CN105968056A - 二芳基嘧啶类化合物，组合物及用途 - Google Patents
二芳基嘧啶类化合物，组合物及用途 Download PDFInfo
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- CN105968056A CN105968056A CN201610365513.1A CN201610365513A CN105968056A CN 105968056 A CN105968056 A CN 105968056A CN 201610365513 A CN201610365513 A CN 201610365513A CN 105968056 A CN105968056 A CN 105968056A
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- amine
- phenyl
- pyrimidinyl
- propenamide
- chloro
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/48—Two nitrogen atoms
Landscapes
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- Organic Chemistry (AREA)
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Abstract
本发明涉及二芳基嘧啶类化合物，组合物及用途，所述二芳基嘧啶类化合物具体为通式(Ⅰ)所示的化合物，通式(Ⅰ)的各取代基如说明书中的定义。本发明还涉及所述通式(Ⅰ)所示的化合物或其药学上可接受的盐或所述的药物组合物通过抑制EGFR表皮因子受体蛋白酪氨酸激酶(Protein tyrosine kinase,PTK)，进而治疗肿瘤疾病，特别是用于治疗非小细胞肺癌、小细胞肺癌、鳞状细胞癌、乳腺癌、淋巴细胞白血病的用途。
Description
技术领域
本发明涉及二芳基嘧啶类化合物，组合物及用途，属于医药技术领域。
背景技术
蛋白酪氨酸激酶(protein tyrosine kinase,PTKs)通过控制细胞的信号传导通路调节细胞的生长、分化、凋亡等一系列生理生化过程。受体型酪氨酸激酶是一类横跨细胞膜相对较大的激酶，其具有配体结合的胞外结构域、跨膜结构域和起激酶作用—在磷酸化特定酪氨酸残基并且由此影响细胞增殖的胞内结构域。在一般人类癌症中(如肺癌、乳腺癌、胃癌、卵巢癌、淋巴瘤)已发现所述激酶的异常表达。蛋白酪氨酸激酶已成为抗肿瘤药物研究开发的重要靶点之一。
表皮生长因子受体酪氨酸激酶(epidermal growth factor receptor tyrosinekinase，EGFR)是最早发现的蛋白酪氨酸激酶之一，EGFR的胞内区有ATP结合位点，EGFR抑制剂可以竞争性与ATP结合位点相结合，从而抑制EGFR的磷酸化过程，阻断下游信号的传导，进而抑制肿瘤细胞的生长、分化和转移(Yun,et al.Cancer Cell 2007,11,217-227)。EGFR作为抗肿瘤靶点的生化过程已被阐明，其晶体结构和活性部位也已比较清楚，以此为靶点的药物吉非替尼(gefitinib)、埃罗替尼(erlotinib)、阿法替尼(afatinib)等已经应用于临床，且随着EGFR结构和活性关系的深入研究，许多效果更佳优秀的EGFR抑制剂(EP0566226、WO9961428、WO0051587、WO0375947、WO0132651、WO9633980、WO9630347、US7709479、US6716847、US6593333、US6251912、CN201080060451.4、CN201110191525.4等)已被发现。然而这些药物不可避免地存在着抗耐药性差的问题。研究表明：氨基酸The790到Met790的突变(T790M)是此类药物产生耐药性的主要诱因。有临床案例数据显示，大约有60％的患者获得性耐药都源于T790M位点的突变所致。因此开发抗耐药性更强、毒性更小、活性更强的新型EGFR抑制剂具有非常重要现实价值。
Osimertinib(AZD9291)是口服不可逆的，T790M突变选择性EGFR抑制剂，在LoVo细胞中对Exon 19缺失的EGFRL858R/T790M和EGFRWT的IC50分别为11.44和493.8nM，于2015年12被美国FDA批准上市(WO2013014448)用于治疗EGFRT790M耐药型肺癌。Rociletinib(CO-1686,AVL-301)是另一种不可逆的，突变选择性EGFRT790M抑制剂，在无细胞试验中作用于EGFRT790M和EGFRWT的Ki分别为21.5nM和303.3nM，目前处于临床Ⅲ期研究研究(WO 2012061299)。其它如HM61713，EGF816，PF-06747775，Avitinib，ASP8273也是进入临床研究的新型EGFRT抑制剂(Ma et al.,J.Med.Chem.,2016，DOI:10.1021/acs.jmedchem.5b00840.)，涉及的专利如：US20120157426、US8563568B2、CN102740847、CN102083800。
发明内容
一方面，本发明提供一种通式(Ⅰ)所示的化合物或其药学上可接受的盐，所述通式(Ⅰ)所示的化合物具有如下结构：
R1选自氯、氟或三氟甲基；
R2选自氢、甲基、乙基、甲氧基、氟、氯、溴、三氟甲基或氰基；
X选自CH2或O；
Y选自O,甲胺基、乙胺基、乙酰胺基或乙磺酰胺基；
n＝1-3。
作为本发明的一种具体实施方式，本发明所述通式(Ⅰ)所示的化合物具有I-1～I-44所示的结构：
本发明以Rociletinib为先导物，在其二芳基嘧啶母核的4-苯胺基部分引入更具柔性的新型结构片段，设计合成了通式(Ⅰ)所示二芳基嘧啶化合物。初步抗肿瘤活性筛选显示，大部分此类化合物具有较强的抑制非小细胞肺癌(NSCLC)细胞增殖能力，部分化合物显示出比Rociletinib更加优良的抗EGFRT790M活性，且部分化合物还对乳腺癌细胞(MCF-7)和淋巴细胞白血病细胞(Ramos)也显示出了较强的抑制效果。作为一类结构新颖的分子，本发明中的化合物具有开发成新型高效EGFR抑制剂的潜力，对治疗相关的肿瘤疾病尤其是非小细胞肺癌、小细胞肺癌、鳞状细胞癌、乳腺癌、淋巴细胞白血病有较大的应用价值。
前述I-1～I-44所示的结构分别具有如下名称：
Ⅰ-1N-[3-[[5-氯-2-[[4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-2N-[3-[[5-氯-2-[[4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-3N-[3-[[5-氯-2-[[4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-4N-[3-[[5-氯-2-[[4-[2-(4-乙酰基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-5N-[3-[[5-氯-2-[[4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-6N-[3-[[5-氯-2-[[4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
Ⅰ-7N-[3-[[5-氯-2-[[4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-8N-[3-[[5-氯-2-[[4-[2-(4-乙酰基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-9N-[3-[[5-氯-2-[[4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-10N-[3-[[5-氯-2-[[4-[2-(4-甲基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-11N-[3-[[5-氯-2-[[4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-12N-[3-[[5-氯-2-[[4-[2-(4-乙酰基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-13N-[3-[[5-氯-2-[[3-氯-4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-14N-[3-[[5-氯-2-[[3-氯-4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-15N-[3-[[5-氯-2-[[3-氯-4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-16N-[3-[[5-氯-2-[[3-氯-4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-17N-[3-[[5-氯-2-[[3-氯-4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-18N-[3-[[5-氯-2-[[3-氯-4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
