CN113831353A - 一种vegfr3小分子抑制剂及其在抗肿瘤药物中的应用 - Google Patents

一种vegfr3小分子抑制剂及其在抗肿瘤药物中的应用 Download PDF

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CN113831353A
CN113831353A CN202110617650.0A CN202110617650A CN113831353A CN 113831353 A CN113831353 A CN 113831353A CN 202110617650 A CN202110617650 A CN 202110617650A CN 113831353 A CN113831353 A CN 113831353A
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欧阳亮
刘捷
张吉发
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Abstract

本发明涉及一种选择性VEGFR3抑制剂及其在抗三阴性乳腺癌药物中的应用，属于抗肿瘤药学技术领域。本发明解决的技术问题是提供一种作为VEGFR3选择性小分子抑制剂的化合物。该化合物包括如下所示的化合物及其药学上可接受的盐，本发明的化合物或其药学上可接受的盐，可以作为VEGFR3抑制剂，具有一定抗三阴性乳腺癌活性，能有效抑制三阴性乳腺癌细胞的生长和转移。

Description

一种VEGFR3小分子抑制剂及其在抗肿瘤药物中的应用
技术领域
本发明涉及一种VEGFR3小分子抑制剂及其在抗肿瘤药物中的应用，属于抗肿瘤药学技术领域。
背景技术
恶性肿瘤严重威胁人类的生命健康。三阴性乳腺癌(Triple-negative breastcancer,TNBC)约 占所有乳腺病理类型的12％-17％，与其他分子分型乳腺癌相比，其肿瘤异质性很高，临床上具有复发高、 转移早和预后差等特点。不仅如此，TNBC的雌激素受体(ER)、孕激素受体(PR)和原癌基因HER-2均为 阴性，致使内分泌治疗或抗HER-2靶向治疗的方案对之疗效甚微。目前晚期TNBC的主要治疗方法是化疗， 治疗的药物以传统的蒽环类、紫杉烷、铂类等药物为主。化疗虽然一定程度上延长了晚期TNBC患者的生 存，但是效果相对有限且毒副作用较强。诸多血管表皮生长因子受体家族(VEGFR1，2，3)抑制剂已用于 乳腺癌治疗，包括sorafenib，telatinib，cediranib，pazopanib，lucitanib，vandetanib，motesanib， lenvatinib等。联合特异性肿瘤免疫细胞治疗PD-1抑制剂pembrolizumab联合lenvatinib已用于早期 TNBC治疗。然而，以上的泛VEGFR抑制剂具有与机制相关的毒性，其中最常见的副作用是高血压、瘘管形 成和可逆性后部白质脑病综合征。因此，寻找更有效、安全的TNBC治疗药物以提高患者的生存率，改善 患者的生活质量具有重要的临床价值和社会意义。
沿淋巴管转移是中晚期TNBC最主要的扩散方式。淋巴管密度与淋巴结转移密切相关，与较差的无 瘤生存期和总生存期密切相关，且瘤内淋巴管或瘤周淋巴管在肿瘤扩散过程中起着关键作用。VEGFR3作为 血管内皮生长因子(VGEF)-C和-D的受体，是介导肿瘤淋巴管生成的重要分子，且在TNBC中过表达。在动 物体内实验中，通过VEGF-C或-D/VEGFR3复合物的异常信号已被证实是淋巴管基因和癌症免疫逃逸的驱动 因素。此外，也有研究证实针对淋巴组织的抗VEGFR3联合紫杉烷治疗TNBC患者可能会取得更好的效果。 因此，VEGFR3可能通过抑制淋巴管生成和血管生成或直接抑制肿瘤生长而成为TNBC的有效治疗靶点。
选择性VEGFR3抑制剂可能克服泛VEGFR抑制剂的副作用。一些含有不同化学骨架的VEGFR3选择 性抑制剂(MAZ51和SAR131675)已经被报道可以减少肿瘤的生长和转移，VEGFR3单抗IMC-3C5已应用于 乳腺癌治疗。到目前为止，FDA还没有批准VEGFR3选择性小分子抑制剂，因此有必要开发高选择性VEGFR3 抑制剂用于TNBC的治疗。
发明内容
本发明解决的技术问题是提供一种作为VEGFR3选择性抑制剂的新化合物。
本发明提供结构式如式I所示的化合物或其药学上可接受的盐：
Figure BDA0003098195480000021
其中，R1为
Figure BDA0003098195480000022
Figure BDA0003098195480000023
R11为氢、烷基、烷氧基、卤 素、N-甲基哌嗪或吗啉；m为1或2；
R2为
Figure BDA0003098195480000024
或氢；R3为
Figure BDA0003098195480000025
或氢；R4为
Figure BDA0003098195480000026
Figure BDA0003098195480000027
R41为氢、烷基、烷基、氰基、氧三氟甲基、三氟甲基或卤素；m 为1或2。
本发明还提供上述化合物或其药学上可接受的盐在制备三阴性乳腺癌TNBC治疗药物中的用途。
进一步的，所述三阴性乳腺癌TNBC治疗药物为VEGFR抑制剂。
进一步的，所述VEGFR抑制剂优选为VEGFR3选择性抑制剂类药物，其用途为用于TNBC转移相关 治疗。
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。
本发明制备的化合物或其药学上可接受的盐，可以作为VEGFR3选择性抑制剂，具有较明显的三阴 性乳腺癌治疗效果。
附图说明
图1A为化合物1-50在1μM下对VEGFR3激酶的体外抑制率柱形图。
图1B为化合物1-50对MDA-MB-231细胞的半数抑制率IC50柱形图。
图1C为化合物1-50在MDA-MB-436细胞的半数抑制率IC50柱形图。
图2A为斑马鱼卵用DMSO,38k和10处理48小时，共聚焦显微镜检测斑马鱼肠下血管长度(length of subintestinal vessels)的图片。
图2B为MDA-MB-231异种移植裸鼠模型通过口服给药38k或10，裸鼠肿瘤体积的变化图片。
图3A为乳腺癌肺转移裸鼠模型通过口服给药38k或10，裸鼠肺转移性结节变化图。
图3B为裸鼠肺部组织H&E染色结果图。
具体实施方式
本发明提供如式I所示的化合物：
Figure BDA0003098195480000031
其中，R1为
Figure BDA0003098195480000032
Figure BDA0003098195480000033
R11为氢、烷基、烷氧基、卤 素、N-甲基哌嗪或吗啉；m为1或2；
Figure BDA0003098195480000034
标识苯环或吡啶环上有m个取代基， 取代基的位置不限，可以为邻位、间位或者对位。
R2为
Figure BDA0003098195480000035
或氢。
R3为
Figure BDA0003098195480000036
或氢。
R4为
Figure BDA0003098195480000037
R41为氢、烷基、烷基、氰基、氧三氟甲基、三氟甲基或卤素；m为1或2。
本发明的优选结构通式对手性结构没有要求，可以为R型也可以为S型。优选如式I所示的结构， 即化学通式为
Figure BDA0003098195480000038
作为一个优选方案，R1为
Figure BDA0003098195480000039
R11为氰基，N-甲基哌嗪 或烷氧基；m为1；R2为氢；R3为氢；R4为
Figure BDA0003098195480000041
Figure BDA0003098195480000042
R41为氢、烷基、烷氧基、氰基、氧三氟甲基、三氟甲基或卤素；m为1或2。
进一步优选的，R1为
Figure BDA0003098195480000043
R11为氰基或N-甲基哌嗪；m为 1；
R4为
Figure BDA0003098195480000044
R41为氢、烷基、 烷氧基、氰基、氧三氟甲基、三氟甲基或卤素；m为1或2。
更优选R1为
Figure BDA0003098195480000045
R4为
Figure BDA0003098195480000046
R41为氢、氰基、氧三氟甲基、三 氟甲基或卤素；m为1或2；更优选R1为
Figure BDA0003098195480000047
R4为
Figure BDA0003098195480000048
下面是本发明的化合物的一些优选结构。
Figure BDA0003098195480000049
Figure BDA00030981954800000410
Figure BDA0003098195480000051
Figure BDA0003098195480000052
Figure BDA0003098195480000053
Figure BDA0003098195480000054
Figure BDA0003098195480000061
Figure BDA0003098195480000062
Figure BDA0003098195480000063
本发明还提供本发明所述的化合物的药学上可接受的盐。所述盐可以为硝酸盐、盐酸盐、硫酸盐 或磷酸盐等。
本发明还提供上述化合物或其药学上可接受的盐在制备治疗三阴性乳腺癌治疗药物中的用途。进 一步的，三阴性乳腺癌治疗药物优选为VEGFR抑制剂。进一步的，所述VEGFR抑制剂优选为VEGFR3选择 性抑制剂，用于三阴性乳腺癌的相关治疗。
