CN116396229A - 一种喹唑啉类化合物的制备及其抗肿瘤应用 - Google Patents
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Abstract
本发明公开了一种喹唑啉类化合物的制备及其抗肿瘤应用，涉及生物医药技术领域，其技术要点为：本发明提供了如通式(I)所示的化合物，或其在药学上可接受的盐。本发明还提供了包含所示化合物的药物组合物以及化合物或组合物在制备抗肿瘤药物中的应用。本发明提供的化合物或药物组合物实现了高效、高选择性、低毒的新骨架EGFR抑制剂，对治疗非小细胞肺癌具备广泛应用前景。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及一种喹唑啉类化合物的制备及其抗肿瘤应用。
背景技术
肺癌占全世界所有癌症患者死亡人数的三分之一，并极易导致癌症患者死亡。肺癌患者主要包括小细胞肺癌患者(SCLC，约占总数的1/5)和非小细胞肺癌患者(NSCLC，约占总数的4/5)。
表皮生长因子受体(EGFR)酪氨酸激酶小分子抑制剂自2003年被批准用于NSCLC的治疗以来，已经取得了一定的疗效。EGFR是一种酪氨酸激酶，在许多正常组织和实体肿瘤中广泛表达。研究表明其在细胞存活，自噬，增殖，肿瘤侵袭，迁移等过程中发挥着重要作用。多种实体肿瘤中都观察到EGFR的异常激活与异常表达，包括肺癌、胰腺癌、乳腺癌、前列腺癌等，尤其是非小细胞肺癌。大约3/4的患者在确诊非小细胞肺癌时已经处于中晚期并表现出转移的症状，并具有较低的生存率。因此，针对EGFR靶点进行抗癌药物的设计和研究对治疗NSCLC等癌症具有广阔的应用前景。
现有的EGFR酪氨酸激酶抑制剂已发展至具有结合EGFR敏感突变和T790M突变位点优势的第三代抑制剂，但耐药性的出现导致其难以发挥理想的抗肿瘤作用。活化的Cdc42相关酪氨酸激酶1(ACK1)又称TNK2，是属于VIII酪氨酸激酶家族的一种结构独特的非受体酪氨酸激酶。ACK1能够整合不同细胞类型的RTK信号，并能够被EGF激活，并能够与EGFR相互作用且促进EGFR内化和溶酶体降解。在许多癌症，包括乳腺癌、肺癌、前列腺癌中，都观察到ACK1的突变和过度表达。同时，ACK1的高表达与一些癌症如高等级基底细胞乳腺癌的预后有显著关系。此外，ACK1的磷酸化可作为某些癌症(如胰腺癌和乳腺癌)的诊断、预测和预后的标志。第三代EGFR抑制剂的耐药机制之一为高磷酸化水平的ACK1通过持续活化下游AKT途径导致的凋亡抑制。研究发现对二者的共同靶向在耐药细胞的小鼠异种移植模型中表现出了显著的疗效，表明联合治疗可能是克服第三代EGFR-TKIs耐药性的一种新的前瞻性方法。
因此，本发明旨在提供一种喹唑啉类化合物的制备及其抗肿瘤应用，以解决上述问题。该抑制剂能够选择性地抑制EGFRL858R/T790M蛋白及下游信号通路，并在相应肿瘤细胞中表现出良好的抗增殖活性，因此针对于此类抑制剂的开发具有很广阔的研究前景。
发明内容
本发明的目的是为了解决上述问题，提供一种喹唑啉类化合物的制备及其抗肿瘤应用。
为了达到上述目的，本发明的技术方案如下：
本发明提供了一种通式(I)所示的化合物，或其在药学上可接受的盐：
其中，R1为：
R2为：
R3为：
R4为：
进一步地，R1为：
R2为：
R3为：
R4为：
进一步地，所述通式(I)所示的化合物为如下化合物：
本发明还提供了一种药物组合物，所述药物组合物包含有效剂量的上述的化合物，或其在药学上可接受的盐的制剂。
本发明还提供了上述的化合物，或其在药学上可接受的盐，或上述的药物组合物在制备抗肿瘤药物中的应用。
进一步地，所述药物为于一种喹唑啉类化合物的制备及其抗肿瘤应用。
进一步地，所述抗肿瘤药物为治疗具有EGFRT790M/L858R过表达特点的肿瘤的药物。
进一步地，所述肿瘤为非小细胞肺癌。
本发明解决技术问题的难度及意义在于：
