CN102827186A - 一类吡啶并五元杂环衍生物及其制备方法和用途 - Google Patents
一类吡啶并五元杂环衍生物及其制备方法和用途 Download PDFInfo
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- CN102827186A CN102827186A CN2011101629784A CN201110162978A CN102827186A CN 102827186 A CN102827186 A CN 102827186A CN 2011101629784 A CN2011101629784 A CN 2011101629784A CN 201110162978 A CN201110162978 A CN 201110162978A CN 102827186 A CN102827186 A CN 102827186A
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- phenyl
- oxy
- pyridin
- compound
- imidazo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类吡啶并五元杂环衍生物或其药学上可接受的盐,其结构如通式1所示。本发明还涉及所述吡啶并五元杂环衍生物或其药学上可接受的盐的制备方法和其在用于制备c-Met抑制剂的药物中的用途。
Description
技术领域
本发明涉及c-Met抑制剂及其合成和应用。更具体而言,涉及一类吡啶并五元杂环衍生物或其药学上可接受的盐及其制备方法和用途。
背景技术
c-Met是一种受体型酪氨酸激酶,在正常细胞与肿瘤细胞中均有表达。这个基因是1984年在George Vande Woude的实验室中首次被发现的,它能够在裸鼠上引起肿瘤。由于这个基因是在经过N-甲基-N’-硝基-N-亚硝基胍(N-Methyl-N’-nitro-N-nitrosoguanidine)处理后被发现的,因此得名‘c-Met’(Stellrecht CM,Gandhi V.MET receptor tyrosine kinase as a therapeuticanticancer target.Cancer Lett,2009,280(1):1-14)。c-Met是肝细胞生长因子(hepatocyte growth factor,HGF,也称分散因子,scatter factor)的细胞表面受体,是一类多效性的细胞活素,能够传递促迁移、抗凋亡和促有丝分裂信号。HGF激活c-Met后会导致细胞分离并向周围运动。当细胞离开它们正常的位置后,会因为细胞分离后的“失巢现象”快速凋亡消除。但是,当c-Met通路被激活后会提供强力的生存信号而阻止“失巢现象”发生,有利于“流浪”细胞在非正常位置“安家落户”。最后,经过迁移、生存和几轮的分裂,迁移细胞们就在远离家乡的新拓居地繁衍生息。这种空间和时间上截然不同却又互补的细胞活性-运动性、抗凋亡和增殖-统称为“侵袭性生长”。在胚胎发育过程中,侵袭性生长在原肠形成期发生。在神经嵴细胞从神经管分离并在胚胎内散布、肌肉细胞前体从生皮肌节脱离开始长距离迁徙以形成四肢以及血管生成时,都会有侵袭性生长发生。一般来说,所有这些器官形成过程都受到HGF/c-Met系统的影响。在一些情况下,生存和扩增信号会强过迁移信号,例如HGF和c-Met还可以调节胎盘和肝脏的生长。
在成人中,侵袭性生长是静止的,但在人体受伤后会重新激活,使剩余细胞扩增迁移来修复受伤组织。实际上,在肝脏、心脏和肾脏受伤后,血浆中的HGF水平会升高,说明HGF的上调(以及相应的c-Met的活化)是机体对器官损伤的应激反应的一部分。HGF在一些退行性疾病(如进行性肾病、肝硬化和肺纤维化等)中的保护性作用也证明了HGF/c-Met通路在组织平衡控制中的重要性(Comoglio PM,Giordano S,Trusolino L.Drug development ofMET inhibitors--targeting oncogene addiction and expedience.Nat Rev DrugDiscov,2008,7(6):504-516)。
正常的HGF/c-Met信号转导在胚胎发育、组织损伤修复中起重要作用,而异常的HGF/c-Met信号转导与肿瘤发生,尤其是侵袭和转移密切相关(GaoGF,Vande Woude GF.HGF/SR-Met signaling in tumor progression.Cell Res,2005,15(1):49-51)。在正常细胞中,原癌基因c-Met mRNA呈低水平表达或不表达,虽然在组织器官切除或损伤后,c-Met的表达会暂时性的增加,但表达水平很快回复正常状态,表明正常细胞有能力通过减少c-Met的表达来控制其对HGF的反应。肿瘤细胞可以通过释放IL-1、FGF-2和PDGF等细胞因子,刺激邻近的成纤维细胞分泌HGF,而有些肿瘤细胞可通过自分泌途径同时过表达c-Met和HGF(Sawade K,Radjabi AR,Shinomiya N,et al.c-Metoverexpression is a prognostic factor in ovarian cancer and an effective targetfor inhibition of peritoneal dissemination and invasion.Cancer Res,2007,67(4):1670-79)。c-Met的过表达可见于人肝癌、胆管癌、胰腺癌、肺癌、甲状腺癌、胸膜间质瘤等,尤其是在发生转移的肿瘤中。它的作用可能包括影响肿瘤细胞间的黏附、促进细胞外基质降解、诱导血管发生以及促进细胞增殖等。这些都说明c-Met是一个重要的肿瘤治疗靶点。
目前,已有c-Met抑制剂进入临床试验阶段,如Exelixis公司的XL-184和XL-180,Pfizer公司的PF-4217903,MethylGene公司的MGCD-265,Johnson&Johnson公司的JNJ-38877605等,但还未有上市药物。C-Met抑制剂研究中主要存在以下问题:临床治疗效果和药代动力学参数不理想,口服生物利用度不高等。因此,研究方向主要集中在新母核的发现上。
发明内容
针对现有技术的不足,本发明人进行了广泛和深入的研究,并最终完成了本发明。
本发明的一个目的是提供一类吡啶并五元杂环衍生物或其药学上可接受的盐。
本发明的另一个目的是提供一类吡啶并五元杂环衍生物或其药学上可接受的盐的制备方法。
本发明的再一个目的是提供一种用作c-Met抑制剂的药物组合物,该组合物包括治疗有效量的一种或多种所述的吡啶并五元杂环衍生物或其药学上可接受的盐以及药学上可接受的载体。
本发明的又一个目的是提供一类吡啶并五元杂环衍生物或其药学上可接受的盐用于制备c-Met抑制剂的药物中的用途。
具体地,本发明提供了一类吡啶并五元杂环衍生物或其药学上可接受的盐,该衍生物具有如下通式1的结构:
其中,R1为H,未取代的或被取代基所取代的C6~10芳基,或者含有1~2个选自N、O和S中的杂原子的五元或六元饱和或不饱和杂环基团,其中,所述的取代基为C1~3烷基、C1~3烷氧基或卤素;
优选地,R1为未取代的或被取代基所取代的苯基,或者含有1~2个选自N和S中的杂原子的五元或六元饱和或不饱和杂环基团,其中,所述的取代基为C1~2烷基或卤素;
更优选地,R1为未取代的或被取代基所取代的苯基,噻吩基,或吡啶基,其中,所述的取代基为甲基或卤素;
R2为H或卤素;
X为N或O;
优选地,本发明提供了一类吡啶并五元杂环衍生物或其药学上可接受的盐,该衍生物具有如下通式2的结构:
其中,R1、R2和R3的定义与通式1相同。
优选地,本发明提供了一类吡啶并五元杂环衍生物或其药学上可接受的盐,该衍生物具有如下通式3的结构:
通式3
其中,R1、R2和R3的定义与通式1相同。
以上所述卤素为氟、氯、溴或碘,优选为氟、氯或溴,更优选为氟或氯。
所述药学上可接受的盐包括但不限于所述吡啶并五元杂环衍生物与盐酸、硫酸、磷酸、甲磺酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸等的加成盐。
