CN117137919A - 一种氨基嘧啶衍生物及其作为egfr酪氨酸激酶抑制剂的应用 - Google Patents
一种氨基嘧啶衍生物及其作为egfr酪氨酸激酶抑制剂的应用 Download PDFInfo
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- CN117137919A CN117137919A CN202310886319.8A CN202310886319A CN117137919A CN 117137919 A CN117137919 A CN 117137919A CN 202310886319 A CN202310886319 A CN 202310886319A CN 117137919 A CN117137919 A CN 117137919A
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Abstract
本发明提供了式Ⅰ所示的一种氨基嘧啶衍生物及其药学上可接受的盐、异构体、溶剂化物和药物组合物。本发明还提供了式Ⅰ所示化合物的制备方法。该化合物可作为EGFRT790M/L858R和EGFRDel19突变的EGFR高选择性配体分子,用于治疗EGFR激酶介导的相关癌症。
Description
本申请是申请日为2021年9月16日、申请号为202111083628.9、发明名称为“一种氨基嘧啶衍生物及其作为EGFR酪氨酸激酶抑制剂的应用”的CN申请的分案申请。
技术领域
本发明涉及医药技术领域。主要涉及一种氨基嘧啶衍生物及其在药物学可接受的盐、异构体、溶剂化物和药物组合物,还涉及其制备方法以及其作为药物的应用。特别是作为治疗EGFR激酶介导的抗癌药物的应用。
背景技术
在临床诊断中,非小细胞肺癌(non-small cell lung cancer,NSCLC)约占所有肺癌的80-85%,约75%的患者发现时已处于中晚期(III期或IV期),在确诊时存在局部晚期或转移性疾病,晚期非小细胞肺癌患者的5年生存率低于5%,此时化学疗法和放射治疗是晚期肺癌患者的主要治疗手段。表皮生长因子受体(epidermal growth factor receptor,EGFR)与肿瘤细胞的增殖、血管生成、肿瘤侵袭、转移及细胞凋亡密切相关,是治疗非小细胞肺癌的重要靶点。EGFR酪氨酸激酶域中的激活突变已被确定为NSCLC的致癌驱动因素,我国约30%的病人具有EGFR突变。近年来,靶向治疗的发展使晚期NSCLC患者的治疗策略从传统的放化疗转为以使用酪氨酸激酶抑制剂(Tyrosine kinase inhibitors,TKIs)为主的靶向治疗。
第一代EGFR TKIs中的代表药物为吉非替尼和厄洛替尼,与EGFR酪氨酸激酶区域可逆结合,针对EGFR-L858R和外显子19缺失突变,取得了较好的临床反应。然而,相关研究表明,接受第一代EGFR TKIs治疗的患者中,在12个月后约50%的患者因发生T790M突变而产生获得性耐药。第二代不可逆抑制剂阿法替尼通过与靠近EGFR-ATP结合位点的半胱氨酸残基(Cys797)发生亲电迈克尔加成反应,生成受体与配体的共价不可逆结合形式,以此克服因EGFR的T790M突变产生的耐药性。但该类抑制剂由于缺乏对野生型EGFR的选择性,临床上有较严重的皮疹和胃肠道副反应发生,导致了其治疗窗狭窄,应用受到限制。第三代EGFRTKI奥希替尼(Osimertinib)不仅有效地克服了因T790M突变而产生的耐药问题,同时具有较好的对野生型EGFR的抑制选择性,极大地降低了毒副作用,在临床上得到了广泛应用。虽然第三代EGFR抑制剂Osimertinib和CO-1686等化合物对具有T790M的耐药患者有良好的治疗效果,但其对野生型EGFR仍存在抑制作用,从而对部分患者造成了皮疹和胃肠道的不良反应。
为了提高药物对耐药EGFR T790M突变的抑制活性,同时降低其对野生型EGFR的抑制作用,有必要进一步开发活性更高,选择性更好,毒性更低的第三代靶向EGFR T790M的选择性抑制剂。
发明内容
本发明的目的是提供一种氨基嘧啶衍生物及包含该化合物的药物组合物,其具有良好的EGFR激酶抑制活性,以及对于耐药突变EGFRT790M/L858R,EGFRdel19突变具有高选择性,可用于治疗EGFR激酶介导的疾病。
本发明提供了式Ⅰ所示的化合物及其药学上可接受的盐、异构体、溶剂化物以及包含上述衍生物的药物组合物,
其中:
R1为取代或未被取代的杂环基,
R2为C1~C6的直链或支链烷基、烯基、炔基、取代或未被取代芳基、取代或未被取代的杂环基。
本发明式Ⅰ分子还可以是其盐的形式,一般是与有机或无机碱或酸形成的盐。
本发明优选生理学可接受的盐。本发明化合物的生理学可接受的盐可以是本发明物质与无机酸、羧酸或磺酸的盐,特别优选的是例如与盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、对甲苯磺酸、甲磺酸、乙磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、steroic、鞣酸形成的盐。其它的酸,如草酸,虽然其本身并非药学上可接受的,但可以用于制备用作中间体的盐,以获得本发明化合物及其药学上可接受的盐。
生理学上可接受的盐同样可以是具有游离羧基的本发明化合物的金属或铵盐。特别优选的是如钠、钾、镁或钙盐、以及得自氨或有机胺如乙胺、二乙胺、三乙胺、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、N-甲基葡糖胺和普鲁卡因、二乙醇胺、三乙醇胺、二环己基胺、二甲基氨基乙醇、精氨酸、赖氨酸或乙二胺的铵盐。
本发明提供了式I化合物的制备方法,本发明中的化合物可以通过多种合成操作来制备,这些操作是所属领域技术人员熟练掌握的。这些化合物的示例性制备方法可以包括(但不限于)下文所述的流程。
本发明式I化合物可以通过以下方案及实施例中所述的示例性方法合成。在具体操作过程中,可以根据需要对方法中的步骤进行扩展或合并。
方案:
Reaction conditions:a.AlCl3,dioxane,reflux;b.p-Toluenesulfonic acidmonohydrate,1-Butanol,80℃;c.DIPEA,DMF,90℃;d.X-R,K2CO3,DMF;e.Fe,NH4Cl,C2H5OH,H2O,reflux/H2,Pd(C),CH3OH,r.t;f.Acryloyl chloride,DCM/Acetone,0℃
其中:R1和R2的定义如上所述。
本发明公开的式I化合物以及化合物的制备方法、药物组成和治疗方案,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域的技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的产品,方法,以及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
本发明的化合物可以以互变异构形式存在,并且本发明同样也包含了该类形式。
本发明的化合物还可以是其可能的溶剂化物。
本发明的化合物还可以含有本发明化合物和药学上可接受的赋形剂的药物组合物,其包括治疗有效量的本发明所述的化合物,或其药学上可接受的盐、异构体、溶剂化物,以及选自下组药物中的一种或多种其他药物:吉非替尼、厄洛替尼、埃克替尼、阿帕替尼、凡德他尼、西妥昔单抗、曲妥珠单抗、帕尼突单抗、马妥珠单抗、尼妥珠单抗、扎鲁姆单抗、帕妥珠单抗、奥西替尼、XL647、CI-1033、BMS-690514、BIBW2992、EKB-569、ARRY-334543、NVP-AEE-788、HK1272、PF00299804、WZ4002、Her2、HSP90抑制剂、CNF2024、阿螺旋霉素、坦螺旋霉素、IPI-504、SNX-5422、NVP-AUY922或其组合。除本发明的化合物,其药学上可接受的盐、异构体、溶剂化物之外,上述药用组合物中的其他药物均为本领域技术人员熟知的药物。
在另一方面,本发明提供了在需要其的受试者中治疗EGFR导致的癌症(包括EGFR突变导致的癌症,例如,带有T790M突变、L858R突变和L858R/T790M双突变的癌症)相关病症的方法,所述方法包括:给予受试者有效量的本发明的化合物。在具体的实施方案中,所述的EGFR导致的癌症选自:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌等。
本发明还涉及一种包含至少一种本发明化合物的药物,其优选的还一起包含一种或多种药理学可接受的赋形剂或载体,并且还涉及其用于上述目的的应用。这里的药用载体包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂。
该活性成分可以具有全身和/或局部作用,因此,其可以通过适宜的途径进行给药,所说的适宜途径如口服、胃肠外、肺、鼻、舌下、舌、颊、直肠、经皮、结膜、局部给药或以植入物的形式给药。
