CN106032359B - 吲唑类化合物及其制备方法和用途 - Google Patents
吲唑类化合物及其制备方法和用途 Download PDFInfo
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- CN106032359B CN106032359B CN201510102633.8A CN201510102633A CN106032359B CN 106032359 B CN106032359 B CN 106032359B CN 201510102633 A CN201510102633 A CN 201510102633A CN 106032359 B CN106032359 B CN 106032359B
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明属药物合成领域，涉及新型吲唑类化合物，其制备方法和应用，以及含有所述化合物作为活性成分的药物组合物，以及其作为药物用以制备治疗与酪氨酸激酶FGFR相关的疾病，特别是FGFR相关的癌症的药物中的用途。本发明的吲唑类化合物化学式如下通式I所示，式中取代基如权利说明书所定义；所属化合物经生物实验结果表明，对成纤维细胞生长因子受体(FGFR)具有良好的抑制活性，可用作制备防治与FGFR相关的疾病的药物，特别是制备治疗与FGFR相关的癌症的药物。
Description
技术领域
本发明属药物合成领域，涉及新型吲唑类化合物，其制备方法和应用，以及含有所述化合物作为活性成分的药物组合物，以及其作为药物用以制备治疗与酪氨酸激酶FGFR相关的疾病，特别是FGFR相关的癌症的药物中的用途。
技术背景
据报道，癌症是目前威胁人类生命健康的头号杀手。据不完全统计，全世界每年约有2000万的新发病例；我国每年的新发病例约为160-200万，死亡130万。由于肿瘤早期具有转移的能力，临床诊断原发肿瘤中约50％的患者已产生远位转移。研究显示，由于肿瘤细胞増长快、易变异，从而产生多药耐药，导致化疗失败。据有关统计，90％以上的化疗失败与肿瘤细胞的多药耐药相关，因此，目前临床上应用的抗肿瘤药物远不能满足治疗的要求。
近年来，分子肿瘤学、分子药理学等学科的发展使肿瘤的本质正在逐步被阐明，人们逐渐认识到细胞癌变的本质是细胞信号转导通路失调导致的细胞无限增殖。研究表明，作为参与细胞信号传导的最为重要的成员，蛋白酪氨酸激酶(protein tyrosine kinases，PTKs，简称酪氨酸激酶)是最常见的生长因子受体，与肿瘤的发生和发展密切相关；酪氨酸激酶的活性过高，导致其下游信号途径激活，从而导致细胞转化、增殖、对抗细胞调亡、促进细胞生存，最终导致肿瘤的形成；因此，近年来抗肿瘤药物的研发趋势开始从传统的细胞毒药物转向针对细胞内异常信号转导的药物，并陆续有相关药物应用于临床。与传统的细胞毒类抗肿瘤药物相比，这类分子靶向药物疗效强、毒副作用小，逐渐成为当前抗肿瘤药物研发的热点。
研究表明受体酪氨酸激酶由于其异常表达激活或基因突变，在肿瘤发生发展、侵袭转移、药物抗性等各个环节均发挥关键作用，已成为抗肿瘤药物研发的重要靶点，其中，成纤维生长因子受体(fibroblast growth factor receptors,FGFRs)是受体酪氨酸激酶家族的重要成员，主要包括FGFR1、FGFR2、FGFR3和FGFR4四种亚型。(Fibroblast GrowthFactors,FGFs)。(Turner N.,Grose R.,Fibroblast growthfactor signalling:fromdevelopment to cancer,NatureReviews Cancer.(2010)10:116-129.Dieci M.V.,Arnedos M.,Andre F.,Soria J.C.,Fibroblast Growth Factor Receptor Inhibitorsas a Cancer Treatment:From a Biologic Rationale to Medical Perspectives,CancerDiscovery.(2013)3:264-279.)由于基因扩增、突变、融合或配体诱导等原因，FGFR各成员持续激活，诱导肿瘤细胞增殖、侵袭、迁移，促进血管生成，促进肿瘤的发生发展；FGFRs在多种肿瘤中高表达并异常激活，如非小细胞肺癌、乳腺癌、胃癌、膀胱癌、子宫内膜癌、***癌、***、结肠癌、食管癌、角质母细胞瘤、骨髓瘤、横纹肌肉瘤等(Dieci MV,Arnedos M,Andre F,Soria JC:Fibroblast growth factor receptor inhibitors as acancer treatment:from abiologic rationale to medicalperspectives.Cancerdiscovery,2013,3,264-79；TurnerN,GroseR:Fibroblast growthfactor signalling:from development to cancer.Nat.Rev.Cancer,2010,10,116-29.)，有研究显示，FGFR1扩增占非小细胞肺癌鳞癌的20％，并通过对FGFR1扩增的肺癌细胞株体外增殖、信号通路等研究显示FGFR选择性抑制剂可以非常有效抑制FGFR1信号通路的活化和细胞的增殖(FrequentandFocalFGFR1Amplification Associates with Therapeutically TractableFGFR1Dependency in Squamous Cell Lung Cancer(vol 3,66er5,2011),Sci TranslMed.(2010).Inhibitor-Sensitive FGFR1Amplification inHumanNon-Small CellLungCancer,PLoSONE.(2011)6:e20351.)