(m,4H)；13CNMR(100MHz,DeuteriumOxide):δ177.68,156.85,152.66,147.81,144.03,139.49,139.10,136.01,134.31,133.55,129.75,128.67,126.10,125.02,121.92,120.60,116.86,116.73,115.26,112.92,110.64,57.46,53.74,49.65,29.30,15.32,10.17(2C).HR-ESI-MS:464.2087[M+H]+,(calcdforC28H25N5O2,464.2081).
实施例17(S)-N-(4-(11-(3-氨基吡咯烷-1-基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-5f)
Figure BDA0003635730810000142
(S)-3-叔丁氧羰基氨基吡咯烷代替N-Boc-1,3-丙二胺，按照实施例16程序合成化合物ZLHQ-5f，收率45％，黄色固体。
1HNMR(600MHz,DMSO-d6):δ10.91(s,1H),8.66(d,J＝23.3Hz,1H),8.54(d,J＝17.5Hz,1H),8.41(d,J＝5.1Hz,1H),8.22(d,J＝7.7Hz,1H),8.11(d,J＝8.8Hz,1H),7.94(d,J＝9.1Hz,1H),7.75(d,J＝8.4Hz,1H),7.68(q,J＝7.5Hz,1H),7.55(d,J＝5.1Hz,1H),7.48(t,J＝7.3Hz,1H),4.41–4.34(m,1H),4.27(dd,J＝9.8,5.6Hz,1H),4.20(td,J＝10.1,9.6,5.0Hz,1H),3.82(dd,J＝9.8,4.7Hz,1H),3.67(p,J＝5.4Hz,1H),2.16(dq,J＝12.5,6.6Hz,1H),2.05(dtt,J＝21.9,11.6,5.1Hz,1H),1.83(dq,J＝12.1,6.3Hz,1H),0.89–0.82(m,4H)；13CNMR(100MHz,DMSO-d6):δ173.42,158.68,158.37,153.40,149.72,149.01,145.42,144.30,133.40,130.30,130.12,127.37,125.28,124.20,122.73,121.78,120.20,117.88,116.30,112.48,111.73,55.95,50.65,50.28,30.54,14.79,8.21(2C).HR-ESI-MS:464.2079[M+H]+,(calcdforC28H25N5O2,464.2081).
实施例18 N-(4-(11-((2-氨基乙基)氨基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-5g)
Figure BDA0003635730810000151
N-Boc-乙二胺代替N-Boc-1,3-丙二胺，按照实施例16程序合成化合物ZLHQ-5g，收率67％，黄色固体。
1HNMR(400MHz,DeuteriumOxide):δ7.87(s,2H),7.51–7.31(m,6H),7.07(t,J＝7.2Hz,1H),6.87(s,1H),4.21(t,J＝6.9Hz,2H),3.37(t,J＝6.8Hz,2H),1.56(q,J＝6.6,4.7Hz,1H),0.97(d,J＝7.7Hz,2H),0.91(t,J＝3.9Hz,2H)；13CNMR(100MHz,DeuteriumOxide):δ177.16,156.87,149.84,147.16,141.42,139.53,136.89,136.65,134.24,130.34,128.67,127.94,125.17,121.76,121.39,120.35,115.55,114.24,114.11,112.94,108.60,42.79,39.34,15.09,10.42(2C).HR-ESI-MS:438.1925[M+H]+,(calcdforC26H23N5O2,438.1925).
