CN114805316B - 二酮氮杂环化合物或其可药用的盐、互变异构体及其制备方法、药物组合物及应用 - Google Patents
二酮氮杂环化合物或其可药用的盐、互变异构体及其制备方法、药物组合物及应用 Download PDFInfo
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- CN114805316B CN114805316B CN202210606356.4A CN202210606356A CN114805316B CN 114805316 B CN114805316 B CN 114805316B CN 202210606356 A CN202210606356 A CN 202210606356A CN 114805316 B CN114805316 B CN 114805316B
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Abstract
本发明公开了具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体、代谢产物、前药、溶剂合物或水合物,药物组合物和应用;本发明克服了现有广谱抗病毒药物结构单一,非共价、非肽类高效小分子抑制剂缺乏等缺陷,提供了如式I所示化合物,对3C样半胱氨酸蛋白酶具有很好的抑制活性,毒副作用较小且对感染性疾病有良好的治疗作用。
Description
技术领域
本发明属于药物化学领域,涉及一种二酮氮杂环化合物、其制备方法、药物组合物及应用,具体涉及二酮氮杂环化合物或其可药用的盐、互变异构体及其制备方法、药物组合物及应用。
背景技术
SARS-CoV-2是一种高致病性、大规模流行的人畜共患病毒,其与SARS-CoV-1和MERS-CoV同属于冠状病毒科。这三种病毒与其他几种冠状病毒HCoV-NL63、HCoV-229E、HCoV-OC43和HCoVHKU1不同,它们能够导致严重的呼吸道疾病。SARS-CoV-2感染的症状从无症状疾病到中度和重度肺炎,以及危及生命的并发症,包括低氧性呼吸衰竭、急性呼吸窘迫综合征、多系统器官衰竭,并最终出现死亡。更可怕的是,这种病毒不仅具有高度传染性,而且可以通过无症状感染者和那些处于症状期和症状前阶段的人进行传播。尽管目前全球已有多种不同的疫苗被批准上市或者获得紧急使用权,但是全球范围内有相当大的一部分群体由于自身的身体条件或者当地的医疗条件的限制而不能接种疫苗。另外,疫苗对SARS-CoV-2变异株的保护效力减弱,特别是近期席卷全球的Omicron毒株。因而,有效的能够抗击变种的新冠药物研发迫在眉睫。
冠状病毒进入宿主细胞后会被分解释放出核衣壳和病毒基因组。宿主细胞核糖体将病毒基因组的开放阅读框架(ORF)1a和ORF1b分别翻译成多聚蛋白pp1a和pp1b,用于编码16个非结构蛋白(nsps),而其余的ORF编码结构蛋白和附属蛋白。3C样半胱氨酸蛋白酶(3CLpro)和木瓜样半胱氨酸蛋白酶(PLpro)催化PP裂解生成nsp2-16,进而形成复制-转录复合体(RTC)。这些蛋白酶活性缺失会导致病毒生命周期停止。并且,3CLpro的结构和功能在冠状病毒中高度保守。3CLpro催化中心突变率极低,不易产生耐药性;3Clpro抑制剂不依赖于诱导免疫反应,而是通过与病毒的主链结合来阻断病毒复制蛋白酶3CLpro,应该对所有变异株有效。3CLpro只切割谷氨酰胺(Gln)残基后的多肽,目前还没有已知的人类蛋白酶显示出与3CLpro相同的切割特异性,因而3CLpro抑制剂的潜在毒性较低。因此,3CLpro是开发口服抗新冠药物的有效靶点。
目前报道的3CLpro抑制剂包括以辉瑞公司开发的PF-07321332为代表的共价拟肽类抑制剂以及以日本Shiongai(盐野义)制药公司开发的S-217622为代表的非共价、非拟肽类小分子抑制剂。目前,辉瑞的新冠口服药物Paxlovid(主要成分为PF-07321332)获得FDA紧急使用授权,成为美国首个获批的口服新冠药物。中国药监局附加条件批准Paxlovid进口注册,用于治疗伴有进展为重症高风险因素的轻至中度新冠患者。PF-07321332是CYP3A4的底物,存在代谢不稳定性,必须与CYP3A4酶抑制剂利托那韦共同服用。CYP3A4酶的活性发生变化会影响Paxlovid的代谢,从而影响Paxlovid的有效性和安全性。S-217622有望摆脱对P450酶抑制剂(如利托那韦)的依赖,实现单药治疗新冠,将适用人群范围扩展,无需顾忌同时需服用的其他药物因P450酶抑制作用而产生的药理反应。尽管S-217622表现出了治疗新冠的巨大潜力,但是目前报道的非共价小分子抑制剂依然非常匮乏,存在结构单一、酶抑制活性较弱、成药性较差等问题。因此,寻找新型、高效、低毒的3CLpro非共价小分子抑制剂具有重要意义,为不同症状的新冠患者提供了更多、更切合临床实际的药物治疗选择。
发明内容
本发明针对现有技术中广谱抗病毒药物结构单一、非共价类高效3CLpro小分子抑制剂缺乏的问题,提供了一种二酮氮杂环化合物、其制备方法、药物组合物及应用。本发明的二酮氮杂环化合物是一种活性显著的3CLpro非共价小分子抑制剂,且对冠状病毒感染性疾病具有较好的治疗作用。
本发明公开了如通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体、代谢产物、前药、溶剂合物或水合物,其结构如下:
其中,R1为氢、氘、C3-10环烷基、C1-6烷基;
R2为卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基或C1-6卤代烷基;
R3为卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基或C1-6卤代烷基;
L为-NR4-、-NHCO-、-CONH-或-NH-NH-;
R4为氢、未取代或R4-1取代的C1-4烷基;
R4-1为氰基、氨基或羟基;
A为
a端与L相连,b端与相连,c端与/>相连;
当A为L为-NR4-时,R4为未取代或R4-1取代的C1-4烷基。
优选的,具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体、代谢产物、前药、溶剂合物或水合物,在R1为C3-10环烷基时,所述的C3-10环烷基为C3-6环烷基;
和/或,当R1为C1-6烷基时,所述的C1-6烷基为C1-4烷基;
和/或,当R2为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当R2为C1-6烷基时,所述的C1-6烷基为C1-4烷基;
和/或,当R2为C1-6烷氧基时,所述的C1-6烷氧基为C1-4烷氧基;
和/或,当R2为C1-6卤代烷基时,所述的C1-6卤代烷基为C1-4卤代烷基;
和/或,当R2为C1-6卤代烷氧基时,所述的C1-6卤代烷氧基为C1-4卤代烷氧基;
和/或,当R3为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当R3为C1-6烷基时,所述的C1-6烷基为C1-4烷基;
和/或,当R3为C1-6烷氧基时,所述的C1-6烷氧基为C1-4烷氧基;
和/或,当R3为C1-6卤代烷基时,所述的C1-6卤代烷基为C1-4卤代烷基;
和/或,当R3为C1-6卤代烷氧基时,所述的C1-6卤代烷氧基为C1-4卤代烷氧基;
和/或,当R4为未取代或R4-1取代的C1-4烷基时,所述的C1-4烷基为甲基、乙基或丙基;
和/或,当R4为未取代或R4-1取代的C1-4环烷基时,所述的R4-1的个数为一个或多个,当存在多个R4-1时,所述的R4-1可相同或不同。
优选的,R1为C3-10环烷基时,所述的C3-10环烷基为环丙基、环丁基、环戊基或环己基;
和/或,当R1为C1-6烷基时,所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基;
和/或,当R2为C1-6烷基时,所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基;
和/或,当R2为C1-6烷氧基时,所述的C1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基;
和/或,当R2为C1-6卤代烷基时,所述的C1-6卤代烷基为三氟甲基;
和/或,当R2为C1-6卤代烷氧基时,所述的C1-6卤代烷氧基为三氟甲氧基;