更优选地,本发明的吡啶并五元环类化合物可选自下表中:
本发明提供了制备所述的吡啶并五元杂环衍生物或其药学上可接受的盐的方法,其按照如下反应方案之一进行:
反应方案1(对应上述通式2所示的吡啶并五元环衍生物或其药学上可接受的盐的制备方法)包括如下步骤:
1)2-氨基-3-羟基吡啶II-1与羧酸II-2在多聚磷酸的作用下环化得到吡啶并噁唑结构的化合物II-3;
2)用过氧化物对化合物II-3中吡啶上的N氧化,得到化合物II-4;
3)用三氯氧磷处理化合物II-4,得到7-氯噁唑并[4,5-b]吡啶II-5;
5)将化合物II-6中的硝基用金属还原剂还原成氨基,得到化合物II-7;
6)化合物II-7与不同的R3片段连接,得到通式2所示化合物II-8,
其中,R1、R2和R3的定义如前所述;
在上述反应方案1中,优选地,步骤1)中所述的2-氨基-3-羟基吡啶II-1与羧酸II-2在多聚磷酸的作用下在180℃~300℃高温共热环化得到吡啶并噁唑结构的化合物II-3;优选地,步骤2)中所用的过氧化物优选为间氯过氧苯甲酸;优选地,步骤4)中在微波条件下180℃~300℃加热对硝基苯酚与化合物II-5中的吡啶环上的氯进行亲核取代,得到化合物II-6;优选地,步骤5)中所用的金属还原剂为锌粉;
或者,
反应方案2(对应上述通式3所示的吡啶并五元环衍生物或其药学上可接受的盐的制备方法)包括如下步骤:
2)III-2中的苯环上的氨基用芴甲氧羰酰氯(Fmoc-Cl)保护后,得到化合物III-3;
3)化合物III-3中吡啶环上的硝基用金属还原剂还原成氨基,得到化合物III-4;
4)化合物III-4在R1COOH和多聚磷酸的作用下,得到吡啶并咪唑环,同时脱去Fmoc保护基,生成化合物III-5;
5)化合物III-5中的氨基与不同的R3片段连接,得到通式3所示化合物III-6;
其中,R1、R2和R3的定义如前所述;
在上述反应方案2中,优选地,步骤1)中所用的碱为叔丁醇钾;优选地,步骤3)中所用的金属还原剂优选为锌粉;优选地,步骤4)中化合物III-4在R1COOH和多聚磷酸的作用下在180℃~300℃高温共热,得到吡啶并咪唑环。
同时,本发明还提供了上述吡啶并五元环衍生物或其药学上可接受的盐用于制备c-Met抑制剂的药物中的用途。
本发明涉及化合物结构新颖,显示出较好的体外c-Met抑制活性,有望用于治疗由与c-Met有关的异常的细胞存活、增殖、分化、凋亡等功能所导致的疾病,如癌症等。
具体实施方式
提供下列实施例仅用来说明本发明,而不应将本发明理解为限定于这些实施例的范围。
实施例
实施例1 1-(4-氟苯基)-N-4-((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯 基)-2-氧代-1,2-二氢吡啶-3-酰胺(化合物1)的制备
步骤1:2-(4-氟苯基)噁唑并[4,5-b]吡啶(1-3)的制备
将1.1g 2-氨基-3-羟基吡啶(1-1)(购自Acros公司,Belgium)和1.4g 4-氟苯甲酸(1-2)(购自Acros公司,Belgium)于80g多聚磷酸中250℃加热4小时。接着,倒入冰与NaOH的混合物中,有沉淀析出。过滤,用1N NaOH洗,水洗至中性,干燥,得浅褐色固体1-3 1.55g,产率72%。
LCMS(ESI):215[M+H]
1H NMR(300MHz,d6-DMSO)δ8.57(d,1H,J=3.4Hz),8.3(m,3H),7.52(m,3H)。
步骤2:7-氯-2-(4-氟苯基)噁唑并[4,5-b]吡啶(1-5)的制备
取化合物1-3 1.2g溶于15mL二氯甲烷中,冰浴,加入间氯过氧苯甲酸溶于25mL二氯甲烷中的溶液。室温搅拌。有固体析出。搅拌4天,TLC示无原料。过滤,滤液用饱和Na2CO3洗涤,水层再用二氯甲烷反萃多次,合并有机层,用饱和氯化钠洗涤后无水硫酸钠干燥,蒸干,得黄色固体1-4 700mg,产率55%。
上一步产物400mg加入10mL三氯氧磷,回流过夜。将反应液倒入冰水中,用NaHCO3中和,乙酸乙酯萃取,饱和氯化钠洗涤,无水硫酸钠干燥,蒸干。过柱纯化,洗脱液石油醚∶乙酸乙酯(8∶1),得白色固体产物1-5 200mg,产率46%。
LCMS(ESI):249[M+H]
1H NMR(300MHz,d6-DMSO)δ8.5(d,1H,J=5.6Hz),8.31(m,2H),7.65(d,1H,J=5.6Hz),7.5(t,2H,J=9.1Hz)。
步骤3:2-(4-氟苯基)-7-(4-硝基苯氧)噁唑并[4,5-b]吡啶(1-7)的制备
取1-5 248mg与350mg 4-硝基苯酚(1-6)(购自Acros公司,Belgium)溶于3mL N-甲基吡咯烷酮中,加入1mL N,N-二异丙基乙胺,微波下200℃,反应2h。用乙酸乙酯稀释,饱和KH2PO4洗,1M Na2CO3洗,干燥蒸干。过柱纯化,洗脱液石油醚∶乙酸乙酯(1∶1),得黄色固体1-7 130mg,产率37%。
LCMS(ESI):352[M+H]
1H NMR(300MHz,d6-DMSO)δ8.5(d,1H,J=5.7Hz),8.35(d,2H,J=8.7Hz),8.19(m,2H),7.56(d,2H,J=9.3Hz),7.46(t,2H,J=8.4Hz),7.19(d,1H,J=5.9Hz)。
步骤4:4-((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯胺(1-8)的制备
取1-7 120mg溶于2mL四氢呋喃和4mL甲醇中,加入135mg锌粉和115mg氯化铵,氩气保护下,室温搅拌过夜。过滤,滤渣用乙酸乙酯洗涤,合并有机层,蒸干,得黄色固体产物1-8 108mg,产率98%。
LCMS(ESI):322[M+H]
1H NMR(300MHz,d6-DMSO)δ8.24(d,1H,J=6Hz),8.14(m,2H),7.37(t,2H,J=8.4Hz),6.96(d,2H,J=8.5Hz),6.66(m,3H)。
步骤5:1-(4-氟苯基)-N-4-((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯基)-2-氧代-1,2-二氢吡啶-3-酰胺(1)的制备
取1-8 32mg、1-9(合成方法参照J.Med.Chem.2008,51,5330-5341)23mg和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸37mg溶于二甲基甲酰胺/乙腈(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺56μL,升至室温,搅拌过夜。有固体析出。过滤,固体过柱,得40mg米色产物1,产率75%。
m.p.284-287℃
LCMS(ESI):537[M+H]
HRMS calcd for C30H18N4O4F2Na:559.1194(M+Na)+;Found:559.1208
1H NMR(300MHz,d6-DMSO)δ12.02(s,1H),8.59(dd,1H,J=7.6,2.9Hz),8.38(d,1H,J=5.7Hz),8.24(m,2H),8.1(d,1H,J=6.6Hz),7.83(d,2H,J=9.3Hz),7.6(m,2H),7.42(m,6H),6.86(d,1H,J=5.8Hz),6.73(t,1H,J=6.8Hz)。
实施例2 N-((4-((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯基)氨基甲 硫酰基)2-2-苯乙酰胺(化合物2)的制备
9mg NaSCN溶于0.5mL丙酮,氩气下,加15μL苯乙酰氯(购自Acros公司,Belgium),室温搅拌5分钟,加0.5mL丙酮,加实施例1中制得的1-8 32mg,不溶。回流过夜。蒸去丙酮,加水,过滤。固体制备板纯化,展开剂二氯甲烷∶甲醇(50∶1),得黄色固体2 20mg,产率40%。
LCMS(ESI):499[M+H]
1H NMR(300MHz,d6-DMSO)δ8.42(d,1H,J=5.5Hz),8.2(m,2H),7.74(d,2H,J=8.4Hz),7.4(m,8H),6.94(d,1H,J=5.5Hz),5.74(s,1H),3.82(s,2H)。
