CN107098903B - 含多环取代的吡唑类激酶活性抑制剂及其用途 - Google Patents
含多环取代的吡唑类激酶活性抑制剂及其用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及4‑(五元杂环并嘧啶/吡啶取代)氨基‑1H‑3‑吡唑甲酰胺类衍生物、它们的制备方法、含有这些化合物的药用组合物以及它们的医疗用途,特别是作为蛋白激酶抑制剂的抗肿瘤用途。
Description
本申请是2014年1月7日提交的名称为“含多环取代的吡唑类激酶活性抑制剂及其用途”的第201480004085.9号中国专利申请的分案申请。
技术领域
本发明涉及药物化学领域,具体涉及4-(五元杂环并嘧啶/吡啶取代)氨基-1H-3-吡唑甲酰胺类衍生物、它们的制备方法、含有这些化合物的药用组合物以及它们的医疗用途,特别是作为蛋白激酶抑制剂的抗肿瘤用途。
背景技术
细胞周期在正常条件下,由一群相关蛋白酶负责进行调控,它们担负着不同的生物功能,包括抑制或促进细胞周期的功能,其中促进细胞周期进行的大多数蛋白都属于激酶,激酶对调控蛋白质进行重要生理功能起着重要的作用,它在生物体内的主要功能是将高能分子三磷酸腺苷(ATP)的磷酸根转移到受体分子上,以调控蛋白质受体的活化或者去活化,蛋白质的活化或者去活化会调控细胞周期,而许多癌细胞中发现这些控制着正常细胞周期的激酶会突然不受调控,所以若是能够抑制这些不受调控的激酶,相信就能抑制癌细胞的不断增生。近年来陆续发现细胞周期依赖性激酶(CDK)、Aurora kinase、Polo-likekinase(PLK)、驱动蛋白(Kinesins spindle protein;KSP)和Checkpoint kinase(CHK)等新型靶标都和细胞周期有着密切的关系。
其中,中心体上Aurora激酶和CDK的共激活是启动细胞有丝分裂必不可少的条件之一,它们在调节整个细胞周期和细胞有丝分裂的过程中彼此关联、互相促进。二者的相关抑制剂研究也较为深入,且多个化合物已进入临床阶段,表现出良好的抗肿瘤药物研发前景。
研究发现,几乎所有的肿瘤都与细胞周期调控机制紊乱所导致的细胞生长失控、分化受阻、凋亡异常有关,而细胞周期蛋白依赖激酶(cyclin-dependent kinases,CDKs)的过度活化是其中的一个重要原因。CDKs是一类重要的丝氨酸/苏氨酸蛋白激酶,其本身并不具有活性,必须与细胞周期蛋白(cyclins)结合后才能产生活性,可催化底物磷酸化,驱动细胞周期各时相进程,依序完成DNA合成和有丝分裂,引起细胞的生长和增殖。同时,CDKs也能与CDKs抑制因子(CDI)结合发挥负调节作用,抑制细胞周期进程,阻止细胞分裂。由于CDKs在调节肿瘤细胞的增殖与凋亡中起关键作用,通过选择性地抑制肿瘤组织中CDKs的活性,可以对肿瘤等恶性增生性疾病的治疗起到积极的作用,所以对CDKs小分子抑制剂的筛选与研究已成为肿瘤治疗和开发新型化疗药物的热点领域之一。
在CDKs调控整个细胞周期的运行中,以CDK1、CDK2、CDK4和CDK6较为重要。由于细胞周期失控是癌变的重要原因,如果能够阻止细胞周期进入S期,DNA的异常复制就不会发生,而G1期进入S期主要是由CDK2/cyclin E调控,因此CDK2抑制剂可以阻止细胞周期进入S期进行DNA复制。此外,在整个细胞周期中,除了掌控G1期进入S期,CDK2/cyclin A还控制了S、G2期的进行,由此可见,CDK2在细胞周期中扮演着相当重要的角色,所以如果能有效抑制CDK2的活性,就可以控制细胞周期的进行,进而达到抑制肿瘤细胞增殖失控的功效。
近年来,一些CDKs小分子抑制剂已陆续公开发表,这些抑制剂大都对CDK2具有良好的抑制作用,主要是通过竞争性地结合于CDKs中ATP活性位点,从而起到抑制CDKs的作用。
Aurora家族也是一种丝/苏氨酸蛋白激酶,目前已知人类细胞中存在3种结构和功能高度相关的Aurora激酶亚型:Aurora A、B和C。它参与调节细胞的有丝分裂过程,包括中心体复制、两极纺锤体的形成以及染色体在纺锤体上的重排等,并可对纺锤体检测点(checkpoint)进行精确监测,中止错误的细胞周期进程并完成修复过程。在整个细胞周期的运行中,Aurora激酶主要作用于M期,它与CDKs共同启动有丝分裂的一系列生化事件。
其中,Aurora A和Aurora B与肿瘤密切相关。首先,Aurora A定位在20q13.2,Aurora B定位在17p13,都在易位、缺失或扩增活跃的染色体区段,意味着它们具有天然的不稳定性,这些研究表明当Aurora A过度表达时,它是一种潜在的致癌基因;而且这两个染色体区在乳腺癌和结直肠癌肿瘤组织中以及乳腺癌、卵巢癌、结肠癌、前列腺癌、神经母细胞瘤和宫颈癌细胞株普遍存在扩增。目前人们对Aurora C的致癌作用研究较少。
Aurora A、B和C在催化区具有很高的同源性,仅有调节区和催化区末端的一小段氨基酸序列存在差异,与抑制剂结合的活性位点则位于铰链区。ATP结构中的嘌呤环可结合于Aurora激酶结构的疏水口袋,并与铰链区的氨基酸残基形成氢键,Aurora激酶抑制剂则可竞争性结合ATP与Aurora激酶的结合位点,也属于ATP竞争性抑制剂。
有文献报道,在G2末期显微注射Aurora激酶抗体可致有丝分裂启动显著延迟,现在认为其机制是Aurora A激酶作为活化的细胞周期蛋白依赖激酶(CDKs)/cyclin复合物的下游效应物,参与完成了启动有丝分裂的一系列生化事件;它与CDKs/cyclin复合物形成正反馈交互活化环,即CDKs/cyclin复合物先激活Aurora激酶,反过来Aurora激酶又促进CDKs的完全活化及该复合物的细胞核内定位,而这两个事件对于启动有丝分裂来说极为重要。总之,在整个细胞周期的运行中,中心体上Aurora激酶和CDKs的共激活是启动细胞有丝分裂必不可少的条件之一,它们在调节细胞周期和细胞有丝分裂的过程中彼此关联,因此若能同时抑制Aurora激酶和CDKs的活性,就能双重抑制肿瘤细胞的过度繁殖,由此可见,开发新型CDKs/Aurora多靶点抑制剂极具价值。
在整个细胞周期中,CDK2除了掌控G1期进入S期,CDK2还控制了S、G2期的细胞运行,因此抑制CDK2就可以阻止细胞周期中DNA的正常复制。而在M期,调节细胞的有丝分裂主要是依靠Aurora A,它在中心体复制、两极纺锤体的形成以及染色体的重排等方面起着不可替代的作用,抑制Aurora A就可以阻止细胞有丝分裂。因此,寻找对CDK和Aurora激酶能同时作用的小分子多靶点抑制剂,多方式影响癌细胞的细胞周期,更好的达到治疗肿瘤的目的。
到目前为止,有大量的CDK2和Aurora A的晶体复合物结构已被解析,抑制剂与靶标的作用模式已非常清晰,为基于结构的多靶点药物设计奠定了基础。通过对比发现,CDK2和Aurora A激酶抑制剂都竞争性的结合于ATP结合口袋中,主要是通过氢键和疏水作用和酶结合。它们与小分子抑制剂的作用模式具有一些共同的特点,其共同的药效作用区域表现如下:即CDK2和Aurora A激酶的三维结构和理化性质如氢键、疏水性以及亲水性的空间分布很相似:1)铰链区(hinger):铰链区为所有ATP竞争性抑制剂的重要作用区域,在此区域往往存在有2-3个关键性的氢键,这两个激酶中参与氢键形成的残基分别为Glu81和Leu83(CDK2);Glu211和Ala213(Aurora A)。另外该区域存在的往往为一些疏水性的平面结构片段,以保证在铰链区还存在有一定的疏水作用。2)疏水区A:指在铰链区与天冬氨酸(CDK2为Asp145,Aurora A为Asp274)之间形成的一个疏水空腔,该区域位置靠近激酶的DFG基序,由于该环区具有一定的柔性,使得该处的疏水性结构片段的选择表现出一定的多样性。3)亲水区:两者的活性位点中都存在有一个亲水性的区域,在这一区域的亲水性基团的引入对化合物的理化性质的调节有着重要的意义。CDK2的亲水区在Gln85附近;Aurora A的亲水区在Leu215附近。这些药效作用区域在空间上有着高度的重叠性,从而使我们设计出CDK/Aurora多靶点的抑制剂成为可能,通过重叠配体方式所产生多靶点药物分子往往具有分子量小,理化性质好,耐药性大为改善的特点。
同时,近年来随着对蛋白激酶研究的深入,基于结构与基因序列,蛋白家族这样概念被不断提出作为参与细胞内多种信号转导调控、结构和功能相似的酶家族。依据磷酸化底物的不同(例如蛋白质-酪氨酸、蛋白质-丝氨酸/苏氨酸、脂质等),可将蛋白激酶分类为多个子家族。蛋白激酶的特征在于它们的调节机制。这些机制包括例如自磷酸化、通过其它激酶的转磷酸作用、蛋白质-蛋白质相互作用、蛋白质-脂类相互作用以及蛋白质-多核苷酸相互作用。单一的蛋白激酶可参与多种机制调节。蛋白激酶的功能在于催化ATP末端的δ-磷酸对蛋白质中丝氨酸、苏氨酸或酪氨酸残基的侧链羟基进行磷酸化,调控其底物活性,介导多数细胞信号转导通路,从而调节很多不同的细胞过程。所述的细胞过程包括但不限于增殖、分化、凋亡、运动、转录、翻译和其它信号过程。磷酸化事件用作分子开关,可调节或调控靶蛋白生物学功能。靶蛋白的磷酸化因响应于多种细胞外信号(激素、神经递质、生长和分化因子等)、细胞周期事件、环境或营养应激等而发生。适合的蛋白激酶在(直接或间接)活化或钝化例如代谢酶、调节蛋白、受体、细胞骨架蛋白、离子通道或泵或者转录因子的信号传导途径中发挥作用。由于蛋白磷酸化控制缺陷造成的信号传导失控与多种疾病有关,所述的疾病包括例如炎症、癌症、糖尿病、变态反应/哮喘、免疫系统的疾病和病症、中枢神经系统的疾病和病症以及血管生成的疾病和病症等。
人类激酶组(humankinome)包含518种蛋白激酶,主要可分为酪氨酸激酶90种、丝氨酸/苏氨酸激酶388种和非经典激酶40种。基于进化分析,Hanks和Hunter通过对人类蛋白激酶进行过几次分类。随着克隆蛋白激酶成员的增加,他们对蛋白激酶的分类越来越系统和详细。他们以系统进化树作为蛋白激酶分类的基础。Hanks和Hunter对1993年6月为止发表的蛋白激酶成员的整个功能域的氨基酸序列进行系统进化分析。此系统进化树中包括4个大的激酶家族:(a)AGC家族,包括环核苷酸依赖家族(PKA和PKG家族),蛋白激酶C家族,B-肾上腺素受体激酶(BARK)家族,核糖体S6激酶家族和其它相关激酶;(b)CaMK家族,包括Ca2+/-钙调素调节的蛋白激酶家族,Snfl/AMPK家族和其它相关蛋白激酶;(c)CMGC家族,包括细胞周期因子依赖蛋白激酶(CDK)家族,Erk(MAP)蛋白激酶家族,糖原合成酶3激酶(GSK3)家族,酪蛋白激酶Ⅱ家族,Clk家族和其他相关激酶;(d)酪氨酸蛋白激酶家族。此系统进化树中还包括许多不属于此四大家族的蛋白激酶。每个大家族可进一步分类为亚家族,其中每大家族中至少显示一个实例,即ABL Abelson激酶;Akt Akt/蛋白激酶B(PKB);EGFR表皮生长因子受体;FGFR纤维母细胞生长因子受体;MLK混合谱系激酶(mixed-lineagekinase);PDGFR血小板衍生生长因子受体;TIE有免疫球蛋白-样酪氨酸激酶和EGF-样结构区;VEGFR血管内皮生长因子受体。同一个家族的成员除了在一级结构上有较高的一致性以外,它们在拓扑结构、调节方式和底物特异性方面具有相似性,进化上相近的成员,功能上也具有相近性。
CMGC是丝氨酸/苏氨酸蛋白激酶中的一类,它们大都磷酸化位于脯氨酸丰富的环境中的丝氨酸或苏氨酸。这一家族的成员在Ⅹ和Ⅺ功能亚域有一较大的插入序列。由于Dyrk(MNB),Dyrk2,Dyrk3都与Yakl有较高同源性,因此应归于一个家族。其中CDK家族作为CMGC中一大类在本文之前有过介绍,如CDK1、CDK2、CDK4和CDK6主要参与调控整个细胞周期的运行中,而其他CDK家族成员参与了其它生物化学过程。以CDK5举例说明,CDK5在正确的神经元发展中是必需的并且其也涉及数种神经元蛋白(例如Tau、NUDE-1、突触蛋白1、DARPP32和Munc18/突触融合蛋白1A复合体)的磷酸化。神经元CDK5通常是通过与p35/p39蛋白结合而活化的。但是,CDK5的活性可以通过与p25(p35的截短形式)的结合而失调。p35至p25的转化以及接下来CDK5活性的失调可以由局部缺血、兴奋性中毒和β-淀粉样肽诱导。因此,p25已经涉及神经变性疾病(例如阿尔茨海默病)的发病机制,并且因此其被关注作为直接治疗这些疾病的靶标。
CDK7是具有cdc2CAK活性并且与细胞周期蛋白H结合的核蛋白。已经表明CDK7是具有RNA聚合酶II C-末端结构域(CTD)活性的TFIIH转录复合体的组分。其通过Tat-介导的生物化学途径而与HIV-1转录的调节有关。CDK8与细胞周期蛋白C结合并且涉及RNA聚合酶II的CTD的磷酸化。类似地,CDK9/细胞周期蛋白-T1复合体(P-TEFb复合体)涉及RNA聚合酶II的延长控制。PTEF-b也需要HIV-1基因组通过与细胞周期蛋白T1相互作用而被病毒反式激活蛋白Tat转录活化。因此,CDK7、CDK8、CDK9和P-TEFb复合体是抗病毒治疗的潜在靶标。
在分子水平调节CDK/细胞周期蛋白复合体的活性需要一系列刺激的和抑制的磷酸化或去磷酸化事件。CDK磷酸化是通过一组CDK活化激酶(CAK)和/或激酶例如wee1、Myt1和Mik1而进行的。去磷酸化是通过磷酸酶例如cdc25(a和c)、pp2a或KAP进行的。
同时,人们发现细胞周期蛋白D1的过度表达与食管癌、乳腺癌、鳞状癌和非小细胞肺癌有关。在肺癌发病机制中,作用抑癌基因的失活是目前研究中的一个热点,抑癌基因p15/MTS2(简称p15基因)编码p15蛋白属于INK4蛋白家族,它作用于细胞周期蛋白依赖激酶(CDK)与细胞周期蛋白(cyclin)复合物,特异性抑制CDK4及CDK16激酶活性,阻止其磷酸化R6蛋白,限制细胞由G1期向S期转变,减少细胞增殖.。
CMGC激酶的另一家族成员丝裂原活化蛋白激酶(mitogen-activated proteinkinase,MAPK)是一类丝氨酸/苏氨酸蛋白激酶,能将细胞外信号转导至细胞及核内,通过保守的三级级联反应(MAPKKK-MAPKK-MAPK)激活转录因子,调节基因表达。该通路存在于大多数细胞中,且与多种细胞功能相关,可参与细胞运动、凋亡、分化及生长增殖等多种生理过程。已确定有4条MAPK信号转导通路:每条信号通路都具有高度特异性,具有独立的功能。在某些程度上几条信号通路间存在着一定的串话(crosstalk)。利用抑制剂或激活剂对各条信号通路进行研究,不仅可以非常好的了解信号通路的作用机制,而且可以为疾病的诊断和治疗创造新的契机,ERK信号通路是研究最透彻的通路之一,其中,MEK是Ras-Raf-MEK-ERK信号转导途径的关键酶,对不同的生长信号调节细胞应答。至今发现7个MEK亚型,分别磷酸化并激活下游的MAPKs,其中MEK1和MEK2激活ERK,MEK3和MEK4激活p38,而MEK5和MEK6激活JNK。因此在ERK信号通路研究中,常以MEK1/MEK2作为肿瘤治疗的靶标,开发具发展前景的抗肿瘤药物。p38MAPK信号通路是MAPK通路的一条重要分支,该通路可被应激刺激(渗透压休克、UV、缺氧)、细胞因子刺激、胰岛素、生长因子刺激激活,甚至在正常的免疫和炎性反应中被活化。同时,近几年另一信号通路p38的研究也成为热点,是临床上治疗风湿性关节炎攻克的主要靶标。.c-Jun N端激酶(JNK)/应激活化蛋白(SAPK)信号通路JNKs(c-Jun N端激酶)是MAPKs家族的重要成员之一。c-Jun属于AP-1转录因子复合物的一个成员,参与控制细胞增殖、转化、生存和死亡。JNK也能磷酸化p53和一些非核蛋白。JNK介导的目标蛋白磷酸化作用极其重要,它能够诱导白细胞介素、VEGF、COX-2、MMP-9、血红素加氧酶-1、ICAM-1,NCX1,GnRHR及其他细胞因子的基因表达。JNK信号通路参与炎症及包括风湿性关节炎、肠易激综合征、动脉粥样硬化在内的自身免疫性疾病。K5/大丝裂素活化蛋白激酶(BMK1)信号通路ERK5/BMK1是MAPK家族最晚发现的信号通路,其胞外应激物有高糖、低氧、血流切应力、活性氧簇(ROS)、渗透压以及各种丝裂原如EGF、NGF等。ERK5/BMK1同样遵循MAPK的级联反应,MEKK 2/3(MAPK-KK)-MEK5(MAPKK)-BMK1/ERK5(MAPK)。一旦激活后,ERK5由胞浆移至核内,并磷酸化大量的下游目标,包括MEF2C、c-Myc、Bim、AP-1等。ERK5在细胞生存、增殖及分化中发挥着重要作用,目前研究发现其与糖尿病肾病、肝纤维化以及肿瘤等病理过程密切相关。
