CN106496222A - 一种咪唑并[1,2‑a]吡啶化合物及其制备方法和应用 - Google Patents
一种咪唑并[1,2‑a]吡啶化合物及其制备方法和应用 Download PDFInfo
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- CN106496222A CN106496222A CN201610807432.2A CN201610807432A CN106496222A CN 106496222 A CN106496222 A CN 106496222A CN 201610807432 A CN201610807432 A CN 201610807432A CN 106496222 A CN106496222 A CN 106496222A
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- imidazo
- hydrogen
- pyridine compounds
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- methyl
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- 239000001257 hydrogen Substances 0.000 claims description 28
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
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- 150000002431 hydrogen Chemical class 0.000 claims description 13
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- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种咪唑并[1,2‑a]吡啶化合物及其应用，所述咪唑并[1,2‑a]吡啶化合物作为一类结构新颖的NEK2小分子抑制剂，可以抑制NEK2激酶活性，同时本发明还公开了所述咪唑并[1,2‑a]吡啶化合物可以通过诱导细胞周期停止和凋亡来抑制肿瘤细胞的增殖及在动物体内抑制肿瘤细胞生长的作用。
Description
技术领域
本发明属于医药合成化工技术领域，具体涉及一种咪唑并[1,2-a]吡啶化合物及其合成方法和应用，所述咪唑并[1,2-a]吡啶化合物作为NEK2抑制剂，可以通过诱导细胞周期停止和凋亡来抑制肿瘤细胞的增殖，在体内和体外均具有良好的抗肿瘤活性。
背景技术
世界卫生组织及其下属的癌症研究机构(IARC)2012年发布研究报告称，全球约诊断1400万例新增癌症病例。全球的一半新发癌症病例发生在亚洲，其中大部分发生在中国[http://china.caixin.com/2014-02-08/100636253.html？cx_from＝news.baidu.com]。据报告估计，20年后，全球每年新发癌症病例将增长至2200万例。与此同时，癌症致死人数将从目前每年约820万人增长至每年约1300万人。NEKS(NIMA-related kinases)激酶是一种丝/苏氨酸蛋白激酶，NEKS家族从NEK1到NEK11共11种蛋白激酶，对细胞有丝分裂和细胞周期调控起着重要作用，和肿瘤关系密切。
其中在哺乳动物中，NEK2(NIMA-related kinase 2)是最具有特征性和代表性的一员，与NIMA的同源性最高，也是目前认为最重要，研究的最多，最深入的一个。NEK2主要位于中心体上，通过对底物蛋白的磷酸化作用参与纺锤体形成与分离，从而调控细胞周期中G2/M期中心体的分离。在人类蛋白中，NEK2与真菌激酶的联系最为密切，作为一种细胞周期调控激酶，其表达与活性在一个细胞周期中是受严格控制的。表达水平G1很低，而S/G2中增加。NEK2在G2期活性增加，通过磷酸化β-catenin，ninein-like protein(Nlp)，中心体NEK2结合蛋白(centrosomal NEK2asspciated protein 1,C-Nap1)及根丝蛋白(rootletin)致使染色体分离。根据细胞分裂周期的不同阶段，NEK2可以分布于细胞核及细胞质中并具有很多其他与细胞周期相关的功能。同时，NEK2的活性还受蛋白质磷酸酶1(proteinphosphatase 1,PP1)的调节，然而有趣的是，PP1又是Akt的关键调节器。NEK2既参与中心体分离又参与染色质凝缩，因此可间接调节中心体或直接干扰染色体，从而影响整个基因组的稳定，导致CIN和肿瘤的诱发、恶化和转移。综上所述，正常细胞内NEK2的过表达可产生致瘤的细胞内环境，在乳腺癌，肺癌，肝癌，前列腺癌，子宫颈癌，胰腺癌等癌症中，都存在NEK2高表达现象。
NEK2作为一种细胞蛋白周期激酶，对有丝分裂调控起着重要作用，与肿瘤的发生、发展恶化及转移是密切相关的。同时肿瘤细胞NEK2过度表达能显著增强药物外排蛋白的活性，进而将化疗药物泵出细胞，产生耐药性。通过抑制肿瘤细胞内NEK2的过表达，可以有效抑制肿瘤细胞的再生、转移、同时可以抑制耐药性的产生，增强药物治疗的敏感性，因此NEK2还可以作为癌症治疗的术后诊断工具，用来评估癌症治疗效果和监测肿瘤患者对治疗的反应。
总的来说，目前已经报道出来的NEK2小分子抑制剂还比较少，尚未见国际专利，仅见文献报道三种骨架结构的NEK2抑制剂[J.Med.Chem.,2010,53,7682-7698；J.Med.Chem.,2011,54,1626-1639；J.Med.Chem.,2012,55,3228-3241；J.Med.Chem.,2011,54,4133-4146]。这些抑制剂细胞活性很不理想，目前尚无具有体内肿瘤抑制效果的抑制剂的报道。
因此，NEK2作为一种新型抗癌靶标，设计合成新型抗肿瘤范围广、激酶活性及选择性好，同时PK、PD数据理想，毒副作用小，可以用于临床前开发的NEK2小分子抑制剂具有巨大的研究价值和应用价值，为癌症的治疗提供有效帮助，为开发具有我国自主知识产权的癌症治疗药物打下坚实基础。
发明内容
本发明目的之一是，提供一种咪唑并[1,2-a]吡啶化合物，其结构如式(1)所示，
其中，R1，R2，R3都为氢，或其中一个为氢时，另两个官能团为硝基、氰基、甲基、卤素等，或其中两个为氢时，另一个官能团为硝基、氰基、甲基、卤素等；
R4为氢或甲基；
R5为哌啶环、烷氧基或含有取代基的杂环如吡唑环等；
优选地，R1，R2，R3都为氢，或其中一或两个为氢时，另两或一个官能团为硝基、氰基、甲基、氟或氯等；
R4为氢或甲基；
R5为哌啶环、烷氧基或含有取代基的杂环如吡唑环等；如
本发明所涉及的一种咪唑并[1,2-a]吡啶化合物，所述咪唑并[1,2-a]吡啶化合物含有一个或多个手性中心时，所对应的对应异构体、非对应异构体及消旋体均包含在本发明内。
本发明包括所涉及的咪唑并[1,2-a]吡啶化合物所对应的各种盐。
一种咪唑并[1,2-a]吡啶化合物，其结构如式(I)所示，
式(I)中，R6为氢，甲基，或Boc(叔丁氧羰基)；R7为氢或甲基；
一种咪唑并[1,2-a]吡啶化合物，其结构如式(II)所示，
式(II)中，R8和R9为氢或甲基；
一种咪唑并[1,2-a]吡啶化合物，其结构如式(III)所示，
式(III)中，R10，R11，R12都为氢；或其中一个为氢时，另两个官能团为硝基、氰基、甲基、卤素等；或其中两个为氢时，另一个官能团为硝基、氰基、甲基、卤素等；
R13为氢或甲基；
优选地，R10，R11，R12都为氢；或其中一个为氢时，另两个官能团为硝基、氰基、甲基、氟或氯等；或其中两个为氢时，另一个官能团为硝基、氰基、甲基、氟或氯等；
R13为氢或甲基。