实施例3 2-苯基-N-((4-((2-对甲苯基)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基) 氨基甲硫酰基)苯乙酰胺(化合物3)和2-苯基-N-(4-((2-对甲苯基)-3H-咪唑并 [4,5]吡啶-7-基)氧)苯基)苯乙酰胺(化合物8)的制备
步骤1:4-(4-氨基苯氧基)-3-硝基吡啶-2-胺(3-3)的制备
8g 4-氨基酚(购自Acros公司,Belgium)溶于80mL干燥二甲基甲酰胺,氩气脱气10min,加入叔丁醇钾5.6g,继续搅拌脱气1h。8g化合物3-1溶于40mL二甲基甲酰胺,加入反应液,氩气保护70℃ 20小时。蒸去溶剂,残留物过柱纯化,洗脱液石油醚∶乙酸乙酯(1∶1),得橙黄色固体3-3 8.8g,收率80%。
LCMS(ESI):246[M+1]
1H NMR(300MHz,d6-DMSO)δ7.94(d,1H,J=5.9Hz),7.06(br s,2H),6.84(d,2H,J=9.3Hz),6.61(d,2H,J=8.6Hz),5.89(d,1H,J=6.2Hz),5.17(br s,2H)。
步骤2:(9H-芴-9-基)甲基(4-((2-氨基-3-硝基吡啶-4-基)氧)苯基)氨基甲酸酯(3-5)的制备
1.36g NaHCO3溶于8mL水,加二氧六环8mL,浑浊。加入3-3 1g,冰浴。滴加芴甲氧羰酰氯(Fmoc-Cl)溶于4mL二氧六环的溶液,室温搅拌过夜。有大量黄色固体析出。蒸去二氧六环,过滤,饱和碳酸氢钠洗,水洗,干燥,得黄色固体3-5 1.5g,产率79%。
LCMS(ESI):469[M+H]
1H NMR(300MHz,d6-DMSO)δ7.97(d,1H,J=5.7Hz),7.91(d,2H,J=7.2Hz),7.74(d,2H,J=7.8Hz),7.38(m,6H),7.11(m,2H),5.9(d,1H,J=6.2Hz),4.51(d,2H,J=6.7Hz),4.31(t,1H,J=6.6Hz)。
步骤3:(9H-芴-9-基)甲基(4-((2,3-二氨基吡啶-4-基)氧)苯基)氨基甲酸酯(3-6)的制备
取3-5 450mg、锌粉625mg和无水氯化钙780mg混悬在20mL 95%乙醇中,回流一小时。黄色褪去,TLC示原料反应完。冷却,过滤,蒸干溶剂,用二氯甲烷∶甲醇(10∶1)过柱纯化,得200mg粉色固体3-6,产率48%。
LCMS(ESI):439[M+1]
1H NMR(300MHz,d6-DMSO)δ9.68(s,1H),7.91(d,2H,J=7.3Hz),7.75(d,2H,J=7.1Hz),7.46-7.32(m,5H),7.23(d,1H,J=5.4Hz),6.94(d,2H,J=8.6Hz),6.65(dd,1H,J=51.5,9.3Hz),5.95(d,1H,J=6Hz),5.54(brs,2H),4.49(d,2H,J=6.8Hz),4.31(t,1H,J=6.2Hz)。
步骤4:4-((2-对甲苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯胺(3-8)的制备
300mg 3-6和100mg对甲基苯甲酸(3-7)(购自Acros公司,Belgium)于9g多聚磷酸中,250℃,5h。倒入冰水,用NaOH溶液中和,有固体析出。过滤,固体用二氯甲烷∶甲醇(4∶1)溶液溶取洗涤。合并有机相蒸干,过柱纯化,流动相二氯甲烷∶甲醇(15∶1),得120mg米色固体3-8,产率56%。
LCMS(ESI):317[M+H]
1H NMR(300MHz,d6-DMSO)δ8.12(m,3H),7.38(d,2H,J=8.2Hz),6.94(d,2H,J=8.3Hz),6.68(d,2H,J=8.3Hz),6.35(d,1H,J=5.7Hz),2.4(s,3H)。
步骤5:2-苯基-N-((4-((2-对甲苯基)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺(3)和2-苯基-N-(4-((2-对甲苯基)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)苯乙酰胺(8)的制备
9mL NaSCN(3-9)溶于0.5mL丙酮,氩气下,加15mL苯乙酰氯(3-10),室温搅拌30分钟,加0.5mL丙酮,加3-8 30mg。回流2小时。蒸去溶剂,制备板纯化,展开剂二氯甲烷∶甲醇(15∶1),得米白色固体3 6mg,产率13%,米白色固体8 7mg,产率17%。
化合物3
LCMS(ESI):494[M+H]
1H NMR(300MHz,d6-DMSO)δ8.12(m,2H),7.74(m,2H),7.3(m,10H),6.48(dd,1H,J=34.9,4.7Hz),3.83(s,1H),3.7(s,1H),3.55(s,1H),2.37(s,3H)。
化合物8
m.p.291-294℃
LCMS(ESI):435[M+H]
1H NMR(300MHz,d6-DMSO)δ8.11(m,2H),7.73(m,2H),7.3(m,10H),6.43(d,1H,J=5.9Hz),3.66(s,2H),3.55(s,1H),2.37(s,3H)。
实施例4 2-苯基-N-((4-((2-(4-吡啶)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基) 氨基甲硫酰基)苯乙酰胺(化合物4)的制备
步骤1:4-((2-(4-吡啶)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯胺(4-2)的制备
270mg 3-6和60mg吡啶-4-羧酸(4-1)(购自Acros公司,Belgium)于10g多聚磷酸中,250℃,5h。倒入冰水,用NaOH溶液中和,有固体析出。过滤,固体用二氯甲烷∶甲醇=4∶1溶液溶取洗涤。合并有机相蒸干,过柱(二氯甲烷∶甲醇=15∶1),得70mg褐色固体4-2,产率51%。
LCMS(ESI):304[M+H]
1H NMR(300MHz,d6-DMSO)δ8.77(d,2H,J=5.8Hz),8.17(m,3H),6.96(d,2H,J=8.7Hz),6.68(d,2H,J=8.3Hz),6.4(d,1H,J=6Hz)。
步骤2:2-苯基-N-((4-((2-(4-吡啶)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺(4)的制备
9mL NaSCN(3-9)溶于0.5mL丙酮,氩气下,加15mL苯乙酰氯(3-10),室温搅拌30分钟,加0.5mL丙酮,加4-2 30mg,加二甲基甲酰胺0.6mL,80℃过夜。蒸去溶剂,制备板纯化,展开剂二氯甲烷∶甲醇(10∶1)。得产物4 15mg,产率39%。
m.p.204-208℃
LCMS(ESI):481[M+H]
1H NMR(300MHz,d6-DMSO)δ8.76(d,2H,J=4.2Hz),8.2(m,3H),7.73(d,2H,J=8.8Hz),7.32(m,8H),6.59(d,1H,J=5.6Hz),3.82(s,2H)。
实施例5 2-苯基-N-((4-((2-(3-噻吩)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基) 氨基甲硫酰基)苯乙酰胺(化合物5)和2-苯基-N-(4-((3-噻吩)-3H-咪唑并[4,5]吡 啶-7-基)氧)苯基)苯乙酰胺(化合物7)的制备
步骤1:4-((2-(3-噻吩)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯胺(5-2)的制备
270mg 3-6和98mg噻吩-3-羧酸(5-1)(购自Acros公司,Belgium)于10g多聚磷酸中,250℃,5h。倒入冰水,用NaOH溶液中和,有固体析出。过滤,固体用二氯甲烷∶甲醇=4∶1溶液溶取洗涤。合并有机相蒸干,过柱(二氯甲烷∶甲醇=15∶1),得80mg褐色固体5-2,产率42%。
LCMS(ESI):309[M+H]
