CN106916112B - 嘧啶衍生物及其制备方法和在医药上的应用 - Google Patents
嘧啶衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- CN106916112B CN106916112B CN201710119496.8A CN201710119496A CN106916112B CN 106916112 B CN106916112 B CN 106916112B CN 201710119496 A CN201710119496 A CN 201710119496A CN 106916112 B CN106916112 B CN 106916112B
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Abstract
本发明涉及一种通式(I)所述的嘧啶衍生物及其制备方法和在医药上的应用，具体而言本发明涉及一种新的嘧啶衍生物、其制备方法、包括其药物组合物以及本发明的化合物药物组合物在医药上的用途，特别作为EGFR靶点抑制剂的用途。
Description
技术领域
本发明涉及一种嘧啶衍生物及其制备方法和在医药上的应用，具体是一种具有EGFR靶点抑制作用的新颖嘧啶衍生物或其立体异构体、水合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、其药物组合物以及其在医药上的应用。
背景技术
细胞表面受体中的受体酪氨酸激酶超家族通过细胞外生长因子对细胞信号的调节起重要的作用。受体酪氨酸激酶能够催化磷酸基团从ATP转移至底物的酪氨酸基团上。当没有配体激活受体酪氨酸激酶时，这些激酶处于未磷酸化的单体状态，其激酶域呈非活性的结构。当配体与受体酪氨酸激酶的胞外段结合时，受体发生寡聚化，并且自磷酸化，增加激酶的催化活性的同时形成了信号蛋白的结合位点，信号蛋白与其结合，从而激活多条信号通路。这些信号通路相互联系，调控细胞的增殖、生存、分化、功能、迁移和凋亡。当受体酪氨酸激酶失去调控，异常激活时，细胞会发生转化成肿瘤细胞，增殖、生长能力和耐药能力提高，具有较强的成血管能力、侵袭力和转移能力(Yarden和Sliwkowski,2001,Nat RevMol Cell Biol,2,127-137)。
ErbB家族属于受体酪氨酸激酶，包含四个成员：表皮生长因子受体(EGFR/HER1/ErbB1)、HER2(neu/ErbB2)、HER3(ErbB3)和HER4(ErbB4)(Olayioye,Neve等,2000,EMBO J,19,3159-3167；Yarden和Sliwkowski,2001,Nat Rev Mol Cell Biol,2,127-137)。他们都含有胞外配体结合域、单跨膜域和胞内酪氨酸激酶和调节域。其功能是催化ATP的磷酸基转移至底物蛋白的酪氨酸基团上。配体依赖的受体寡聚化导致受体调节域的自磷酸化，从而发生胞内信号转导，最终引起细胞增殖。该信号通路与肿瘤的发生和发展密切相关。在多种肿瘤中，超活化的ErbB受体，尤其是EGFR，会导致生长因子信号的失调控。EGFR的激活通常是由于过表达或突变引起的持续活化或配体的自分泌表达。因此抑制EGFR是一个备受关注的抗肿瘤策略。许多靶向EGFR的小分子抑制剂相继被开发，其中一些已经运用于临床治疗。
第一代的EGFR激酶抑制剂如吉非替尼、厄罗替尼在临床上能有效治疗非小细胞肺癌，尤其是那些含有EGFR激酶域发生激活突变的非小细胞肺癌(Mok,Wu等,2009,N Engl JMed,361,947-957；Rosell,Moran等,2009,N Engl J Med,361,958-967)。最常见的EGFR激活突变是L858R和delE746_A750，相对于野生型的EGFR，这些突变能够增加受体对吉非替尼和厄罗替尼的亲和力，而降低受体对ATP的亲和力(Carey,Garton等,2006,Cancer Res,66,8163-8171；Yun,Boggon等,2007,Cancer Cell,11,217-227)。但是，临床上，由于获得性耐药的出现，吉非替尼和厄罗替尼的运用最终受到了限制。超过50％的肺癌患者都会出现获得性耐药，其中超过90％都含有EGFR的T790M看门残基突变(Kobayashi,Boggon等,2005,NEngl J Med,352,786-792；Pao,Miller等,2005,PLoS Med,2,e73)。T790M突变并非从空间构象上阻碍药物的结合，而是恢复受体对ATP的亲和力，与野生型相当(Yun,Mengwasser等,2008,Proc Natl Acad Sci U S A,105,2070-2075)。