糖原合酶激酶-3(GSK-3)是丝氨酸-苏氨酸激酶,该酶在人体中以两种普遍存在的表达的同种型(GSK3α和βGSK3β)存在。GSK3涉及在胚胎发育、蛋白质合成、细胞增殖、细胞分化、微管动力学、细胞运动和细胞凋亡中起作用。同样GSK3涉及疾病状态的进程,所述的疾病状态例如糖尿病、癌症、阿尔茨海默病、中风、癫痫、运动神经元疾病和/或头部创伤。在系统发育方面,GSK3与细胞周期蛋白依赖性激酶(CDK)是最相关的。
GSK3形成了哺乳动物胰岛素响应途径的一部分并且能够磷酸化,并且因此钝化糖原合酶。通过GSK3的抑制,糖原合酶活性增量调节并且因此糖原合成已经因此被认为是对抗II型或非胰岛素依赖性糖尿病(NIDDM)(其中机体组织对胰岛素刺激变得有抗性的病症)的潜在的方法。抑制GSK3(例如通过“哺乳动物雷帕霉素靶标”蛋白(mTOR)的钝化)可以增量调节蛋白的生物合成。最后,通过促细胞分裂原活化的蛋白激酶(MAPK)途径通过激酶(例如促细胞分裂原活化的蛋白激酶活化的蛋白激酶1(MAPKAP-K1或RSK))磷酸化GSK3来调节GSK3活性已经有一些证据。这些数据表明GSK3的活性可以由促细胞分裂的、胰岛素/或氨基酸刺激来调节。
除此之外,GSK3β在脊椎动物Wnt信号传导途径中是关键组分。已经表明该生物化学途径对于正常的胚胎发育是关键的并且调节正常组织中的细胞增殖。在对Wnt刺激响应中GSK3变为抑制的。这可以引起GSK3底物(例如Axin、腺瘤性结肠息肉(APC)基因产物和β-联蛋白)的去磷酸化。Wnt途径的异常调节与许多癌症有关。APC和/或β-联蛋白中的突变在结肠直肠癌和其它肿瘤中是很普遍的。也表明β-联蛋白在细胞粘附中很重要。因此,GSK3也可以在某种程度上调节细胞粘附过程。除了已经描述的生物化学途径,也有涉及GSK3在通过细胞周期蛋白-D1的磷酸化来调节细胞分裂中的数据、GSK3在转录因子(例如c-Jun、CCAAT/增强子结合蛋白α(C/EBPα)、c-Myc和/或其它底物,例如活化的T-细胞的核因子(NFATc)、热休克因子(HSF-1)和c-AMP响应元件结合蛋白(CREB))的磷酸化的数据。虽然具有组织特异性,但是GSK3也在调节细胞凋亡中发挥作用。GSK3在通过前凋亡机制调节细胞凋亡中的作用可能与可以发生神经元凋亡的医学病症特别有关。这些病症的实例是头部创伤、中风、癫痫、阿尔茨海默病和运动神经元疾病、进行性核上麻痹、皮质基底节变性和皮肤病。体外已经表明GSK3能够过度磷酸化与蛋白Tau有关的微管。Tau的过度磷酸化破坏了其与微管的正常结合并且也可以引起细胞内Tau纤丝的形成。相信这些纤丝的逐步富集引起了最终的神经元功能障碍和变性。因此,通过抑制GSK3而抑制Tau磷酸化可以提供限制和/或预防神经变性作用的方法。
蛋白酪氨酸激酶(protein tyrosine kinases,PTKs)作为另一类重要的蛋白激酶家族,它催化ATP的γ磷酸基转到许多重要蛋白质的酪氨酸残基上,使酚羟基磷酸化,在一般的正常细胞中(神经细胞除外),蛋白质的酪氨酸磷酸化是极少发生的。虽然磷酸化的酪氨酸仅占体内磷酸化氨基酸0.5‰,但是一系列证据表明,酪氨酸磷酸化在许多细胞调节过程中起着重要作用。它传递细胞信号,是信号传递过程中的重要因子。蛋白酪氨酸激酶参与一系列细胞功能,与细胞生长、分化、增殖密切相关。在细胞的恶性生长和增殖中,酪氨酸激酶起着非常重要的作用,酪氨酸激酶功能的失调,会导致其下游信号途径激活,,引起细胞增殖调节紊乱,最终导致肿瘤形成。所以酪氨酸激酶抑制剂可对恶性肿瘤有预防和治疗作用。
根据(PTKs)是否存在于细胞膜受体可将其分为非受体酪氨酸激酶(NonreceptorTyrosine Kinases,简称NRTKs)和受体酪氨酸激酶(Receptor Tyrosine Kinases,简称RTKs)。目前发现受体酪氨酸激酶(RTKs)58种。这些蛋白激酶的结构上都存在一个由约270氨基酸残基构成的催化结构区,这个结构区非常相似。受体型的酪氨酸激酶(PTKs)则是一种具有跨膜结构的蛋白,通常具有一个细胞外结构域、一个跨膜区以及一个细胞内激酶域。癌症临床研究表明,这些受体及其配体与很多肿瘤都有重要联系,很多癌症出现了相关生长因子的过量表达,导致过量的酪氨酸磷酸化信号传入细胞,其中包括血小板衍生生长因子(PDGF)受体(PDGF受体α和β)、集落刺激因子(CSF-I)受体(CSF-1R,c-Fms)、FLT-3和干细胞因子受体(c-kit)等,与多种细胞增生及炎症等疾病有关。其中,FLT3基因位于染色体13q12,是1991年发现的早期造血生长因子受体基因,其编码的FLT3受体属于第III类酪氨酸激酶(RTK)受体家族成员。当FLT-3受体的细胞膜外结构域与其内源性配体结合后,FLT-3形成同源或异源二聚体复合物,致使其酪氨酸激酶活性被激活,活化环开启,促使底物蛋白连接到ATP结合位点上,进一步催化底物蛋白的磷酸化,从而介导一系列下游信号转导,导致细胞的增殖和分化。FLT-3受体广泛分布于骨髓造血干/祖细胞、胸腺、淋巴、胎盘、大脑、生殖腺等多种组织中。但FLT-3基因突变(主要包括近膜结构域的内部串联重复突变和酪氨酸激酶区域的点突变)、过度表达则会导致急性髓细胞性白血病等多种血液系统恶性肿瘤疾病的发生,因此,将FLT-3作为靶点用于肿瘤治疗已经成为研究的热点,特别是在血液学恶性肿瘤中,FLT3以高水平表达或者FLT3突变引起不受控制的FLT3受体和下游分子通道诱导,可能的Ras活化。血液学恶性肿瘤包括"白血病、淋巴瘤(非霍奇金淋巴瘤)、霍奇金病(也称为霍奇金淋巴瘤)和骨髓瘤一例如,急性淋巴细胞白血病(ALL)、急性粒细胞白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、慢性嗜中性粒细胞白血病(CNL)、急性未分化细胞白血病(AUL)、退行发育性大细胞性淋巴瘤(ALCL)、幼淋巴细胞白血病(PML)、幼年型粒-单核细胞白血病(JMML)、成人T细胞ALL、伴有三谱系(trilineage)脊髓发育不良的AML(AML/TMDS)、混合型谱系白血病(MLL)、脊髓发育不良综合征(MDSs)、骨髓增生异常(MPD)、多发性骨髓瘤(MM)和脊髓肉瘤。
同时,受体酪氨酸激酶胞外结构区可结合特异性配基如生长因子,而细胞内结构区达到激酶(自身)磷酸化。被受体酪氨酸激酶介导的信号传导通路和生物学过程集中在血管生成,大量研究表明显示了在血管生成中选择涉及被受体酪氨酸激酶活化的通路。通路活化,例如通过VEGFR或PDGFR可导致各种血管生成过程,如细胞增殖,迁移,生存和血管通透性。这与系列的血管类疾病密不可分。
目前发现的32种非受体酪氨酸激酶(NRTKs),通常持续或暂时位于胞浆,或者在细胞内侧与跨膜蛋白结合,所以它们又被称作胞浆型酪氨酸激酶,在肿瘤组织中nPTKs常被激活,促进细胞增殖、抵抗细胞凋亡,促使肿瘤发生和发展。非受体酪氨酸激酶主要包括SRC、ABL、JAK、ACK、CSK、FAK、FES、FRK、TEC、SYK等10个家族。细胞因子(cytokine)能够通过多种途径进行细胞内信号转导,从而参与调控细胞生长和凋亡过程。细胞因子靶细胞生长,分化和凋亡过程。细胞因子受体通常在胞质没有PTKs结构域,但是在细胞因子靶细胞中在有nrPTKs一次介导细胞因子与其受体结合后的信号转导。其中JAK激酶与其下游的STAT组成了重要的信号途径。许多细胞因子都能激活JAK/STAT信号途径,当细胞因子与其受体结合引起细胞质受体的构象改变,进而激活与受体结合引起细胞胞质受体的构象改变,进而激活与受体关联的JAK激酶家族,JAK激酶促使相应的STAT磷酸化而激活,激活的STAT从受体上游离,形成二聚体后进入细胞核,与GAS增强家族成员结合,从而激活转录、诱导细胞转化,调控某些与细胞增殖和存活相关基因的表达,在肿瘤中的发生中起重要的作用。
目前,受体酪氨酸激酶如血管内皮生长因子受体现阶段研究较多的是EGFR和VEGFR酪氨酸激酶抑制剂,是以血管生成抑制被发展为一种癌全身治疗策略。早期上市的蛋白激酶抑制剂主要是针对单一靶点的单靶点抑制剂,虽然刚上市时在肿瘤治疗中取得了令人瞩目的成就,但是随着使用时间的延长及治疗病例的增多,问题逐渐暴露出来。相比较多靶点激酶抑制剂则显示出一定的优势。由于同时靶向多个激酶分子和多条信号通路,不但可以避免单一靶点突变造成的耐药性,而且可以显著扩大其抗瘤谱。单一靶点抑制剂SU5416和SU6668开发的失败进一步提示,多靶点激酶抑制剂应将成为未来的主流发展方向。SU5416和SU6668分别靶向KDR和PDGFR-β,都因疗效不佳而终止于临床III期和II期,但同样靶向KDR等多个激酶的Sunitinib却最终成功上市。现在研究的化合物大多是针对多靶点设计的,这是因为多靶点比单一靶点抑制活性和病人耐受性都好。现在上市的和在临床研究的小分子酪氨酸抑制剂根据化学结构只要分为以下几类:喹唑啉类、吲哚酮类、哒嗪类、氰基喹啉类和吡咯并嘧啶类等结构。三种抗血管生成酪氨酸激酶抑制剂(TKIs),舒尼替尼(sunitinib),索拉非尼(sorafenib)和帕唑帕尼(pazopanib),与血管生成激酶有不同结合能力最近被批准治疗晚期癌症(肾细胞癌,胃肠道间质瘤,和肝细胞癌)患者。许多其它抗血管生成TKIs正在I-III期临床试验研究。除了它们有益的抗肿瘤活性,用这些药物还曾观察到临床耐受性和毒性。
长期大剂量使用紫杉烷类注射液已造成病人耐药现象并导致疗效下降,越来越多的证据表明,耐药现象会限制靶点受体酪氨酸激酶抑制剂的疗效。因而,开发新一代的抗癌药物,具有重要的意义。同时研究表明激酶类疾病存在内源性的相关联,单一的靶标作用难以真正抑制其发生。
由于CDK及Auraro A其相关蛋白在增殖细胞中协调和推动细胞周期中的关键性作用,可用于增殖性障碍例如癌症治疗(应用通常靶向CDK或特异性CDK的疗法),也可以用于治疗其它病症例如病毒感染、自身免疫疾病和神经变性疾病等。当与存在的或新的治疗剂组合用于治疗时,CDK靶向治疗也可以在前面描述的疾病的治疗中提供临床益处。与许多目前的抗肿瘤剂相比,且相对于前文中的酪氨酸激酶,CDK的突变及其抑制剂的耐药情况发生情况少,靶向抗癌治疗具有潜在的优势,且不直接与DNA相互作用并且因此可以降低继发性肿瘤发生的危险。
小分子多靶点的CDK抑制剂,如flavopiridol和UCN201,已经在Ⅰ、Ⅱ期临床试验中显示出良好的抗肿瘤活性。但多数抑制剂为单一家族抑制剂,这方面许多公司都开展了这类的抑制剂研究,如处于I/II期研究阶段的新型小分子多细胞周期蛋白依赖性激酶抑制剂AT7519作用于CDK1/cyclin B,CDK2/Cyclin A,CDK3/Cyclin E等多个靶点,同时,AT7519也可通过下调同家族蛋白抑制剂GSK-3β磷酸化而诱导GSK-3β激活,从而导致细胞凋亡。相对而言,跨激酶蛋白家族的抑制剂的结构类型目前报道尚不多,选择性的作用于多个疾病特征性的靶点的激酶抑制剂的研发具有其突破性的意义。
发明内容
本发明在研究了大量具有选择性的CDK2、Aurora A小分子抑制剂的基础上,根据CDK2、Aurora A的晶体结构模型,利用计算机辅助药物设计手段分别搭建了CDK2、Aurora A抑制剂的构效关系模型和药物虚拟筛选模型,在此基础上采用碎片增长的计算机辅助药物设计方法构建相关化合物库,通过虚拟筛选,确定并合成了一系列以4-(五元杂环并嘧啶/吡啶取代)氨基-1H-3-吡唑甲酰胺为母核的全新结构的化合物,药理试验显示,本发明的化合物均具有优良的CDK2、Aurora A双重抑制活性的同时,还对多个CMCG家族及TK家族激酶具有抑制活性。对多种肿瘤细胞株具有强的抑制活性,部分化合物优于目前已报道的CDK2抑制剂AT-7519,Aurora A抑制剂AT-9283及多靶点抑制剂十字苞碱。
本发明的技术方案如下:
通式(I)的化合物或其药学上可接受的盐及互变异构体:
其中R1、R2、R3各自独立地表示氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
X、Y各自独立地表示N原子或CH原子团;其中CH原子团可任选被R4取代,R4可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
Z、M各自独立地表示NH、O、S或CH原子团,且Z、M必需有一个为NH、O或S;其中CH或NH原子团各自独立地可任选被R5取代,R5可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
A1各自独立地表示NH、O、S或亚烷基原子团;其中NH原子团或亚烷基原子团各自独立地可任选被R6取代,R6可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
A2各自独立地表示亚烷基、C(O)NH、C(O)、NHC(O)、亚烷基-C(O)、C(O)-亚烷基、亚烷基-C(O)-亚烷基或NHC(O)NH;上述基团各自独立地可任选被R7取代,R7可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
Q1是选自芳基或Het,其中芳基或Het各自独立地可任选被一个或多个R8取代,R8可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
Q2是选自芳基或Het,其中芳基或Het各自独立地可任选被一个或多个R9取代,R9可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
烷基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;
亚烷基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基失去一个氢原子形成的基团;
烷氧基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被氧取代;
烷硫基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中各碳原子任选被硫取代;
烷氧基烷基为如上定义的烷氧基与烷基连接;
芳基为选自苯基、萘基、苊基或四氢萘基的碳环,其各自任选被1、2或3个取代基取代,各取代基独立地选自氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
芳烷基、二芳基烷基为如上定义的芳基与烷基连接;
Het为选自哌啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环;或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环;各单环或双环杂环任选被1、2或3个取代基取代,各取代基独立选自卤素、卤代烷基、羟基、烷基或烷氧基;