；在乳腺癌当中，FGFR1所在的染色体(8p11–12)区域的扩增约占到ER阳性患者的10％，并且其与FGFR1mRNA的高表达以及病人的预后不良相关(Dieci MV,Arnedos M,Andre F,Soria JC:Fibroblast growthfactor receptorinhibitors as a cancer treatment:from abiologic rationale tomedicalperspectives.Cancer discovery,2013,3,264-79)；FGFR2基因扩增或者突变导致FGFR2信号通路的异常激活主要与胃癌、三阴性乳腺癌、子宫内膜癌等相关；胃癌组织中FGFR2的扩增率为5％-10％(Matsumoto K,Arao T,Hamaguchi T,Shimada Y,Kato K,OdaI,Taniguchi H,Koizumi F,Yanagihara K,Sasaki H,Nishio K,Yamada Y:FGFR2geneamplification and clinicopathologicalfeatures in gastric cancer.Br.J.Cancer,2012,106,727-32.)，有研究对313例胃癌组织分析显示，FGFR2的扩增与肿瘤大小、局部浸润程度、***转移情况以及远端转移的发生显著相关，而且具有FGFR2扩增的胃癌一般为进展性肿瘤，具有较差的预后，病人总体存活率相对较低(JungEJ,JungEJ,Min SY,Kim MA,Kim WH:Fibroblast growth factor receptor 2gene amplification status and itsclinicopathologic significance in gastric carcinoma.Humanpathology,2012,43,1559-66.)；FGFR2扩增在难治性的三阴性乳腺癌中占到4％；子宫内膜癌是常见的妇科生殖道肿瘤，FGFR2的突变大约占到子宫内膜癌的12％；在非侵袭性膀胱癌中FGFR3突变占到50％-60％，侵袭性膀胱癌中FGFR3突变占到10％-15％；在多发性骨髓瘤中FGFR3t(4；14)(p16.3；q32)基因重排占到15–20％(Dieci MV,Arnedos M,Andre F,Soria JC:Fibroblastgrowthfactor receptor inhibitors as a cancer treatment:from abiologicrationale to medicalperspectives.Cancer discovery,2013,3,264-279)，此外，在肝癌中多种亚型的FGFR及其配体FGFs具有异常的表达及活化，如FGFR2、FGFR3、FGFR4、FGF19、FGF2、FGF5、FGF8、FGF9等；多项临床前及临床研究均表明FGF/FGFR轴线异常激活在肝癌中的重要性(ChengAL,Shen YC,Zhu AX:Targeting Fibroblast Growth Factor ReceptorSignaling in Hepatocellular Carcinoma.Oncology-Basel,2011,81,372-80.)；不容忽视的是，FGF/FGFR轴线的异常活化与EGFR抑制剂、新生血管抑制剂以及内分泌治疗等的耐药密切相关(Nicholas T,Richard G:Fibroblast growth factor signalingfromdevelopment to cancer.NatureReviews,2010,10,116-129.)。因此，靶向FGFR抑制剂的研发已成为抗肿瘤药物研究的前沿热点。
基于分子靶向抗肿瘤药物研发的现状，本申请的发明人拟提供新的吲唑类化合物及其在制备抗肿瘤药物的应用，尤其是制备治疗与酪氨酸激酶FGFR相关的疾病药物的中的应用。
发明内容
本发明的目的在于提供新的吲唑类化合物及其在制备抗肿瘤药物的应用，尤其是制备治疗与酪氨酸激酶FGFR相关的疾病药物的中的应用。
本发明提供了具有通式I结构的吲唑类化合物或其药学上可接受的盐，具体涉及一种含哌啶或哌嗪的吲唑类化合物，该类化合物可以有效地抑制FGFR的活性，从而发挥防治肿瘤的作用。
本发明的目的之二在于，提供通式I所示化合物的制备方法。
本发明的目的之三在于，提供包含通式I所示化合物或其药学上可接受的盐的药物组合物。
本发明提供了具有如下通式I所示化合物或其药学上可接受的盐：
式中，A环代表五元或六元的芳环，以及含氮、氧、硫原子的杂芳环；
B环代表五元或六元的芳环，以及含氮、氧、硫原子的杂芳环；
R1代表氢、卤素、三氟甲基、甲氧基、乙氧基、异丙氧基、异丁氧基、氰基、C1－C20的直链或含支链的烃基；
R2代表氢、
本发明的具有如下通式I所示化合物或其药学上可接受的盐，其中所述选自如下结构式的基团：
本发明的具有如下通式I所示化合物或其药学上可接受的盐，其中所述选自如下结构式的基团：
本发明提供的通式I化合物的药学上可接受的盐，其包括：与盐酸、硫酸、氢溴酸、磷酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸等，或天冬氨酸、谷氨酸等酸性氨基酸形成酯后再与无机碱形成的盐，如钠、钾、钙、铝盐及铵盐；或与有机碱形成的盐，与甲胺盐、乙胺盐、乙醇胺盐等；或与赖氨酸、精氨酸、鸟氨酸等碱性氨基酸形成酯后的盐酸、氢溴酸、硫酸、磷酸等无机酸的盐，或与甲酸、乙酸、苦味酸、甲磺酸、乙磺酸等有机酸的盐。
本发明所述通式I化合物的制备方法按如下所示通式，
(1)采用逐步缩合或片段缩合的方法制备片段C；
(2)片段C与D缩合制得中间体F；
所用缩合方法可以为酰氯法，酰氟法，混合酸酐法或使用如下缩合剂：N,N-二环己基亚胺、1-[3-二甲氨基]-丙基-3-乙基碳二酰亚胺盐酸盐或7-氮杂苯并唑-1-基-氧(三-(二甲胺基)膦)六氟磷酸盐；
(3)片段F去除叔丁酯保护基，所用试剂为浓盐酸、氯化氢乙酸乙酯溶液、氯化氢二氧六环溶液、溴化氢乙酸乙酯溶液、溴化氢二氧六环溶液、溴化氢醋酸溶液、氟化氢、三氟乙酸或其组合；
(4)去除叔丁酯保护基的片段F与E偶联反应得通式I所示化合物；
所用偶联方法为suzuki偶联，或使用如下钯催化剂：四(三苯基膦)钯、1,1'-二(二苯膦基)二茂铁二氯化钯、酸酸钯。
本发明中，优选的化合物具有如下结构：