Ⅰ-19N-[3-[[5-氯-2-[[3-氯-4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-20N-[3-[[5-氯-2-[[3-氯-4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-21N-[3-[[5-氟-2-[[4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-22N-[3-[[5-氟-2-[[4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-23N-[3-[[5-氟-2-[[4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-24N-[3-[[5-氟-2-[[4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-25N-[3-[[5-氟-2-[[4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-26N-[3-[[5-氟-2-[[4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
Ⅰ-27N-[3-[[5-氟-2-[[4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-28N-[3-[[5-氟-2-[[4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-29N-[3-[[5-三氟甲基-2-[[4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-30N-[3-[[5-三氟甲基-2-[[4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-31N-[3-[[5-三氟甲基-2-[[4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-32N-[3-[[5-三氟甲基-2-[[4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-33N-[3-[[5-三氟甲基-2-[[4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-35N-[3-[[5-三氟甲基-2-[[4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
Ⅰ-36N-[3-[[5-三氟甲基-2-[[4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-36N-[3-[[5-三氟甲基-2-[[4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-37N-[3-[[5-氯-2-[[3-氟-4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-38N-[3-[[5-氯-2-[[3-氟-4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-39N-[3-[[5-氯-2-[[3-甲氧基-4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-40N-[3-[[5-氯-2-[[3-甲氧基-4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-41N-[3-[[5-氯-2-[[3-氰基-4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-42N-[3-[[5-氯-2-[[3-氰基-4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
Ⅰ-43N-[3-[[5-氯-2-[[3-乙基-4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
Ⅰ-44N-[3-[[5-氯-2-[[3-乙基-4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺。
另一方面，本发明提供一种药物组合物，其含有有效剂量的本发明所述通式(Ⅰ)所示的化合物或其药学上可接受的盐，及药用载体，所述药物组合物例如为脂质体或纳米粒。
本发明所述化合物由于它们在药物中的可能用途，式(Ⅰ)化合物的盐优选药物可接受的盐。本发明的化合物为碱，其中所需盐形式可以通过本领域已知的合适方法制备，包括用无机酸处理游离碱，所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等、或用有机酸处理游离碱、所述有机酸例如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、羟基乙酸、水杨酸、吡喃糖苷酸(pyranosidy1acid)，例如葡糖醛酸或半乳糖醛酸，α-羟基酸，例如柠檬酸或酒石酸，氨基酸，例如天冬氨酸或谷氨酸，芳香酸，例如苯甲酸或肉桂酸，磺酸，例如p-甲苯磺酸、甲磺酸、乙磺酸等。药学上可接受的盐的实施例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙酸盐(propiolates)、草酸盐、丙二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐(phenylbutrates)、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、羟基乙酸盐、酒石酸盐、苦杏仁酸盐和磺酸盐、例如二甲苯磺酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐和萘-2- 磺酸盐。
本发明的药物组合物通常含有一种本发明化合物。然而，在一些实施方案中，本发明的药物组合物含有超过一种本发明的化合物。另外，本发明的药物组合物还可任选包括一种或多种其它药学活性化合物。
本发明还提供所述二芳基嘧啶类化合物，组合物通过抑制EGFR表皮因子受体酪氨酸激酶，进而抑制肿瘤增殖的用途。具体地，该用途为主要用于治疗非小细胞肺癌、小细胞肺癌、鳞状细胞癌、乳腺癌、淋巴细胞白血病的药物中。
本发明提供所示的化合物或其药学上可接受的盐或本发明所述的药物组合物在制备EGFR表皮因子受体蛋白酪氨酸激酶抑制剂中的应用。
本发明提供所述通式(Ⅰ)所示的化合物或其药学上可接受的盐或本发明所述的药物组合物在制备治疗肿瘤的药物中的用途。优选地，所述肿瘤选自非小细胞肺癌、小细胞肺癌、鳞状细胞癌、乳腺癌或淋巴细胞白血病。更优选地，所述用途主要通过抑制EGFR表皮因子受体蛋白酪氨酸激酶实现的。
具体实施方式
以下结合具体实施例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1目标分子的制备
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)使用的硅胺板采用的规格是0.15mm-0.2mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
本发明使用的原料主要购自可购买自国药集团化学试剂有限公司，北京偶合科技有限公司、阿拉丁化学试剂有限公司、达瑞化学品等公司。
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，为20℃-30℃。
本发明采用的技术方案如下：
化合物(Ⅰ)的合成路线.试剂及条件:(a)ArNH2,DIPEA,1,4-二氧六环,rt,2h,91％；b)ArNH2,DIPEA,1,4-二氧六环,60℃,2h,49–72％；(c)Fe-NH4Cl,MeOH-H2O,80℃tort,62–85％；(d)乙酰氯,NaHCO3,丙酮,10min,43–68％.