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可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瓻中的粉 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，也可与其他抗三阴性乳腺癌化合物组 合作为活性成分。
在治疗三阴性乳腺癌时，可通过同时、序贯或单独给予各种治疗成分实现这种联合治疗。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。
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1-50的合成。
化合物1-21采用如下反应式合成：
Figure RE-GDA0003380904760000071
Figure BDA0003098195480000072
Regents and conditions:(a)1-Boc-piperazine,DMF,Et3N,90℃.；(b)boronicacid or boronic acid pinacol ester derivatives,Pd(PPh3)4,Cs2CO3,1,4-dioxane,100℃；(c)TFA,DCM,r.t.；(e) DCM,2-chloroethanesulfonyl chloride,Et3N,0℃；(e)tert-butyl(S)-3-methylpiperazine-1-carboxylate,DMF,Et3N,90℃；(f) 4-(4-Methyl-1-piperazinyl)phenylboronic acid pinacol ester,Pd(PPh3)4,Cs2CO3,1,4-dioxane,100 ℃。
中间体3制备。
将原料2溶于50ml DMSO中，然后加入1-Boc-哌嗪和DIEA在90℃条件下反应至完全，将反应液 倒入250ml水中，用二氯甲烷萃取(3×50ml)，合并有机相然后用饱和食盐水洗涤，最后无水硫酸钠干 燥。减压浓缩后得中间体3,黄色固体收率90％。
中间体(3)1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.33(s,1H),4.18–3.98(m,4H),3.87–3.66(m,4H),1.5(s,9H)。
化合物1-21和30合成通法。
将中间体3和碳酸铯溶于20ml二氧六环，加入硼酸衍生物和1mL水。在反应瓶中抽真空，注入 氩气(3次)，然后加入四三苯基磷钯。反应混合物在100℃下搅拌16h，然后冷却至室温。有机层在减压 下被过滤和浓缩，得到棕色固体。粗产物经硅胶(二氯甲烷/甲醇,30/1)柱层析纯化得中间体4a-4t，黄色 固体收率40％-60％。
中间体4a-4t用5ml二氯甲烷溶解，加入三氟乙酸2.5mL。将混合物在室温下搅拌6小时。用饱 和碳酸氢钠中和反应溶液，用二氯甲烷(3×30ml)萃取。分离出的有机层用饱和氯化钠水溶液洗涤，无 水硫酸钠干燥，减压浓缩成黄色固体。将以上黄色固体用3ml二氯甲烷溶解，并加入三乙胺，在0℃下加 入2-氯乙烷磺酰氯。室温搅拌30min后，真空蒸发反应混合物，粗产物经硅胶(二氯甲烷/甲醇,10/1) 柱层析纯化得到化合物1-21和30。以下为化合物1-21和30的核磁检测结果。
化合物1 1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.70–7.64(m,2H),7.46–7.39(m,3H), 6.48-6.42(m,1H),6.30(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.16–3.93(m,4H),3.42 –3.27(m,4H).13C NMR(101MHz,CDCl3)δ169.0(s),158.3(s),152.6(s),140.8(s),133.3(s), 132.0(s),129.7(s),129.2(s),129.0(s),126.5(s),118.5(s),114.8(s),46.9(s),45.4(s).HRMS (ESI)(m/z):(M+Na)+calcd for C18H18N4O2S2409.0763,found409.0771。
化合物2 1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.75(d,J＝3.9Hz,2H),7.54(s,1H),6.48 -6.42(m,1H),6.31(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.12–4.02(m,4H),3.46– 3.26(m,4H),1.62(s,3H).13C NMR(101MHz,DMSO)δ169.2(s),158.2(s),153.6(s),137.7(s),136.1 (s),133.5(s),133.0(s),130.3(s),127.2(s),120.3(s),119.1(s),117.7(s),111.2(s),46.4 (s),45.6(s)。
化合物3 1H NMR(400MHz,CDCl3)δ8.52(d,J＝10.1Hz,1H),7.44–7.34(m,2H),7.19- 7.17(m,1H),6.94(d,J＝8.2Hz,1H),6.48-6.42(m,1H),6.32-6.28(m,1H),6.10(d,J＝9.8 Hz,1H),4.04-4.02(m,4H),3.89(s,3H),3.84(d,J＝5.1Hz,2H),3.46–3.25(m,2H).13C NMR (101MHz,CDCl3)δ169.6(s),158.4(s),155.9(s),153.1(s),139.5(s),137.2(s),136.6(s),132.2 (s),132.1(s),128.6(s),128.5(s),118.99(s),118.13(s),115.41(s),118.6(s),116.5(s),55.9 (s),46.9(s),46.5(s),45.3(s),43.0(s)。
化合物4 1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.83–7.65(m,4H),7.51(s,1H),6.48 -6.42(m,1H),6.30(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.21–3.94(m,4H),3.48 –3.16(m,4H).13C NMR(101MHz,CDCl3)δ169.51,158.46,153.14,138.66,136.74,132.01,130.51, 129.73,126.68,126.21,126.17,122.58,118.21,116.46,46.85,45.34.HRMS(ESI)(m/z):(M+ Na)+calcd for C19H19F3N4O2S2477.0641,found 477.0637。
化合物5 1H NMR(400MHz,CDCl3)δ8.49(s,1H),7.59(d,J＝8.6Hz,2H),7.28(s,1H), 6.96(t,J＝13.2Hz,2H),6.45(dd,J＝16.6,9.8Hz,1H),6.30(d,J＝16.6Hz,1H),6.10(d, J＝9.8Hz,1H),4.12–3.98(m,4H),3.87(s,3H),3.43–3.24(m,4H).13C NMR(101MHz,CDCl3) δ160.35,158.06,152.22,140.91,132.01,129.66,127.82,125.93,114.61,113.38,55.46,46.86, 45.36.HRMS(ESI)(m/z):(M+Na)+calcd for C19H20N4O3S2440.0860,found 440.0822。
化合物6 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.42–7.28(m,2H),7.08-7.03(m,1H),6.48-6.41(m,1H),6.30(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.00–3.91(m,4H),3.33–3.29(m,4H).13C NMR(101MHz,DMSO)δ169.22,158.20,153.63,137.66,136.09,133.47,132.97,130.33,127.22,120.23,119.11,117.67,111.16,46.39,45.59.HRMS(ESI)(m/z): (M+Na)+calcd for C19H17N5O2S2434.0691,found 434.0716。
化合物7 1H NMR(400MHz,CDCl3)δ8.48(s,1H),7.87–7.41(m,4H),6.95(d,J＝8.5Hz,1H),6.57–6.39(m,1H),6.30(d,J＝16.6Hz,1H),6.09(d,J＝10.0Hz,1H),4.43– 3.73(m,8H),3.70–2.98(m,8H).13C NMR(101MHz,CDCl3)δ168.60,157.98,152.23,151.61,141.12,132.17,132.02,129.62,128.79,128.58,128.46,127.45,124.48,118.83,115.41,112.72, 66.73,48.57,46.86,45.37.HRMS(ESI)(m/z):(M+Na)+calcd forC22H25N5O3S2494.1321,found 494.1291。
