CN111454278A - Pak1抑制剂及其合成和在制备抗肿瘤药物中的应用 - Google Patents

Pak1抑制剂及其合成和在制备抗肿瘤药物中的应用 Download PDF

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CN111454278A
CN111454278A CN202010410796.3A CN202010410796A CN111454278A CN 111454278 A CN111454278 A CN 111454278A CN 202010410796 A CN202010410796 A CN 202010410796A CN 111454278 A CN111454278 A CN 111454278A
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张瑾
姚大红
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Abstract

本发明涉及靶向PAK1抑制剂及其在制备抗肿瘤药物中的应用，属于医药技术领域。本发明所述的化合物或其药学上可接受的盐结构式如下：其中，R1为5‑10元芳基或杂芳基、C3‑C6环烷基，所述的5‑10元芳基或杂芳基、C3‑C6环烷基可以被一个或多个如下的取代基取代：C1‑C6烷基、C1‑C6烷氧基、卤代C1‑C6烷基、卤素；R2为C1‑C6烷基、C1‑C6烷氧基、C3‑C6环烷基、6‑10元芳基、5‑10杂环基或杂芳基、C2‑C6烯基，所述的C1‑C6烷基、6‑10元芳基、5‑10杂环基或杂芳基、C2‑C6烯基可以被一个或多个卤素、C1‑C6烷基取代。本发明的化合物或其药学上可接受的盐或其药物组合物可以作为PAK1抑制剂用于抗肿瘤药物的制备。

Description

PAK1抑制剂及其合成和在制备抗肿瘤药物中的应用
技术领域
本发明涉及靶向PAK1抑制剂及其在制备抗肿瘤药物中的应用，属于医药技术领域。
背景技术
乳腺癌是世界范围内的女性中除宫颈癌之外最高发的恶性肿瘤，其紧随肺癌和结肠癌成 为世界上最常见的三种癌症之一。统计表明，仅2012年，全球就有170万女性被确诊为乳腺 癌，更令人触目惊心的是，有50万患者死于乳腺癌。数据显示，女性一生中平均有12.5％的 概率患乳腺癌，尤其是继承有害突变BRCA1或BRCA2基因的女性罹患乳腺癌的风险更高。 就目前全世界的医疗水平来讲，一般认为没有远端转移的早期乳腺癌患者是可以治愈的，但 是对于转移性乳腺癌患者，只能通过各种辅助治疗策略来延长患者的生存期，提高患者的生 命质量，治愈的可能性很低。在所有的乳腺癌类型中，三阴性乳腺癌(TNBC)是恶性程度 最高，预后最差的亚型。TNBC表现为雌激素受体(ER)，孕激素受体(PR)和人表皮生长 因子受体2(Her-2)均为阴性，这些特点使TNBC对一些常规乳腺癌的靶标并不响应。目前， 临床上治疗TNBC的主要方法为化疗，临床上密集型，高剂量的化疗会产生巨大的毒性并易 产生耐药，肿瘤一旦复发或转移后往往面临无药可用的情况，治疗效果很不理想。此外靶向 治疗和免疫治疗是近年来TNBC治疗研究的热点，随着生物技术的发展，小分子靶向治疗成 为最为活跃的研究领域。近年来，TNBC治疗的一些新靶标被陆续发现，并取得了一些可喜 的进展：PARP抑制剂，PI3K抑制剂，MEK抑制剂及热休克蛋白90(HSP90)抑制剂等均表 现出一定的治疗潜力。但是，PARP抑制剂Olaparib仅仅在BRCA1/2突变的TNBC中显示出 较强的敏感性，在散发型的三阴性乳腺癌中疗效不佳，其他三个PARP抑制剂Veliparib，Talazoparib和Niraparib更是仅处于研发阶段，临床效果仍未可知。PI3K及MEK抑制剂单独使用疗效并不显著，目前主要与PARP抑制剂联合使用，能够增加其敏感性。目前免疫治疗也被用于TNBC的治疗，但反应率较低，且安全性尚不明确。综上，由于TNBC本身具有高 度的异质性，难以找到统一的治疗靶标，目前临床上缺乏有效的治疗药物。
因此，在TNBC药物治疗领域，如何发现新的治疗靶标，有针对性的设计出新型靶向治 疗小分子药物，并深入探讨其作用机制是解决临床问题的关键，具有重要的研究意义和价值。 PAK1作为一个重要的癌基因，在乳腺癌中异常高表达，针对其设计靶向性的小分子抑制剂， 是治疗乳腺癌，也别是三阴性乳腺癌重要的策略。
发明内容
本发明解决的技术问题是提供一种新型的靶向PAK1抑制剂或其药学上可接受的盐及其 制备和用途。
本发明提供如式Ⅰ所示的化合物或其药学上可接受的盐：
Figure BDA0002493134950000021
R1为5-10元芳基或杂芳基、C3-C6环烷基，所述的5-10元芳基或杂芳基、C3-C6环烷基可以被一个或多个如下的取代基取代：C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤 素；
R2为C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、6-10元芳基、5-10杂环基或杂芳基、C2-C6烯基，所述的C1-C6烷基、6-10元芳基、5-10杂环基或杂芳基、C2-C6烯基可以被一 个或多个卤素、C1-C6烷基取代。
本发明优选式Ⅰ所示的化合物或其药学上可接受的盐：
R1为5-6元芳基或杂芳基、C3-C6环烷基，所述的5-6元芳基或杂芳基、C3-C6环烷基可以被一个或多个如下的取代基取代：C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基、卤素；
优选地，R1为苯基、环丙基、环丁基、环戊基、环己基，所述R1可以被一个或多个如下的取代基取代：C1-C4烷基、C1-C4烷氧基、CF3、卤素；
本发明优选式Ⅰ所示的化合物或其药学上可接受的盐：
R2为C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、苯基、5-6元杂环基或杂芳基、C2-C6烯基，所述的C1-C4烷基、苯基、5-6元杂环基或杂芳基、C2-C6烯基可以被一个或多个卤 素、C1-C4烷基取代；