第三代EGFR-TKIs对非小细胞肺癌晚期患者的EGFR突变和EGFRT790M突变具有高度的选择性。尽管第三代EGFR-TKIs的疗效已经在临床一线和二线环境中得到证实，但是患者在经过一段时间治疗后不可避免的会再次出现耐药。在奥西替尼治疗中已经发现了EGFR获得性突变，例如C797S，L792F/H和L718Q。此外，从激活信号分子，包括MET，BRAF，PIK3CA，AXL，和Src家族激酶(SFK)，到osimertinib介导活性的旁路诱导上皮-间充质转换(EMT)，也很大程度上促进了第三代EGFR TKI中的获得耐药性。迄今为止除了针对特定个体的化学疗法和局部消融疗法外，还没有其他明确的治疗选择。值得注意的是，到目前为止，有一半的肿瘤对第三代EGFR-TKIs的耐药机制还没有明确。因此阐明第三代EGFR-TKIs的耐药机制及寻找新的策略克服第三代EGFR-TKIs的耐药具有重要的科学意义和临床应用价值。
与现有技术相比，本方案的有益效果：
1、本发明提供的如式(I)所示的化合物，或其在药学上可接受的盐实现了高效、高选择性、低毒的新骨架EGFR抑制剂，对治疗非小细胞肺癌具备广泛应用前景；
2、本发明提供的如式(I)所示的化合物，或其在药学上可接受的盐具有很强的抑制活性以及高选择性；
3、本发明提供的如式(I)所示的化合物，或其在药学上可接受的盐是一种具有全新化学骨架的，对EGFRL858R/T790M有良好选择性的第三代EGFR抑制剂，此外，该化合物或药物组合物与ACK1抑制剂联合用药有效的克服28f的耐药，在体内也显著的抑制肿瘤的生长，其为EGFRL858R/T790M/ACK1双靶药物的设计打下了良好的基础。
附图说明
图1是现有的代表性的第一代、第二代和第三代EGFR激酶抑制剂的化学结构；
图2A是本发明实施例中28f处理后裸鼠H1975细胞异种移植模型的肿瘤体积的变化；
图2B是本发明实施例中28治疗结束后裸鼠H1975细胞异种移植模型的肿瘤重量分析；
图2C是本发明实施例中28f治疗期间裸鼠H1975细胞异种移植模的体重变化；
图3A是本发明实施例中28f与ACK1抑制剂联合治疗对耐药细胞增殖的影响；
图3B是本发明实施例中28f与三种ACK1抑制剂联用后的药物联用指数；
图3C是本发明实施例中28f与达沙替尼处理后裸鼠28fR细胞异种移植模型的肿瘤体积的变化；
图3D是本发明实施例中28f与达沙替尼治疗结束后裸鼠28fR细胞异种移植模型的肿瘤重量分析；
图3E是本发明实施例中28f与达沙替尼治疗期间裸鼠28fR细胞异种移植模型的体重变化；
图4是本发明实施例中H1975、HCC827、A549和A431对应的半数抑制浓度柱状图。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案，下面将结合本发明的实施例及附图，对本发明的技术方案进行进一步详细地描述，显然，所描述的实施例仅仅是本发明一部分的实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都应当属于本发明保护的范围。下面将结合实施例来详细说明本发明。
本发明实施例提供的方案如上述发明内容所述，提供了通式(I)所示的化合物，或其在药学上可接受的盐：
还提供了一种包含上述化合物或其在药学上可接受的盐的组合物，以及上述化合物或组合物在制备抗肿瘤药物中的应用。
以下为本发明方案的具体实施：
实施例1：优选化合物的合成
化合物采用如下反应式合成：
(a)为TEA,Ph3PO,BTC,PhCl,85℃；(b)m-phenylenediamine,DIPEA,isopropanol,80℃；(c)为acryloyl chloride,TEA,THF,0℃；(d)为aniline derivatives,TFA,sec-butanol,80℃。
1.中间体25-27的合成通法
