CN113993590A - 新型egfr抑制剂 - Google Patents
新型egfr抑制剂 Download PDFInfo
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- CN113993590A CN113993590A CN202080044132.8A CN202080044132A CN113993590A CN 113993590 A CN113993590 A CN 113993590A CN 202080044132 A CN202080044132 A CN 202080044132A CN 113993590 A CN113993590 A CN 113993590A
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- egfr
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- acid
- cancer
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
本发明提供了具有如本文所述的通式(I)的新型化合物，
Description
本发明提供化合物，该化合物是含有T790M/L858R、T790M/L858R/C797S、L858R、L858R/C797S的EGFR突变体的选择性变构抑制剂，还提供该化合物的制造、含有该化合物的药物组合物以及该化合物作为治疗活性物质的用途。
本发明提供了式(I)的新型化合物
或药用盐。
HER家族受体酪氨酸激酶是细胞生长、分化和存活的中介因子。该受体家族包括四个不同成员，即，表皮生长因子受体(EGFR、ErbBl或HER1)、HER2(ErbB2)、HER3(ErbB3)和HER4(ErbB4)。配体结合后，该受体形成同二聚体和异二聚体，随后内源性酪氨酸激酶活性的激活导致受体自身磷酸化和下游信号传导分子的激活(Yarden,Y.,Sliwkowski,MX.Untangling the ErbB signalling network.Nature Review Mol CellBiol.2001Feb；2(2):127-37)。已经证明，过表达或突变所致的EGFR失调牵涉到多种类型的人类癌症中，包括结直肠癌、胰腺癌、神经胶质瘤、头颈部肿瘤和肺癌，特别是非小细胞肺癌(NSCLC)，并且多年来已经研发了多种EGFR靶向剂(Ciardiello,F.,and Tortora,G.(2008).EGFR antagonists in cancer treatment.The New England journal ofmedicine 358,1160-1174)。埃罗替尼
EGFR酪氨酸激酶的一种可逆抑制剂，已经在许多国家被批准用于治疗复发性NSCLC。
在其肿瘤具有体细胞激酶结构域突变的NSCLC患者子集中观察到了令人印象深刻的EGFR酪氨酸激酶抑制剂的单剂活性，但野生型EGFR患者的临床有益效果大为降低(Paez,J.et al.(2004).EGFR mutations in lung cancer:correlation with clinicalresponse to gefitinib therapy.Science(New York,NY 304,1497-1500)。最常见的EGFR体细胞突变是外显子19缺失(其中δ746-750是最普遍的突变)和外显子21氨基酸取代(其中L858R是最频繁的突变)(Sharma SV,Bell DW,Settleman J,Haber DA.Epidermal growthfactor receptor mutations in lung cancer.Nat Rev Cancer.2007Mar；7(3):169-81)。