第二代的EGFR激酶抑制剂普遍具有喹啉结构，是不可逆的EGFR抑制剂。不同于吉非替尼，它们含有亲电子能力，能够与EGFR中保守的半胱氨酸基团(Cys 797)发生迈克尔加成反应。这些化合物的共价性质使它们相较于可逆的抑制剂，具有更强的占据ATP位点的能力，因此，尽管T790M突变能够增加ATP的亲和力，这类抑制剂在临床前模型中还是足以抑制EGFR T790M(Engelman,Zejnullahu等,2007,Cancer Res,67,11924-11932；Li,Ambrogio等,2008,Oncogene,27,4702-4711)。但是，现有的不可逆抑制剂在细胞系模型上，抑制EGFRT790M突变的能力还是低于抑制仅有EGFR激活突变的能力，并且在临床上可用到的浓度下，这类化合物在体外无法抑制EGFR T790M(Yuza,Glatt等,2007,Cancer Biol Ther,6,661-667；Godin-Heymann,Ulkus等,2008,Mol Cancer Ther,7,874-879)。由于EGFR T790M对ATP的亲和力与野生型的EGFR对ATP的亲和力相似，喹唑啉类的EGFR抑制剂在抑制EGFR T790M的同时，也会抑制野生型的EGFR。在临床上，同时抑制野生型EGFR会导致患者出现皮疹和腹泻，这会限制第二代EGFR抑制剂的使用剂量，以至于药物的血浆浓度用不足以抑制T790M，使这类药物的临床有效性受到较大的限制。例如CI-1033、HKI-272和PF00299804，在临床上针对吉非替尼和厄罗替尼耐药的非小细胞肺癌的治疗非常有限，并且会发生剂量依赖的腹泻和皮疹(Janne,von Pawel等,2007,J Clin Oncol,25,3936-3944；Advani,Coiffier等,2010,J Clin Oncol,28,2085-2093)。
为了能够特异性针对EGFR T790M进行抑制，第三代EGFR突变选择性抑制剂问世。这类不可逆抑制剂比起第二代喹啉类化合物，对EGFR T790M具有更高的选择性，在临床上可能具有更高的活性和更好的耐受。例如共价的嘧啶类EGFR抑制剂WZ4002，在体外实验中，相比喹啉类化合物，对EGFR T790M的选择性高30-100倍，而对野生型EGFR抑制则低100倍。在EGFR T790M衍生的动物肺癌模型中，也展现出较好的药效(Zhou,Ercan等,2009,Nature,462,1070-1074)。另一突变选择性抑制剂co-1686，在体外对EGFR T790M的选择性比对野生型EGFR高10-25倍。能选择性地抑制EGFR的突变，包括耐药突变T790M和激活突变(L858R,del19)，而对野生型EGFR无抑制。在体外，口服co-1686能够导致T790M突变的肿瘤衰退，并且不介导肿瘤细胞发生进一步的耐药突变(Walter,Sjin等,2013,Cancer Discov,3,1404-1415)。
为了满足临床需求，需要继续研发在能够有效克服T790M突变的浓度下不产生明显毒副作用的EGFR抑制剂。
CN102482277描述了式I的表皮生长因子受体抑制剂，其结构式如下：
Z1及Z2分别独立为N或CR5；Z3及Z4分别独立为N或C，其中RA及RB在Z3或Z4为N时不存在，其中，Z1、Z2、Z3或Z4的至少一个为N；X为O、S或NR6；Y为不存在、CO、O、S或NR6；专利公开了WZ-4002等一系列化合物，与本发明化合物不同，不认为此专利中具体描述是本发明的一部分。
CN103269704描述了杂环嘧啶化合物，以及治疗与EGFR激酶活性相关的疾病的方法，结构如下所示：
本发明的目的在于提供一种疗效好、耐受性好、选择性高或毒副作用低的EGFR抑制剂，及其在制备治疗癌症相关药物中的用途，所述的癌症包括头颈癌、卵巢癌、膀胱癌、宫颈癌、食道癌、胃癌、乳腺癌、内膜癌、结肠癌、肺癌、脑瘤、非小细胞肺癌、胰腺癌、实体肿瘤、结直肠肿瘤或恶性胶质瘤等。
发明内容
本发明涉及一种通式(I)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药：
其中，W选自O或NH，优选O；
R1选自H、F、Cl、Br或CF3，优选Cl或CF3，更优选Cl；
R2选自甲基或乙酰基，优选甲基。
本发明优选方案，一种通式(I)所述的化合物，其中该化合物选自如下结构之一：