和/或,当R3为C1-6烷基时,所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基;
和/或,当R3为C1-6烷氧基时,所述的C1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基;
和/或,当R3为C1-6卤代烷基时,所述的C1-6卤代烷基为三氟甲基;
和/或,当R3为C1-6卤代烷氧基时,所述的C1-6卤代烷氧基为三氟甲氧基;
和/或,当R4为R4-1取代的C1-4烷基时,所述的R4-1取代的C1-4烷基为
优选的,当R1为氢、氘或C1-6烷基;
R2为卤素;
R3为卤素;
L为-NR4-或-NH-NH-;
R4为氢、未取代或R4-1取代的C1-4烷基;
R4-1为氰基或羟基;
A为
a端与L相连,b端与相连,c端与/>相连。
进一步地,如式I所示化合物为以下任一化合物:
本发明还公开了具有通式I所示结构的二酮氮杂环合化合物或其药学上可接受的盐、互变异构体、代谢产物、前药、溶剂合物或水合物制备方法:
包括步骤:在溶剂中,化合物II与化合物III在碱/缩合剂、碱/催化剂/配体或碱的作用下生成化合物I;
其中,X为氨基、羧基、-NH-NH2或-NHR4,Y为卤素或C1-3烷硫基,Y与A的a端相连;R1、R2、R3、R4、L和A如前所述。
上述的反应的条件和操作与本领域该类反应常规的条件和操作相同。
一种药物组合物,含有治疗有效量的具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体、代谢产物、前药、溶剂合物或水合物,及药学上可接受的载体或辅料。
本发明还公开了具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体、代谢产物、前药、溶剂合物或水合物的应用,用于制备3C样半胱氨酸蛋白酶抑制剂;或用于制备治疗和/或预防病毒感染性疾病的药物。
本发明还公开了上述药物组合物的应用,用于制备3C样半胱氨酸蛋白酶抑制剂;或用于制备治疗和/或预防病毒感染性疾病的药物。
进一步地,所述的病毒包括但不限于严重急性呼吸综合征相关冠状病毒-2(SARS-CoV-2)、中东呼吸综合征相关冠状病毒(MERS-CoV)、严重急性呼吸综合征相关冠状病毒(SARS-CoV)、甲型流感病毒、乙型流感病毒、西班牙流感病毒、沙粒病毒、布尼亚病毒、狂犬病毒、禽流感病毒、骨髓灰质炎病毒、鼻病毒、腺病毒、埃博拉病毒、肠病毒、甲型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒、肠病毒、HIV病毒、艾柯病毒、丝状病毒、麻疹病毒、黄热病病毒、日本脑炎病毒、西尼罗河病毒、新城病病毒、RS病毒、水泡性口炎病毒、流行性腮腺炎病毒、登革热病毒、柯萨奇病毒、轮状病毒或烟草花叶病毒。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种:粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药,包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂;气雾剂:如鼻腔喷雾剂或吸入剂;适于胃肠外给药的液体剂型;栓剂以及锭剂。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;有机酸盐还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。优选地,以常规方式使盐与碱或酸接触,再分离母体化合物,由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。
本发明的“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体,比如烯胺和亚胺之间的互变:
术语“代谢产物”是指式I所示化合物或其盐通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化、酶促裂解等产生。因此,本发明包括本发明的化合物的代谢产物,包括使本发明的化合物与哺乳动物接触足够得到其代谢产物的一段时间的方法而产生的化合物。
代谢产物的鉴定典型地通过制备本发明化合物的放射性标记的同位素、将其以可检测的剂量(例如,大于约0.5mg/kg)非肠道给予动物,例如大鼠、小鼠、豚鼠、猴或人,允许充分的时间以发生代谢(典型地约30秒到30小时)和从尿、血液或其它生物样本分离其转化产物。这些产物容易分离,因为它们是被标记的(其它通过利用能够结合存在于代谢物中的抗原表位的抗体分离)。以常规的方式确定代谢物结构,例如,通过MS,LC/MS或NMR分析。通常,代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方法进行的。只要代谢物产物不是以其它方式在体内不能被发现,否则它们可用于本发明化合物的治疗剂量给药的检定测定法。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式I所示化合物)的任何化合物是在本发明的范围和主旨内的前药。例如,含有羧基的化合物可形成生理上可水解的酯,其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药,这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时,可使用肠胃外给药。
本领域技术人员可以理解,根据本领域中使用的惯例,本申请描述基团的结构式中所使用的是指,相应的基团通过该位点与式I所示化合物中的其它片段、基团进行连接。
本发明中的“取代”可为一个或多个,当存在多个“取代”时,所述的“取代”可为相同或不同。
术语“多个”可以列举例如2个、3个或4个。
术语“卤素”包括氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基及其类似烷基。
术语“烷氧基”是指基团-O-RY,其中,RY为如上文所定义的烷基。
术语“环烷基”是指饱和的单环或多环的烷基。所述的单环环烷基优选具有3~7个环碳原子、更优选3-6个碳原子的单价饱和的环状烷基,例如环丙基、环丁基、环戊基或环己基。所述的多环环烷基的每个环均是饱和的,可为具有4~10个碳原子的二环或三环环烷基。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
有益效果:与现有技术相比,本发明具有如下优点:
(1)本发明的二酮氮杂环化合物对3C样半胱氨酸蛋白酶具有很好的抑制活性,其酶抑制活性测试实验中本发明化合物的半抑制浓度最低可达0.009μM,远低于阳性对照0.028μM;
(2)本发明二酮氮杂环化合物对感染性疾病具有良好的治疗作用,其Vero E6细胞中本发明化合物对病毒感染的抑制活性EC50最低可达0.20μM,明显优于阳性对照0.58μM,在病毒感染小鼠模型中本发明化合物能够抑制病毒滴度至最低检出限;
(3)本发明二酮氮杂环化合物毒副作用较小,对Vero E6细胞的细胞毒IC50大于100μM。
附图说明
图1为本发明实施例38中阳性对照组和化合物S11在小鼠感染模型中的抗感染活性示意图;
图2为本发明实施例38中阳性对照组和化合物S22在小鼠感染模型中的抗感染活性示意图;
图3为本发明实施例38中阳性对照组和化合物S31在小鼠感染模型中的抗感染活性示意图。
具体实施方式
下面结合附图及实施例对本发明作进一步描述。
实施例1
化合物S1的合成:
步骤一:化合物2的合成
将化合物1(15g,98.7mmol)溶于无水DMF(200mL)中,0℃下加入DBU(15.8g,103.6mmol),然后缓慢滴加叔丁基异氰酸酯(7)(10.3g,103.6mmol),滴加完毕后,0℃下反应过夜。次日,向上述反应液中加入DBU(18g,118.4mmol)和CDI(19.2g,118.4mmol),然后转移至室温,搅拌反应6h。将反应液转至0℃,加入稀盐酸淬灭反应,EA萃取(100mL×3),饱和食盐水洗涤(200mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(PE:EA=3:1)得到化合物2(19g,80%)。1H NMR(300MHz,Chloroform-d)δ11.26(s,1H),4.27(q,J=7.1Hz,2H),1.62(s,9H),1.37–1.27(m,3H).