以化合物1-1为例，本发明的化合物的制备过程如下：
本发明提供了一种药物组合物，该药物组合物含有治疗有效量的上述通式I的化合物或其药学上可接受的盐，以及含有一种或多种药学上可接受的载体；该药用组合物还可以进一步包含气味剂、香味剂、赋形剂或稀释液等。
本发明进一步提供了通式I所示化合物或其药学上可接受盐在制备防治肿瘤的药物中的应用。
本发明进行了体外FGFR1抑制活性测试，结果显示，本发明的化合物显示出较好的FGFR1抑制活性，其中化合物1-8、1-13、1-15、1-16、1-17对于FGFR1的抑制活性IC50值小于10nM；
本发明的化合物进行了人胃癌细胞SNU16的体外增殖抑制作用测试，结果显示，所述的化合物显示出较好的对人胃癌细胞SNU16的增殖抑制作用。
本发明中，所采用的药效学试验方法，是本领域技术人员所熟知的方法；
本发明中，所用的FGFR1激酶由本实验室利用昆虫杆状病毒表达***表达纯化蛋白激酶区重组蛋白所获得。
本发明的化合物可以进一步研制开发新型的FGFR抑制剂和抗肿瘤药物。
本发明的含哌嗪或哌啶的新型吲唑类化合物尤其可制备FGFR抑制剂和抗肿瘤药物。鉴于异常激活FGFR信号传导，将导致乳腺癌、卵巢癌、膀胱癌、黑色素瘤、胃癌、子宫内膜癌等多种肿瘤的发生，，因此，本发明所述的恶性肿瘤包括FGFR信号通路异常激活所致的相关肿瘤，包括乳腺癌、卵巢癌、膀胱癌、黑色素瘤、胃癌、子宫内膜癌等多种肿瘤。
具体实施方式
实施例1：合成化合物1-1，4-(4-乙基哌嗪-1-基)-N-(6-苯基-1H-吲唑-3-基)苯甲酰胺
步骤1.按如下反应式合成6-溴-1H-吲唑-3-胺：
氮气保护下，4-溴-2-氟-苯腈(5g，25.13mmol)溶于20mL正丁醇中，加入水合肼(1.04mL，50.26mmol)，加热回流4h。冷至室温后，析出大量固体。抽滤并用石油醚洗涤滤饼，干燥后得白色固体4.759g，收率85.7％。1HNMR(400MHz,DMSO-d6)δ11.52(brs,1H),7.64(d,1H,J＝8.5Hz),7.37-7.52(m,1H),7.02(dd,1H,J＝8.5,1.6Hz),5.47(brs,2H).ESI-MS(m/z):[M+H]+＝213.0(calcd 212.05).
步骤2.按如下反应式合成1-叔丁氧羰基-3-胺基-6-溴-1H-吲唑：
氮气保护下，6-溴-1H-吲唑-3-胺(4.759g，22.43mmol)溶于20mL四氢呋喃中，冰浴条件下加入二碳酸二叔丁酯(5.385g，24.67mmol)，4-二甲氨基吡啶(1.0g,8.19mmol)。室温反应3h后，TLC(石油醚/乙酸乙酯＝1/1)显示原料消失，反应混合物减压浓缩，残余物中加入1mol/L盐酸调至酸性，乙酸乙酯萃取。萃取液用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余物硅胶柱层析(石油醚/乙酸乙酯＝2/1)得黄色固体6.964g，收率88.8％。1HNMR(400MHz,DMSO-d6)δ8.12(s,1H),7.80(d,J＝8.4Hz,1H),7.45(dd,J＝8.4,1.7Hz,1H),6.44(s,2H),1.57(s,9H).ESI-MS(m/z):[M+H]+＝313.0(Calcd:312.16).
步骤3.按如下反应式合成甲基4-(4-乙基哌嗪-1-基)苯甲酸甲酯：
氮气保护下，4-氟苯甲酸甲酯(3.0mL，20.69mmol)溶于20mL DMSO中，依次加入K2CO3(5.718g，41.38mmol)，N-乙基哌嗪(1.93mL,24.83mmol)。120℃反应过夜，反应降至室温后，加入乙酸乙酯和饱和食盐水各50mL振摇分层，水层用乙酸乙酯(50mL×3)萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，残余物硅胶柱层析(二氯甲烷/甲醇＝10/1)得白色固体4.405g，收率85.8％。ESI-MS(m/z):[M+H]+＝249.2(Calcd:248.15).
步骤4.按如下反应式合成甲基4-(4-乙基哌嗪-1-基)苯甲酸：
氮气保护下，甲基4-(4-乙基哌嗪-1-基)苯甲酸甲酯(4.405g，17.75mmol)溶于15mL甲醇、15mL水中，加入NaOH固体(1.420g，35.5mmol)。加热回流2h后，反应降至室温，反应混合物减压浓缩，残余物中加入1mol/L盐酸调至酸性，乙酸乙酯萃取。萃取液用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余物硅胶柱层析(二氯甲烷/甲醇＝10/1)得黄色固体3.009g，收率72.4％。ESI-MS(m/z):[M+H]-＝233.5(Calcd:234.14).
步骤5.按如下反应式合成1-叔丁氧羰基-6-溴-3-(4-乙基哌嗪-1-基)-苯甲酰胺)-1H-吲唑基：
氮气保护下，甲基4-(4-乙基哌嗪-1-基)苯甲酸(3.009g，12.85mmol)溶于15mL二氯甲烷中，冰浴条件下加入草酰氯(2.2mL，25.70mmol)。反应回流2h后，反应混合物减压浓缩，加入20mL二氯甲烷反复浓缩两次。残留物在冰浴条件下加入1-叔丁氧羰基-3-胺基-6-溴-1H-吲唑(4.011g，12.85mmol)的吡啶溶液(20mL)中，室温反应过夜。TLC(二氯甲烷/甲醇＝5/1)显示原料消失，反应混合物减压浓缩，残余物中加入1mol/L盐酸调至酸性，乙酸乙酯萃取。萃取液用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余物硅胶柱层析(二氯甲烷/甲醇＝2/1)得黄色固体3.136g，收率46.3％。1HNMR(400MHz,DMSO-d6):δ12.86(brs,1H),10.56(brs,1H),7.94(d,J＝8.7Hz,2H),7.61-7.70(m,1H),7.17(d,J＝9.9Hz,1H),6.99(d,J＝9.0Hz,2H),3.29(t,J＝7.4Hz,4H),2.51-2.56(m,4H),2.36(q,J＝7.1Hz,2H),1.52(s,9H),1.02(t,J＝7.2Hz,3H).ESI-MS(m/z):[M+H]+＝528.2(Calcd:527.10).
