CN116925085A - Irak降解剂及其用途 - Google Patents
Irak降解剂及其用途 Download PDFInfo
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- CN116925085A CN116925085A CN202310910651.3A CN202310910651A CN116925085A CN 116925085 A CN116925085 A CN 116925085A CN 202310910651 A CN202310910651 A CN 202310910651A CN 116925085 A CN116925085 A CN 116925085A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
本发明提供了式I所示的的化合物及其在制备药物中的用途。本发明提供了一种新的具有IRAK4降解作用的化合物,能够有效降解IRAK4或者以其他方式抑制IRAK4的活性。在IRAK4介导的疾病包括免疫性疾病、肿瘤、阿尔茨海默病和纤维化疾病等疾病中具有非常好的应用前景,为临床上筛选和/或制备与IRAK4活性相关的疾病的药物提供了一种新的选择。
Description
技术领域
本发明涉及一类具有IRAK降解作用的化合物及其在制备药物中的用途。
背景技术
蛋白质降解是一种高度受调和必需的维持细胞稳态的进程。泛素-蛋白水解酶复合体通路(Ubiquitin-proteasome pathway,UPP)在体内的作用在于将过量蛋白质的选择性鉴别和去除,并且使错误折叠或异常蛋白质降解。泛素分子通过E3泛素连接酶与末端赖氨酸残基通过共价键进行连接,从而对蛋白质进行标记再通过蛋白酶体进行降解成为小肽,并最终消化成其组成氨基酸,产生的氨基酸再用作新蛋白质的构建模块。UPP在多个细胞过程的占有中心地位,并且如果有缺陷或不平衡,那么其引起多种疾病的发病机理。UPP是调节几乎所有细胞进程的核心,所述细胞进程包括抗原加工、凋亡、细胞器生物发生、细胞周期、DNA转录和修复、分化和发育、免疫反应和炎症、神经和肌肉退化、神经网络的形态发生、细胞表面受体的调节、离子通道和分泌途径、对应激和细胞外调节剂的响应、核糖体生物发生和病毒感染。有缺陷的蛋白酶体降解与多种临床病症有关,所述病症包括阿尔茨海默病、帕金森病、亨廷顿病、肌营养不良、心血管疾病和癌症等。
蛋白降解靶向嵌合体(PROTAC)是一种有效的降解致病蛋白的手段,将与靶蛋白可结合的小分子通过链接部分与E3连接酶包括CRBN、VHL、MDM2、DRAF等可结合的小分子形成异双功能分子,通过模拟泛素-蛋白酶体途径(UPP)将目标蛋白泛素化,从而实现蛋白酶体对目标蛋白的降解。相比小分子抑制剂,蛋白降解靶向嵌合体一个潜在的优势在于其可以除去致病蛋白所有的功能。
目前发现有超过600种E3泛素连接酶促进不同蛋白质的体内泛素化,其可分为四个家:HECT结构域E3家族、U-box E3家族、单体RING E3家族和多亚基E3家族。Cereblon(CRBN)连接酶是PROTAC技术中应用最为广泛的E3连接酶。Cereblon属于Cullin RING E3泛素连接酶,是一种442个氨基酸的蛋白质,形成Cullin-4-RING E3 ubiquitin ligase(CRL4)复合物,并与适配器蛋白受损的DNA结合蛋白1(DDB1)相互作用。在CRL4复合物中,CRBN充当底物特异性受体。已知的CRBN配体包括沙利度胺和其他衍生的免疫调节酰亚胺药物。CRBN与配体结合后,CRBN的E3泛素连接酶活性被重新调节,导致转录因子Ikaros和Aiolos的募集增加,从而引发随后的泛素化和蛋白酶体降解。目前,CRBN作为PROTAC中的E3连接酶,已经成功地用于靶向30多种不同的蛋白质,包括与各种癌症有关的蛋白质(SunX.et al.,2019)、免疫功能紊乱相关蛋白质(Bassi et al.,2018)、神经退行性疾病相关蛋白(Silva et al.,2019)和丙型肝炎病毒蛋白(de Wispelaere et al.,2019)。大多数以CRBN为靶向的PROTAC采用泊马利多明、4-羟基沙利度胺、烷基连接的沙利度胺衍生物或来那度胺的衍生物。然而,开发更优的CRBN配体是可能的。这些全新的CRBN配体将为PROTAC技术的发展提供了更多的选择。
IRAK4属于一种丝氨酸/苏氨酸激酶,是介导白介素-1(IL-1)受体家族(IL-1,IL-18和IL-33受体)和病原体识别Toll样受体(TLR)信号的关键蛋白。研究表明,当识别外来病原体和炎症应激时,在胞外配体作用下,白介素-1受体或TLR受体招募衔接蛋白髓样分化初级反应蛋白(Myd88),进而与IRAK4形成复合物,激活NF-κB轻链增强子和激活蛋白1(AP-1),导致细胞产生各种炎症因子的,如肿瘤坏死因子α(TNFα)、IL-6等,从而诱发各种免疫性疾病,如银屑病、化脓性汗腺炎、特异性皮炎、类风湿性关节炎、系统性红斑狼疮等的发生。此外,IRAK4已被证实与淋巴细胞性白血病和淋巴瘤、阿尔茨海默病、纤维化疾病有关。因此,IRAK4是一个极具吸引力药物开发靶标。
现阶段,各大制药公司相继推进IRAK4小分子抑制剂进入临床,用于血液瘤、银屑病、类风湿性关节、肠炎、系统性红斑狼疮等。其中,辉瑞公司研究的IRAK4抑制剂PF-06650833进入了二期临床研究阶段。早期的临床结果表明,PF-06650833有良好的安全性,药效显示PF-06650833能够抑制IRAK4所介导的炎症通路,这些临床数据充分说明了IRAK4是一个经临床验证的成药靶点,有望治疗多种疾病。
近来研究表明,除了IRAK4的激酶活性介导的炎症信号通路,IRAK4蛋白骨架同样可激活某些炎症信号通路。在人皮肤成纤维细胞中,通过ATP竞争性的小分子抑制IRAK4不能够有效抑制IL-1β刺激下IL-6和TNF-α的释放。此外,IRAK4的敲除可有效去除IL-1、IL-8及TLR配体介导的炎症反应。因此,通过ATP竞争性的小分子抑制剂抑制剂不能够完全去除由IRAK4蛋白介导的炎症信号通路。由此可见,通过小分子抑制剂靶向IRAK4有其治疗局限性。
蛋白降解靶向嵌合体(PROTAC)是一种有效的降解致病蛋白的手段,将与目标蛋白可结合的小分子通过链接部分与E3连接酶包括CRBN、VHL、MDM2、DRAF等可结合的小分子形成异双功能分子,通过模拟泛素-蛋白酶体途径(UPP)将目标蛋白泛素化,从而实现蛋白酶体对目标蛋白的降解。相比小分子抑制剂,蛋白降解靶向嵌合体一个潜在的优势在于其可以除去致病蛋白所有的功能,从而使蛋白降解靶向嵌合体相较于小分子,表现出更为广泛及更加深度的炎症因子抑制,有希望解决小分子有限的临床药效。此外,GSK的科学家证明了将IRAK4小分子抑制剂通过链接片段与E3连接酶CRBN及VHL的配体相结合组成蛋白降解靶向嵌合体(PROTAC)可实现IRAK4蛋白的降解。同时Kymera及Avinas针对IRAK4进行了相应的PROTAC设计。这些新兴的技术为靶向IRAK4提供了一种全新的治疗手段。
发明内容
本发明提供了一种式I所示的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐:
其中,
R1选自-NR1aR1b、4~10元杂环基、5~12元桥杂环基或5~12元螺杂环基,其中所述杂环基、桥杂环基、螺杂环基可任选被一个、两个或三个R11取代;
R1a、R1b分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