步骤二:化合物3的合成
将化合物2(19g,78.8mmol)溶于乙腈(240mL)中,向上述溶液中加入化合物8(26g,118.8mmol)和K2CO3(16.4g,118.8mol),反应液加热回流反应3h。反应液冷却至室温,抽滤,滤液浓缩,柱层析分离纯化(PE:EA=30:1)得到化合物3(25.8g,85%)。1H NMR(300MHz,Chloroform-d)δ7.30(dtt,J=8.0,5.0,1.0Hz,1H),6.94(td,J=8.1,5.0Hz,1H),5.10(s,2H),4.28(q,J=7.1Hz,2H),1.37(s,9H),1.33(t,J=7.1Hz,3H).
步骤三:化合物4的合成
将化合物3(20g,51.9mmol)溶于TFA(39mL)中,室温下搅拌反应6h,停止搅拌,减压蒸掉TFA,乙醚打浆,抽滤,收集滤饼,真空干燥,制得化合物4(15.4g,90%)。1H NMR(300MHz,Chloroform-d)δ9.22(s,1H),7.32(dtt,J=8.1,5.0,1.0Hz,1H),6.94(td,J=8.0,5.0Hz,1H),5.02(s,2H),4.32(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).
步骤四:化合物5的合成
化合物4(15g,45.6mmol)溶于无水DMF(80mL)中,向上述溶液中加入化合物9(11.4g,68.4mmol)和K2CO3(18.9g,136.8mol),反应液升温至60℃,搅拌反应4h。反应液冷却至室温,加水(100mL)淬灭反应,DCM萃取(100mL×3),合并有机相,饱和食盐水洗涤(200mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(DCM:MeOH=80:1)得到化合物5(7.7g,40%)。
步骤五:化合物6的合成
将化合物5(7.7g,18.2mmol)溶于甲醇中,0℃下加入NaOH水溶液(1M,27.4mmol,27mL),转移至室温搅拌反应5h。将反应液转移至0℃,2N HCl溶液调节pH至2~3,固体析出,抽滤,收集滤饼,真空干燥制得化合物6,无需纯化直接投入下一步反应。
步骤六:化合物S1的合成
将化合物6(6.5g,16.4mmol)溶于无水DMF(30mL)中,向上述溶液中加入化合物10(3.3g,18mmol),HATU(8.2g,21.32mmol)和DIPEA(8.6mL,49.2mmol),室温下搅拌反应过夜。停止反应,向反应液中加水淬灭反应,EA萃取(50mL×3),合并有机相,饱和食盐水洗涤(50mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(DCM:MeOH=100:1)得到化合物S1(6.0g,65%)。1H NMR(500MHz,DMSO-d6,DCl in D2O)δ9.91(s,1H),8.23(s,1H),8.08(d,J=1.5Hz,1H),7.67(d,J=1.8Hz,1H),7.56(s,1H),7.06–6.91(m,2H),5.17(s,2H),5.08(s,2H),4.03(s,3H),3.95(s,3H).m/z(ESI-MS):560.1[M+H]+.
实施例2
化合物S2的合成
步骤一的反应过程和反应条件均同实施例1,只需将化合物1替换成相应的原料化合物11即可,步骤二、步骤三和步骤四按照实施例1中的方法进行。
步骤五:化合物15的合成
将化合物15(10g,24.3mmol)置于封管中,加入氨/甲醇(7M,17mL,121mmol),反应液升温至50℃,搅拌反应过夜。冷却至室温,减压浓缩,乙醚打浆,抽滤,收集滤饼,真空干燥制得化合物16,无需进一步纯化,直接投入下一步反应。
步骤六:化合物S2的合成
反应过程和反应条件均同实施例1,只需将化合物10替换相应的原料化合物17即可。1H NMR(500MHz,DMSO-d6,DCl in D2O)δ8.28–8.23(m,2H),7.77(d,J=1.8Hz,1H),7.56(s,1H),7.50–7.42(m,1H),7.21(s,1H),6.99(td,J=8.0,5.0Hz,1H),5.19(s,2H),5.08(s,2H),4.03(s,3H),3.95(s,3H).m/z(ESI-MS):560.1[M+H]+.
实施例3
化合物S3的合成
将化合物18(675mg,3mmol)溶于无水THF(12mL),氮气保护,0℃下向上述溶液中滴加LiHMDS(1M,4.5mL,4.5mmol),然后将化合物15(824mg,2mmol)的THF溶液缓慢滴加至上述溶液中,0℃下反应2h,转移至室温反应1h。然后,将反应液转移至0℃,加入饱和氯化铵溶液淬灭反应,EA萃取(10mL×3),饱和食盐水洗涤(10mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(DCM:MeOH=20:1)得到化合物S3(288mg,25%)。1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.27(s,1H),8.00(d,J=1.5Hz,1H),7.69(d,J=1.4Hz,1H),7.46(s,1H),7.13(dtt,J=8.0,5.0,1.0Hz,1H),6.96(td,J=7.9,5.0Hz,1H),5.05(d,J=1.1Hz,2H),4.68(d,J=12.5Hz,1H),4.44(t,J=7.3Hz,1H),4.37–4.26(m,3H),4.02(s,3H),3.94(s,3H),3.88(q,J=6.9Hz,2H).m/z(ESI-MS):576.2[M+H]+.
以下实施例4~实施例10中的化合物S4~S10的合成参照实施例3的合成方法,只需更换相应的原料即可。
实施例4
化合物S4的合成
1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.22(s,1H),8.00(d,J=1.5Hz,1H),7.78(d,J=1.5Hz,1H),7.46(s,1H),7.37(dtt,J=8.0,5.0,1.0Hz,1H),6.96(td,J=8.0,4.9Hz,1H),5.04(d,J=1.1Hz,2H),4.68(d,J=12.5Hz,1H),4.49(t,J=5.5Hz,2H),4.30(d,J=12.6Hz,1H),4.03(s,3H),3.96(s,3H),2.87(t,J=5.5Hz,2H).m/z(ESI-MS):585.2[M+H]+.