根据本发明的具体实施方案，本发明的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中所述的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐或者它们的组合，优选的，所述的盐选自盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、肉桂酸盐、乳酸盐、丙二酸盐、琥珀酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或者它们的组合。
本发明还提供了一种药物组合物，所述的组合物包括：有效剂量的本发明所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂。
根据本发明的具体实施方案，本发明的药物组合物还进一步包括一种或多种其他治疗剂。
根据本发明的具体实施方案，本发明的药物组合物中所述的其他治疗剂包括：顺铂(cisplatin)，卡铂(carboplatin)，奥沙利铂(oxaliplatin)，达卡巴嗪(dacarbazine)，替莫唑胺(temozolomide)，丙卡巴肼(procarbazine)，甲氨蝶呤(methotrexate)，氟尿嘧啶(fluorouracil)，阿糖胞苷(cytarabine)，吉西他滨(gemcitabine)，巯基嘌呤(mercaptopurine)，氟达拉滨(fludarabine)，长春碱(vinblastine)，长春新碱(vincristine)，长春瑞滨(vinorelbine)，紫杉醇(paclitaxel)，多西紫杉醇(docetaxel)，拓扑替康(topotecan)，伊立替康(irinotecan)，依托泊苷(etoposide)，曲贝替定(trabectedin)，更生霉素(dactinomycin)，多柔比星(doxorubicin)，表柔比星(epirubicin)，道诺霉素(daunorubicin)，米托蒽醌(mitoxantrone)，博来霉素(bleomycin)，丝裂霉素C(mitomycin)，伊沙匹隆(ixabepilone)，他莫昔芬(tamoxifen)，氟他胺(flutamide)，西罗莫司(sirolimus)，Afatinib(afatinib)，alisertib，amuvatinib，阿帕替尼(apatinib)，阿西替尼(axitinib)，硼替佐米(bortezomib)，波舒替尼(bosutinib)，布立尼布(brivanib)，卡博替尼(cabozantinib)，西地尼布(cediranib)，crenolanib，克卓替尼(crizotinib)，dabrafenib(达拉非尼)，dacomitinib，达鲁舍替(danusertib)，达沙替尼(dasatinib)，多韦替尼(dovitinib)，厄洛替尼(erlotinib)，foretinib，ganetespib，gefitinib(吉非替尼)，依鲁替尼(ibrutinib)，埃克替尼(icotinib)，伊马替尼(imatinib)，iniparib，拉帕替尼(lapatinib)，lenvatinib，linifanib，linsitinib，马赛替尼(masitinib)，momelotinib，莫替沙尼(motesanib)，来那替尼(neratinib)，尼罗替尼(nilotinib)，niraparib，oprozomib，olaparib，帕唑帕尼(pazopanib)，pictilisib，ponatinib，quizartinib，regorafenib，rigosertib，rucaparib，ruxolitinib，塞卡替尼(saracatinib)，saridegib，索拉非尼(sorafenib)，舒尼替尼(sunitinib)，tasocitinib，telatinib，tivantinib，tivozanib，tofacitinib，trametinib，凡德他尼(vandetanib)，veliparib，威罗菲尼(vemurafenib)，vismodegib，volasertib，阿仑单抗(alemtuzumab)，贝伐单抗(bevacizumab)，brentuximab vedotin，卡妥索单抗(catumaxomab)，西妥昔单抗(cetuximab)，地诺单抗(denosumab)，吉妥珠单抗(gemtuzumab)，伊匹单抗(ipilimumab)，尼妥珠单抗(nimotuzumab)，奥法木单抗(ofatumumab)，帕尼单抗(panitumumab)，利妥昔单抗(rituximab)，托西莫单抗(tositumomab)，曲妥珠单抗(trastuzumab)或它们的组合。