步骤6.按如下反应式合成1-叔丁氧羰基-3-(4-(4-乙基哌嗪-1-基)-苯甲酰胺)-6-苯基-1H-吲唑基：
氮气保护下，1-叔丁氧羰基-6-溴-3-(4-乙基哌嗪-1-基)-苯甲酰胺)-1H-吲唑基(100mg，0.190mmol)溶于2mL二氧六环中，依次加入苯硼酸(46.3mg，0.380mmol)、碳酸铯(185.7mg，0.570mmol)，Pd(dppf)Cl2(20mg)。120℃反应2h后，反应降至室温，反应混合物减压浓缩，加入乙酸乙酯和饱和食盐水各50ml萃取分层，水层用乙酸乙酯50mL继续萃取，合并有机层，饱和氯化钠洗，无水硫酸钠干燥，减压蒸去溶剂，残余物硅胶柱层析(二氯甲烷/甲醇＝10/1)得白色固体47.4mg，收率47.5％。ESI-MS(m/z):[M+H]+＝526.5(Calcd:526.22).
步骤7.按如下反应式合成4-(4-乙基哌嗪-1-基)-N-(6-苯基-1H-吲唑-3-基)苯甲酰胺：
氮气保护下，1-叔丁氧羰基-3-(4-(4-乙基哌嗪-1-基)-苯甲酰胺)-6-苯基-1H-吲唑基(47.4mg，0.090mmol)溶于2mL二氯甲烷，冰浴条件下加入1mL三氟乙酸中。冰浴条件反应2h后，反应混合物减压浓缩，并加入10mL二氯甲烷反复浓缩两次。加入1mol/L氢氧化钠水溶液调pH至碱性，并用乙酸乙酯萃取，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，残余物硅胶柱层析(二氯甲烷/甲醇＝10/1)得白色固体36.5mg，收率95.4％。1HNMR(400MHz,DMSO-d6)δ12.81(brs,1H),10.54(brs,1H),8.00(d,J＝8.9Hz,2H),7.80(d,J＝8.5Hz,1H),7.75(d,J＝7.3Hz,2H),7.66(s,1H),7.51(t,J＝7.6Hz,2H),7.35-7.44(m,2H),7.03(d,J＝8.9Hz,2H),3.37(s,4H),2.49-2.59(m,4H),2.41(s,2H),1.06(t,J＝7.1Hz,3H)。ESI-MS(m/z):[M+H]+＝426.6(Calcd:426.22).。
实施例2：合成化合物1-2，4-(4-乙基哌嗪-1-基)-N-(6-吡啶基-1H-吲唑-3-基)苯甲酰胺
步骤1.按如下反应式合成N-(6-溴-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)苯甲酰胺：
氮气保护下，1-叔丁氧羰基-6-溴-3-(4-乙基哌嗪-1-基)-苯甲酰胺)-1H-吲唑基(300mg，0.569mmol)溶于15mL二氯甲烷，冰浴条件下加入5mL三氟乙酸中。冰浴条件反应2h后，反应混合物减压浓缩，并加入10mL二氯甲烷反复浓缩两次。加入1mol/L氢氧化钠水溶液调pH至碱性，并用乙酸乙酯萃取，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，残余物硅胶柱层析(二氯甲烷/甲醇＝10/1)得白色固体220.9mg，收率90.9％。1HNMR(400MHz,DMSO-d6):δ12.86(brs,1H),10.56(brs,1H),7.94(d,J＝8.7Hz,2H),7.61-7.70(m,1H),7.17(d,J＝9.9Hz,1H),6.99(d,J＝9.0Hz,2H),3.29(t,J＝7.4Hz,4H),2.51-2.56(m,4H),2.36(q,J＝7.1Hz,2H),1.02(t,J＝7.2Hz,3H).ESI-MS(m/z):[M+H]+＝428.2(Calcd:427.10).