本发明还提供了一种通过多次运用Mitsunobu reaction、Miyaura boration、Suzuki cross-coupling、Buchwald-Hartwig cross-coupling和SN2反应来合成式(1)咪唑并[1,2-a]吡啶化合物的方法。
Mitsunobu reaction涉及到溶剂、温度、反应时间、催化剂等。此反应所用溶剂包括但不限于DCM、THF等，所用催化剂包括但不限于DIAD,DEAD及DBAD。
Miyaura boration发生涉及到溶剂、碱、催化剂等。此反应所用底物包括但不限于三氟甲磺酸酯化合物及卤代物等。溶剂包括但不限于1，4-dioxane，DMF，DMSO、THF，甲苯等。所用催化剂包括但不限于Pd2(dba)3,Pd(PPh3)4,Pd(dppf)Cl2·DCM,PdCl2(PPh3)4。所用碱包括但不限于Na2CO3,Ba(OH)2,K3PO4,Cs2CO3,K2CO3,TlOH,KF,CsF,Bu4F,NaOH,M+(-O-alkyl)等。
SN2反应涉及到溶剂、碱、底物等。所以此反应所用底物包括但不限于卤代物、三氟甲磺酸酯及甲磺酸酯化合物，溶剂包括但不限于DMF，DMSO、乙腈，碱包括但不限于Na2CO3,Cs2CO3,K2CO3,TlOH,NaOH等。
本发明还提供了将如上所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在体外作为NEK2抑制剂中的应用。
本发明还提供了将如上所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在制备NEK2抑制剂中的应用。
本发明还提供了将如上所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在体外抑制肿瘤细胞活性中的应用。
本发明还提供了将如上所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在制备诱导肿瘤细胞周期停止、诱导肿瘤细胞凋亡、和抑制肿瘤细胞增殖的药物中的应用。
其中，所述肿瘤细胞为胃癌细胞、结肠癌细胞、B细胞淋巴瘤细胞、胰腺癌细胞、乳腺癌细胞或肝癌细胞。
本发明如上所述的式(1)所示的咪唑并[1,2-a]吡啶化合物作为NEK2抑制剂，在动物体内具有明显的肿瘤抑制效果，且没有明显的毒副作用。
本发明还提供了所述式(1)咪唑并[1,2-a]吡啶化合物作为NEK2抑制剂，可以通过诱导细胞周期停止和凋亡来抑制肿瘤细胞的增殖，在体内和体外均具有良好的抗肿瘤活性。
本发明还提供了一种式(1)咪唑并[1,2-a]吡啶化合物在调控肿瘤细胞生长中的应用。本发明中，式(1)咪唑并[1,2-a]吡啶化合物为NEK2小分子抑制剂，能够有效抑制肿瘤细胞增殖及肿瘤生长，可以作为先导化合物用于抗癌药物的进一步开发。
本发明中，肿瘤细胞包括但不限于胃癌细胞、结肠癌细胞、B细胞淋巴瘤细胞、胰腺癌细胞、乳腺癌细胞和肝癌细胞。
本发明研究表明化合物MBM-17(IC50＝3nM)和MBM-55(IC50＝1nM)具有非常高效的NEK2抑制效果，且选择性好。另外，它们可以通过诱导细胞周期停止和凋亡来抑制肿瘤细胞的增殖。更为重要的是，其相应的琥珀酸盐MBM-17S(49.5％TGI)和MBM-55S(36.0％TGI)具有明显的肿瘤抑制效果，且没有明显的毒副作用。总的来说化合物MBM-17和MBM-55是目前已知的NEK2抑制活性最好的化合物，同时也是唯一具有体内抑瘤活性的化合物，因此它们具有良好的肿瘤治疗潜力，为后续候选药物的开发提供指导和帮助。
本发明的有益效果在于，本发明的式(1)咪唑并[1,2-a]吡啶化合物具有显著的抑制肿瘤细胞增殖及肿瘤生长的能力。
附图说明
图1为MBM-17和MBM-55诱导细胞G2/M期阻滞并且使>4N的细胞累积；(A)流式细胞仪检测将MBM-17以浓度0.25-1μM作用于HCT-116和MGC-803细胞24h后的细胞周期分布情况，仅显示了代表性的数据；(B)将(A)图中细胞各个周期比例进行定量。数值均以三组独立实验的Mean±SD表示；(C)流式细胞术检测将MBM-55以浓度0.5μM和1μM作用于HCT-116细胞24h后的细胞周期分布情况，代表性的数据没有显示；(D)将(C)图中细胞各个周期比例进行定量，数值均以三组独立实验的Mean±SD表示。
图2为MBM-17和MBM-55诱导细胞凋亡；(A)MBM-17以浓度0.25-1μM作用于HCT-116和MGC-803细胞24h后检测细胞凋亡情况；(B)MBM-55分别以浓度0.5μM和1μM作用于HCT-116细胞24h后检测细胞凋亡情况，采用AnnexinⅤ/PI染色方法利用流式细胞术进行细胞凋亡检测，凋亡细胞和定量数据均在图像中显示，数值均以三组独立实验的Mean±SD表示；***/###P＜0.001,**/##P＜0.01,*/#P＜0.05vs对照组。
图3为MBM-17S和MBM-55S的体内抗肿瘤活性，HCT-116异种移植瘤裸鼠模型，其中溶剂对照组，MBM-17S组，MBM-55S组，给予药物一天两次，伊立替康组一周两次，治疗21天；(A)肿瘤接种后的瘤体积记录情况，数值以Mean±SEM(n＝5)表示。(B)较初始治疗时的体重变化情况，**P＜0.01,*P＜0.05vs-.溶剂对照组。
具体实施方式
结合以下具体实施例和附图，对本发明作进一步的详细说明，本发明的保护内容包括但不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。
一种咪唑并[1,2-a]吡啶化合物制备方法：
Scheme 1:
首先，化合物2-氨基-4-羟基吡啶2与氯乙醛环化高收率的得到化合物6，随后通过Mitsunobu反应与N-Boc-4-羟基哌啶反应，接着NIS碘化反应，TAF脱Boc。4-溴水杨酸化合物11在硫酸催化下和甲醇在回流条件下过夜反应生成化合物12甲酯，接着通过Mitsunobu反应和SN2反应合成芳基醚13，随后通过Miyaura boration合成芳基硼酸酯14。最后芳基硼酸酯14和碘化物10通过Suzuki偶联反应，得到化合物15，在氨解便得到目标化合物16。
Scheme 2:
或者也可以通过路线二来合成目标化合物，首先12氨解后通过Mitsunobu或SN2反应反应合成芳基醚18，接着通过Miyaura boration合成芳基硼酸酯19，然后其在与碘代物8反应，便可以直接合成目标分子。其中，化合物20a在TFA条件下可以脱去Boc保护基，得到化合物21a。
一种咪唑并[1,2-a]吡啶化合物制备方法:
Scheme 3:
化合物氯乙醛与2-氨基-4溴吡啶关环得到化合物23，接着与N-甲基哌嗪通过Buchwald coupling得到24,24随后与NIS反应得到碘代物25。接着碘代物25与芳基硼酸酯14通过Suzuki coupling合成26，氨解便可以得到目标分子27；或者碘代物25直接与含有酰胺基的芳基硼酸酯19通过Suzuki coupling一步合成目标分子。
一种咪唑并[1,2-a]吡啶化合物制备方法:
Scheme 4:
化合物17首先通过Miyaura boration化合成中间体35，让后在与一系列溴代物通过SN2反应生成芳基醚36。4-溴吡唑37通过SN2反应生成38，然后先后通过Miyauraboration、Suzuki coupling及碘化反应合成碘化物41，接着再与含有酰胺基的芳基硼酸酯19通过Suzuki coupling一步合成目标分子。
实施例1：咪唑并[1,2-a]吡啶化合物16的合成
合成路线：
将2-氨基-4-羟基吡啶(4.4g,40.0mmol),溶解在200mL EtOH后，加入氯乙醛(16.5mL,100mmol),搅拌回流过夜。浓缩反应液，柱层析得白色固体6咪唑并[1，2-a]吡啶-7-醇，收率88％。1H NMR(400MHz,MeOD)δ8.56(d,J＝8.2Hz,1H),7.93(d,J＝1.7Hz,1H),7.74(d,J＝1.9Hz,1H),7.05-7.01(m,2H).