实施例5
化合物S5的合成
1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.23(s,1H),8.01(dd,J=15.9,1.6Hz,2H),7.59(s,1H),7.38(dtt,J=7.9,4.9,1.0Hz,1H),6.98(td,J=8.0,5.0Hz,1H),5.05(d,J=1.1Hz,2H),4.97(s,2H),4.68(d,J=12.5Hz,1H),4.30(d,J=12.6Hz,1H),4.03(s,3H),3.95(s,3H)..m/z(ESI-MS):571.2[M+H]+.
实施例6
化合物S6的合成
1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.15(s,1H),7.98(d,J=1.5Hz,1H),7.77(d,J=1.7Hz,1H),7.45(dtt,J=8.0,5.0,1.1Hz,1H),7.30(s,1H),6.91(td,J=8.0,5.0Hz,1H),5.07(d,J=0.9Hz,2H),4.68(d,J=12.5Hz,1H),4.30(d,J=12.6Hz,1H),4.03(s,3H),3.95(s,3H),3.73(s,3H).m/z(ESI-MS):546.2[M+H]+.
实施例7
化合物S7的合成
1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.20(s,1H),8.02(s,1H),7.89(d,J=1.8Hz,1H),7.53(d,J=1.5Hz,1H),7.43(s,1H),7.18(dtt,J=8.0,4.9,1.1Hz,1H),6.97–6.89(m,2H),4.99(d,J=1.1Hz,2H),4.68(d,J=12.5Hz,1H),4.30(d,J=12.6Hz,1H),4.02(s,3H),3.95(s,3H).m/z(ESI-MS):547.2[M+H]+.
实施例8
化合物S8的合成
1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.22(s,1H),8.03(s,1H),7.88(d,J=1.5Hz,1H),7.57(dd,J=5.0,1.5Hz,1H),7.51(tt,J=5.0,1.0Hz,1H),7.00(d,J=8.0Hz,1H),6.93(t,J=8.0Hz,1H),6.19(d,J=6.6Hz,1H),5.00(d,J=1.1Hz,2H),4.68(d,J=12.5Hz,1H),4.30(d,J=12.6Hz,1H),4.02(s,3H),3.95(s,3H).m/z(ESI-MS):547.2[M+H]+.
实施例9
化合物S9的合成
1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.16(s,1H),8.05(d,J=1.4Hz,1H),7.75(d,J=1.3Hz,1H),7.52(s,1H),7.20(dtd,J=7.9,5.0,1.0Hz,1H),7.01(td,J=8.0,5.0Hz,1H),6.41(qd,J=6.2,1.0Hz,1H),5.02(s,1H),4.68(d,J=1.1Hz,2H),4.03(s,3H),3.95(s,3H),1.57(d,J=6.2Hz,3H).m/z(ESI-MS):546.2[M+H]+.
实施例10
化合物S10的合成
1H NMR(500MHz,500MHz,DMSO-d6,DCl in D2O)δ8.11(s,1H),8.06(d,J=1.5Hz,1H),7.75(d,J=1.4Hz,1H),7.52(s,1H),7.41(dtd,J=8.1,5.1,1.0Hz,1H),6.94(td,J=8.0,5.0Hz,1H),6.50(s,1H),5.34(dd,J=6.0,1.1Hz,1H),4.69(d,J=12.4Hz,1H),4.30(d,J=12.6Hz,1H),4.03(s,3H),3.95(s,3H),1.76(q,J=6.0Hz,1H),1.17–1.07(m,2H),0.87–0.78(m,2H).m/z(ESI-MS):572.1[M+H]+.
实施例11
化合物S11的合成
步骤一:化合物20的合成
将化合物19(5g,34.5mmol)和LiBr(3g,34.5mmol)溶于无水DMF(100mL)中,氮气保护,0℃下向上述溶液中分批加入NaH(60%,1.7g,41.4mmol),0℃下搅拌反应1h。然后将化合物8(8.5g,38mmol)的DMF溶液缓慢滴加至上述混悬液中,滴加完毕,将反应液转至室温,搅拌反应30min。然后,将反应液转移至0℃,稀盐酸淬灭反应,EA萃取(50mL×3),饱和食盐水洗涤(50mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(PE:EA=3:1)得到化合物20(2g,20%)。1H NMR(300MHz,Chloroform-d)δ9.22(s,1H),7.18–7.10(m,1H),6.97(td,J=8.1,5.0Hz,1H),5.69(s,1H),4.97(s,2H).
步骤二:化合物21的合成
将化合物20(2g,6.90mmol)溶于无水DMF(20mL)中,向上述溶液中加入化合物9(1.7g,10.4mmol)和K2CO3(1.4g,10.4mol),反应液升温至60℃,搅拌反应4h。反应液冷却至室温,加水(20mL)淬灭反应,DCM萃取(20mL×3),合并有机相,饱和食盐水洗涤(20mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(DCM:MeOH=50:1)得到化合物21(1.2g,45%)。1HNMR(500MHz,Chloroform-d)δ8.27(s,1H),7.13(dtt,J=8.0,4.9,1.0Hz,1H),6.96(td,J=8.0,5.0Hz,1H),5.67(s,1H),4.97(s,2H),4.63(s,2H),4.06(s,3H).
步骤三:化合物S11的合成
将化合物21(363mg,0.943mmol)溶于无水1,4-二氧六环(5mL),向上述溶液中加入化合物10(mg,1.41mmol),Pd(OAc)2(21mg,0.094mmol),xantphos(82.0mg,0.141mmol)和CsCO3(430mg,1.32mmol),反应液加热回流反应1h。冷却至室温,减压浓缩,柱层析分离纯化(DCM:MeOH=30:1)得到化合物S11(425mg,85%)。1H NMR(500MHz,DMSO-d6)δ9.32(s,1H),8.52(d,J=1.4Hz,1H),8.21(s,1H),8.01(d,J=1.7Hz,1H),7.52(s,1H),7.35(dtt,J=8.0,5.1,1.0Hz,1H),6.98(td,J=7.9,5.0Hz,1H),5.17(s,2H),5.01(d,J=1.1Hz,2H),4.64(s,1H),4.02(s,3H),3.93(s,3H).m/z(ESI-MS):531.1[M+H]+.
以下实施例12~21中的化合物S12~S21的合成参照实施例11的合成方法,只需更换相应的原料即可。
实施例12
化合物S12的合成
1H NMR(500MHz,DMSO-d6)δ8.50(d,J=1.6Hz,1H),8.23(s,1H),8.16(s,1H),7.83(d,J=1.5Hz,1H),7.27–7.18(m,2H),6.97(td,J=8.0,4.9Hz,1H),5.13(s,2H),5.01(d,J=0.9Hz,2H),4.62(s,1H),4.03(s,3H),3.96(s,3H).m/z(ESI-MS):581.2[M+H]+.
实施例13
化合物S13的合成
1H NMR(500MHz,DMSO-d6)δ9.07(s,1H),8.38(dd,J=5.1,1.5Hz,1H),8.21(s,1H),8.01(d,J=1.6Hz,1H),7.61(tt,J=5.0,1.0Hz,1H),7.17(d,J=8.1Hz,1H),6.96(t,J=8.0Hz,1H),5.16(s,2H),5.01(d,J=0.9Hz,2H),4.64(s,1H),4.02(s,3H),3.95(s,3H).m/z(ESI-MS):531.2[M+H]+.