化合物8 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.55(d,J＝8.8Hz,2H),7.25(s,1H), 6.95(d,J＝8.8Hz,2H),6.48-6.41(m,1H),6.29(d,J＝16.6Hz,1H),6.09(d,J＝9.9Hz, 1H),4.11–3.94(m,4H),3.38–3.24(m,8H),2.69–2.51(m,4H),2.37(s,3H).13C NMR(101 MHz,CDCl3)δ168.60,157.95,152.20,151.53,141.22,132.01,129.62,127.39,124.02,118.86, 115.65,112.56,54.86,48.25,46.84,46.10,45.37.HRMS(ESI)(m/z):(M+H)+calcd for C23H28N6O2S2 485.1763,found 485.1788。
化合物9 1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.70(d,J＝8.3Hz,2H),7.56–7.45(m,3H),6.48-6.42(m,1H),6.30(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.20–3.97 (m,4H),3.94–3.43(m,4H),3.40–3.21(m,4H),2.51-2.39(m,4H),2.34(s,3H).13C NMR(101MHz,CDCl3)δ169.46,165.72,164.72,162.31,158.36,153.18,145.30,145.15,139.11, 139.03,134.75,128.93,127.93,127.88,126.96,117.83,116.77,110.28,109.90,47.10,46.15, 45.13,41.38.HRMS(ESI)(m/z):(M+H)+calcd forC24H28N6O3S2513.1730,found 513.1713。
化合物10 1H NMR(400MHz,CDCl3)δ8.53(s,1H),8.09(s,1H),7.97–7.73(m,4H),7.58 –7.48(m,3H),6.49-6.42(m,1H),6.31(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.15 –4.00(m,4H),3.45–3.29(m,4H).13C NMR(101MHz,CDCl3)δ169.20,158.28,152.74,140.80, 133.45,133.33,132.03,130.61,129.68,128.98,128.23,127.83,127.06,126.88,125.68,123.85, 118.57,115.11,46.89,45.38.HRMS(ESI)(m/z):(M+Na)+calcdfor C22H20N4O2S2459.0919,found 459.0920。
化合物11 1H NMR(400MHz,CDCl3)δ8.99(dd,J＝4.1,1.5Hz,1H),8.59(s,1H),8.49(d,J＝8.5Hz,1H),8.22(d,J＝8.5Hz,1H),7.83–7.75(m,1H),7.54(dd,J＝7.4,1.4Hz,2H),7.35(s,1H),6.43(dd,J＝16.6,9.8Hz,1H),6.28(d,J＝16.6Hz,1H),6.08(d,J＝9.8Hz,1H),4.08–4.00(m,4H),3.39–3.28(m,4H).13C NMR(101MHz,CDCl3)δ170.05,158.50,152.97,150.76,148.37,137.13,133.56,132.16,132.06,132.01,131.98,131.71,130.87,129.67, 128.99,128.88,128.58,128.46,126.95,121.87,120.02,117.71,46.85,45.34.HRMS(ESI)(m/z): (M+H)+calcd for C21H20N5O2S2438.1060,found 438.1053。
化合物12 1H NMR(400MHz,CDCl3)δ8.53(s,1H),8.06(d,J＝8.2Hz,1H),7.96(d,J＝7.6Hz,2H),7.91–7.83(m,2H),7.59(t,J＝7.4Hz,1H),7.49(t,J＝7.7Hz,2H),7.44 (s,1H),7.43–7.34(m,2H),6.46(dd,J＝16.6,9.8Hz,1H),6.30(d,J＝16.6Hz,1H),6.10 (d,J＝9.8Hz,1H),4.12–3.96(m,4H),3.41–3.27(m,4H).13C NMR(101MHz,CDCl3)δ168.83,158.15,152.76,137.77,135.29,134.32,132.01,131.55,129.72,129.55,128.21,126.96,125.78, 124.26,124.06,120.24,117.87,116.61,116.45,113.95,53.48,46.84,45.37.HRMS(ESI)(m/z): (M+Na)+calcd for C26H23N5O4S3588.0794,found 588.0804。
化合物13 1H NMR(400MHz,CDCl3)δ8.81(d,J＝5.1Hz,1H),8.55(d,J＝5.9Hz,2H),7.94–7.88(m,1H),7.71(s,1H),6.49-6.42(m,1H),6.31(d,J＝16.6Hz,1H),6.11(d, J＝9.8Hz,1H),4.24–4.04(m,4H),3.49–3.23(m,4H).13C NMR(101MHz,CDCl3)δ169.73,158.51,153.37,148.49,145.03,132.16,132.06,131.96,128.57,128.45,117.98,117.34,46.86, 45.33.HRMS(ESI)(m/z):(M+Na)+calcd for C17H16ClN5O2S2444.0362,found444.0326。
化合物14 1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.47(d,J＝2.3Hz,1H),7.83(dd,J＝8.6,2.5Hz,1H),7.31(s,1H),6.84(d,J＝8.6Hz,1H),6.45(dd,J＝16.6,9.8Hz,1H),6.30(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.09–4.01(m,4H),3.99(s,3H),3.39 –3.29(m,4H).13C NMR(101MHz,CDCl3)δ169.08,164.47,158.20,152.71,144.79,137.35,136.64, 132.00,129.69,123.00,118.39,114.49,111.38,53.83,46.85,45.35.HRMS(ESI)(m/z):(M+Na)+ calcd for C18H19N5O3S2440.0866,found 440.0822。
化合物15 1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.53(d,J＝1.2Hz,1H),8.07–7.98(m,1H),7.43(s,1H),7.06(dd,J＝8.4,2.9Hz,1H),6.45(dd,J＝16.6,9.8Hz,1H),6.31 (d,J＝16.6Hz,1H),6.11(d,J＝9.7Hz,1H),4.16–3.98(m,4H),3.46–3.28(m,4H).13C NMR(101MHz,DMSO)δ168.91,158.14,153.37,145.55,145.40,140.34,140.26,133.54,132.97,130.33,128.19,119.13,117.61,110.77,110.39,46.42,45.62.HRMS(ESI)(m/z):(M+Na)+calcd for C17H16FN5O2S2428.0591,found 428.0622。
化合物16 1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.24(s,1H),8.11(dd,J＝8.4,2.2Hz,1H),7.74(s,1H),6.45(dd,J＝16.6,9.7Hz,1H),6.31(d,J＝16.6Hz,1H),6.10(d,J ＝9.8Hz,1H),4.20–3.99(m,4H),3.41–3.20(m,4H).13C NMR(101MHz,CDCl3)δ169.53,158.57,153.68,147.30,147.13,141.01,140.97,132.06,132.06,132.03,129.81,129.75,128.58, 120.99,120.88,117.72,117.12,117.08,46.85,45.31.HRMS(ESI)(m/z):(M+Na)+calcd for C17H15BrFN5O2S2505.9730,found 505.9727。