将化合物24(10.0mmol)溶解在异丙醇(100mL)中，然后加入3-硝基苯胺(1.11g，8.0mmol)，二异丙基乙胺(6.61mL，40.0mmol)加热至80℃反应，TLC显示3-硝基苯胺反应完毕时，减压抽滤，将滤饼经过柱层析色谱(石油醚/乙酸乙酯，2/1)纯化得黄色固体25。
将中间体25(4.0mmol)，水合肼(497μL，16.0mmol)，雷尼镍(0.47g，8.0mmol)加入甲醇中，冰浴条件下反应，TLC检测反应显示中间体25反应完毕时，减压抽滤，浓缩，经柱层析色谱纯化后得到黄色固体26。
向溶解有中间体26(2.0mmol)的四氢呋喃(15mL)溶液中加入丙烯酰氯(304μL，4.0mmol)和TEA(834μL，6.0mmol)，冰浴条件下搅拌反应，TLC检测显示中间体26反应完毕。减压浓缩，通过柱层析色谱(石油醚/乙酸乙酯，2/1)分离得灰色固体27。
2.化合物28a-p的合成通法
将中间体27(0.5mmol)，4-(4-甲基哌嗪-1-基)苯胺(0.08g，0.4mmol)和TFA(111μL，1.5mmol)加入仲丁醇中，80℃搅拌反应，使用TLC监测反应，当27a反应完全时，经过柱层析色谱分离得到棕色固体目标化合物28。
化合物28a，棕色固体(收率为32％)；mp 115.6–117.3℃.1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.60(s,1H),8.91(s,1H),8.37(d,J＝7.1Hz,1H),8.23(s,1H),7.70(s,2H),7.62(q,J＝8.1,7.5Hz,2H),7.54(d,J＝8.4Hz,1H),7.42(d,J＝8.4Hz,1H),7.33(t,J＝8.1Hz,1H),7.22(t,J＝7.6Hz,1H),6.81(d,J＝8.5Hz,2H),6.60–6.46(m,1H),6.28(d,J＝17.0Hz,1H),5.77(d,J＝10.0Hz,1H),3.09–2.96(m,4H),2.44(t,J＝4.8Hz,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,158.9,157.0,152.5,146.2,140.2,139.6,133.8,133.4,132.5,129.1,127.2,125.8,123.7,121.8,120.5,118.4,116.3,115.3,112.1,55.2,49.5,46.3,34.8,30.9.HPLCpurity:98.55％.HRMS(ESI)(m/z):[M+H]+for C28H29N7Ocalcd,480.2506；found,480.2500[M+H]+
化合物28b，棕色固体(收率为51％)；mp 118.7–121.3℃.1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.51(s,1H),8.77(s,1H),8.19(s,2H),7.69(d,J＝8.5Hz,2H),7.63(d,J＝8.0Hz,1H),7.53–7.43(m,2H),7.39–7.26(m,2H),6.80(d,J＝8.6Hz,2H),6.50(dd,J＝17.0,10.1Hz,1H),6.29(d,J＝17.0Hz,1H),5.77(d,J＝10.0Hz,1H),3.08–2.93(m,4H),2.44(d,J＝8.5Hz,7H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,158.5,156.6,150.7,146.1,140.3,139.5,135.1,134.0,132.5,131.0,129.1,127.3,125.7,122.7,120.4,118.4,116.3,115.2,114.4,111.8,55.2,49.5,46.2,21.4.HPLCpurity:99.45％.HRMS(ESI)(m/z):[M+H]+for C29H31N7O calcd,494.2663；found,494.2655[M+H]+.