卤素为选自氟、氯、溴或碘的取代基;
卤代烷基为具有1-6个碳原子的直链或支链饱和烃基,或为具有3-6个碳原子的环状饱和烃基,或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;其中一个或多个碳原子被一个或多个卤原子取代。
本发明的优选方案在于:
其中R1、R2、R3各自独立地表示氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基或芳基;
X、Y各自独立地表示N原子或CH原子团;其中CH原子团可任选被R4取代,R4可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基或芳基;
Z、M各自独立地表示NH、O、S或CH原子团,且Z、M必需有一个为NH、O或S;其中CH或NH原子团各自独立地可任选被R5取代,R5可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基或芳基;
A1各自独立地表示NH、O、S或亚烷基原子团;其中NH原子团或亚烷基原子团各自独立地可任选被R6取代,R6可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基或芳基;
A2各自独立地表示亚烷基、C(O)NH、C(O)、NHC(O)、亚烷基-C(O)、C(O)-亚烷基、亚烷基-C(O)-亚烷基或NHC(O)NH;上述基团各自独立地可任选被R7取代,R7可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基或芳基;
Q1是选自芳基或Het,其中芳基或Het各自独立地可任选被一个或多个R8取代,R8可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基或芳基;
Q2是选自芳基或Het,其中芳基或Het各自独立地可任选被一个或多个R9取代,R9可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基或芳基。
本发明的另一优选方案在于:
其中R1、R2、R3各自独立地表示氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
X、Y各自独立地表示N原子或CH原子团;其中CH原子团可任选被R4取代,R4可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Z、M各自独立地表示NH、O、S或CH原子团,且Z、M必需有一个为NH、O或S;其中CH或NH原子团各自独立地可任选被R5取代,R5可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
A1各自独立地表示NH、O、S或亚烷基原子团;其中NH原子团或亚烷基原子团各自独立地可任选被R6取代,R6可以氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
A2各自独立地表示亚烷基、C(O)NH、C(O)、NHC(O)、亚烷基-C(O)、C(O)-亚烷基、亚烷基-C(O)-亚烷基或NHC(O)NH;上述基团各自独立地可任选被R7取代,R7可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Q1是选自芳基或Het,其中芳基或Het各自独立地可任选被一个或多个R8取代,R8可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Q2是选自芳基或Het,其中芳基或Het各自独立地可任选被一个或多个R9取代,R9可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基。
本发明的另一优选方案在于:
其中R1、R2、R3各自独立地表示氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
X、Y各自独立地表示N原子或CH原子团;其中CH原子团可任选被R4取代,R4可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Z、M各自独立地表示NH、O、S或CH原子团,且Z、M必需有一个为NH、O或S;其中CH或NH原子团各自独立地可任选被R5取代,R5可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
A1各自独立地表示NH、O、S或亚烷基原子团;其中NH原子团或亚烷基原子团各自独立地可任选被R6取代,R6可以氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
A2各自独立地表示亚烷基、C(O)NH、C(O)、NHC(O)、亚烷基-C(O)、C(O)-亚烷基、亚烷基-C(O)-亚烷基或NHC(O)NH;上述基团各自独立地可任选被R7取代,R7可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Q1是选自下列的芳香环或取代的芳香环:苯基、萘基、吡咯基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基,上述基团各自独立地可任选被一个或多个R8取代,R8可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Q2是选自下列的芳香环:苯基、萘基、吡唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基,或C3-C8的脂肪族碳环,或下列的脂肪族杂环:四氢吡咯基、哌啶基、吗啉基、甲基哌嗪基;上述基团各自独立地可任选被一个或多个R8取代,R8可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基。
本发明的另一优选方案在于:
其中R1、R2、R3各自独立地表示氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
X、Y各自独立地表示N原子或CH原子团;其中CH原子团可任选被R4取代,R4可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Z、M各自独立地表示NH、O、S或CH原子团,且Z、M必需有一个为NH、O或S;其中CH或NH原子团各自独立地可任选被R5取代,R5可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
A1各自独立地表示NH、O、S或亚烷基原子团;其中NH原子团或亚烷基原子团各自独立地可任选被R6取代,R6可以氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
A2各自独立地表示亚烷基、C(O)NH、C(O)、NHC(O)、亚烷基-C(O)、C(O)-亚烷基、亚烷基-C(O)-亚烷基或NHC(O)NH;上述基团各自独立地可任选被R7取代,R7可以是氢、烷基、氰基、卤素、卤代烷基、羟基、巯基、烷氧基、烷硫基或烷氧基烷基;
Q1是选自下列的芳香环或取代的芳香环:苯基、萘基、吡咯基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基,取代基可以是1~2个卤素或三氟甲基;
Q2是选自下列的芳香环:苯基、萘基、吡唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基,或C3-C8的脂肪族碳环,或下列的脂肪族杂环:四氢吡咯基、哌啶基、吗啉基、甲基哌嗪基。
本发明的另一优选方案在于:
其中R1、R2、R3各自独立地表示氢、C1-C4烷基;
X、Y各自独立地表示N原子或CH原子团;
Z、M各自独立地表示NH、O、S或CH原子团,且Z、M必需有一个为NH、O或S;
A1各自独立地表示NH、O、S或CH2原子团;
A2各自独立地表示链状C1-C4亚烷基、C(O)NH、C(O)、NHC(O);
Q1是选自下列的芳香环或取代的芳香环:苯基、萘基、吡咯基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基,取代基可以是1~2个卤素或三氟甲基;
Q2是选自下列的芳香环:苯基、萘基、吡唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基,或C3-C8的脂肪族碳环,或下列的脂肪族杂环:四氢吡咯基、哌啶基、吗啉基、甲基哌嗪基。
本发明的另一优选方案在于:
其中R1、R2、R3各自独立地表示氢、甲基;
A1表示NH;
A2表示CH2;
Q1表示苯基;
Q2表示吗啉基、甲基哌嗪基。
根据本发明,药学上可接受的盐包括通式I化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸。此外还包括无机碱的酸式盐,如:含有碱性金属阳离子、碱土金属阳离子、铵阳离子盐。当存在硫时,其可以在相邻原子和基团的性质允许时以-S-、-S(O)-或-S(O)2-存在。
通式I的化合物优选以下结构化合物:
4-(4-噻吩并[2,3-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-1)
4-(4-噻吩并[2,3-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-2)
4-(4-(6-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-3)
4-(4-(6-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-4)
4-(4-(5-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-5)
4-(4-(5-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-6)
4-(4-(5,6-二甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-7)
4-(4-(5,6-二甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-8)
4-(4-噻吩并[3,2-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-9)
4-(4-噻吩并[3,2-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-10)
4-(4-(7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-11)
4-(4-(7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-12)
4-(4-(6-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-13)
4-(4-(6-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-14)
4-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-15)
4-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-16)
4-(4-(5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-17)
4-(4-(5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-18)
4-(4-(6-甲基-5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-19)
4-(4-(6-甲基-5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-20)
4-(4-呋喃并[2,3-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-21)
4-(4-呋喃并[2,3-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-22)
4-(4-呋喃并[3,2-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-23)
4-(4-呋喃并[3,2-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-24)
4-(4-噻吩并[3,2-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-25)
4-(4-噻吩并[3,2-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-26)
4-(4-(2-甲基噻吩并[3,2-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-27)
4-(4-(2-甲基噻吩并[3,2-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-28)
4-(7-噻吩并[2,3-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-29)
4-(7-噻吩并[2,3-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-30)
4-(7-(3-甲基噻吩并[2,3-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-31)
4-(7-(3-甲基噻吩并[2,3-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-32)
4-(4-呋喃并[3,2-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-33)
4-(4-呋喃并[3,2-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-34)
4-(4-(2-甲基呋喃并[3,2-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-35)
4-(4-(2-甲基呋喃并[3,2-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-36)
4-(7-呋喃并[2,3-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-37)
4-(7-呋喃并[2,3-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-38)
4-(7-呋喃并[3,2-b]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-39)