实施例19 N-(4-(11-((4-氨基丁基)氨基)苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-5i)
Figure BDA0003635730810000161
N-Boc-1,4-丁二胺代替N-Boc-1,3-丙二胺，按照实施例13程序合成化合物ZLHQ-5i，收率57％，黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.93(s,1H),8.93(s,1H),8.53(d,J＝1.7Hz,1H),8.44(d,J＝5.2Hz,1H),8.33(d,J＝7.0Hz,1H),8.18–8.09(m,4H),7.99(d,J＝9.0Hz,1H),7.83(d,J＝8.4Hz,1H),7.79–7.67(m,2H),7.50(t,J＝7.5Hz,1H),4.00(q,J＝6.2Hz,2H),2.87(s,2H),2.09(td,J＝7.5,3.9Hz,1H),1.83(dq,J＝23.8,7.8Hz,4H),0.90–0.82(m,4H)；13CNMR(100MHz,DMSO-d6):δ173.34,172.45,157.84,153.36,149.16,148.88,133.13,132.90,131.27,124.06,122.55,121.96,118.21,118.06,112.98,111.56,44.39,39.08,28.23,24.81,21.56,14.73,8.16.HR-ESI-MS:466.2216[M+H]+,(calcdforC28H27N5O2,466.2238).
实施例20 N-(4-(11-((3-吗啉丙基)氨基)-10H-吲哚啉[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-1a)
Figure BDA0003635730810000162
7-2代替7-1，按照实施例3程序合成化合物ZLHQ-1a，收率68％，黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.95(s,1H),8.95(s,1H),8.55(s,1H),8.47(d,J＝5.2Hz,1H),8.26(t,J＝6.8Hz,1H),8.12(d,J＝8.9Hz,1H),7.80(d,J＝8.3Hz,1H),7.70(d,J＝5.6Hz,3H),7.35(d,J＝8.4Hz,1H),4.17(s,2H),3.59(m,4H),2.51(m,4H),2.08(ddd,J＝12.4,5.7,3.7Hz,3H),1.92(s,2H),0.89–0.83(m,4H).HR-ESI-MS:521.2636[M+H]+,(calcdforC31H32N6O2,521.2660).
实施例21 N-(4-(11-吗啉-10H-吲哚并[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲胺(ZLHQ-1c)
Figure BDA0003635730810000163
7-2代替7-1，按照实施例4程序合成化合物ZLHQ-1c，收率55％，白色固体。
1HNMR(400MHz,DMSO-d6):δ10.98(s,1H),8.60(s,1H),8.54(d,J＝2.4Hz,1H),8.45(dd,J＝10.9,6.6Hz,2H),8.33–8.18(m,2H),7.79–7.65(m,2H),7.59(dd,J＝5.3,1.9Hz,1H),7.38(td,J＝7.1,6.2,1.8Hz,1H),4.07–4.01(m,4H),3.91(t,J＝4.5Hz,4H),2.08(td,J＝7.6,3.9Hz,1H),0.90–0.84(m,4H)；13CNMR(100MHz,DMSO-d6):δ173.49,158.83,158.51,153.53,149.28,148.37,144.21,138.95,133.82,132.24,129.19,124.95,123.84,122.62,121.27,120.36,117.40,113.58,111.36,67.15(2C),52.70(2C),14.79,8.28(2C).HR-ESI-MS:464.2059[M+H]+,(calcdforC28H25N5O2,464.2081).
实施例22 N-(4-(11-((3-氨基丙基)氨基)-10H-吲哚啉[3,2-b]喹啉-2-基)吡啶-2-基)环丙烷甲酰胺(ZLHQ-1e)
Figure BDA0003635730810000171
化合物7-2代替化合物7-1，按照实施例13程序合成化合物ZLHQ-1e，收率61％，黄色固体。
1HNMR(400MHz,DMSO-d6):δ10.90(s,1H),8.80(d,J＝27.7Hz,1H),8.56(d,J＝1.6Hz,1H),8.41(dd,J＝10.8,6.1Hz,1H),8.24(d,J＝7.7Hz,1H),8.10(dd,J＝9.2,4.0Hz,1H),7.86(dd,J＝8.9,1.9Hz,1H),7.74–7.46(m,3H),7.21(q,J＝7.5Hz,2H),6.67(brs,1H),3.93(d,J＝28.4Hz,2H),3.16–2.81(m,2H),2.07(td,J＝7.8,3.9Hz,1H),1.93–1.71(m,2H),0.91–0.82(m,4H)；13CNMR(100MHz,DMSO-d6):δ173.29,153.37,149.93,148.81,146.67,145.76,143.69,136.76,131.49,130.32,129.07,124.92,122.14,121.42,121.19,119.61,119.36,118.08,117.75,112.59,111.43,79.65,42.79,38.14,31.97,14.74,8.13.HR-ESI-MS:451.2255[M+H]+,(calcdforC27H26N6O,451.2241).