化合物28c，棕色固体(收率为54％)；mp 198.0–200.2℃.1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.50(s,1H),8.69(s,1H),8.16(s,1H),7.83(d,J＝2.7Hz,1H),7.68(d,J＝8.5Hz,2H),7.60(d,J＝8.1Hz,1H),7.51(d,J＝8.9Hz,1H),7.42–7.30(m,3H),6.80(d,J＝8.9Hz,2H),6.50(dd,J＝16.9,10.1Hz,1H),6.30(d,J＝16.9Hz,1H),5.77(d,J＝10.1Hz,1H),3.89(s,3H),3.02(t,J＝4.9Hz,4H),2.46(t,J＝5.0Hz,4H),2.22(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,158.3,156.0,154.7,147.7,145.9,140.3,139.7,139.6,134.2,132.5,129.1,127.3,124.3,120.1,118.7,116.4,115.3,114.7,111.9,103.7,56.3,55.2,49.5,46.2,34.8,30.9.HPLCpurity:98.65％.HRMS(ESI)(m/z):[M+H]+for C29H31N7O2calcd,510.2612；found,510.2604[M+H]+.
化合物28d，棕色固体(收率为52％)；mp 104.5–106.1℃.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.46(s,1H),8.86(s,1H),8.35–8.18(m,2H),7.73(s,2H),7.56(d,J＝22.4Hz,2H),7.31(t,J＝8.1Hz,1H),6.86–6.77(m,4H),6.55(dd,J＝17.2,10.2Hz,1H),6.28(d,J＝16.9Hz,1H),5.76(d,J＝9.9Hz,1H),3.88(s,3H),3.02(t,J＝4.9Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,163.4,158.5,157.5,154.8,146.2,140.4,139.6,133.9,132.6,129.0,127.1,125.2,120.6,118.1,116.3,115.0,114.3,112.9,106.3,105.6,55.8,55.2,49.5,46.3,34.9,30.9.HPLCpurity:99.07％.HRMS(ESI)(m/z):[M+H]+for C29H31N7O2 calcd,510.2612；found,510.2605[M+H]+.
化合物28e，棕色固体(收率为47％)；mp 104.5–105.4℃.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.34(s,1H),8.67(s,1H),8.22(s,1H),7.77(s,1H),7.71(d,J＝8.4Hz,2H),7.53(dd,J＝15.4,8.1Hz,2H),7.32(t,J＝8.1Hz,1H),6.87(s,1H),6.80(d,J＝8.7Hz,2H),6.54(dd,J＝17.0,10.1Hz,1H),6.28(d,J＝16.9Hz,1H),5.76(d,J＝10.0Hz,1H),3.90(s,6H),3.01(t,J＝4.8Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,157.7,156.4,154.9,149.4,146.1,145.9,140.5,139.6,134.3,132.5,129.0,127.2,120.2,118.3,116.4,114.9,114.4,106.0,104.9,103.6,56.6,56.6,56.0,56.0,55.2,49.6,46.3.HPLCpurity:96.25％.HRMS(ESI)(m/z):[M+H]+for C30H33N7O3 calcd,540.2718；found,540.2710[M+H]+.
化合物28f，棕色固体(收率为55％)；mp 117.2–119.5℃.1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.56(s,1H),8.92(s,1H),8.34–8.21(m,2H),7.70(d,J＝8.2Hz,3H),7.58–7.45(m,3H),7.33(t,J＝8.1Hz,1H),6.89–6.77(m,2H),6.53(dd,J＝17.0,10.1Hz,1H),6.29(d,J＝17.0Hz,1H),5.77(d,J＝9.9Hz,1H),3.02(t,J＝4.9Hz,4H),2.43(t,J＝4.9Hz,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,158.5,156.9,156.1,151.9,149.5,146.2,140.1,139.7,139.6,133.7,132.5,129.2,128.0,127.2,122.6,122.3,120.6,118.3,116.3,115.3,108.3,55.2,49.5,46.3,34.8,30.9.HPLCpurity:98.09％.HRMS(ESI)(m/z):[M+H]+for C28H28FN7O calcd,498.2412；found,498.2404[M+H]+.