优选地，R2为C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、苯基、
Figure BDA0002493134950000022
C2-C6烯 基，所述的R2可以被一个或多个卤素、C1-C4烷基取代；
本发明优选如下所示的化合物或其药学上可接受的盐：
Figure BDA0002493134950000031
Figure BDA0002493134950000041
本发明还提供了所述化合物的合成方法，其合成路线如下：
Figure BDA0002493134950000042
或
Figure BDA0002493134950000051
本发明还提供一种药物组合物，它是包含有效剂量的上述化合物或其药学上可接受的盐 的制剂。可以通过本领域已知的方法将本发明化合物制成以下形式：片剂、胶囊剂、水性或 油性溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、凝胶剂、喷鼻剂、栓剂、用于吸入的细小分 散的粉剂或气雾剂或喷雾剂、用于胃肠道外(包括静脉内、肌内或输注)的无菌水性或油性溶 液或混悬剂或无菌乳剂。可采用无菌水或水-丙二醇溶液作为溶剂来制备液体制剂，还可将活 性组分配制在聚乙二醇水溶液中。用于口服给予的水性溶液可通过将活性组分溶解在水中并 按需要加入合适的着色剂、矫味剂、稳定剂和增稠剂来制备。口服使用的水性混悬剂可通过 将细小分散的活性组分与粘性物质一道分散在水中，所述粘性物质如为天然合成胶、树脂、 甲基纤维素、羧甲基纤维素和其他药剂领域已知的悬浮剂。
药物组合物可为单位剂量形式。在这些形式中，将所述组合物分成含适量活性组分的单 位剂量。该单位剂量形式可为包装制剂，包装中包括分隔量的制剂，例如盒装片剂、胶囊剂 和在管形瓶或安瓿中的粉剂。单位剂量形式还可为胶囊剂、扁囊剂或片剂或其可为适当数量 的任何这些包装形式。
本发明的药物组合物，其活性成分可仅为本发明的化合物，也可与其他抗肿瘤化合物组 合作为活性成分。
本发明还提供上述化合物或其药学上可接受的盐或其药物组合物在制备PAK1抑制剂中 的应用。
本发明还提供了上述化合物或其药学上可接受的盐或其药物组合物在制备抗肿瘤药物中 的用途。
在治疗肿瘤过程中，可采用本发明的化合物或药物组合物与其他抗肿瘤药进行联合治疗。
在治疗肿瘤时，可通过同时、序贯或单独给予各种治疗成分可实现这种联合治疗。此类 组合产品应用有效剂量范围内的本发明化合物和准许剂量范围内的其他药学活性剂。
附图说明
图1为MDA-MB-231细胞用化合物27处理24和48小时，MTT检测细胞存活率。
图2为MDA-MB-231细胞用0，2.5，5，10μM化合物27处理48小时，PI流式细胞术 检测细胞周期分布的图。
图3A为MDA-MB-231细胞用5μM化合物27处理48小时，免疫荧光检测p-cdc2表达 的图；图3B为MDA-MB-231细胞用0，2.5，5，10μM化合物27处理48小时，免疫印迹检 测cdc25c,p-cdc2,CyclinB1和β-actin表达的图。
具体实施方式
下面结合实施例对本发明的具体实施方式做进一步的描述，并不因此将本发明限制在所 述的实施例范围之中。
实施例1化合物1～17的合成
化合物1～17采用如下反应式合成：
Figure BDA0002493134950000061
合成路线和条件：(i)三乙胺,二氯甲烷,室温,16h；(ii)S8，吗啉，乙醇，室温，12h；(iii)KSCN，酰氯衍 生物，乙腈，回流，6h；
中间体1制备
4-哌酮盐酸盐(1.54g,10mmol)溶于30ml二氯甲烷，室温下加入三乙胺(2.02g,20mmol)，30min后加入二碳酸二叔丁酯(3.27g,15mmol)，搅拌16h。反应液用水(3×30ml) 洗涤，合并后有机层用饱和的碳酸氢钠和盐水洗涤，然后用无水硫酸钠干燥。减压去除溶剂后得到粗产物。经重结晶得到白色固体，收率为79％。1H-NMR(400MHz,CDCl3),δ(ppm):3.72(4H,t,J＝6.1Hz),2.44(4H,t,J＝6.1Hz),1.49(9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):207.7,154.5,80.4,42.9,42.9,41.1,41.1,28.4,28.4,28.4
中间体2合成
在无水乙醇(200ml)中加入叔丁基4-恶哌啶-1-羧酸盐(30.0mmol)、2-氰乙酰胺(30.0 mmol)、硫(30.0mmol)，再加入吗啉(30.0mmol)。回流8小时，将反应液冷却至室温，过滤， 用30ml x 3的无水乙醇洗涤，减压去除溶剂。粗品经95％乙醇(30ml)结晶，得白色固体，收 率78％。1H-NMR(400MHz,DMSO-d6),δ(ppm):6.98(2H,s),6.59(2H,brs),4.27(2H,s),3.50 (2H,t,J＝5.4Hz),2.67(2H,t,J＝5.4Hz),1.42(9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm): 168.0,160.1,154.2,129.8,112.6,107.7,79.6,42.5,41.9,28.5,28.5,28.5,26.5；
化合物1-17合成通法
取KSCN(117.0mg,1.2mmol)溶于10ml乙腈中，室温下滴加含R1COCl(1.2eq)的二氯甲烷溶液(2ml)。反应液加热回流10min，加入中间体4(1mmol)，回流6h。反应结束后冷 却至室温，过滤，滤饼用无水乙醇清洗，得黄色固体。
以下为化合物1-17的核磁检测结果。
化合物1,收率83％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.46(1H,s),11.73(1H,s),7.97 (2H,d,J＝6.6Hz),7.71(1H,br.s),7.66(2H,d,J＝6.6Hz),7.53(1H,t,J＝6.7Hz),7.35(1H,br. s),4.52(2H,s),3.57(2H,t,J＝5.0Hz),2.78(2H,t,J＝5.0Hz),1.44(9H,s)；13C-NMR(100MHz, DMSO-d6),δ(ppm):174.6,167.5,166.4,154.2,141.5,133.6,132.5,129.2,129.2,129.0,128.9, 128.9,125.2,122.8,79.7,43.0,42.3,28.5,28.5,28.5,25.5；HRMS(ESI)+calculated for C21H25N4O4S2,[M+H]+:m/z 461.1317,found461.1319.