1H NMR(300MHz,d6-DMSO)δ13.45(s,1H),8.4(s,1H),8.08(d,1H,J=5.5Hz),7.84(d,1H,J=4.9Hz),7.76(m,1H),6.93(m,2H),6.67(d,2H,J=8.3Hz),6.34(d,1H,J=5.7Hz)。
步骤2:2-苯基-N-((4-((2-(3-噻吩)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺(5)和2-苯基-N-(4-((3-噻吩)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)苯乙酰胺(7)的制备
9mL NaSCN(3-9)溶于0.5mL丙酮,氩气下,加15mL苯乙酰氯(3-10),室温搅拌30分钟,加0.5mL丙酮,加5-2 30mg。回流2小时。蒸去溶剂,制备板纯化,展开剂二氯甲烷∶甲醇(10∶1),得产物5 8mg,产率18%,产物7 6mg,产率20%。
化合物5
m.p.217-220℃
LCMS(ESI):486[M+H]
1H NMR(300MHz,CDCl3)δ12.39(s,1H),11.75(s,1H),8.36(s,1H),8.16(d,1H,J=4.5Hz),7.75(m,4H),7.3(m,8H),6.54(d,1H,J=6Hz),3.82(s,2H)。
化合物7
m.p.276-278℃
LCMS(ESI):427[M+H]
1H NMR(300MHz,CDCl3)δ10.5(s,1H),8.1(d,1H,J=5.7Hz),7.81(d,1H,J=5Hz),7.72(m,3H),7.26(m,8H),6.43(d,1H,J=5.4Hz),3.65(s,2H)。
实施例6 2-苯基-N-((4-((2-苯基-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基 甲硫酰基)苯乙酰胺(化合物6)和2-苯基-N-(4-(苯基-3H-咪唑并[4,5]吡啶-7-基) 氧)苯基)苯乙酰胺(化合物9)的制备
步骤1:4-((2-苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯胺(6-2)的制备
130mg 3-6和40mg苯甲酸(6-1)(购自Acros公司,Belgium)于9g多聚磷酸中,250℃,4h。倒入NaOH与冰的混合物,用NaOH调pH 10-12。搅拌30min,冷冻干燥。加二氯甲烷∶甲醇(4∶1)混合溶剂搅拌,过滤,蒸干,过柱纯化,洗脱液二氯甲烷∶甲醇(15∶1),得棕色固体6-2 20mg。产率23%。
LCMS(ESI):304[M+H]
1H NMR(300MHz,CDCl3)δ8.32(d,2H,J=7.4Hz),8.21(d,1H,J=6Hz),7.54(m,3H),7.07(d,2H,J=8.6Hz),6.76(d,2H,J=9Hz),6.54(d,1H,J=5.8Hz)。
步骤2:2-苯基-N-((4-((2-苯基-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺(6)和2-苯基-N-(4-(苯基-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)苯乙酰胺(9)
9mg NaSCN(3-9)溶于0.5mL丙酮,氩气下,加15mL苯乙酰氯(3-10),室温搅拌30分钟,加0.5mL丙酮,加6-2 22mg。回流2小时。蒸去溶剂,制备板纯化,展开剂二氯甲烷∶甲醇(10∶1),得化合物6 6mg,产率17%,化合物9 10mg,产率32%。
化合物6
LCMS(ESI):480.1[M+H]
1H NMR(300MHz,d6-DMSO)δ12.42(s,1H),8.23(m,3H),7.74(d,2H,J=7.9Hz),7.56(m,3H),7.37(m,3H),7.28(m,4H),6.58(d,1H,J=5.6Hz),4.11(s,1H),3.85(s,2H)。
化合物9
LCMS(ESI):421.3[M+H]
1H NMR(300MHz,d6-DMSO)δ13.63(s,1H),8.23(m,4H),7.73(d,2H,J=8.0Hz),7.54(m,3H),7.36(m,4H),7.23(m,3H),6.46(d,1H,J=5.3Hz),3.67(s,2H)。
实施例7 1-(4-氟苯基)-2-氧代-N-(4-((2-对甲苯基-3H-咪唑并[4,5-b]吡啶 -7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(化合物10)的制备
步骤1:1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-羧酸甲酯(10-3)
1g 2-氧代-2H-吡喃-3-甲酸甲酯(10-1)(购自Acros公司,Belgium)溶于9mL二甲基甲酰胺,0℃加入0.62mL 4-氟苯胺(10-2)(购自Acros公司,Belgium),搅拌7小时,有大量黄色固体。加入1.62g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和0.2g 4-二甲氨基吡啶(DMAP),室温过夜,反应液变深色溶液。蒸去二甲基甲酰胺,H2O/EtOAc萃取,干燥,蒸干。过柱,洗脱液乙酸乙酯∶石油醚(2∶1)。得浅黄色固体10-3 900mg,产率57%。
LCMS(ESI):248[M+H]
1H NMR(300MHz,d6-DMSO)δ8.11(dd,1H,J=7.1,2.8Hz),7.94(dd,1H,J=7.1,2.2Hz),7.48(m,2H),7.36(m,2H),6.4(t,1H,J=7.1Hz),3.74(s,3H)。
步骤2:1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酸(10-4)
10-3 300mg加2mL 2N NaOH,于65℃搅拌3小时,固体溶解。冷却,加2N HCl至pH=1,大量白色固体析出,室温搅拌。过滤,固体用水洗,干燥,得白色固体产物10-4 270mg,产率96%。
LCMS(ESI):234[M+H]
1H NMR(300MHz,d6-DMSO)δ8.48(dd,1H,J=7.3,2.3Hz),8.2(dd,1H,J=6.1,2.2Hz),7.61(m,2H),7.42(t,2H,J=9Hz),6.78(t,1H,J=6.4Hz)。
步骤3:1-(4-氟苯基)-2-氧代-N-(4-((2-对甲苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(10)
3-8 27mg、10-4 20mg和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯32mg溶于二甲基甲酰胺/乙腈(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺51μL,升至室温,搅拌过夜。有固体析出。加1N NaOH,溶解,室温搅拌半小时,蒸干溶剂,加水。过滤,固体用10%NaOH洗,固体干燥。制备板纯化,展开剂二氯甲烷∶甲醇(15∶1),得白色固体10 18mg,产率40%。
m.p.>300℃
LCMS(ESI):532[M+H]
1H NMR(300MHz,d6-DMSO)δ13.52(br s,1H),11.97(br s,1H),8.59(dd,1H,J=7.3,2.2Hz),8.12(m,3H),7.8(d,2H,J=8.9Hz),7.61(m,2H),7.4(m,4H),7.23(d,2H,J=8.8Hz),6.72(t,1H,J=7Hz),6.51(d,1H,J=5.5Hz),2.38(s,3H)。
实施例8 1-(4-氟苯基)-2-氧代-N-(4-((2-(4-吡啶基)-3H-咪唑并[4,5-b]吡 啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(化合物11)的制备