化合物17 1H NMR(400MHz,DMSO)δ8.47(s,1H),8.44(s,1H),7.58(s,1H),6.85(dd, J＝16.5,10.0Hz,1H),6.18(dd,J＝16.9,13.3Hz,2H),3.99(s,3H),3.97(d,J＝5.2Hz, 2H),3.31(d,J＝9.5Hz,2H),3.26–3.21(m,3H),2.52–2.48(m,3H).13C NMR(101MHz,DMSO) δ168.85,158.00,153.22,136.69,134.41,132.97,130.30,126.66,123.23,120.56,120.12,117.05, 113.59,46.38,45.49.HRMS(ESI)(m/z):(M+Na)+calcd forC17H17F3N6O2S2481.0699,found 481.0699。
化合物18 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.81(s,1H),7.64(s,1H),7.42–7.31 (m,5H),7.13(s,1H),6.47-6.41(m,1H),6.31-6.27(m,1H),6.09(d,J＝9.8Hz,1H),5.35 (s,2H),4.08–3.93(m,4H),3.45–3.22(m,4H).13C NMR(101MHz,DMSO)δ168.34,157.89, 152.34,137.26,135.75,132.01,131.91,129.64,129.04,128.77,128.49,127.92,118.26,116.70, 113.90,113.51,56.49,46.80,45.34.HRMS(ESI)(m/z):(M+H)+calcd for C22H22N6O2S2489.1150,found 489.1138。
化合物19 1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.14(s,1H),6.47-6.41(m,1H),6.27 (d,J＝16.6Hz,1H),6.09(d,J＝9.8Hz,1H),4.19-3.94(m,4H),3.51-3.24(m,4H),2.53 (s,3H),2.36(s,3H).13C NMR(101MHz,CDCl3)δ169.49,167.00,158.35,158.25,152.90,132.03, 129.68,128.32,118.60,117.55,110.11,46.82,45.29,12.12,11.15.HRMS(ESI)(m/z):(M+Na)+ calcd for C17H19N5O3S2428.0823,found 428.0822。
化合物20 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.34(d,J＝5.1Hz,1H),7.30–7.27(m,1H,7.25(s,1H),7.08(dd,J＝5.0,3.7Hz,1H),6.45(dd,J＝16.6,9.9Hz,1H),6.29(d, J＝16.6Hz,1H),6.09(d,J＝9.9Hz,1H),4.07–3.88(m,4H),3.37–3.21(m,4H).13C NMR(101MHz,CDCl3)δ168.80,158.02,152.77,136.27,133.86,132.02,129.67,128.25,126.24, 125.87,118.08,114.87,46.77,45.34.HRMS(ESI)(m/z):(M+H)+calcd forC16H16N4O2S3415.0329, found 415.0328。
化合物21 1H NMR(400MHz,CDCl3)δ8.46(s,1H),6.96(s,1H),6.47-6.40(m,1H),6.30 (t,J＝10.9Hz,2H),6.09(d,J＝9.8Hz,1H),3.99–3.94(m,4H),3.34–3.29(m,4H),2.53 –2.39(m,2H),2.32–2.19(m,2H),1.85–1.78(m,2H),1.72-1.69(m,2H).13C NMR(101MHz,CDCl3)δ168.07,157.89,152.47,143.27,132.00,130.80,129.61,128.77,118.13,112.63, 46.76,45.32,26.74,25.85,22.43,21.91.HRMS(ESI)(m/z):(M+Na)+calcd forC18H22N4O2S2413.1071, found 413.1076。
化合物30 1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.54(d,J＝8.7Hz,2H),7.23(s,1H), 6.96(d,J＝8.7Hz,2H),6.43(dd,J＝16.6,9.9Hz,1H),6.27(d,J＝16.6Hz,1H),6.07(d, J＝9.9Hz,1H),4.95(d,J＝3.0Hz,1H),4.53(d,J＝13.6Hz,1H),3.84–3.53(m,3H),3.37 –3.22(m,4H),3.04–2.79(m,2H),2.67–2.49(m,4H),2.37(s,3H),1.52(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ168.72,157.77,152.21,151.53,140.77,132.03,129.42,127.35, 124.07,118.61,115.65,112.77,54.89,49.96,49.52,48.32,46.15,45.56,40.94,15.35.HRMS (ESI)(m/z):(M+H)+calcd for C24H30N6O2S2499.1928,found 499.1944。
化合物22-29和化合物48-50的合成通法：
Figure RE-GDA0003380904760000111
Regents and conditions:(a) 1-Boc-piperazine/(S)-tert-Butyl-3-ethylpiperazine-1-carboxylate,THF,DIEA,r.t.；(b) N-methyl-L-prolinol/1-methyl-2-piperidinemethanol,THF,NaH,0℃-80℃ reflux；(c) 4-fluorobenzonitrile/2-methoxy-5-iodopyridine/1-(4-iodophenyl)-4-methylpiperazine,Pd(PPh3)4, AgOAc,cyclopentyl methyl ether,100℃；(d)TFA,DCM,r.t.；(e)DCM,sulfonyl chlorideanalogues/acryloyl chloride,Et3N,0℃；(f)DCM,sulfonyl chloride analogues/acryloyl chloride, Et3N,0℃。
将原料8、1-Boc-哌嗪和三乙胺加入反应瓶中，四氢呋喃(300ml)溶解并在室温下搅拌12h。反应 完全后加入水并用乙酸乙酯提取(3×150毫升)，将有机层结合，用200mL饱和食盐水溶液洗涤，用无水 硫酸钠干燥。经减压浓缩处理后，获得的中间体9a-9b为翠绿色固体，收率为90-95％。
化合物9a或9b、4-碘苯腈/5-碘-2-甲氧基吡啶/1-(4-碘苯基)-4-甲基哌嗪、Pd(PPh3)4和醋酸银(I) 用环戊基甲基醚(10mL)溶解。反应混合物在氩气气氛下，100℃下搅拌16h，真空蒸发干燥，得到粗产物， 经硅胶层析(二氯甲烷/甲醇,10/1)纯化得到化合物10a-10d为黄色固体，收率为40-50％。
中间体10a-10d用5ml二氯甲烷溶解，加入三氟乙酸2.5mL。将混合物在室温下搅拌6小时。用 饱和碳酸氢钠中和反应溶液，用二氯甲烷(3×30ml)萃取。分离出的有机层用饱和氯化钠水溶液洗涤， 无水硫酸钠干燥，减压浓缩成黄色固体。将以上黄色固体用3ml二氯甲烷溶解，并加入三乙胺，在0℃下 加入磺酰氯衍生物。室温搅拌30min后，真空蒸发反应混合物，粗产物经硅胶(二氯甲烷/甲醇,10/1)柱 层析纯化得到化合物22-29和48-50。以下为化合物22-29和48-50的核磁检测结果。
化合物22 1H NMR(400MHz,CDCl3)δ7.70(s,4H),7.47(s,1H),6.45(dd,J＝16.6,9.8 Hz,1H),6.30(d,J＝16.6Hz,1H),6.11(d,J＝9.8Hz,1H),4.44(dd,J＝10.6,5.0Hz,1H), 4.25(dd,J＝10.6,6.4Hz,1H),4.05(t,J＝5.1Hz,4H),3.33(t,J＝5.1Hz,4H),3.12(dd, J＝8.8,6.6Hz,1H),2.50(s,3H),2.31(td,J＝9.4,7.1Hz,1H),2.14–2.00(m,1H),1.91 –1.73(m,2H).13C NMR(101MHz,CDCl3)δ172.26,161.82,159.76,136.01,134.36,132.84,132.02, 129.73,126.29,118.52,117.23,113.50,111.43,69.68,62.85,57.18,46.69,45.31,43.64,29.43, 25.54,23.83.HRMS(ESI)(m/z):(M+H)+calcd forC25H28N6O3S2525.1746,found 525.1737。