实施例23 N-(4-(11-吗啉基苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环丁基甲酰胺(ZLHQ-2a)
Figure BDA0003635730810000181
中间体化合物10-2代替化合物10-1，按照实施例4程序合成化合物ZLHQ-2a，收率71％，白色固体。
1HNMR(400MHz,CDCl3):δ8.76(d,J＝1.7Hz,1H),8.64–8.56(m,1H),8.40(d,J＝7.8Hz,1H),8.38–8.31(m,2H),8.07(s,1H),8.02(dd,J＝8.8,2.1Hz,1H),7.66–7.58(m,2H),7.47(ddd,J＝8.0,6.9,1.3Hz,1H),7.41(dd,J＝5.3,1.7Hz,1H),4.14–4.07(ddd,4H),3.78–3.71(ddd,4H),3.32–3.19(m,1H),2.52–2.37(m,2H),2.35–2.22(m,2H),2.15–1.85(m,2H)；13CNMR(150MHz,CDCl3):δ156.78,141.85,135.35,133.38,131.54,131.17,130.51,124.10,120.97,117.40,114.02,113.13,109.94,106.69,106.44,105.77,105.72,105.49,100.68,95.13,94.83,50.49(2C),35.70(2C),23.92,8.20(2C).,1.02.HR-ESI-MS:479.2058[M+H]+,(calcdforC29H26N4O3,479.2078).
实施例24 N-(4-(11-吗啉基苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环戊烷甲酰胺(ZLHQ-2b)
Figure BDA0003635730810000182
中间体化合物10-3代替化合物10-1，按照实施例4程序合成化合物ZLHQ-2b，收率73％，白色固体。没有找到合适的氘代溶剂来溶解该化合物，无核磁共振数据。HR-ESI-MS：493.2213[M+H]+,(calcdforC20H28N4O3,493.2234).
实施例25 N-(4-(11-吗啉基苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)环己烷甲酰胺(ZLHQ-2c)
Figure BDA0003635730810000183
中间体化合物10-4代替化合物10-1，按照实施例4程序合成化合物ZLHQ-2c，收率56％，白色固体。
1HNMR(400MHz,CDCl3):δ8.70(d,J＝1.7Hz,1H),8.51(d,J＝2.1Hz,1H),8.36(d,J＝7.7Hz,1H),8.30(d,J＝5.3Hz,1H),8.26(d,J＝8.9Hz,1H),7.98(dd,J＝8.8,2.1Hz,1H),7.67–7.54(m,2H),7.44(t,J＝7.6Hz,1H),7.37(dd,J＝5.3,1.7Hz,1H),4.06(m,J＝4.6Hz,4H),3.71(t,J＝4.5Hz,4H),2.33(tt,J＝11.8,3.6Hz,1H),2.00–1.92(m,2H),1.83(dd,J＝13.3,3.7Hz,2H),1.73–1.44(m,3H),1.38–1.14(m,3H)；13CNMR(100MHz,CDCl3):δ175.54,158.83,152.39,150.47,148.52,148.00,147.32,141.07,138.24,134.43,131.18,129.69,127.07,123.83,123.36,122.83,122.51,122.41,117.68,112.20,112.13,67.44(2C),52.62(2C),46.39,29.64(2C),25.62,25.57(2C).HR-ESI-MS:507.2371[M+H]+,(calcdforC21H30N4O3,507.2391).