治疗抗性频繁出现，经常是由于该受体的ATP位点内的T790M二次突变。所研发的一些突变体选择性不可逆抑制剂具有抵抗T790M突变体的高活性，但其功效可能被C797S的获得性突变损害，即与所述抑制剂形成关键共价键的半胱氨酸残基的获得性突变(Thress,K.S.et al.Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.Nat.Med.21,560–562(2015))。据Wang进一步报告，C797S突变是对靶向T790M的EGFR抑制剂产生耐药性的主要机制(Wang etal.EGFR C797S mutation mediates resistance to third-generation inhibitors inT790M-positive non-small cell lung cancer,J Hematol Oncol.2016；9:59)。Yang描述了引起对奥西替尼的耐药性的其他突变，例如，L718Q(Yang et al,Investigating NovelResistance Mechanisms to Third-Generation EGFR Tyrosine Kinase InhibitorOsimertinib in Non–Small Cell Lung Cancer Patients,Clinical Cancer Research,DOI:10.1158/1078-0432.CCR-17-2310)Lu et al.(Targeting EGFRL858R/T790M andEGFRL858R/T790M/C797S resistance mutations in NSCLC:Current developments inmedicinal chemistry,Med Res Rev 2018；1-32)在一篇综述文章中报告了在NSCLC治疗中靶向EGFRL858R/T790M和EGFRL858R/T790M/C797S耐药性突变。
由于大多数可用的EGFR酪氨酸激酶抑制剂靶向该激酶的ATP-位点为靶标，对于以不同方式，例如，通过靶向耐药性EGFR突变体而发挥作用的新治疗剂存在序曲。
近期研究表明，有目的地靶向变构位点可导致突变体选择性抑制剂(Jia etal.Overcoming EGFR(T790M)and EGFR(C797S)resistance with mutant-selectiveallosteric inhibitors,June 2016,Nature 534,129-132)
确实仅对生成特异性地抑制含有T790M/L858R、T790M/L858R/C797S、L858R、L858R/C797S的EGFR突变体的选择性分子存在需求，该选择性分子可用于癌症特别是含有T790M和C797S的EGFR突变体的治疗性和/或预防性治疗。
WO2009158369描述了某些杂环抗细菌剂。WO2016183534描述了某些适合作为EBNA1抑制剂的杂环化合物。WO2011128279描述了某些适合作为mGluR5调节因子的杂环化合物。
术语“药用盐”是指那些保留游离碱或游离酸的生物有效性和特性的盐，其并非在生物学上或其他方面所不希望的。这些盐用无机酸诸如盐酸、氢溴酸、硫酸、硝酸、磷酸等(特别是盐酸)和有机酸诸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲基磺酸、乙基磺酸、对甲苯磺酸、水杨酸、N-乙酰基半胱氨酸等形成。此外，这些盐可通过将无机碱或有机碱加入游离酸中来制备。衍生自无机碱的盐包括但不限于钠、钾、锂、铵、钙、镁盐等。衍生自有机碱的盐包括但不限于以下各项的盐：伯胺、仲胺和叔胺、取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂(诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚亚胺树脂等)。特别的式(I)化合物的药用盐为盐酸盐、甲磺酸盐和柠檬酸盐。
缩写"uM"意指“微摩尔”，与符号"μM"等同。
缩写"uL"意指“微升”，与符号"μL"等同。
缩写"ug"意指“微克”，与符号"μg"等同。
式(I)化合物可以含有若干不对称中心，并且可以以光学纯对映体、对映体的混合物(例如外消旋体)、光学纯非对映体、非对映体的混合物、非对映外消旋体或非对映外消旋体的混合物存在。
根据Cahn-Ingold-Prelog规范，不对称碳原子可以是"R"或"S"构型。
此外，本发明的一个实施例是如本文所述的式(I)化合物及其药用盐，更特别地是如本文所述的式(I)的化合物。
如本文所述的式(I)化合物的制造工艺也是本发明的目的。
应认识到，本发明中式I化合物可在官能团处衍生化以提供能够在体内转化回母体化合物的衍生物。
本发明的某一实施方案涉及如本文所述的式I化合物或其药用盐，其用作治疗活性物质。