化合物2,收率74％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.47(1H,s),11.63(1H,s),7.89 (2H,d,J＝8.0Hz),7.66(1H,br.s),7.37(1H,br.s),7.34(2H,d,J＝8.0Hz),4.51(2H,s),3.57(2H, t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),2.39(3H,s),1.44(9H,s)；13C-NMR(100MHz,DMSO-d6), δ(ppm):174.3,170.7,166.3,154.2,141.3,135.5,128.9,127.8,127.3,126.1,125.2,122.7,79.7, 43.0,42.3,36.9,28.5,28.5,28.5,25.4；HRMS(ESI)+calculated for C22H27N4O4S2,[M+H]+:m/z 475.1474,found 475.1477.
化合物3,收率87％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.38(1H,s),11.84(1H,s),7.69 (1H,br.s),7.50(1H,d,J＝7.4Hz),7.44(1H,t,J＝7.4Hz),7.33(1H,br.s),7.31(1H,d,J＝8.4 Hz),7.29(1H,t,J＝8.4Hz),4.51(2H,s),3.57(2H,t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),2.39 (3H,s),1.44(9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,169.5,166.4,154.2,141.6, 136.5,134.4,131.4,131.1,128.9,128.6,125.9,125.1,122.6,79.7,43.0,42.3,28.5,28.5,28.5,25.5, 19.9；HRMS(ESI)+calculated for C22H27N4O4S2,[M+H]+:m/z 475.1474,found 475.1476.
化合物4,收率86％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.46(1H,s),11.66(1H,s),7.83 (1H,s),7.76(1H,d,J＝7.5Hz),7.67(1H,br.s),7.47(1H,d,J＝7.5Hz),7.42(1H,t,J＝7.5Hz), 7.37(1H,br.s),4.51(2H,s),3.57(2H,t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),2.39(3H,s),1.44 (9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.7,167.5,166.3,154.2,141.4,138.3,134.2, 132.3,129.6,129.0,128.8,126.3,125.2,122.7,79.7,43.0,42.3,28.5,28.5,28.5,25.4,21.3；HRMS (ESI)+calculated for C22H27N4O4S2,[M+H]+:m/z 475.1474,found 475.1474.
化合物5,收率88％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.41(1H,s),11.92(1H,s),7.68 (1H,br.s),7.63(1H,d,J＝7.5Hz),7.33(1H,br.s),6.92(2H,s),4.51(2H,s),3.57(2H,t,J＝5.0 Hz),2.79(2H,t,J＝5.0Hz),2.26(3H,s),2.22(6H,s),1.44(9H,s)；13C-NMR(100MHz, DMSO-d6),δ(ppm):174.3,170.3,166.4,154.2,141.7,139.2,134.4,134.4,133.5,128.9,128.4, 128.4,125.2,122.6,79.7,43.0,42.3,28.5,28.5,28.5,25.4,21.2,19.4,19.4；HRMS(ESI)+ calculated for C24H31N4O4S2,[M+H]+:m/z 503.1787,found503.1788.
化合物6,收率81％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.48(1H,s),11.84(1H,s),8.00 (2H,d,J＝8.8Hz),7.66(1H,br.s),7.37(1H,br.s),7.06(2H,d,J＝8.8Hz),4.51(2H,s),3.86(3H, s),3.57(2H,t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),1.44(9H,s)；13C-NMR(100MHz,DMSO-d6), δ(ppm):174.8,166.7,166.3,163.7,154.2,141.4,131.5,131.5,128.9,125.1,124.1,122.8,114.2, 114.2,79.7,56.1,43.0,42.3,28.5,28.5,28.5,25.5；HRMS(ESI)+calculated for C22H27N4O5S2, [M+H]+:m/z 491.1423,found 491.1425.