Ⅰ-b的合成
取Ⅰ-a(23.44mmol)和DIPEA(4.5g,35.16mmol)于50mL二氧六环中，慢慢加入3-硝基苯胺(3.8g,23.44mmol)，升温60℃，反应5小时后，反应完毕，冷却，加入400mL水，析出黄白色固体，抽滤，烘干，得白色固体，未纯化直接下一步反应。
Ⅰ-c的合成
取Ⅰ-b(23.44mmol)和三氟乙酸(4.5g,35.16mmol)于2-BuOH(50ml)中，慢慢加入取代芳胺(3.44mmol)，升温100℃，反应8小时后，反应完毕，冷却，倒入饱和碳酸氢钠溶液中，析出固体，抽滤，水洗，烘干硅胶柱层析分离，得浅褐色固体。
Ⅰ-d的合成
取I-c(1.9g,6.8mmol)和氯化铵(0.73g,13.6mmol)于反应瓶，加入MeOH(15mL)和水(15mL)，搅拌下加入铁粉(1.5g,27.2mmol)，升温60℃反应2小时，趁热抽滤，水相用乙酸乙酯萃取(100mL×3)，合并乙酸乙酯层，饱和食盐水洗一次，无水硫酸钠干燥，减压蒸干得黄色半固体I-d。
目标物(Ⅰ)的合成
取I-d(2.1g,9.7mmol)溶于20mL乙腈中，加入碳酸氢钠(1.6g,19.4mmol)，和甲基哌嗪(1.2g,11.64mmol)，升温60℃反应5小时，反应完毕后抽干溶剂，加水200mL，未析出固体，水相用乙酸乙酯萃取(100mL x 3)，合并乙酸乙酯层，饱和食盐水洗涤一次，无水硫酸钠干燥，减压蒸干得目标分子(Ⅰ)。
根据以上方法合成了目标分子，所合成目标分子的理化数据如下：(Ⅰ-1)N-[3-[[5-氯-2-[[4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.61(t,2H),3.68-3.70(t,2H,J＝4.4),3.89-3.91(t,2H,J＝5.2),4.52(t,2H),4.85(br,1H),5.74-5.77(dd,1H,J＝2.8,8.4),6.24-6.28(dd,1H,J＝2,15.2),6.45-6.53(dd,1H,J＝10,6.8),6.61-6.77(d,2H,J＝8.8),7.26-7.30(t,1H,J＝8),7.43-7.45(d,1H,J＝8.4),7.47-7.49(d,1H,J＝7.6),7.54-7.58(d,2H,J＝9.2),7.97(s,1H),8.06-8.07(d,1H,J＝3.6),9.07(s,1H),9.31(s,1H),10.23(s,1H).MS(ESI),m/z:495[M+H]+.
(Ⅰ-2)N-[3-[[5-氯-2-[[4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.47(s,3H),3.63(t,2H),3.64-3.74(t,2H,J＝4.4),3.88-3.90(t,2H,J＝5.2),4.51(t,2H),4.88(br,1H),5.72-5.75(dd,1H,J＝2.8,8.4),6.27-6.29(dd,1H,J＝2,15.2),6.41-6.52(dd,1H,J＝10,6.8),6.59-6.73(d,2H,J＝8.8),7.23-7.33(t,1H,J＝8),7.45-7.48(d,1H,J＝8.4),7.50-7.51(d,1H,J＝7.6),7.52-7.59(d,2H,J＝9.2),7.98(s,1H),8.03-8.05(d,1H,J＝3.6),9.10(s,1H),9.32(s,1H),10.21(s,1H).MS(ESI),m/z:508[M+H]+.
(Ⅰ-3)N-[3-[[5-氯-2-[[4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.23(t,2H),3.43(q,2H),3.61(t,2H),3.63-3.73(t,2H,J＝4.4), 3.85-3.91(t,2H,J＝5.2),4.52(t,2H),4.89(br,1H),5.70-5.74(dd,1H,J＝2.8,8.4),6.25-6.27(dd,1H,J＝2,15.2),6.42-6.54(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.25-7.36(t,1H,J＝8),7.44-7.47(d,1H,J＝8.4),7.51-7.53(d,1H,J＝7.6),7.56-7.63(d,2H,J＝9.2),7.91(s,1H),8.02-8.07(d,1H,J＝3.6),9.13(s,1H),9.36(s,1H),10.21(s,1H).MS(ESI),m/z:522[M+H]+.
(Ⅰ-4)N-[3-[[5-氯-2-[[4-[2-(4-乙酰基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.14(s,3H),3.59(t,2H),3.61-3.75(t,2H,J＝4.4),3.84-3.90(t,2H,J＝5.2),4.51(t,2H),4.87(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.27-6.29(dd,1H,J＝2,15.2),6.40-6.55(dd,1H,J＝10,6.8),6.61-6.73(d,2H,J＝8.8),7.26-7.38(t,1H,J＝8),7.45-7.49(d,1H,J＝8.4),7.53-7.57(d,1H,J＝7.6),7.59-7.67(d,2H,J＝9.2),7.93(s,1H),8.04-8.15(d,1H,J＝3.6),9.15(s,1H),9.39(s,1H),10.26(s,1H).MS(ESI),m/z:536[M+H]+.
(Ⅰ-5)N-[3-[[5-氯-2-[[4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(m,2H),3.59(t,2H),3.61-3.72(t,2H,J＝4.4),3.90-3.95(t,2H,J＝5.2),4.51(t,2H),4.89(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.23-6.27(dd,1H,J＝2,15.2),6.46-6.52(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.23-7.33(t,1H,J＝8),7.44-7.46(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59-7.63(d,2H,J＝9.2),7.98(s,1H),8.03-8.11(d,1H,J＝3.6),9.10(s,1H),9.33(s,1H),10.24(s,1H).MS(ESI),m/z:509[M+H]+.
(Ⅰ-6)N-[3-[[5-氯-2-[[4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
1H NMR(DMSO-d6):δ1.38(m,2H),2.58(s,3H),2.69(t,2H),2.61-2.72(t,4H,J＝4.4),2.90-2.95(t,4H,J＝5.2),4.01(t,2H),4.89(br,1H),5.10(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.23-6.27(dd,1H,J＝2,15.2),6.46-6.52(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.23-7.33(t,1H,J＝8),7.44-7.46(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59-7.63(d,2H,J＝9.2),7.98(s,1H),9.33(s,1H),10.24(s,1H).MS(ESI),m/z:509[M+H]+.
(Ⅰ-7)N-[3-[[5-氯-2-[[4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.37(t,3H),1.38(m,2H),3.02(q,2H),3.58(t,2H),3.61-3.70(t,4H,J＝4.4),3.90-3.93(t,4H,J＝5.2),4.50(t,2H),4.87(br,1H),5.10(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.23-6.25(dd,1H,J＝2,15.2),6.46-6.51(dd,1H,J＝10,6.8),6.60-6.71(d,2H,J＝8.8),7.23-7.31(t,1H,J＝8),7.44-7.46(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59-7.62(d,2H,J＝9.2),7.97(s,1H),9.32(s,1H),10.22(s,1H).MS(ESI),m/z:537[M+H]+.