将咪唑并[1，2-a]吡啶-7-醇(218mg,1.63mmol),N-Boc-4-羟基哌啶(654mg,3.25mmol)and Ph3P(1.71g,6.52mmol)溶于THF(30mL)，然后将溶于THF(10mL)的DBAD(748mg,3.25mmol)在0℃滴入反应液中，室温反应完全后，加入水淬灭反应，真空旋干柱层析得产物7(250mg,48％)。1H NMR(400MHz,CDCl3)δ7.96(d,J＝7.4Hz,1H),7.47(d,J＝1.3Hz,1H),7.42(s,1H),6.88(d,J＝2.3Hz,1H),6.50(dd,J＝7.4,2.4Hz,1H),4.57–4.45(m,1H),3.71(ddd,J＝11.3,6.8,3.8Hz,2H),3.35(ddd,J＝13.4,7.9,3.8Hz,2H),2.04-1.92(m,2H),1.83-1.72(m,2H),1.48(s,9H).
化合物8(6.12g,13.81mmol)，溶解于130mL DCM中，加入15mL TFA室温搅拌4h。0℃加入100mL 2M的氢氧化钠水溶液淬灭反应，PH此时为碱性，有白色固体生成，抽滤得到一部分产物。滤出液用DCM萃取，合并有机相，无水硫酸钠干燥，浓缩共得白色固体化合物9共4.87克，直接用于下一步反应。化合物9(0.53g,14.87mmol)，溶解于18mL DCM及9mL乙醇中，加入37％的甲醛水溶液(37％w/w in water,0.7mL,9.3mmol),AcOH(0.125g,1.85mmol,1.2eq),NaBH(OAc)3(0.6 6g,1.85mmol,2.0eq),室温搅拌3h。加入饱和NaHCO3溶液淬灭反应，浓缩除去有机相后，DCM萃取，合并有机相，无水硫酸钠干燥，柱层析得白色固体化合物10，两步收率57％。1H NMR(400MHz,CDCl3)δ7.93(d,J＝7.5Hz,1H),7.51(s,1H),6.87(d,J＝2.4Hz,1H),6.62(dd,J＝7.5,2.4Hz,1H),4.41-4.32(m,1H),2.75-2.64(m,2H),2.26–2.24(m,5H),2.12–2.01(m,2H),1.90–1.81(m,2H).HRMS(ESI)m/z calcd for C13H17N3OI(M+H)+358.0416,found358.0427.
2-羟基-4-溴苯甲酸(5.0g,23.1mmol)溶解于20mL无水甲醇中，加入1.7mL硫酸。反应液搅拌回流24h。将反应液加入冰水，浓缩除去甲醇后，EA萃取，加入饱和NaHCO3溶液洗涤有机相，无水硫酸钠干燥，浓缩共得红褐色固体2-羟基-4-溴苯甲酸甲酯12共5.31克，直接用于下一步反应。
(S)-1-[2-(三氟甲基)苯基]乙醇(1.25g,6.58mmol),2-羟基-4-溴苯甲酸甲酯(1.97g,8.55mmol),
Ph3P(2.24g,8.55mmol)溶于40mL DCM，在0℃滴加溶解于10mLDCM的DBAD
(1.97g,8.55mmol)溶液，加完后室温搅拌约5h。加入30mL H2O淬灭反应，DCM萃取，合并有机相，无水硫酸钠干燥，柱层析得化合物13b共2.89g。
化合物13b(2.645g,6.58mmol),联硼酸频那醇酯(2.73g,1.5eq),KOAc(1.4g,2.0eq)溶解于20mL
dioxane，加入Pd(dppf)Cl2.DCM(0.29g,0.05eq)，氩气保护90℃搅拌过夜。硅藻土抽滤、浓缩，柱层析得化合物14b共2.74g。收率92.6％。
化合物14b(1.23g，3.44mmol),化合物10(1.86g，4.14mmol,1.2eq),K2CO3(0.95g,6.88mmol,2.0eq)溶解于1,4-dioxane/H2O(4/1,17.6mL)，加入Pd(PPh3)4(0.95g，0.826mmol,0.2eq)，氩气保护90℃搅拌3h。硅藻土抽滤、浓缩，柱层析得淡黄色固体化合物15，收率56％。1H NMR(400MHz,CDCl3)δ7.94-7.84(m,2H),7.69(s,1H),7.67(s,1H),7.56(t,J＝7.6Hz,1H),7.43(s,1H),7.39(t,J＝7.6Hz,1H),7.05(d,J＝7.9Hz,1H),6.88(s,1H),6.86(d,J＝1.8Hz,1H),6.39(dd,J＝7.5,2.1Hz,1H),5.81(d,J＝6.1Hz,1H),4.40-4.31(m,1H),3.96(s,3H),2.80-2.62(m,2H),2.30(s,3H),2.26-2.12(m,2H),2.11-2.01(m,2H),1.94-1.79(m,2H),1.73(d,J＝6.1Hz,3H).HRMS(ESI)m/z calcd for C30H30N3O4NaF3(M+Na)+576.2086,found 576.2088.
化合物15b(1.237g，2.236mmol)溶解在13mL 7M氨甲醇溶液于一封管中，90℃搅拌4d。旋干柱层析得白色固体16b共0.955g，收率80％。1H NMR(400MHz,MeOD)δ7.95(d,J＝8.1Hz,1H),7.71(m,2H),7.66(d,J＝7.6Hz,1H),7.56(t,J＝7.6Hz,1H),7.46(t,J＝7.6Hz,1H),7.32(s,1H),7.06(dd,J＝8.1,1.5Hz,1H),6.97(d,J＝2.3Hz,1H),6.78(d,J＝1.1Hz,1H),6.62(d,J＝6.1Hz,1H),5.83(q,J＝6.0Hz,1H),4.88(m,1H),3.53(m,2H),3.41(m,2H),2.96(s,3H),2.32(m,2H),2.15(m,2H),1.73(d,J＝6.2Hz,3H).HRMS(ESI)m/z calcd forC29H29N4O3Na F3(M+Na)+561.2089,found 561.2082.