实施例26 N-(4-(11-吗啉基苯并呋喃[3,2-b]喹啉-2-基)吡啶-2-基)苯甲酰胺(ZLHQ-2d)
Figure BDA0003635730810000191
中间体化合物10-5代替化合物10-1，按照实施例4程序合成化合物ZLHQ-2d，收率45％，白色固体。
1HNMR(400MHz,CDCl3)δ8.81(d,J＝1.7Hz,1H),8.54(d,J＝2.1Hz,1H),8.38–8.29(m,2H),8.23(d,J＝8.8Hz,1H),7.98(dd,J＝8.9,2.1Hz,1H),7.93(dd,J＝7.1,1.9Hz,2H),7.65–7.36(m,8H),4.04(q,J＝6.9,5.7Hz,4H),3.66(q,J＝5.7Hz,4H)；13CNMR(100MHz,CDCl3):δ170.33,162.79,156.42,154.50,152.13,151.09,142.45,138.35,136.34,135.28,133.36,132.76(2C),131.26(2C),131.09,127.84,127.27,126.93,126.41,126.13,121.99,116.39,116.12,71.37(2C),56.59(2C).HR-ESI-MS:501.1921[M+H]+,(calcdforC31H24N4O3,501.1921).
实施例27 11-吗啉-2-(吡啶-4-基)苯并呋喃[3,2-b]喹啉(ZLHQ-3a)
Figure BDA0003635730810000201
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4-吡啶硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-3a，收率87％，白色固体。
1HNMR(400MHz,CDCl3):δ8.78–8.72(m,2H),8.53(d,J＝2.1Hz,1H),8.37(dd,J＝14.6,8.0Hz,2H),7.97(dd,J＝8.8,2.1Hz,1H),7.71–7.59(m,4H),7.48(td,J＝7.3,6.9,1.2Hz,1H),4.11–4.04(m,4H),3.74–3.67(m,4H)；13CNMR(150MHz,CDCl3):δ158.92,150.46(2C),148.84,148.07,147.58,141.39,137.72,134.46,131.10,130.50,126.74,123.75,122.78,122.49,122.45,121.77(2C),112.19(2C),67.52(2C),52.63(2C).HR-ESI-MS:382.1550[M+H]+,(calcdforC24H19N3O2,382.1550).
实施例28 11-吗啉-2-(吡啶-3-基)苯并呋喃[3,2-b]喹啉(ZLHQ-3b).
Figure BDA0003635730810000202
3-吡啶硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-3b，收率66％，白色固体。
1HNMR(400MHz,CDCl3)δ9.03(d,J＝2.3Hz,1H),8.67(dd,J＝4.8,1.6Hz,1H),8.45(d,J＝2.1Hz,1H),8.37(dd,J＝13.8,8.2Hz,2H),8.04(dt,J＝7.9,2.0Hz,1H),7.93(dd,J＝8.8,2.1Hz,1H),7.70–7.58(m,2H),7.51–7.42(m,2H),4.15–4.03(m,4H),3.70(t,J＝4.6Hz,4H)；13CNMR(150MHz,CDCl3):δ158.86,148.75,148.54,148.43,147.00,141.41,137.59,136.37,134.57,134.31,130.99,130.38,127.25,123.85,123.81,123.70,122.78,122.44,122.10,112.16,67.52(2C),52.58(2C).HR-ESI-MS:382.1540[M+H]+,(calcdforC24H19N3O2,382.1550).
实施例29 2-(6-氟吡啶-3-基)-11-吗啉基苯并呋喃[3,2-b]喹啉(ZLHQ-3c)
Figure BDA0003635730810000211
2-氟吡啶-5-硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-3c，收率80％，白色固体。
1HNMR(400MHz,CDCl3):δ8.59(d,J＝2.6Hz,1H),8.41–8.30(m,3H),8.15–8.10(m,1H),7.86(dd,J＝8.9,2.1Hz,1H),7.69–7.59(m,2H),7.47(t,J＝7.3Hz,1H),7.10(dd,J＝8.5,3.0Hz,1H),4.09–4.02(m,4H),3.68(t,J＝4.5Hz,4H)；13CNMR(100MHz,CDCl3):δ164.48,162.09,158.89,148.75,147.17,146.17,146.02,141.54,139.89,139.82,137.31,134.66,134.61,133.16,130.95,130.66,126.96,123.95,123.68,122.89,122.31,121.97,112.16,109.94,109.57,67.50,52.54.HR-ESI-MS:400.1443[M+H]+,(calcdforC24H18FN3O2,400.1456).