每个R11分别独立选自氢、卤素、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-OR12、-C0~2亚烷基-NR12R13、-C0~2亚烷基-C(O)R12、-C0~2亚烷基-NR12C(O)R13、-C0~2亚烷基-C(O)NR12R13、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
R12、R13分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
n1、n2分别独立选自0、1或2;
U选自N或CRU;
RU选自氢或C1~6烷基;
V选自化学键、O、S或CRV1RV2;
RV1、RV2分别独立选自氢或C1~6烷基;
A环选自5元芳杂环、6元芳杂环,其中所述芳杂环可任选被一个、两个或三个RA取代;
每个RA分别独立选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
表示单键或双键;
X选自CRX或NRX;
Y选自N或C(O);
Z选自N或C;
Q选自N或CRQ;
RX选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-ORX1、-C0~2亚烷基-NRX1RX2、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
RX1、RX2分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
RQ选自氢、卤素、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基。
在一些优选的实施方案中,当A环选自5元芳杂环时,Y选自C(O)。
V选自化学键是指U和A环通过化学键直接连接。
表示单键或双键是指本领域技术人员能够根据X、Y、Z自由选择化学上可行的单键或双键。
进一步地,
R1选自-NR1aR1b、5元含氮杂环基、6元含氮杂环基、7元含氮杂环基、8元含氮杂环基、6元含氮桥杂环基、7元含氮桥杂环基、8元含氮桥杂环基、9元含氮桥杂环基、10元含氮桥杂环基、6元含氮螺杂环基、7元含氮螺杂环基、8元含氮螺杂环基、9元含氮螺杂环基或10元含氮螺杂环基,其中所述杂环基、桥杂环基、螺杂环基可任选被一个、两个或三个R11取代。
更进一步地,
R1选自
进一步地,
n1选自0,n2选自1;或n1选自1,n2选自0;或n1选自1,n2选自1;或n1选自2,n2选自1;或n1选自1,n2选自2;
U选自N或CH;
V选自化学键、O或CH2;
Q选自N或CH。
在本发明的一些实施方案中,式I所示的化合物具有式IIa或式IIb所示的结构:
其中,
A环选自6元芳杂环,其中所述芳杂环可任选被一个、两个或三个RA取代;
每个RA分别独立选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
RX选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-ORX1、-C0~2亚烷基-NRX1RX2、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
RX1、RX2分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基。
在本发明的一些实施方案中,进一步地,
A环选自
RX选自氢或C1~6烷基。优选地,RX选自甲基。
在本发明的一些实施方案中,式I所示的化合物具有式III所示的结构:
其中,
A环选自5元芳杂环、6元芳杂环,其中所述芳杂环可任选被一个、两个或三个RA取代;
每个RA分别独立选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
RX选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-ORX1、-C0~2亚烷基-NRX1RX2、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
RX1、RX2分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基。
在本发明的一些实施方案中,进一步地,
A环选自
RX选自氢或C1~6烷基。优选地,RX选自甲基。
在本发明的一些具体实施方案中,所述化合物具体包括:
本发明还提供了任一上述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗和预防白介素-1受体相关激酶4(IRAK4)信号转导通路、白细胞介素-6(IL-6)受体和肿瘤坏死因子α(TNFα)中的一种或多种相关或介导的疾病。本发明的发明人发现,本发明的化合物作为IRAK4降解剂能够有效降解IRAK4,或者有效抑制通路的下游分子白细胞介素-6(IL-6)受体、肿瘤坏死因子α(TNFα)等进而抑制IRAK4。
进一步地,所述的疾病包括癌症、神经退行性疾病、病毒性疾病、自身免疫性疾病、炎性疾病、遗传性疾病、激素相关疾病、代谢紊乱性疾病、与器官移植有关的疾病、免疫缺陷疾病、骨破坏性疾病、增生性疾病、传染病、凝血酶诱导的血小板聚集、肝病、T细胞活化导致的病变、心血管疾病。
本发明还提供了一种药物组合物,包括任一上述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,加上药学上可接受的辅料制备而成的制剂。
本发明的有益效果至少包括:本发明公开的具有IRAK4降解作用的化合物能够有效降解IRAK4或者以其他方式抑制IRAK4的活性。在IRAK4介导的疾病包括免疫性疾病、肿瘤、阿尔茨海默病和纤维化疾病等疾病中具有非常好的应用前景,为临床上筛选和/或制备与IRAK4活性相关的疾病的药物提供了一种新的选择。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,CoLumbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
“可任选被取代”是指“取代”可以但不必须发生,该说明包括发生或不发生的情形。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1~4烷基”是指包含1~4个碳原子的烷基。
本发明中所述的“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C1~6烷基是指具有1至6个成员原子,例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其他基团为例如C1~6烷氧基。
本发明中所述的“亚烷基”是指具有指定数目个碳原子的二价饱和脂族烃基。“Ca~b亚烷基”是指具有a至b个碳原子的亚烷基基团。亚烷基基团包括支链和直链烃基基团。例如,“C1~6亚烷基”意在包括亚甲基、亚乙基、亚丙基、2-甲基亚丙基、二甲基亚乙基、亚戊基等等。因此,术语“亚丙基”可以通过下列结构例举:同样地,术语“二甲基亚丁基”可以例如通过下列结构的任一种例举:/>又例如,“C0亚烷基”意在指此处为化学键,通过化学键直接连接两部分。
本发明中所述的“烯基”是指具有指定数目个碳原子且具有至少1个乙烯基不饱和位点(>C=C<)的直链或支链烃基基团。例如,Ca-b烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
本发明中所述的“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如,C2-6炔基意在包括乙炔基、丙炔基等。