4-(7-呋喃并[3,2-b]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-40)
4-(4-呋喃并[2,3-b]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-41)
4-(4-呋喃并[2,3-b]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-42)
4-(7-(1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-43)
4-(7-(1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-44)
4-(7-(2-甲基-1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-45)
4-(7-(2-甲基-1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-46)
4-(4-(2-甲基噻吩并[3,2-d]嘧啶)基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-47)
4-(4-(2-甲基噻吩并[3,2-d]嘧啶)基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-48)
本发明的部分化合物制备方法如下:
方法一:
方法二:
方法三:
方法四:
本发明化合物都可以用上述或类似上述的制备方法制备得到,根据取代基的不同和取代基位置的不同选用相应的原料即可。
在式(I)化合物中,包括吡唑基团可以是下列两种互变异构体形式A和B中的任何一种。
互变异构体形式的其它实例包括例如酮-、烯醇-和烯醇化物-形式,如例如在下列互变异构体对中:酮/醇(以下说明的)、亚胺/烯胺、酰胺/亚胺醇、脒/脒、亚硝基/肟、硫酮/烯硫醇以及硝基/酸式-硝基中。
式(I)化合物及其亚组作为是CMGC家族激酶,特别选自CDK细胞周期蛋白激酶、GSK糖原合成激酶、促分裂素原活化蛋白激酶(MAPK)和CDK-样激酶(CLK)家族激酶。优选的化合物是抑制一种或多种CDK激酶、GSK激酶及MAPK激酶的化合物,所述激酶选自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDk7、CDK9、GSK3、CHK2、ERK7、FGFR、VEGFR、JAk、JNK、KDR、PDGFR、C-SCR、Aurora和FLT3。
本发明化合物还被视为TK家族激酶抑制,特别是选自受体酪氨酸家族抑制剂及非受体酪氨酸家族抑制剂,其中特别选自受体激酶家族抑制剂,表皮生长因子受体(EGFR)家族、血小板生长因子受体(PDGFR)家族、神经生长因子受体(NGFR)、成纤维细胞生长因子受体(FGFR)家族、肝细胞生长因子受体(HGFR)家族、血管内皮生长因子受体(VEGFR)以及胰岛素受体(INSR)家族等等RTKs非受体酪氨酸激酶主要包括SRC、ABL、JAK、ACK、CSK、FAK、FES、FRK、TEC、SYK等10个家族.作为它们调节或抑制CMGC家族和TK家族激酶的结果,预期它们可用于提供对细胞增殖,分化及相关信号转导过程中的异常的阻止或恢复性的控制手段。因此将证实可用于治疗或预防细胞信号转导失调与紊乱,例如肿瘤。还可以想象本发明的化合物可用于治疗如下疾病,例如炎症,病毒感染,II型或非胰岛素依赖糖尿病、自身免疫疾病。头部创伤、中风、癫痫,神经性疾病(如阿尔默兹海姆症)、运动神经元疾病。
本发明化合物还被视为糖原合成酶激酶-3(GSK3)的抑制剂。作为它们调节或抑制CDK激酶和糖原合成酶激酶的活性的结果,预期它们可用于提供对异常分化细胞的细胞周期阻止性或恢复性控制的手段。因此,可以预见,这些化合物将证实可用于治疗或预防增殖紊乱,例如癌症。还可以想象本发明的化合物可用于治疗下列病症,例如病毒感染、II型或非胰岛素依赖型糖尿病、自身免疫性疾病、头部创伤、中风、癫痫、神经变性疾病(如阿尔茨海默氏病)、运动神经元疾病、进行性核上性麻痹、皮质基底节变性和皮克氏病。本发明的化合物对其有用的疾病状态和病症的一个亚组包括病毒感染、自身免疫性疾病和神经变性疾病。可被抑制的肿瘤实例包括但不限于癌:例如膀胱癌、乳腺癌、结肠癌(例如结肠直肠癌肺癌)GSK3b可通过调节糖原合成酶、p27和等蛋白因子,以及参与胞内经典的信号通路等方式,调控癌细胞的分化增殖与凋亡,通过参与单胺神经受体的行为调控作用,在神经精神类疾病的发病机制中起到重要作用,同时还能通过通路以外的其他因子和通路介导神经退行性疾病的发生,因此,成为各种重大疾病治疗中炙手可热的抑制靶点。
本发明包括本发明的化合物抑制细胞或受试者的FLT3激酶活性、或治疗与FLT3激酶活性或表达有关的病症的用途。
可以被抑制的癌症的实例包括但是不限于癌症,例如膀胱癌、乳腺癌、结肠癌(例如结肠直肠癌,例如结肠腺癌和结肠腺瘤)、肾癌、表皮癌、肝癌、肺癌(例如腺癌、小细胞肺癌和非小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌(例如外分泌胰腺癌)、胃癌、宫颈癌、甲状腺癌、前列腺癌或皮肤癌(例如鳞状细胞癌);淋巴谱系的造血肿瘤(例如白血病、急性淋巴性白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、多毛细胞淋巴瘤或伯基特淋巴瘤);骨髓谱系的造血肿瘤(例如急性或慢性髓性白血病、骨髓发育不良综合症或早幼粒细胞白血病);甲状腺滤泡癌;间充质起源的肿瘤(例如纤维肉瘤或横纹肌肉瘤),中枢或外周神经系统的肿瘤(例如星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤);黑素瘤;精原细胞瘤;恶性畸胎瘤;骨肉瘤;着色性干皮病;keratoctanthoma;甲状腺滤泡癌;卡波西肉瘤,B-细胞淋巴瘤和慢性淋巴细胞白血病。
本发明的化合物作为作为CMGC及TK双家族激酶活性抑制剂的用途可以利用下文实施例中所述的测定法来测量,给定化合物所表现的活性水平可通过IC50值来限定。
下面是部分药理学试验及结果:
(1)目标化合物的CDK2抑制活性测定
所合成的化合物用荧光共振能量转移(FRET)法测定对CDK2/A的抑制活性,并与阳性对照药比较,筛选出活性较好的化合物。CDK2/A通过纯化或直接购买试剂盒获得。
具体方法:CDK2/A用激酶稀释液稀释至合适浓度后使用。激酶反应混合物中含CDK2/A、peptide substrate、HEPES(pH7.5)、BRIJ-35、MgCl2和EDTA。CDK2 phospho-peptide substrate用作100%磷酸化对照,不加ATP用作0%磷酸化对照。室温下反应1h后,向反应体系中加入适度稀释的Development Reagent A。室温下继续反应1h,加入StopReagent中止反应。激发波长400nm,同时检测波长为445nm(coumarin)和520nm(fluorescein)的荧光强度。按公式计算受试化合物抑制率。
(2)目标化合物的Aurora A抑制活性测定
所合成的化合物用荧光共振能量转移(FRET)法测定对Aurora A的抑制活性,并与阳性对照药比较,筛选出活性较好的化合物。Aurora A通过纯化或直接购买试剂盒获得。
具体方法:Aurora A用激酶稀释液稀释至合适浓度后使用。激酶反应混合物中含Aurora A、peptide substrate、HEPES(pH7.5)、BRIJ-35、MgCl2和EDTA。Aurora A phospho-peptide substrate用作100%磷酸化对照,不加ATP用作0%磷酸化对照。室温下反应1h后,向反应体系中加入适度稀释的Development Reagent A。室温下继续反应1h,加入StopReagent中止反应。激发波长400nm,同时检测波长为445nm(coumarin)和520nm(fluorescein)的荧光强度。按公式计算受试化合物抑制率。
(3)CDK2、Aurora A抑制活性结果
(4)目标化合物的多靶点筛选
试验方法基于RCB公司开发的HotSpot的激酶筛选平台,使用标准放射性标记的激酶试验法,激酶(通过克隆到杆状病毒并表达激酶域的活性实验测定IC50值,杆状病毒使用FastBac杆状病毒表达系统。)及底物及流程(原理:Substrate+[33P]-ATP 33P-Substrate+ADP)可检测待测化合物与342激酶及与突变变异型相关的疾病之间的相互作用,是目前最具综合性的,对作用于人类激酶的化合物进行高通量筛选的系统。激酶实验使用10μM ATP,[33P]ATP,及生物素肽段,使用SA-闪光板测定33P的合并率。实验使用多种浓度的,用一系列DMSO储液稀释。使用不同浓度对应的数据回归曲线分析测定IC50值,或单一浓度进行抑制率检测。所合成的化合物对342个激酶进行单剂量10μM双孔复筛,依据标准筛选流程,其中阳性对照要十字苞碱(Staurosporine)以4倍稀释得到10个剂量,起始浓度为10μM,其他阳性对照药则以3倍浓度得到10个剂量,起始浓度为20μM。所测342个激酶为:由美国宾夕法尼亚州的Reaction Biology提供。DMSO购自美国Sigma公司。
所测激酶:ABL1(1)、ABL2/ARG(2)、ACK1(3)、AKT1(4)、AKT2(5)、AKT3(6)、ALK(7)、ALK1/ACVRL1(8)、ALK2/ACVR1(9)、ALK3/BMPR1A(10)、ALK4/ACVR1B(11)、ALK5/TGFBR1(12)、ALK6/BMPR1B(13)、ARAF(14)、ARK5/NUAK1(15)、ASK1/MAP3K5(16)、Aurora A(17)、Aurora B(18)、Aurora C(19)、AXL(20)、BLK(21)、BMPR2(22)、BMX/ETK(23)、BRAF(24)、BRK(25)、BRSK1(26)、BRSK2(27)、BTK(28)、c-Kit(29)、c-MER(30)、c-MET(31)、c-Src(32)、CAMK1a(33)、CAMK1b(34)、CAMK1d(35)、CAMK1g(36)、CAMK2a(37)、CAMK2b(38)、CAMK2d(39)、CAMK2g(40)、CAMK4(41)、CAMKK1(42)、CAMKK2(43)、CDC7/DBF4(44)、CDK1/cyclin A(45)、CDK1/cyclin B(46)、CDK1/cyclin E(47)、CDK16/cyclin Y(PCTAIRE)(48)、CDK2/cyclin A(49)、CDK2/Cyclin A1(50)、CDK2/cyclin E(51)、CDK3/cyclin E(52)、CDK4/cyclin D1(53)、CDK4/cyclin D3(54)、CDK5/p25(55)、CDK5/p35(56)、CDK6/cyclin D1(57)、CDK6/cyclinD3(58)、CDK7/cyclin H(59)、CDK9/cyclin K(60)、CDK9/cyclin T1(61)、CHK1(62)、CHK2(63)、CK1a1(64)、CK1d(65)、CK1epsilon(66)、CK1g1(67)、CK1g2(68)、CK1g3(69)、CK2a(70)、CK2a2(71)、CLK1(72)、CLK2(73)、CLK3(74)、CLK4(75)、COT1/MAP3K8(76)、CSK(77)、CTK/MATK(78)、DAPK1(79)、DAPK2(80)、DCAMKL1(81)、DCAMKL2(82)、DDR1(83)、DDR2(84)、DLK/MAP3K12(85)、DMPK(86)、DMPK2(87)、DRAK1/STK17A(88)、DYRK1/DYRK1A(89)、DYRK1B(90)、DYRK2(91)、DYRK3(92)、DYRK4(93)、EGFR(94)、EPHA1(95)、EPHA2(96)、EPHA3(97)、EPHA4(98)、EPHA5(99)、EPHA6(100)、EPHA7(101)、EPHA8(102)、EPHB1(103)、EPHB2(104)、EPHB3(105)、EPHB4(106)、ERBB2/HER2(107)、ERBB4/HER4(108)、ERK1(109)、ERK2/MAPK1(110)、ERK5/MAPK7(111)、ERK7/MAPK15(112)、FAK/PTK2(113)、FER(114)、FES/FPS(115)、FGFR1(116)、FGFR2(117)、FGFR3(118)、FGFR4(119)、FGR(120)、FLT1/VEGFR1(121)、FLT3(122)、FLT4/VEGFR3(123)、FMS(124)、FRK/PTK5(125)、FYN(126)、GCK/MAP4K2(127)、GLK/MAP4K3(128)、GRK1(129)、GRK2(130)、GRK3(131)、GRK4(132)、GRK5(133)、GRK6(134)、GRK7(135)、GSK3a(136)、GSK3b(137)、Haspin(138)、HCK(139)、HGK/MAP4K4(140)、HIPK1(141)、HIPK2(142)、HIPK3(143)、HIPK4(144)、HPK1/MAP4K1(145)、IGF1R(146)、IKKa/CHUK(147)、IKKb/IKBKB(148)、IKKe/IKBKE(149)、IR(150)、IRAK1(151)、IRAK4(152)、IRR/INSRR(153)、ITK(154)、JAK1(155)、JAK2(156)、JAK3(157)、JNK1(158)、JNK2(159)、JNK3(160)、KDR/VEGFR2(161)、KHS/MAP4K5(162)、LATS1(163)、LATS2(164)、LCK(165)、LCK2/ICK(166)、LIMK1(167)、LIMK2(168)、LKB1(169)、LOK/STK10(170)、LRRK2(171)、LYN(172)、LYN