化合物23 1H NMR(400MHz,CDCl3)δ7.70(s,4H),7.47(s,1H),6.45(dd,J＝16.6,9.8 Hz,1H),6.31(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.50(dd,J＝11.1,4.3Hz,1H), 4.36(dd,J＝11.1,5.0Hz,1H),4.05(t,J＝5.1Hz,4H),3.33(t,J＝5.0Hz,4H),2.98–2.84(m,1H),2.40(s,3H),2.37–2.26(m,1H),2.15(td,J＝11.2,4.5Hz,1H),1.67–1.46 (m,4H),1.39–1.21(m,2H).13C NMR(101MHz,CDCl3)δ172.26,161.82,159.76,136.01,134.36,132.84,132.02,129.73,126.29,118.52,117.23,113.50,111.43,69.68,62.85,57.18,46.69,45.31, 43.64,29.43,25.54,23.83.HRMS(ESI)(m/z):(M+H)+calcd forC26H30N6O3S2539.1903,found 539.1894。
化合物24 1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.1Hz,2H),7.47(d,J＝8.1Hz,2H),7.39(s,1H),6.48-6.41(m,1H),6.30(d,J＝16.6Hz,1H),6.10(d,J＝9.8Hz,1H),4.46 -4.42(m,1H),4.26-4.22(m,1H),4.12–3.96(m,4H),3.93–3.64(m,4H),3.48(s,4H), 3.37–3.25(m,4H),3.12(t,J＝7.7Hz,1H),2.79–2.63(m,1H),2.51(s,3H),2.33(s, 3H),2.13–1.80(m,5H).13C NMR(101MHz,CDCl3)δ171.92,169.59,161.69,159.59,135.82, 135.41,135.06,132.14,131.98,129.73,128.71,128.59,128.04,127.76,127.40,126.00,115.60,113.55,70.09,64.06,57.66,46.67,45.34,41.70,29.70,29.01,22.95.HRMS(ESI)(m/z):(M+ H)+calcd for C30H39N7O4S2626.2587,found 626.2578。
化合物25 1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.2Hz,2H),7.47(d,J＝8.0Hz,2H),7.37(s,1H),6.43(dd,J＝16.6,9.8Hz,1H),6.28(d,J＝16.5Hz,1H),6.08(d,J＝9.9Hz,1H),4.60(d,J＝13.7Hz,1H),4.43(dt,J＝10.5,4.7Hz,1H),4.22(ddd,J＝10.1,6.6,3.2Hz,1H),3.89–3.33(m,10H),3.26–2.66(m,6H),2.50(s,3H),2.33(s,3H),2.12–1.94 (m,2H),1.52(t,J＝6.9Hz,3H),1.34–1.23(m,3H).13C NMR(101MHz,CDCl3)δ172.12,169.60,161.72,159.31,135.44,135.36,135.14,132.03,129.51,128.04,125.96,115.80,113.30,70.13, 64.04,57.67,49.94,49.42,46.05,45.53,41.72,40.90,29.70,29.07,22.98,15.45.HRMS(ESI) (m/z):(M+H)+calcd for C31H41N7O4S2640.2734,found 640.2734。
化合物26 1H NMR(400MHz,CDCl3)δ8.41(d,J＝2.4Hz,1H),7.79-7.77(m,1H),7.22(s,1H),6.81(d,J＝8.6Hz,1H),6.48-6.41(m,1H),6.30(d,J＝16.6Hz,1H),6.10(d,J ＝9.8Hz,1H),4.49–4.39(m,1H),4.29–4.20(m,1H),4.04–4.00(m,4H),3.98(s,3H), 3.34–3.30(m,4H),3.12(t,J＝7.6Hz,1H),2.74-2.67(m,1H),2.50(s,3H),2.35–2.26 (m,1H),1.95–1.81(m,4H).13C NMR(101MHz,DMSO)δ170.72,163.78,161.51,159.14,144.43,137.12,132.95,131.66,130.29,123.64,117.05,113.25,111.28,64.07,57.43,53.90,46.30,45.60, 41.65,28.84,22.97.HRMS(ESI)(m/z):(M+H)+calcd forC24H30N6O4S2531.1849,found 531.1843。
化合物27 1H NMR(400MHz,CDCl3)δ7.50(d,J＝8.7Hz,2H),7.27(s,1H),6.94(d,J＝8.8Hz,2H),6.44(dd,J＝16.6,9.8Hz,1H),6.29(d,J＝16.6Hz,1H),6.09(d,J＝9.8Hz,1H),4.43(dd,J＝10.6,4.9Hz,1H),4.23(dd,J＝10.6,6.5Hz,1H),4.07–3.92(m,4H),3.38–3.23(m,8H),3.17-3.09(m,1H),2.73-2.66(m,1H),2.62–2.56(m,4H),2.49(s, 3H),2.36(s,3H),2.11–1.99(m,1H),1.83–1.72(m,4H).13C NMR(101MHz,CDCl3)δ171.13,161.27,159.19,151.20,137.60,132.01,129.62,127.01,124.58,115.76,113.89,112.58,69.92, 64.08,57.65,54.90,48.45,46.67,46.12,45.37,41.65,29.02,22.93.HRMS(ESI)(m/z):(M+ H)+calcd for C29H39N7O3S2598.2588,found 598.2629。
化合物28 1H NMR(400MHz,CDCl3)δ7.49(d,J＝8.8Hz,2H),7.16(s,1H),6.94(d,J＝8.8Hz,2H),6.43(dd,J＝16.6,9.9Hz,1H),6.28(d,J＝16.6Hz,1H),6.08(d,J＝9.9Hz,1H),4.57(d,J＝13.1Hz,1H),4.42(dd,J＝10.6,4.9Hz,1H),4.21(dd,J＝10.6,6.6Hz,1H),3.80–3.50(m,4H),3.30–3.25(m,4H),3.11(t,J＝7.6Hz,1H),3.01–2.91(m,1H),2.86-2.79(m,1H),2.74–2.66(m,1H),2.61–2.57(m,4H),2.50(s,3H),2.37(s,3H), 2.30(dd,J＝16.9,9.2Hz,2H),2.09-2.03(m,2H),1.89–1.78(m,3H),1.51(d,J＝6.8 Hz,3H).13CNMR(101MHz,CDCl3)δ171.30,161.22,158.93,151.16,137.21,132.03,129.43,126.97,124.67,115.79,113.64,112.83,69.72,64.20,57.60,54.89,49.96,49.33,48.46,45.57,41.63, 40.80,29.71,28.99,22.90,15.41.HRMS(ESI)(m/z):(M+H)+calcd forC31H43N7O3S2612.2801,found 612.2748。
化合物29 1H NMR(400MHz,CDCl3)δ7.26–7.17(m,1H),7.15–7.05(m,1H),6.62–6.39(m,1H),6.28(d,J＝16.6Hz,1H),6.18–6.05(m,1H),4.47–4.28(m,1H),4.25– 4.10(m,1H),4.08–3.91(m,6H),3.90–3.73(m,2H),3.37–3.22(m,2H),1.96–1.75 (m,2H),1.48–1.37(m,1H),1.20(d,J＝3.3Hz,1H),1.11–0.99(m,2H),0.93–0.79(m, 2H).13C NMR(101MHz,CDCl3)δ172.17,161.74,159.77,132.01,129.62,119.64,119.56,112.24,70.08,64.06,57.67,46.56,45.35,41.68,29.06,22.94.HRMS(ESI)(m/z):(M+H)+calcdfor C18H25N5O3S2424.1476,found 424.1472。