本发明还提供了所述的化合物或其立体异构体、水合物、酯、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者所述的药物组合物在作为一种EGFR/HER2受体酪氨酸激酶抑制剂在制备药物制剂的应用，特别是在用于制备用于治疗和/或预防过度增殖性疾病的药物制剂中的应用。
根据本发明的具体实施方案，本发明的化合物或其立体异构体、水合物、酯、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者所述的药物组合物的应用中，所述过度增殖性疾病包括脑瘤、非小细胞肺癌、表皮鳞癌、膀胱癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、子宫颈癌、子宫内膜癌、结直肠癌、肾癌、食管腺癌、食管鳞状细胞癌、实体瘤、非霍奇金淋巴瘤、肝癌、肺癌，胃癌、皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤和鼻咽癌，优选非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌和结肠癌。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中无特殊说明，反应在氮气氛下进行。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温。
室温为最适宜的反应温度，为20℃～30℃。
本文所用的其他符号具有下列意义：
s:单峰
d：二重峰；
t：三重峰；
q：四重峰；
m：多重峰；
br：宽峰；
J：耦合常数；
Hz：赫兹；
Bn：苄基；
Me：甲基；
Et：乙基；
Ts：对甲苯磺酰基；
TBS：叔丁基二甲基硅基；
Boc：叔丁氧羰基；
Ac：乙酰基。
实施例1：N-(3-(5-氯-2-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺)嘧啶-4-基)氧基苯基)-2-丙烯酰胺(化合物1)
N-[3-[5-chloro-2-[3-fluoro-2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide
第一步：2,5-二氯-4-(3-硝基苯氧基)嘧啶(1B)
2,5-dichloro-4-(3-nitrophenoxy)pyrimidine
将间硝基苯酚(5g，35.9mmol)溶于N,N-二甲基甲酰胺(80mL)中，加入碳酸钾(9.9g，71.8mmol)，向反应瓶中缓慢滴加2,4,5-三氯嘧啶(1A)(6.6g，35.9mmol)，60℃反应2小时。 反应完毕后，冷却至室温，加入乙酸乙酯(80mL)，用水洗涤(80mL×3)，饱和食盐水洗涤(80mL×1)，无水硫酸钠干燥，过滤，将滤液减压浓缩得黄色固体状的2,5-二氯-4-(3-硝基苯氧基)嘧啶(1B)粗产品(9.5g，产率92.2％)，未经进一步纯化直接用于下步反应。
1H NMR(400MHz,DMSO-d6):δ8.88(s,1H),8.30(t,1H),8.27–8.20(m,1H),7.89–7.78(m,2H).
第二步：1-(2-氟-3-甲氧基-4-硝基苯基)-4-甲基哌嗪(1D)
1-(2-fluoro-3-methoxy-4-nitrophenyl)-4-methylpiperazine
将1,2-二氟-3-甲氧基-4-硝基苯(1C)(5g，26.4mmol)溶于二甲基亚砜(100mL)中，加入1-甲基哌嗪(3.2g，31.7mmol)，碳酸钾(7.3g，52.8mmol)，70℃反应20小时。反应液冷却至室温，加入水(100mL)，用二氯甲烷萃取(100mL×1)，水洗涤(100mL×2)，无水硫酸钠干燥，过滤，将滤液减压浓缩得黄色固体状的1-(2-氟-3-甲氧基-4-硝基苯基)-4-甲基哌嗪(1D)粗品(6g，产率85％)，未经进一步纯化直接用于下步反应。
1H NMR(400MHz,CDCl3):δ7.70(dd,1H),6.64(dd,1H),4.03(d,3H),3.34–3.23(m,4H),2.60(dd,4H),2.37(s,3H).