30mg 4-2、24mg 10-4和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯37mg溶于二甲基甲酰胺/乙腈(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺59μL,升至室温,搅拌过夜。有固体析出。加1N NaOH,溶解,室温搅拌半小时,蒸干溶剂,加水。过滤,固体用10%NaOH洗,固体干燥。制备板纯化,展开剂二氯甲烷∶甲醇(10∶1),得浅棕色固体11 25mg,产率48%。
m.p.>300℃
LCMS(ESI):519[M+H]
1H NMR(300MHz,d6-DMSO)δ12.0(s,1H),8.77(d,2H,J=5Hz),8.59(dd,1H,J=7.3,2.1Hz),8.16(m,4H),7.83(d,2H,J=8.3Hz),7.61(m,2H),7.42(t,2H,J=9.1Hz),7.28(m,2H),6.72(t,1H,J=6.9Hz),6.54(d,1H,J=5.6Hz)。
实施例9 1-(4-氟苯基)-2-氧代-N-(4-((2-(4-氟苯基)-3H-咪唑并[4,5-b]吡 啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(化合物12)的制备
步骤1:4-((2-(4-氟苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯胺(12-2)的制备
250mg 3-6和80mg 4-氟苯甲酸(12-1)(购自Acros公司,Belgium)于16g多聚磷酸中,250℃,4h。倒入冰水,用NaOH溶液调至pH碱性。将水相溶液冷冻干燥,残渣用二氯甲烷∶甲醇(4∶1)溶液溶取洗涤。合并有机相蒸干,过柱纯化,洗脱液二氯甲烷∶甲醇(15∶1),得白色固体12-2 90mg,产率49%。
LCMS(ESI):215[M+H]
1H NMR(300MHz,d6-DMSO)δ13.56(br s,1H),8.27(m,2H),8.08(d,1H,J=5.1Hz),7.41(t,2H,J=8.9Hz),6.95(m,2H),6.65(d,2H,J=9.1Hz),6.35(d,1H,J=5.4Hz),5.12(br s,2H)。
步骤2:1-(4-氟苯基)-2-氧代-N-(4-((2-(4-氟苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(12)的制备
化合物12-2 32mg、10-4 26mg和O-苯并三氮唑-N,N,N′,N′-四甲基脲四氟硼酸酯42mg溶于DMF/CH3CN(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺63μL,升至室温,搅拌过夜,氩气保护。有固体析出。加1N NaOH,溶解,室温搅拌半小时,蒸干溶剂,加水。过滤,固体用10%NaOH洗,固体干燥。制备板纯化,展开剂二氯甲烷∶甲醇(15∶1),得浅黄色固体产物12 16mg,产率30%。
m.p.>300℃
LCMS(ESI):536[M+H]
HRMS calcd for C30H19N5O3F2Na:558.1354(M+Na)+;Found:558.1365
1H NMR(300MHz,d6-DMSO)δ11.99(s,1H),8.58(dd,1H,J=7.4,1.5Hz),8.08(dd,1H,J=6.6,2Hz),7.8(d,2H,J=8.6Hz),7.59(m,2H),7.4(m,9H),6.72(t,1H,J=7Hz),6.51(d,1H,J=5.3Hz)。
实施例10 1-(4-氟苯基)-2-氧代-N-(4-((2-苯基-3H-咪唑并[4,5-b]吡啶-7- 基)氧)苯基)-1,2-二氢吡啶-3-酰胺(化合物13)的制备
6-2 20mg、10-4 16mg和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯26mg溶于二甲基甲酰胺/乙腈(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺39μL,升至室温,搅拌过夜。有固体析出。加1N NaOH,溶解,室温搅拌半小时,蒸干溶剂,加水。过滤,固体用10%NaOH洗,固体干燥。制备板纯化,展开剂二氯甲烷∶甲醇(15∶1)。得白色固体13 15mg,产率44%。
m.p.>300℃
LCMS(ESI):518[M+H]
HRMS calcd for C30H20N5O3FNa:540.1448(M+Na)+;Found:540.1457
1H NMR(300MHz,d6-DMSO)δ11.99(s,1H),8.58(dd,1H,J=7.2,2.4Hz),8.2(m,3H),8.1(dd,1H,J=6,1.7Hz),7.82(d,2H,J=9Hz),7.57(m,5H),7.42(t,2H,J=9.1),7.26(d,2H,J=8.3Hz),6.72(t,1H,J=7.1Hz),6.51(d,1H,J=5.5Hz)。
13C NMR(100MHz,d6-DMSO)δ170.5,161.9(d,J=244.8Hz),161.8,161.1,158.0,152.3,151.6,144.7,143.9,141.9,136.4,134.6,134.3,129.4,129.3,128.3,128.1,126.7,121.2,120.6,120.1,116.3,116.0,107.0,102.8。
实施例11 N-(4-((2-(3,4-二氟苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯 基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺(化合物14)的制备
步骤1:4-((2-(3,4-二氟苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯胺(14-2)的制备
300mg 3-6和108mg 3,4-二氟苯甲酸(14-1)(购自Acros公司,Belgium)于16g多聚磷酸中,250℃,5h。倒入冰水,用NaOH溶液中和,有固体析出。过滤,固体用二氯甲烷∶甲醇(4∶1)溶液溶取洗涤。合并有机相蒸干,过柱纯化,洗脱液二氯甲烷∶甲醇(15∶1)。得棕色固体产物14-2 80mg,产率35%。
LCMS(ESI):339[M+H]
1H NMR(300MHz,d6-DMSO)δ8.15(m,3H),7.65(m,1H),6.95(m,2H),6.66(d,2H,J=8.3Hz),6.36(d,1H,J=5.7Hz)。
步骤2:N-(4-((2-(3,4-二氟苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺(14)的制备
22mg 14-2、17mg 10-4和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯28mg溶于二甲基甲酰胺/乙腈(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺41μL,升至室温,搅拌过夜。有固体析出。加1N NaOH,溶解,室温搅拌半小时,蒸干溶剂,加水。过滤,固体用10%NaOH洗,固体干燥。得固体产物14 16mg,产率46%。
LCMS(ESI):630[M+H]
1H NMR(300MHz,d6-DMSO)δ8.6(dd,1H,J=7.4,1.6Hz),8.25(m,2H),8.12(dd,2H,J=6.3,1.6Hz),7.83(d,2H,J=8.9Hz),7.64(m,3H),7.43(t,2H,J=8.9Hz),7.27(d,2H,J=8.7Hz),6.73(t,1H,J=7Hz),6.53(d,1H,J=5.3Hz)。
实施例12 1-(4-氟苯基)-2-氧代-N-(4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡 啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(化合物15)的制备