B(173)、MAPKAPK2(174)、MAPKAPK3(175)、MAPKAPK5/PRAK(176)、MARK1(177)、MARK2/PAR-1Ba(178)、MARK3(179)、MARK4(180)、MEK1(181)、MEK2(182)、MEK3(183)、MEKK1(184)、MEKK2(185)、MEKK3(186)、MELK(187)、MINK/MINK1(188)、MKK4(189)、MKK6(190)、MLCK/MYLK(191)、MLCK2/MYLK2(192)、MLK1/MAP3K9(193)、MLK2/MAP3K10(194)、MLK3/MAP3K11(195)、MNK1(196)、MNK2(197)、MRCKa/CDC42BPA(198)、MRCKb/CDC42BPB(199)、MSK1/RPS6KA5(200)、MSK2/RPS6KA4(201)、MSSK1/STK23(202)、MST1/STK4(203)、MST2/STK3(204)、MST3/STK24(205)、MST4(206)、MUSK(207)、MYLK3(208)、MYO3b(209)、NEK1(210)、NEK11(211)、NEK2(212)、NEK3(213)、NEK4(214)、NEK5(215)、NEK6(216)、NEK7(217)、NEK9(218)、NLK(219)、OSR1/OXSR1(220)、P38a/MAPK14(221)、P38b/MAPK11(222)、P38d/MAPK13(223)、P38g(224)、p70S6K/RPS6KB1(225)、p70S6Kb/RPS6KB2(226)、PAK1(227)、PAK2(228)、PAK3(229)、PAK4(230)、PAK5(231)、PAK6(232)、PASK(233)、PBK/TOPK(234)、PDGFRa(235)、PDGFRb(236)、PDK1/PDPK1(237)、PHKg1(238)、PHKg2(239)、PIM1(240)、PIM2(241)、PIM3(242)、PKA(243)、PKAcb(244)、PKAcg(245)、PKCa(246)、PKCb1(247)、PKCb2(248)、PKCd(249)、PKCepsilon(250)、PKCeta(251)、PKCg(252)、PKCiota(253)、PKCmu/PRKD1(254)、PKCnu/PRKD3(255)、PKCtheta(256)、PKCzeta(257)、PKD2/PRKD2(258)、PKG1a(259)、PKG1b(260)、PKG2/PRKG2(261)、PKN1/PRK1(262)、PKN2/PRK2(263)、PKN3/PRK3(264)、PLK1(265)、PLK2(266)、PLK3(267)、PLK4/SAK(268)、PRKX(269)、PYK2(270)、RAF1(271)、RET(272)、RIPK2(273)、RIPK3(274)、RIPK5(275)、ROCK1(276)、ROCK2(277)、RON/MST1R(278)、ROS/ROS1(279)、RSK1(280)、RSK2(281)、RSK3(282)、RSK4(283)、SGK1(284)、SGK2(285)、SGK3/SGKL(286)、SIK1(287)、SIK2(288)、SIK3(289)、SLK/STK2(290)、SNARK/NUAK2(291)、SRMS(292)、SRPK1(293)、SRPK2(294)、SSTK/TSSK6(295)、STK16(296)、STK22D/TSSK1(297)、STK25/YSK1(298)、STK32B/YANK2(299)、STK32C/YANK3(300)、STK33(301)、STK38/NDR1(302)、STK38L/NDR2(303)、STK39/STLK3(304)、SYK(305)、TAK1(306)、TAOK1(307)、TAOK2/TAO1(308)、TAOK3/JIK(309)、TBK1(310)、TEC(311)、TESK1(312)、TGFBR2(313)、TIE2/TEK(314)、TLK1(315)、TLK2(316)、TNIK(317)、TNK1(318)、TRKA(319)、TRKB(320)、TRKC(321)、TSSK2(322)、TSSK3/STK22C(323)、TTBK1(324)、TTBK2(325)、TXK(326)、TYK1/LTK(327)、TYK2(328)、TYRO3/SKY(329)、ULK1(330)、ULK2(331)、ULK3(332)、VRK1(333)、VRK2(334)、WEE1(335)、WNK1(336)、WNK2(337)、WNK3(338)、YES/YES1(339)、ZAK/mLTK(340)、ZAP70(341)、ZIPK/DAPK3(342)。
部分化合物试验结果如附图1所示:化合物对进200个激酶(Kinase No.标记于外圈)抑制活性达到90%以上,同时选择性的对GMGC家族:CDK家族激酶CDK6/cyclin D1(57)、CDK6/cyclin D3(58)、CDK4/cyclin D1(53)、CDK4/cyclin D3(54)、CDK5/p35(56)、GSK3b激酶(137),CDK5/p25(55)、CDK16/cyclin Y PIM1(48)、DAPK2(98)、ERK7/MAPK15(112)以及TK家族:KDR/VEGFR2(161)、FLT1/VEGFR1(121)、FLT4/VEGR3(123)、FLT3(122)。其抑制活性在99%以上。
同时针对GMGC家族及TK家族的激酶对所发明化合物进行IC50测试,以起始浓度为1μM,在100%DMSO溶液中制备每个化合物10个点3倍浓度系列稀释液,反应液中含20μMATP,激酶及其底物生物素肽。通过使用定量、精密、敏感、检测相关33P标记的同位素标记方法测试,以判断筛选"hits。其中%trl=[(待测化合物信号-阳性对照信号)/(阴性对照信号-阳性对照信号)]%阴性对照=DMSO、(100%Ctrl);阳性对照=对照化合物(0%Ctrl)。通过标准的剂量-反应曲线,使用Hill方程计算IC50;用PrismGraphpad5计算IC50部分结果如下表所示:
激酶筛选结果表明,所合成化合物对激酶酪氨酸蛋白激酶受体(RTK)家族的FGFR1、FGFR2、KDR/VEGFR2、FLT1/VEGFR1、FLT3、FLT4/VEGFR3和CGCM家族的CDK激酶、GSK3b、JAK、ERK7/MAPK15等激酶表现出活性和选择性,尤其对激酶CDK,GSK3b以及FLT3具有极高的活性和选择性。而同时对VEGFR和CDK现出的抑制活性具有特殊的意义。
(4)目标化合物的体外抗肿瘤活性测定
用MTT法测定对乳腺癌细胞株MDA231、胃癌细胞株MGC803、胃癌细胞株BSG823、白血病细胞株K562、乳腺癌细胞株MCF7、耐药乳腺癌细胞株MCF7、白血病细胞株NB4、肝癌细胞株HEPG2、脐静脉血管内皮细胞株HUVEC、肺癌细胞株A549、结肠癌细胞株HCT116、大细胞肺癌细胞株H460、肝癌细胞7721、肺癌细胞H1299等肿瘤细胞株的抑制作用。
MTT法利用活细胞线粒体中存在与NADP相关的脱氢酶能使外源性的MTT还原成难溶性的蓝紫色结晶物(Formazan),并沉积在细胞中,而死细胞无此功能。再用二甲基亚砜(DMSO)或三联液(10%SDS-5%异丁醇-0.01mol/L HCL)溶解细胞中的紫色结晶物,用酶联免疫检测仪在570nm波长处测定其OD值间接反应其活细胞量。
具体方法:将处于细胞对数生长期的要进行实验的肿瘤细胞按一定的细胞量接种于96孔培养板内,培养24h后加入所筛的样品(悬浮细胞接板后可直接加),细胞在37℃、5%CO2条件下继续培养48小时后,加入MTT继续培养4小时,用DMSO溶解结晶,在酶标仪下进行检测。
部分目标化合物对结肠癌细胞HCT116、肝癌细胞7721、肺癌细胞H1299的体外抗肿瘤活性结果如下:
目标化合物I-1对乳腺癌细胞株MDA231、胃癌细胞株MGC803、胃癌细胞株BSG823、白血病细胞株K562、乳腺癌细胞株MCF7、耐药乳腺癌细胞株MCF7、白血病细胞株NB4、肝癌细胞株HEPG2、脐静脉血管内皮细胞株HUVEC、肺癌细胞株A549、结肠癌细胞株HCT116、大细胞肺癌细胞株H460的体外抗肿瘤活性结果如下:
细胞株 | I-1(IC<sub>50</sub>/μM) | AT-7519(IC<sub>50</sub>/μM) |
MDA231 | 5.45 | 2.58 |
MGC803 | 2.27 | 1.93 |
BSG823 | 20.73 | 16.72 |
K562 | 3.20 | 3.24 |
MCF7 | 0.42 | 2.04 |
耐药MCF7 | 3.73 | 22.10 |
NB4 | 0.74 | 0.62 |
HEPG2 | 25.24 | 53.58 |
HUVEC | 2.54 | 5.67 |
A549 | 50.26 | 53.52 |
HCT116 | 0.25 | 2.63 |
H460 | 2.72 | 5.63 |
药理测试结果表明,本发明化合物具有多重激酶抑制活性,可用于预防或治疗与蛋白激酶抑制剂有关的临床疾病,这些疾病可以是:黑色素瘤、肝癌、肾癌、急性白血病、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、结肠直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓增生异常综合症、食管癌、胃肠道癌或间皮瘤等。
药物制剂
可单独施用活性化合物,也可作为药物组合(例如制剂)的形式出给,所述组合化合物包含至少一种本发明的活性化合物和一种或多种可药用载体、助剂、赋形剂、稀释剂、填充剂、稳定剂、防腐剂。另一方面。本发明提供了药物合物形式的所合成化合物及其亚型,例如本文所定义的式(I)化合物及其亚组。药物组合可以是任意适于口服、胃肠道外、局部、鼻内、眼用、耳用、直肠、阴道内或头皮给药的形式。当组合物意欲用于胃肠道外给药时,它们可被配制成静脉内、肌内、腹膜内、皮下给药或者通过注射、输注或其它递送手段直接递送至靶器官或组织的形式。部分制剂制备方法如:1、冻干制剂:将等量配制的本文定义的式(I)的化合物及其亚组放入50mL小瓶中并且冻干。在冻干期间,在-45℃下应用一步冷冻方法冷冻组合物。将温度升至-10℃退火,然后降低至-45℃冷冻,随后在25℃进行第一步干燥时间约3400分钟,随后升温至50℃进行第二步干燥。第一步干燥和第二步干燥过程中的压力设为80毫托。2、片剂:252 mg含有所合成化合物的片剂组合物如下制备:按照已知方式将50mg化合物与作为稀释剂的197mg乳糖(BP)以及作为润滑剂的:3mg硬脂酸镁混合并压片。3、胶囊剂:胶囊剂如下制备:将100mg所合成化合物与100mg乳糖混合,将所得混合物填充入标准的不透明硬明胶胶囊中。4、(iii)注射剂I注射给药的胃肠道外组合物如下制备:所合成化合物(例如盐形式)溶于含有10%丙二醇的水中,得到活性化合物的浓度为1.5重量%。然后将溶液过滤除菌,灌装在安瓿中,密封。5、(iv)注射剂II供注射的胃肠道外组合物如下制备:在水中溶解所合成化合物(2mg/mL)和甘露糖醇(50mg/mL),无菌过滤该溶液,灌装在可密封的1ml小瓶或安瓿中。6、(iv)皮下注射剂皮下给药组合物如下制备:将所合成化合物与药物级玉米油混合,得到浓度为5mg/mL。将组合物灭菌,灌装在适合的容器中。
本发明还提供了如本文所定义的结构(I)化合物及其亚组作为抗真菌剂的用途。这些化合物可以用在动物医学中(例如治疗哺乳动物,例如人),或者用在植物的处理中(例如农业和园艺),或者用作一般性的抗真菌剂,例如用作防腐剂和消毒剂。另一方面,本发明提供了农业(包括园艺)用途的抗真菌组合物,该组合物包含如上所定义的式(I)化合物及其亚组、例如结构(I)以及农业上可接受的稀释剂或载体。
例如:采用下列方案测定所合成化合物的抗真菌活性,包括近平滑念珠菌(Candidaparapsilosis)、热带念珠菌(Candida tropicalis)、白色念珠菌-ATCC 36082和新型隐球菌(Cryptococcus neoformans)。在4℃下,在Sabourahd葡萄糖琼脂斜面上维持测试微生物。每一微生物的单态混悬液如下制备:于27℃在转鼓上,在含有氨基酸(DifC0,Detr0it,MiCh.)(pH7.0)和0.05吗啉丙磺酸(MOPS)的酵母-氮基肉汤(YNB)中,使酵母生长过夜。然后将混悬液离心,用0.85%NaCl洗涤两次,然后将经洗涤的细胞混悬液用声波处理4秒(BransonSonifier,350型,Danbury,Conn.)。在血细胞计数器中计数单态(singlet)芽生孢子,在0.85%NaCl中调节至所需浓度。采用肉汤微量稀释技术的修改方法测定测试化合物的活性。将测试化合物在DMSO中稀释至1.0mg/mL比率,然后在含有MOPS的YNB肉汤(pΗ7·0)中稀释至64μg/mL(使用氟康唑作为对照),得到每种化合物的工作溶液。采用96孔板,用YNB肉汤准备第1和3至12孔,在第2至11孔制备化合物溶液的十倍稀释液(浓度范围为64至0.125μg/mL)。第1431孔充当分光光度测定的无菌对照和空白。第12孔充当生长对照。向微量板第2至11孔每孔接种10μ1(最终接种物数目为104个生物/mL)。将经接种的板在35℃下温育48小时用润方混合器(Vorte-Genie 2Mixer,Scientific Industries,Inc.,Bolemia7N.Y.)振荡板2分钟后,通过测量420nm下的吸光度(Automatic MicroplateReader,DuPont Instruments,Wilmington,Del.),按分光光度法测定MIC值。MIC终点被定义为表现出生长与对照孔相比减少约50%(或以上)的最低药物浓度。在浊度测定中,这被定义为小孔浊度为<50%对照的最低药物浓度(IC50)。最小细胞溶解浓度(MCC)如下确定:在Sabourahd葡萄糖琼脂(SDA)板上移种96孔板的所有小孔,在35℃下温育1至2天,然后检查存活性。
部分测试结果如下表:
本发明还提供了治疗植物或种子真菌感染的方法,该方法包括用抗真菌有效量的如上所定义的杀真菌组合物处理植物或种子。
将所合成化合物溶于丙酮,随后在丙酮中系列稀释,得到一定范围的所需浓度。加入9体积0.05%Tween-20TM水溶液或Triton X-100TM,这因病原体而异,得到最终处理体积。然后采用下列方案,使用组合物来测试本发明化合物对抗番茄叶枯病(致病疫霉(Phytophthora infestans))的活性。使番茄(Rutgers品种)种子在无土泥炭类罐装混合物中生长,直至幼苗高10-20cm。然后向植物喷洒测试化合物至溢流,比率100ppm。24小时后,向测试植物喷洒蔓延疫霉的孢子囊水混悬液进行接种,在露室(dew chamber)内保存过夜。然后将植物转移至温室,直至疾病在未经处理的对照植物上形成。
部分化合物测试如下所示:
a++++:大于60%的枯叶现象,+++:40-60%的枯叶现象,++:15-40%的枯叶
现象,+:0-15%的枯叶现象,—:无枯叶现象。
附图说明
图1是示出部分化合物对342个激酶的抑制率,其中激酶以编号(见上文)表示。
具体实施方式
熔点用b形熔点管测定,介质为甲基硅油,温度计未校正;IR谱用Nicolet Impact410型红外光谱仪测定,KBr压片;1HNMR用JEOL FX90Q型傅立叶变换核磁共振仪、BRUKERACF-300型核磁共振仪和BRUKER AM-500型核磁共振仪完成(TMS内标);MS用Nicolet2000型傅立叶变换质谱仪和MAT-212型质谱仪测定;微波反应用CEM Discover单模微波仪。
实施例1
4-甲基-1-(4-硝基苄基)哌嗪(I-a)
在500mL单颈瓶中加入对硝基溴苄10g(46.3mmol)和二氯甲烷100mL,在冰水浴下(0-5℃)缓慢滴加N-甲基哌嗪4.7g(47.0mmol)和三乙胺7.1g(70.3mmol)的二氯甲烷20mL混合液,加毕加热回流1hr,TLC检测原料消失(乙酸乙酯∶石油醚=1∶2)。将氯仿150mL和饱和碳酸氢钠溶液100mL加入反应液中,于室温剧烈搅拌30min。反应液用氯仿萃取(100mL×3),合并有机层,分别用水和饱和氯化钠各洗一次(100mL×1)。无水硫酸镁干燥,过滤,减压蒸除溶剂得淡黄色固体8.5g,收率78.1%,产品无需进一步纯化,直接投入下一步反应。
1H-NMR[300MHz,DMSO-d6]:δ2.15(3H,s,-CH3),2.3-2.5(8H,m,-CH2-×4),3.5(2H,s,-CH2-),7.5(2H,d,J=8.7Hz,ArH),8.1(2H,d,J=8.7Hz,ArH).