该活性成分还可以以适于这些给药途径的给药形式进行给药。
适于口服给药的有可以迅速和/或以改变的方式传递活性成分的公知的给药形式,如片剂(未包衣片或包衣片,如具有肠包衣或莫包衣的片剂)、胶囊、糖衣片、颗粒、小药丸、粉剂、乳剂、混悬液和气雾剂。
采用胃肠外给药可能可避免吸收步骤(静脉内、动脉内、心内、脊柱内或腰髓内给药)或者包含吸收(肌内、皮下、皮内、经皮或腹膜内给药)。适于胃肠外给药的给药形式特别是用于注射和输入的溶液、混悬液、乳剂、冷冻干燥物和无菌粉末形式的制剂。
适于其他给药途径的有例如吸入(特别是粉末吸入、喷雾)的药物、鼻滴剂/溶液、喷雾剂;用于舌、舌下或颊给药的片剂或胶囊、栓剂、用于耳朵和眼睛的制剂、阴道胶囊、水性混悬液(洗剂、振摇混合物)、亲脂性混悬液、软膏、乳膏、乳液、糊剂、撒粉或植入物,如斯腾特固定模。
可以用本身已知的方法将该活性成分转化成所述的给药形式。其可以用惰性无毒的适宜药用赋形剂来实现。其特别是包括载体(例如微晶纤维素)、溶剂(例如液体聚乙二醇)、乳化剂(例如十二烷基硫酸钠)、分散剂(例如聚乙烯吡咯烷酮)、合成和天然生物聚合物(例如蛋白质)、稳定剂(例如抗氧剂和抗坏血酸)、着色剂(例如无机颜料如氧化铁)或矫味剂和/或掩味剂。在适宜的情况中,所说的活性成分可以以微囊包封的形式存在于一种或多种上述载体中。
除本发明式Ⅰ的化合物外,上述药物制剂还可以包含其他药物活性成分。
在具体实施方式和实施例中,本发明的其他目的和优点对于本领域技术人员显而易见。
具体实施方式
本发明提供了式Ⅰ所示的化合物及其药学上可接受的盐、异构体、溶剂化物和药物组合物。
其中:
R1为
其中A为甲基或者乙基;B为氢或者甲基
R2为甲基,或选自下组中的任意一种:
优选化合物的具体结构如下,但它们不代表对本发明的限制。
与现有技术相比,本发明的主要优点在于:本发明化合物对EGFRT790M/L858R突变型酶和细胞具有高抑制活性,且对EGFR野生型酶和细胞具有低抑制活性,因此具有高选择性。
具体实施例
提供以下实施例以便为本领域技术人员提供如何进行制备和评估本文请求保护的方法和对化合物的完整公开说明。本实施例仅仅示例本发明而非限制本发明的范围。
化合物合成方法。
本发明化合物可参照本领域常规方法,并使用合适试剂、原料和本领域技术人员已知的纯化方法制备。
下面更为具体地描述本发明式I结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以通过将任选本说明书中所描述的或本领域已知的各种合成方法的进行组合来更方便的制得,这样的组合可由本发明所属领域的技术人员更容易的进行。
下面的实施例是本发明优选的说明性优选方案,对本发明不构成任何限制。
实施例1甲基N-(2-((2-氨基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)N-甲基甘氨酸乙酯(ZJT-4-M)的合成
A.3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(ZJT-1)的合成
将2,4-二氯嘧啶(120.0g,0.81mol)加入到2L反应瓶中,加入880ml 1,4-dioxane,搅拌溶解,分批加入无水AlCl3(120.0g,0.90mol),快速搅拌直到AlCl3形成乳状均匀分散,然后将1-甲基吲哚(110.0g,0.84mol)倒入反应液中,升温到80℃保温反应3小时,TLC检测反应完全,1-甲基吲哚完全消失,展开剂为石油醚:乙酸乙酯=1:1。将反应液趁热缓慢倒入2.5L纯化水中,剧烈搅拌,析出固体,倒完后继续搅拌1小时,抽滤,用1L纯化水洗涤滤饼。固体50℃真空干燥过夜,得到粗品210.0g。将粗品加热溶解于3.2L乙腈与320ml纯化水的混合溶液中,缓慢冷却至10℃析晶2小时,抽滤,用200ml乙腈淋洗滤饼,50℃真空干燥过夜,得ZJT-1产品162.0g,收率82.3%。1H-NMR(400MHz,DMSO-d6)δppm 8.54(d,J=5.5Hz,1H),8.52(s,1H),8.45-8.39(m,1H),7.83(d,J=5.5Hz,1H),7.61-7.56(m,1H),7.35-7.26(m,2H),3.90(s,3H)。ESI-MS m/z:244.06[M+H]+。
B.N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺(ZJT-2)的合成
将ZJT-1(15.00g,0.062mol)加入到2L反应瓶中,再加入700mL正丁醇,4-氟-2-甲氧基-5-硝基苯胺(12.63g,0.068mol),对甲苯磺酸·一水物(14.15g,0.074mol)搅拌溶解,控制温度在110℃反应6小时,TLC显示ZJT-1基本反应完全,反应液中析出大量固体。搅拌降温至室温,过滤得到黄色固体,TLC显示固体中残留少量SM3和对甲苯磺酸。将所得固体用500ml乙腈+500ml纯化水混合液打浆1小时,抽滤,得到的固体TLC显示极少SM3残留,母液中基本不含产品,含有大量ZJT-1和SM3,滤饼再次用500ml乙腈+500ml纯化水混合液打浆1小时,抽滤,所得产品TLC显示不含杂质。将产品50℃真空干燥过夜,得ZJT-2产品17.38g,收率71.32%。1H-NMR(400MHz,Chloroform-d)δppm 8.31(d,J=5.5Hz,1H),8.15(s,1H),8.05(d,J=8.0Hz,1H),8.01(d,J=7.5Hz,1H),7.69(s,1H),7.20(t,J=2.8Hz,1H),7.18(s,1H),7.15(d,J=5.6Hz,1H),6.84(d,J=12.5Hz,1H),6.71(d,J=12.3Hz,1H),3.92(s,3H),3.82(s,3H)。ESI-MS m/z:394.13[M+H]+。
C.2-甲氧基-N4-甲基-N1-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-N4-(2-(甲基氨基)乙基)-5-硝基苯-1,4-二胺(ZJT-3)的合成
将21.96g ZJT-2(0.056mol)加入到500ml烧瓶中,再加入5.91g N,N’-二甲基乙二胺(0.067mol),10.86g DIPEA(0.084mol),250ml DMF,搅拌不溶解,升温后逐渐溶清,控制温度在90℃反应9小时,TLC显示ZJT-2基本反应完全,反应液由黄色变为红色。搅拌降温至室温,向反应液中加入1L纯化水打浆1小时,过滤,所得产品TLC显示不含杂质。将产品50℃真空干燥过夜,得产品17.84g,收率69.10%。1H-NMR(400MHz,DMSO-d6)δppm 8.62(s,1H),8.36(d,J=8.2Hz,1H),8.34(s,1H),8.32(d,J=5.4Hz,1H),8.12(s,1H),7.52(d,J=8.2Hz,1H),7.25(ddd,J=8.2,7.0,1.2Hz,1H),7.21(d,J=5.4Hz,1H),7.12(t,J=7.0Hz,1H),6.87(s,1H),3.96(s,3H),3.88(s,3H),3.31(s,1H),3.28(d,J=6.4Hz,2H),2.84(s,3H),2.73(t,J=6.5Hz,2H),2.30(s,3H)。ESI-MS m/z:462.23[M+H]+。
D.甲基N-(2-((5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-硝基苯基)(甲基)氨基)乙基)-N-甲基甘氨酸酯(ZJT-3-M)的合成
将ZJT-3(0.50g,1.08mmol)加入到50ml烧瓶中,加入20ml DMF溶清,再加入溴乙酸甲酯(0.22g,1.30mmol)和K2CO3(0.22g,1.62mmol),控制温度在室温反应30min,TLC显示ZJT-3反应完全(DCM:MeOH=20:1)。向反应液中加入200ml纯化水和150ml EA打浆10分钟后分层萃取,TLC显示水层无目标物,故分出有机层,分别用纯化水和饱和食盐水洗涤,得到的产品用无水硫酸钠干燥过夜,TLC显示产品几乎不含杂质,粗产品ZJT-3-M直接进行下一步反应。ESI-MS m/z:534.24[M+H]+。
E.甲基N-(2-((2-氨基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)N-甲基甘氨酸乙酯(ZJT-4-M)的合成
将上一步骤中的ZJT-3-M粗产品置于120ml氢化反应釜中,使用Pd/C作催化剂反应小试,产品反应不完全,故改用Raney Ni作催化剂,加入适量Raney Ni后,加入50ml CH3OH,反应釜密闭后通入10atm氢气,室温反应过夜,TLC显示ZJT-3-B反应完全(DCM:MeOH=10:1)。反应液铺硅藻土抽滤,滤饼中的活性Raney Ni液封保存,滤液减压蒸干溶剂后放入鼓风箱中干燥,由于产品在柱层析中及溶液中极易变质,故干燥后的粗产品直接进行下一步反应。