化合物7,收率71％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.43(1H,s),11.84(1H,s),7.90 (2H,d,J＝8.6Hz),7.75(2H,d,J＝8.6Hz),7.67(1H,br.s),7.35(1H,br.s),4.51(2H,s),3.57(2H, t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),1.44(9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm): 174.5,166.7,166.4,154.2,141.5,131.9,131.9,131.7,131.3,131.3,129.0,127.5,125.2,122.7, 79.7,43.0,42.3,28.5,28.5,28.5,25.5；HRMS(ESI)+calculated for C21H24BrN4O4S2,[M+H]+:m/z 539.0422,found 539.0425.
化合物8,收率77％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.32(1H,s),12.11(1H,s),7.69 (1H,br.s),7.63(1H,d,J＝7.5Hz),7.55(2H,d,J＝7.6Hz),7.45(2H,d,J＝7.6Hz),7.32(1H,br. s),4.52(2H,s),3.57(2H,t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),1.44(9H,s)；13C-NMR(100MHz, DMSO-d6),δ(ppm):174.1,166.5,166.7,166.4,154.2,141.7,134.8,132.5,130.5,130.0,129.8, 128.9,127.6,125.2,122.6,79.7,43.0,42.3,28.5,28.5,28.5,25.4；HRMS(ESI)+calculated for C21H24FN4O4S2,[M+H]+:m/z 479.1223,found479.1226.
化合物9,收率79％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.34(1H,s),11.86(1H,s),7.71 (1H,d,J＝7.2Hz),7.69(1H,br.s),7.65(1H,t,J＝7.2Hz),7.37(1H,br.s),7.36(1H,t,J＝7.0 Hz),7.34(1H,d,J＝7.0Hz),4.51(2H,s),3.57(2H,t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),1.44 (9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):173.9,166.4,164.5,160.6,158.9,154.2,141.6, 134.6,130.9,129.0,125.0,122.6,122.5,116.7,116.5,79.7,43.0,42.3,36.9,28.5,28.5,28.5,25.5； HRMS(ESI)+calculated forC21H24FN4O4S2,[M+H]+:m/z 479.1223,found 479.1227.
化合物10,收率77％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.43(1H,s),11.84(1H,s),7.98 (2H,d,J＝8.6Hz),7.67(1H,br.s),7.61(1H,d,J＝8.6Hz),7.36(1H,br.s),4.51(2H,s),3.57(2H, t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),1.44(9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm): 174.5,166.5,166.4,154.2,141.5,138.4,131.3,131.2,131.2,129.0,128.9,128.9,122.7,114.2, 114.2,79.7,43.0,42.3,28.5,28.5,28.5,25.4；HRMS(ESI)+calculated for C21H24ClN4O4S2, [M+H]+:m/z 495.0927,found 495.0931.
化合物11,收率78％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.47(1H,s),11.63(1H,s),7.90 (2H,d,J＝8.0Hz),7.67(1H,br.s),7.37(1H,br.s),7.34(2H,d,J＝8.0Hz),4.51(2H,s),3.57(2H, t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),1.44(9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm): 174.7,167.3,166.3,154.2,144.1,141.4,129.5,129.3,129.0,125.1,122.8,127.5,125.2,122.7, 79.7,43.0,42.3,28.5,28.5,28.5,21.6；HRMS(ESI)+calculated for C21H24ClN4O4S2,[M+H]+:m/z 495.0927,found 495.0931.
化合物12,收率65％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.42(1H,s),11.88(1H,s),8.03 (1H,s),7.90(1H,d,J＝7.7Hz),7.72(1H,d,J＝7.8Hz),7.69(1H,br.s),7.56(1H,dd,J＝7.8 7.7 Hz),7.37(1H,br.s),4.51(2H,s),3.57(2H,t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),1.44(9H,s)； 13C-NMR(100MHz,DMSO-d6),δ(ppm):174.4,166.4,166.2,154.2,141.7,134.5,133.5,133.2, 130.8,129.0,128.9,127.9,125.2,122.7,79.7,43.0,42.3,28.5,28.5,28.5,25.4；HRMS(ESI)+ calculated for C21H24ClN4O4S2,[M+H]+:m/z495.0927,found 495.0928.
化合物13,收率68％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.45(1H,s),12.07(1H,s),8.33 (1H,s),8.24(1H,d,J＝7.8Hz),8.02(1H,d,J＝7.8Hz),7.78(2H,t,J＝7.8Hz),7.68(1H,br.s), 7.36(1H,br.s),4.52(2H,s),3.57(2H,t,J＝5.0Hz),2.80(2H,t,J＝5.0Hz),1.44(9H,s)； 13C-NMR(100MHz,DMSO-d6),δ(ppm):174.4,166.4,166.2,154.2,141.5,133.6,133.4,130.1, 129.9,129.6,129.2,129.0,128.4,126.1,126.0,125.6,125.2,79.7,43.0,42.3,28.5,28.5,28.5,25.4； HRMS(ESI)+calculated forC22H24F3N4O4S2,[M+H]+:m/z 529.1191,found 529.1195.