本发明的某一实施方案涉及如本文所述的式I化合物或其药用盐，其用于癌症特别是非小细胞肺癌的治疗性和/或预防性治疗。
本发明的某一实施方案涉及如本文所述的式I化合物或其药用盐，其用于非小细胞肺癌的治疗性和/或预防性治疗。
本发明的某一实施方案涉及如本文所述的式I化合物或其药用盐，其用于制造用于癌症特别是非小细胞肺癌的治疗性和/或预防性治疗的药物。
本发明的某一实施方案涉及一种药物组合物，其包含如本文所述的式I化合物或其药用盐和药用佐剂物质。
本发明的某一实施方案涉及通过将如本文所述的式I化合物或其药用盐施用至患者而用于癌症特别是非小细胞肺癌的治疗性和/或预防性治疗的方法。
本发明的某一实施方案涉及如本文所述的式I化合物或其药用盐，其作为药物用于苦于癌症特别是非小细胞肺癌的具有EGFR激活突变的患者的治疗性和/或预防性治疗中，包括确定所述患者的EGFR激活突变状态，然后将如本文所述的式I化合物或其药用盐施用至所述患者。
本发明的某一实施方案涉及如本文所述的式I化合物或其药用盐，其作为药物用于苦于癌症特别是非小细胞肺癌的具有EGFR突变T790M/L858R、T790M/L858R/C797S、L858R和/或L858R/C797S的患者的治疗性和/预防性治疗中，包括确定所述患者的EGFR激活突变状态，然后将如本文所述的式I化合物或其药用盐施用至所述患者。
本发明的某一实施方案涉及如本文所述的式I化合物或其药用盐，其作为药物用于苦于癌症特别是非小细胞肺癌的具有使用
EGFR突变试验v2确定的EGFR激活突变的患者的治疗性和/或预防性治疗中，包括确定所述患者的EGFR激活突变状态，然后将如本文所述的式I化合物或其药用盐施用至所述患者。
此外，本发明包括式I化合物的以其相应氘代形式下的全部取代基(只要适用)。
式I化合物含有一个或多个不对称中心，并可因此作为外消旋体、外消旋混合物、单个对映异构体、非对映异构混合物和个体非对映异构体出现。可存在另外的不对称中心，取决于分子上各种取代基的特性。每个此类不对称中心将独立地产生两个光学异构体，并且本发明旨在将混合物中或作为纯或部分纯化的化合物的全部可能的光学异构体和非对映异构体包括在本发明中。本发明意为涵盖该化合物的全部此类异构体形式。这些非对映异构体的独立合成或其色谱分离可通过如本领域已知的对本文所公开的方法做适宜改变而实现。可通过对晶体产物或晶体中间体的x射线晶体学测定其绝对立体化学，若必要，可使用含有已知绝对构型的不对称中心的试剂对这些产物或中间体进行衍生化。若需要，可将化合物的外消旋混合物分离，使得个体对映异构体被分离出来。该分离可通过本领域周知的方法实施，诸如将化合物的外消旋混合物与对映异构纯化合物偶联以形成非对映异构混合物，之后通过标准方法诸如分级结晶法或色谱法进行个体非对映异构体的分离。
在一些提供光学纯对映异构体的实施方案中，光学纯对映异构体意为该化合物含有按重量计>90％的所希望的异构体，特别是按重量计>95％的所希望的异构体，或更特别是按重量计>99％的所希望的异构体，所述重量百分比基于该化合物的异构体的总重量。可通过手性选择性合成或通过对映异构体分离来制备手性纯化合物或手性富集化合物。对映异构体分离可对最终产物实施或者可对合适的中间体实施。
此外，本发明的一个实施例是如本文所述的式(I)化合物，其根据本文所述的方法中的任一者进行制造。
测定程序
HTRF Phospho EGFR TMLRCS测定(细胞的)
细胞系和培养基
从Crownbio(San Diego,CA,USA)获得BaF3-TMLRCS细胞系。在37℃、5％CO2下，将细胞保持在以10％胎牛血清(FBS)(Gibco)补充的RPMI ATCC(Gibco 31870)+2mM谷氨酰胺+0.5μg/ml嘌呤霉素中。
规程
如上所述，向Greiner Bio-One,Nr.784-08微量滴定板预填充12.5nl的待试验化合物(剂量应答)的DMSO溶液或仅DMSO，然后将细胞以12.5μl生长培养基/孔中20000细胞/孔的量转移到该微量滴定板。以300x g将板旋转30秒后，将细胞在37℃、5％CO2、95％湿度下孵育4小时。向该化合物混合液中加入4μl/孔的补充裂解缓冲液(Cis-bio，Phospho-EGFRHTRF试剂盒，64EG1PEH)进行细胞裂解，之后通过振荡(400rpm)在室温孵育30分钟。然后冷冻该板，并在-80℃过夜储存。次日，将板解冻后，加入4μl的在检测缓冲液中制备的抗-Phospho-EGFR穴合物和抗-Phospho-EGFR-d2抗体混合物溶液。然后将带盖的板在室温下赋予4小时，之后使用Envision读板器(Perkin Elmer)读取616和665 nm的荧光发射。使用665比616个信号乘以10000的归一化比率，以与上述类似的方式分析数据。