实施例2甲基N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)-N-甲基甘氨酸乙酯(CSJ-I-M)的合成
将ZJT-4-M粗产品置于100ml烧瓶中,加入20ml DCM使产品溶清,加入K2CO3(0.45g,3.24mmol),反应液降温至0℃搅拌20min后,缓慢滴加丙烯酰氯(0.20g,2.16mmol),低温条件下保温反应20min,TLC显示ZJT-4-M反应完全(DCM:MeOH:NH3·H2O=50:5:1)。反应液抽滤,除去K2CO3固体,母液加入40ml甲醇室温搅拌1小时后,减压蒸干溶剂,得到的产品用硅胶制备板进行纯化(展开剂DCM:MeOH=15:1),得终产品0.18g,橙红色固体,三步反应总收率29.91%。1H-NMR(400MHz,Chloroform-d)δppm 9.87(s,1H),9.66(s,1H),9.12(s,1H),8.38(d,J=5.3Hz,1H),8.09-8.04(m,1H),7.77(s,1H),7.42-7.39(m,1H),7.29-7.27(m,1H),7.26(s,1H),7.21(d,J=5.4Hz,1H),6.79(s,1H),6.47(s,1H),6.46(s,1H),5.76-5.70(m,1H),4.00(s,3H),3.89(s,3H),3.71(s,3H),3.34(s,2H),2.93(t,J=5.8Hz,2H),2.68(s,3H),2.56(s,2H),2.41(s,3H)。ESI-MS m/z:558.2823[M+H]+。
实施例3N-(2-((2-(苄基(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-I-B)的合成
合成方法同CSJ-I-M,得终产品0.11g,淡黄色固体,三步反应总收率17.74%。1H-NMR(400MHz,Chloroform-d)δppm 9.89(s,1H),9.84(s,1H),9.11(s,1H),8.39(d,J=5.3Hz,1H),8.07(dd,J=7.5,1.8Hz,1H),7.72(s,1H),7.40(d,J=2.3Hz,1H),7.38(d,J=1.2Hz,1H),7.36(s,1H),7.35(d,J=1.0Hz,1H),7.33(d,J=0.9Hz,1H),7.32-7.30(m,1H),7.29-7.27(m,1H),7.26(s,1H),7.21(d,J=5.3Hz,1H),6.77(s,1H),6.46-6.37(m,1H),6.20(s,1H),5.57(d,J=10.2Hz,1H),3.98(s,3H),3.87(s,3H),3.58(s,2H),2.91(s,2H),2.60(s,3H),2.40(s,2H),2.25(s,3H)。ESI-MS m/z:576.31[M+H]+。
实施例4N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-4-溴-N-甲基苯甲酰胺(CSJ-I-C)的合成
合成方法同CSJ-I-M,得终产品0.18g,淡黄色固体,三步反应总收率24.98%。1H-NMR(400MHz,Chloroform-d)δppm 9.85(s,1H),9.05(s,1H),8.77(s,1H),8.38(d,J=5.3Hz,1H),8.09-8.05(m,1H),7.76(s,1H),7.50(d,J=1.7Hz,1H),7.48(s,1H),7.42-7.39(m,1H),7.36(d,J=5.1Hz,1H),7.30(dd,J=7.1,1.6Hz,1H),7.29-7.27(m,1H),7.23(s,1H),7.21(s,1H),6.79(s,1H),6.47(s,1H),6.39(s,1H),5.63(s,1H),3.98(s,3H),3.89(s,3H),3.69(s,2H),3.22(s,2H),2.87(s,3H),2.73(s,3H)。ESI-MS m/z:668.20[M+H]+。
实施例5N-(2-((2-((4-溴苄基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-I-F)的合成
合成方法同CSJ-I-M,得终产品0.12g,淡黄色固体,三步反应总收率17.02%。1H-NMR(400MHz,Chloroform-d)δppm 9.89(s,1H),9.68(s,1H),9.10(s,1H),8.39(d,J=5.2Hz,1H),8.09-8.04(m,1H),7.73(s,1H),7.45(s,1H),7.43(s,1H),7.41-7.38(m,1H),7.29-7.27(m,1H),7.26(d,J=1.5Hz,1H),7.24(s,1H),7.22(s,1H),7.20(s,1H),6.76(s,1H),6.42(dd,J=16.8,1.8Hz,1H),6.15(dd,J=16.9,10.1Hz,1H),5.61(d,J=10.4Hz,1H),3.99(s,3H),3.87(s,3H),3.49(d,J=8.4Hz,2H),2.91(t,J=5.8Hz,2H),2.60(s,3H),2.38(s,2H),2.23(s,3H)。ESI-MS m/z:654.2185[M+H]+。
实施例6(E)-N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-N-甲基丁-2-烯酰胺(CSJ-I-J)的合成
合成方法同CSJ-I-M,得终产品0.18g,淡黄色固体,三步反应总收率30.12%。1H-NMR(400MHz,Chloroform-d)δppm 9.85(d,J=22.2Hz,1H),9.05(s,1H),8.80(s,1H),8.38(t,J=5.1Hz,1H),8.08-8.04(m,1H),7.75(s,1H),7.42-7.38(m,1H),7.20(d,J=5.5Hz,1H),6.93(dt,J=14.3,7.1Hz,1H),6.76(d,J=11.0Hz,1H),6.48(d,J=9.3Hz,1H),6.42(d,J=12.6Hz,1H),6.24(dd,J=14.7,2.0Hz,1H),6.01(d,J=15.2Hz,1H),5.78(d,J=9.4Hz,1H),5.72(dd,J=9.3,2.5Hz,1H),3.99(s,3H),3.89(d,J=2.7Hz,3H),3.58(t,J=6.1Hz,2H),3.09(t,J=6.2Hz,2H),2.96(d,J=5.5Hz,3H),2.67(d,J=9.7Hz,3H),1.90-1.77(m,3H)。ESI-MS m/z:554.2874[M+H]+。
实施例7N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-N-甲基丁-3-烯酰胺(CSJ-I-K)的合成
合成方法同CSJ-I-M,得终产品0.27g,淡黄色固体,三步反应总收率45.19%。1H-NMR(400MHz,Chloroform-d)δppm 9.85(d,J=22.1Hz,1H),9.06(s,1H),8.79(d,J=16.1Hz,1H),8.38(t,J=5.6Hz,1H),8.08-8.04(m,1H),7.77(s,1H),7.42-7.38(m,1H),7.30-7.27(m,1H),7.22-7.19(m,1H),6.92(tq,J=14.9,7.1Hz,1H),6.79-6.74(m,1H),6.55-6.47(m,1H),6.47-6.42(m,1H),6.24(d,J=14.9Hz,1H),6.04-5.91(m,1H),5.74(ddd,J=12.5,9.2,2.6Hz,1H),5.20-5.08(m,1H),3.99(d,J=1.3Hz,3H),3.89(d,J=1.6Hz,3H),3.55(dt,J=29.9,6.2Hz,2H),3.15-3.04(m,3H),2.97(d,J=5.5Hz,2H),2.71-2.66(m,3H),1.97-1.83(m,2H)。ESI-MS m/z:554.2874[M+H]+。
实施例8N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-N-甲基丙烯酰胺(CSJ-I-L)的合成
合成方法同CSJ-I-M,得终产品0.04g,淡黄色固体,三步反应总收率6.87%。1H-NMR(400MHz,Chloroform-d)δppm 9.84(d,J=16.3Hz,1H),9.05(s,1H),8.78(s,1H),8.52(s,1H),8.38(t,J=5.4Hz,1H),8.09-8.04(m,1H),7.75(d,J=6.3Hz,1H),7.41-7.37(m,1H),7.29(dd,J=7.1,1.7Hz,1H),7.21(dd,J=7.2,5.2Hz,1H),6.75(s,1H),6.55(dd,J=16.8,10.2Hz,1H),6.50-6.45(m,1H),6.44-6.39(m,1H),6.38-6.33(m,1H),5.80-5.72(m,1H),5.72-5.62(m,1H),3.98(d,J=1.6Hz,3H),3.89(s,3H),3.59(t,J=6.2Hz,2H),3.11(t,J=6.2Hz,2H),2.97(d,J=5.7Hz,3H),2.67(d,J=18.8Hz,3H)。ESI-MS m/z:540.2719[M+H]+。