步骤2.按如下反应式合成4-(4-乙基哌嗪-1-基)-N-(6-吡啶基-1H-吲唑-3-基)苯甲酰胺：
氮气保护下，N-(6-溴-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)苯甲酰胺(100mg，0.234mmol)溶于2mL二氧六环中，依次加入4-吡啶硼酸(57.5mg，0.468mmol)、碳酸铯(228.7mg，0.792mmol)，Pd(dppf)Cl2(20mg)。120℃反应2h后，反应降至室温，反应混合物减压浓缩，加入乙酸乙酯和饱和食盐水各50ml萃取分层，水层用乙酸乙酯50mL继续萃取，合并有机层，饱和氯化钠洗，无水硫酸钠干燥，减压蒸去溶剂，残余物硅胶柱层析(二氯甲烷/甲醇＝10/1)得白色固体17.7mg，收率17.8％。1H NMR(400MHz,DMSO-d6)δ12.85(brs,1H),10.56(brs,1H),8.00(d,J＝8.8Hz,2H),7.77(d,J＝8.4Hz,1H),7.58-7.63(m,1H),7.41-7.54(m,4H),7.08-7.14(m,1H),7.04(d,J＝8.9Hz,2H),3.34(s,4H),2.51(s,4H),2.41(s,2H),1.06(t,J＝7.1Hz,3H)。ESI-MS(m/z):[M+H]+＝427.4(Calcd:426.22).。
实施例3：合成化合物1-3，4-(4-乙基哌嗪-1-基)-N-(6-(1-甲基-1H-吡唑-3-基)-1H-吲唑-3-基)苯甲酰
合成方法类同化合物1-2的制备方法，共获得白色固体21.9mg，收率21.8％。1HNMR(400MHz,DMSO-d6)δ12.67(brs,1H),10.46(brs,1H),8.23(s,1H),7.98(d,J＝8.8Hz,2H),7.94(s,1H),7.68(d,J＝8.5Hz,1H),7.57(s,1H),7.30(d,J＝8.5Hz,1H),7.02(d,J＝8.8Hz,2H),3.89(s,3H),3.34(s,4H),2.51(s,4H),2.41(d,J＝6.7Hz,2H),1.06(t,J＝7.2Hz,3H).ESI-MS(m/z):[M+H]+＝430.4(Calcd:429.23).。
实施例4：合成化合物1-4，4-(4-乙基哌嗪-1-基)-N-(6-(3-甲氧基苯基)-1H-吲唑-3-基)苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得白色固体31.9mg，收率29.9％。1HNMR(400MHz,DMSO-d6)δ12.79(brs,1H),10.53(brs,1H),7.99(d,J＝8.9Hz,2H),7.77(d,J＝8.5Hz,1H),7.67(s,1H),7.37(d,J＝8.6Hz,1H),7.03(d,J＝9.0Hz,2H),6.85(d,J＝2.2Hz,2H),6.54(t,J＝2.2Hz,1H),3.84(s,6H),3.29-3.35(m,4H),2.50-2.52(m,4H),2.39(q,J＝7.1Hz,2H),1.05(t,J＝7.2Hz,3H).ESI-MS(m/z):[M+H]+456.0(Calcd:455.23).。
实施例5：合成化合物1-5，N-(6-(4-氰基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得白色固体39.0mg，收率37.0％。1HNMR(400MHz,DMSO-d6)δ12.94(brs,1H),10.52(brs,1H),7.93-8.08(m,6H),7.85(d,J＝8.5Hz,1H),7.78(s,1H),7.44(d,J＝8.6Hz,1H),7.03(d,J＝8.6Hz,2H),3.34(s,4H),2.51(s,4H),2.40(q,J＝6.7Hz,2H),1.06(t,J＝7.1Hz,3H)。ESI-MS(m/z):[M+H]+451.1(Calcd:450.22).。
实施例6：合成化合物1-6，4-(4-乙基哌嗪-1-基)-N-(6-(4-三氟甲基苯基)-1H-吲唑-3-基)苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得白色固体45.2mg，收率39.2％。1HNMR(400MHz,DMSO-d6)δ12.92(brs,,1H),10.57(brs,1H),7.95-8.05(m,4H),7.85(d,J＝8.4Hz,3H),7.77(s,1H),7.44(d,J＝8.6Hz,1H),7.03(d,J＝8.8Hz,2H),3.34(s,4H),2.51(s,4H),2.41(q,J＝7.2Hz,2H),1.06(t,J＝7.1Hz,3H).。ESI-MS(m/z):[M+H]+＝494.2(Calcd:493.21)。
实施例7：合成化合物1-7，N-(6-(3-乙氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得白色固体45.2mg，收率39.2％。1HNMR(400MHz,DMSO-d6)δ12.80(brs,1H),10.54(brs,1H),8.00(d,J＝8.9Hz,2H),7.78(d,J＝8.5Hz,1H),7.66(s,1H),7.35-7.43(m,2H),7.29(d,J＝7.8Hz,1H),7.24(s,1H),7.03(d,J＝8.9Hz,2H),6.96(dd,J＝8.1,1.9Hz,1H),4.13(q,J＝6.9Hz,2H),3.33(s,4H),2.46-2.59(m,4H),2.41(s,2H),1.37(t,J＝8.0Hz,3H),1.06(t,J＝7.1Hz,3H)。ESI-MS(m/z):[M+H]+＝470.2(Calcd:469.25)。
实施例8：合成化合物1-8，N-(6-(3-异丙氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得白色固体50.9mg，收率45.0％。1HNMR(400MHz,DMSO-d6)δ12.79(brs,1H),10.54(brs,1H),8.00(d,J＝8.8Hz,2H),7.78(d,J＝8.5Hz,1H),7.65(s,1H),7.35-7.41(m,2H),7.27(d,J＝7.9Hz,1H),7.22(s,1H),7.03(d,J＝8.9Hz,2H),6.95(dd,J＝8.2,1.9Hz,1H),4.72-4.78(m,1H),3.34(s,4H),2.51(s,4H),2.40(s,2H),1.32(d,J＝6.0Hz,6H),1.06(t,J＝7.1Hz,3H)。ESI-MS(m/z):[M+H]+＝484.2(Calcd:483.26)。
实施例9：合成化合物1-9，N-(6-(3-异丁氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体29.4mg，收率25.3％。1HNMR(400MHz,DMSO-d6)δ12.79(brs,1H),10.54(brs,1H),8.00(d,J＝8.9Hz,2H),7.78(d,J＝8.5Hz,1H),7.67(s,1H),7.37-7.40(m,2H),7.29(d,J＝7.9Hz,1H),7.23-7.26(m,1H),7.03(d,J＝9.0Hz,2H),6.96(dd,J＝8.1,1.8Hz,1H),3.85(d,J＝6.5Hz,2H),3.34(s,4H),2.51(s,4H),2.40(s,2H),2.03-2.09(m,1H),1.06(t,J＝7.2Hz,3H),1.02(d,J＝6.7Hz,6H)。ESI-MS(m/z):[M+H]+＝498.3(Calcd:497.28)。