MS m/z(ESI):270.2[M+1].
第三步：3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺(1E)
3-fluoro-2-methoxy-4-(4-methylpiperazin-1-yl)aniline
将1-(2-氟-3-甲氧基-4-硝基苯基)-4-甲基哌嗪(1D)(6g，22.2mmol)溶于乙醇(80mL)和二氯甲烷(20mL)的混合溶剂中，加入钯碳(1.8g)，氢气氛围下，室温反应20小时。过滤，将滤液减压浓缩得灰色固体状的3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺(1E)粗品(4.6g，产率87％)，未经进一步纯化直接用于下步反应。
1H NMR(400MHz,CDCl3):δ6.57(t,1H),6.43(dd,1H),3.90(d,3H),3.69(s,2H),3.06(d,4H),2.69(s,4H),2.41(s,3H).
MS m/z(ESI):240.2[M+1].
第四步：5-氯-N-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-4-(3-硝基苯氧基)嘧啶-2-胺(1F)
5-chloro-N-[3-fluoro-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-4-(3-nitrophenoxy)pyrimidin-2-amine
将2,5-二氯-4-(3-硝基苯氧基)嘧啶(1B)(0.5g，1.7mmol)和3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺(1E)(0.487g，2.04mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入对甲苯磺酸(0.439g，2.55mmol)，120℃反应2小时。反应完毕后，冷却至室温，加入水(30mL)，用二氯甲烷萃取(30mL×1)，水洗涤(30mL×1)，饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇＝(v/v)100/1～15/1)，得黄色固体状的5-氯-N-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-4-(3-硝基苯氧基)嘧啶-2-胺(1F)(0.7g，产率84.33％)。
1H NMR(400MHz,CDCl3):δ8.33(s,1H),8.25(dd,1H),8.11(t,1H),7.80(d,1H),7.71(t,1H),7.65–7.55(m,1H),7.20(d,1H),6.29(t,1H),3.92(d,3H),3.47–3.20(m,8H),2.88(s,3H).
MS m/z(ESI):489.3[M+1].
第五步：4-(3-氨基苯氧基)-5-氯-N-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)嘧啶-2-胺(1G)
4-(3-aminophenoxy)-5-chloro-N-[3-fluoro-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine
将5-氯-N-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-4-(3-硝基苯氧基)嘧啶-2-胺(1F)(0.75g，1.5mmol)溶于乙醇(30mL)和水(10mL)的混合溶剂中，加入铁粉(0.3g，5mmol)，氯化铵(0.35g，5mmol)，90℃反应2小时，冷却至室温，加入水(60mL)，用二氯甲烷萃取(60mL×2)，饱和食盐水洗涤(60mL×1)，无水硫酸钠干燥，过滤，将滤液减压浓缩，得到类白色固体状的4-(3-氨基苯氧基)-5-氯-N-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)嘧啶-2-胺(1G)(0.58g，产率82％)。
1H NMR(400MHz,CDCl3):δ8.25(s,1H),7.53(s,1H),7.23(dd,2H),6.71(dd,1H),6.56(dd,1H),6.50(t,1H),6.42(t,1H),3.92(d,3H),3.56(s,4H),3.31(s,2H),3.09(s,2H),2.88(s,3H).
MS m/z(ESI):459.3[M+1].