实施例30 2-(1-甲基-1H-吡唑-4-基)-11-吗啉基苯并呋喃[3,2-b]喹啉(ZLHQ-3d)
Figure BDA0003635730810000212
1-甲基-4-吡唑硼酸频哪醇酯代替化合物10-1，按照实施例4程序合成化合物ZLHQ-3d，收率79％，白色固体。
1HNMR(400MHz,CDCl3):δ8.38(d,J＝7.7Hz,1H),8.30(d,J＝2.0Hz,1H),8.25(d,J＝8.7Hz,1H),7.93–7.89(m,1H),7.81(dd,J＝8.8,2.0Hz,1H),7.76(s,1H),7.66–7.58(m,2H),7.46(ddd,J＝8.1,6.8,1.4Hz,1H),4.11–4.04(m,4H),4.02(s,3H),3.68(t,J＝4.5Hz,4H)；13CNMR(100MHz,CDCl3):δ158.70,147.40,146.5,141.47,137.02,130.64,129.92,129.49,127.30,126.81,124.07,123.59,123.11,122.89,122.30,119.06,112.06,67.57,52.49(2C),39.24(2C).HR-ESI-MS:385.1651[M+H]+,(calcdforC23H20N4O2,385.1659).
实施例31 11-吗啉-2-(1H-吡唑-4-基)苯并呋喃[3,2-b]喹啉(ZLHQ-3e)
Figure BDA0003635730810000221
(1H-吡唑-4-基)硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-3e，收率61％，白色固体。
1HNMR(400MHz,CDCl3):δ8.40–8.25(m,2H),8.20(dq,J＝10.3,6.4,5.9Hz,1H),8.00(q,J＝7.1,6.1Hz,2H),7.88(dt,J＝11.2,5.9Hz,1H),7.63(ddt,J＝15.7,11.6,6.9Hz,2H),7.47(dt,J＝15.9,7.8Hz,1H),4.08(dt,J＝9.8,4.7Hz,4H),3.74–3.59(m,4H),3.45–3.26(m,1H)；13CNMR(100MHz,CDCl3):δ162.57,151.22,149.93,145.29,141.34,134.77,133.51,133.12,131.07,127.86,127.82,127.66,126.34,126.30,126.11,123.16,116.00,71.40(2C),56.31(2C).HR-ESI-MS:371.1490[M+H]+,(calcdforC22H18N4O2,371.1503).
实施例32 2-(3-甲氧基苯基)-11-吗啉基苯并呋喃[3,2-b]喹啉(ZLHQ-4a)
Figure BDA0003635730810000222
3-甲氧基苯硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-4a，收率77％，白色固体。
1HNMR(400MHz,CDCl3):δ8.36(d,J＝2.1Hz,1H),8.33(d,J＝7.7Hz,1H),8.24(d,J＝8.8Hz,1H),7.88(dd,J＝8.8,2.1Hz,1H),7.61–7.49(m,2H),7.42–7.33(m,2H),7.26(dt,J＝7.6,1.3Hz,1H),7.23–7.15(m,2H),4.04–3.94(m,4H),3.84(s,3H),3.63(t,J＝4.5Hz,4H)；13CNMR(150MHz,CDCl3):δ159.15,157.74,146.92,145.83,141.32,140.28,136.57(2C),129.74,129.07,128.80,126.79,122.69,122.57,121.86,121.36,120.76,118.86,112.27,111.83,111.07,66.52,54.36,51.53.HR-ESI-MS:411.1692[M+H]+,(calcdforC26H22N2O3,411.1703).