本发明中所述的“化学键”是指该处通过化学单键直接相连;
本发明中所述的“卤素”为氟、氯、溴或碘。
本发明中所述的“卤素烷基”、“卤素取代的烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如C1~4卤素烷基指氢原子被一个或多个卤素原子取代的包含1~4个碳原子的烷基。还例如三氟甲基、二氟甲基等。
本发明中所述的“=O”、“=S”等取代基是指氧原子或硫原子取代两个氢原子以形成双键,或取代孤对电子以形成双键。
本发明中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。
本发明中所述的“-C(O)R”、“-S(O)2R”等中的氧原子是与碳原子或硫原子或磷原子以双键相连,R与碳原子或硫原子以单键相连。本发明中所述的“-C(O)NRR”、“-S(O)2NRR”等中的氧原子是与碳原子或硫原子以双键相连,氮原子与碳原子或硫原子以单键相连,R与氮原子以单键相连。本发明中所述的“-NRC(O)R”、“-NRS(O)2R”等中一个R是与氮原子以单键相连,另一个R是与碳原子或硫原子以单键相连,氮原子与碳原子或硫原子以单键相连,氧原子是与碳原子或硫原子以双键相连。
本发明中所述的“碳环”、“碳环基”是指具有多个碳原子且没有环杂原子且具有单个环或多个环(稠合)的饱和或部分饱和的环状基团。其中,碳原子包含其氧化态,例如C(O)。对于具有不含环杂原子的芳族和非芳族环的多环体系,当连接点位于非芳族碳原子时,适用术语的“碳环”、“碳环基”(例如5,6,7,8,-四氢化萘-5-基)。术语的“碳环”、“碳环基”包括环烯基基团,诸如环己烯基。碳环基基团的实例包括例如,环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双碳环基环体系的碳环基基团的实例是双环己基、双环戊基、双环辛基等。下面例举并命名两种此类双碳环基多环结构:双环己基和/>双环己基。
本发明中所述的“桥环”是指具有多个碳原子且没有环杂原子的多个环桥连形成的饱和或部分饱和的环状基团。术语“桥环”还包括金刚烷体系金刚烷基包括但不限于以下结构
本发明中所述的“杂环”、“杂环基”是指包含至少一个杂原子的且具有单个环或多个环(稠合)的饱和环或非芳香性的不饱和环;其中杂原子指氮原子、氧原子、硫原子等。其中,碳原子、杂原子包含其氧化态,例如C(O)、S(O)、S(O)2等。对于具有含有环杂原子的芳族和非芳族环的多环体系,也适用术语“杂环”、“杂环基”,例如通常表示多个环原子的饱和或部分不饱和单环或二环环系统。单环饱和杂环基的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基、部分不饱和杂环基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基。
本发明中所述的“桥杂环”是指包含至少一个杂原子的多个环桥连形成的饱和或部分饱和的环状基团。
本发明中所述的“芳环”、“芳基”是指具有多个碳原子的芳烃基团。芳基通常包含单环、二环或三环芳基。此外,本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。
本发明中所述的“芳杂环”、“芳杂环基”是指包含至少一个杂原子的芳香性不饱和环;其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂环芳基例如代表:吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明中的术语“本发明的化合物”或“本发明的活性成分”可互换使用,指通式化合物的立体异构体、对映异构体,或其药用盐。该术语还包括外消旋体、光学异构体、同位素化合物(如氘代化合物)或先导物。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-两种几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、氟和氯同位素。本发明中的化合物,或对映体,非对映体,异构体,或药用盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。例如氚,即3H和碳14,即14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用披露在示例中的方案可以制备。在本申请中,术语“药用盐”包括药用酸加成盐。
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗白介素-1受体相关激酶4(IRAK4)信号转导通路、白细胞介素-6(IL-6)受体和肿瘤坏死因子α(TNFα)中的一种或多种相关或介导的疾病。在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。本文所用术语“药用”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药用赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本文所用术语“预防”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
在某些实施方式中,本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
具体实施方式
以下通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例中无特殊说明,反应的温度为室温,室温是指20~25℃。所有温度以℃(摄氏度)表示。
过夜为14±1h。
高效液相色谱(HPLC)测定条件:Waters高压液相色谱仪(e2695/e2487)。分析型高效液相色谱条件:C18柱(3.5μm,4.6x 75mm),紫外检测波段为220和254nm,洗脱条件5-95%乙腈(含0.1%V/V TFA或10mmol NH4CO3)梯度洗10分钟。
反相纯化使用GiLson GX-281反相制备色谱仪或者Biotage IsoLera One快速纯化系统。
NMR的测定是用Bruker AvanceIII 400或600核磁仪,NMR位移(δ)以10-6(ppm)的单位给出。溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCL3)和氘代甲醇(CD3OD)等,内标为四甲基硅烷(TMS)。
本发明的已知的起始原料、试剂和溶剂等可以采用或按照本领域已知的方法来合成,或可购买于成都金山化学试剂有限公司、上海毕得医药科技有限公司和上海泰坦科技股份有限公司等。
本发明的已知的起始原料、试剂和溶剂等可以采用或按照本领域已知的方法来合成,或可购买于成都金山化学试剂有限公司、上海毕得医药科技有限公司和上海泰坦科技股份有限公司等。
在上述讨论和下述实施例中,下列缩写具有如下含义。如果某一缩写没有定义,则它具有通常被接受的含义。MPLC为中压制备色谱;TLC为薄层色谱;MeOH为甲醇;EtOH为乙醇;DMAP是指4-二甲氨基吡啶;DMF为N,N-二甲基甲酰胺;DMA为N,N-二甲基乙酰胺;EA为乙酸乙酯;THF为四氢呋喃;DMSO为二甲基亚砜;DCM为二氯甲烷;DCE为二氯乙烷;MTBE为甲基叔丁基醚;Boc2O为二碳酸二叔丁酯;Boc为叔丁基氧羰基;SEMCl为2-(三甲硅烷基)乙氧甲基氯;SEM为2-(三甲硅烷基)乙氧甲基;CbzCl为苄氧甲酰氯;Cbz为苄氧甲酰基;FmocCl为氯甲酸-9-芴基甲酯;Fmoc为9-芴基甲氧基甲酰基;MsCl为甲磺酰氯;Ms为甲磺酰基;TBSCl为叔丁基二甲基氯硅烷;TBS为叔丁基二甲基氯硅基;TBDPSCl为叔丁基二苯基氯硅烷;TBDPS为叔丁基二苯基硅基;TBAF为四丁基氟化铵;NBS为N-溴代丁二酰亚胺;TFA为三氟乙酸;DBU为1,8-二氮杂二环十一碳-7-烯;DIPEA为N,N-二异丙基乙胺;TEA为三乙胺;HATU为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯;HBTU为2-(苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