(Ⅰ-8)N-[3-[[5-氯-2-[[4-[2-(4-乙酰基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(m,2H),2.36(s,2H),3.55(t,2H),3.60-3.72(t,4H,J＝4.4),3.91-3.95(t,4H,J＝5.2),4.50(t,2H),4.86(br,1H),5.10(br,1H),5.72-5.75(dd,1H,J＝2.8,8.4),6.23-6.26(dd,1H,J＝2,15.2),6.46-6.52(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.23-7.33(t,1H,J＝8),7.44-7.46(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59-7.61(d,2H,J＝9.2),7.96(s,1H),9.33(s,1H),10.25(s,1H).MS(ESI),m/z:551[M+H]+.
(Ⅰ-9)N-[3-[[5-氯-2-[[4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,2H,J＝5.2),4.51(s,2H),4.89(br,1H),5.10(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.23-6.27(dd,1H,J＝2,15.2),6.46-6.52(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.23-7.33(t,1H,J＝8),7.44-7.46(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59-7.63(d,2H,J＝9.2),7.98(s,1H),9.33(s,1H),10.24(s,1H).MS(ESI),m/z:509[M+H]+.
(Ⅰ-10)N-[3-[[5-氯-2-[[4-[2-(4-甲基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.27(s,3H),2.45-2.47(t,4H,J＝4.4),2.48-2.49(t,4H,J＝5.2),3.68(s,2H),4.89(br,1H),5.10(br,1H),5.92-5.98(dd,1H,J＝2.8,8.4),6.23-6.27(dd,1H,J＝2,15.2),6.46-6.52(dd,1H,J＝10,6.8),6.60-6.71(d,2H,J＝8.8),7.23-7.33(t,1H,J＝8),7.44-7.46(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59-7.62(d,2H,J＝9.2),7.88(s,1H),,9.33(s,1H),10.24(s,1H).MS(ESI),m/z:479[M+H]+.
(Ⅰ-11)N-[3-[[5-氯-2-[[4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.32(q,3H),2.28(t,2H),3.54(s,2H),3.65-3.73(t,4H,J＝4.4),3.92-3.95(t,4H,J＝5.2),4.35(br,1H),4.91(br,1H),5.73-5.80(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.49-6.60(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.25-7.31(t,1H,J＝8),7.45-7.48(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.58-7.66(d,2H,J＝9.2),7.98(s,1H),9.32(s,1H),10.24(s,1H).MS(ESI),m/z:493[M+H]+.
(Ⅰ-12)N-[3-[[5-氯-2-[[4-[2-(4-乙酰基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.59(s,3H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(s,2H),4.89(br,1H),4.91(br,1H),5.72-5.79(dd,1H,J＝2.8,8.4),6.23-6.25(dd,1H,J＝2,15.2),6.45-6.52(dd,1H,J＝10,6.8),6.60-6.78(d,2H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.47(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59-7.63(d,2H,J＝9.2),7.98(s,1H),9.34(s,1H),10.24(s,1H).MS(ESI),m/z:507[M+H]+.
(Ⅰ-13)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.59(t,2H),3.61(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.88(br,1H),4.90(br,1H),5.72-5.79(dd,1H,J＝2.8,8.4),6.22-6.26(dd,1H,J＝2,15.2),6.45-6.51(dd,1H,J＝10,6.8),6.59(d,1H,J＝8.8),6.71(d,1H,J＝8.8),7.22-7.32(t,1H,J＝8),7.43-7.65(d,1H,J＝8.4),7.52-7.53(d,1H,J＝7.6),7.58(s,1H,J＝9.2),7.97(s,1H),9.32(s,1H),10.23(s,1H).MS(ESI),m/z:530[M+H]+.
(Ⅰ-14)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.89(s,3H),3.58(t,2H),3.61(t,2H),3.61-3.71(t,4H,J＝4.4),3.93-3.95(t,4H,J＝5.2),4.89(br,1H),4.91(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.22-6.27(dd,1H,J＝2,15.2),6.45-6.52(dd,1H,J＝10,6.8),6.58(d,1H,J＝8.8),6.72(d,1H,J＝8.8),7.22-7.30(t,1H,J＝8),7.43-7.66(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59(s,1H,J＝9.2),7.96(s,1H),9.33(s,1H),10.24(s,1H).MS(ESI),m/z:543[M+H]+.
(Ⅰ-15)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.87(t,3H),3.58(q,2H),3.62(t,2H),3.64(t,2H),3.61-3.72(t,4H,J＝4.4),3.93-3.94(t,4H,J＝5.2),4.79(br,1H),4.91(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.22-6.29(dd,1H,J＝2,15.2),6.45-6.53(dd,1H,J＝10,6.8),6.59(d,1H,J＝8.8),6.73(d,1H,J＝8.8),7.22-7.31(t,1H,J＝8),7.43-7.56(d,1H,J＝8.4),7.52-7.59(d,1H,J＝7.6),7.58(s,1H,J＝9.2),7.95(s,1H),9.33(s,1H),10.25(s,1H).MS(ESI),m/z:557[M+H]+.
(Ⅰ-16)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.62-3.72(t,2H,J＝4.4),3.91-3.95(t,2H,J＝5.2),4.50(s,2H),4.79(br,1H),4.92(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.22-6.26(dd,1H,J＝2,15.2),6.48-6.52(dd,1H,J＝10,6.8),6.58(d,1H,J＝8.8),6.72(d,1H,J＝8.8),7.22-7.31(t,1H,J＝8),7.43-7.56(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.58(s,1H,J＝9.2),7.86(s,1H),9.32(s,1H),10.14(s,1H).MS(ESI),m/z:500[M+H]+.
(Ⅰ-17)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(m,2H),3.23(t,2H),3.46(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.89(br,1H),4.91(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.22-6.27(dd,1H,J＝2,15.2),6.45-6.52(dd,1H,J＝10,6.8),6.58(d,1H,J＝8.8),6.72(d,1H,J＝8.8),7.22-7.30(t,1H,J＝8),7.43-7.56(d,1H,J＝8.4),7.52-7.57(d,1H,J＝7.6),7.59(s,1H,J＝9.2),7.96(s,1H),9.33(s,1H),10.24(s,1H).MS(ESI),m/z:544[M+H]+.