化合物28g，棕色固体(收率为52％)；mp 145.6–147.1℃.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.69(s,1H),8.96(s,1H),8.65(s,1H),8.14(s,1H),7.83–7.56(m,4H),7.48(d,J＝8.2Hz,1H),7.42–7.28(m,2H),6.80(d,J＝8.5Hz,2H),6.49(dd,J＝16.9,10.2Hz,1H),6.29(d,J＝17.0Hz,1H),5.77(d,J＝12.1Hz,1H),3.14–2.95(m,4H),2.43(t,J＝4.9Hz,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,158.0,157.3,151.6,146.4,139.9,139.5,136.2,133.4,132.4,129.2,128.0,127.3,126.0,120.8,118.6,116.2,115.5,113.5,55.2,49.4,46.3.HPLCpurity:99.60％.HRMS(ESI)(m/z):[M+H]+forC28H28BrN7O calcd,558.1611；found,558.1605[M+H]+.
化合物28h，棕色固体(收率为38％)；mp 140.7–143.2℃.1H NMR(600MHz,DMSO-d6)δ10.31(s,1H),9.58(s,1H),9.01(s,1H),8.69(s,1H),8.18(s,1H),7.76(d,J＝8.7Hz,1H),7.61(s,2H),7.46(d,J＝8.3Hz,2H),7.23(t,J＝8.1Hz,1H),7.12(d,J＝8.8Hz,1H),6.79–6.65(m,2H),6.51–6.42(m,1H),6.19(d,J＝17.0Hz,1H),5.67(d,J＝10.2Hz,1H),2.95(s,4H),2.41(s,4H),2.17(s,3H).13C NMR(150MHz,DMSO-d6)δ163.6,151.8,146.2,141.5,140.0,139.6,133.6,132.5,131.9,129.1,128.1,127.2,124.8,120.7,116.3,115.3,114.2,55.0,49.2,46.0.HPLCpurity:99.31％.HRMS(ESI)(m/z):[M+H]+for C28H28IN7Ocalcd,606.1473；found,606.1461[M+H]+.
化合物28i，棕色固体(收率为41％)；mp 158.7–160.6℃.1H NMR(600MHz,DMSO-d6)δ11.09(s,1H),10.49(s,1H),10.17–9.91(m,1H),9.52(s,1H),8.87(s,1H),8.34(s,1H),7.96(s,1H),7.80(s,1H),7.48(t,J＝26.9Hz,3H),7.33(d,J＝7.9Hz,1H),7.01–6.64(m,3H),6.26(d,J＝17.0Hz,1H),5.73(d,J＝10.1Hz,1H),3.06(s,4H),2.44(s,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.8,147.0,140.0,132.8,129.0,127.3,126.8,121.5,120.8,120.6,116.2,116.0,55.2,49.2,49.0,49.0,46.3.HPLCpurity:99.63％.HRMS(ESI)(m/z):[M+H]+for C28H28N8O3 calcd,525.2357；found,525.2349[M+H]+.
化合物28j，浅黄色固体(收率为39％)；mp 119.8–121.7℃.1H NMR(600MHz,DMSO-d6)δ10.95(s,1H),9.89(s,1H),9.58(s,1H),8.90(s,2H),7.97–7.61(m,4H),7.54(s,2H),7.33(d,J＝7.8Hz,1H),6.85(s,2H),6.72(s,1H),6.27(d,J＝17.0Hz,1H),5.75(d,J＝10.2Hz,1H),3.05(s,4H),2.49–2.37(m,4H),2.22(s,3H).13C NMR(150MHz,DMSO-d6)δ163.7,158.1,154.8,146.6,139.9,133.3,132.7,129.0,128.9,126.9,126.0,124.2,122.3,121.0,116.1,55.2,49.3,46.3.HPLC purity:99.61％.HRMS(ESI)(m/z):[M+H]+forC29H28F3N7O calcd,548.2380；found,548.2369[M+H]+.