结果如表1所示
式(I)化合物及其药用盐可以用作药物(例如，以药物制剂的形式)。药物制剂可内部给药，诸如经口(例如，以片剂、包衣片剂、糖衣丸、硬和软明胶胶囊、溶液、乳剂或混悬剂的形式)、经鼻(例如，以鼻喷雾剂的形式)、经直肠(例如，以栓剂的形式)或经眼部局部(例如，以溶液、软膏、凝胶剂或水溶性聚合物***物的形式)给药。但是，也可通过肠胃外诸如肌内、静脉内或眼内(例如，以无菌注射液的形式)给药。
式(I)化合物及其药用盐可与药学上惰性的无机或有机助剂一起加工以生产片剂、包衣片剂、糖衣丸、硬明胶胶囊、注射液或外用制剂。例如，可使用乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等本身作为片剂、糖衣丸和硬明胶胶囊的助剂。
用于软明胶胶囊的合适的助剂为例如植物油、蜡、脂肪、半固体物质和液体多元醇等。
用于制备溶液和糖浆的合适的助剂为例如水、多元醇、蔗糖、转化糖、葡萄糖等。
用于注射液的合适的助剂为例如水、醇、多元醇、甘油、植物油等。
用于栓剂的合适的助剂为例如天然或硬化油、蜡、脂肪、半固体或液体多元醇等。
用于局部眼用制剂的合适的助剂为例如环糊精、甘露醇或本领域已知的许多其他载体和赋形剂。
此外，药物制剂可以含有防腐剂、增溶剂、增粘物质、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、香料、用于改变渗透压的盐、缓冲剂掩模剂或抗氧化剂。它们还可以含有其他有治疗价值的物质。
剂量可以在宽范围内变化，当然将适合每种特定情况下的各种要求。一般而言，口服给药的日剂量为每kg体重约0.1mg至20mg、优选为每kg体重约0.5mg至4mg(例如每人约300mg)应当是合适的，其优选地分为1-3个单独的剂量(可由例如相同的量组成)。在局部给药的情况下，该制剂可包含按重量计0.001％至15％的药物，并且所需剂量可介于0.1mg至25mg之间，其每天或每周给药一次、或每天给药多次(2至4次)或每周给药多次。但是，显而易见的是，当显示为适用时，可超过本文中给出的上限或下限。
包含本发明的化合物的药物组合物的制备：
以下组合物的片剂按常规方式进行制造：
制造程序
1.将成分1、2、3和4混合并与纯化水一起造粒。
2.在50℃干燥颗粒。
3.令颗粒通过合适的研磨设备。
4.加入成分5，混合三分钟；在合适的压机上压制。
制造以下组合物的胶囊：
制造程序
1.将成分1、2和3在合适的混合器中混合30分钟。
2.加入成分4和5，并混合3分钟。
3.填充到合适的胶囊中。
首先在混合器中将式I化合物与乳糖和玉米淀粉混合，然后在粉碎机中粉碎。使混合物返回混合器；向其中加入滑石粉，并且混合均匀。利用机器将混合物装填到合适的胶囊中，例如硬明胶胶囊。
制造以下组合物的注射液：
| 成分 | mg/注射液 |
| 式I化合物 | 3 |
| 聚乙二醇400 | 150 |
| 乙酸 | 适量，将pH调节至5.0 |
| 注射用水 | 至1.0ml |
本发明通过以下实例示出，这些实例不具有限制性。
如果制备例以对映异构体的混合物的形式获得，则纯对映异构体可通过本文所述的方法或本领域的技术人员所知的方法获得，该方法如手性色谱法或结晶法。
实例1
(2RS)-2-(6，7-二氢-5H-吡咯并[1，2-c]咪唑-1-基)-2-[6-[2-[4-[(4-羟基-1-哌啶基)甲基]苯基]乙炔基]-1-氧代-4-(三氟甲基)异吲哚啉-2-基]-N-噻唑-2-基-乙酰胺
步骤1：2-(6，7-二氢-5H-吡咯并[1，2-c]咪唑-1-基)-2-氧代-乙酸乙酯
将二氧化硒(22.85g，205.94mmol，2当量)加入2-(6，7-二氢-5H-吡咯并[1，2-c]咪唑-1-基)乙酸乙酯(20.0g，102.97mmol)溶解在200ml的1，4-二噁烷中的溶液中。将反应混合物在80℃下搅拌5小时。将反应混合物在真空下浓缩以给出残余物。通过快速层析在硅胶柱上纯化粗产物，用石油醚：乙酸乙酯2:1到乙酸乙酯:乙醇10:1的梯度洗脱，以获得浅褐色油状的所希望的2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-氧代-乙酸乙酯(定量产率)，MS：m/e＝209.1(M+H+)。