实施例10：合成化合物1-10，N-(6-(噻吩-2-基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体36.6mg，收率30.3％。1HNMR(400MHz,DMSO-d6)δ12.78(brs,1H),10.54(brs,1H),7.99(d,J＝8.8Hz,2H),7.75(d,J＝8.5Hz,1H),7.67(s,1H),7.60(dd,J＝8.6,4.3Hz,2H),7.41(d,J＝8.5Hz,1H),7.18(dd,J＝4.9,3.7Hz,1H),7.03(d,J＝8.9Hz,2H),3.34(s,4H),2.51(s,4H),2.41(d,J＝8.0Hz,2H),1.06(t,J＝7.2Hz,3H)。ESI-MS(m/z):[M+H]+＝432.3(Calcd:431.18)。
实施例11：合成化合物1-11，N-(6-(2,6-二甲基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体20.4mg，收率19.2％。1HNMR(400MHz,DMSO-d6)δ12.75(brs,1H),10.56(brs,1H),8.02(d,J＝8.7Hz,2H),7.77(d,J＝8.3Hz,1H),7.18(d,J＝8.4Hz,2H),7.14(d,J＝8.2Hz,2H),7.07(d,J＝8.6Hz,2H),6.82(d,J＝8.3Hz,1H),3.37-3.43(m,4H),2.54-2.68(m,4H),2.35(q,J＝7.2Hz,2H),2.01(s,6H),1.14(t,J＝7.0Hz,3H)。ESI-MS(m/z):[M+H]+＝454.3(Calcd:453.25)。
实施例12：合成化合物1-12，N-(6-(2-氯-4-三氟甲基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体38.4mg，收率21.1％。1HNMR(400MHz,DMSO-d6)δ12.94(brs,1H),10.59(brs,1H),7.99-8.03(m,3H),7.82(t,J＝9.1Hz,2H),7.75(d,J＝8.0Hz,1H),7.55(s,1H),7.15(d,J＝8.4Hz,1H),7.04(d,J＝8.8Hz,2H),3.35(s,4H),2.58(s,4H),2.45(s,2H),1.07(t,J＝7.0Hz,4H)。ESI-MS(m/z):[M+H]+＝528.1(Calcd:527.17).。
实施例13：合成化合物1-13，N-(6-(3-氟-5-甲氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体44.1mg，收率36.3％。1HNMR(400MHz,DMSO-d6)δ12.86(brs,1H),10.59(brs,1H),8.00(d,J＝8.9Hz,2H),7.80(d,J＝8.5Hz,1H),7.72(s,1H),7.40(dd,J＝8.6,1.3Hz,1H),7.12-7.21(m,2H),7.03(d,J＝9.0Hz,2H),6.87(d,J＝10.9Hz,1H),3.87(s,3H),3.32(s,4H),2.51(s,4H),2.39(q,J＝7.1Hz,2H),1.05(t,J＝7.2Hz,3H)。ESI-MS(m/z):[M+H]+＝473.8(Calcd:473.22).。
实施例14：合成化合物1-14，N-(6-(3-甲氧基苯基)-1H-吲唑-3-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得黄色固体71.4mg，收率65.0％。1HNMR(400MHz,DMSO-d6)δ12.88(brs,1H),10.86(brs,1H),8.11(d,J＝7.2Hz,1H),7.82(d,J＝8.5Hz,1H),7.70(s,1H),7.62(d,J＝7.3Hz,1H),7.54-7.56(m,1H),7.40-7.42(m,1H),7.31(d,J＝7.9Hz,1H),7.25-7.29(m,1H),6.98(dd,J＝8.1,1.9Hz,1H),3.86(s,3H)。ESI-MS(m/z):[M+H]+＝344.8(Calcd:343.13).。
实施例15：合成化合物1-15，N-(6-(3-氟-5-甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体54.3mg，收率16.9％。1HNMR(400MHz,DMSO-d6)δ12.86(brs,1H),10.56(brs,1H),7.99(d,J＝8.8Hz,2H),7.79(d,J＝8.5Hz,1H),7.72(s,1H),7.40(d,J＝8.6Hz,1H),7.12-7.20(m,2H),7.03(d,J＝9.0Hz,2H),6.82-6.91(m,1H),3.87(s,3H),3.37(s,4H),2.49(s,4H),2.26(s,3H)。ESI-MS(m/z):[M+H]+＝460.8(Calcd:459.21).。
实施例16：合成化合物1-16，N-(6-(3-氟-5-甲氧基苯基)-1H-吲唑-3-基)-4-(4-(二甲氨基)哌啶-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体74.3mg，收率16.0％。1HNMR(400MHz,DMSO-d6)δ12.87(brs,1H),10.54(brs,1H),7.99(d,J＝8.7Hz,2H),7.79(d,J＝8.5Hz,1H),7.72(s,1H),7.40(d,J＝8.8Hz,1H),7.11-7.22(m,2H),7.04(d,J＝8.8Hz,2H),6.87(d,J＝10.9Hz,1H),3.98(d,J＝12.2Hz,2H),3.87(s,3H),2.84(t,J＝12.0Hz,2H),2.59(s,1H),2.35(s,6H),1.92(s,2H),1.51(d,J＝10.8Hz,2H)。ESI-MS(m/z):[M+H]+＝488.3(Calcd:487.24).。
实施例17：合成化合物1-17，N-(6-(3-氟-5-甲氧基苯基)-1H-吲唑-3-基)-4-(4-(3S,5R)-3,5-二甲基-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体66.5mg，收率26.0％。HNMR(400MHz,DMSO-d6)δ12.87(brs,1H),10.56(brs,1H),7.99(d,J＝8.8Hz,2H),7.79(d,J＝8.6Hz,1H),7.72(s,1H),7.40(d,J＝8.5Hz,1H),7.14-7.18(m,2H),7.04(d,J＝9.0Hz,2H),6.87(d,J＝10.9Hz,1H),4.47(brs,1H),3.87(s,3H),3.82(s,2H),2.96(s,2H),2.32-2.38(m,2H),1.11(s,3H),1.08(s,3H)。ESI-MS(m/z):[M+H]+＝473.8(Calcd:473.22).。