化合物28k，浅黄色固体(收率为43％)；mp 102.4–103.6℃.1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.41(d,J＝18.0Hz,2H),7.74(s,3H),7.55(t,J＝8.0Hz,1H),7.44–7.23(m,5H),6.81(d,J＝8.5Hz,2H),6.71–6.60(m,1H),6.27(d,J＝16.9Hz,1H),5.74(d,J＝10.4Hz,1H),3.03(t,J＝5.0Hz,4H),2.44(t,J＝5.1Hz,4H),2.21(s,3H).13C NMR(150MHz,DMSO-d6)δ163.7,155.3,146.5,140.1,139.5,138.1,133.3,133.2,132.6,129.4,128.7,127.1,125.9,124.5,120.7,116.2,115.2,109.4,55.2,49.4,46.3.HPLC purity:97.49％.HRMS(ESI)(m/z):[M+H]+for C28H28ClN7O calcd,514.2177；found,514.2108[M+H]+.
化合物28l，浅黄色固体(收率为41％)；mp 101.1–102.9℃.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.04(s,1H),8.40(d,J＝8.8Hz,1H),8.17(s,1H),7.65(s,3H),7.52(d,J＝8.0Hz,1H),7.41(d,J＝2.2Hz,1H),7.33(t,J＝8.1Hz,1H),7.24(d,J＝8.7Hz,1H),6.84(d,J＝24.9Hz,3H),6.51(dd,J＝17.0,10.1Hz,1H),6.29(d,J＝16.9Hz,1H),5.77(d,J＝10.1Hz,1H),3.01(d,J＝5.1Hz,4H),2.43(t,J＝5.0Hz,4H),2.20(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,153.7,151.9,146.5,139.9,139.7,139.6,138.1,133.3,132.5,129.2,128.5,127.3,125.9,125.4,124.3,121.8,120.9,116.2,115.5,110.8,55.2,49.4,46.3,34.8,30.9.HPLC purity:98.71％.HRMS(ESI)(m/z):[M+H]+for C28H28ClN7Ocalcd,514.2177；found,514.2107[M+H]+.
化合物28m，黄色固体(收率为47％)；mp 139.6–141.5℃.1H NMR(600MHz,DMSO-d6)δ11.06(s,1H),9.86–9.50(m,2H),8.86(s,1H),8.47(s,1H),8.18(s,2H),7.82(d,J＝7.6Hz,2H),7.51(s,1H),7.36–7.26(m,1H),7.19(t,J＝7.6Hz,1H),6.86(s,2H),6.78(s,1H),6.27(d,J＝17.0Hz,1H),5.73(d,J＝10.1Hz,1H),3.05(s,4H),2.44(t,J＝4.7Hz,4H),2.21(s,3H).13C NMR(150MHz,DMSO-d6)δ163.8,148.8,146.2,140.0,133.9,133.1,132.9,129.2,129.0,126.7,122.8,121.5,120.2,116.2,114.6,113.6,55.2,49.4,46.3.HPLCpurity:99.36％.HRMS(ESI)(m/z):[M+H]+for C28H28ClN7O calcd,514.2177；found,514.2109[M+H]+.
化合物28n，浅黄色固体(收率为32％)；mp 113.1–114.2℃.1H NMR(600MHz,DMSO-d6)δ10.76(s,1H),9.37(s,1H),8.85(s,1H),8.42(s,1H),7.85–7.66(m,2H),7.59(s,2H),7.39–7.19(m,3H),6.99(s,1H),6.80(s,2H),6.65(s,1H),6.26(d,J＝16.9Hz,1H),5.74(d,J＝10.1Hz,1H),3.03(s,4H),2.44(s,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ163.7,160.3,157.9,157.2,154.9,146.4,140.0,139.6,133.6,133.5,133.4,132.7,129.2,127.0,122.1,120.7,116.1,58.4,55.2,55.2,49.4,46.3.HPLCpurity:99.14％.HRMS(ESI)(m/z):[M+H]+for C28H28FN7O calcd,498.2412；found,498.2403[M+H]+.