第六步：N-(3-(5-氯-2-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)嘧啶-4-基)氧基苯基)-2-丙烯酰胺(化合物1)
N-[3-[5-chloro-2-[3-fluoro-2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide
将4-(3-氨基苯氧基)-5-氯-N-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)嘧啶-2-胺(1G)(0.58g，1.3mmol)溶于吡啶(30mL)中，依次加入丙烯酸(0.374g，5.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1g，5.2mmol)，室温反应2小时，减压浓缩，加入二氯甲烷(50mL)，依次用水洗涤(50mL×2)，饱和碳酸氢钠洗涤(50mL×2)，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇＝(v/v)100/1→20/1)，得到类 白色固体状的N-(3-(5-氯-2-(3-氟-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)嘧啶-4-基)氧基苯基)-2-丙烯酰胺(化合物1)(0.25g，产率39％)。
1H NMR(400MHz,CDCl3):δ8.25(s,1H),7.64(s,1H),7.56(d,2H),7.47(s,2H),7.41(t,1H),7.01–6.94(m,1H),6.42(dd,1H),6.38–6.31(m,1H),6.25(dd,1H),5.76(dd,1H),3.89(d,3H),3.06–2.96(m,4H),2.59(s,4H),2.36(s,3H).
MS m/z(ESI):513.0[M+1].
生物测试例
测试例1：测试癌细胞生长抑制
连续传代肿瘤细胞经胰蛋白酶消化，悬于培养基，计数后种入96孔细胞培养板。非小细胞肺癌细胞NCI-H1975每孔10000个细胞，人上皮细胞癌细胞A431细胞系每孔10000个细胞，在37℃，5％CO2孵箱中，培养过夜。第二天每种细胞取6个孔加入30μl 50％三氯乙酸固定；其余各孔分别加入得自实施例的化合物或。待测化合物以DMSO配置成溶液，最高浓度10μM，按下述方法5倍稀释10个待测浓度。对于NCI-H1975、A431细胞系，用含0.1％FBS的培养基梯度稀释待测，并使其为终浓度2倍。将种植NCI-H1975、A431细胞的96孔细胞培养板培养基换为新鲜含0.1％FBS的培养基(每孔100ul)，再加入100ul含2倍终浓度的待测化合物和WZ-4002。各96孔细胞培养板在37℃，5％CO2细胞培养箱孵育72小时。然后每孔加入50μl50％三氯乙酸，置于4℃冰箱中固定1小时。
将各孔中的三氯乙酸弃去，用300μl双蒸水洗5次。室温下干燥后，每孔加入50μl0.4％SRB(Sulforhodamine-B)染料溶液(1％乙酸/0.4％SRB)，反应15min。弃去各孔的染料溶液，用1％乙酸洗6-7次，室温干燥。各孔加入200μl 10mM Tris溶液(PH＝10.5)，振荡溶解。用酶标仪测定各孔490nm吸光度。以待测化合物浓度为0的孔的读数为对照，使用origin7.5计算和分析待测化合和WZ-4002的半效抑制浓度(IC50)。
本发明化合物的抗肿瘤细胞增殖活性通过以上的试验进行测定，测得的IC50值见表1。
表1抗肿瘤细胞增殖活性试验结果
结论：化合物1对T790M突变的的非小细胞肺癌细胞系具有较强的抑制增殖作用，相比对照化合物具有更高的选择性。
Claims (9)
1.一种如下结构所示的化合物或其药学上可接受的盐，其中所述的化合物选自：
2.根据权利要求1所述的化合物药学上可接受的盐，其中其药学上可接受的盐中所述的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐或者它们的组合。
3.一种药物组合物，所述的组合物包括：有效剂量的根据权利要求1-2中任一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂。
4.根据权利要求3所述的药物组合物，所述的组合物进一步包括一种或多种其他治疗剂。