(Ⅰ-18)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
1H NMR(DMSO-d6):δ1.38(m,2H),2.38(s,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.84(br,1H),4.86(br,1H),5.72-5.75(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.46-6.48(dd,1H,J＝10,6.8),6.60(d,1H,J＝8.8),7.23(t,1H,J＝8),7.44(s,1H,J＝8.4),7.52-7.554(d,1H,J＝7.6),7.59-7.66(d,2H,J＝9.2),7.98(s,1H),9.32(s,1H),10.25(s,1H).MS(ESI),m/z:557[M+H]+.
(Ⅰ-19)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(m,2H),1.43(t,3H),2.39(q,2H),3.58(t,2H),3.61-3.712(t,4H,J＝4.4),3.90-3.96(t,4H,J＝5.2),4.50(t,2H),4.85(br,1H),4.86(br,1H),5.72-5.75(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.46-6.49(dd,1H,J＝10,6.8),6.62(d,1H,J＝8.8),7.23(t,1H,J＝8),7.44(s,1H,J＝8.4),7.52-7.554(d,1H,J＝7.6),7.59-7.66(d,2H,J＝9.2),7.99(s,1H),9.33(s,1H),10.24(s,1H).MS(ESI),MS(ESI),m/z:571[M+H]+.
(Ⅰ-20)N-[3-[[5-氯-2-[[3-氯-4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),2.59(q,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(s,2H),4.85(br,1H),4.87(br,1H),5.72-5.77(dd,1H,J＝2.8,8.4),6.23-6.27(dd,1H,J＝2,15.2),6.46-6.57(dd,1H,J＝10,6.8),6.60-6.77(d,2H,J＝8.8),7.27(d,1H,J＝8),7.44(d,1H,J＝8.4),7.58(s,1H,J＝7.6),7.59-7.68(d,2H,J＝9.2),7.99(s,1H),9.32(s,1H),10.25(s,1H).MS(ESI),m/z:527[M+H]+.
(Ⅰ-21)N-[3-[[5-氟-2-[[4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,2H,J＝5.2),4.51(t,2H),4.58(br,1H),4.85(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.23-6.26(dd,1H,J＝2,15.2),6.46-6.55(dd,1H,J＝10,6.8),6.60(D,1H,J＝8.8),6.68(d,1H,J＝8),7.25(s,1H)7.44-7.48(d,1H,J＝8.4),7.52-7.56(d,1H,J＝7.6),7.59-7.64(d,2H,J＝9.2),7.88(s,1H),9.32(s,1H),10.26(s,1H).MS(ESI),m/z:480[M+H]+.
(Ⅰ-22)N-[3-[[5-氟-2-[[4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.38(s,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.86(br,1H),4.87(br,1H),5.75-5.78(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.46-6.50(dd,1H,J＝10,6.8),6.60-6.70(d,2H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.59-7.66(d,2H,J＝9.2),7.99(s,1H),9.23(s,1H),10.15(s,1H).MS(ESI),m/z:493[M+H]+.
(Ⅰ-23)N-[3-[[5-氟-2-[[4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),2.59(q,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.94(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.46-6.55(dd,1H,J＝10,6.8),6.60-6.74(d,2H,J＝8.8),7.26-7.33(t,1H,J＝8),7.44-7.52(d,1H,J＝8.4),7.52-7.58(d,1H,J＝7.6),7.59-7.68(d,2H,J＝9.2),7.88(s,1H),9.34(s,1H),10.26(s,1H).MS(ESI),m/z:507[M+H]+.
(Ⅰ-24)N-[3-[[5-氟-2-[[4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1 3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.87(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.46-6.48(dd,1H,J＝10,6.8),6.60-6.71(d,2H,J＝8.8),7.23-7.31(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.61(d,1H,J＝7.6),7.59-7.68(d,2H,J＝9.2),7.99(s,1H),9.32(s,1H),10.28(s,1H).MS(ESI),m/z:449[M+H]+.
(Ⅰ-25)N-[3-[[5-氟-2-[[4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(m,2H),3.59(t,2H),3.61-3.72(t,42H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.86(br,1H),5.72-5.75(dd,1H,J＝2.8,8.4),6.23-6.29(dd,1H,J＝2,15.2),6.46-6.53(dd,1H,J＝10,6.8),6.60-6.73(d,2H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.47(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.59-7.64(d,2H,J＝9.2),7.99(s,1H),9.34(s,1H),10.25(s,1H).MS(ESI),m/z:494[M+H]+.
(Ⅰ-26)N-[3-[[5-氟-2-[[4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
1H NMR(DMSO-d6):δ1.38(m,2H),2.67(s,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.91(br,1H),5.74-5.78(dd,1H,J＝2.8,8.4),6.25-6.27(dd,1H,J＝2,15.2),6.46-6.54(dd,1H,J＝10,6.8),6.62-6.72(d,2H,J＝8.8),7.25-7.33(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.56(d,1H,J＝7.6),7.59-7.65(d,2H,J＝9.2),7.98(s,1H),
(Ⅰ-27)N-[3-[[5-氟-2-[[4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),2.68(q,2H),1.48(m,2H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.88(br,1H),5.72-5.73(dd,1H,J＝2.8,8.4),6.23-6.25(dd,1H,J＝2,15.2),6.46-6.55(dd,1H,J＝10,6.8),6.60-6.73(d,2H,J＝8.8),7.23-7.31(t,1H,J＝8),7.44-7.47(d,1H,J＝8.4),7.52-7.58(d,1H,J＝7.6),7.59-7.64(d,2H,J＝9.2),7.96(s,1H),9.23(s,1H),10.18(s,1H).MS(ESI),m/z:492[M+H]+.
(Ⅰ-28)N-[3-[[5-氟-2-[[4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),3.59(q,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,2H,J＝5.2),4.51(s 2H),4.85(br,1H),4.92(br,1H),5.72-5.84(dd,1H,J＝2.8,8.4),6.23-6.31(dd,1H,J＝2,15.2),6.46-6.53(dd,1H,J＝10,6.8),6.60-6.73(d,2H,J＝8.8),7.23-7.35(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.59-7.65(d,2H,J＝9.2),7.99(s,1H),9.34(s,1H),10.28(s,1H).MS(ESI),m/z:477[M+H]+.