化合物28o，棕色固体(收率为39％)；mp 109.2–121.4℃.1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.67(s,1H),9.01(s,1H),8.54–8.38(m,1H),8.17(s,1H),7.78–7.46(m,4H),7.33(t,J＝8.1Hz,1H),7.17–7.02(m,2H),6.90–6.73(m,2H),6.52(dd,J＝16.9,10.2Hz,1H),6.28(d,J＝16.9Hz,1H),5.76(d,J＝10.0Hz,1H),3.02(t,J＝4.9Hz,4H),2.43(t,J＝5.0Hz,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ166.8,164.4,163.6,146.4,140.0,139.7,139.6,133.4,132.5,129.1,127.2,126.8,125.4,120.9,118.6,116.2,115.5,110.7,110.5,109.2,55.2,49.4,46.3,34.8,30.9.HPLCpurity:99.68％.HRMS(ESI)(m/z):[M+H]+for C28H28FN7O calcd,498.2412；found,498.2401[M+H]+.
化合物28p，棕色固体(收率为44％)；mp 105.1–106.2℃.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.72(s,1H),9.09(s,1H),8.20(d,J＝8.3Hz,1H),8.11(s,1H),7.69(s,2H),7.60(s,1H),7.52(d,J＝10.6Hz,1H),7.48(d,J＝11.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.21–7.11(m,1H),6.80(d,J＝8.6Hz,2H),6.49(dd,J＝16.9,10.1Hz,1H),6.29(d,J＝17.0Hz,1H),5.78(d,J＝10.0Hz,1H),3.02(t,J＝4.9Hz,4H),2.43(t,J＝4.9Hz,4H),2.20(s,3H).13C NMR(100MHz,DMSO-d6)δ163.6,158.0,157.2,154.7,146.4,143.4,139.8,139.6,133.5,132.4,129.2,127.4,120.6,119.6,119.0,117.8,117.6,116.2,115.7,113.8,55.2,49.4,46.3,34.8,30.9.HPLCpurity:98.17％.HRMS(ESI)(m/z):[M+H]+forC28H28FN7O calcd,498.2412；found,498.2401[M+H]+.
实施例2：化合物的激酶活性测定
本实验的目的是检测本发明的化合物对体外EGFR激酶抑制活性，以下表1、表2、表3、表4为17a-n、20a-b、23a-e、28a-p、32a-d、33a-n对EGFRL858R/T790M激酶抑制活性和4种细胞的抗增殖活性。结果见如下表1、表2、表3和表4所示。
表1.17a-n对EGFRL858R/T790M激酶抑制活性和4种细胞的抗增殖活性。
表2.20a-b对EGFRL858R/T790M激酶抑制活性和4种细胞的抗增殖活性。
表3.23a-e对EGFRL858R/T790M激酶抑制活性和4种细胞的抗增殖活性。
表4.28a-p对EGFRL858R/T790M激酶抑制活性和4种细胞的抗增殖活性。
a数值是三个独立实验的平均值。
b采用MTT法检测化合物的抗增殖活性，数值是三个独立实验的平均值。
表5.32a-d对EGFRL858R/T790M激酶抑制活性和4种细胞的抗增殖活性。
表6.33a-n对EGFRL858R/T790M激酶抑制活性和4种细胞的抗增殖活性。
实验结果表明，各个化合物的抑制活性都较好，其中最优化合物28f对EGFRT790M/L858R的抑制作用最强，最具选择性。
实施例3：化合物28f的体内抗肿瘤活性实验
本实验的目的是检测本发明的优选化合物的体内抗肿瘤效果。在H1975的异种移植小鼠模型中，将化合物28f进行腹腔注射，剂量为5、10或20mg/kg，每天1次；并将奥希替尼10mg/kg作为阳性对照。