实施例2：咪唑并[1,2-a]吡啶化合物21的合成
将4-溴-2-羟基苯甲酸甲酯(4.6g)溶解在异丙醇(20mL)中，然后加入氨水(40mL)，50℃反应5h后旋干得到粗产物4-溴-2-羟基苯甲酰胺直接用于下一步反应。
将4-溴-2-羟基苯甲酰胺(8.64g,40.0mmol)溶解于DMF(80mL)中，然后加入2-(三氟甲基)苄溴(11.5g,1.2eq)和K2CO3(6.08g,1.1eq),然后50℃反应6h。待反应完全后加入EA(500mL)稀释,用水洗(2 250mL),饱和食盐水洗(150mL),Na2SO4干燥后浓缩旋干，柱层析EA:PE＝1:10得化合物18c(12.4g,82.9％).1H NMR(400MHz,CDCl3)δ8.09(d,J＝8.4Hz,1H),7.77(d,J＝7.8Hz,1H),7.62(t,J＝6.1Hz,2H),7.53(dt,J＝8.3,4.2Hz,1H),7.40(s,1H),7.31–7.23(m,1H),7.18(d,J＝1.2Hz,1H),5.97(s,1H),5.37(s,2H).
化合物18c(2.9g)溶解在1,4-dioxane(30mL)后加入联硼酸频那醇酯(2.95g,1.5eq),Pd(dppf)Cl2·DCM(316.4mg,5％)和KOAc(1.52g,2.0eq).然后用氮气置换气体，90℃反应过夜.硅藻土抽滤后旋干滤液，柱层析(1-2％MeOH/DCM)纯化得到化合物19c(2.61g,80.1％).1H NMR(400MHz,DMSO)δ7.86(d,J＝7.7Hz,1H),7.82(d,J＝7.8Hz,1H),7.74(t,J＝7.7Hz,2H),7.62(d,J＝7.6Hz,1H),7.54(s,1H),7.51(s,1H),7.37(d,J＝7.9Hz,2H),5.38(s,2H),1.30(s,12H).
化合物8(133.0mg,0.30mmol)和19c(127.2mg,0.36mmol，1.2eq)溶于DMF/H2O(10/1，3.3mL)中，加入K2CO3(82.9mg,0.6mmol 2.0eq)和Pd(PPh3)4(34.7mg,0.03mmol 0.10eq)，然后80℃反应10h.硅藻土抽滤后旋干滤液，柱层析(2-10％MeOH/DCM)得到化合物20.1HNMR(400MHz,CDCl3)δ8.34(d,J＝8.1Hz,1H),8.03(d,J＝7.5Hz,1H),7.78(d,J＝7.8Hz,1H),7.71–7.60(m,3H),7.58(s,1H),7.52(t,J＝7.5Hz,1H),7.28(dd,J＝6.3,1.6Hz,1H),7.07(s,1H),6.94(d,J＝1.9Hz,1H),6.58–6.48(m,1H),6.52(dd,J＝7.5,2.3Hz,1H),6.15(s,1H),5.48(s,2H),4.60–4.47(m,1H),3.85–3.66(m,2H),3.49–3.26(m,2H),2.17(s,1H),2.08–1.93(m,2H),1.90–1.73(m,2H),1.48(s,9H).RMS(ESI)m/z calcd for C32H34N4O5F3(M+H)+611.2481,found 611.2457.
化合物20(51.0mg,0.084mmol)溶于DCM(4mL)中加入TFA(0.5mL),然后室温搅拌反应过于。浓缩旋干得粗产物用DCM、PE及MeOH打浆得灰白色固体21，收率60％。1H NMR(400MHz,MeOD)δ8.58(d,J＝7.5Hz,1H),8.16(d,J＝7.9Hz,1H),8.04(s,1H),7.86–7.79(m,2H),7.72(t,J＝7.5Hz,1H),7.61(t,J＝7.8Hz,1H),7.57–7.38(m,3H),7.18(d,J＝7.8Hz,1H),5.56(s,2H),3.56–3.41(m,2H),3.33(s,2H),2.41–2.27(m,2H),2.24–2.09(m,2H).HRMS(ESI)m/z calcd for C27H26N4O3F3(M+H)+511.1957,found 511.1947.
实施例3：咪唑并[1,2-a]吡啶化合物的20d合成
将碘化物10(71.4mg,0.20mmol)和硼酸酯19d(106mg,0.30mmol，1.5eq)溶解在DMF/H2O(10/1，2.2mL)中后，加入K2CO3(55.3mg,0.40mmol 2.0eq)和Pd(PPh3)4(23.1mg,0.02mmol 0.10eq),然后80℃反应12h.硅藻土抽滤后旋干滤液，柱层析(2-10％MeOH/DCM)纯化得到化合物20d(75mg，78％).1H NMR(400MHz,DMSO)δ8.35(s,1H),7.94(d,J＝7.6Hz,1H),7.79(s,1H),7.66(s,1H),7.59(s,1H),7.53(d,J＝6.5Hz,2H),7.48–7.32(m,4H),7.31–7.19(m,2H),6.74(s,1H),5.40(s,2H),4.85(s,1H),3.28–3.06(m,4H),2.85(s,3H),2.30–1.87(m,4H).HRMS(ESI)m/z calcd for C27H29N4O3(M+H)+457.2240,found 457.2222.
实施例4：咪唑并[1,2-a]吡啶化合物16c的合成
咪唑并[1,2-a]吡啶化合物16c的合成同21,(20％yield)。1H NMR(400MHz,MeOD)δ8.25(t,J＝10.0Hz,1H),8.10(d,J＝8.1Hz,1H),7.79(t,J＝7.6Hz,1H),7.68(t,J＝7.6Hz,1H),7.64–7.53(m,2H),7.33(dd,J＝8.1,1.3Hz,1H),7.24(d,J＝1.0Hz,1H),6.99(d,J＝1.8Hz,1H),6.69(dd,J＝7.6,2.1Hz,1H),5.56(s,2H),4.67–4.53(m,1H),3.22–3.07(m,1H),3.05–2.88(m,1H),2.67(s,3H),2.30–2.13(m,2H),2.09–1.93(m,1H).
实施例5：咪唑并[1,2-a]吡啶化合物27b的合成
合成路线：
化合物2-氨基-4-溴吡啶22(5.0g)和2-氯乙醛(40percent wt aqueoussolution,12mL,2.5eq)溶于无水乙醇(50mL)中，加入NaHCO3(4.89g,2.0eq)后，回流反应6h。硅藻土抽滤，真空旋干有机溶剂后，加入EA(60mL)稀释，水洗，饱和食盐水水，Na2SO4干燥后旋干柱层析得棕色固体23(4.38g,78％)。1H NMR(400MHz,CDCl3)δ7.99(d,J＝7.1Hz,1H),7.81(s,1H),7.59(s,1H),7.56(s,1H),6.88(dd,J＝7.2,1.6Hz,1H).