化合物14,收率73％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.44(1H,s),12.00(1H,s),8.14 (2H,d,J＝7.6Hz),7.91(2H,d,J＝7.6Hz),7.68(1H,br.s),7.35(1H,br.s),4.52(2H,s),3.58(2H, t,J＝5.0Hz),2.80(2H,t,J＝5.0Hz),1.44(9H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm): 174.4,166.5,166.4,154.2,141.6,136.6,133.3,132.9,132.6,130.2,130.2,129.1,125.7,125.7, 125.6,122.9,122.7,79.7,43.0,42.3,28.5,28.5,28.5,25.6,25.5；HRMS(ESI)+calculated for C22H24F3N4O4S2,[M+H]+:m/z 529.1191,found529.1193.
化合物15,收率85％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.31(1H,s),12.18(1H,s),7.79 (2H,dd,J＝8.0 1.2Hz),7.71(1H,br.s),7.63(2H,dd,J＝8.0 1.2Hz),7.48(1H,t,J＝7.9Hz), 7.32(1H,br.s),4.52(2H,s),3.57(2H,t,J＝5.0Hz),2.81(2H,t,J＝5.0Hz),1.44(9H,s)； 13C-NMR(100MHz,DMSO-d6),δ(ppm):173.8,166.5,165.8,154.2,141.7,137.1,132.6,132.3, 129.1,129.0,128.6,128.2,125.4,122.5,79.7,43.0,42.3,28.5,28.5,28.5,25.6；HRMS(ESI)+ calculated for C21H23Cl2N4O4S2,[M+H]+:m/z529.0538,found 529.0543.
化合物16,收率66％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.20(1H,s),11.47(1H,s),7.59 (1H,br.s),7.34(1H,br.s),4.48(2H,s),3.54(2H,t,J＝5.0Hz),2.75(2H,t,J＝5.0Hz),1.79(2H, d,J＝12.0Hz),1.74(2H,d,J＝12.0Hz),1.63(1H,m),1.43(9H,s),1.37–1.16(6H,m)； 13C-NMR(100MHz,DMSO-d6),δ(ppm):177.1,174.8,166.2,154.2,141.2,128.9,125.1,122.8, 79.7,44.1,43.0,42.3,29.0,29.0,29.0,28.5,28.5,28.5,25.6,25.4；HRMS(ESI)+calculated for C21H31N4O4S2,[M+H]+:m/z 467.1787,found 467.1788.
化合物17,收率89％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.44(1H,s),11.78(1H,s),8.06 (2H,t,J＝8.6Hz),7.67(1H,br.s),7.37(1H,br.s),7.35(2H,t,J＝8.6Hz),4.51(2H,s),3.57(2H, t,J＝5.0Hz),2.79(2H,t,J＝5.0Hz),2.26(3H,s),2.22(6H,s),1.44(9H,s)；13C-NMR(100MHz, DMSO-d6),δ(ppm):174.3,170.3,166.4,154.2,141.7,139.2,134.4,134.4,133.5,128.9,128.4, 128.4,125.2,122.6,79.7,43.0,42.3,28.5,28.5,28.5,25.4,21.2,19.4,19.4；HRMS(ESI)+ calculated for C20H25N4O4S3,[M+H]+:m/z481.1038,found 481.1043.
实施例2 18-31的合成
Figure RE-GDA0002545486770000111
合成路线和条件：(i)三氟乙酸，CH2Cl2，室温；(ii)CH2Cl2,酰氯衍生物，三乙胺，室温。
中间体3制备
取中间体3(1.0mmol)溶于10ml二氯甲烷中，再加入10ml三氟乙酸，室温反应4小时， 减压脱除溶剂后，加水30ml，用1N NaOH碱化至pH＝9，过滤得到灰色固体，收率87％。1H-NMR(400MHz,DMSO-d6),δ(ppm):10.15(1H,s),9.97(1H,s),8.94(2H,s),8.16(1H,s),8.15(1H,d,J＝7.5Hz),7.92(1H,d,J＝7.5Hz),7.71(1H,t,J＝7.5Hz),6.65(1H,s),4.22(2H,s), 3.32(2H,t,J＝5.4Hz),3.17(2H,t,J＝5.4Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.6, 166.4,166.2,141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9, 127.0,126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.1,42.1,26.4；HRMS(ESI)+calculated for C17H16F3N4O2S2,[M+H]+:m/z 429.0667,found429.0669.
化合物18-31合成通法
取THF 20ml加入中间体3(214.2mg,0.5mmol)和三乙胺(101.1mg,1mmol)，滴加含1.2eq的酰氯衍生物的二氯甲烷3ml，反应液在室温下搅拌4小时。反应完成后，蒸出溶剂并加入50ml水，用乙酸乙酯萃取，有机层用饱和的碳酸氢钠和盐水洗涤，无水硫酸钠干燥。粗品经硅胶柱色谱分离(二氯甲烷/甲醇10:1)纯化为黄色固体。
化合物18,收率67％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.50(1H,s),12.12(1H,s),8.38 (1H,s),8.33(1H,d,J＝7.8Hz),8.03(1H,d,J＝7.8Hz),7.61(2H,t,J＝7.8Hz),7.71(1H,br.s), 7.68(2H,d,J＝7.7Hz),7.56(2H,d,J＝7.7Hz),7.40(1H,br.s),4.83(2H,s),3.60(2H,t,J＝5.0 Hz),2.95(2H,t,J＝5.0Hz),2.43(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.6,166.4, 166.2,141.8,141.4,136.9,136.4,133.6,133.3,131.3,130.1,129.8,129.8,129.6,129.4,129.4, 129.2,128.9,128.4,127.1,127.0,126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.1,42.1,26.4, 19.2；HRMS(ESI)+calculatedfor C25H21F3N4O3S2,[M+H]+:m/z 547.1085,found 547.1091.