化合物48 1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.54(d,J＝8.7Hz,2H),7.32(s,1H), 6.95(d,J＝8.8Hz,2H),4.12–3.91(m,4H),3.71–3.53(m,4H),3.42–3.24(m,6H),2.70–2.54(m,4H),2.37(s,3H),1.18(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ168.62,158.06, 157.56,152.42,139.85,127.46,118.34,116.54,113.84,54.11,47.34,46.31,44.83,42.91,35.84, 29.61,29.33,27.23,15.60.HRMS(ESI)(m/z):(M+Na)+calcd forC25H33N7OS 466.2357,found 466.2384。
化合物49 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.55(d,J＝8.2Hz,2H),7.38(d,J＝7.8Hz,2H),7.33(s,1H),7.30(d,J＝7.2Hz,1H),7.07(t,J＝6.6Hz,2H),6.95(d,J＝8.2Hz,2H),6.47(s,1H),4.15–3.96(m,4H),3.76–3.70(m,4H),3.37–3.20(m,4H), 2.69–2.53(m,4H),2.37(s,3H).13C NMR(101MHz,CDCl3)δ167.71,157.81,155.92,151.80,151.22,140.43,138.96,138.93,128.85,128.74,127.26,124.26,123.36,122.79,120.70,119.35, 118.45,115.82,113.34,54.64,48.00,46.32,45.74,43.16.HRMS(ESI)(m/z):(M+H)+calcd for C28H31N7OS 514.2382,found 514.2384。
化合物50 1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.54(d,J＝8.3Hz,2H),7.33(s,1H), 7.27–7.19(m,2H),6.95(d,J＝8.4Hz,2H),6.85(d,J＝8.5Hz,2H),6.42(s,1H),4.15–3.96(m,4H),3.78(s,3H),3.76–3.70(m,4H),3.37–3.20(m,4H),2.69–2.53(m,4H), 2.37(s,3H).13C NMR(101MHz,CDCl3)δ168.43,157.92,156.18,155.59,152.23,151.43,140.44,131.60,127.31,124.21,122.73,118.47,115.68,114.20,113.19,55.50,54.88,48.30,46.28,46.11, 43.18.HRMS(ESI)(m/z):(M+H)+calcd for C29H33N7OS 544.2492,found544.2489。
化合物31-34和化合物35-47的合成通法。
Figure RE-GDA0003380904760000131
Regents and conditions:(a)TFA,DCM,r.t.；(b)DCM,sulfonyl chlorideanalogues/acryloyl chloride,Et3N,0℃；(c)CH3CN,isocyanate derivatives,Et3N,80℃,reflux。
化合物31-34合成方法。
中间体4e用5ml二氯甲烷溶解，加入三氟乙酸2.5mL。将混合物在室温下搅拌6小时。用饱和碳 酸氢钠中和反应溶液，用二氯甲烷(3×30ml)萃取。分离出的有机层用饱和氯化钠水溶液洗涤，无水硫 酸钠干燥，减压浓缩成黄色固体5e。将以上黄色固体用3ml二氯甲烷溶解，并加入三乙胺，在0℃下加入 磺酰氯衍生物。室温搅拌30min后，真空蒸发反应混合物，粗产物经硅胶(二氯甲烷/甲醇,10/1)柱层析 纯化得到化合物31-34。以下为化合物31-34的核磁检测结果。
化合物31 1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.60–7.46(m,5H),7.41(d,J＝6.6Hz,2H),7.24(s,1H),6.94(d,J＝8.8Hz,2H),6.68(d,J＝15.5Hz,1H),4.02(t,J＝5.0 Hz,4H),3.38(t,J＝5.0Hz,4H),3.28(t,J＝5.0Hz,4H),2.58(t,J＝5.0Hz,4H),2.36(s, 3H).13C NMR(101MHz,CDCl3)δ168.61,157.93,152.22,151.47,144.38,141.13,132.29,131.24, 129.17,128.38,127.40,124.13,120.60,118.81,115.69,112.63,54.82,48.21,46.83,46.03,45.51. HRMS(ESI)(m/z):(M+H)+calcd for C29H32N6O2S2561.2099,found561.2101。
化合物32 1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.46(d,J＝8.3Hz,2H),7.18(s,1H), 6.87(d,J＝8.3Hz,2H),3.91(t,J＝4.9Hz,4H),3.30(dt,J＝67.5,4.9Hz,8H),2.92(q, J＝7.4Hz,2H),2.51(s,4H),2.29(s,3H),1.32(t,J＝7.4Hz,3H).13C NMR(101MHz,CDCl3) δ168.65,158.05,152.24,151.49,141.17,127.40,124.11,118.88,115.69,112.63,54.84,48.23, 47.33,46.06,45.60,44.11,7.81.HRMS(ESI)(m/z):(M+H)+calcdfor C23H30N6O2S2487.1943,found 487.1944。
化合物33 1H NMR(400MHz,CDCl3)δ8.48(s,1H),7.55(d,J＝8.8Hz,2H),7.27(s,1H), 6.96(d,J＝8.8Hz,2H),4.04–3.86(m,4H),3.46–3.37(m,4H),3.34–3.24(m,8H),2.67–2.56(m,4H),2.39(s,3H),1.69–1.51(m,6H).13C NMR(101MHz,CDCl3)δ168.65,158.10,152.22,151.51,140.98,127.36,124.07,118.83,115.63,112.75,54.88,48.30,47.39,46.92,46.19, 25.57,23.78.HRMS(ESI)(m/z):(M+H)+calcd for C26H35N7O2S2542.2360,found 542.2366。
化合物34 1H NMR(400MHz,CDCl3)δ8.49(s,1H),7.56(d,J＝8.7Hz,2H),7.27(s,1H), 6.96(d,J＝8.7Hz,2H),4.07–3.97(m,4H),3.52–3.41(m,4H),3.35–3.24(m,4H),2.65–2.56(m,4H),2.37(s,3H),2.33-2.25(s,1H),1.27–1.14(m,2H),1.08–0.94(m,2H). 13CNMR(101MHz,CDCl3)δ168.50,157.90,152.17,151.50,140.99,127.33,123.91,118.77,115.56, 112.66,54.86,48.24,46.96,46.16,45.93,25.50,4.42.HRMS(ESI)(m/z):(M+H)+calcd for C24H30N6O2S2499.1941,found 499.1944。
化合物35-47合成方法。
将化合物5e、异氰酸乙酯和三乙胺的混合物溶于乙腈中，80℃搅拌过夜。反应混合物在真空中浓 缩，残渣经硅胶层析(二氯甲烷/甲醇,10/1)纯化得到所需化合物35-47。以下为化合物35-47的核磁检测 结果。
化合物35 1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.54(d,J＝8.7Hz,2H),7.32(s,1H), 6.95(d,J＝8.8Hz,2H),4.12–3.91(m,4H),3.71–3.53(m,4H),3.42–3.24(m,6H),2.70–2.54(m,4H),2.37(s,3H),1.18(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ168.62,158.06, 157.56,152.42,139.85,127.46,118.34,116.54,113.84,54.11,47.34,46.31,44.83,42.91,35.84, 29.61,29.33,27.23,15.60.HRMS(ESI)(m/z):(M+Na)+calcd forC25H33N7OS 466.2357,found 466.2384。