(Ⅰ-29)N-[3-[[5-三氟甲基-2-[[4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.92(br,1H),5.72-5.84(dd,1H,J＝2.8,8.4),6.23-6.31(dd,1H,J＝2,15.2),6.46-6.53(dd,1H,J＝10,6.8),6.60-6.73(d,2H,J＝8.8),7.23-7.35(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.59-7.65(d,2H,J＝9.2),7.99(s,1H),9.34(s,1H),10.28(s,1H).MS(ESI),m/z:530[M+H]+.
(Ⅰ-30)N-[3-[[5-三氟甲基-2-[[4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.38(s,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.79(br,1H),4.85(br,1H),5.62-5.72(dd,1H,J＝2.8,8.4),6.33-6.37(dd,1H,J＝2,15.2),6.56-6.62(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.13-7.23(t,1H,J＝8),7.54-7.56(d,1H,J＝8.4),7.51-7.54(d,1H,J＝7.6),7.58-7.63(d,2H,J＝9.2),7.88(s,1H),9.23(s,1H),10.25(s,1H).MS(ESI),m/z:543[M+H]+.
(Ⅰ-31)N-[3-[[5-三氟甲基-2-[[4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),2.59(q,2H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.91(br,1H),5.76-5.78(dd,1H,J＝2.8,8.4),6.25-6.27(dd,1H,J＝2,15.2),6.46-6.51(dd,1H,J＝10,6.8),6.60-6.74(d,2H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.58(d,1H,J＝7.6),7.59-7.64(d,2H,J＝9.2),7.97(s,1H),9.32(s,1H),10.18(s,1H).MS(ESI),m/z:557[M+H]+.
(Ⅰ-32)N-[3-[[5-三氟甲基-2-[[4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.85(br,1H),4.87(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.23-6.29(dd,1H,J＝2,15.2),6.46-6.56(dd,1H,J＝10,6.8),6.60-6.71(d,2H,J＝8.8),7.23-7.32(t,1H,J＝8),7.44-7.49(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.59-7.67(d,2H,J＝9.2),7.99(s,1H),9.34(s,1H),10.25(s,1H).MS(ESI),m/z:500[M+H]+.
(Ⅰ-33)N-[3-[[5-三氟甲基-2-[[4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(m,2H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.89(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.23-6.26(dd,1H,J＝2,15.2),6.46-6.53(dd,1H,J＝10,6.8),6.60-6.73(d,2H,J＝8.8),7.23-7.35(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.59(d,1H,J＝7.6),7.59-7.66(d,2H,J＝9.2),7.98(s,1H),9.35(s,1H),10.18(s,1H).MS(ESI),m/z:544[M+H]+.
(Ⅰ-34)N-[3-[[5-三氟甲基-2-[[4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
1H NMR(DMSO-d6):δ1.38(m,2H),2.78(s,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.79(br,1H),4.85(br,1H),5.72-5.77(dd,1H,J＝2.8,8.4),6.21-6.27(dd,1H,J＝2,15.2),6.46-6.54(dd,1H,J＝10,6.8),6.60-6.73(d,2H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.47(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.59-7.65(d,2H,J＝9.2),7.94(s,1H),9.30(s,1H),10.34(s,1H).MS(ESI),m/z:557[M+H]+.
(Ⅰ-35)N-[3-[[5-三氟甲基-2-[[4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),1.48(m,2H),2.78(q,2H)3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.88(br,1H),5.72-5.79(dd,1H,J＝2.8,8.4),6.25-6.27(dd,1H,J＝2,15.2),6.44-6.52(dd,1H,J＝10,6.8),6.60-6.72(d,2H,J＝8.8),7.23-7.36(t,1H,J＝8),7.44-7.47(d,1H,J＝8.4),7.52-7.57(d,1H,J＝7.6),7.59-7.68(d,2H,J＝9.2),7.97(s,1H),9.35(s,1H),10.09(s,1H).MS(ESI),m/z:571[M+H]+.
(Ⅰ-36)N-[3-[[5-三氟甲基-2-[[4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(s,3H),2.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(s,2H),4.85(br,1H),4.88(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.46-6.58(dd,1H,J＝10,6.8),6.60-6.78(d,2H,J＝8.8),7.23-7.35(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.56(d,1H,J＝7.6),7.59-7.64(d,2H,J＝9.2),7.97(s,1H),9.33(s,1H),10.19(s,1H).MS(ESI),m/z:527[M+H]+.
(Ⅰ-37)N-[3-[[5-氯-2-[[3-氟-4-[2-(4-吗啡啉)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.87(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.22-6.27(dd,1H,J＝2,15.2),6.43-6.52(dd,1H,J＝10,6.8),6.64(d,1H,J＝8.8),6.72(d,1H J＝8.8),7.25-7.33(t,1H,J＝8),7.43-7.46(d,1H,J＝8.4),7.51-7.54(d,1H,J＝7.6),7.58(S,1H,J＝9.2),7.97(s,1H),9.35(s,1H),10.28(s,1H).MS(ESI),m/z:514[M+H]+.
(Ⅰ-38)N-[3-[[5-氯-2-[[3-氟-4-[2-(4-甲基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.68(S,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.89(br,1H),5.72-5.79(dd,1H,J＝2.8,8.4),6.23-6.29(dd,1H,J＝2,15.2),6.46-6.55(dd,1H,J＝10,6.8),6.60(d,1H,J＝8.8),6.74(d,1H,J＝8.8),7.23-7.35(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.54(d,1H,J＝7.6),7.59(S,1H,J＝9.2),7.99(s,1H),9.35(s,1H),10.25(s,1H).MS(ESI),m/z:527[M+H]+.
(Ⅰ-39)N-[3-[[5-氯-2-[[3-甲氧基-4-[2-(4-乙基-1-哌嗪基)乙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),2.89(q,2H),2.93(s,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.76(br,1H),4.85(br,1H),5.72-5.80(dd,1H,J＝2.8,8.4),6.23-6.31(dd,1H,J＝2,15.2),6.46-6.54(dd,1H,J＝10,6.8),6.60(d,1H,j＝8.8),6.75(d,1H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.51(d,1H,J＝8.4),7.52-7.57(d,1H,J＝7.6),7.59(s,1H,J＝9.2),7.81(s,1H),9.35(s,1H),10.28(s,1H).MS(ESI),m/z:553[M+H]+.