化合物19,收率72％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.50(1H,s),12.12(1H,s),8.38 (1H,s),8.33(1H,d,J＝7.8Hz),8.03(1H,d,J＝7.8Hz),7.61(2H,t,J＝7.8Hz),7.71(1H,br.s), 7.68(2H,d,J＝7.7Hz),7.56(2H,d,J＝7.7Hz),7.40(1H,br.s),4.83(2H,s),3.60(2H,t,J＝5.0 Hz),2.95(2H,t,J＝5.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,171.1,166.4,166.2, 141.8,141.4,135.3,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0, 126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.1,42.1,26.4；HRMS(ESI)+calculated for C24H19ClF3N4O3S2,[M+H]+:m/z567.0539,found 567.0539.
化合物20,收率76％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.50(1H,s),12.12(1H,s),8.38 (1H,s),8.33(1H,d,J＝7.8Hz),8.03(1H,d,J＝7.8Hz),7.61(2H,t,J＝7.8Hz),7.71(1H,br.s), 7.68(2H,d,J＝7.7Hz),7.56(2H,d,J＝7.7Hz),7.40(1H,br.s),4.83(2H,s),3.60(2H,t,J＝5.0 Hz),2.95(2H,t,J＝5.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,171.1,166.4,166.2, 141.8,141.4,135.3,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0, 126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.1,42.1,26.4；HRMS(ESI)+calculated for C24H19ClF3N4O3S2,[M+H]+:m/z567.0539,found 567.0547.
化合物21,收率75％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.33(1H,s),11.97(1H,s),8.26 (1H,s),8.16(1H,d,J＝7.8Hz),7.95(1H,d,J＝7.8Hz),7.71(2H,t,J＝7.8Hz),7.58(1H,br.s), 7.26(1H,br.s),4.54(2H,s),3.62(2H,t,J＝5.0Hz),2.81(2H,t,J＝5.0Hz),2.04(3H,s)； 13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,169.2,166.4,166.2,141.8,141.4,133.6,133.3, 130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0,126.0,125.6,125.2,123.4,122.8, 122.5,121.6,43.1,42.1,26.4,21.6；HRMS(ESI)+calculated for C19H18F3N4O3S2,[M+H]+:m/z 471.0772,found 471.0774.
化合物22,收率76％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.45(1H,s),12.04(1H,s),8.33 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.77(2H,t,J＝7.8Hz),7.64(1H,br.s), 7.36(1H,br.s),4.63(2H,s),3.75(2H,t,J＝5.0Hz),2.98(1H,m),2.88(2H,t,J＝5.0Hz),1.03 (6H,d,J＝6.2Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):175.3,174.5,166.4,166.2,141.8, 141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0,126.0,125.6, 125.2,123.4,122.8,122.5,121.6,43.1,42.1,30.8,26.4,19.7,19.7；HRMS(ESI)+calculated for C21H22F3N4O3S2,[M+H]+:m/z 499.1085,found 499.1087.
化合物23,收率72％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.41(1H,s),12.05(1H,s),8.33 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.77(2H,t,J＝7.8Hz),7.64(1H,br.s), 7.34(1H,br.s),4.62(2H,s),3.70(2H,t,J＝5.0Hz),2.86(2H,t,J＝5.0Hz),2.31(2H,d,J＝6.9 Hz),2.04(1H,m),0.91(6H,d,J＝6.4Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,170.9, 166.4,166.2,141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9, 127.0,126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.1,42.1,41.7,26.4,23.0,22.9,22.6； HRMS(ESI)+calculated forC22H24F3N4O3S2,[M+H]+:m/z 513.1242,found 513.1244.
化合物24,收率78％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.40(1H,s),12.06(1H,s),8.33 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.66(2H,t,J＝7.8Hz),7.35(1H,br.s), 7.26(1H,br.s),4.64(2H,s),3.83(2H,t,J＝8.0Hz),3.72(2H,t,J＝5.0Hz),2.96(2H,t,J＝8.0 Hz),2.87(2H,t,J＝5.0Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,172.5,166.4,166.2, 141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0,126.0, 125.6,125.2,123.4,122.8,122.5,121.6,43.1,42.1,41.1,37.1,26.4；HRMS(ESI)+calculated for C20H19ClF3N4O3S2,[M+H]+:m/z 519.0539,found 519.0540.
化合物25,收率65％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.47(1H,s),12.11(1H,s),8.38 (1H,s),8.28(1H,d,J＝7.8Hz),8.07(1H,d,J＝7.8Hz),7.70(1H,br.s),7.41(1H,br.s),6.73(1H, dd,J＝14.4,7.5Hz),6.67(1H,d,J＝14.4Hz),4.73(2H,s),3.87(2H,t,J＝5Hz),2.91(2H,d,J＝ 5.0Hz),1.93(3H,d,J＝7.5Hz)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,166.4,166.2, 165.2,141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0, 126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.1,42.1,26.4,18.2；HRMS(ESI)+calculated for C21H20F3N4O3S2,[M+H]+:m/z497.0929,found 497.0933.