步骤2：2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-羟基亚氨基-乙酸乙酯
在室温下，将盐酸羟胺(6.42g，92.45mmol，1.1当量)和醋酸钠(13.79g，168.1mmol，2当量)加入2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-氧代-乙酸乙酯(实例1，步骤1)(17.5g，84.05mmol)溶解在145ml乙醇中的溶液中。将反应混合物在80℃下搅拌3.5小时。将反应混合物浓缩，以水萃取，并使用乙醇/THF/乙酸乙酯1:1:8的混合物萃取五次。将有机层浓缩至干。获得黄色固体状的所希望的2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-羟基亚氨基-乙酸乙酯(15g，80％产率)，MS:m/e＝224.1(M+H+)，并直接用于下一步骤。
步骤3：(2RS)-2-氨基-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)乙酸乙酯
在室温下，将Pd/C(30.0g，67.2mmol，1当量，10％)加入2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-羟基亚氨基-乙酸乙酯(实例1，步骤2)(15.0g，67.2mmol)溶解在225ml乙醇和120ml THF中的溶液中。在45℃下，用H2将混合物氢化24小时。过滤反应混合物，并在真空下浓缩滤液。获得褐色油状的所希望的(2RS)-2-氨基-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)乙酸乙酯(定量产率)，MS:m/e＝210.1(M+H+)，并直接用于下一步骤。
步骤4：(2RS)-2-氨基-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)乙酸乙酯盐酸
盐
在25℃下，将(2RS)-2-氨基-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)乙酸乙酯(实例1，步骤3)(15.0g,82.79mmol)在HCl/EtOH(300ml，1200mmol，14.5当量，2.5mol/L)中的溶液搅拌36小时。在低于25℃下，将反应混合物在真空下浓缩以给出褐色油状的残余物。将150ml乙腈加入残余物中，收集沉淀的黄色固体并在低于25℃下真空干燥以给出黄色固体状的所希望的(2RS)-2-氨基-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)乙酸乙酯盐酸盐(定量产率)，MS：m/e＝210.1(M+H+)。
步骤5：5-碘-2-甲基-3-(三氟甲基)苯甲酸
将2-甲基-3-(三氟甲基)苯甲酸(3.4g,16.9mmol)溶解于20ml硫酸中。在室温下，加入1,3-二碘-5,5-二甲基咪唑烷-2,4-二酮(3.35g，8.82mmol，0.52当量)。在室温下，将混合物搅拌1小时。将反应混合物倒在水上，并滤出所得沉淀。干燥固体，以获得淡黄色固体状的所希望的产物(5.6g，定量产率)，MS:m/e＝329.1(M-H+)。
步骤6：5-碘-2-甲基-3-(三氟甲基)苯甲酸甲酯
将5-碘-2-甲基-3-(三氟甲基)苯甲酸(5.6g,16.6mmol)溶解于40ml DMF中。在室温下，加入碳酸钾(4.6g，33.3mmol，2当量)和碘甲烷(1.09ml，2.48g，17.5mmol，1.05当量)。将该混合物搅拌2.5小时。用乙酸乙酯和饱和NaHCO3溶液萃取反应混合物。用乙酸乙酯反萃取水层。用水洗涤有机层。合并有机层，用无水硫酸钠干燥，过滤并浓缩至干。粗产物通过快速层析在硅胶柱上纯化，用乙酸乙酯:庚烷0:100至50:50的梯度洗脱。获得白色固体状的所希望的产物(4.5g，71％产率)。
步骤7：2-(溴甲基)-5-碘-3-(三氟甲基)苯甲酸甲酯