26mg 5-2、20mg 10-4和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯32mg溶于二甲基甲酰胺/乙腈(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺51μL,升至室温,搅拌过夜。有固体析出。加1N NaOH,溶解,室温搅拌半小时,蒸干溶剂,加水。过滤,固体用10%NaOH洗,固体干燥。制备板纯化。得白色固体15 32mg,产率73%。
m.p.298-300℃
LCMS(ESI):524[M+H]
HRMS calcd for C28H18N5O3FSNa:546.1012(M+Na)+;Found:546.1029
1H NMR(300MHz,d6-DMSO)δ8.58(dd,1H,J=6.6,1.8Hz),8.31(d,1H,J=1.5Hz),8.1(m,2H),7.8(m,3H),7.7(m,1H),7.6(m,2H),7.41(t,2H,J=8.3Hz),7.22(d,2H,J=8.5Hz),6.71(t,1H,J=6.7Hz),6.45(d,1H,J=5.7Hz)。
13C NMR(100MHz,d6-DMSO)δ166.5,161.9(d,J=244.8Hz),161.8,161.2,153.6,150.2,149.1,144.9,143.9,136.4,135.4,135.3,132.6,129.4,129.3,127.6,126.5,125.9,121.4,121.0,120.5,116.3,116.0,107.0,104.2。
实施例13 N-(4-氟苯基)-N-(4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7- 基)氧)苯基)环丙基-1,1-二酰胺(化合物16)的制备
步骤1:1-((4-氟苯基)甲氨酰基)环丙羧酸(16-2)的制备
4.24克16-1(购自Acros公司,Belgium)溶于40mL无水四氢呋喃,氩气保护下,冷却到0℃,滴加5.52mL三乙胺,搅拌30分钟,加入2.36mL二氯亚砜,0℃下继续搅拌30分钟。将3.44mL对氟苯胺(10-2)溶于20mL无水四氢呋喃,滴入反应液,0℃下搅拌1.5小时。反应液用乙酸乙酯稀释,用1N氢氧化钠溶液和饱和氯化钠溶液洗涤,乙酸乙酯层用无水硫酸钠干燥,蒸干,所得固体用少量冷乙酸乙酯洗涤干燥,得白色固体产物16-2 3克,产率42%。
LCMS(ESI):224[M+H]
1H NMR(300MHz,CD3OD)δ7.54(m,2H),7.04(t,2H,J=8.8Hz),1.63(d,4H,J=5.7Hz)。
步骤2:N-(4-氟苯基)-N-(4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)环丙基-1,1-二酰胺(16)的制备
31mg 5-2、47mg 16-2、110mg HATU和0.1mL N,N-二异丙基乙胺溶于2mL二甲基甲酰胺,室温搅拌过夜。蒸去大部分溶剂,残留物用乙酸乙酯稀释,用1N氢氧化钠溶液和饱和氯化钠溶液洗涤,乙酸乙酯层用无水硫酸钠干燥,蒸干。所得粗产物过柱纯化,洗脱液为二氯甲烷∶甲醇(10∶1),得浅褐色固体16 40mg,产率79%。
LCMS(ESI):514[M+H]
1H NMR(300MHz,d6-DMSO)δ10.16(s,1H),10.06(s,1H),8.35(s,1H),8.14(s,1H),7.82(s,1H),7.75(m,3H),7.64(m,2H),7.22(m,2H),7.15(t,2H,J=9.1Hz),6.45(d,1H,J=5.7Hz),1.45(s,4H)。
实施例14 N-(4-氟苯基)-N-(4-((2-苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧) 苯基)环丙基-1,1-二酰胺(化合物17)的制备
6-2 22mg、16-2 16.3mg、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐15.3mg、1-羟基苯并三唑10mg和N,N-二异丙基乙胺38μM溶于二甲基甲酰胺5ml中,120℃微波反应30min。加25mL水稀释反应液,用二氯甲烷(25mL*3)萃取,合并萃取液蒸干,过柱纯化。得白色固体24.7mg,产率67%。
LCMS(ESI):508[M+H]
1H NMR(300MHz,d6-DMSO)δ10.17(s,1H),10.08(s,1H),8.23(d,2H,J=8.2Hz),8.16(d,1H,J=5.3Hz),7.74(d,2H,J=8.8Hz),7.65(m,2H),7.55(m,2H),7.22(d,1H,J=9.1Hz),7.16(t,2H,J=8.8Hz),6.47(d,1H,J=6.1Hz),1.47(s,4H)。
实施例15 1-(4-氟苯基)-2-氧代-5-苯基-N-(4((2-对甲苯基-3H-咪唑并 [4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(化合物18)的制备
步骤1:2-羟基-5-苯基尼古丁酸(18-3)的制备
218mg 2-羟基-5-溴-3-吡啶羧酸(18-1)(购自Acros公司,Belgium)、159mg苯硼酸(18-2)(购自Acros公司,Belgium)和600mg Cs2CO3于5mL二甲基甲酰胺中,加入0.5mL水,氩气脱气10min后,加入80mg Pd(PPh3)4,氩气保护下,110℃过夜。蒸去大部分溶剂后,有固体析出。过滤,干燥得浅黄色固体产物18-3 100mg,产率50%。
LCMS(ESI):216[M+H]
1H NMR(300MHz,d6-DMSO)δ8.62(d,1H,J=2.9Hz),8.29(d,1H,J=2.4Hz),7.66(d,2H,J=7.7Hz),7.46(t,2H,J=7.0Hz),7.3(t,1H,J=7.2Hz)。
步骤2:1-(4-氟苯基)-2-氧代-5-苯基-1,2-二氢吡啶-3-甲酸甲酯(18-5)的制备
将18-3 100mg溶于3mL甲醇,0℃滴加0.3mL SOCl2,0℃搅拌1小时,至60℃ 2小时。蒸去甲醇,加饱和碳酸氢钠搅拌,有白色固体,过滤,水洗,干燥,得米色固体18-4 100mg。
300mg 18-4和480mg 4-氟苯硼酸(购自Acros公司,Belgium)置于8mL二氧六环中,加入48mg醋酸铜和0.3mL吡啶,80℃,过夜,补加4-氟苯硼酸约100mg,80℃,4小时。过滤,滤液蒸干,过柱,得200mg米色固体18-5,总收率45%。
LCMS(ESI):324[M+H]
1H NMR(300MHz,CDCl3)δ8.55(d,1H,J=2.7Hz),7.77(d,1H,J=2.5Hz),7.46-7.38(m,7H),7.19(m,2H),3.93(s,3H)。
步骤3:1-(4-氟苯基)-2-氧代-5-苯基-1,2-二氢吡啶-3-甲酸(18-6)的制备
300mg 18-5与5mL 2N NaOH于80℃,2小时。冷至室温,1N HCl酸化,固体过滤,洗涤,干燥,得米色固体18-6 250mg,产率88%。
LCMS(ESI):310[M+H]
1H NMR(300MHz,CDCl3)δ14.0(br,1H),8.92(d,1H,J=2.7Hz),7.86(d,1H,J=2.7Hz),7.5-7.4(m,7H),7.28(m,2H)。
步骤4:1-(4-氟苯基)-2-氧代-5-苯基-N-(4((2-对甲苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺(18)的制备
22mg 3-8、22mg 18-6和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯27mg溶于二甲基甲酰胺/乙腈(1∶1)1mL中,0℃,加入N,N-二异丙基乙胺42μL,升至室温,搅拌过夜。有固体析出。加1N NaOH,溶解,室温搅拌半小时,蒸干溶剂,加水。过滤,固体用10%NaOH洗,固体干燥。得米色固体产物18 13mg,产率31%。
LCMS(ESI):608[M+H]