实施例2
4-(4-硝基苄基)吗啉(I-b)
在500mL单颈瓶中加入对硝基溴苄10g(46.5mmol)和二氯甲烷100mL,在冰水浴下(0-5℃)缓慢滴加吗啉4.1g(47.1mmol)和三乙胺7.1g(70.3mmol)的二氯甲烷20mL混合液,加毕加热回流1hr,TLC检测原料消失(乙酸乙酯∶石油醚=1∶2)。将氯仿150mL和饱和碳酸氢钠溶液100mL加入反应液中,于室温剧烈搅拌30min。反应液用氯仿萃取(100mL×3),合并有机层,分别用水和饱和氯化钠各洗一次(100mL×1)。无水硫酸镁干燥,过滤,减压蒸除溶剂得淡黄色固体(I-b)8.7g,收率84.5%,产品无需进一步纯化,直接投入下一步反应。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,m,-NCH2-×2),3.3-3.5(6H,m,-OCH2-×2,-CH2-),6.9(2H,d,J=8.7Hz,ArH),7.6(2H,d,J=8.7Hz,ArH).
实施例3
4-((4-甲基-1-哌嗪基)甲基)苯胺(I-c)
在500mL单颈瓶中加入I-a粗品8.5g(36.2mmol)、FeO(OH)/C催化剂2.0g和95%乙醇100mL,加热回流,缓慢滴加水合肼25mL和95%乙醇20mL的混合液,TLC检测原料消失(甲醇∶氯仿=1∶15)。趁热抽滤,滤饼用热的乙醇洗两次(30mL×2),减压蒸除溶剂得白色固体,真空干燥得(I-c)6.7g,收率90.3%。产品无需进一步纯化,直接投入下一步反应。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.3-2.5(8H,m,-CH2-×4),3.5(2H,s,-CH2-),4.0(2H,s,-NH2),7.5(2H,d,J=8.7Hz,ArH),8.1(2H,d,J=8.7Hz,ArH).
实施例4
4-((4-吗啉基)甲基)苯胺(I-d)
在500mL单颈瓶中加入I-b粗品8.5g(38.3mmol)、FeO(OH)/C催化剂2.0g和95%乙醇100mL,加热回流,缓慢滴加水合肼25mL和95%乙醇20mL的混合液,TLC检测原料消失(甲醇∶氯仿=1∶20)。趁热抽滤,滤饼用热的乙醇洗两次(30mL×2),减压蒸除溶剂得白色固体,真空干燥得(I-d)6.6g,收率89.7%。产品无需进一步纯化,直接投入下一步反应。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,m,-NCH2-×2),3.2(4H,m,-OCH2-×2),3.5(2H,s,-CH2-),4.9(2H,s,-NH2),6.5(2H,d,J=8.4Hz,ArH),6.9(2H,d,J=8.4Hz,ArH).
实施例5
N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-硝基-1H-3-吡唑甲酰胺(I-e)
在250mL圆底烧瓶中加入I-c粗品7.5g(36.6mmol)、4-硝基-1H-吡唑-3-甲酸6.3g(40.1mmol)、EDC·HCl 8.4g(44.0mmol)、HOBt 6.0g(44.4mmol)和无水DMF100 mL,室温搅拌24hr。TLC检测原料消失(甲醇∶氯仿=1∶10)。将反应液到入冰水200mL中,析出大量淡黄色固体,静置,抽虑得黄色固体,所得粗品用乙酸乙酯和甲醇混合溶剂重结晶得(I-e)11.1g,收率88.2%。mp:194-196℃,MS[M+H]+345.3。
1H-NMR[300MHz,DMSO-d6]:δ2.2(3H,s,-CH3),2.3-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.6(2H,d,J=8.4Hz,ArH),8.8(1H,s,ArH),10.6(1H,s,-NHCO-),14.2(1H,s,-NH-,Pyrazole).
实施例6
N-(4-((4-吗啡啉基)甲基)苯基)-4-硝基-1H-3-吡唑甲酰胺(I-f)
在250mL圆底烧瓶中加入I-d粗品7.5g(39.0mmol)、4-硝基-1H-吡唑-3-甲酸6.3g(40.1mmol)、EDC·HCl 8.4g(44.0mmol)、HOBt 6.0g(44.4mmol)和无水DMF100 mL,室温搅拌24hr。TLC检测原料消失(甲醇∶氯仿=1∶20)。将反应液到入冰水200mL中,析出大量淡黄色固体,静置,抽虑得黄色固体,所得粗品用乙酸乙酯和甲醇混合溶剂重结晶得(I-f)11.6g,收率89.7%。mp:208-210℃,MS[M+H]+332.4。
1H-NMR[300MHz,DMSO-d6]:δ2.4(4H,t,J=4.1Hz,-NCH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.1Hz,-OCH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.6(2H,d,J=8.4Hz,ArH),8.9(1H,s,ArH),10.7(1H,s,-NHCO-),14.2(1H,s,Pyrazole).
实施例7
N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺(I-g)
在250mL单颈瓶中加入I-e 6.0g(17.4mmol)、FeO(OH)/C催化剂2g和95%乙醇100mL,加热回流,缓慢滴加水合肼25mL和95%乙醇20mL的混合液,TLC检测原料消失(甲醇∶氯仿=1∶10)。趁热抽滤,滤饼用热的乙醇洗两次(30mL×2),减压蒸除溶剂得类白色固体,所得粗品用乙酸乙酯和甲醇混合溶剂重结晶得(I-g)3.5g,产率63.9%。mp:199-201℃,MS[M+H]+315.8。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.3-2.5(8H,m,-CH2-×4),3.3(2H,s,-CH2-),4.7(2H,s,-NH2),7.1-7.2(3H,m,ArH),7.7(2H,d,ArH),9.7(1H,s,-NHCO-),12.7(1H,s,Pyrazole).
实施例8
N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺(I-h)
在250mL单颈瓶中加入I-f 6.0g(18.1mmol)、FeO(OH)/C催化剂2g和95%乙醇100mL,加热回流,缓慢滴加水合肼25mL和95%乙醇20mL的混合液,TLC检测原料消失(甲醇∶氯仿=1∶10)。趁热抽滤,滤饼用热的乙醇洗两次(30mL×2),减压蒸除溶剂得类白色固体,所得粗品用乙酸乙酯和甲醇混合溶剂重结晶得(I-h)3.2g,产率58.6%。mp:216-218℃,MS[M+H]+302.0。
1H-NMR[300MHz,DMSO-d6]:δ2.5(4H,m,-NCH2-×2),3.3(2H,s,-CH2-),3.6(4H,m,-OCH2-×2),4.7(2H,s,-NH2),7.2(3H,m,ArH),7.7(2H,d,J=8.4Hz,ArH),9.7(1H,s,-NHCO-),12.7(1H,s,Pyrazole)。
实施例9
4-(4-噻吩并[2,3-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-1)
在50mL单颈瓶中加入N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺129mg(0.41mmol)、4-氯噻吩并[2,3-d]嘧啶70mg(0.41mmol)和50%乙酸水溶液25mL,加热回流,TLC检测原料消失(甲醇∶氯仿=1∶10),反应液冷却至室温,用饱和氢氧化钠水溶液调节pH到8-9,乙酸乙酯萃取3次(50ml×3),合并萃取液,无水硫酸镁干燥,抽滤后减压蒸除溶剂得淡黄色固体,粗品经柱层析(流动相:甲醇∶氯仿=1∶15),得(I-1)70mg,收率37.8%。mp:285-287℃,[M+H]+449.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.5(1H,d,J=5.4Hz,ArH),7.7-7.8(3H,m,ArH),8.5(1H,s,ArH),8.6(1H,s,ArH),10.0(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例10
4-(4-噻吩并[2,3-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-2)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺124mg(0.41mmol)和4-氯噻吩[2,3-d]并嘧啶70mg(0.41mmol)为原料,得(I-2)78mg,收率43.6%。mp:262-265℃,MS[M+H]+436.2。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.5(4H,t,J=4.2Hz,-CH2-×2),7.3(2H,d,J=8.4,ArH),7.5(1H,d,J=6.0Hz,ArH),7.7-7.8(3H,m,ArH),8.5(1H,s,ArH),8.6(1H,s,ArH),9.9(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例11
4-(4-(6-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-3)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺120mg(0.38mmol)和4-氯-6-甲基噻吩并[2,3-d]嘧啶70mg(0.38mmol)为原料,得(I-3)75mg,收率42.9%。mp:235-238℃,MS[M+H]+463.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),7.2(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.5(2H,s,ArH),9.8(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例12
4-(4-(6-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-4)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺118mg(0.38mmol)和4-氯-6-甲基噻吩并[2,3-d]嘧啶70mg(0.38mmol)为原料,得(I-4)80mg,收率47%。mp:>280℃,MS[M+H]+450.3。
1H-NMR[300MHz,DMSO-d6]:δ2.4(4H,t,J=4.2Hz,-CH2-×2),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),7.2(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.5(2H,s,ArH),9.8(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例13
4-(4-(5-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-5)
制备方法类似于(I-5),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺120mg(0.38mmol)和4-氯-5-甲基噻吩并[2,3-d]嘧啶70mg(0.38mmol)为原料,得(I-5)72mg,收率41.1%。mp:245-247℃,MS[M+H]+463.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),2.8(3H,s,-CH3),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.6(1H,s,ArH),8.7(1H,s,ArH),10.2(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例14
4-(4-(5-甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-6)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺118mg(0.38mmol)和4-氯-5-甲基噻吩并[2,3-d]嘧啶70mg(0.38mmol)为原料,得(I-6)64mg,收率37.6%。mp:>280℃,MS[M+H]+450.3。
1H-NMR[300MHz,DMSO-d6]:δ2.4(4H,t,J=4.2Hz,-CH2-×2),2.8(3H,s,-CH3),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.6(1H,s,ArH),8.7(1H,s,ArH),10.2(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例15
4-(4-(5,6-二甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-7)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺111mg(0.35mmol)和4-氯-5,6-二甲基噻吩并[2,3-d]嘧啶70mg(0.35mmol)为原料,得(I-7)66mg,收率39.3%。mp:264-267℃,MS[M+H]+477.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),2.6(3H,s,-CH3),2.8(3H,s,-CH3),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.6(1H,s,ArH),8.7(1H,s,ArH),10.2(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole)
实施例16
4-(4-(5,6-二甲基噻吩并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-8)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺110mg(0.35mmol)和4-氯-5,6-二甲基噻吩并[2,3-d]嘧啶70mg(0.35mmol)为原料,得(I-8)73mg,收率44.5%。mp:254-256℃,MS[M+H]+464.3。
1H-NMR[300MHz,DMSO-d6]:δ2.4(4H,t,J=4.2Hz,-CH2-×2),2.6(3H,s,-CH3),2.8(3H,s,-CH3),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.6(1H,s,ArH),8.7(1H,s,ArH),10.2(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例17
4-(4-噻吩并[3,2-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-9)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺129mg(0.41mmol)和4-氯噻吩并[3,2-d]嘧啶70mg(0.41mmol)为原料,得(I-9)88mg,收率47.8%。mp:>280℃,MS[M+H]+449.3。
1H-NMR[300MHz,DMSO-d6]:δ2.2(3H,s,-CH3),δ2.3-2.5(8H,m,-CH2-×4),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.5(1H,d,J=5.3Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.2(1H,d,J=5.3Hz,ArH),8.5(1H,s,ArH),8.7(1H,s,ArH),9.7(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例18
4-(4-噻吩并[3,2-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-10)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺128mg(0.41mmol)和4-氯噻吩并[3,2-d]嘧啶70mg(0.41mmol)为原料,得(I-10)93mg,收率52.0%。mp:275-277℃,MS[M+H]+436.3。
1H-NMR[300MHz,DMSO-d6]:δ2.4(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.5(1H,d,J=5.2Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.3(1H,d,J=5.2Hz,ArH),8.5(1H,s,ArH),8.7(1H,s,ArH),9.7(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例19
4-(4-(7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-11)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺144mg(0.46mmol)和4-氯-7H-吡咯并[2,3-d]嘧啶70mg(0.46mmol)为原料,得(I-11)63mg,收率32.0%。mp:229-230℃,MS[M+H]+432.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.5(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例20
4-(4-(7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-12)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺142mg(0.46mmol)和4-氯-7H-吡咯并[2,3-d]嘧啶70mg(0.46mmol)为原料,得(I-12)70mg,收率36.6%。mp:213-214℃,MS[M+H]+419.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.4Hz,-CH2-×2),2.4(2H,s,-CH2-),3.6(4H,t,J=4.4Hz,-CH2-×2),6.5(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例21
4-(4-(6-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-13)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺132mg(0.42mmol)和4-氯-6-甲基-7H-吡咯并[2,3-d]嘧啶70mg(0.42mmol)为原料,得(I-13)56mg,收率23.0%。mp:268-270℃,MS[M+H]+446.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(11H,m,-CH2-×4,-CH3),3.4(2H,s,-CH2-),6.5(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例22
4-(4-(6-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-14)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺130mg(0.42mmol)和4-氯-6-甲基-7H-吡咯并[2,3-d]嘧啶70mg(0.42mmol)为原料,得(I-14)61mg,收率33.7%。mp:271-273℃,MS[M+H]+433.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(7H,m,-CH2-×2,-CH3),2.4(2H,s,-CH2-),3.6(4H,t,J=4.4Hz,-CH2-×2),6.5(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例23
4-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-15)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺132mg(0.45mmol)和4-氯-5-甲基-7H-吡咯并[2,3-d]嘧啶70mg(0.45mmol)为原料,得(I-15)53mg,收率28.3%。mp:258-261℃,MS[M+H]+446.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例24
4-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-16)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺130mg(0.45mmol)和4-氯-5-甲基-7H-吡咯并[2,3-d]嘧啶70mg(0.45mmol)为原料,得(I-16)62mg,收率34.3%。mp:267-269℃,MS[M+H]+433.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.4Hz,-CH2-×2),2.4(2H,s,-CH2-),2.6(3H,s,-CH3),3.6(4H,t,J=4.4Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例25
4-(4-(5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-17)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺144mg(0.46mmol)和4-氯-5H-吡咯并[3,2-d]嘧啶70mg(0.46mmol)为原料,得(I-17)50mg,收率25.4%。mp:261-263℃,MS[M+H]+432.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.2(1H,s,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例26
4-(4-(5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-18)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺142mg(0.46mmol)和4-氯-5H-吡咯并[3,2-d]嘧啶70mg(0.46mmol)为原料,得(I-18)67mg,收率35.1%。mp:258-260℃,MS[M+H]+419.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.4Hz,-CH2-×2),2.4(2H,s,-CH2-),3.6(4H,t,J=4.4Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.2(1H,s,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例27