实施例
以下是中间体的制备例:
中间体1的合成:叔丁基(3-(二氟甲基)-1-((反式)-4-甲酰基环已基)-1H-吡唑-4-基)氨基甲酸酯
步骤一:中间体1b的合成
化合物1a(850g,3.47mmol)加入至甲醇中,加入1/200的浓硫酸,65℃回流反应12h。反应完全后,加入碳酸钠饱和溶液,调ph至7,过滤浓缩,加入EA 2000mL,饱和盐水萃取三次400mL x 3无水硫酸钠干燥,,浓缩,得到化合物1b(900g),直接投入一步。
步骤二:中间体1c的合成
化合物1b(900g)加入THF(6000mL)中,在-20℃下,少量多次加入氢化锂铝150g。反应完全后,依次加入和氢化锂铝等量水,等量15%氢氧化钠水溶液,3倍量水溶液淬灭,过滤,浓缩,即可得到化合物1c(410g)。
步骤三:中间体1d的合成
冰水浴下,化合物1c(400g)加入DCM(6000mL),化合物4(251g),滴加TBSCl 521g的DCM溶液,常温反应12h,反应完全后,浓缩,加入水(2000mL)洗3次,DCM洗2次水相,饱和盐水1000mL萃取有机相1次,无水硫酸钠干燥,浓缩即可得到化合物1d(737g)。
步骤四:中间体1e的合成
化合物1d(720g,2.95mol)溶于DCM(10L),快速滴加TsCl 940克的二氯甲烷溶液(2eq),慢慢滴加DMAP的DCM溶液,30℃反应12h。反应完全后,加水2L,DCM 2L萃取2次,10%柠檬酸萃取有机相1次,饱和NaHCO3洗1次,饱和盐水洗一次,无水硫酸钠干燥,过滤,浓缩,硅胶柱层析得到化合物6(760g)。
步骤五:中间体1f的合成
3-(二氟甲基)-4-硝基-1H-吡唑(73.64g)加入DMF(1L),碳酸铯(1.4eq),反应10min,加入化合物1e(180g),60℃反应12h,加入水2500mL,石油醚500mL萃取3次,500mL水洗2次,饱和盐水500mL洗石油醚一次,无水硫酸钠干燥,浓缩过层析柱,即可得到化合物1f(52.6g)。
步骤六:中间体1g的合成
化合物8(52.6g),加入甲醇500mL,三乙胺1eq,(Boc)2O(3eq),常温搅拌10min,加入钯碳0.05eq,氢气置换3次,常温反应过夜。反应完全后,过滤浓缩即得化合物9(62g)。
步骤七:中间体1h的合成
化合物1g(62g)加入THF 300mL,冰水浴下,滴加HF.py(2eq),自然回温,搅拌12h。反应完全后,加水和EA萃取3次,饱和碳酸氢钠洗有机相1次,饱和盐水洗有机相一次,无水硫酸钠干燥,浓缩,过层析柱得化合物(39.6g)。ESI-LCMS:m/z 346[M+1],1.45min。
步骤八:叔丁基(3-(二氟甲基)-1-((反式)-4-甲酰基环已基)-1H-吡唑-4-基)氨基甲酸酯1的合成
化合物1h(39.6g)加入DCM 250mL,冰水浴下,少量多次加入DMP(1.3eq),搅拌3h。反应完全后,饱和碳酸氢钠调ph到7,过滤,分液,无水硫酸钠干燥,浓缩,过层析柱得化合物1(31g)。ESI-LCMS:m/z 344[M+1],1.55min。
中间体2的合成:5-吗啉基吡唑并[1,5-a]嘧啶-3-羧酸
步骤一:中间体2b的合成
将5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯(2.25g,10mmol)溶解于10毫升乙腈,然后加入吗啉(1.31g,15mmol)和DIPEA(2.58g,20mmol),然后加热回流2小时。反应完全后,加入10毫升水并析出固体,冷却后过滤,并用水冲洗滤饼,收集固体,烘干得到5-吗啉基吡唑并[1,5-a]嘧啶-3-羧酸乙酯2.55克。LCMS(ESI)m/z:[M+1]=277。
步骤二:中间体2的合成
将5-吗啉基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(2.55g,9.2mmol)溶解于20毫升甲醇,然后加入氢氧化钠(800毫克)的水(10毫升)溶液,室温搅拌16小时。反应完全后,加入1M的稀盐酸将pH值调至5-6左右并有固体析出。减压除去有机溶剂,然后过滤,并用水冲洗固体。收集固体并且烘干得到5-吗啉基吡唑并[1,5-a]嘧啶-3-羧酸2.01克。LCMS(ESI)m/z:[M+1]=249。
中间体3的合成:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)吡唑[1,5-a]嘧啶-3-羧酸
中间体3的制备方法类似于中间体2的制备。
中间体4的合成:5-(1,4-氧氮杂庚烷-4-基)吡唑[1,5-a]嘧啶-3-羧酸
中间体4的制备方法类似于中间体2的制备。
中间体5至7的合成:中间体5至7的制备方法类似于中间体2的制备,编号与结构如表1所示。
表1:中间体5至7的编号与结构
中间体8的合成:3-(4-(6-(4-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)吡啶-3-基)-3-甲基-1H-吲唑-1-基)哌啶-2,6-二酮
步骤一:中间体8c的合成
化合物8a(600mg),化合物8b(870mg)溶于6mL二氧六环与水的混合溶液(10/1,V/V)中,在氮气保护下,相继加入K2CO3(515mg),Pd(dppf)Cl2(136mg),抽真空,转换氮气3遍,加热至95℃,反应至4小时,将反应液过滤,浓缩,分散于5mL乙腈中,加入387mg CDI,加热至回流,反应完毕,浓缩,过柱得8c 400mg。LCMS(ESI)m/z:[M+1]=505.24。
步骤二:中间体8d的合成
化合物8c(400mg,0.794mmol)加入至二氯甲烷(8mL)中,随后加入HCl/dioxane(8mL)室温反应1小时。LCMS监控,浓缩得到化合物5d粗品400mg,LCMS(ESI)m/z:[M+1]=404.46。
步骤三:化合物8e的合成
化合物8d(400mg,0.990mmol)和化合物1(309mg,0.900mmol)以及分子筛(400mg)加入至DMF/THF(1/5)(4mL)中,加入三乙胺(273mg,2.701mmol),冰盐浴,-10℃,搅拌0.5h。加入醋酸(162mg,2.701mmol),醋酸硼氢化钠(573mg,2.701mmol),-10℃,反应3h,LCMS监控,加入水淬灭,过滤,滤液乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,硅胶柱层析(DCM:MeOH=10:1)得到化合物8e(544mg,收率75.17%)。LCMS(ESI)m/z:[M+1]=731.83
步骤四:化合物8的合成
化合物8e(544mg,0.743mmol)加入至二氯甲烷(6mL)中,随后加入HCl/dioxane(6mL),室温搅拌1h。LCMS监控,直接浓缩,得到化合物8粗品LCMS(ESI)m/z:[M+1]=631.72。
中间体9的合成:3-(4-(6-(4-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)嘧啶-5-基)-3-甲基-1H-吲唑-1-基)哌啶-2,6-二酮