实施例18：合成化合物1-18，N-(6-(3-氟-5-甲氧基苯基)-1H-吲唑-3-基)-5-(4-甲基-哌嗪-1-基)吡嗪-2-甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体37.1mg，收率37.4％。1HNMR(400MHz,DMSO-d6)δ12.95(brs,1H),10.42(brs,1H),8.80(s,1H),8.44(s,1H),7.94(d,J＝8.4Hz,1H),7.74(s,1H),7.42(d,J＝8.3Hz,1H),7.05-7.25(m,2H),6.87(d,J＝10.9Hz,1H),3.87(s,7H),2.70(s,4H),2.42(s,3H)。ESI-MS(m/z):[M+H]+＝462.0(Calcd:461.20).。
实施例19：合成化合物1-19，N-(6-(3-氟-5-甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基-1,4-高哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体30.1mg，收率33.4％。1HNMR(400MHz,DMSO-d6)δ12.83(brs,1H),10.44(brs,1H),7.97(d,J＝8.4Hz,2H),7.79(d,J＝8.0Hz,1H),7.71(s,1H),7.39(d,J＝8.1Hz,1H),7.14-7.18(m,2H),6.85-6.89(m,1H),6.80(d,J＝7.9Hz,2H),3.87(s,7H),3.63-3.65(m,2H),3.53(t,J＝6.8Hz,2H),2.70-2.78(m,2H),2.55-2.62(m,2H),2.48-2.51(m,4H),2.36(s,3H)。ESI-MS(m/z):[M+H]+＝474.0(Calcd:473.22).。
实施例20：合成化合物1-20，N-(6-(2-氟-5-甲氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体28.3mg，收率30.8％。1HNMR(400MHz,DMSO-d6)δ:12.96(brs,1H),10.59(brs,1H),8.01(d,J＝8.5Hz,2H),7.79(d,J＝8.5Hz,1H),7.63(s,1H),7.24-7.30(m,2H),7.09-7.11(m,1H),7.05(d,J＝8.0Hz,2H),6.97-7.00(m,1H),3.82(s,3H),3.39-3.50(m,4H),2.68-2.80(m,4H),2.51-2.62(m,2H),1.11(t,J＝7.2Hz,3H).ESI-MS(m/z):[M+H]+＝474.0(Calcd:473.22).。
实施例21：合成化合物1-21，N-(6-(2-氟-3-甲氧基苯基)-1H-吲唑-3-基)-4-(4-乙基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体29.0mg，收率31.0％。1HNMR(400MHz,DMSO-d6)δ:12.85(brs,1H),10.57(brs,1H),8.00(d,J＝8.9Hz,2H),7.79(d,J＝8.5Hz,1H),7.58(s,1H),7.19-7.28(m,3H),7.12-7.15(m,1H),7.03(d,J＝9.0Hz,2H),3.90(s,3H),3.25-3.41(m,4H),2.54-2.66(m,4H),2.41-2.48(m,2H),1.08(t,J＝7.4Hz,3H).ESI-MS(m/z):[M+H]+＝474.0(Calcd:473.22).。
实施例22：合成化合物1-22，N-(6-(2-氟-3-甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基-1,4-高哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体32.1mg，收率34.3％。1HNMR(400MHz,DMSO-d6)δ:12.86(brs,1H),10.56(brs,1H),7.99(d,J＝8.9Hz,2H),7.79(d,J＝8.2Hz,1H),7.58(s,1H),7.19-7.21(m,3H),7.12-7.15(m,1H),7.04(d,J＝7.8Hz,2H),3.90(s,3H),3.82-3.85(m,2H),2.95(s,2H),2.34-2.40(m,2H),1.12(s,3H),1.10(s,3H).ESI-MS(m/z):[M+H]+＝474.0(Calcd:473.22).。
实施例23：合成化合物1-23，N-(6-(2-氟-3-甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基-1,4-高哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体22.1mg，收率25.8％。1HNMR(400MHz,DMSO-d6)δ:12.84(brs,1H),10.47(brs,1H),7.97(d,J＝8.5Hz,2H),7.78(d,J＝8.2Hz,1H),7.58(s,1H),7.20-7.26(m,3H),7.12-7.15(m,1H),6.81(d,J＝7.8Hz,2H),3.90(s,3H),3.63-3.66(m,2H),3.54(t,J＝6.2Hz,2H),2.80(s,2H),2.65(s,2H),2.40(s,3H),1.96-2.03(m,2H).ESI-MS(m/z):[M+H]+＝474.0(Calcd:473.22).。
实施例24：合成化合物1-24，N-(6-(2-氟-3-甲氧基苯基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体19.2mg，收率22.5％。1HNMR(400MHz,DMSO-d6)δ:12.87(brs,1H),10.57(brs,1H),7.98(d,J＝8.2Hz,2H),7.76(d,J＝8.2Hz,1H),7.56(s,1H),7.19-7.24(m,3H),7.10-7.13(m,1H),7.02(d,J＝7.8Hz,2H),3.88(s,3H),3.24-3.39(s,4H),2.44-2.52(s,4H),2.31(s,3H).ESI-MS(m/z):[M+H]+＝460.0(Calcd:459.20).。
实施例25：合成化合物1-25，N-(6-(2-氟-3-甲氧基苯基)-1H-吲唑-3-基)-5-(4-甲基-哌嗪-1-基)吡嗪-2-甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体23.2mg，收率24.8％。1HNMR(400MHz,DMSO-d6)δ:12.93(brs,1H),10.40(brs,1H),8.78(s,1H),8.41(s,1H),7.94(d,J＝8.2Hz,1H),7.59(s,1H),7.20-7.28(m,3H),7.12-7.15(m,1H),3.90(s,3H),3.72-3.83(m,4H),2.42-2.51(m,4H),2.26(s,3H).ESI-MS(m/z):[M+H]+＝462.1(Calcd:461.20).。