(Ⅰ-40)N-[3-[[5-氯-2-[[3-甲氧基-4-[2-(4-吗啡啉基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ2.38(s,3H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(s,2H),4.76(br,1H),4.85(br,1H),5.72-5.79(dd,1H,J＝2.8,8.4),6.23-6.28(dd,1H,J＝2,15.2),6.46-6.53(dd,1H,J＝10,6.8),6.60(d,1H,J＝8.8),6.73(d,1H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.49(d,1H,J＝8.4),7.52-7.56(d,1H,J＝7.6),7.59(S,1H,J＝9.2),7.99(s,1H),9.34(s,1H),10.35(s,1H).MS(ESI),m/z:496[M+H]+.
(Ⅰ-41)N-[3-[[5-氯-2-[[3-氰基-4-[2-(4-吗啉基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(m,2H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,2H,J＝5.2),4.51(t,2H),4.81(br,1H),4.85(br,1H),5.72-5.78(dd,1H,J＝2.8,8.4),6.23-6.35(dd,1H,J＝2,15.2),6.46-6.54(dd,1H,J＝10,6.8),6.60(d,1H,J＝8.8),6.76(d,1H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.48(d,1H,J＝8.4),7.52-7.57(d,1H,J＝7.6),7.63(s,1H,J＝9.2),7.99(s,1H),9.38(s,1H),10.28(s,1H).MS(ESI),m/z:535[M+H]+.
(Ⅰ-42)N-[3-[[5-氯-2-[[3-氰基-4-[2-(4-甲基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰
1H NMR(DMSO-d6):δ1.38(m,2H),2.78(s,3H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.84(br,1H),4.85(br,1H),5.72-5.76(dd,1H,J＝2.8,8.4),6.23-6.24(dd,1H,J＝2,15.2),6.46-6.56(dd,1H,J＝10,6.8),6.60(d,1H,J＝8.8),6.72(d,1H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.45(d,1H,J＝8.4),7.52-7.56(d,1H,J＝7.6),7.65(s,1H,J＝9.2),8.01(s,1H),9.35(s,1H),10.28(s,1H).MS(ESI),m/z:548[M+H]+.
(Ⅰ-43)N-[3-[[5-氯-2-[[3-乙基-4-[2-(4-乙基-1-哌嗪基)丙氧基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),1.48(m,2H),2.38(q,2H),2.48(q,2H),3.59(t,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.51(t,2H),4.85(br,1H),4.91(br,1H),5.72-5.81(dd,1H,J＝2.8,8.4),6.23-6.29(dd,1H,J＝2,15.2),6.46-6.53(dd,1H,J＝10,6.8),6.60(d,1H,J＝8.8),6.73(d,1H,J＝8.8),7.23-7.34(t,1H,J＝8),7.44-7.45(d,1H,J＝8.4),7.52-7.55(d,1H,J＝7.6),7.64(s,1H,J＝9.2),8.02(s,1H),9.23(s,1H),10.31(s,1H).MS(ESI),m/z:565[M+H]+.
(Ⅰ-44)N-[3-[[5-氯-2-[[3-乙基-4-[2-(4-乙基-1-哌嗪基)甲基]苯基]胺]-4-嘧啶基]胺]苯基]-2-丙烯酰胺
1H NMR(DMSO-d6):δ1.38(t,3H),1.48(t,3H),2.98(q,2H),3.59(q,2H),3.61-3.72(t,4H,J＝4.4),3.90-3.95(t,4H,J＝5.2),4.77(br,1H),4.85(br,1H),5.72-5.75(dd,1H,J＝2.8,8.4),6.23-6.24(dd,1H,J＝2,15.2),6.46-6.57(dd,1H,J＝10,6.8),6.60(d,1H,J＝8.8)-,6.76(d,1H,J＝8.8),7.23-7.35(t,1H,J＝8),7.44-7.45(d,1H,J＝8.4),7.52-7.56(d,1H,J＝7.6),7.64(d,1H,J＝9.2),7.97(s,1H),9.27(s,1H),10.18(s,1H).MS(ESI),m/z:521[M+H]+.
目标分子成盐的方法
有机酸盐的制备方法：取目标分子(1mmol)溶于10mL无水甲醇中，冰浴下，慢慢滴加有机酸(1mmol)的5mL无水甲醇溶液，滴加完毕，于此温度下搅拌30分钟，然后常温蒸除甲醇，即得目标分子的有机酸盐。通过该方法制备了化合物Ⅰ-9的盐酸盐(Ⅰ-9-1)、氢溴酸盐(Ⅰ-9-2)、硫酸盐盐(Ⅰ-9-3)，氢溴酸盐(Ⅰ-9-4)；
无机酸盐的制备方法：取目标分子(1mmol)溶于10mL无水甲醇中，冰浴下，慢慢滴加无机酸(1mmol)的5mL干燥乙醚，滴加完毕，于此温度下搅拌30分钟，然后常温蒸除溶剂，即得目标分子的无机酸盐。通过该方法制备了化合物Ⅰ-9的马来酸盐(Ⅰ-9-5)、琥珀酸盐(Ⅰ-9-6)、富马酸盐(Ⅰ-9-7)。
目标分子组合物的制备
取等摩尔量(1mmol)的上述两个目标分子于无水甲醇中(5mL)，室温搅拌10分钟，常温蒸除溶剂，即得目标分子的组合物。通过该方法制备了(Ⅰ-9)-(Ⅰ-11)、(Ⅰ-5)-(Ⅰ-9)、(Ⅰ-9)-(Ⅰ-20)三个组合物。