实施例33(4-(11-吗啉基苯并呋喃[3,2-b]喹啉-2-基)苯基)甲醇(ZLHQ-4b)
Figure BDA0003635730810000231
4-羟甲基苯硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-4b，收率66％，白色固体。
1HNMR(400MHz,CDCl3):δ8.39(d,J＝7.7Hz,1H),8.28(d,J＝2.0Hz,1H),8.24(d,J＝8.7Hz,1H),7.70(dd,J＝8.7,2.0Hz,1H),7.67–7.57(m,3H),7.50–7.38(m,4H),4.74–4.69(m,2H),3.96(dd,J＝5.6,3.6Hz,4H),3.68–3.62(m,4H),2.54(s,1H)；13CNMR(150MHz,CDCl3):δ158.75,148.11,146.58,141.32,141.26,138.27,137.58,137.34,130.79,130.48,129.84(2C),129.24,129.07,128.02(2C),127.99,124.17,123.60,123.35,122.85,122.41,112.10,67.50,63.20(2C),52.51(2C).HR-ESI-MS:411.1692[M+H]+,(calcdforC26H22N2O3,411.1703).
实施例34 2-(2,3-二氢苯并[b][1,4]二氧六环-6-基)-11-吗啉代苯并呋喃
[3,2-b]喹啉(ZLHQ-4c)
Figure BDA0003635730810000232
苯并-1,4-二氧六环-6-硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-4c，收率75％，白色固体。
1HNMR(400MHz,CDCl3):δ8.41–8.34(m,2H),8.28(d,J＝8.8Hz,1H),7.90(dd,J＝8.9,2.1Hz,1H),7.68–7.56(m,2H),7.45(ddd,J＝8.0,6.7,1.5Hz,1H),7.30–7.21(m,3H),7.02(d,J＝8.3Hz,1H),4.34(s,4H),4.09–4.02(m,4H),3.68(t,J＝4.5Hz,4H)；13CNMR(100MHz,CDCl3):δ158.74,147.81,146.73,143.96,143.56,141.42,137.30,137.18,134.39,130.61,129.85,127.57,123.88,123.53,123.02,122.29,120.94,120.43,117.90,116.11,112.07,67.56(2C),64.50(2C),52.51(2C).HR-ESI-MS:439.1638[M+H]+,(calcdforC27H22N2O4,439.1652).
实施例35 2-(2,3-二氢苯并[d][1,3]二氧杂环戊烯-5-基)-11-吗啉代苯并呋喃[3,2-b]喹啉(ZLHQ-4d)
Figure BDA0003635730810000241
苯并[d][1,3]二氧杂环戊烯-5-基硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-4d，收率55％，白色固体。
1HNMR(400MHz,CDCl3):δ8.38(d,J＝7.7Hz,1H),8.34(d,J＝2.1Hz,1H),8.28(d,J＝8.8Hz,1H),7.88(dd,J＝8.8,2.2Hz,1H),7.68–7.57(m,2H),7.46(ddd,J＝8.0,6.7,1.4Hz,1H),7.24–7.16(m,2H),6.97(d,J＝8.5Hz,1H),6.05(s,2H),4.09–4.02(m,4H),3.69(t,J＝4.5Hz,4H)；13CNMR(100MHz,CDCl3):δ158.75,148.44,147.85,147.46,146.69,141.43,137.52,137.32,135.21,130.68,129.86,127.69,123.85,123.57,122.96,122.32,121.10,121.04,112.08,108.87,107.79,101.32(2C),67.56(2C),52.52(2C).HR-ESI-MS:425.1477[M+H]+,(calcdforC26H20N2O4,425.1496).