实施例26：合成化合物1-26，N-(6-(2-氟-3-甲氧基苯基)-1H-吲唑-3-基)-4-(4-(二甲氨基)哌啶-1-基)-苯甲酰胺
合成方法类同化合物1-2的制备方法，共获得固体35.4mg，收率33.8％。1HNMR(400MHz,DMSO-d6)δ:12.96(brs,1H),10.55(brs,1H),7.98(d,J＝8.0Hz,2H),7.78(d,J＝7.8Hz,1H),7.59(s,1H),7.20-7.26(m,3H),7.11-7.14(m,1H),7.02(d,J＝8.2Hz,2H),3.95(s,2H),3.90(s,3H),2.80-2.86(m,2H),2.19(s,6H),1.82-1.86(m,2H),1.43-1.48(m,2H).ESI-MS(m/z):[M+H]+＝488.3(Calcd:487.24).。
实施例27：体外FGFR1抑制活性测试
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，150mMNaCl,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 MgCl2,0.5mM MnCl2,0.2mMNa3VO4,1mM DTT)稀释的ATP溶液50μL，终浓度5μM。化合物用DMSO稀释成合适的浓度，1μL/孔或者或含相应浓度的DMSO(阴性对照孔)，再加入用49μL反应缓冲液稀释的FGFR1激酶域重组蛋白启动反应，每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次。加入一抗PY99稀释液100μL/孔，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稀释液100μL/孔，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 H2SO450μL/孔中止反应，用可调波长式微孔板酶标仪SPECTRAMAX 190读数，波长为490nm；
样品的抑制率通过下列公式求得：
抑制率(％)＝[1-(化合物的OD值-无ATP对照孔OD值)/(阴性对照OD值-无ATP对照孔OD值)]×100％
IC50值采用酶标仪随机附带软件以四参数法回归求得；
结果表明(如表1所示)，本发明的化合物显示出较好的FGFR1抑制活性，其中化合物1-8、1-13、1-15、1-16、1-17对于FGFR1的抑制活性IC50值小于10nM。
表1是本发明化合物的FGFR1的体外抑制活性结果。
表1
实施例28：化合物对FGFR2介导的肿瘤细胞增殖能力的影响试验
采用CCK-8细胞计数试剂盒(Dojindo)检测本发明的化合物对SNU16细胞的增殖抑制作用，具体步骤包括：处于对数生长期的SNU16细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)，待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm；
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：
抑制率(％)＝[(OD对照孔-OD给药孔)/OD对照孔]×100％
IC50值采用酶标仪随机附带软件以四参数法回归求得。
结果表明(如表2所示)，本发明的化合物对人胃癌细胞SNU16的体外增殖抑制作用测试，结果显示，所述化合物显示出较好的对人胃癌细胞SNU16的增殖抑制作用。
表2是本发明化合物对人胃癌细胞SNU16的体外增殖抑制作用。
表2
Claims (8)
1.一种吲唑类化合物或其药学上可接受的盐，所述化合物是下述化合物中的一种：
2.根据权利要求1所述的化合物或其药学上可接受的盐，所述化合物是下述化合物中的一种：
3.一种制备权利要求1～2任一项所述的化合物或其药学上可接受的盐的方法，其特征是，其按通式I，包括如下步骤：
(1)采用逐步缩合或片段缩合的方法制备片段C；
(2)片段C与D缩合制得中间体F，
所述的缩合方法为酰氯法，酰氟法或混合酸酐法，或使用缩合剂：N,N-二环己基亚胺、1-[3-二甲氨基]-丙基-3-乙基碳二酰亚胺盐酸盐或7-氮杂苯并唑-1-基-氧(三-(二甲胺基)膦)六氟磷酸盐；
(3)片段F脱除叔丁酯保护基，所用试剂为浓盐酸、氯化氢乙酸乙酯溶液、氯化氢二氧六环溶液、溴化氢乙酸乙酯溶液、溴化氢二氧六环溶液、溴化氢醋酸溶液、氟化氢、三氟乙酸或其组合；
(4)脱除叔丁酯保护基的片段F与E偶联反应得权利要求1～2所示化合物；所用偶联方法为suzuki偶联，或使用如下催化剂：四(三苯基膦)钯、1,1'-二(二苯膦基)二茂铁二氯化钯、或酸酸钯；
其中R1,R2，A环，B环，为权利要求1，2所示化合物的相应位置的取代基。
4.一种药物组合物，其特征是，该组合物含有治疗有效量的权利要求1～2任一项所述的化合物或其药学上可接受的盐。
5.根据权利要求4所述的药物组合物，其特征是，所述的化合物或其药学上可接受的盐占该药物组合物总重量的20％～99％。
6.根据权利要求4或5所述的药物组合物，其特征是，该组合物进一步包含一种或多种药学上可接受的载体、气味剂、香味剂、赋形剂或稀释液。
7.权利要求1～2任一项所述的化合物或其药学上可接受的盐在制备防治肿瘤药物中的用途，其中，所述肿瘤是与酪氨酸激酶FGFR相关的肿瘤。
8.根据权利要求7所述的用途，其特征是，所述的肿瘤是乳腺癌、卵巢癌、膀胱癌、黑色素瘤、胃癌或子宫内膜癌。
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| WO2005085227A1 (en) * | 2004-03-02 | 2005-09-15 | Smithkline Beecham Corporation | Inhibitors of akt activity |
| WO2006003276A1 (fr) * | 2004-06-04 | 2006-01-12 | Aventis Pharma S.A. | Indazoles substitues, compositions les contenant, procede de fabrication et utilisation |
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| WO2005085227A1 (en) * | 2004-03-02 | 2005-09-15 | Smithkline Beecham Corporation | Inhibitors of akt activity |
| WO2006003276A1 (fr) * | 2004-06-04 | 2006-01-12 | Aventis Pharma S.A. | Indazoles substitues, compositions les contenant, procede de fabrication et utilisation |
| CN102595899A (zh) * | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | 作为wnt/b-联蛋白信号传导途径抑制剂的吲唑及其治疗用途 |
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