将化合物7-溴咪唑并[1,2-a]吡啶23(487.9mg,1.0eq),N-甲基哌嗪(0.83mL,3.0eq),Pd2(dba)3(45.8mg,2％),Xantphos(86.8mg,6％)和t-BuONa(0.36g,1.5eq)溶于甲苯(3.5mL)中，100℃下反应12h。硅藻土抽滤，真空旋干后有机溶剂后柱层析(1-10％MeOH/DCM)得白色固体24(476mg,88.0％)。1H NMR(400MHz,CDCl3)δ7.88(d,J＝7.5Hz,1H),7.41(d,J＝0.8Hz,1H),7.31(s,1H),6.77(d,J＝1.7Hz,1H),6.56(dd,J＝7.5,2.3Hz,1H),3.21(t,J＝4.8Hz,4H),2.54(t,J＝4.8Hz,4H),2.32(s,3H).
将24(476mg,1.0eq)溶于乙腈(7.0mL)中，加入NIS(495.0mg,1.0eq)后反应半小时。旋干溶剂后柱层析(eluted with MeOH:DCM＝1:100-1:5)得黄色固体25(576mg,75％)。1H NMR(400MHz,CDCl3)δ7.82(d,J＝7.4Hz,1H),7.40(s,1H),6.66-6.69(m,2H),3.20-3.23(m,4H),2.50-2.51(m,4H),2.28(s,3H)。
将化合物25(430mg,1.26mmol)和19c(822mg,1.88mmol，1.5eq)溶于1,4-dioxane/H2O(4/1,4mL)中，加入Cs2CO3(821mg,2.52mmol 2.0eq)和Pd(dppf)Cl2·DCM(34.7mg,0.03mmol 0.10eq)90℃反应10h.硅藻土抽滤，真空旋干后有机溶剂后柱层析(2-10％MeOH/DCM)得白色固体26b(165mg,25％).将化合物26b(150mg)溶于7M氨甲醇溶液(15.0mL)，在封管中90℃反应六天.浓缩反应液柱层析(1-10％MeOH/DCM)的产物27b(43mg,30％).1H NMR(400MHz,MeOD)δ8.12(d,J＝7.7Hz,1H),8.01(d,J＝8.0Hz,1H),7.71(t,J＝7.8Hz,2H),7.60(t,J＝7.5Hz,1H),7.54–7.44(m,2H),7.24(d,J＝8.1Hz,1H),7.16(s,1H),6.78(d,J＝7.7Hz,1H),6.68(s,1H),5.46(s,2H),3.34–3.24(m,4H),2.62–2.51(m,4H),2.30(s,3H).
实施例6：咪唑并[1,2-a]吡啶化合物29a的合成
将化合物25(102.6mg,0.30mmol)和19a(156.9mg,0.36mmol)溶于DMF/H2O(10/1,3.3mL),然后加入K2CO3(82.9mg,0.6mmol)和Pd(PPh3)4(34.7mg,0.03mmol)，90℃反应10h.硅藻土抽滤，真空旋干有机溶剂后柱层析(2-10％MeOH/DCM)得白色固体29a(119.3mg,76％).1H NMR(400MHz,CDCl3)δ8.29(d,J＝8.2Hz,1H),7.93(d,J＝2.7Hz,1H),7.79(d,J＝7.7Hz,1H),7.72(d,J＝7.7Hz,1H),7.68(d,J＝7.8Hz,1H),7.57(t,J＝7.5Hz,1H),7.43(t,J＝7.7Hz,1H),7.39(s,1H),7.18(dd,J＝8.2,1.5Hz,1H),6.86(d,J＝1.4Hz,1H),6.79(d,J＝2.3Hz,1H),6.51(dd,J＝7.7,2.5Hz,1H),5.97(s,1H,b),5.94(q,J＝6.3Hz,1H),3.27(t,J＝5.2Hz,4H),2.58(t,J＝5.2Hz,4H),2.36(s,3H),1.81(d,J＝6.2Hz,3H).HRMS(ESI)m/zcalcd for C28H29N5O2F3(M+H)+524.2273,found 524.2289.
实施例7：咪唑并[1,2-a]吡啶化合物29b的合成
咪唑并[1,2-a]吡啶化合物29b的合成同29a。收率，70％。
1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.1Hz,1H),8.06(d,J＝7.7Hz,1H),7.77(d,J＝7.8Hz,1H),7.69–7.48(m,5H),7.31–7.23(m,2H),7.08(s,1H),6.84(s,1H),6.62(dd,J＝7.7,1.8Hz,1H),5.91(s,1H),5.49(s,2H),3.30(t,J＝4.8Hz,4H),2.59(t,J＝4.8Hz,4H),2.37(s,3H).
实施例8：咪唑并[1,2-a]吡啶化合物42b的合成
化合物36的合成：4-溴吡唑(22.0g)溶于DMF(75mL)中，加入K2CO3(51.8g,2.5eq)和二甲氨基氯乙烷盐酸，然后室温反应两天。加入EA(500mL)稀释,然后依次用水和饱和食盐水洗，Na2SO4干燥旋干后柱层析(1-20％MeOH/DCM)得36(21.85g,66.5％)。H NMR(400MHz,CDCl3)δ7.50(s,1H),7.44(s,1H),4.18(t,J＝6.5Hz,2H),2.71(t,J＝6.5Hz,2H),2.25(s,6H).
化合物37的合成：化合物36(2.5g,11.46mmol)溶解在1,4-二氧六环(12.5mL)中，加入联硼酸频那醇酯(4.37g,1.5eq),Pd(dppf)Cl2·DCM(468mg,5％)和KOAc(2.81g,2.5eq)。反应液100℃反应12h.硅藻土抽滤，真空旋干后有机溶剂后的粗产物37共6.7g直接用于下一步反应。
化合物37(1.3eq)溶于DMF(169.3mL)中，加入7-溴咪唑并[1,2-a]吡啶(3.48g)，1NNa2CO3水溶液(26.64mL)和Pd(dppf)Cl2·DCM(0.05eq),然后反应液80℃反应过夜.硅藻土抽滤,真空旋干有机溶剂后柱层析(2-10％MeOH/DCM)得白色固体31(4.88g,72％).1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.0Hz,1H),7.81(s,1H),7.80(s,1H),7.66(s,1H),7.59(s,1H),7.52(s,1H),6.92(d,J＝6.9Hz,1H),4.26(t,J＝6.5Hz,2H),2.80(t,J＝6.5Hz,2H),2.29(s,6H).