实施例14
化合物S14的合成
1H NMR(500MHz,DMSO-d6)δ8.80(s,1H),8.52(d,J=1.4Hz,1H),8.17(s,1H),8.01(d,J=1.7Hz,1H),7.51(s,1H),7.25–7.18(m,1H),6.74(t,J=8.0Hz,1H),5.17(s,2H),4.94(d,J=0.9Hz,2H),4.61(s,1H),4.02(s,3H),3.92(s,3H),2.25(s,3H).m/z(ESI-MS):527.2[M+H]+.
实施例15
化合物S15的合成
1H NMR(500MHz,DMSO-d6)δ9.08(s,1H),8.62(d,J=1.4Hz,1H),8.20(s,1H),7.97(d,J=1.5Hz,1H),7.67(s,1H),7.32(dt,J=4.9,1.0Hz,1H),7.25(d,J=8.1Hz,1H),5.20(s,2H),4.97(d,J=1.1Hz,2H),4.62(s,1H),4.03(s,3H),3.95(s,3H).m/z(ESI-MS):597.2[M+H]+.
实施例16
化合物S16的合成
1H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.17(s,1H),7.98(d,J=1.8Hz,1H),7.51(s,1H),7.20–7.12(m,2H),7.00(td,J=8.1,5.0Hz,1H),6.36(qd,J=6.2,1.0Hz,1H),5.20(s,1H),4.70–4.60(m,2H),4.03(s,1H),3.94(s,3H),1.51(d,J=6.2Hz,3H).m/z(ESI-MS):545.2[M+H]+.
实施例17
化合物S17的合成
1H NMR(500MHz,DMSO-d6)δ8.17(s,1H),7.98(d,J=1.8Hz,1H),7.52(s,1H),7.37(m,2H),7.04(d,J=1.5Hz,1H),6.97(td,J=8.0,4.9Hz,1H),5.17(s,1H),4.63(d,J=2.5Hz,2H),4.03(s,1H),3.95(s,3H),1.88(h,J=6.0Hz,1H),1.17–1.07(m,2H),0.81–0.72(m,2H)..m/z(ESI-MS):571.2[M+H]+.
实施例18
化合物S18的合成
1H NMR(500MHz,DMSO-d6)δ8.17(s,1H),7.98(d,J=1.8Hz,1H),7.52(s,1H),7.37(m,2H),7.04(d,J=1.5Hz,1H),6.97(td,J=8.0,4.9Hz,1H),5.17(s,1H),4.63(d,J=2.5Hz,2H),4.03(s,1H),3.95(s,3H),1.88(h,J=6.0Hz,1H),1.17–1.07(m,2H),0.81–0.72(m,2H)..m/z(ESI-MS):607.2[M+H]+.
实施例19
化合物S19的合成
1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.99(d,J=1.5Hz,1H),7.87(d,J=1.4Hz,1H),7.47(s,1H),7.27(d,J=8.0Hz,1H),7.10(dt,J=5.0,1.0Hz,1H),6.21(s,1H),5.11(s,2H),5.04(d,J=1.1Hz,2H),4.32(t,J=7.3Hz,1H),4.13(t,J=6.8Hz,2H),4.03(s,3H),3.94(s,3H),3.87(q,J=6.9Hz,2H).m/z(ESI-MS):607.2[M+H]+.
实施例20
化合物S20的合成
1H NMR(500MHz,DMSO-d6)δ8.59(d,J=6.6Hz,1H),8.29(s,1H),7.89(d,J=1.8Hz,1H),7.63(d,J=1.5Hz,1H),7.48–7.39(m,2H),6.98(td,J=8.1,5.0Hz,1H),6.49(d,J=6.6Hz,1H),5.35(s,2H),4.94(d,J=0.9Hz,2H),4.62(s,1H),4.03(s,3H),3.95(s,3H).m/z(ESI-MS):546.2[M+H]+.
实施例21
化合物S21的合成
1H NMR(500MHz,DMSO-d6)δ8.58(d,J=6.6Hz,1H),8.27(s,1H),7.90(d,J=1.6Hz,1H),7.68(s,1H),7.58(d,J=1.7Hz,1H),7.03(dtt,J=8.1,5.0,1.0Hz,1H),6.96(td,J=8.1,5.0Hz,1H),5.80(s,2H),5.35(s,2H),4.96(d,J=0.9Hz,1H),4.62(s,1H),4.03(s,3H),3.95(s,3H).m/z(ESI-MS):580.2[M+H]+.
实施例22
化合物S22的合成
步骤一:化合物23的合成
将化合物22(11.2mL,98.4mmol)溶于无水THF(100mL),氮气保护,-78℃向上述溶液中缓慢滴加LDA(1M,1mL,98.4mmol),滴加完毕后,继续搅拌反应30min。然后,向上述溶液中滴加化合物8(26.3g,118.1mmol),转移至室温搅拌反应3h。将反应液转移至0℃,加入饱和氯化铵溶液淬灭反应,DCM萃取(20mL×3),合并有机相,饱和食盐水洗涤(20mL),无水Na2SO4干燥,过滤,浓缩,真空干燥制得化合物23,无需纯化直接投入下一步反应。
步骤二:化合物24的合成
将脲27(4.3g,72.5mmol)溶于无水甲醇(150ml)中,氮气保护,0℃下将化合物23(20g,72.5mmol)的甲醇溶液缓慢滴加至上述溶液中,滴加完毕后,反应液加热回流,搅拌反应24h。待反应完全后,向上述溶液中加入热水和稀盐酸,然后将反应液转移至0℃,搅拌过夜。次日,抽滤,冰水洗涤,收集滤饼,真空干燥,制得化合物24(11.04g,56%)。1H NMR(300MHz,DMSO-d6)δ8.13(s,2H),7.11(dtt,J=8.1,5.0,1.0Hz,1H),6.93(td,J=8.0,5.0Hz,1H),3.90(t,J=8.5Hz,1H),3.42(dd,J=8.5,1.1Hz,2H).
步骤三:化合物25的合成
将化合物24(11g,40.6mmol)溶于无水DMF(80mL)中,向上述溶液中加入K2CO3(8.4g,60.9mmol)和化合物9(7.5g,44.7mmol),反应液加热至50℃,搅拌反应4h。冷却至室温,加入水淬灭反应,EA萃取(50mL×3),饱和食盐水洗涤(50mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(DCM:MeOH=40:1)得到化合物25(6.7g,45%)。1H NMR(300MHz,DMSO-d6)δ8.21(d,J=8.4Hz,2H),7.01(dtt,J=8.0,4.9,1.0Hz,1H),6.87(td,J=8.0,5.0Hz,1H),5.02(d,J=12.4Hz,2H),4.86(d,J=12.5Hz,1H),4.01(s,2H),3.85(t,J=8.5Hz,1H),3.46(ddd,J=13.9,8.4,0.9Hz,1H),3.26(ddd,J=14.1,8.5,1.1Hz,1H).