实施例9甲基(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)(甲基)氨基甲酸酯(CSJ-I-N)的合成
合成方法同CSJ-I-M,得终产品0.20g,淡黄色固体,三步反应总收率34.09%。1H-NMR(400MHz,Chloroform-d)δppm 9.74(s,1H),9.67(s,1H),8.67(s,1H),8.49(s,1H),8.11(s,1H),8.10(s,1H),7.58(s,1H),7.47(s,1H),7.25(d,J=2.3Hz,1H),6.71(s,1H),6.41(s,1H),6.16(d,J=2.2Hz,1H),5.73(s,1H),5.06(d,J=10.9Hz,1H),4.13(t,J=6.7Hz,3H),3.40(s,3H),3.01(s,3H),2.88(s,2H),2.84(s,2H),2.65(s,3H),2.38(s,3H)。ESI-MSm/z:544.2667[M+H]+。
实施例10N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-N-甲基丁-2-乙酰胺(CSJ-I-R)的合成
合成方法同CSJ-I-M,得终产品0.15g,淡黄色固体,三步反应总收率25.19%。1H-NMR(400MHz,Chloroform-d)δppm 9.86(d,J=12.7Hz,1H),9.07(s,1H),8.74(s,1H),8.61(s,1H),8.37(dd,J=5.4,1.6Hz,1H),8.05(dd,J=5.9,3.5Hz,1H),7.78(s,1H),7.42-7.38(m,1H),7.29(dd,J=3.0,1.2Hz,1H),7.21(t,J=5.4Hz,1H),6.76(d,J=11.6Hz,1H),6.58(dd,J=16.8,9.9Hz,1H),6.46(dd,J=11.1,1.7Hz,1H),5.77(ddd,J=17.8,9.1,2.7Hz,1H),3.99(d,J=2.3Hz,3H),3.90(d,J=2.0Hz,3H),3.69-3.55(m,2H),3.08(q,J=2.5,1.9Hz,3H),2.80(s,2H),2.68(d,J=7.2Hz,3H),1.94(d,J=41.2Hz,3H)。ESI-MS m/z:552.2717[M+H]+。
实施例11N-(4-甲氧基-2-(甲基(2-(甲基(2-甲基烯丙基)氨基)乙基)氨基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-I-X)的合成
合成方法同CSJ-I-M,得终产品0.22g,橙红色固体,三步反应总收率37.77%。1H-NMR(400MHz,Chloroform-d)δppm 9.91(s,1H),9.75(s,1H),9.11(s,1H),8.38(d,J=5.3Hz,1H),8.07(d,J=7.4Hz,1H),7.70(s,1H),7.40(d,J=7.4Hz,1H),7.29-7.27(m,1H),7.26(d,J=1.2Hz,1H),7.21(d,J=5.3Hz,1H),6.79(s,1H),6.48(d,J=17.2Hz,1H),6.41(d,J=9.7Hz,1H),5.71(d,J=9.8Hz,1H),4.99(s,1H),4.92(s,1H),3.99(s,3H),3.89(d,J=1.3Hz,3H),2.96(s,2H),2.84(s,2H),2.67(s,3H),2.38(s,2H),2.22(s,3H),1.84(s,3H)。ESI-MS m/z:540.3081[M+H]+。
实施例12N-(2-((2-(but-3-en-1-yl(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-I-Y)的合成
合成方法同CSJ-I-M,得终产品0.13g,砖红色固体,三步反应总收率22.32%。1H-NMR(400MHz,Chloroform-d)δppm 9.87(s,1H),9.80(s,1H),9.10(s,1H),8.38(d,J=5.2Hz,1H),8.06(d,J=7.3Hz,1H),7.74-7.69(m,1H),7.42-7.38(m,1H),7.28(dd,J=4.6,2.0Hz,1H),7.26(d,J=0.9Hz,1H),7.21(d,J=5.3Hz,1H),6.78(s,1H),6.47(d,J=16.5Hz,1H),6.38(s,1H),5.79(s,1H),5.72(d,J=10.3Hz,1H),5.07(d,J=17.1Hz,1H),5.01(d,J=9.9Hz,1H),4.00(s,3H),3.89(s,3H),2.93(d,J=18.3Hz,2H),2.88(s,2H),2.70(s,3H),2.51(s,2H),2.38(s,2H),2.26(s,3H)。ESI-MS m/z:540.4091[M+H]+。
实施例13N-(4-甲氧基-2-(甲基(2-(甲基(丙-2-炔-1-基)氨基)乙基)氨基)氨基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-I-Z)的合成
合成方法同CSJ-I-M,得终产品0.15g,淡黄色固体,三步反应总收率26.55%。1H-NMR(400MHz,Chloroform-d)δppm 9.89(s,1H),9.86(s,1H),9.12(s,1H),8.39(d,J=5.3Hz,1H),8.10-8.04(m,1H),7.74(s,1H),7.43-7.38(m,1H),7.30(dd,J=7.1,1.7Hz,1H),7.28(d,J=2.8Hz,1H),7.21(d,J=5.3Hz,1H),6.80(s,1H),6.46(dd,J=16.9,2.2Hz,1H),6.37(t,J=13.0Hz,1H),5.75-5.66(m,1H),4.00(s,3H),3.89(s,3H),3.41(d,J=2.4Hz,2H),2.91(t,J=5.7Hz,2H),2.70(s,3H),2.45(s,2H),2.34(s,3H),2.24(t,J=2.3Hz,1H)。ESI-MS m/z:524.28[M+H]+。
实施例14N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(CSJ-II-D)的合成
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A.1-乙基-4-硝基-1H-吡唑的合成
将4-硝基吡唑(1.00g,8.84mmol)加入到50ml烧瓶中,加入20ml DMF搅拌溶解,加入K2CO3(2.44g,17.68mmol),室温搅拌下缓慢加入碘乙烷(2.51g,17.68mmol),室温反应1小时,TLC检测反应完全,4-硝基吡唑完全消失,且无杂质点,展开剂比例为石油醚:乙酸乙酯=3:1。将反应液缓慢倒入200ml纯化水中,剧烈搅拌,再加入200ml乙酸乙酯,剧烈搅拌30min后分层萃取,TLC检测水层仍有目标物荧光。分离出水层,用150ml乙酸乙酯萃取,TLC检测水层无目标物荧光,有机层合并,分别用纯化水和饱和食盐水洗涤,再用无水硫酸钠干燥过夜。过夜后产品抽滤,滤饼用乙酸乙酯淋洗,母液减压旋蒸除去溶剂,得到的产品50℃真空干燥过夜,得1-乙基-4-硝基-1H-吡唑粗产品1.32g。1H-NMR(400MHz,DMSO-d6)δppm8.91(d,J=0.6Hz,1H),8.26(d,J=0.8Hz,1H),4.21(q,J=7.2Hz,2H),1.41(t,J=7.3Hz,3H)。ESI-MS m/z:142.06[M+H]+。
B.1-乙基-1H-吡唑-4-胺的合成
将1-乙基-4-硝基-1H-吡唑(1.00g,7.09mmol)加入到100ml烧瓶中,加入15ml乙醇使其溶清;取氯化铵(0.76g,14.18mmol)于小烧瓶中,加入4ml纯化水溶清,将氯化铵水溶液加入到溶解的原料中,升温至85℃回流状态后,加入还原铁粉(1.98g,35.45mmol),保温反应4小时,TLC检测原料全部反应完,展开剂比例为DCM:MeOH=10:1。粗产品加入1.2equ硅胶拌样,柱层析纯化(DCM:MeOH=150:1),得1-乙基-1H-吡唑-4-胺0.59g,收率74.92%。1H-NMR(400MHz,DMSO-d6)δppm 7.02(d,J=0.9Hz,1H),6.88(d,J=0.9Hz,1H),3.92(q,J=7.3Hz,2H),3.75(p,J=7.3Hz,2H),1.27(t,J=7.3Hz,3H)。ESI-MS m/z:112.09[M+H]+。