中间体9的合成制备方法步骤一到四同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=632.71。
中间体10的合成:3-(4-(6-(4-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)吡啶-3-基)-3-甲基-2-氧杂-2,3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮
中间体10的合成制备方法步骤一到四同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=648.2。
中间体11的合成:3-(4-(1-(1-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌啶-4-基)-1H-吡唑-4-基)-3-甲基-2-氧杂-2.3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮
中间体11的合成制备方法步骤一到四同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=636.2。
中间体12的合成:3-(4-((1-(1-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌啶-4-基)甲基)-1H-吡唑-4-基)-3-甲基-2-氧杂-2.3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮
中间体12的合成制备方法步骤一到四同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=650.3。
中间体13的合成:3-(4-(2-((1-(1-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌啶-4-基)氧基)嘧啶-5-基)-3-甲基-1H-吲唑-1-基)哌啶-2,6-二酮
步骤一:化合物13b的合成
化合物13a(2g)和联硼酸频那醇酯(2.13g)以及醋酸钾(1.1g)加入二氧六环(20mL)中,随后加入Pd(dppf)Cl2(0.204g),氮气保护,85℃反应过夜。LCMS监控,过滤,浓缩滤液,硅胶柱层析(PE:EA=1:1)浓缩得到化合物13b(900mg)。LCMS(ESI)m/z:[M+1]=405.13。
中间体13的合成制备方法步骤二到五同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=647.72。
中间体14的合成:3-(4-(6-((1-(1-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌啶-4-基)氧基)吡啶-3-基)-3-甲基-1H-吲唑-1-基)哌啶-2,6-二酮
步骤一、化合物14b的合成:
化合物14a(5g)和联硼酸频那醇酯(5.1g)以及醋酸钾(2.631g)加入至二氧六环(50mL)中,随后加入Pd(dppf)Cl2(0.490g),氮气保护,85℃反应过夜。LCMS监控,过滤,浓缩滤液,硅胶柱层析(PE:EA=1:1)浓缩得到化合物14b(5.327g)。LCMS(ESI)m/z:[M+1]=404.31。
中间体14的合成制备方法步骤二到五同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=646.73。
中间体15的合成:3-(4-(6-((1-(1-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌啶-4-基)氧基)吡啶-3-基)-3-甲基-2-氧杂-2.3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮
中间体15的合成制备方法步骤一到五同中间体14的合成制备方法步骤一到五。LCMS(ESI)m/z:[M+1]=663.37。
中间体16的合成:3-(5-(6-(4-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)吡啶-3-基)-3-甲基-1H-吲唑-1-基)哌啶-2,6-二酮
中间体16的合成制备方法步骤一到四同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=632.37。
中间体17至19的合成:中间体17至19的制备方法类似于中间体16的制备,编号与结构如表2所示。
表2:中间体17至19的编号与结构
中间体20的合成:1-(7-(6-(4-(((1r,4r)-4-(4-胺基-3-(二氟甲基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)吡啶-3-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2,4-(1H,3H)-二酮
中间体20的合成制备方法步骤一到四同中间体8的合成制备方法步骤一到四。LCMS(ESI)m/z:[M+1]=633.3。
以下是制备本发明化合物的实施例。
实施例一:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)吡啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)-5-吗啉吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-1)
化合物2(92mg)加入至乙腈(2mL)中,加入NMI(94mg),TCFH(121mg),室温下搅拌15分钟,随后加入溶于DMF的化合物8(180mg),室温搅拌过夜。LCMS监控,浓缩,加水析出固体,过滤,固体通过高压反相制备得化合物TM-1(37.87mg)。LCMS(ESI)m/z:[M+1]=862.66;1HNMR(400MHz,DMSO-d6)δ11.08(s,1H),9.40(s,1H),8.83(d,J=7.9Hz,1H),8.39(s,1H),8.29(S,1H),8.2(d,J=2.7Hz,1H),7.66(dd,J=8.7,2.5Hz,1H),7.54(d,J=8.5Hz,1H),7.41(dd,J=8.5,7.0Hz,1H),7.35–6.67(m,4H),5.80(dd,J=11.8,5.1Hz,1H),4.21(t,J=11.8Hz,1H),3.89–3.52(m,12H),3.05–2.67(m,4H),2.36–2.12(m,6H),2.10–1.92(m,4H),1.86–1.63(m,4H),1.31–1.01(m,4H)。
实施例二:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4R)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)吡啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-2)