步骤四:化合物26的合成
将化合物25(6.7g,18.3mmol)和BTAC(366mg,3.66mmol)混悬于POCl3(4.3mL,45.8mmol)中,氮气保护下将反应液升温至50℃,搅拌反应过夜。冷却至室温,减压浓缩。然后,在0℃下向所得的残渣中缓慢加入冰渣,将最后的泥浆状液体至于0℃下静置8h。抽滤,冰水洗涤,收集滤饼,真空干燥,制得化合物26(3.5g,50%)。1H NMR(300MHz,DMSO-d6)δ8.26(s,2H),7.20(dtt,J=8.0,5.0,1.0Hz,1H),6.95(td,J=8.0,5.0Hz,1H),4.63(s,2H),4.06(s,2H),3.85(d,J=0.9Hz,3H).
步骤五:化合物S22的合成
将化合物26(363mg,0.943mmol)溶于无水1,4-二氧六环(5mL),向上述溶液中加入化合物10(mg,1.41mmol),Pd(OAc)2(21mg,0.094mmol),xantphos(82.0mg,0.141mmol)和CsCO3(430mg,1.32mmol),反应液加热回流反应1h。冷却至室温,减压浓缩,柱层析分离纯化(DCM:MeOH=30:1)得到化合物S22(375mg,75%)。1H NMR(500MHz,DMSO-d6)δ8.55(d,J=1.4Hz,2H),8.17(s,1H),8.01(d,J=1.7Hz,1H),7.53(s,1H),7.22(dtt,J=8.0,4.9,1.0Hz,2H),6.97(td,J=8.0,5.0Hz,1H),4.61(s,2H),4.02(s,2H),3.93(s,3H),3.78(d,J=1.1Hz,3H).m/z(ESI-MS):531.1[M+H]+.
以下实施例23~30中的化合物S23~S30的合成参照实施例22的合成方法,只需更换相应的原料即可。
实施例23
化合物S23的合成
1H NMR(500MHz,DMSO-d6)δ8.57(dd,J=4.9,1.6Hz,2H),8.17(s,1H),8.01(d,J=1.8Hz,1H),7.55(tt,J=5.0,1.0Hz,1H),7.17(d,J=8.1Hz,1H),6.98(t,J=8.0Hz,2H),4.61(s,2H),4.02(s,3H),3.95(s,3H),3.79(d,J=1.1Hz,2H).m/z(ESI-MS):531.2[M+H]+.
实施例24
化合物S24的合成
1H NMR(500MHz,DMSO-d6)δ8.57(dd,J=4.9,1.6Hz,1H),8.22(s,1H),8.01(d,J=1.8Hz,1H),7.29–7.20(m,3H),7.17(d,J=8.1Hz,2H),4.25(s,2H),4.02(s,3H),3.94(s,3H),3.68(d,J=1.1Hz,2H).m/z(ESI-MS):531.2[M+H]+.
实施例25
化合物S25的合成
1H NMR(500MHz,DMSO-d6)δ8.64(d,J=1.4Hz,1H),8.20(s,1H),7.97(d,J=1.5Hz,1H),7.67(s,1H),7.21(dtt,J=8.0,4.9,1.0Hz,2H),6.98(td,J=8.0,5.0Hz,2H),4.61(s,2H),4.03(s,2H),3.95(s,3H),3.74(d,J=0.9Hz,3H).m/z(ESI-MS):565.2[M+H]+.
实施例26
化合物S26的合成
1H NMR(500MHz,DMSO-d6)δ9.95(d,J=6.6Hz,2H),9.73(s,1H),8.17(s,1H),7.89(d,J=1.8Hz,1H),7.53(d,J=1.7Hz,1H),7.46(s,1H),7.33(dtd,J=7.9,5.0,1.0Hz,1H),6.93(td,J=7.9,5.0Hz,1H),6.74(d,J=6.6Hz,1H),4.31–4.21(m,3H),4.02(s,2H),3.95(s,3H),1.51(d,J=7.0Hz,3H).m/z(ESI-MS):560.2[M+H]+.
实施例27
化合物S27的合成
1H NMR(500MHz,DMSO-d6)δ8.16(s,1H),7.89(d,J=1.8Hz,1H),7.53(d,J=1.7Hz,1H),7.46(s,1H),7.23(dtt,J=8.0,5.1,1.0Hz,1H),6.98(td,J=8.1,5.0Hz,2H),6.83(d,J=6.6Hz,2H),4.25(s,2H),4.03(s,3H),3.95(s,3H),3.69(d,J=0.9Hz,2H).m/z(ESI-MS):546.2[M+H]+.
实施例28
化合物S28的合成
1H NMR(500MHz,DMSO-d6)δ9.85(s,1H),8.22(s,1H),7.99(d,J=1.5Hz,1H),7.85(d,J=1.4Hz,1H),7.47(s,1H),7.06(dtt,J=8.0,4.9,1.0Hz,1H),6.98(td,J=8.1,5.0Hz,1H),4.32(t,J=7.3Hz,2H),4.26(s,2H),4.17(t,J=6.8Hz,2H),4.03(s,2H),3.94(s,3H),3.85(q,J=6.9Hz,2H),3.78(d,J=1.1Hz,2H).m/z(ESI-MS):575.2[M+H]+.
实施例29
化合物S29的合成
1H NMR(500MHz,DMSO-d6)δ8.55(d,J=1.5Hz,1H),8.17(s,1H),7.98(d,J=1.7Hz,1H),7.53(s,1H),7.33(dtd,J=7.9,4.9,1.0Hz,2H),6.99(td,J=8.1,5.0Hz,2H),4.62(d,J=2.9Hz,2H),4.45(qd,J=6.9,1.0Hz,1H),4.03(s,2H),3.94(s,3H),1.48(d,J=6.8Hz,3H).m/z(ESI-MS):545.2[M+H]+.
实施例30
化合物S30的合成
1H NMR(500MHz,DMSO-d6)δ8.53(d,J=1.5Hz,1H),8.18(s,1H),7.98(d,J=1.5Hz,1H),7.51(s,1H),7.39(dtd,J=8.1,5.1,1.1Hz,2H),6.98(td,J=8.0,5.0Hz,2H),4.25(s,2H),4.03(s,2H),3.94(s,3H),3.58(dd,J=6.7,1.0Hz,1H),1.96(dt,J=6.7,5.9Hz,1H),1.26–1.12(m,5H).m/z(ESI-MS):571.2[M+H]+.
实施例31
化合物S31的合成
步骤一:化合物28的合成
将化合物27(14.5g,100mmol)溶于无水DMF(200mL)中,向上述溶液中加入CsCO3(49g,150mmol)和化合物8(24.8g,110mmol),反应液升温至50℃,搅拌反应5h。待反应液冷却至室温,加水淬灭反应,DCM萃取(200mL×3),合并有机相,饱和食盐水洗涤(200mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(PE:EA=3:1)得到化合物28(13.1g,45%)。1H NMR(500MHz,Chloroform-d)δ7.10(dtt,J=8.1,5.0,1.0Hz,1H),6.96(td,J=8.0,5.0Hz,1H),5.37(d,J=0.9Hz,2H),3.77(s,2H).