C.2-氯-N-(1-乙基-1H-吡唑-4-基)嘧啶-4-胺(inter-1-D)的合成
将1-乙基-1H-吡唑-4-胺(1.00g,9.00mmol)加入到50ml烧瓶中,加入12ml DMF使其溶清,加入K2CO3(2.48g,18.00mmol)后反应液降温至0℃搅拌20min,再缓慢加入2,4-二氯嘧啶(1.60g,10.80mmol),保温反应2小时,TLC检测1-乙基-1H-吡唑-4-胺基本全部反应完,展开剂比例为DCM:MeOH=10:1。粗产品加入1.2equ硅胶拌样,柱层析纯化(DCM:MeOH=80:1),得inter-1-D 1.16g,收率57.78%。1H-NMR(400MHz,DMSO-d6)δppm 10.02(s,1H),8.01(d,J=5.9Hz,1H),7.94-7.86(m,1H),7.54-7.44(m,1H),6.62-6.55(m,1H),4.08(q,J=7.3Hz,2H),1.32(t,J=7.3Hz,3H)。ESI-MS m/z:224.07[M+H]+。
D.N-(2-(二甲基氨基)乙基)-5-甲氧基-N-甲基-2-硝基苯-1,4-二胺(inter-2)的合成
将4-氟-2-甲氧基-5-硝基苯胺(1.00g,5.40mmol),N,N,N’-三甲基乙烷-1,2-二胺(0.66g,6.50mmol),DIPEA(0.90g,7.00mmol),DMA 10ml加入到50ml反应瓶中,升温到90℃保温反应6小时,TLC检测反应基本完全,展开剂比例为DCM:MeOH=50:1。粗产品加入1.2equ硅胶拌样,柱层析纯化(DCM:MeOH=80:1),得inter-2 0.89g,收率61.46%。1H-NMR(400MHz,Chloroform-d)δppm 7.27(s,1H),6.62(s,1H),3.92(d,J=0.7Hz,3H),3.76(s,2H),3.23-3.14(m,2H),2.81(d,J=0.5Hz,3H),2.60-2.51(m,2H),2.29(d,J=1.1Hz,6H)。ESI-MS m/z:269.16[M+H]+。
E.N-(4-(((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)-N-(1-乙基-1H-吡唑-4-基)嘧啶-2,4-二胺(inter-3-D)的合成
将inter-1-D(1.16g,5.20mmol),inter-2(1.53g,5.72mmol),对甲苯磺酸·一水物(1.19g,6.24mmol),正丁醇30ml加入到100ml反应瓶中,控制温度在90℃反应4小时,TLC显示inter-1-D和inter-2基本反应完全,展开剂比例为DCM:MeOH=10:1。搅拌降温至室温,向反应液中加入饱和NaHCO3水溶液,将反应液pH调至7~8,再加入150ml乙酸乙酯,打浆1小时后萃取,TLC检测显示水层无目标物荧光,分离出有机层,分别用纯化水和饱和NaCl水溶液洗涤,再用无水硫酸钠干燥过夜。粗产品加入1.2equ硅胶拌样,柱层析纯化(DCM:MeOH:NH3·H2O=300:5:1),得inter-3-D 1.58g,收率66.95%。1H-NMR(400MHz,DMSO-d6)δppm9.33(s,1H),8.46(s,1H),7.95(d,J=4.6Hz,1H),7.90(s,1H),7.88(s,1H),7.41(d,J=0.8Hz,1H),6.81(s,1H),6.09(d,J=5.8Hz,1H),4.05-3.99(m,2H),3.93(s,3H),3.24(t,J=6.9Hz,2H),2.82(s,3H),2.51(q,J=1.8Hz,3H),2.46(dd,J=7.5,6.4Hz,2H),2.15(s,6H)。ESI-MS m/z:456.25[M+H]+。
F.N-(2-(二甲基氨基)乙基)-N-(4-(((1-乙基-1H-吡唑-4-基)氨基)嘧啶-2-基)-5-甲氧基-N-甲基苯-1,2,4-三胺(inter-4-D)的合成
将inter-3-D(1.58g,3.47mmol)加入到100ml烧瓶中,加入乙醇13ml使其溶清;取氯化铵(0.56g,10.41mmol)于小烧瓶中,加入纯化水3ml溶清,将氯化铵水溶液加入到溶解的原料中,升温至85℃回流状态后,加入还原铁粉(0.97g,17.35mmol),保温反应4小时,TLC检测原料全部反应完,展开剂比例为DCM:MeOH=10:1。由于产品在柱层析中及溶液中极易变质,故干燥后的粗产品直接进行下一步反应。ESI-MS m/z:426.28[M+H]+。
G.N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(CSJ-II-D)的合成
将inter-4-D粗产品置于100ml烧瓶中,加入20ml丙酮使产品溶清,加入K2CO3(1.44g,10.41mmol),反应液降温至0℃搅拌20min后,缓慢滴加丙烯酰氯(0.63g,6.94mmol),低温条件下保温反应30min,TLC显示inter-4-D反应完全(DCM:MeOH:NH3·H2O=50:5:1)。反应液抽滤,除去K2CO3固体,母液加入40ml甲醇室温搅拌1小时后,减压蒸干溶剂,得到的产品用硅胶制备板进行纯化(展开剂DCM:MeOH=10:1),得终产品CSJ-II-D 0.54g,棕黄色固体,两步反应总收率33.45%。1H-NMR(400MHz,Chloroform-d)δppm 10.10(s,1H),9.63(s,1H),7.93(d,J=5.9Hz,1H),7.56(s,1H),7.48(s,1H),7.43(s,1H),7.28(s,1H),6.74(s,1H),6.51(s,1H),6.38(dd,J=16.9,1.9Hz,1H),6.01(d,J=5.9Hz,1H),5.73-5.62(m,1H),4.11(q,J=7.4Hz,2H),3.84(s,3H),2.94(s,2H),2.69(s,3H),2.46(s,2H),2.36(s,6H),1.46(t,J=7.3Hz,3H)。ESI-MS m/z:480.2830[M+H]+。
实施例15N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-II-A)的合成
合成方法同CSJ-II-D,取inter-3-A(0.50g,1.13mmol)进行反应,得终产品CSJ-II-A 0.09g,淡黄色固体,两步反应总收率17.07%。1H-NMR(400MHz,Chloroform-d)δppm9.12(s,1H),7.99(d,J=5.9Hz,1H),7.32(d,J=2.4Hz,1H),6.75(s,1H),6.73(s,1H),6.69(s,1H),6.42(dd,J=17.0,1.6Hz,1H),6.25(s,1H),5.79(dd,J=10.2,1.6Hz,1H),4.25(s,3H),3.91(s,3H),3.84(s,3H),3.14(d,J=6.7Hz,2H),2.79(s,2H),2.68(s,3H),2.55(s,6H)。ESI-MS m/z:466.2673[M+H]+。
实施例16N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-II-B)的合成
合成方法同CSJ-II-D,取inter-3-B(0.50g,1.13mmol)进行反应,得终产品CSJ-II-B 0.08g,淡黄色固体,两步反应总收率15.17%。1H-NMR(400MHz,Chloroform-d)δppm7.86(d,J=6.2Hz,1H),7.74(d,J=8.0Hz,1H),7.67(s,1H),7.49(s,1H),6.84(s,1H),6.76(s,1H),6.39(d,J=16.9Hz,1H),6.09(d,J=6.1Hz,1H),5.78(dd,J=10.2,1.6Hz,1H),4.16(s,6H),3.91(s,3H),3.87(s,3H),3.24(s,2H),3.01(s,2H),2.69(s,3H),2.67(s,3H)。ESI-MS m/z:466.2673[M+H]+。
实施例17N-(5-((4-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(CSJ-II-C)的合成