实施例2 目标分子生物活性评价
1、体外对受体酪氨酸激酶抑制活性测试方法
制备激酶检测缓冲液
①在室温融解激酶检测缓冲液(Kinase Detection Buffer)，观察是否有沉淀。
②如果出现沉淀，就在37℃孵育(Kinase Detection Buffer)15分钟并经常摇动，溶解沉淀。或者，小心吸走上清，去除沉淀。
制备激酶检测试剂
①使用前在室温平衡激酶检测缓冲液(Kinase Detection Buffe)r和(KinaseDetection Substrate)。
②将激酶检测缓冲液(Kinase Detection Buffer)全部倒进装有激酶检测底物(Kinase Detection Substrate)的棕色瓶中，使冻干粉底物溶解，这样就制成了激酶检测试剂。
③轻轻震荡、涡旋或颠倒混匀，成为均质溶液，底物应在1分钟内溶解。
④激酶检测试剂配好后应立即使用，或分装存于-20℃，我们认为配好的试剂经过几次冻融后循环信号活性都没有损失。
制作ATP转化成ADP的标准曲线
①用1x激酶反应缓冲液(kinase reaction buffer)稀释试剂盒提供的UltraPure ATP和ADP，制成900μL 50μM ATP和500μL 50μM ADP。
②将上一步配好的50μM ATP和50μM ADP溶液按表1所示在384孔板A1-A12中混合，模拟每个转化百分比的ATP和ADP的浓度，混合好。
表1.制备50μM系列ATP+ADP标准品
③每孔加入5μL的ADP-GloTM试剂来终止激酶反应。在室温孵育40分钟。
④每孔加入10μL激酶检测试剂(Kinase Detection Reagent)将ADP转化成ATP，并引进萤光素酶和萤光素来检测ATP。
⑤在室温孵育30-60分钟，用多功能酶标仪测量萤光并记录萤光值。
⑥绘制ATP转化成ADP的标准曲线。
确定激酶抑制物的IC50值
①按照promega试剂盒说明书配制1x激酶反应缓冲液(kinase reactionbuffer)，2.5x 50ng/μL激酶和2.5x 0.5μg/μL底物和125μM ATP。
②在无酶对照孔中加入3μL 1x激酶反应缓冲液(kinase reaction buffer)，2μL2.5x0.5μg/μL底物和125μM ATP。在阴性对照孔中加入1μL 1x激酶反应缓冲液(kinasereaction buffer)，2μL 2.5x 50ng/μL激酶，2μL 2.5x 0.5μg/μL底物和125μM ATP。在测试孔中加入1μL 5x待测药物，2μL 2.5x 50ng/μL激酶，2μL 2.5x 0.5μg/μL底物和125μM ATP。
③混合好平板，孵育60分钟。
④每孔加入5μL的ADP-GloTM试剂来终止激酶反应。在室温孵育40分钟。
⑤每孔加入10μL激酶检测试剂(Kinase Detection Reagent)将ADP转化成ATP，并引进萤光素酶和萤光素来检测ATP。在室温孵育30-60分钟，用多功能酶标仪测量萤光并记录萤光值。
⑥结果分析
2、细胞生长实验(MTT检测法)
细胞接种：收集对数生长期细胞，调整细胞悬液浓度,以每孔7x103个细胞,每孔体积100μL接种到96孔板，每组设4个复孔(边缘孔用无菌PBS填充)；
细胞培养：细胞贴壁后，0％FBS RPMI-1640饥饿8h,对照组用10％FBSRPMI-1640培养,，37℃，5％CO2培养箱中继续培养(按实验要求分别培养不同时间)；
呈色：三组细胞分别于培养72h后加入10μL MTT溶液(5mg/mL)，4h后终止培养，每孔加入100μL三联液，于摇床上低速振荡10min，使结晶充分溶解；
比色：在酶联免疫检测仪上测定各孔光度值(OD值)，选择570nm波长，以无细胞的即RPMl-1640培养液空白孔调零，测各孔的吸光度值。实验重复三次
记录结果：细胞生长抑制率＝(对照组吸光度值一实验组吸光度值)/对照组吸光度值×100％，细胞增殖率＝(实验组吸光度值/对照组吸光度值)×100；
绘制细胞生长曲线：以时间为横坐标，抑制率/增殖率为纵坐标绘制细胞生长曲线。
在GraphPad软件中的GraphPad Prism作图软件中针对抑制剂浓度做图，以便由log[抑制剂]相对于反应，可变斜率模型估算出IC50。
测试结果
表2显示所获得的化合物在抑制EGFR酪氨酸激酶和抗肿瘤细胞增殖中的活性效果。
以上生物活性结果表明，本发明中的分子对EGFR和EGFRT790M激酶有较强的抑制效果，大部分化合物达到纳摩尔水平的活性级别，且有将近一半的化合物的有效抑制浓度IC50值小于10nmol，明显优于吉非替尼和rociletinib。抗细胞增殖活性结果揭示，大部分化合物对肺癌耐药型细胞H1975有非常有效的抑制作用，其中化合物Ⅰ-5(27nmol)和Ⅰ-9(33nmol)还显示出了优于Rociletinib(37nmol)的活性。此外，该系列分子还表现出对乳腺癌细胞MCF-7和白血病细胞ramos的抑制作用，有效半数抑制浓度在5-10μmol之间，预示此类分子有进一步开发成在抗乳腺癌和白血病药物方面的用途。
Claims (7)
1.一种通式(Ⅰ)所示的化合物或其药学上可接受的盐，所述通式(Ⅰ)所示的化合物具有如下结构：
其中，
R1选自选氯、氟或三氟甲基；
R2选自氢、甲基、乙基、甲氧基、氟、氯、溴、三氟甲基或氰基；
X选自CH2或O；
Y选自O,甲胺基、乙胺基、乙酰胺基或乙磺酰胺基；
n＝1-3。
2.如权利要求1所述的通式(Ⅰ)所示的化合物或其药学上可接受的盐，其中，所述通式(Ⅰ)所示的化合物具有I-1～I-44所示的结构：
3.一种药物组合物，其含有有效剂量的权利要求1或2所述通式(Ⅰ)所示的化合物或其药学上可接受的盐，及药用载体；所述药物组合物例如为脂质体或纳米粒。
4.权利要求1或2所述通式(Ⅰ)所示的化合物或其药学上可接受的盐或权利要求3所述的药物组合物在制备EGFR表皮因子受体蛋白酪氨酸激酶抑制剂中的应用。
5.权利要求1或2所述通式(Ⅰ)所示的化合物或其药学上可接受的盐或权利要求3所述的药物组合物在制备治疗肿瘤的药物中的用途。
6.根据权利要求5所述的用途，其中，所述肿瘤选自非小细胞肺癌、小细胞肺癌、鳞状细胞癌、乳腺癌或淋巴细胞白血病。
7.根据权利要求5所述的用途，其中，所述用途主要通过抑制EGFR表皮因子受体蛋白酪氨酸激酶实现的。
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