5.根据权利要求4所述的药物组合物，其中所述的其他治疗剂是顺铂(cisplatin)，卡铂(carboplatin)，奥沙利铂(oxaliplatin)，达卡巴嗪(dacarbazine)，替莫唑胺(temozolomide)，丙卡巴肼(procarbazine)，甲氨蝶呤(methotrexate)，氟尿嘧啶(fluorouracil)，阿糖胞苷(cytarabine)，吉西他滨(gemcitabine)，巯基嘌呤(mercaptopurine)，氟达拉滨(fludarabine)，长春碱(vinblastine)，长春新碱(vincristine)，长春瑞滨(vinorelbine)，紫杉醇(paclitaxel)，多西紫杉醇(docetaxel)，拓扑替康(topotecan)，伊立替康(irinotecan)，依托泊苷(etoposide)，曲贝替定(trabectedin)，更生霉素(dactinomycin)，多柔比星(doxorubicin)，表柔比星(epirubicin)，道诺霉素(daunorubicin)，米托蒽醌(mitoxantrone)，博来霉素(bleomycin)，丝裂霉素C(mitomycin)，伊沙匹隆(ixabepilone)，他莫昔芬(tamoxifen)，氟他胺(flutamide)，西罗莫司(sirolimus)，阿法替尼(afatinib)，alisertib，amuvatinib，阿帕替尼(apatinib)，阿西替尼(axitinib)，硼替佐米(bortezomib)，波舒替尼(bosutinib)，布立尼布(brivanib)，卡博替尼(cabozantinib)，西地尼布(cediranib)，crenolanib，克卓替尼(crizotinib)，dabrafenib(达拉非尼)，dacomitinib，达鲁舍替(danusertib)，达沙替尼(dasatinib)，多韦替尼(dovitinib)，厄洛替尼(erlotinib)，foretinib，ganetespib，gefitinib(吉非替尼)，依鲁替尼(ibrutinib)，埃克替尼(icotinib)，伊马替尼(imatinib)，iniparib，拉帕替尼(lapatinib)，lenvatinib，linifanib，linsitinib，马赛替尼(masitinib)，momelotinib，莫替沙尼(motesanib)，来那替尼(neratinib)，尼罗替尼(nilotinib)，niraparib，oprozomib，olaparib，帕唑帕尼(pazopanib)，pictilisib，ponatinib，quizartinib，regorafenib，rigosertib，rucaparib，ruxolitinib，塞卡替尼(saracatinib)，saridegib，索拉非尼(sorafenib)，舒尼替尼(sunitinib)，tasocitinib，telatinib，tivantinib，tivozanib，tofacitinib，trametinib，凡德他尼(vandetanib)，veliparib，威罗菲尼(vemurafenib)，vismodegib，volasertib，阿仑单抗(alemtuzumab)，贝伐单抗(bevacizumab)，brentuximab vedotin，卡妥索单抗(catumaxomab)，西妥昔单抗(cetuximab)，地诺单抗(denosumab)，吉妥珠单抗(gemtuzumab)，伊匹单抗(ipilimumab)，尼妥珠单抗(nimotuzumab)，奥法木单抗(ofatumumab)，帕尼单抗(panitumumab)，利妥昔单抗(rituximab)，托西莫单抗(tositumomab)，曲妥珠单抗(trastuzumab)或它们的组合。
6.权利要求1-2中任一项所述的化合物或其药学上可接受的盐或者权利要求3-5中任一项所述的药物组合物在作为EGFR受体酪氨酸激酶抑制剂在制备药物制剂中的应用。
7.权利要求1-2中任一项所述的化合物或其药学上可接受的盐或者权利要求3-5中任一项所述的药物组合物在制备用于治疗和/或预防过度增殖性疾病的药物制剂中的应用。
8.根据权利要求7所述的应用，其中所述的过度增殖性疾病选自脑瘤、非小细胞肺癌、鳞状上皮细胞、膀胱癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、子宫颈癌、子宫内膜癌、结直肠癌、肾癌、食管腺癌、食管鳞状细胞癌、实体瘤、非霍奇金淋巴瘤、肝癌、肺癌，皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤及鼻咽癌中的一种或多种。
9.根据权利要求7所述的应用，其中所述过度增殖性疾病选自非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌及结肠癌中的一种或多种。
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