合成方法同CSJ-II-D,取inter-3-C(0.50g,1.10mmol)进行反应,得终产品CSJ-II-C 0.21g,淡黄色固体,两步反应总收率39.89%。1H-NMR(400MHz,Chloroform-d)δppm9.94(s,1H),9.78(s,1H),7.98(d,J=5.8Hz,1H),7.47(s,1H),7.42(s,1H),6.72(s,1H),6.58(s,1H),6.42(d,J=1.8Hz,1H),6.37(d,J=1.8Hz,1H),5.82(d,J=5.8Hz,1H),5.70-5.66(m,1H),3.85(s,3H),3.83(s,3H),2.99(s,2H),2.70(s,3H),2.53(s,2H),2.42(s,6H),2.18(s,3H)。ESI-MS m/z:480.2829[M+H]+。
实施例18甲基N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-N-甲基甘氨酸酯(CSJ-III-M)的合成
A.2-氯-N-(1-甲基-1H-吡唑-3-基)嘧啶-4-胺(med-1)的合成
将1-甲基-1H-吡唑-3-胺(23.00g,0.237mol),2,4-二氯嘧啶(35.06g,0.237mol),K2CO3(49.13g,0.355mol)加入到500ml反应瓶中,加入1,4-二氧六环200ml作溶剂,升温到80℃保温反应10小时,TLC检测反应基本完全,展开剂比例为DCM:MeOH=10:1。反应液中有大量固体析出,抽滤,滤饼用正己烷洗涤,得到淡黄色固体,TLC检测无原料。再用1L纯化水洗涤滤饼,除去K2CO3固体。产品于50℃真空干燥过夜,得20.55g,收率41.48%。1H-NMR(400MHz,DMSO-d6)δppm 10.45(s,1H),8.17(d,J=12.3Hz,1H),7.76(dd,J=19.6,2.2Hz,1H),7.63(d,J=2.2Hz,1H),6.97(s,1H),3.49-3.25(m,3H)。ESI-MS m/z:210.06[M+H]+。
B.N-(4-氟-2-甲氧基-5-硝基苯基)-N-(1-甲基-1H-吡唑-3-基)嘧啶-2,4-二胺(med-2)的合成
将med-1(20.00g,0.095mol),4-氟-2-甲氧基-5-硝基苯胺(19.58g,0.105mol),对甲苯磺酸·一水物(21.68g,0.114mol)加入到1L反应瓶中,再加入正丁醇480mL搅拌溶解,控制温度在90℃反应8小时,TLC显示med-1基本反应完全(DCM:MeOH=10:1),反应液中析出大量固体。搅拌降温至室温,过滤得到黄色固体,TLC显示固体中残留少量4-氟-2-甲氧基-5-硝基苯胺和对甲苯磺酸。将所得固体用无水乙醚洗涤,过滤,得到的固体TLC显示极少4-氟-2-甲氧基-5-硝基苯胺残留,母液中基本不含产品,所得产品TLC显示不含杂质。将产品50℃真空干燥过夜,得产品29.88g,收率87.60%。1H-NMR(400MHz,DMSO-d6)δppm 9.82(s,1H),9.01(d,J=8.5Hz,1H),8.05(d,J=5.8Hz,1H),7.90(s,1H),7.55(d,J=2.2Hz,1H),7.32(d,J=13.3Hz,1H),6.49(s,2H),4.01(s,3H),3.76(s,3H)。ESI-MS m/z:360.12[M+H]+。
C.N-(2-甲氧基-4-(甲基(2-(甲基氨基)乙基)氨基)-5-硝基苯基)-N(1-甲基-1H-吡唑-3-基)嘧啶-2,4-二胺(med-3)的合成
将med-2(28.24g,0.056mol),N,N’-二甲基乙二胺(8.32g,0.094mol),K2CO3(16.17g,0.117mol)加入到500ml烧瓶中,再加入DMF 250ml作溶剂,室温下搅拌不溶解,升温后逐渐溶清,控制温度在90℃反应9小时,TLC显示med-2基本反应完全(DCM:MeOH=10:1),反应液由黄色变为红色。搅拌降温至室温,向反应液中加入1L纯化水打浆1小时,再加入500ml乙酸乙酯,剧烈搅拌后萃取,TLC检测水层仍有产物,故水层再次进行萃取,直至水层中无产物荧光。有机相合并,分别用纯化水和饱和食盐水洗涤,无水硫酸钠干燥。粗产品进行柱层析纯化(DCM:MeOH=30:1),得med-3 22.35g,收率67.08%。1H-NMR(400MHz,DMSO-d6)δppm 9.72(s,1H),8.55(s,1H),7.99(d,J=5.7Hz,1H),7.73(s,1H),7.50(d,J=2.2Hz,1H),6.82(s,1H),6.44(s,2H),3.94(s,3H),3.75(s,3H),3.23(t,J=6.5Hz,2H),2.80(s,3H),2.67(t,J=6.5Hz,2H),2.51(p,J=1.8Hz,1H),2.28(s,3H)。ESI-MS m/z:428.22[M+H]+。
D.甲基N-(2-((5-甲氧基-4-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-2-硝基苯基)(甲基)氨基)乙基)-N-甲基甘氨酸酯(med-3-M)的合成
将med-3(0.50g,1.17mmol)加入到50ml烧瓶中,加入DMF 18ml将其溶清,再加入溴乙酸甲酯(0.21g,1.40mmol),CsCO3(0.57g,1.75mmol),室温反应1小时,TLC显示med-3反应完全(DCM:MeOH=20:1)。向反应液中加入200ml纯化水和150ml乙酸乙酯打浆10分钟,TLC检测水层无产物荧光,分出有机层,分别用纯化水和饱和食盐水洗涤,得到的产品用无水硫酸钠干燥过夜,得med-3-M粗品0.55g,收率94.83%,粗产品直接进行下一步反应。ESI-MS m/z:500.23[M+H]+。
E.甲基N-(2-((2-氨基-5-甲氧基-4-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-N-甲基甘氨酸酯(med-4-M)的合成
将med-3-M(0.48g,0.90mmol)粗品置于200ml氢化反应釜中,加入0.05g Pd/C作催化剂,再加入80ml CH3OH,反应釜密闭后通入10atm氢气,控制温度在30℃反应6小时,TLC显示med-3-M反应完全(DCM:MeOH=10:1)。反应液铺硅藻土抽滤,滤液减压蒸干溶剂后放入鼓风箱中干燥,得med-4-M粗品0.44g,收率97.78%。由于产品在柱层析中及溶液中极易变质,故干燥后的粗产品直接进行下一步反应。
F.甲基N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-N-甲基甘氨酸酯(CSJ-III-M)的合成
将med-4-M(0.52g,1.10mmol)粗品置于100ml烧瓶中,加入20ml DCM使其溶清,加入K2CO3(0.46g,3.30mmol),反应液降温至0℃搅拌20min后,缓慢滴加丙烯酰氯(0.20g,2.20mmol),低温条件下保温反应20min,TLC显示med-4-M反应完全(DCM:MeOH:NH3·H2O=50:5:1)。反应液抽滤,除去K2CO3固体,母液加入40ml甲醇室温搅拌1小时后,减压蒸干溶剂,得到的产品用硅胶制备板进行纯化(展开剂DCM:MeOH=10:1),得终产品CSJ-III-M 0.06g,淡黄色固体,三步反应总收率10.53%。1H-NMR(400MHz,Chloroform-d)δppm 9.79(s,1H),9.54(s,1H),8.13(d,J=5.9Hz,1H),7.47(s,1H),7.27(s,1H),7.25(d,J=2.3Hz,1H),6.82(s,1H),6.74(s,1H),6.72(d,J=5.3Hz,1H),6.42(d,J=3.1Hz,1H),6.16(s,1H),5.71-5.68(m,1H),3.85(d,J=0.6Hz,3H),3.84(s,3H),3.70(d,J=0.6Hz,3H),3.33(s,2H),2.91(d,J=5.8Hz,2H),2.66(s,3H),2.54(t,J=5.8Hz,2H),2.40(s,3H)。ESI-MS m/z:524.2729[M+H]+。
实施例19甲基(2-((2-丙烯酰胺基-5-甲氧基-4-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)(甲基)氨基甲酸酯(CSJ-III-N)的合成
合成方法同CSJ-III-M,取med-3(0.50g,1.17mmol)进行反应,得终产品CSJ-III-N0.24g,淡黄色固体,三步反应总收率34.43%。1H-NMR(400MHz,Chloroform-d)δppm 9.75(d,J=17.1Hz,1H),8.64(s,1H),8.46(s,1H),8.14(d,J=5.8Hz,1H),7.42(s,1H),7.27(s,1H),7.26(d,J=2.3Hz,1H),7.24(s,1H),6.71(s,1H),6.41(d,J=2.9Hz,1H),6.16(d,J=2.2Hz,1H),5.73(s,1H),3.85(s,3H),3.84(s,3H),3.70(s,3H),3.39(d,J=18.5Hz,2H),3.02(s,3H),2.83(s,2H),2.65(s,3H)。ESI-MS m/z:510.2572[M+H]+。