化合物TM-2的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=874.29;1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.51(d,J=6.3Hz,1H),8.78(d,J=7.7Hz,1H),8.40(d,J=4.3Hz,1H),8.26(d,J=5.6Hz,1H),8.20(d,J=2.5Hz,1H),7.66(dd,J=8.7,2.5Hz,1H),7.58–7.52(m,1H),7.41(dd,J=8.5,7.0Hz,1H),7.32–6.77(m,3H),6.45(d,J=7.8Hz,1H),5.80(dd,J=11.8,5.1Hz,1H),5.18(d,J=84.5Hz,1H),4.77(d,J=16.5Hz,1H),4.20(t,J=11.7Hz,1H),3.86–3.71(m,2H),3.69–3.43(m,6H),2.97–2.66(m,4H),2.40–1.58(m,15H),1.27–0.92(m,3H)。
实施例三:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)吡啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)-5-(1,4-氧氮杂庚烷-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-3)
化合物TM-3的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=876.73;1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.31(s,1H),8.78(d,J=7.9Hz,1H),8.40(s,1H),8.27(s,1H),8.21(s,1H),7.67(d,J=8.6Hz,1H),7.55(d,J=8.5Hz,1H),7.41(dd,J=8.5,7.0Hz,1H),7.32–6.78(m,4H),5.80(dd,J=11.8,5.1Hz,1H),4.26–3.51(m,13H),3.05–2.60(m,5H),2.37–1.65(m,15H),1.23-1.06(m,3H)。
实施例四:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)嘧啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)-5-吗啉吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-4)
化合物TM-4的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=863.13;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.40(s,1H),8.83(d,J=7.9Hz,1H),8.50(s,2H),8.39(s,1H),8.29(s,1H),7.69–7.56(m,1H),7.43(dd,J=8.5,7.0Hz,1H),7.29–6.78(m,3H),5.81(dd,J=11.8,5.2Hz,1H),4.20(t,J=8.0Hz,1H),3.87–3.86(m,12H),2.94–2.66(m,4H),2.47–2.17(m,7H),2.10–1.91(m,4H),1.86–1.60(m,4H),1.30–1.01(m,3H)。
实施例五:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4R)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)嘧啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-5)
化合物TM-5的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=875.21;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.51(d,J=6.3Hz,1H),8.78(d,J=7.7Hz,1H),8.50(s,2H),8.39(d,J=4.3Hz,1H),8.26(d,J=5.6Hz,1H),7.58(d,J=8.6Hz,1H),7.43(dd,J=8.5,7.0Hz,1H),7.30–6.78(m,3H),6.45(d,J=7.8Hz,1H),5.81(dd,J=11.8,5.2Hz,1H),5.28(s,0.5H),5.07(s,0.5H),4.77(d,J=17.3Hz,1H),4.27-4.16(m,1H),3.89–3.44(m,6H),2.92-2.66(m,4H),2.50-2.42(m,4H),2.35-2.16(m,5H),2.11–1.90(m,4H),1.85-1.61(m,4H),1.30–0.99(m,3H)。
实施例六:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)嘧啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)-5-(1,4-氧氮杂庚烷-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-6)
化合物TM-6的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=877.43;1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.31(s,1H),8.78(d,J=8.0Hz,1H),8.50(s,2H),8.39(s,1H),8.27(s,1H),7.58(dd,J=8.6,0.9Hz,1H),7.43(dd,J=8.5,7.0Hz,1H),7.31–6.93(m,2H),6.83(d,J=8.0Hz,1H),5.81(dd,J=11.8,5.1Hz,1H),4.44–3.54(m,12H),2.99–2.62(m,4H),2.47-2.42(m,4H),2.31-2.15(m,5H),2.12–1.87(m,6H),1.84–1.61(m,4H),1.30–1.01(m,3H)。
实施例七:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)吡啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)-5-吗啉吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-7)
化合物TM-7的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=878.50;1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.40(s,1H),8.83(d,J=7.9Hz,1H),8.39(s,1H),8.17(d,J=2.5Hz,1H),7.69–7.54(m,1H),7.25–6.80(m,7H),5.43(dd,J=12.7,5.3Hz,1H),4.24–4.17(m,1H),3.85–3.69(m,8H),3.60–3.49(m,4H),3.01–2.59(m,8H),2.24–0.80(m,17H)。
实施例八:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4R)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)吡啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-8)