将5-碘-2-甲基-3-(三氟甲基)苯甲酸甲酯(实例1，步骤6)(4.8g,11.8mmol)溶解于60ml三氟甲苯中，并且在室温下加入N-溴琥珀酰亚胺(2.34g，13.1mmol，1当量)和AIBN(200mg，1.2mmol，0.1当量)。在110℃下，将该混合物搅拌3小时。冷却反应混合物，用水萃取，并且用乙酸乙酯萃取两次。用无水硫酸钠干燥有机层，并浓缩至干。粗产物通过快速层析在硅胶柱上纯化，用乙酸乙酯:庚烷0:100至30:70的梯度洗脱，以获得无色油状的所希望的产物(4.94g，75％纯度，75％产率)。
步骤8：(2RS)-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-[6-碘-1-氧代-4-
(三氟甲基)异吲哚啉-2-基]乙酸乙酯
将(2RS)-2-氨基-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)乙酸乙酯盐酸盐(实例1，步骤4)(930mg，3.78mmol，1当量)溶解在1.5ml的DMF中。在室温下，加入2-(溴甲基)-5-碘-3-(三氟甲基)苯甲酸甲酯(实例1，步骤7)(1.6g,3.78mmol)和三乙胺(1.6ml，11.3mmol，3当量)。将混合物在室温下搅拌30分钟，再在100℃搅拌1小时。用水萃取反应混合物，并且用乙酸乙酯萃取两次。有机层用盐水萃取，以硫酸钠干燥，并浓缩至干。粗产物通过快速层析在硅胶柱上纯化，用二氯甲烷:甲醇100:0至90:10的梯度洗脱，以获得深褐色油状的所希望的产物(1.13g，56％产率)，MS:m/e＝520.0(M+H+)。
步骤9：(2RS)-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-[6-碘-1-氧代-4-
(三氟甲基)异吲哚啉-2-基]-N-噻唑-2-基-乙酰胺
将(2RS)-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-[6-碘-1-氧代-4-(三氟甲基)异吲哚啉-2-基]乙酸乙酯(实例1，步骤8)(550mg,1.06mmol)溶解于20ml甲醇和20mlTHF中。在室温下，加入LiOH(1M水溶液)(1.27ml，1.27mmol，1.2当量)。将混合物在室温下搅拌1小时。将反应混合物在真空下浓缩，并将残余物溶解于20ml DMF中。在室温下，加入噻唑-2-胺(138mg，1.38mmol，1.3当量)、Hunig碱(0.92ml，5.3mmol，5当量)和HATU(480mg，1.27mmol，1.2当量)。在室温下，将混合物搅拌30分钟。用水萃取反应混合物，并且用乙酸乙酯萃取两次。有机层用水萃取，以硫酸钠干燥，并浓缩至干。粗产物通过快速层析在硅胶柱上纯化，用二氯甲烷:甲醇100:0至90:10的梯度洗脱，以获得橙色半固体状的所希望的产物(420mg，68％产率)，MS:m/e＝574.0(M+H+)。
步骤10：1-[(4-乙炔基苯基)甲基]哌啶-4-醇
将4-乙炔基苯甲醛(2.8g,21.5mmol)溶解于85ml二氯甲烷中。在室温下，加入哌啶-4-醇(2.1g，21.5mmol，1.0当量)和三乙酰氧基硼氢化钠(7.75g，36.6mmol，1.7当量)。在室温下，将混合物搅拌5小时。用水萃取反应混合物，并且用二氯甲烷萃取两次。有机层用盐水萃取，以硫酸钠干燥，并浓缩至干。粗产物通过快速层析在硅胶柱上纯化，用二氯甲烷:甲醇100:0至80:20的梯度洗脱，以获得淡黄色固体状的所希望的产物(3.06g，66％产率)，MS:m/e＝216.3(M+H+)。
步骤11：(2RS)-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-[6-[2-[4-[(4-羟
基-1-哌啶基)甲基]苯基]乙炔基]-1-氧代-4-(三氟甲基)异吲哚啉-2-基]-N-噻唑-2-基-
乙酰胺
将(2RS)-2-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-1-基)-2-[6-碘-1-氧代-4-(三氟甲基)异吲哚啉-2-基]-N-噻唑-2-基-乙酰胺(实例1，步骤9)(210mg,0.37mmol)和1-[(4-乙炔基苯基)甲基]哌啶-4-醇(实例1，步骤10)(118mg，0.55mmol，1.5当量)溶解于4ml DMF中。加入三乙胺(111mg，0.15ml，1.1mmol，3当量)、双(三苯基膦)二氯化钯(II)(13mg，0.018mmol，0.05当量)、三苯基膦(10mg，0.04mmol，0.1当量)和碘化铜(I)(3mg，0.018mmol，0.05当量)，并将混合物在80℃下搅拌2小时。用水萃取反应混合物，并且用乙酸乙酯萃取两次。有机层用盐水萃取，以硫酸钠干燥，并浓缩至干。粗产物通过快速层析在硅胶柱上纯化，用二氯甲烷:甲醇100:0至90:10的梯度洗脱，以获得白色固体状的所希望的产物(144mg，59％产率)，MS:m/e＝661.4(M+H+)。