咪唑并[1,2-a]吡啶化合物42b的合成同29a,收率67％。1H NMR(400MHz,MeOD)δ8.55(s,1H),8.02–7.95(m,2H),7.79(d,J＝7.4Hz,1H),7.75–7.65(m,2H),7.65–7.58(m,2H),7.58–7.51(m,1H),7.44(s,1H),7.12(dd,J＝8.1,1.3Hz,1H),7.00(dd,J＝7.2,1.7Hz,1H),6.79(d,J＝1.1Hz,1H),5.84(q,J＝5.4Hz,1H),4.73(t,J＝5.6Hz,2H),3.88(t,J＝5.6Hz,2H),3.08(s,6H),1.76(d,J＝6.0Hz,3H).13C NMR(101MHz,MeOD)δ169.27,157.00,147.09,142.16,139.29(s),134.74,133.82,133.50,133.15,131.70,131.05,130.03,128.00,127.55(d,J＝5.9Hz),127.28(d,J＝5.3Hz),126.02,125.36,124.54,123.49,121.95,121.26,114.19,113.91,111.12,74.93,58.21,47.66,44.50,25.10.
实施例9：咪唑并[1,2-a]吡啶化合物MBM-17的合成
咪唑并[1,2-a]吡啶化合物MBM-17的合成同29a,收率67％。1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.1Hz,1H),8.16(dd,J＝7.2,0.8Hz,1H),7.85(d,J＝5.1Hz,2H),7.75(s,1H),7.73(s,2H),7.50–7.40(m,5H),7.32(dd,J＝8.1,1.5Hz,1H),7.20(d,J＝1.4Hz,1H),6.95(dd,J＝7.2,1.8Hz,1H),5.77(s,1H),5.30(s,2H),4.28(t,J＝6.3Hz,2H),2.82(t,J＝6.3Hz,2H),2.31(s,6H).13C NMR(101MHz,CDCl3)δ166.26,157.46,147.42,136.84,135.28,134.32,134.00,133.76,129.93,129.16,128.86,127.74,127.12,124.50,123.44,120.71,120.30,119.95,112.34,112.16,112.16,111.78,71.40,59.05,50.68,45.65.
实施例10：咪唑并[1,2-a]吡啶化合物44的合成
将化合物35(425mg,1.62mmol)和3-氯苄溴(331.9mg,1.62mmol)溶于丙酮(8mL)中，加入K2CO3(425mg,1.78mmol),然后回流反应两天。待反应完全后，硅藻土抽滤，旋干滤液得粗产物43白色固体660mg直接用于下一步反应。
将碘化物41(76.2mg,0.20mmol)和粗产物43(154.7mg,0.40mmol 2.0eq)溶于DMF/H2O(10/1,2.2mL)后，加入K2CO3(55.3mg,0.40mmol 2.0eq)和Pd(PPh3)4(46.2mg,0.044mmol0.20eq)，然后80℃反应12h.待反应完全后，硅藻土抽滤，旋干滤液柱层析(2-10％MeOH/DCM得白色固体产物44(62mg,60.2％)。1H NMR(400MHz,DMSO)δ8.49(s,1H),8.43(d,J＝7.1Hz,1H),8.23(s,1H),7.93(d,J＝7.5Hz,2H),7.85(s,1H),7.71(s,1H),7.64(s,2H),7.56–7.40(m,4H),7.35(d,J＝7.9Hz,1H),7.21(d,J＝6.9Hz,1H),5.42(s,2H),4.54(t,J＝5.8Hz,2H),2.76(s,6H),2.50(s,2H).13C NMR(101MHz,DMSO)δ166.09,156.17,146.58,139.17,137.49,133.81,133.29,132.42,131.65,130.58,129.30,128.83,128.04,127.41,126.20,124.51,124.17,122.57,120.30,119.27,111.73,11.64,110.96,69.06,56.11,46.71,43.13.HRMS(ESI)m/z calcd for C28H28N6O2Cl(M+H)+515.1962,found 515.1944.
实施例11：咪唑并[1,2-a]吡啶化合物MBM-55的合成
咪唑并[1,2-a]吡啶化合物MBM-55的合成同29a,收率72％.1H NMR(400MHz,DMSO)δ9.60(s,1H),8.52(s,1H),8.48(d,J＝7.2Hz,1H),8.27(s,1H),8.04–7.90(m,2H),7.87(s,1H),7.69(s,1H),7.64(s,1H),7.58–7.47(m,1H),7.44–7.32(m,3H),7.23(d,J＝5.7Hz,2H),5.43(s,2H),4.58(t,J＝6.1Hz,2H),3.61(t,J＝6.1Hz,2H),2.83(s,6H).19F NMR(376MHz,DMSO)δ-112.71(dd,J＝15.6,9.2Hz).13C NMR(101MHz,DMSO)δ166.07,162.24(d,J＝243.9Hz),156.18,146.41,139.52(d,J＝7.6Hz),137.66,133.57,132.30,131.58,130.70(d,J＝8.2Hz),129.41,128.98,124.67,124.23,123.59(d,J＝2.4Hz),122.68,120.33,119.27,114.89(d,J＝20.9Hz),114.33(d,J＝22.0Hz),111.74,111.66,110.86,69.13,55.77,46.35,42.87.HRMS(ESI)m/z calcd for C28H28N6O2F(M+H)+499.2258,found499.2278.
实施例12：咪唑并[1,2-a]吡啶化合物42f的合成
咪唑并[1，2-a]吡啶化合物42f的合成同29a,收率66％。1H NMR(400MHz,DMSO)δ8.56(d,J＝7.2Hz,1H),8.43(s,1H),8.13(s,1H),7.97(d,J＝8.0Hz,1H),7.90(s,1H),7.86(s,1H),7.68–7.64(m,1H),7.61(s,1H),7.56(s,1H),7.52(s,1H),7.49–7.44(m,1H),7.41–7.36(m,1H),7.34–7.27(m,2H),7.24(dd,J＝7.4,1.7Hz,1H),5.47(s,2H),4.29(t,J＝6.3Hz,2H),2.86(t,J＝6.1Hz,2H),2.30(s,6H).19F NMR(376MHz,DMSO)δ-117.84(s),-118.35(s).HRMS(ESI)m/z calcd forC28H28N6O2F C28H28N6O2F(M+H)+499.2258,found499.2252.
实施例13：咪唑并[1,2-a]吡啶化合物42d的合成
咪唑并[1,2-a]吡啶化合物42d的合成同29a,收率55％。1H NMR(400MHz,MeOD)δ8.36(d,J＝7.2Hz,1H),8.24(s,1H),8.11(d,J＝8.0Hz,1H),8.00(s,1H),7.89(s,1H),7.83(d,J＝7.5Hz,1H),7.79–7.70(m,3H),7.67(d,J＝7.6Hz,1H),7.41(s,1H),7.37(d,J＝8.0Hz,1H),7.19(dd,J＝7.2,1.5Hz,1H),5.49(s,2H),4.35(t,J＝6.6Hz,2H),2.90(t,J＝6.6Hz,2H),2.34(s,6H).19F NMR(376MHz,MeOD)δ-64.02(s).13C NMR(101MHz,DMSO)δ166.13,156.20,146.78,138.17,136.51,133.89,132.55,131.61(d,J＝4.4Hz),129.72,129.64,129.32(q,J＝31.8Hz),128.29,124.77(q,J＝3.8Hz),124.36,124.21(q,J＝3.9Hz),124.14(d,J＝270.7Hz),124.05,122.69,119.66,119.25,111.72,111.60,110.72,69.16,58.31,49.53,44.96.HRMS(ESI)m/z calcd for C29H28N6O2F3(M+H)+549.2226,found549.2215.