化合物36 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.55(d,J＝8.2Hz,2H),7.38(d,J＝7.8Hz,2H),7.33(s,1H),7.30(d,J＝7.2Hz,1H),7.07(t,J＝6.6Hz,2H),6.95(d,J＝8.2Hz,2H),6.47(s,1H),4.15–3.96(m,4H),3.76–3.70(m,4H),3.37–3.20(m,4H), 2.69–2.53(m,4H),2.37(s,3H).13C NMR(101MHz,CDCl3)δ167.71,157.81,155.92,151.80,151.22,140.43,138.96,138.93,128.85,128.74,127.26,124.26,123.36,122.79,120.70,119.35, 118.45,115.82,113.34,54.64,48.00,46.32,45.74,43.16.HRMS(ESI)(m/z):(M+H)+calcd for C28H31N7OS 514.2382,found 514.2384。
化合物37 1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.54(d,J＝8.3Hz,2H),7.33(s,1H), 7.27–7.19(m,2H),6.95(d,J＝8.4Hz,2H),6.85(d,J＝8.5Hz,2H),6.42(s,1H),4.15–3.96(m,4H),3.78(s,3H),3.76–3.70(m,4H),3.37–3.20(m,4H),2.69–2.53(m,4H), 2.37(s,3H).13C NMR(101MHz,CDCl3)δ168.43,157.92,156.18,155.59,152.23,151.43,140.44,131.60,127.31,124.21,122.73,118.47,115.68,114.20,113.19,55.50,54.88,48.30,46.28,46.11, 43.18.HRMS(ESI)(m/z):(M+H)+calcd for C29H33N7OS 544.2492,found544.2489。
化合物38 1H NMR(400MHz,CDCl3)δ8.42(s,1H),7.91(s,1H),7.60–7.55(m,4H),7.54 (d,J＝8.8Hz,2H),7.33(s,1H),6.95(d,J＝8.8Hz,2H),4.07–3.97(m,4H),3.84–3.74(m,4H),3.73–3.48(m,4H),3.30(dd,J＝10.8,5.8Hz,4H),2.39(s,3H).13C NMR(101MHz,CDCl3)δ167.93,157.82,154.75,151.88,151.32,143.93,140.65,133.22,133.04,127.29,124.14, 119.50,119.30,118.53,118.49,115.78,113.14,105.18,54.70,48.03,46.35,45.86,43.33.HRMS (ESI)(m/z):(M+H)+calcd for C29H30N8OS 539.2309,found 539.2336。
化合物39 1H NMR(400MHz,DMSO)δ8.75(s,1H),8.39(s,1H),7.76(s,1H),7.67(d,J＝8.8Hz,2H),7.54(d,J＝8.9Hz,2H),7.30(d,J＝8.9Hz,2H),7.01(d,J＝8.9Hz,2H),4.07–3.92(m,4H),3.75–3.64(m,4H),3.27–3.19(m,4H),2.70-2.50(m,4H),2.25(s, 3H).13C NMR(101MHz,CDCl3)δ167.93,157.76,155.28,152.53,151.51,139.99,138.80,128.66, 127.48,125.83,123.47,121.49,118.11,115.53,114.88,54.85,47.81,46.42,46.16,43.65.HRMS (ESI)(m/z):(M+H)+calcd for C28H30ClN8OS 548.1984,found548.1994。
化合物40 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.54(d,J＝8.7Hz,2H),7.41(d,J＝8.9Hz,2H),7.33(s,1H),7.16(d,J＝8.6Hz,2H),6.95(d,J＝8.7Hz,2H),6.57(s,1H),4.14–3.99(m,4H),3.92–3.66(m,4H),3.38–3.17(m,4H),2.59(dd,J＝17.5,12.7Hz, 4H),2.38(s,3H).13C NMR(101MHz,CDCl3)δ167.88,157.86,155.58,151.86,151.27,144.58,140.59,137.88,127.29,124.26,121.52,121.47,118.52,115.84,113.25,54.67,48.02,46.38, 45.78,43.20.HRMS(ESI)(m/z):(M+H)+calcd for C29H30F3ClN8O2S 598.2199,found598.2207。
化合物41 1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.10(t,J＝8.1Hz,1H),7.55(d,J＝8.7Hz,2H),7.34(s,1H),7.16–7.04(m,2H),7.03–6.91(m,3H),6.64(d,J＝3.5Hz, 1H),4.18–3.99(m,4H),3.88–3.66(m,4H),3.38–3.20(m,4H),2.68–2.46(m,4H), 2.37(s,3H).13C NMR(101MHz,CDCl3)δ168.49,157.90,154.30,153.88,152.25,151.45,140.57,127.33,127.23,127.13,124.61,124.58,124.20,123.31,123.23,121.63,118.50,115.68,114.79, 114.60,113.09,54.89,48.32,46.22,46.14,43.16.HRMS(ESI)(m/z):(M+H)+calcd for C28H30FClN8OS 532.2286,found 532.2289。
化合物42 1H NMR(400MHz,DMSO)δ8.83(s,1H),8.39(s,1H),7.76(s,1H),7.66(d,J＝8.7Hz,2H),7.53–7.43(m,1H),7.33–7.22(m,2H),7.01(d,J＝8.8Hz,2H),6.81– 6.71(m,1H),4.08–3.93(m,4H),3.77–3.61(m,4H),3.28–3.13(m,4H),2.48–2.40 (m,4H),2.23(s,3H).13C NMR(101MHz,DMSO)δ167.71,163.84,161.45,157.76,155.17,152.53, 151.55,143.00,138.82,130.34,130.25,127.48,123.44,118.11,115.51,114.86,108.59,108.38,106.57,106.31,54.91,47.87,46.41,46.24,43.65.HRMS(ESI)(m/z):(M+H)+calcd forC28H30FClN8OS 532.2285,found 532.2289。
化合物43 1H NMR(400MHz,CDCl3)δ8.47(s,1H),8.17-8.14(m,1H),7.55(d,J＝8.8Hz,2H),7.34(s,1H),7.14(s,1H),7.01-6.94(m,4H),6.90–6.83(m,1H),4.14–4.02 (m,4H),3.90(s,3H),3.82–3.72(m,4H),3.35–3.25(m,4H),2.66–2.53(m,4H),2.36 (s,3H).13CNMR(101MHz,CDCl3)δ168.48,157.92,154.63,152.27,151.45,147.68,140.42,128.48,127.31,124.22,122.39,121.26,119.12,118.47,115.66,113.20,109.79,55.81,55.78,54.92, 48.37,46.29,46.19,43.04.HRMS(ESI)(m/z):(M+H)+calcd for C29H33N7OS544.2486,found 544.2489。
化合物44 1H NMR(400MHz,CDCl3)δ8.47(s,1H),8.03-7.97(m,1H),7.55(d,J＝8.7Hz,2H),7.33(s,1H),6.95(d,J＝8.8Hz,2H),6.90–6.80(m,2H),6.50(d,J＝2.7Hz,1H),4.18–3.98(m,4H),3.87–3.66(m,4H),3.41–3.20(m,4H),2.71–2.51(m,4H),2.38 (s,3H).13C NMR(101MHz,CDCl3)δ168.50,157.90,154.42,152.25,151.42,140.59,127.33,124.23, 123.42,123.38,123.31,123.28,123.15,123.13,123.06,123.04,118.50,115.71,113.07,111.36, 111.14,103.69,103.46,103.43,103.19,54.85,48.26,46.19,46.07,43.14.HRMS(ESI)(m/z): (M+H)+calcd for C28H29F2N7OS 550.2194,found550.2195。