化合物26,收率81％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.51(1H,s),12.12(1H,s),8.38 (1H,s),8.29(1H,d,J＝7.8Hz),8.07(1H,d,J＝7.8Hz),7.84(2H,t,J＝7.8Hz),7.72(1H,br.s), 7.40(1H,br.s),5.32(1H,br.s),5.15(1H,br.s),4.72(2H,s),3.77(2H,t,J＝5.0Hz),2.92(2H,t,J ＝5.0Hz),1.97(3H,s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,170.7,166.4,166.2,141.8, 141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0,126.0,125.6, 125.2,123.4,122.8,122.5,121.6,115.7,43.1,42.1,26.4,20.6；HRMS(ESI)+calculated for C21H20F3N4O3S2,[M+H]+:m/z497.0929,found 497.0931.
化合物27,收率61％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.41(1H,s),12.03(1H,s),8.33 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.78(2H,t,J＝7.8Hz),7.65(1H,br.s), 7.32(1H,br.s),4.64(2H,s),3.94(4H,t,J＝3.9Hz),2.92(2H,d,J＝5.0Hz),2.11(1H,m),0.77 (4H,br.s)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,171.9,166.4,166.2,141.8,141.4, 133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9,127.0,126.0,125.6,125.2, 123.4,122.8,122.5,121.6,43.1,42.1,26.4,14.4,7.47,7.47；HRMS(ESI)+calculated for C21H20F3N4O3S2,[M+H]+:m/z 497.0929,found497.0932.
化合物28,收率68％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.41(1H,s),12.05(1H,s),8.33 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.77(2H,t,J＝7.8Hz),7.64(1H,br.s), 7.34(1H,br.s),4.61(2H,s),3.70(2H,t,J＝5.0Hz),3.43(1H,m),2.82(2H,t,J＝5.0Hz),2.22 (1H,m),2.19-2.12(3H,m),1.92(1H,m),1.76(1H,m)；13C-NMR(100MHz,DMSO-d6),δ(ppm): 174.5,172.9,166.4,166.2,141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4, 129.2,128.9,127.0,126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.5,42.3,37.1,36.8,36.8, 26.4,17.9；HRMS(ESI)+calculated for C22H22F3N4O3S2,[M+H]+:m/z 511.1085,found 511.1086.
化合物29,收率78％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.44(1H,s),12.05(1H,s),8.33 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.77(2H,t,J＝7.8Hz),7.64(1H,br.s), 7.34(1H,br.s),4.61(2H,s),3.74(2H,t,J＝5.0Hz),2.88(2H,t,J＝5.0Hz),2.68(1H,m), 1.71-1.64(4H,m),1.37-1.33(4H,m)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,170.0, 166.4,166.2,141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9, 127.0,126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.5,42.3,40.8,29.7,29.7,26.4,26.0,21.8； HRMS(ESI)+calculated forC23H23F3N4O3S2,[M+H]+:m/z 525.1242,found 539.1268.
化合物30,收率73％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.44(1H,s),12.05(1H,s),8.33 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.77(2H,t,J＝7.8Hz),7.64(1H,br.s), 7.34(1H,br.s),4.61(2H,s),3.74(2H,t,J＝5.0Hz),2.88(2H,t,J＝5.0Hz),2.68(1H,m), 1.71-1.64(5H,m),1.37-1.33(5H,m)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,170.0, 166.4,166.2,141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9, 127.0,126.0,125.6,125.2,123.4,122.8,122.5,121.6,43.5,42.3,40.8,29.7,29.7,26.4,26.0,26.0, 21.8；HRMS(ESI)+calculated forC24H26F3N4O3S2,[M+H]+:m/z 539.1398,found 539.1398.
化合物31,收率71％，1H-NMR(400MHz,DMSO-d6),δ(ppm):14.46(1H,s),12.03(1H,s),8.32 (1H,s),8.23(1H,d,J＝7.8Hz),8.01(1H,d,J＝7.8Hz),7.77(2H,t,J＝7.8Hz),7.63(1H,br.s), 7.32(1H,br.s),4.39(2H,s),3.61(4H,t,J＝3.9Hz),3.43(2H,d,J＝5.0Hz),3.17(4H,t,J＝3.9 Hz),2.86(2H,t,J＝5.0Hz),2.50(1H,m)；13C-NMR(100MHz,DMSO-d6),δ(ppm):174.5,166.4, 166.2,163.2,141.8,141.4,133.6,133.3,130.1,129.8,129.8,129.6,129.4,129.4,129.2,128.9, 127.0,126.0,125.6,125.2,123.4,122.8,122.5,121.6,66.4,66.4,45.4,44.3,30.8,30.8,25.4； HRMS(ESI)+calculated forC23H24F3N4O4S2,[M+H]+:m/z 541.1191,found 541.1193.