实施例14：咪唑并[1,2-a]吡啶化合物42e的合成
咪唑并[1,2-a]吡啶化合物42e的合成同29a,收率50％。1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.1Hz,1H),8.05(d,J＝7.2Hz,1H),7.89–7.81(m,2H),7.79–7.68(m,4H),7.65–7.56(m,3H),7.38–7.30(m,1H),7.12(s,1H),6.91(dd,J＝7.2,1.7Hz,1H),5.85(s,1H),5.36(d,J＝9.1Hz,2H),4.29(t,J＝6.5Hz,2H),2.83(t,J＝6.5Hz,2H),2.32(s,6H).19F NMR(376MHz,CDCl3)δ-62.58(s).HRMS(ESI)m/z calcd for C29H28N6O2F3(M+H)+549.2226,found549.2249.
实施例15：咪唑并[1,2-a]吡啶化合物45的合成
咪唑并[1,2-a]吡啶化合物45的合成同44,收率19％。1H NMR(400MHz,DMSO)δ8.80–8.67(m,2H),8.38(s,1H),8.31–8.23(m,1H),8.06(s,1H),7.96(d,J＝7.9Hz,1H),7.67–7.57(m,1H),7.55(d,J＝6.7Hz,1H),7.50(d,J＝7.1Hz,1H),7.41(d,J＝8.4Hz,1H),7.33–7.23(m,2H),5.38(s,2H),4.64(t,J＝5.9Hz,2H),3.67(t,J＝6.0Hz,2H),2.87(s,6H),2.38(s,3H).13C NMR(101MHz,DMSO)δ165.95,156.50,138.29(s),136.66,134.17,131.48,130.39,130.20,126.25(s),125.97,125.20(s),123.87(s),120.26(s),119.40(s),113.82,112.95,68.96,55.52,46.33,42.76,18.56.HRMS(ESI)m/z calcd forC29H31N6O2(M+H)+495.2508,found495.2507.
实施例16：咪唑并[1,2-a]吡啶化合物46的合成
咪唑并[1,2-a]吡啶化合物46的合成同44,收率19％。1H NMR(400MHz,MeOD)δ8.39(d,J＝6.8Hz,1H),8.29(s,1H),8.12(d,J＝7.8Hz,1H),8.07(s,1H),7.77(s,1H),7.62(d,J＝7.7Hz,2H),7.50–7.33(m,3H),7.22(d,J＝7.0Hz,1H),5.52(s,2H),4.53(s,2H),3.27(s,2H),2.77(s,6H).13C NMR(101MHz,MeOD)δ169.44,158.28,148.32,138.72,137.58,134.87,134.51,133.79,133.63,132.58,132.21,131.81,129.97,129.55,129.35,125.53,122.96,122.23,121.29,113.56,113.26,111.92,69.88,58.98,49.71,44.77.HRMS(ESI)m/z calcdfor C28H27N6O2Cl2(M+H)+549.1573,found 549.1559.
实施例17：咪唑并[1,2-a]吡啶化合物47的合成
咪唑并[1,2-a]吡啶化合物47的合成同44,收率68％。1H NMR(400MHz,DMSO)δ8.48(d,J＝9.0Hz,2H),8.24(s,1H),7.95(s,1H),7.91(d,J＝8.0Hz,1H),7.86(s,2H),7.74(d,J＝8.2Hz,1H),7.70(s,1H),7.63(s,1H),7.55(dd,J＝8.2,1.7Hz,1H),7.42(s,1H),7.37(d,J＝8.0Hz,1H),7.21(dd,J＝7.2,1.4Hz,1H),5.42(s,2H),4.55(t,J＝6.1Hz,2H),3.53(t,J＝6.1Hz,2H),2.78(s,6H).13C NMR(101MHz,DMSO)δ166.10,156.02,146.57,137.88,137.51,133.86,132.37,131.57,131.25,130.85,130.60,129.67,129.25,128.84,127.91,124.57,124.15,122.81,120.31,119.30,111.72,111.55,110.98,68.41,56.02,46.63,43.06.HRMS(ESI)m/z calcd for C28H27N6O2Cl2(M+H)+549.1573,found 549.1555.
实施例18：咪唑并[1,2-a]吡啶化合物48的合成
咪唑并[1,2-a]吡啶化合物48的合成同44,,收率74％1H NMR(400MHz,DMSO)δ8.71(d,J＝6.8Hz,1H),8.66(s,1H),8.37(s,1H),8.16(s,1H),8.04(s,1H),8.01–7.94(m,2H),7.89–7.79(m,2H),7.71–7.57(m,3H),7.54(s,1H),7.51–7.42(m,2H),5.55(s,1H),4.62(t,J＝6.0Hz,2H),3.66(t,J＝6.0Hz,2H),2.94–2.81(m,6H).13C NMR(101MHz,DMSO)δ165.88,156.09,139.40,138.12,133.69,133.42,131.70,129.85,129.63,129.40(s),125.85,125.84,123.70,120.44,119.69,117.19,113.22,112.61,110.99,68.39,55.61,46.29,42.81.HRMS(ESI)m/zcalcd for C29H28N7O2(M+H)+506.2304,found 506.2308.
实施例19：咪唑并[1,2-a]吡啶化合物49的合成
咪唑并[1,2-a]吡啶化合物49的合成同44,,收率49％。1H NMR(400MHz,MeOD)δ8.36(dd,J＝20.8,7.1Hz,1H),8.29–8.11(m,2H),8.05(d,J＝8.0Hz,1H),7.98(d,J＝4.2Hz,1H),7.87(d,J＝7.7Hz,1H),7.77(t,J＝7.2Hz,1H),7.72–7.59(m,2H),7.54(d,J＝18.9Hz,1H),7.41–7.27(m,1H),7.16(d,J＝7.0Hz,1H),5.73(s,1H),4.35(t,J＝6.3Hz,2H),2.93(t,J＝6.4Hz,2H),2.37(d,J＝1.5Hz,6H)
实施例20：咪唑并[1,2-a]吡啶化合物MBM-17S的合成
将MBM-17(664mg,1.38mmol)溶于DCM(40mL)中，加入溶于10ML丙酮中的丁二酸(326mg,2.76mmol)溶液，室温搅拌过夜，有固体析出，抽滤干燥后的淡黄色固体MBM-17S(858mg,87％).1H NMR(400MHz,CD3OD)δ8.34(d,J＝7.2Hz,1H),8.30(s,1H),8.18(d,J＝8.1Hz,1H),8.09(s,1H),7.80–7.74(m,2H),7.59–7.52(m,2H),7.51–7.41(m,4H),7.40–7.34(m,1H),7.22(dd,J＝7.2,1.6Hz,1H),5.44(s,2H),4.52(t,J＝6.2Hz,2H),3.30(d,J＝6.3Hz,2H),2.66(s,6H),2.57(s,8H).13C NMR(100MHz,CD3OD)δ177.27,169.27,158.84,148.27,138.76,137.61,134.85,133.71,132.21,130.02,129.59,128.90,126.34,125.62,122.27,120.97,113.54,111.87,72.21,59.52–58.47,44.61,30.83.HRMS(ESI)m/z calcdfor C28H29N6(M+H)+481.2352,found 481.2364.