步骤二:化合物29的合成
将化合物28(10g,34.5mmol)溶于无水DMF(90mL)中,0℃下向上述溶液中分批加入NaH(1.5g,37.9mmol),维持0℃搅拌反应1h,然后将化合物9(6.3g,37.9mmol)的DMF溶液缓慢滴加至上述溶液中,滴加完毕后,将反应液转移至室温,搅拌反应6h。停止反应,将反应液转移至0℃,加入饱和氯化铵淬灭反应,DCM萃取(100mL×3),合并有机相,饱和食盐水洗涤(100mL),无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(DCM:MeOH=30:1)得到化合物29(8.6g,65%)。1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.28(dtt,J=8.0,4.9,1.0Hz,1H),6.96(td,J=8.0,5.0Hz,1H),5.21(dd,J=13.4,1.1Hz,1H),5.00(dd,J=13.4,0.9Hz,1H),4.08(s,2H),3.68(t,J=8.4Hz,2H),3.34(dd,J=13.2,8.4Hz,1H),3.18(dd,J=13.2,8.4Hz,1H).
步骤三:化合物S31的合成
将化合物29(363mg,0.943mmol)溶于无水1,4-二氧六环(5mL),向上述溶液中加入化合物10(mg,1.41mmol),Pd(OAc)2(21mg,0.094mmol),xantphos(82.0mg,0.141mmol)和CsCO3(430mg,1.32mmol),反应液加热回流反应1h。冷却至室温,减压浓缩,柱层析分离纯化(DCM:MeOH=30:1)得到化合物S31(425mg,85%)。1H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.01(dd,J=20.3,1.5Hz,2H),7.54(s,2H),7.27–7.19(m,2H),6.97(td,J=8.0,5.0Hz,1H),5.19(dd,J=13.4,1.1Hz,1H),5.05(dd,J=13.4,0.9Hz,1H),4.11–4.03(m,3H),3.93(s,3H),3.38(dd,J=13.2,8.6Hz,1H),3.24(dd,J=13.1,8.5Hz,1H).m/z(ESI-MS):531.1[M+H]+.
以下实施例32~35中的化合物S32~S35的合成参照实施31的合成方法进行,只需更换相应的原料即可。
实施例32
化合物S32的合成
1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.01(d,J=1.5Hz,1H),7.91(d,J=1.8Hz,1H),7.48(s,1H),7.29(dtt,J=8.0,5.1,1.0Hz,1H),6.98(td,J=8.1,5.0Hz,1H),5.20(dd,J=13.4,0.9Hz,1H),5.01(dd,J=13.4,1.1Hz,2H),4.60(t,J=7.3Hz,1H),4.44(dt,J=12.6,6.8Hz,1H),4.24(dt,J=12.6,6.8Hz,1H),4.06(s,2H),3.95(s,3H),4.00–3.81(m,3H),3.46(dd,J=13.2,8.4Hz,1H),3.29(dd,J=13.2,8.4Hz,1H)..m/z(ESI-MS):575.2[M+H]+.
实施例33
化合物S33的合成
1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.01(d,J=1.5Hz,1H),7.91(d,J=1.8Hz,1H),7.48(s,1H),7.29(dtt,J=8.0,5.1,1.0Hz,1H),6.98(td,J=8.1,5.0Hz,1H),5.20(dd,J=13.4,0.9Hz,1H),5.01(s,2H),4.06(s,2H),3.95(s,3H),4.00–3.81(m,3H),3.46(dd,J=13.2,8.4Hz,1H),3.29(dd,J=13.2,8.4Hz,1H).m/z(ESI-MS):546.2[M+H]+.
实施例34
化合物S34的合成
1H NMR(500MHz,DMSO-d6)δ8.24(s,2H),8.06(d,J=1.6Hz,1H),7.98(d,J=1.6Hz,1H),7.52(s,2H),7.12(dtd,J=7.9,5.0,1.0Hz,1H),6.98(td,J=8.0,5.0Hz,1H),5.97(qd,J=6.2,1.0Hz,1H),4.15–4.05(m,3H),3.95(s,3H),3.46(dd,J=13.2,8.6Hz,1H),3.25(dd,J=13.1,8.5Hz,1H),1.47(d,J=6.2Hz,3H).m/z(ESI-MS):545.2[M+H]+.
实施例35
化合物S35的合成
1H NMR(500MHz,DMSO-d6)δ8.25(s,2H),8.06(d,J=1.6Hz,1H),7.98(d,J=1.6Hz,1H),7.52(s,1H),7.17(dtd,J=7.9,4.9,1.0Hz,2H),6.97(td,J=8.0,5.0Hz,1H),5.58(dd,J=6.0,0.9Hz,1H),4.14–4.04(m,3H),3.95(s,3H),3.41(dd,J=13.1,8.5Hz,1H),3.24(dd,J=13.1,8.5Hz,1H),1.90(p,J=6.0Hz,1H),1.12(ddd,J=10.5,9.8,5.8Hz,2H),0.81(ddd,J=10.1,9.6,5.7Hz,2H).m/z(ESI-MS):571.2[M+H]+.