Claims (12)
1.一种式(I)化合物
或药用盐。
2.根据权利要求1所述的式(I)化合物，其中所述化合物是
3.根据权利要求1或2中任一项所述的化合物，其用作治疗活性物质。
4.一种药物组合物，其包含根据权利要求1或2中任一项所述的化合物以及治疗惰性载体。
5.根据权利要求1或2中任一项所述的化合物，其用于治疗或预防癌症。
6.根据权利要求1至2中任一项所述的化合物，其用于治疗或预防非小细胞肺癌。
7.根据权利要求1至2中任一项所述的化合物或药用盐用于治疗或预防癌症的用途。
8.根据权利要求1至2中任一项所述的化合物或药用盐用于治疗或预防非小细胞肺癌的用途。
9.根据权利要求1至2中任一项所述的化合物用于制备治疗或预防癌症的药物的用途。
10.根据权利要求1至2中任一项所述的化合物用于制备治疗或预防非小细胞肺癌的药物的用途。
11.一种用于治疗或预防癌症的方法，所述方法包括施用有效量的根据权利要求1至2中任一项所述的化合物。
12.一种用于治疗或预防非小细胞肺癌的方法，所述方法包括施用有效量的根据权利要求1至2中任一项所述的化合物。
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| US20180290975A1 (en) * | 2015-06-30 | 2018-10-11 | Dana-Farber Cancer Institute, Inc. | Inhibitors of egfr and methods of use thereof |
| WO2018220149A1 (en) * | 2017-06-02 | 2018-12-06 | F. Hoffmann-La Roche Ag | Compounds |
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| WO2016183534A1 (en) | 2015-05-14 | 2016-11-17 | The Wistar Institute Of Anatomy And Biology | Ebna1 inhibitors and methods using same |
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| AR121167A1 (es) | 2022-04-27 |
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| TW202115073A (zh) | 2021-04-16 |
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| AU2020296933A1 (en) | 2021-12-02 |
| WO2020254547A1 (en) | 2020-12-24 |
| EP3986566C0 (en) | 2023-08-30 |
| EP3986566A1 (en) | 2022-04-27 |
| ZA202108775B (en) | 2022-09-28 |
| TW202115070A (zh) | 2021-04-16 |
| AR119207A1 (es) | 2021-12-01 |
| EP3986567C0 (en) | 2023-08-30 |
| CO2021016967A2 (es) | 2022-01-17 |
| EP3986567A1 (en) | 2022-04-27 |
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| JP2022537771A (ja) | 2022-08-29 |
| CL2021003373A1 (es) | 2022-10-07 |
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