实验测定的肿瘤生长曲线如图2中的A所示，口服奥希替尼显著诱导了肿瘤消退。而28f(20mg/kg/day)展现出与奥希替尼相当的抗肿瘤活性，且在给药结束时几乎完全抑制裸鼠的肿瘤负荷。在5mg/kg及10mg/kg条件下28f也能够一定程度导致肿瘤显著消退。在治疗过程中，28f的体内抗肿瘤效果具有剂量依赖性，包括体积及重量(图2中B所示)。此外，测量的裸鼠体重数据显示，所有剂量的28f给药均没有明显影响动物体重，表明其在动物中有良好的耐受性(图2中的C所示)。
实施例4：化合物28f与ACK1抑制剂联用的体外克服耐药研究
本实验的目的是验证本发明的优选化合物28f与ACK1抑制剂联用在体外克服耐药的效果。
通过MTT实验探索了28f与3种ACK1抑制剂(AIM-100，达沙替尼，伯舒替尼)的联用是否能够有效抑制耐药细胞的生长与增殖。在指定比例的药物浓度下，受试细胞的存活率如图3A所示。可以发现，AIM-100在一系列浓度梯度下几乎不表现对28fR的有效抗增殖能力，而与28f联用后，则有显著的抗增殖效果。同样的，尽管达沙替尼和伯舒替尼对28fR表现出一定的抗增殖效果，但与适当比例的28f联用时，同样产生了更好的对28fR的抑制能力。此外，三种ACK1抑制剂与28f在指定比例下的药物联用指数小于1，表明良好的协同效应(图3中的B所示)。特别的，28f与ACK1的高选择性抑制剂AIM-100以1：2的比例联用时其CI值均小于0.2，展现出高效的协同作用及显著增强的对28f耐药的H1975细胞的生长抑制作用。总之，上述实验结果表明，28f与三种ACK1抑制剂AIM-100，达沙替尼及伯舒替尼的分别联用均能产生协同抗增殖效果。图3中的A为28f与三种ACK1抑制剂在指定浓度及比例处理后，MTT方法测定细胞存活率。图3中的B为28f与三种ACK1抑制剂联用后的药物联用指数。
实施例5：化合物28f与ACK1抑制剂联用的体内克服耐药研究
本实验的目的是验证本发明的优选化合物28f与ACK1抑制剂联用在体内克服耐药的效果。在28f耐药的H1975的异种移植小鼠模型中，鉴定了28f与达沙替尼的联用的抗肿瘤效果。化合物28f以20mg/kg的剂量进行腹腔注射。与达沙替尼类似，化合物28f仅表现出非常有限的抑制肿瘤生长的作用，与之相反的是，28f与达沙替尼联合使用非常显著地抑制了28fR异种移植瘤的生长，包括肿瘤的体积与重量。并且，如图3中的E所示，28f与达沙替尼的组合在22天的实验期间对小鼠体重的影响与对照组没有显著区别，表明两种化合物的联用具有一定的安全性。图3中的C为用指定浓度的28f和达沙替尼处理后肿瘤体积的变化。图3中的D为治疗结束后肿瘤重量分析。图3中的E为治疗期间体内模型的体重变化。
综上所述，28f是一种具有全新化学骨架的，对EGFRL858R/T790M有良好选择性的第三代EGFR抑制剂。此外，28f与ACK1抑制剂联合用药有效的克服28f的耐药，在体内也显著的抑制肿瘤的生长。这为本申请发明人接下来的EGFRL858R/T790M/ACK1双靶药物的设计打下了良好的基础。
以上具体实施例仅仅是对本发明的解释，其并不是对本发明的限制，本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本发明的权利要求范围内都受到专利法的保护。
Claims (8)
1.一种通式(I)所示的化合物，或其在药学上可接受的盐：
其中，R1为：
R3为：
2.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于：
R1为：
R2为：
R3为：
R4为：
3.如权利要求1所述的化合物或其药学上可接受的盐，其特征在于：所述通式(I)所示的化合物为如下化合物：
4.一种药物组合物，其特征是：所述药物组合物包含有效剂量的如权利要求1～3任一项所述的化合物，或其在药学上可接受的盐的制剂。
5.如权利要求1～3任一项所述的化合物，或其在药学上可接受的盐，或如权利要求4所述的药物组合物在制备抗肿瘤药物中的应用。
6.如权利要求5所述的应用，其特征是：所述药物为于喹唑啉类化合物的制备及其抗肿瘤应用。
7.如权利要求6所述的应用，其特征是：所述抗肿瘤药物为治疗具有EGFR T790M/L858R过表达特点的肿瘤的药物。
8.如权利要求7所述的应用，其特征是：所述肿瘤为非小细胞肺癌。
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