实施例36
SARS-CoV-2病毒3C样半胱氨酸蛋白酶(3CLpro)酶抑制活性测试实验
1.3CLpro蛋白表达与纯化
将全长3CLpro蛋白的基因序列构建在表达载体pET28a(+)载体中并转入大肠杆菌BL21(DE3)感受态细胞,在终浓度0.5mM IPTG,25℃条件下诱导12小时后用Ni-NTA柱纯化。纯化得到的蛋白经SDS检测,纯度大于90%的部分用于进一步用GE蛋白质层析纯化系统AKTA Pure的Superdex 200 10/300GL纯化,得到纯度大于95%的蛋白,使用Nano Drop测定蛋白浓度,分装并液氮速冻后放入-80℃保存。
2.SARS-CoV-2 3CLpro酶活筛选体系的建立与抑制剂抑制率及药物IC50的计算
通过荧光共振能量转移(FRET)技术测定SARS-CoV-2 3CLpro活性及化合物对SARS-CoV-2 3CLpro的抑制活性。测定试验中使用带有SARS-CoV-2 3CLpro切割位点(箭头所示)的荧光底物(Dabcyl-KTSAVLQ↓SGFRKM-E(Edans)-NH2)和Tris-HCl缓冲液(20mMTris-HCl,150mM NaCl,10mM EDTA,pH 7.5)。化合物由100%DMSO溶解。10μl化合物与40μlSARS-CoV-2 3CLpro(终浓度0.5μM,Tris-HCl缓冲液稀释)在25℃孵育10min,通过添加50μl荧光底物(终浓度20μM)引发反应。使用放射共振能量转移荧光分光光度计在340nm激发波长和490nm吸收波长下检测由于3CLpro催化的底物裂解而产生的Dabcyl荧光信号。SARS-CoV-2 3CLpro动力学常数(Vmax和Km)是通过将数据拟合到Michaelis Menten方程中得出的,V=Vmax×[S]/(Km+[S])。然后根据公式kcat=Vmax/[E],计算kcat。使用Tris-HCl缓冲液将化合物按倍数稀释法进行梯度稀释,并使用上述相同终浓度的SARS-CoV-2 3CLpro和荧光底物体系进行测定。分别在存在和不存在目标化合物的情况下,确定3CLpro催化多肽底物水解的内在(V0i)和表观(Vappi,Kappi)催化参数的值。目标化合物与Mpro结合的表观抑制常数(Kappi)由Vappi对固定底物浓度([S])下抑制剂浓度([I])的依赖性根据方程Vappi=Vapp×[I]/(Kappi+[I])得出。目标化合物与3CLpro结合的内在抑制常数(Ki)的值根据方程Kappi=Ki×(1+[S]/Km)计算得出。化合物的抑制曲线由GraphPad Prism 8.0软件绘制并计算IC50值。的抑制其结活果性,如下活表性优1于所阳示,性对实照施S例-2化17合62物2。对SARS-CoV-2病毒3CLpro具有较好
表1、SARS-CoV-2病毒3CLpro酶抑制活性
实施例37
细胞毒性以及抗SARS-CoV-2病毒感染药效测试实验
Vero E6细胞毒性测试:采用CCK8法检测待测化合物对哺乳动物Vero E6细胞中的细胞毒性。Vero E6细胞加入到96孔板中,培养过夜。然后,细胞与不同浓度的待测化合物共孵育48h。除掉孔板中的培养基,换成新鲜无血清的培养基,加入10%CCK8试剂,再在37℃孵育1h,随后采用酶标仪检测450nm处吸光度值。
筛选无细胞毒性或细胞毒性较小的化合物进行抗病毒感染的测试,具体操作包括以下步骤:
①接种细胞:取处于对数生长期的Vero-E6细胞,吸出培养液,用胰酶消化细胞,细胞计数为:1×106个/mL;取上述细胞4mL,加入培养基6mL,制备得到细胞密度为4×105个/mL的细胞悬液,接种到96孔板中,每孔100μl,每孔细胞4×104个。②药物预处理细胞:将细胞培养基更换为含有2%FBS的DMEM培养基,加入相应浓度的药物和DMSO,每孔100μl,之后置于37℃培养箱,预处理1h。③病毒感染:取病毒0.3mL,加入45mL培养基,混匀,将病毒稀释至100TCID50/0.05mL;弃去细胞板中的药物培养基垂直悬滴病毒稀释液至96孔板内,加样体积50μl/孔,同时加入相应的药物培养基(含有相应浓度的药物),加样体积50μl/孔,混匀;④孵育:将加好样的细胞培养板在震荡器上混匀,置于37℃培养箱,孵育1h。孵育结束后,吸去接种有细胞的病毒-血清混合液,加入相应浓度的药物和对照组DMSO,加样体积100μl/孔(100TCID50/孔),置于37℃CO2培养箱中培养48h;⑤收集上清液体检测病毒RNA,用4%的多聚甲醛固定染色进行免疫荧光染色分析。
具体实验结果如表2所示,实施例化合物细胞毒性较小,对SARS-CoV-2病毒感染具有较好的抑制活性,优于阳性对照S-217662,且具有较好的选择指数。
表2、待测化合物的细胞毒性和抗SARS-CoV-2病毒感染活性
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实施例38
化合物S11、S22和S31的体内抗感染活性测试
雌性BALB/c小鼠,首先通过腹腔注射氯胺酮/甲苯噻嗪(50mg/kg/5mg/kg)使其麻醉,然后将SARS-CoV-2γ株(1×104TCID50/只)通过鼻内接种构建感染模型,阴性对照组小鼠滴入相同体积的生理盐水。造模成功后,分为空白对照组、S-217622阳性对照组和给药组,每组6只。将化合物S-217622和S11分别混悬于0.5%甲基纤维素,造模成功后立即口服给药一次,12h后给药一次。S11的给药剂量为2mg/kg,8mg/kg,16mg/kg和32mg/kg,S-217622给药剂量为32mg/kg。病毒感染24h后,观察小鼠肺部病毒滴度。
如图1、图2和图3所示,化合物S11、S22和S31给药两次后,相对于空白对照组,显著降低感染小鼠的肺匀浆中的病毒滴度,且呈剂量依赖性。阳性对照S-217622以及化合物S11、S22和S31在16mg/kg和32mg/kg给药剂量下病毒滴度达到最低检出限;由此可以看出,本发明化合物的具有较好的体内抗感染活性,对COVID-19具有较好的治疗作用。
Claims (10)
1.一种具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体,其特征在于,通式I结构如下:
其中,R1为氢、氘、C1-6烷基;
R2为卤素;
R3为卤素;
L为-NR4-或-NH-NH-;
R4为R4-1取代的C1-4烷基;
R4-1为羟基;
a端与L相连,b端与相连,c端与/>相连。
2.根据权利要求1所述的具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体,其特征在于,当R1为C1-6烷基时,所述的C1-6烷基为C1-4烷基;
和/或,当R2为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当R3为卤素时,所述的卤素为氟、氯、溴或碘;
和/或,当R4为R4-1取代的C1-4烷基时,所述的C1-4烷基为甲基、乙基或丙基。
3.根据权利要求1所述的具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体,其特征在于,当R1为C1-6烷基时,所述的C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基;
和/或,当R4为R4-1取代的C1-4烷基时,所述的R4-1取代的C1-4烷基为
4.根据权利要求1所述的具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体,其特征在于,R1为氢、氘或C1-6烷基;
R2为卤素;
R3为卤素;
L为NR4-或-NH-NH-;
R4为R4-1取代的C1-4烷基;
R4-1为羟基;
A为
a端与L相连,b端与相连,c端与/>相连。
5.根据权利要求1所述的具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体,其特征在于,所述的如式I所示化合物为以下任一化合物:
6.一种如权利要求1-5中任一项所述的具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体的制备方法,其特征在于,所述制备方法为,在溶剂中,化合物II与化合物III在碱/缩合剂、碱/催化剂/配体或碱的作用下生成化合物I;
其中,X为氨基、-NH-NH2,Y为卤素或C1-3烷硫基,Y与A的a端相连,R1、R2、R3、R4、L和A如权利要求1-5所述。
7.一种药物组合物,其特征在于,所述药物组合物含有治疗有效量的一种或多种权利要求1-5中任一所述的具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体,及药学上可接受的载体或辅料。
8.一种如权利要求1-5任一项所述具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体的应用,其特征在于,用于制备3C样半胱氨酸蛋白酶抑制剂。
9.一种如权利要求7所述的药物组合物的应用,其特征在于,用于制备3C样半胱氨酸蛋白酶抑制剂。
10.一种权利要求1-5任一项所述具有通式I所示结构的二酮氮杂环化合物或其药学上可接受的盐、互变异构体或权利要求7所述的药物组合物在制备治疗和/或预防病毒感染性疾病的药物中的应用,其特征在于,所述的病毒包括严重急性呼吸综合征相关冠状病毒-2SARS-CoV-2、中东呼吸综合征相关冠状病毒MERS-CoV、严重急性呼吸综合征相关冠状病毒SARS-CoV、甲型流感病毒、乙型流感病毒、肠病毒、柯萨奇病毒。
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