实施例36(2-(11-吗啉代苯并呋喃[3,2-b]喹啉-2-基)苯基)甲醇(ZLHQ-4f)
Figure BDA0003635730810000242
2-羟甲基苯硼酸代替化合物10-1，按照实施例4程序合成化合物ZLHQ-4f，收率69％，白色固体。
1HNMR(400MHz,DMSO-d6):δ8.41(d,J＝2.1Hz,1H),8.29(d,J＝7.6Hz,1H),8.22(d,J＝8.8Hz,1H),8.06(dd,J＝8.8,2.1Hz,1H),7.81(dd,J＝8.3,2.2Hz,3H),7.78–7.70(m,1H),7.57–7.46(m,3H),5.28(brs,1H),4.59(s,2H),4.00–3.93(m,4H),3.65(t,J＝4.5Hz,4H)；13CNMR(150MHz,DMSO-d6):δ158.61,147.52,146.78,142.67,140.93,138.64,137.68,137.17,131.66,130.22,127.88,127.79,127.50,127.30,126.70,124.37,123.67,122.82,122.28,121.60,112.93,67.21(2C),63.09,52.70(2C).HR-ESI-MS:411.1712[M+H]+,(calcdforC26H22N2O3,411.1703).
实施例37：目标化合物抗肿瘤细胞增值活性的评价
用MTT法测定。将指数期生长的细胞接种于96孔板(每孔3×103个)并培养过夜。然后分别加入不同浓度的化合物并孵育72小时。此后，每孔加入20μL10％MTT(5mg/mL，PBS)试剂，放培养箱中再孵育4h。随后，弃上清液，加入100μLDMSO，振荡8min。在酶标仪上在490nm处测量细胞的吸光度。生长抑制百分比＝100–100×(OD样品-OD空白)/(OD对照-OD空白)。使用非线性回归分析(生长百分比对浓度)计算IC50值，详见表1-3。
表1.化合物ZLHQ-1的抗增殖活性
Figure BDA0003635730810000251
/>
Figure BDA0003635730810000252
aGI50值是至少两次独立实验的平均值±SD，一式三份。
表2：化合物ZLHQ-2、3、4的抗增殖活性
Figure BDA0003635730810000253
/>
Figure BDA0003635730810000261
/>
Figure BDA0003635730810000271
aGI50值是至少两次独立实验的平均值±SD，一式三份。
表3：化合物ZLHQ-5的抗增殖活性
Figure BDA0003635730810000272
Figure BDA0003635730810000273
/>
Figure BDA0003635730810000281
aGI50值是至少两次独立实验的平均值±SD，一式三份。
经过三轮结构优化，发现了细胞毒活性良好的一系列化合物，它们细胞毒活性明显强于白叶藤碱母核，证明我们的优化是效果显著的。接下来，我们挑选活性较好的化合物测试其酶活力。
实施例38：抗增殖活性较好的化合物的CDK2酶活力评价
使用Mobilityshift测定法、Dinaciclib和Palbociclib作为参考标准进行检测。选择6个抗肿瘤细胞增值活性较好的化合物进行CDK2的酶活力测定，详见表4。发现了CDK2活性最好的为化合物ZLHQ-5f。
表4：抗肿瘤细胞增殖活性较好的化合物的CDK2和CDK4酶活力评价
Figure BDA0003635730810000282
/>
Figure BDA0003635730810000291
aIC50数据测试一次。b1μM时的抑制百分比。c10μM时的抑制百分比。dND：未测试。
实施例39：化合物ZLHQ-5f抗TopoI活性研究