化合物TM-8的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=890.40;1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.50(d,J=6.2Hz,1H),8.78(d,J=7.7Hz,1H),8.39(d,J=4.2Hz,1H),8.26(d,J=5.6Hz,1H),8.17(d,J=2.4Hz,1H),7.72–7.57(m,1H),7.44–6.69(m,5H),6.45(d,J=7.7Hz,1H),5.43(dd,J=12.7,5.4Hz,1H),5.28(s,0.5H),5.07(s,0.5H),4.77(d,J=17.3Hz,1H),4.25-4.15(m,1H),4.07–3.42(m,9H),3.02–2.85(m,5H),2.80–2.61(m,3H),2.19(d,J=7.1Hz,2H),2.10–1.00(m,11H)。
实施例九:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)吡啶-2-基)哌嗪-1-基)甲基)环己基)-1H-吡唑-4-基)-5-(1,4-氧氮杂庚烷-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-9)
化合物TM-9的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=892.40;1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.31(s,1H),8.78(d,J=7.9Hz,1H),8.39(s,1H),8.16(s,1H),7.63(d,J=9.8Hz,1H),7.53–6.36(m,6H),5.43(dd,J=12.7,5.4Hz,1H),4.28-4.14(m,1H),3.91–3.63(m,8H),3.10–2.60(m,8H),2.24–0.84(m,20H)。
实施例十:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(4-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)-1H-吡唑-1-基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)-5-吗啉吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-10)
化合物2 59mg分散在无水乙腈4mL中、加入NMI(60mg)、TCFH(77mg),氮气保护下室温水浴搅拌0.5h;取样1滴加四氢吡咯1滴淬灭并超声30秒,用乙腈稀释检测LCMS,检测到化合物C全部反应完全生成活性酯。加入化合物11(123mg)的DMF 2mL溶液,体系25~30℃反应过夜。LCMS监控,所得目标分子量。50℃减压浓缩除去乙腈,加水4mL,室温水浴搅拌析晶0.5h,过滤,水淋洗3次,得到固体粗品,用DMSO 2mL溶解固体,过滤,送制备:得到化合物TM-10(53.56mg,Y=34%),白色固体。LCMS(ESI)m/z:[M+1]=866.40;1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.40(s,1H),8.83(d,J=8.0Hz,1H),8.38(s,1H),8.29(s,1H),8.02(s,1H),7.60(d,J=0.8Hz,1H),7.34–7.19(m,1H),7.11(d,J=7.0Hz,1H),7.04(t,J=7.8Hz,1H),6.90(dd,J=8.1,6.5Hz,2H),5.41(dd,J=12.7,5.4Hz,1H),4.18(d,J=11.7Hz,2H),3.91–3.59(m,8H),3.05(s,3H),3.01–2.86(m,3H),2.83–2.59(m,2H),2.35–1.43(m,15H),1.37–1.02(m,3H)。
实施例十一:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4R)-4-((4-(4-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)-1H-吡唑-1-基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-11)
化合物TM-11的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=878.39;1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),9.43(d,J=6.1Hz,1H),8.71(d,J=7.7Hz,1H),8.32(d,J=4.3Hz,1H),8.19(d,J=5.5Hz,1H),7.95(s,1H),7.54(s,1H),7.27–6.72(m,4H),6.38(d,J=7.8Hz,1H),5.35(dd,J=12.7,5.4Hz,1H),5.21(s,0.5H),5.00(s,0.5H),4.70(dd,J=17.1,2.4Hz,1H),4.19–3.98(m,2H),3.86–3.34(m,4H),2.99(s,3H),2.91–2.76(m,3H),2.76–2.53(m,2H),2.24–1.78(m,15H),1.77–1.45(m,4H),1.25–0.93(m,3H)。
实施例十二:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-(4-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)-1H-吡唑-1-基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)-5-(1,4-氧氮杂-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-12)
依次加入化合物4(62mg)、无水乙腈(4mL)、NMI(60mg)、TCFH(77mg),氮气保护下室温水浴搅拌0.5h;取样1滴加四氢吡咯1滴淬灭并超声30秒,用乙腈稀释检测LCMS,检测到化合物C全部反应完全生成活性酯。加入化合物11(123mg)的DMF(2mL)溶液,体系25~30℃反应过夜。LCMS监控,所得目标分子量。50℃减压浓缩除去乙腈,加水(4mL),室温水浴搅拌析晶0.5h,过滤,水淋洗3次,得到固体粗品,用DMSO(2mL)溶解固体,过滤,送制备:得到化合物TM-12(68.88mg),白色固体。LCMS(ESI)m/z:[M+1]=880.39;1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),9.24(s,1H),8.71(d,J=7.9Hz,1H),8.32(s,1H),8.20(s,1H),8.00–7.84(m,1H),7.53(d,J=0.7Hz,1H),7.22–7.11(m,1H),7.11–7.02(m,1H),6.97(t,J=7.8Hz,1H),6.87–6.75(m,2H),5.34(dd,J=12.7,5.4Hz,1H),4.19–3.56(m,10H),2.98(s,3H),2.94–2.79(m,3H),2.75–2.55(m,3H),2.21–1.38(m,16H),1.30–0.91(m,3H)。