4-(4-(6-甲基-5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-19)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺132mg(0.42mmol)和4-氯-6-甲基-5H-吡咯并[3,2-d]嘧啶70mg(0.42mmol)为原料,得(I-19)55mg,收率29.4%。mp:265-267℃,MS[M+H]+446.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例28
4-(4-(6-甲基-5H-吡咯并[3,2-d]嘧啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-20)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺130mg(0.42mmol)和4-氯-6-甲基-5H-吡咯并[3,2-d]嘧啶70mg(0.42mmol)为原料,得(I-20)69mg,收率38.1%。mp:268-270℃,MS[M+H]+433.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.4Hz,-CH2-×2),2.4(2H,s,-CH2-),2.6(3H,s,-CH3),3.6(4H,t,J=4.4Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.4(1H,s,ArH),8.6(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例29
4-(4-呋喃并[2,3-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-21)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺143mg(0.45mmol)和4-氯呋喃并[2,3-d]嘧啶70mg(0.45mmol)为原料,得(I-21)45mg,收率23.0%。mp:255-257℃,MS[M+H]+433.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),7.1(1H,d,J=2.5Hz,ArH),7.2(2H,d,J=8.4Hz,ArH),7.7(2H,d,J=8.4Hz,ArH),8.0(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例30
4-(4-呋喃并[2,3-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-22)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺141mg(0.45mmol)和4-氯呋喃并[2,3-d]嘧啶70mg(0.45mmol)为原料,得(I-22)53mg,收率27.9%。mp:>280℃,MS[M+H]+420.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),7.1(1H,d,J=2.5Hz,ArH),7.3(2H,d,J=8.2Hz,ArH),7.8(2H,d,J=8.2Hz,ArH),8.0(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例31
4-(4-呋喃并[3,2-d]嘧啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-23)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺143mg(0.45mmol)和4-氯呋喃并[3,2-d]嘧啶70mg(0.45mmol)为原料,得(I-23)71mg,收率36.2%。mp:277-279℃,MS[M+H]+433.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),7.2(2H,d,J=8.4Hz,ArH),7.7(2H,d,J=8.4Hz,ArH),7.8(1H,d,J=2.5Hz,ArH),8.2(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例32
4-(4-呋喃并[3,2-d]嘧啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-24)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺141mg(0.45mmol)和4-氯呋喃并[3,2-d]嘧啶70mg(0.45mmol)为原料,得(I-24)80mg,收率42.1%。mp:271-273℃,MS[M+H]+420.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),7.3(2H,d,J=8.2Hz,ArH),7.7(2H,d,J=8.2Hz,ArH),7.8(1H,d,J=2.5Hz,ArH),8.2(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例33
4-(4-噻吩并[3,2-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-25)
将N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺129mg(0.41mmol)、4-氯噻吩并[3,2-c]吡啶70mg(0.41mmol)和冰醋酸1mL溶解在8mL异丙醇中,在190℃下,微波反应(300W)30分钟,减压蒸处异丙醇,蒸馏水将所得固体溶解,用饱和氢氧化钠水溶液调节pH到8-9,用乙酸乙酯萃取3次(50mL×3),合并萃取液,无水硫酸镁干燥,抽滤后减压蒸除溶剂得到淡黄色固体,粗品经柱层析(流动相:甲醇∶氯仿=1∶15),得(I-25)67mg,收率36.4%。mp:268-270℃,MS[M+H]+448.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.4Hz,ArH),7.5(1H,d,J=5.4Hz,ArH),7.7-7.8(3H,m,ArH),7.9(1H,d,J=8.0Hz,ArH),8.5(1H,s,ArH),10.0(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例34
4-(4-噻吩并[3,2-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-26)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺128mg(0.41mmol)和4-氯噻吩并[3,2-c]吡啶70mg(0.41mmol)为原料,得(I-26)71mg,收率39.7%。mp:269-271℃,MS[M+H]+435.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.5(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.4Hz,ArH),7.5(1H,d,J=5.4Hz,ArH),7.7-7.8(3H,m,ArH),7.9(1H,d,J=8.0Hz,ArH),8.5(1H,s,ArH),9.9(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例35
4-(4-(2-甲基噻吩并[3,2-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-27)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺121mg(0.38mmol)和4-氯-2-甲基噻吩并[3,2-c]吡啶70mg(0.38mmol)为原料,得(I-27)68mg,收率38.6%。mp:267-269℃,MS[M+H]+462.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.6(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.2(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.5(1H,s,ArH),10.0(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例36
4-(4-(2-甲基噻吩并[3,2-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-28)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺119mg(0.38mmol)和4-氯-2-甲基噻吩并[3,2-c]吡啶70mg(0.38mmol)为原料,得(I-28)59mg,收率34.5%。mp:265-267℃,MS[M+H]+449.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),3.5(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.2(1H,s,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.5(1H,s,ArH),9.9(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例37
4-(7-噻吩并[2,3-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-29)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺129mg(0.41mmol)和7-氯噻吩并[2,3-c]吡啶70mg(0.41mmol)为原料,得(I-29)56mg,收率30.4%。mp:274-276℃,MS[M+H]+448.3。
1H-NMR[300MHz,DMSO-d6]:δ2.2(3H,s,-CH3),δ2.3-2.5(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.4Hz,ArH),7.5(1H,d,J=5.3Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.2(1H,d,J=5.3Hz,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例38
4-(7-噻吩并[2,3-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-30)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺128mg(0.41mmol)和7-氯噻吩并[2,3-c]吡啶70mg(0.41mmol)为原料,得(I-30)81mg,收率45.3%。mp:271-273℃,MS[M+H]+435.3。
1H-NMR[300MHz,DMSO-d6]:δ2.4(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.4Hz,ArH),7.5(1H,d,J=5.2Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.3(1H,d,J=5.2Hz,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例39
4-(7-(3-甲基噻吩并[2,3-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-31)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺121mg(0.38mmol)和7-氯-3-甲基噻吩并[2,3-c]吡啶70mg(0.38mmol)为原料,得(I-31)71mg,收率40.3%。mp:258-260℃,MS[M+H]+462.3。
1H-NMR[300MHz,DMSO-d6]:δ2.2(3H,s,-CH3),δ2.3-2.5(8H,m,-CH2-×4),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.2(1H,s,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例40
4-(7-(3-甲基噻吩并[2,3-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-32)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺119mg(0.38mmol)和7-氯-3-甲基噻吩并[2,3-c]吡啶70mg(0.38mmol)为原料,得(I-32)73mg,收率42.7%。mp:275-277℃,MS[M+H]+449.3。
1H-NMR[300MHz,DMSO-d6]:δ2.4(4H,t,J=4.2Hz,-CH2-×2),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.4Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.3(1H,s,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例41
4-(4-呋喃并[3,2-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-33)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺120mg(0.46mmol)和4-氯呋喃并[3,2-c]吡啶70mg(0.46mmol)为原料,得(I-33)75mg,收率38.1%。mp:268-270℃,MS[M+H]+432.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.1(1H,d,J=2.5Hz,ArH),7.2(2H,d,J=8.4Hz,ArH),7.7(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.0(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例42
4-(4-呋喃并[3,2-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-34)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺119mg(0.46mmol)和4-氯呋喃并[3,2-c]吡啶70mg(0.46mmol)为原料,得(I-34)68mg,收率35.6%。mp:268-271℃,MS[M+H]+419.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.1(1H,d,J=2.5Hz,ArH),7.3(2H,d,J=8.2Hz,ArH),7.8(2H,d,J=8.2Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.0(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例43
4-(4-(2-甲基呋喃并[3,2-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-35)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺144mg(0.42mmol)和4-氯-2-甲基呋喃并[3,2-c]吡啶70mg(0.42mmol)为原料,得(I-35)47mg,收率25.1%。mp:274-276℃,MS[M+H]+446.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.1(1H,s,ArH),7.2(2H,d,J=8.4Hz,ArH),7.7(2H,d,J=8.4Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例44
4-(4-(2-甲基呋喃并[3,2-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-36)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺142mg(0.42mmol)和4-氯-2-甲基呋喃并[3,2-c]吡啶70mg(0.42mmol)为原料,得(I-36)63mg,收率34.8%。mp:275-277℃,MS[M+H]+433.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.1(1H,s,ArH),7.3(2H,d,J=8.2Hz,ArH),7.8(2H,d,J=8.2Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例45
4-(7-呋喃并[2,3-c]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-37)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺132mg(0.46mmol)和7-氯呋喃并[2,3-c]吡啶70mg(0.46mmol)为原料,得(I-37)45mg,收率22.8%。mp:258-261℃,MS[M+H]+432.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.2(2H,d,J=8.4Hz,ArH),7.7(2H,d,J=8.4Hz,ArH),7.8(1H,d,J=2.5Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.3(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例46
4-(7-呋喃并[2,3-c]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-38)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺130mg(0.46mmol)和7-氯呋喃并[2,3-c]吡啶70mg(0.46mmol)为原料,得(I-38)47mg,收率24.6%。mp:268-272℃,MS[M+H]+419.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.2Hz,ArH),7.7(2H,d,J=8.2Hz,ArH),7.8(1H,d,J=2.5Hz,ArH),7.9(1H,d,J=8.0Hz,ArH),8.3(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例47
4-(7-呋喃并[3,2-b]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-39)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺144mg(0.46mmol)和7-氯呋喃并[3,2-b]吡啶70mg(0.46mmol)为原料,得(I-39)48mg,收率24.4%。mp:268-270℃,MS[M+H]+432.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.2(2H,d,J=8.4Hz,ArH),7.4(1H,s,ArH),7.7(2H,d,J=8.4Hz,ArH),7.8(1H,d,J=2.5Hz,ArH),8.2(1H,d,J=8.0Hz,ArH),8.3(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例48
4-(7-呋喃并[3,2-b]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-40)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺142mg(0.46mmol)和7-氯呋喃并[3,2-b]吡啶为70mg(0.46mmol)原料,得(I-40)53mg,收率27.7%。mp:275-278℃,MS[M+H]+419.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH2-×2),6.7(1H,d,J=8.0Hz,ArH),7.3(2H,d,J=8.2Hz,ArH),7.7(2H,d,J=8.2Hz,ArH),7.8(1H,d,J=2.5Hz,ArH),8.2(1H,d,J=8.0Hz,ArH),8.3(1H,d,J=2.5Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例49
4-(4-呋喃并[2,3-b]吡啶基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-41)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺144mg(0.46mmol)和4-氯呋喃并[2,3-b]吡啶为70mg(0.46mmol)原料,得(I-41)64mg,收率32.5%。mp:273-276℃,MS[M+H]+432.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),6.7(1H,d,J=8.0Hz,ArH),7.1(1H,d,J=2.5Hz,ArH),7.2(2H,d,J=8.4Hz,ArH),7.7(2H,d,J=8.4Hz,ArH),8.0(1H,d,J=2.5Hz,ArH),8.2(1H,d,J=8.0Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例50
4-(4-呋喃并[2,3-b]吡啶基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-42)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺142mg(0.46mmol)和4-氯呋喃并[2,3-b]吡啶为70mg(0.46mmol)原料,得(I-42)56mg,收率29.3%。mp:269-271℃,MS[M+H]+419.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH3×2),6.7(1H,d,J=8.0Hz,ArH),7.1(1H,d,J=2.5Hz,ArH),7.3(2H,d,J=8.2Hz,ArH),7.8(2H,d,J=8.2Hz,ArH),8.0(1H,d,J=2.5Hz,ArH),8.2(1H,d,J=8.0Hz,ArH),8.4(1H,s,ArH),9.7(1H,s,-NHCO-),10.2(1H,s,-NH-),13.4(1H,s,Pyrazole).