1H NMR(300MHz,d6-DMSO)δ12.0(s,1H),8.85(d,1H,J=2.7Hz),8.45(d,1H,J=2.8Hz),8.12(m,3H),7.83(d,2H,J=8.6Hz),7.71(m,4H),7.40(m,8H),7.25(m,1H),6.49(d,1H,J=5.7Hz),2.36(s,3H)。
实施例16 N-(3-氟-4((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯 基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺(化合物19)的制备
步骤1:3-氟-4-((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯胺(19-3)的制备
1-5 99mg与128mg 2-氟-4-硝基苯酚(19-1)(购自Acros公司,Belgium)溶于1.6mL N-甲基吡咯烷酮中,加入0.4mL N,N-二异丙基乙胺,微波下200℃,反应2h。用乙酸乙酯稀释,饱和KH2PO4洗,1M Na2CO3洗,干燥蒸干。过柱纯化,洗脱液石油醚∶乙酸乙酯(1∶1),得黄色固体19-2 100mg,产率68%。
上一步产物19-2 100mg溶于1.5mL四氢呋喃和3mL甲醇的混合溶剂中,加入锌粉105mg,再加入氯化铵90mg,氩气保护,室温搅拌过夜。过滤,乙酸乙酯洗涤,蒸干,过柱,洗脱液石油醚∶乙酸乙酯(1∶1)。得棕黄色固体19-3 52mg。产率60%。
LCMS(ESI):340[M+H]
1H NMR(300MHz,CDCl3)δ8.36(d,1H,J=6.1Hz),8.29(m,2H),7.22(t,2H,J=8.8Hz),7.07(t,1H,J=8.8Hz),6.66(d,1H,J=5.6Hz),6.57(dd,1H,J=12,2.7Hz),6.50(m,1H),3.87(br s,2H)。
步骤2:N-(3-氟-4((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺(19)的制备
19-3 26mg、10-4 18mg和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯29mg溶于二甲基甲酰胺/乙腈(1∶1)2mL中,0℃,加入N,N-二异丙基乙胺44μL,升至室温,搅拌过夜。有固体析出。过滤,固体过柱,得15mg米色产物19,产率37%。
m.p.277-280℃
LCMS(ESI):555[M+H]
1H NMR(300MHz,CDCl3)δ12.05(s,1H),8.76(dd,1H,J=7.4,2.5Hz),8.38(d,1H,J=5.4Hz),8.27(m,2H),7.99(dd,1H,J=12.2,2.2Hz),7.65(dd,1H,J=6.8,2.5Hz),7.4(m,3H),7.28(m,2H),7.21(m,3H),6.71(d,1H,J=5.4Hz),6.64(t,1H,J=7Hz)。
实施例17 N-(3-氟-4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯 基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺(化合物20)的制备
步骤1:4-(4-氨基-2-氟苯氧基)-3-硝基吡啶-2-胺(20-2)的制备
2.42g 2-氟-4-氨基酚(20-1)(购自Acros公司,Belgium)溶于30mL干燥二甲基甲酰胺,氩气脱气10min,加入叔丁醇钾2.19g,继续搅拌脱气1h。3g 2-氨基-3-硝基-4-氯吡啶(3-1)溶于10mL二甲基甲酰胺,加入反应液中,氩气保护70℃ 20小时。蒸去溶剂,残留物过柱纯化,石油醚∶乙酸乙酯=1∶1,得橙黄色固体20-2 3.7g,产率80%。
LCMS(ESI):265[M+H]
1H NMR(300MHz,d6-DMSO)δ7.98(d,1H,J=5.9Hz),7.15(br s,2H),7.0(t,1H,J=8.9Hz),6.51(dd,1H,J=13.4,2.3Hz),6.42(dd,1H,J=8.8,2.2Hz),5.93(d,1H,J=5.8Hz)。
步骤2:(9H-芴-9-基)甲基(4-((2,3-二氨基吡啶-4-基)氧)-3-氟苯基)氨基甲酸酯(20-4)的制备
NaHCO35.34g溶于60mL水,加二氧六环60mL,浑浊。加入20-2 3.7g,冰浴。滴加芴甲氧羰酰氯4.5g溶于少量二氧六环的溶液,室温搅拌过夜。有大量黄色固体析出。蒸去二氧六环,过滤,饱和碳酸氢钠洗,水洗,干燥,得粗产物黄色固体20-3 7g。
将上一步产物5g、锌粉7.5g和无水氯化钙9.4g混悬在240mL95%乙醇中,回流一小时。黄色褪去,TLC示原料反应完。冷却,过滤,蒸干溶剂,用二氯甲烷/甲醇(10∶1)过柱纯化,得3.5g粉色固体20-4,产率76%。
LCMS(ESI):457[M+H]
1H NMR(300MHz,d6-DMSO)δ7.91(d,2H,J=7.4Hz),7.74(d,2H,J=7.7Hz),7.33(m,8H),6.0(d,1H,J=5.9Hz),4.53(d,2H,J=5.9Hz),4.31(t,1H,J=6.2Hz)。
步骤3:3-氟-4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯胺(20-5)的制备
657mg 20-4和211mg噻吩-3-羧酸(5-1)于25g多聚磷酸中,250℃,5h。倒入冰水,用NaOH溶液中和,有固体析出。过滤,固体用二氯甲烷∶甲醇(4∶1)溶液溶取洗涤。合并有机相蒸干,过柱纯化,洗脱液二氯甲烷∶甲醇(15∶1),得80mg紫红色固体20-5。产率20%。
LCMS(ESI):327[M+H]
1H NMR(300MHz,d6-DMSO)δ8.33(s,1H),8.09(d,1H,J=5Hz),7.82(d,1H,J=3.2Hz),7.74(m,1H),7.05(m,1H),6.54(dd,1H,J=13.3,2.4Hz),6.45(dd,1H,J=8.6,2Hz),6.34(d,1H,J=5Hz)。
步骤4:N-(3-氟-4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺(20)的制备
20-5 32mg、10-4 23mg和O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯37mg溶于二甲基甲酰胺/乙腈2mL中,0℃,加入N,N-二异丙基乙胺57μL,升至室温,搅拌过夜。有固体析出。加1N NaOH搅拌半小时,蒸去溶剂,残留物加水搅拌,过滤,固体用1N NaOH洗,水洗至中性,干燥,得黄色固体20 20mg,产率40%。
m.p.>300℃
LCMS(ESI):542[M+H]
1H NMR(300MHz,d6-DMSO)δ8.59(dd,1H,J=7.4,2.5Hz),8.13(dd,2H,J=6.8,2.2Hz),8.04(d,1H,J=13.2Hz),7.83(s,1H),7.74(m,1H),7.6(m,3H),7.43(m,5H),6.73(t,1H,J=6.8Hz),6.47(d,1H,J=5.7Hz)。
实验实施例
1.生物活性测定
c-Met激酶分子水平抑制实验:
将酶反应底物Poly(Glu,Tyr)4∶1用无钾离子的PBS(10mM磷酸钠缓冲液,150mM NaCl,pH7.2-7.4)稀释成20μg/mL,125μL/孔包被酶标板,置37℃反应12-16小时。弃去孔中液体后洗板,用200μL/孔的T-PBS(含0.1%Tween-20的PBS)洗板三次,每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