实施例20N-(4-甲氧基-2-(甲基(2-(甲基(2-甲基烯丙基)氨基)乙基)氨基)-5-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-III-X)的合成
合成方法同CSJ-III-M,取med-3(0.50g,1.17mmol)进行反应,得终产品CSJ-III-X0.05g,淡黄色固体,三步反应总收率8.46%。1H-NMR(400MHz,Chloroform-d)δppm 9.71(s,1H),9.62(s,1H),8.60(s,1H),8.33(d,J=7.5Hz,1H),8.11(d,J=6.1Hz,1H),7.63(s,1H),7.49(d,J=13.4Hz,1H),7.29(s,1H),7.25(s,1H),6.70(s,1H),6.57-6.50(m,1H),6.42(d,J=2.8Hz,1H),6.40(s,1H),6.18(s,1H),3.91(d,J=3.7Hz,2H),3.84(s,3H),3.82(s,3H),3.57(t,J=6.2Hz,2H),3.08(q,J=7.5,6.9Hz,3H),2.97(s,3H),2.67(s,3H),2.62(s,2H)。ESI-MS m/z:506.2623[M+H]+。
实施例21N-(2-((2-(but-3-en-1-yl(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-III-Y)的合成
合成方法同CSJ-III-M,取med-3(0.50g,1.17mmol)进行反应,得终产品CSJ-III-Y0.10g,淡黄色固体,三步反应总收率16.91%。1H-NMR(400MHz,Chloroform-d)δppm 9.78(s,1H),9.72(s,1H),8.65(s,1H),8.48(s,1H),8.14(d,J=5.8Hz,1H),7.44(s,1H),7.26(d,J=2.4Hz,1H),7.23(s,1H),6.71(s,1H),6.69(s,1H),6.41(s,1H),6.16(s,1H),5.73(s,1H),5.12(s,1H),5.06(s,1H),4.14(t,J=6.7Hz,3H),3.85(s,3H),3.84(s,3H),3.40(s,2H),3.01(s,2H),2.83(s,2H),2.65(s,3H),2.38(s,2H)。ESI-MS m/z:506.25[M+H]+。
实施例22N-(4-甲氧基-2-(甲基(2-(甲基(丙-2-炔-1-基)氨基)乙基)氨基)氨基)-5-((4-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(CSJ-III-Z)的合成
合成方法同CSJ-III-M,取med-3(0.50g,1.17mmol)进行反应,得终产品CSJ-III-Z0.09g,淡黄色固体,三步反应总收率15.72%。1H-NMR(400MHz,Chloroform-d)δppm 9.80(s,1H),9.74(s,1H),8.12(d,J=5.9Hz,1H),7.52(s,1H),7.43(s,1H),7.25(d,J=2.3Hz,1H),6.75(s,1H),6.73(s,1H),6.42(dd,J=17.0,1.9Hz,1H),6.31(dd,J=17.0,10.0Hz,1H),6.17-6.13(m,1H),5.68(dd,J=9.9,1.9Hz,1H),3.85(s,3H),3.84(s,3H),3.41(d,J=2.4Hz,2H),2.89(t,J=5.7Hz,2H),2.69(s,3H),2.45(t,J=5.6Hz,2H),2.34(s,3H),2.24(t,J=2.4Hz,1H)。ESI-MS m/z:490.2672[M+H]+。
实施例23化合物对激酶的抑制活性测试
在酶水平测定了实施例中所列21个化合物对19del突变和L858R/T790M双突变EGFR的抑制活性,以及对野生型EGFR的抑制活性。评价方法和结果如下文所述。
1.实验材料和仪器
用于生物活性评价的实验耗材
2.实验步骤
2.1化合物储液的制备
所有化合物溶于DMSO,制备成10mM的储液。三个月内使用的化合物室温储存于干燥器内,其它的可以在-20℃长期储存。
工作液的制备:
所有化合物都用DMSO稀释,起始浓度1000nM,进行3倍梯度稀释,10个浓度点。
阳性参比化合物Osimertinib用DMSO稀释,起始浓度1000nM,在EGFR Del19和EGFRT790M/L858R实验中,进行4倍梯度稀释,10个浓度点;在EGFR WT实验中,进行3倍梯度稀释,10个浓度点。
制备1000X positive control(1mM,Osimertinib)和1000X vehicle control(100%DMSO)。
振荡器上震荡5min。
制备缓冲液:1体积的enzymatic buffer 5X加4体积的蒸馏水;5mM MgCl2;1mMDTT;1mM MnCl2。
2.2激酶EGFR del 19的滴定(5μl TK-substrate-biotin and ATP)
a)使用Echo 550将化合物稀释液转移到测定板(784075,Greiner)的每个孔中。
b)密封测定板,以1000g离心复合板1min。
c)在1x激酶缓冲液中制备2X EGFR Del19。
d)将5μl 2X EGFR Del19加入384孔测定板(784075,Greiner)。
e)将板在1000g下离心30s,在室温下离心10分钟。
f)在1X激酶缓冲液中制备2x TK-substrate-biotin和ATP混合物。
g)通过添加5μl TK-substrate-biotin和ATP来开始反应。
h)将板以1000g离心30秒。密封测定板,RT 40min。
i)在HTRF检测缓冲液中准备4X Sa-XL 665。
j)将5μl Sa-XL 665和5μl TK-antibody-Cryptate添加到测定板的每个孔中。
k)以1000g离心板30s,RT 1h。
l)在Envision 2104读板器上读取615nm(Cryptate)和665nm(XL665)的荧光信号。
2.3激酶EGFR T790M/L858R的滴定(5μl TK-substrate-biotin and ATP)
a)使用Echo 550将化合物稀释液转移到测定板(784075,Greiner)的每个孔中。
b)密封测定板,以1000g离心复合板1min。
c)在1x激酶缓冲液中制备2X EGFR T790M L858R。
d)将5μl 2X EGFR T790M L858R加入384孔测定板(784075,Greiner)。
e)将板在1000g下离心30s,在室温下离心10分钟。
f)在1X激酶缓冲液中制备2x TK-substrate-biotin和ATP混合物。
g)通过添加5μl TK-substrate-biotin和ATP来开始反应。
h)将板以1000g离心30秒。密封测定板,RT 40min。
i)在HTRF检测缓冲液中准备4X Sa-XL 665。
j)将5μl Sa-XL 665和5μl TK-antibody-Cryptate添加到测定板的每个孔中。
k)以1000g离心板30s,RT 1h。
l)在Envision 2104读板器上读取615nm(Cryptate)和665nm(XL665)的荧光信号。
2.4EGFR WT的滴定(5μl TK-substrate-biotin and ATP)
a)使用Echo 550将化合物稀释液转移到测定板(784075,Greiner)的每个孔中
b)密封测定板,以1000g离心复合板1min。
c)在1x激酶缓冲液中制备2X EGFR wt。
d)将5μl 2X EGFR wt加入384孔测定板(784075,Greiner)。
e)将板在1000g下离心30s,在室温下离心10分钟。
f)在1X激酶缓冲液中制备2x TK-substrate-biotin和ATP混合物。
g)通过添加5μl TK-substrate-biotin和ATP来开始反应。
h)将板以1000g离心30秒。密封测定板,RT 40min。
i)在HTRF检测缓冲液中准备4X Sa-XL 665。
j)将5μlSa-XL 665和5μl TK-antibody-Cryptate添加到测定板的每个孔中。
k)以1000g离心板30s,RT 1h。
l)在Envision 2104读板器上读取615nm(Cryptate)和665nm(XL665)的荧光信号。
3.数据分析
计算每个孔665/615nm的比值
计算%Inhibition:
%Inhibition=100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100.