试验例1化合物1～31的PAK1激酶抑制活性
本实验的目的是检测本发明的化合物对体外PAK1抑制活性(表1)。PAK1酶活反应都在 30℃下反应40分钟。50μl反应混合物包含40mM Tris,pH 7.4,10mM MgCl2,0.1mg/mlBSA, 1mM DTT,50M ATP,0.2ug/ml PAK1和100uM脂质底物。在化合物用10％DMSO和5μl的稀释液稀释，加入到反应混合物中，使DMSO的最终浓度为1％。采用发光激酶检测试剂盒 和ADP-Glo发光激酶检测试剂盒进行检测。通过测量激酶反应后溶液中剩余ATP的数量来测量激酶活性。本实验的发光信号与ATP的存在量有关，与激酶活性呈负相关。IC50值计算采用GraphPad软件的非线性回归和归一化剂量响应拟合。
表1化合物1～31激酶激动活性
Figure BDA0002493134950000141
Figure BDA0002493134950000151
实验结果表明，本发明的化合物大多对PAK1显示出较强的抑制活性，其中化合物27显 示出最强的抑制活性，其IC50＝210nM。表明该类化合物是PAK1的强效抑制剂。
试验例2候选化合物抗增殖活性评价
本实验的目的是检测本发明的化合物在体外对乳腺癌MDA-MB-231细胞的抗增值活性。 细胞存活实验是采用MTT法进行测定。MDA-MB-231细胞分散在96孔板中，控制密度为5 ×104cells/ml，细胞孵育24小时候后，加入不同浓度的化合物，孵育所需时间后，向每个空 中加入5mg/ml的3-(4,5-dimetrylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)，继续孵 育4小时后，移除缓冲液，加入150μl的DMSO以溶解生成的晶体。在570nm用荧光酶 标仪测定吸光度。
Figure BDA0002493134950000161
Figure BDA0002493134950000171
结果显示本发明中的化合物在20μM浓度时能够有效的抑制MDA-MB-231细胞的增值， 具有潜在的抗增值活性。为了进一步检测27对肿瘤细胞的增殖抑制效力，我们利用MTT法 测试了化合物27对MDA-MB-231细胞的抗增殖活性，结果显示化合物27能够显著的抑制肿 瘤细胞的增殖，其IC50为4.674μM，结果见图1。
试验例3化合物27诱导肿瘤细胞G2期细胞周期阻滞
为了检测化合物27是否能够诱导肿瘤细胞周期变化，我们使用PI流式细胞术对不同浓 度的化合物27处理后的MDA-MB-231细胞进行检测，结果显示随着化合物27浓度的增加， 细胞明显的阻滞于G2期，且表现为浓度依赖，见图2。
试验例4化合物27诱导肿瘤细胞PAK1-cdc25c-cdc2/CyclinB1通路的抑制
为了探索化合物27诱导G2细胞周期阻滞的原因，使用免疫荧光和免疫印迹对相关通路 蛋白进行检测，结果发现化合物27抑制cdc25c和CyclinB1的表达，并抑制cdc25c对cdc2 的磷酸化，证明PAK1-cdc25c-cdc2/CyclinB1通路的抑制，结果见图3。

Claims (9)

1.式Ⅰ所示的化合物或其药学上可接受的盐：
Figure FDA0002493134940000011
R1为5-10元芳基或杂芳基、C3-C6环烷基，所述的5-10元芳基或杂芳基、C3-C6环烷基可以被一个或多个如下的取代基取代：C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤素；
R2为C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、6-10元芳基、5-10杂环基或杂芳基、C2-C6烯基，所述的C1-C6烷基、6-10元芳基、5-10杂环基或杂芳基、C2-C6烯基可以被一个或多个卤素、C1-C6烷基取代。
2.根据权利要求1所述的化合物或其药学上可接受的盐，
其中，R1为5-6元芳基或杂芳基、C3-C6环烷基，所述的5-6元芳基或杂芳基、C3-C6环烷基可以被一个或多个如下的取代基取代：C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基、卤素；
优选地，R1为苯基、环丙基、环丁基、环戊基、环己基，所述R1可以被一个或多个如下的取代基取代：C1-C4烷基、C1-C4烷氧基、CF3、卤素。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐，
R2为C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、苯基、5-6元杂环基或杂芳基、C2-C6烯基，所述的C1-C4烷基、苯基、5-6元杂环基或杂芳基、C2-C6烯基可以被一个或多个卤素、C1-C4烷基取代；
优选地，R2为C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、苯基、
Figure FDA0002493134940000012
C2-C6烯基，所述的R2可以被一个或多个卤素、C1-C4烷基取代。
4.如下所述的化合物或其药学上可接受的盐：
Figure FDA0002493134940000021
Figure FDA0002493134940000031
5.如权利要求1所述的化合物或其药学上可接受的盐的制备方法，其合成路线如下：
Figure FDA0002493134940000032
Figure FDA0002493134940000041
6.一种药物组合物，包含有效剂量的权利要求1～4中任何一项所述的化合物或其药学上可接受的盐和药学上可接受的赋形剂。
7.权利要求1～4中任何一项所述的化合物或其药学上可接受的盐或权利要求6所述的药物组合物在制备PAK1抑制剂中的应用。
8.权利要求1～4中任何一项所述的化合物或其药学上可接受的盐或权利要求6所述的药物组合物在制备抗肿瘤药物中的应用。
9.如权利要求8所述的应用，其特征在于，所述的肿瘤为乳腺癌、胃癌。
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