实施例21：咪唑并[1,2-a]吡啶化合物MBM-55S的合成
将MBM-55(696mg,1.40mmol)溶于DCM(100mL)中，加入溶于10ML丙酮中的丁二酸(329mg,2.79mmol)溶液，室温搅拌过夜，有固体析出，抽滤干燥后的淡黄色固体(800mg,78％).1H NMR(400MHz,CD3OD)δ8.35(d,J＝7.1Hz,1H),8.30(s,1H),8.14(d,J＝8.0Hz,1H),8.08(s,1H),7.81–7.73(m,2H),7.52–7.44(m,1H),7.42–7.35(m,3H),7.35–7.29(m,1H),7.22(d,J＝6.9Hz,1H),7.18–7.11(m,1H),5.43(s,2H),4.56(t,J＝6.0Hz,2H),3.39(t,J＝6.0Hz,2H),2.74(s,6H),2.56(s,8H).13C NMR(100MHz,CD3OD)δ177.28,169.38,164.51(d,JC-F＝243.6Hz),158.1,148.18,140.46,138.89,134.76,133.61,132.20,131.88(d,JC-F＝8.3Hz),130.12,126.30,125.60,124.55,122.71,122.32,121.06,116.23(d,JC-F＝21.2Hz),115.53(d,JC-F＝22.3Hz),113.54,111.85,71.29,58.43,44.33,30.78.HRMS(ESI)m/z calcd for C28H28N6O2F(M+H)+499.2258,found 499.2271.
实施例22式(1)咪唑并[1,2-a]吡啶化合物的选择性及体外抗肿瘤活性评价
本发明在细胞水平上的研究表明，式(1)咪唑并[1,2-a]吡啶化合物可作为对AurA激酶有非常好的选择性，同时对多种肿瘤细胞具有很好的抑制作用。
表1、Nek2抑制剂对AurA激酶和肿瘤细胞中的抗癌活性
表2：MBM-55在一系列激酶中的选择性
表2表明化合物MBM-55对多种激酶均有很好的选择性。
实施例23
图1和2表明化合物MBM-17和MBM-55可以通过诱导细胞周期停止和凋亡来抑制肿瘤细胞的增殖。
PI染色结合流式细胞术分析化合物对肿瘤细胞周期分布的影响：
将处于对数生长期的MGC-803或HCT-116细胞种于6孔板，24h后给予相应浓度的MBM-17或MBM-55，药物作用24h后，收细胞，70％乙醇固定，PI染色后流式细胞仪检测细胞周期分布情况。
AnnexinⅤ/PI染色结合流式细胞术进行细胞凋亡检测：
将处于对数生长期的MGC-803或HCT-116细胞种于6孔板，24h后给予相应浓度的MBM-17或MBM-55，药物作用24h后，收细胞，AnnexinⅤ/PI染色后直接流式细胞仪术检测细胞凋亡情况。
实施例24：MBM-17S和MBM-55S体内调控肿瘤生长实验
在HCT-116异种移植瘤模型上进行MBM-17S和MBM-55S的体内药效学评价。实验选用4～5周龄的雌性裸鼠，在其左前肢腋窝皮下注射HCT-116细胞悬液。待肿瘤体积达到100mm3左右时进行随机分组，分为4组，分别为溶剂对照组，MBM-17S组(20mg/kg),MBM-55S组(20mg/kg)，伊立替康组(10mg/kg)每组5只，分组后当天给予药物。其中溶剂对照组、MBM-17S组和MBM-55S组给药次数为一天两次，伊立替康组为一周两次。给药后于每周三次测量老鼠的瘤体积和体重，共治疗观察21天。
化合物MBM-17和MBM-55的琥珀酸盐MBM-17S(49.5％TGI)和MBM-55S(36.0％TGI)具有明显的肿瘤抑制效果，且没有明显的毒副作用。总的来说化合物MBM-17和MBM-55是目前已知的NEK2抑制活性最好的化合物，同时也是唯一具有体内抑瘤活性的化合物，因此它们具有良好的肿瘤治疗潜力，为后续候选药物的开发提供指导和帮助。
Claims (10)
1.一种咪唑并[1,2-a]吡啶化合物，其特征在于，其结构如式(1)所示，
其中：
R1，R2，R3都为氢；或其中一个为氢时，另两个官能团为硝基、氰基、甲基、卤素；或其中两个为氢时，另一个官能团为硝基、氰基、甲基、卤素；
R4为氢或甲基；
R5为哌啶环、烷氧基或含有取代基的杂环。
2.如权利要求1所述的咪唑并[1,2-a]吡啶化合物，其特征在于，所述咪唑并[1,2-a]吡啶化合物含有一个或多个手性中心时，为所对应的对应异构体、非对应异构体及消旋体。
3.如权利要求1所述的咪唑并[1,2-a]吡啶化合物，其特征在于，本发明包括所涉及的一种咪唑并[1,2-a]吡啶化合物所对应的各种盐。
4.如权利要求1所述的咪唑并[1,2-a]吡啶化合物，其特征在于，所述R5选自：
5.一种咪唑并[1,2-a]吡啶化合物，其特征在于，其结构如式(I)～(III)所示，
其中：
式(I)中，R6为氢、甲基，或叔丁氧羰基；R7为氢或甲基；
式(II)中，R8和R9为氢或甲基；
式(III)中，R10，R11，R12都为氢，或其中一个为氢时，另两个官能团为硝基、氰基、甲基、卤素；R13为氢或甲基。
6.将如权利要求1～5之任一项所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在体外作为NEK2抑制剂中的应用。
7.将如权利要求1～5之任一项所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在制备NEK2抑制剂中的应用。
8.将如权利要求1～5之任一项所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在体外抑制肿瘤细胞活性中的应用。
9.将如权利要求1～5之任一项所述的式(1)所示的咪唑并[1,2-a]吡啶化合物在制备诱导肿瘤细胞周期停止、诱导肿瘤细胞凋亡、和抑制肿瘤细胞增殖及肿瘤生长的药物中的应用。
10.将如权利要求8或9所述的应用，其特征在于，所述肿瘤为胃癌、结肠癌、B细胞淋巴瘤、胰腺癌、乳腺癌或肝癌。
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| CN110003202A (zh) * | 2019-03-25 | 2019-07-12 | 华东师范大学 | 咪唑并[1,2-a]吡啶类衍生物的制备方法和应用 |
| WO2019238424A1 (en) * | 2018-06-15 | 2019-12-19 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereof for the treatment of diseases |
| CN114702501A (zh) * | 2022-04-27 | 2022-07-05 | 中山大学 | 一种具有抗肿瘤功效的咪唑类肽脱甲酰基酶抑制剂 |
| JP2022534576A (ja) * | 2019-05-29 | 2022-08-02 | ガラパゴス・ナムローゼ・フェンノートシャップ | 疾患の治療のための新規化合物及びその医薬組成物 |
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