计算化合物的IC50和Plot效应剂量曲线:
使用GraphPad 6.0,通过将%Inhibition和化合物浓度的对数拟合为非线性回归(剂量响应-可变斜率)来计算IC50值。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:log of inhibitor concentration;Y:%Inhibition
4.试验结果
计算%Inhibition后,以受试化合物浓度的对数为横坐标,酶抑制率平均值为纵坐标绘制剂量效应曲线,结果显示9个化合物的IC50值小于70nM,分别为第一类目标化合物中的CSJ-I-B,CSJ-I-M,CSJ-I-X,CSJ-I-Y;第二类目标化合物中的CSJ-II-A,CSJ-II-B,CSJ-II-C,CSJ-II-D;和第三类目标化合物中的CSJ-III-Z。
阳性对照药Osimertinib及合成的化合物对激酶EGFRdel19,激酶EGFRT790M/L858R,激酶EGFRWT测试结果如下所示:
化合物的IC50值
实施例24化合物对相关肿瘤细胞的抑制活性测试
在细胞水平挑选了实施例23中在酶水平上对EGFRT790M/L858R和EGFRdel19具有良好抑制活性,且对EGFRWT具有良好选择性的活性化合物,测定了其对HCC-827细胞(EGFRdel19)和NCI-H1975细胞(EGFRT790M/L858R)的抑制活性,以及对NCI-H1299,A549(EGFRWT)的抑制活性。评价方法和结果如下文所述。
1.实验材料和仪器
1.1用于生物活性评价的实验耗材
2实验步骤
2.1化合物储液的制备
选取化合物CSJ-I-B,CSJ-I-F,CSJ-I-C,CSJ-I-R,CSJ-I-Z,CSJ-I-Y溶于DMSO,制备成10mM的储液。三个月内使用的化合物室温储存于干燥器内,其它的可以在-20℃长期储存。
工作液的制备:
上述化合物及阳性参比化合物Osimertinib和Gefitinib都用DMSO稀释,起始浓度1000nM,在NCI-H1975,HCC-827,NCI-H1299,A549细胞实验中,进行3倍梯度稀释,10个浓度点。振荡器上震荡5min。
2.2细胞加药
2.2.1处于对数生长期的NCI-H1975,HCC-827,NCI-H1299,A549细胞种于96孔板中,每孔3000-4000细胞量,将培养板在培养箱预培养24小时(在37℃,5% CO2的条件下)。
2.2.2更换孔板中的培养基,向培养板加入100μl相应浓度的化合物及阳性药。
2.2.3将培养板在培养箱孵育一段72小时,向每孔加入10μl CCK-8溶液,将培养板在培养箱内孵育1-4小时。
2.2.4用酶标仪测定在450nm处的吸光度。
3数据分析
计算%Inhibition:
%Inhibition=100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100.
计算化合物的IC50和Plot效应剂量曲线:
使用GraphPad 6.0,通过将%Inhibition和化合物浓度的对数拟合为非线性回归(剂量响应-可变斜率)来计算IC50值。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:log of inhibitor concentration;Y:%Inhibition
4试验结果
计算%Inhibition后,以受试化合物浓度的对数为横坐标,酶抑制率平均值为纵坐标绘制剂量效应曲线,拟合出IC50值,结果显示:
CSJ-I-B,CSJ-I-F,CSJ-I-C,CSJ-I-R,CSJ-I-Z,CSJ-I-Y对NCI-H1975,HCC-827,NCI-H1299,A549具有增殖抑制活性。化合物CSJ-I-B,CSJ-I-R,CSJ-I-Z,CSJ-I-Y四个化合物与AZD9291(IC50=0.0148μM)相比具有更高的活性。6个化合物对NCI-H1975的抗增殖活性均高于A549或H1299,其中,化合物CSJ-I-Z(IC50=0.00258μM)对NCI-H1975细胞的活性优于AZD9291(IC50=0.0148μM,对HCC-827细胞的活性(IC50=0.00363μM)与AZD9291(IC50=0.00173μM)相当。NCI-H1975细胞中的抑制活性相比,化合物CSJ-I-Z在A549和NCI-H1299中的选择性分别为38760倍和27548倍,是AZD9291的1685倍和143倍。与奥西替尼和吉非替尼相比,所有靶化合物对EGFRWT细胞的选择性均有所提高,说明其副作用较小。
上述化合物及阳性参比化合物Osimertinib和Gefitinib对NCI-H1975,HCC-827,NCI-H1299,A549细胞的测试结果如下所示:
化合物的IC50值
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Claims (8)
1.一种药物组合物,其包含至少一种如下所示的化合物或其药学可接受的盐、异构体或溶剂化物,和至少一种赋形剂,
2.如权利要求1所述的药物组合物在制备作为EGFR抑制剂或用于治疗EGFR激酶介导的癌症的药物中的用途。
3.如权利要求2所述的用途,其中所述的EGFR激酶介导的癌症为EGFR突变导致的癌症,
优选地,所述的EGFR激酶介导的癌症选自:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、组织细胞性淋巴癌和鼻咽癌,或者
优选地,所述的EGFR突变导致的癌症为带有T790M突变、L858R突变或L858R/T790M双突变的癌症。
4.化合物CSJ-I-Z或其药学可接受的盐、异构体或溶剂化物在制备作为EGFR抑制剂或用于治疗EGFR激酶介导的癌症的药物中的用途,
5.如权利要求4所述的用途,其中所述的EGFR激酶介导的癌症为EGFR突变导致的癌症,
优选地,所述的EGFR激酶介导的癌症选自:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、组织细胞性淋巴癌和鼻咽癌,或者
优选地,所述的EGFR突变导致的癌症为带有T790M突变、L858R突变或L858R/T790M双突变的癌症。
6.下列化合物或其药学可接受的盐、异构体或溶剂化物,
7.如权利要求6所述的化合物或其药学可接受的盐、异构体或溶剂化物在制备作为EGFR抑制剂或用于治疗EGFR激酶介导的癌症的药物中的用途。
8.如权利要求7所述的用途,其中所述的EGFR激酶介导的癌症为EGFR突变导致的癌症,
优选地,所述的EGFR激酶介导的癌症选自:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、组织细胞性淋巴癌和鼻咽癌,或者
优选地,所述的EGFR突变导致的癌症为带有T790M突变、L858R突变或L858R/T790M双突变的癌症。
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