彗星实验以确定化合物ZLHQ-5f对TopoI的抑制作用。结果如图3所示，图3中琼脂糖凝胶电泳图谱显示不同浓度的化合物ZLHQ-5f对DNATopoI活性的影响；泳道1，DNA对照；泳道2，拓扑I+DNA；泳道3，20μM喜树碱(CPT)+DNA+TopoI；泳道4：20μMZLHQ-5f+DNA+TopoI，泳道5：100μMZLHQ-5f+DNA+TopoI，泳道6：500μMZLHQ-5f+DNA+TopoI。图3表明化合物ZLHQ-5f可以恢复DNA超螺旋，表现出显著的TopoI抑制活性。

Claims (6)

1.一种白叶藤碱衍生物或其药学上可接受的盐，选自：
Figure FDA0004237014800000011
Figure FDA0004237014800000021
Figure FDA0004237014800000031
2.一种如权利要求1所述结构化合物的制备方法，其特征在于，制备方法包括以下步骤：
(1)将苯氧乙酸经氯化亚砜氯化得到酰氯化合物2；再将化合物2与2-氨基-5-溴苯甲酸进行酰胺缩合得化合物5-1；随后用多聚磷酸作为脱水剂，130℃下反应2小时，得化合物6-1；再经由三氯氧磷回流氯化得中间体化合物7-1；
或者将2-氨基-5-溴苯甲酸，经氯乙酰氯进行酰胺缩合得化合物4；再同5-10eq苯胺亲核取代得化合物5-2；随后用多聚磷酸作为脱水剂，130℃下反应2小时，得化合物6-2；再经由三氯氧磷回流氯化得中间体化合物7-2，
Figure FDA0004237014800000041
(2)使用脂肪胺，在两个中间体化合物7-1或中间体化合物7-2的11位点进行亲核取代，粗处理后再同硼酸酯或硼酸进行Suzuki偶联，得到化合物ZLHQ-1b、化合物ZLHQ-1d、化合物ZLHQ-1f、化合物ZLHQ-5j、化合物ZLHQ-5k、化合物ZLHQ-5m、化合物ZLHQ-1a、化合物ZLHQ-1c、化合物ZLHQ-2a、化合物ZLHQ-2b、化合物ZLHQ-2c、化合物ZLHQ-2d、或者带有boc保护基的产物化合物；
(3)带有boc保护基的产物化合物，再在酸性溶剂中脱Boc得到化合物ZLHQ-5c、化合物ZLHQ-5h、化合物ZLHQ-5a、化合物ZLHQ-5b、化合物ZLHQ-5d、化合物ZLHQ-5e、化合物ZLHQ-5f、化合物ZLHQ-5g、化合物ZLHQ-5i或者化合物ZLHQ-1e；
所述步骤(2)中硼酸酯或硼酸为中间体化合物10；
所述中间体化合物10的制备过程为，2-氨基-4-溴吡啶5g与酰氯在THF溶剂中酰胺缩合，得到产物9，然后进行宫浦反应，110℃氮气保护12h得到中间体化合物10，
Figure FDA0004237014800000042
所述酰氯为环丙酰氯，环丁酰氯，环戊酰氯，环己酰氯或者苯甲酰氯；
所述步骤(2)中脂肪胺为3-(4-吗啉基)-1-丙胺、吗啉、N，N-二甲基乙烷-1,2-二胺、(S)-吡咯烷-3-醇、四氢吡咯、4-叔丁氧羰基氨基哌、丙醇胺、N-Boc-1,3-丙二胺、N-Boc-哌嗪、N-Boc-高哌嗪、3-叔丁氧羰基氨基哌啶、(R)-3-叔丁氧羰基氨基吡咯烷、(S)-3-叔丁氧羰基氨基吡咯烷、N-Boc-乙二胺或者N-Boc-1,4-丁二胺。
3.根据权利要求2所述结构化合物的制备方法，其特征在于，步骤(3)中酸性溶剂为二氯甲烷与三氟乙酸等体积比的混合物或者盐酸乙酸乙酯。
4.如权利要求1所述化合物或其药学上可用的盐在制备抗肿瘤药物中的应用。
5.如权利要求1所述化合物ZLHQ-1d、ZLHQ-5e、ZLHQ-5f、ZLHQ-5h、ZLHQ-5j或其药学上可用的盐在制备CDK2抑制剂中的应用。
6.如权利要求1所述化合物ZLHQ-5f或其药学上可用的盐在制备CDK2/Topo I抑制剂中的应用。
CN202210505333.4A 2022-05-10 2022-05-10 作为CDK2/Topo I抑制剂的白叶藤碱衍生物及其制备方法和抗肿瘤的应用 Active CN115160310B (zh)

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