每孔加入用反应缓冲液(50mM HEPES pH 7.4,50mM MgCl2,0.5mMMnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP溶液50μL,终浓度5μM。将待测试化合物(即上述制备的化合物1-20)用1%DMSO稀释成合适的浓度,10μL/孔,再加入用40μL反应缓冲液稀释的c-Met酪氨酸激酶蛋白。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次(每次实验需设无酶对照孔三孔及相应DMSO浓度的对照孔),加入一抗PY99 100μL/孔(p-Tyr(PY99),Cell Sinaling Technology,抗体用含BSA 5mg/mL的T-PBS1∶1000稀释),37℃摇床反应0.5小时。T-PBS洗板三次。加入二抗辣根过氧化物酶标记羊抗鼠的IgG 100μL/孔(抗体用含BSA 5mg/mL的T-PBS1∶2000稀释),37℃摇床反应0.5小时。T-PBS洗板三次。加入2mg/mL的OPD显色液100μL/孔(用含有0.03%H2O2的0.1M柠檬酸-柠檬酸钠缓冲液(pH=5.4)稀释),25℃避光反应1-10分钟(OPD溶解时需用超声,显色液需现配现用)。加入2M H2SO4 50μL/孔中止反应,用可调波长式微孔板酶标仪SPECTRA MAX190读数,波长为492nm。
样品的抑制率通过下列公式求得:
IC50值通过抑制曲线以四参数拟合计算。
2.生物活性测试结果
化合物1-20都显示出对c-Met的抑制活性,其中1、2、8、9、19、20 IC50值在大于10μM水平,化合物7的IC50值在1-10μM之间,化合物3、6、14、17、18的IC50值在0.1-1μM之间,具有较强的抑制活性,化合物4、5、10、11、12、13、15、16的IC50值小于100nM,具有很强的c-Met抑制活性。
Claims (10)
2.根据权利要求1所述的吡啶并五元杂环衍生物或其药学上可接受的盐,其中,R1为未取代的或被取代基所取代的苯基,或者含有1~2个选自N和S中的杂原子的五元或六元饱和或不饱和杂环基团,其中,所述的取代基为C1~2烷基或卤素。
3.根据权利要求2所述的吡啶并五元杂环衍生物或其药学上可接受的盐,其中,R1为未取代的或被取代基所取代的苯基,噻吩基,或吡啶基,其中,所述的取代基为甲基或卤素。
6.根据权利要求1所述的吡啶并五元杂环衍生物或其药学上可接受的盐,所述衍生物选自下列化合物中:
1-(4-氟苯基)-N-4-((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯基)-2-氧代-1,2-二氢吡啶-3-酰胺;
N-((4-((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯基)氨基甲硫酰基)2-2-苯乙酰胺;
2-苯基-N-((4-((2-对甲苯基)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺;
2-苯基-N-((4-((2-(4-吡啶)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺;
2-苯基-N-((4-((2-(3-噻吩)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺;
2-苯基-N-((4-((2-苯基-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)氨基甲硫酰基)苯乙酰胺;
2-苯基-N-(4-((3-噻吩)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)苯乙酰胺;
2-苯基-N-(4-((2-对甲苯基)-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)苯乙酰胺;
2-苯基-N-(4-(苯基-3H-咪唑并[4,5]吡啶-7-基)氧)苯基)苯乙酰胺;
1-(4-氟苯基)-2-氧代-N-(4-((2-对甲苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺;
1-(4-氟苯基)-2-氧代-N-(4-((2-(4-吡啶基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺;
1-(4-氟苯基)-2-氧代-N-(4-((2-(4-氟苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺;
1-(4-氟苯基)-2-氧代-N-(4-((2-苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺;
N-(4-((2-(3,4-二氟苯基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺;
1-(4-氟苯基)-2-氧代-N-(4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺;
N-(4-氟苯基)-N-(4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)环丙基-1,1-二酰胺;
N-(4-氟苯基)-N-(4-((2-苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)环丙基-1,1-二酰胺;
1-(4-氟苯基)-2-氧代-5-苯基-N-(4((2-对甲苯基-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1,2-二氢吡啶-3-酰胺;
N-(3-氟-4((2-(4-氟苯基)噁唑并[4,5-b]吡啶-7-基)氧)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺;和
N-(3-氟-4-((2-(3-噻吩基)-3H-咪唑并[4,5-b]吡啶-7-基)氧)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-酰胺。
7.一种制备权利要求1所述的吡啶并五元杂环衍生物或其药学上可接受的盐的方法,包括以下步骤:
反应方案1:
1)2-氨基-3-羟基吡啶II-1与羧酸II-2在多聚磷酸的作用下环化得到吡啶并噁唑结构的化合物II-3;
2)用过氧化物对化合物II-3中吡啶上的N氧化,得到化合物II-4;
3)用三氯氧磷处理化合物II-4,得到7-氯噁唑并[4,5-b]吡啶II-5;
5)将化合物II-6中的硝基用金属还原剂还原成氨基,得到化合物II-7;
6)化合物II-7与不同的R3片段连接,得到通式2所示化合物II-8,
其中,R1、R2和R3的定义与权利要求1相同;
或者,
反应方案2:
2)III-2中的苯环上的氨基用芴甲氧羰酰氯(Fmoc-Cl)保护后,得到化合物III-3;
3)化合物III-3中吡啶环上的硝基用金属还原剂还原成氨基,得到化合物III-4;
4)化合物III-4在R1COOH和多聚磷酸的作用下,得到吡啶并咪唑环,同时脱去Fmoc保护基,生成化合物III-5;
5)化合物III-5中的氨基与不同的R3片段连接,得到通式3所示化合物III-6;
其中,R1、R2和R3的定义与权利要求1相同。
8.根据权利要求7所述的方法,其中,在所述的反应方案1中,步骤1)中所述的2-氨基-3-羟基吡啶II-1与羧酸II-2在多聚磷酸的作用下在180℃~300℃高温共热环化得到吡啶并噁唑结构的化合物II-3;步骤2)中所用的过氧化物为间氯过氧苯甲酸;步骤4)中在微波条件下180℃~300℃加热,对硝基苯酚与化合物II-5中的吡啶环上的氯进行亲核取代,得到化合物II-6;和/或步骤5)中所用的金属还原剂为锌粉;
在所述的反应方案2中,步骤1)中所用的碱为叔丁醇钾;步骤3)中所用的金属还原剂优选为锌粉;和/或步骤4)中化合物III-4在R1COOH和多聚磷酸的作用下在180℃~300℃高温共热,得到吡啶并咪唑环。
9.一种用作c-Met抑制剂的药物组合物,该组合物包括治疗有效量的一种或多种如权利要求1所述的吡啶并五元杂环衍生物或其药学上可接受的盐以及药学上可接受的载体。
10.根据前述权利要求1~6中任一项所述的吡啶并五元杂环衍生物或其药学上可接受的盐用于制备c-Met抑制剂的药物中的用途。
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