实施例51
4-(7-(1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-43)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺145mg(0.46mmol)和7-氯-1H-吡咯并[2,3-c]吡啶70mg(0.46mmol)为原料,得(I-43)64mg,收率32.3%。mp:279-282℃,MS[M+H]+431.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,d,J=8.0Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.0(1H,d,J=8.0Hz,ArH),8.2(1H,s,ArH),8.4(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例52
4-(7-(1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-44)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺143mg(0.46mmol)和7-氯-1H-吡咯并[2,3-c]吡啶70mg(0.46mmol)为原料,得(I-44)52mg,收率27.1%。mp:265-267℃,MS[M+H]+420.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.4Hz,-CH2-×2),2.4(2H,s,-CH2-),3.6(4H,t,J=4.4Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,d,J=8.0Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.0(1H,d,J=8.0Hz,ArH),8.2(1H,s,ArH),8.4(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例53
4-(7-(2-甲基-1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-45)
制备方法类似于(I-25),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺132mg(0.42mmol)和7-氯-2-甲基-1H-吡咯并[2,3-c]吡啶70mg(0.42mmol)为原料,得(I-45)49mg,收率26.2%。mp:276-278℃,MS[M+H]+445.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.4(8H,m,-CH2-×4),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,d,J=8.0Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.0(1H,d,J=8.0Hz,ArH),8.4(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例54
4-(7-(2-甲基-1H-吡咯并[2,3-c]吡啶基)氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-46)
制备方法类似于(I-25),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺131mg(0.42mmol)和7-氯-2-甲基-1H-吡咯并[2,3-c]吡啶70mg(0.42mmol)为原料,得(I-46)73mg,收率40.1%。mp:254-258℃,MS[M+H]+432.3。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.4Hz,-CH2-×2),2.4(2H,s,-CH2-),2.6(3H,s,-CH3),3.6(4H,t,J=4.4Hz,-CH2-×2),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,d,J=8.0Hz,ArH),7.6(1H,s,ArH),7.8(2H,d,J=8.4Hz,ArH),8.0(1H,d,J=8.0Hz,ArH),8.4(1H,s,ArH),9.2(1H,s,-NHCO-),10.2(1H,s,-NH-),12.0(1H,s,Pyrrole),13.4(1H,s,Pyrazole).
实施例55
4-(4-(2-甲基噻吩并[3,2-d]嘧啶)基氨基)-N-(4-((4-甲基-1-哌嗪基)甲基)苯基)-1H-3-吡唑甲酰胺(I-47)
制备方法类似于(I-1),以N-(4-((4-甲基-1-哌嗪基)甲基)苯基-4-氨基-1H-3-吡唑甲酰胺120mg(0.38mmol)和4-氯-2-甲基噻吩并[3,2-d]嘧啶70mg(0.38mmol)为原料,得(I-47)85mg,收率49.7%。mp:>280℃,MS[M+H]+463.3。
1H-NMR[300MHz,DMSO-d6]:δ2.1(3H,s,-CH3),2.2-2.5(8H,m,-CH2-×4),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,d,J=4.1Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.2(1H,d,J=4.1Hz,ArH),8.6(1H,s,ArH),9.6(1H,s,-NHCO-),10.3(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例56
4-(4-(2-甲基噻吩并[3,2-d]嘧啶)基氨基)-N-(4-((4-吗啡啉基)甲基)苯基)-1H-3-吡唑甲酰胺(I-48)
制备方法类似于(I-1),以N-(4-((4-吗啡啉基)甲基)苯基)-4-氨基-1H-3-吡唑甲酰胺119mg(0.38mmol)和4-氯-2-甲基噻吩并[3,2-d]嘧啶70mg(0.38mmol)为原料,得(I-48)93mg,收率54.4%。mp:259-262℃,MS[M+H]+450.2。
1H-NMR[300MHz,DMSO-d6]:δ2.3(4H,t,J=4.2Hz,-CH2-×2),2.6(3H,s,-CH3),3.4(2H,s,-CH2-),3.6(4H,t,J=4.2Hz,-CH3×2),7.3(2H,d,J=8.4Hz,ArH),7.4(1H,d,J=4.1Hz,ArH),7.8(2H,d,J=8.4Hz,ArH),8.2(1H,d,J=4.1Hz,ArH),8.5(1H,s,ArH),9.7(1H,s,-NHCO-),10.4(1H,s,-NH-),13.5(1H,s,Pyrazole).
实施例57
1、实验材料
试剂、药品及耗材:化合物1,化合物1的甲磺酸盐(IS),化合物2,化合物2的甲磺酸盐(2S),乙腈,乙酸乙酯,甲醇,色谱柱Hypersil ODS(4.6mmX 200mm,5mm),离心管,EP管,枪头,橡胶手套,1mL注射器等。
2、主要仪器
Agilent 1200高效液相色谱仪(美国安捷伦科技有限公司);水浴恒温振荡器SHZ-88(金坛市文化仪器厂有限公司);KQ3200DB型超声波清洗器(昆山市超声仪器有限公司);UV-2102PCS型紫外分光光度仪(上海龙尼柯仪器有限公司);TGL-16台式离心机(上海安亭科学仪器厂);XW-80A旋涡混合器(上海精科实业有限公司);瑞士梅特勒-托利多PL203电子天平(瑞士)。实验动物:健康雄性Wistar大鼠,体重(200士20)g(中国药科大学动物中心提供)。
3、方法与结果
水中溶解度的测定:取过量的样品于50ml三角瓶中,并加入10ml蒸馏水,并于25℃下恒温振荡器中振荡72h,将溶液于10000rpm离心15min后,取上清液过0.22μm的微孔滤膜除去未溶解的药物,取2ml续滤液用甲醇定容至10ml,20μL进样测定药物的含量。得到结果如表1。
表1水中溶解度的测定
由表1结果可知:化合物I-1及化合物I-2成甲磺酸盐(I-1-S)及(I-2-S)后在水中的溶解度增加。
4、油水分配系数(LogP)的测定
将正辛醇和蒸馏水互相饱和24h,然后精密称取一定量的样品于50ml容量瓶中,用水饱和的正辛醇定容(样品完全溶解),随后取10ml样品的正辛醇溶液于50ml的三角瓶中,接着加入10ml正辛醇饱和的蒸馏水,25℃下,125rpm恒温振荡器中振荡72h。分别测定实验前正辛醇储备液和实验后正辛醇层中药物的浓度,从而计算样品的油水分配系数。结果见表2。
表2油水分配系数
由表2结果可知:化合物I-1及化合物I-2成甲磺酸盐(I-1-S)和(I-2-s)后的油水分配系数(LogP)变化不大。
3.稳定性考察:
3.1血浆样品的处理
精密吸取大鼠血浆300μL并含30μL甲醇,2ml乙酸乙酯,旋涡3min,4000rpm离心15min,量取上清液,移至另一离心管中,下层同法提取1次,合并上清液,在氮气流下吹干。用甲醇150μL复溶后,过0.22μm微孔滤膜,取20μL进样。
3.2在血浆中的稳定性
别将化合物I-1和I-2标准溶液定量稀释于血浆中,分别于0、l、2、4、6、8、12、24h取样,按“3.1”项下方法处理,进样20μL记录色谱图峰面积,确定药物浓度,考察1和2在血浆中的稳定性。结果见表3。
表3在血浆中稳定性结果
结果:由上表可知化合物1和2在血浆中24h均稳定。
4动物实验
4.1设计及经时血药浓度数据
精密称取药物适量,配制含3mg/mL药物的CMC-Na水溶液。取健康雄性Wistar大鼠12只,随机分为2组,每组6只。第1组为口服给药2,第2组为口服给药2。给药剂量均为30mg/kg(相当于每只大鼠给药2ml),大鼠给药前禁食12h,自由饮水,给药后分别于0.5、1、1·5、2、2.5、3、5、8、12、24h静脉窦取血0.6mL,加入经肝素钠润洗过的EP管中,4000r/min离心15min取上层血浆,精密量取血浆300μL,进样测定记录色谱图和峰面积,计算1和2血药浓度,绘制平均药-时曲线。结果见表4和5。
表4化合物1大鼠口服后经时血药浓度(ng*ml/1)
表5化合物2大鼠口服后经时血药浓度(ng·ml/1)
4.2数据处理
采用DAS2.0程序对单剂量口服给药后的血药浓度数据表4、5结果进行处理。应用拟合度法及AIC判别法进行模型判断,拟合度越大、AIC越小,模型拟合越好的原则,口服给药均符合二室模型。采用统计距参数比较2种药物的药代动力学参数。结果见表6。
表6大鼠口服1和2药代动力学参数(AUC:药时曲线下面积;Tmax:药峰时间;T1/2:半衰期;MRT:平均滞留时间;Cmax:药峰浓度)
由表6结果可知:化合物1和2均具有可接受的药代动力学参数。
实施例58
药物对动物移植性肿瘤S180的抑制作用
1试验材料及动物
受试药物:化合物I-1阳性药物名称:AT7519购买自Jinan Great Chemical Co.,Ltd。品系和来源:ICR小鼠,清洁级;扬州大学比较医学中心提供,许可证号:SCXK(苏)2007-0001;体重:18-22g;性别:雌性;饲料:颗粒饲料,由江苏省协同医药生物工程有限责任公司供给;饲养条件:空调房间,温度18-240C,相对湿度70%。瘤株来源:S180由江苏省肿瘤药物研究所提供。仪器:YJ-875型医用净化工作台(苏州净化设备厂)。
2、实验方法
取ICR小鼠,按移植性肿瘤研究法,接种实体型瘤(在无菌操作下取瘤块,称重,用玻璃组织匀浆器研磨,磨匀后放入无菌容器内,加生理盐水稀释成1:3的细胞悬液,容器置冰块上,用空针抽吸,每次抽吸前将细胞混匀,每只小鼠右前肢腋窝皮下接种0.2ml),接种后24小时称鼠重,并随机分为5组,每组10只。各给药组于接种24小时后(d1)第一次给药,静脉注射给药,每天给药一次,共给药7次,给药体积均为0.4ml/20g。于接种后第8天(d8)处死荷瘤小鼠称重,并分离瘤块称重,所得数据进行统计学处理(t检验)。剂量设置:共设5组
模型对照组;阳性对照组:AT7519 15mg/kg;待测药:30mg/kg;待测药:15mg/kg;待测药:7.5mg/kg
4、实验结果:
*P<0.05**P<0.01与模型对照组比较
5、实验结论
结果表明,与模型对照组相比,待测药(30mg/kg和15mg/kg)对S180的肿瘤生长有极显著的抑制作用(P<0.01),待测药7.5mg/kg剂量对S180的肿瘤生长有显著的抑制作用(P<0.05)。待测药(30mg/kg和15mg/kg)对实验动物体重有显著抑制作用(P<0.05)。
Claims (14)
2.权利要求1的化合物,其特征在于:
其中R1、R2、R3各自独立地表示氢、烷基;
X表示N原子;
Y表示N原子或CH原子团;
Z、M各自独立地表示NH、S或CH原子团,且Z、M必需有一个为NH或S;
A1表示NH原子团;
A2表示亚甲基;
Q1表示苯基;
Q2表示吗啉基或甲基哌嗪基;
烷基为具有1-6个碳原子的直链或支链饱和烃基。
3.权利要求2的化合物,其特征在于:
其中R1、R2、R3各自独立地表示氢或甲基;
X表示N原子;
Y表示N原子或CH原子团;
Z、M各自独立地表示NH、S或CH原子团,且Z、M必需有一个为NH或S;
A1表示NH原子团;
A2表示亚甲基;
Q1表示苯基;
Q2表示吗啉基或甲基哌嗪基。
4.权利要求3的化合物,其特征在于:
其中R1、R2、R3各自独立地表示氢或甲基;
X表示N原子;
Y表示N原子或CH原子团;
Z、M各自独立地表示S或CH原子团,且Z、M必需有一个为S;
A1表示NH原子团;
A2表示亚甲基;
Q1表示苯基;
Q2表示吗啉基或甲基哌嗪基。
5.权利要求3的化合物,其特征在于:
其中R1、R2、R3各自独立地表示氢或甲基;
X表示N原子;
Y表示N原子或CH原子团;
Z、M各自独立地表示NH或CH原子团,且Z、M必需有一个为NH;
A1表示NH原子团;
A2表示亚甲基;
Q1表示苯基;
Q2表示吗啉基或甲基哌嗪基。
6.权利要求1-5任一项的化合物或其药学上可接受的盐,其中药学上可接受的盐包括通式(I)化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸,此外还包括无机碱的酸式盐。
7.一种药物组合物,其中含有权利要求1-6任一项所述的化合物和药学上可接受的载体。
8.权利要求1-6任一项所述的化合物在制备用于预防或治疗与CDK2、Aurora A有关的临床病症的药物中的用途。
9.权利要求8的用途,其中与CDK2、Aurora A有关的疾病选自黑色素瘤、肝癌、肾癌、急性白血病、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、胰腺癌、卵巢癌、乳腺癌、骨髓增生异常综合症、食管癌、胃肠道癌和间皮瘤。
10.权利要求8的用途,其中与CDK2、Aurora A有关的疾病选自结肠直肠癌。
11.权利要求1-6任一项所述的化合物在制备用于预防或治疗与CMGC家族和TK家族激酶有关的临床病症的药物中的用途。
12.权利要求1-6任一项所述的化合物在制备用于预防或治疗与GSK3b、FLT3、KDR、VEGFR有关的临床病症的药物中的用途。
13.权利要求12的用途,其中所述的临床病症包括炎症、病毒感染、II型或非胰岛素依赖糖尿病、自身免疫疾病、头部创伤、中风、癫痫、阿尔默兹海姆症或运动神经元疾病。
14.权利要求1-6任一项所述的化合物在制备抗真菌剂中的用途。
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CA2897366C (en) | 2021-01-05 |
CN103012428A (zh) | 2013-04-03 |
AU2014204633A1 (en) | 2015-08-27 |
US9550792B2 (en) | 2017-01-24 |
JP2016504395A (ja) | 2016-02-12 |
EP2955185A1 (en) | 2015-12-16 |
KR102136628B1 (ko) | 2020-07-23 |
CN105189517B (zh) | 2017-07-18 |
EP2955185A4 (en) | 2016-06-08 |
EP2955185B1 (en) | 2021-01-06 |
CN107098903A (zh) | 2017-08-29 |
CA2897366A1 (en) | 2014-07-17 |
PT2955185T (pt) | 2021-02-23 |
BR112015016327A8 (pt) | 2018-01-23 |
ES2863175T3 (es) | 2021-10-08 |
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