化合物44 1H NMR(400MHz,DMSO)δ8.76(s,1H),8.39(s,1H),7.76(s,1H),7.67(d,J＝8.6Hz,2H),7.50(d,J＝8.8Hz,2H),7.46–7.40(m,2H),7.01(d,J＝8.7Hz,1H),4.04 -3.95(m,4H),3.75–3.65(m,4H),3.26–3.18(m,4H),2.48–2.41(m,4H),2.23(s,3H). 13C NMR(101MHz,DMSO)δ167.71,157.77,155.23,152.54,151.56,140.43,138.81,131.57,127.49,123.43,121.89,118.11,115.52,114.87,113.75,54.91,47.87,46.43,46.24,43.66.HRMS(ESI) (m/z):(M+H)+calcd for C29H29ClF3N7OS 616.1778,found 616.1868。
化合物45 1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.57(d,J＝8.6Hz,2H),7.36(s,1H), 7.31–7.25(m,1H),7.17(d,J＝7.6Hz,2H),6.97(d,J＝8.7Hz,2H),6.27(s,1H),4.09–3.95(m,4H),3.81–3.66(m,4H),3.35–3.24(m,4H),3.17-3.07(m,2H),2.66–2.56 (m,4H),2.37(s,3H),1.22(d,J＝6.6Hz,12H).13C NMR(101MHz,CDCl3)δ168.15,157.91,156.76,152.10,151.38,146.70,140.42,132.08,127.96,127.30,124.25,123.37,118.47,115.76,113.32, 54.80,48.21,46.42,45.99,43.40,28.66,23.64.HRMS(ESI)(m/z):(M+H)+calcdfor C34H43N7OS 598.3315,found 598.3323。
化合物46 1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.45–8.41(m,1H),7.56(d,J＝8.5Hz,2H),7.35(s,1H),7.32–7.29(m,1H),7.24–7.14(m,1H),6.95(dd,J＝10.2,6.2Hz, 3H),4.23–4.01(m,4H),3.89–3.72(m,4H),3.30(dd,J＝8.3,3.2Hz,4H),2.75–2.50 (m,4H),2.38(s,3H).13C NMR(101MHz,CDCl3)δ168.20,157.86,154.09,152.04,151.40,140.77,128.02,127.96,127.85,127.33,124.19,120.46,119.16,118.55,116.41,115.76,115.31,115.10, 113.05,54.79,48.18,46.17,43.16.HRMS(ESI)(m/z):(M+H)+calcd forC29H29F4N7OS 600.2144,found 600.2163。
试验例1化合物1-50的激酶抑制活性及MDA-MB-231和MDA-MB-436细胞的抗增殖活性。
实验结果表明，本发明的化合物均对VEGFR3具有抑制活性及抗三阴性乳腺癌细胞增殖活性，其中， 化合物31，36，38，39，40，45的效果较好，最优的，化合物45(记为38k)对VEGFR3具有较强的抑制 活性及三阴性乳腺癌细胞抑制活性。
试验例2化合物45(38k)抑制斑马鱼体内血管生成和体内抗肿瘤活性研究
利用绿色荧光蛋白标记血管内皮细胞的转基因斑马鱼来鉴定38k的体内抗血管生成作用。用3μM 或10μM浓度的38k溶液处理斑马鱼胚胎24h，同时以3μM浓度的10作为对照化合物。用荧光显微镜 观察38k和10对斑马鱼肠下血管(siv)的影响。与10相比，38k对斑马鱼siv具有相当的抑制活性。其中， 38k有效抑制了正常血管生成的形成，其疗效与10相似(图2A)。通过小鼠异种移植瘤模型研究了38k 的体内抗肿瘤效能。MDA-MB-231异种移植瘤的裸鼠分别口服38k(50、25mg/kg)和10(25mg/kg)。在相 同浓度(25mg/kg)下，化合物38k和10均显著降低了肿瘤体积。剂量为50mg/kg时，38k的抑制活性最 强，生长抑制率为61.9％(图2B)。
试验例3化合物45(38k)体内抗转移活性研究
通过肉眼和肺组织H&E染色检查肺转移结节。在相同的浓度(25mg/kg)下，38k组和10个治疗组 的肺转移结节更少(图3A)，38k(50mg/kg)能够显著抑制肺转移性结节的形成(图3B)。

Claims (9)

1.一种VEGFR3抑制剂，其特征在于：结构式如式I或式II所示的化合物或其药学上可接受的盐：
Figure RE-FDA0003380904750000011
其中，R1为
Figure RE-FDA0003380904750000012
Figure RE-FDA0003380904750000013
R11为氢、烷基、烷氧基、卤素、N-甲基哌嗪或吗啉；m为1或2；
R2为
Figure RE-FDA0003380904750000014
或氢；
R3为
Figure RE-FDA0003380904750000015
或氢；
R4为
Figure RE-FDA0003380904750000016
R41为氢、烷基、烷氧基、氰基、氧三氟甲基、三氟甲基或卤素；m为1或2。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于：R2为氢。
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，其特征在于：R3为氢。
4.根据权利要求3所述的化合物或其药学上可接受的盐，其特征在于：
R1为
Figure RE-FDA0003207942920000017
R11为氰基，N-甲基哌嗪或烷氧基；m为1；
R4为
Figure RE-FDA0003207942920000018
R41为氢、烷基、烷氧基、氰基、氧三氟甲基、三氟甲基或卤素；m为1或2；
优选R1为
Figure RE-FDA0003207942920000021
R11为氰基或N-甲基哌嗪；m为1；
R4为
Figure RE-FDA0003207942920000022
R41为氢、烷基、烷氧基、氰基、氧三氟甲基、三氟甲基或卤素；m为1或2；
更优选R1为
Figure RE-FDA0003207942920000023
R4为
Figure RE-FDA0003207942920000024
R41为氢、氰基、氧三氟甲基、三氟甲基或卤素；m为1或2；
更优选R1为
Figure RE-FDA0003207942920000025
R4为
Figure 1
。
5.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于：所述式I化合物为如下化合物：
Figure RE-FDA0003380904750000031
Figure RE-FDA0003380904750000041
Figure RE-FDA0003380904750000051
Figure RE-FDA0003380904750000061
6.权利要求1-5任一项所述的化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
7.根据权利要求6所述的用途，其特征在于：所述抗肿瘤药物为VEGFR3抑制剂类药物。
8.根据权利要求6所述的用途，其特征在于：所述抗肿瘤药物为治疗三阴性乳腺癌的药物。
9.一种药物组合物，其特征在于：它是包含有效剂量的权利要求1-8任一项所述的化合物或其药学上可接受的盐的制剂。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035423A1 (en) * 2010-09-15 2012-03-22 Katholieke Universiteit Leuven, K.U. Leuven R&D Anti-cancer activity of novel bicyclic heterocycles
CN104981247A (zh) * 2012-09-06 2015-10-14 普莱希科公司 用于激酶调节的化合物和方法及其适应症
CN112047948A (zh) * 2019-06-06 2020-12-08 山东轩竹医药科技有限公司 Kras突变体抑制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012035423A1 (en) * 2010-09-15 2012-03-22 Katholieke Universiteit Leuven, K.U. Leuven R&D Anti-cancer activity of novel bicyclic heterocycles
CN104981247A (zh) * 2012-09-06 2015-10-14 普莱希科公司 用于激酶调节的化合物和方法及其适应症
CN112047948A (zh) * 2019-06-06 2020-12-08 山东轩竹医药科技有限公司 Kras突变体抑制剂

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