实施例十三:5-((1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4S)-4-((4-(4-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)-1H-吡唑-1-基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-13)
化合物TM-13的制备方法同实施例一TM11的制备方法。LCMS(ESI)m/z:[M+1]=878.39。
实施例十四:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-((4-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)-1H-吡唑-1-基)甲基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)-5-(1,4-氧氮杂-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-14)
化合物TM-14的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=894.39;1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.30(s,1H),8.76(d,J=7.9Hz,1H),8.37(s,1H),8.27(s,1H),7.92(s,1H),7.60(s,1H),7.33–6.69(m,3H),5.41(dd,J=12.7,5.5Hz,1H),4.26–4.09(m,1H),4.09–3.62(m,10H),3.07(s,3H),3.00–2.60(m,5H),2.22–1.98(m,5H),1.98–1.70(m,8H),1.62–1.40(m,3H),1.32–1.15(m,2H),1.02(q,J=12.6Hz,2H)。
实施例十五:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-((5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)嘧啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)-5-吗啉吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-15)
化合物TM-15的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=877.83;1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.40(s,1H),8.83(d,J=7.9Hz,1H),8.82(s,2H),8.38(s,1H),8.29(s,1H),7.65(d,J=8.6Hz,1H),7.47(dd,J=8.5,7.0Hz,1H),7.28–6.96(m,2H),6.91(d,J=8.0Hz,1H),5.83(dd,J=11.8,5.1Hz,1H),5.11–4.97(m,1H),4.26–4.08(m,1H),3.94–3.63(m,8H),3.08–2.65(m,6H),2.36–1.51(m,18H),1.06(q,J=12.6Hz,2H)。
实施例十六:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4R)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)嘧啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-16)
化合物TM-16的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=890.45;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.50(d,J=6.1Hz,1H),8.78(d,J=7.7Hz,1H),8.74(s,2H),8.39(d,J=4.2Hz,1H),8.26(d,J=5.6Hz,1H),7.65(d,J=8.5Hz,1H),7.47(dd,J=8.5,7.0Hz,1H),7.30–6.97(m,2H),6.86(d,J=7.8Hz,0.5H),6.45(d,J=7.8Hz,0.5H),5.83(dd,J=11.9,5.1Hz,1H),5.28(s,0.5H),5.13–4.99(m,1.5H),4.77(d,J=16.5Hz,1H),4.25–4.13(m,1H),3.94–3.43(m,4H),3.02–2.61(m,6H),2.37–1.53(m,20H),1.17–1.00(m,2H)。
实施例十七:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-((5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)嘧啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)-5-(1,4-氧氮杂庚烷-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-17)
化合物TM-17的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=890.45;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.31(s,1H),8.78(d,J=8.0Hz,1H),8.74(s,2H),8.39(s,1H),8.27(s,1H),7.65(d,J=8.5Hz,1H),7.47(dd,J=8.5,7.0Hz,1H),7.25–6.95(m,2H),6.83(d,J=8.0Hz,1H),5.83(dd,J=11.9,5.1Hz,1H),5.14–4.94(m,1H),4.19(t,J=11.8Hz,1H),4.13–3.59(m,8H),3.05–2.64(m,6H),2.41–1.55(m,20H),1.06(q,J=12.6Hz,2H)。
实施例十八:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4R)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)吡啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-18)
化合物TM-18的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=889.89;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.50(d,J=6.2Hz,1H),8.78(d,J=7.7Hz,1H),8.39(d,J=4.3Hz,1H),8.31–8.17(m,2H),7.80(dd,J=8.5,2.5Hz,1H),7.59(dd,J=8.7,0.8Hz,1H),7.43(dd,J=8.5,7.0Hz,1H),7.32–6.96(m,2H),6.91–6.83(m,1.5H),6.45(d,J=7.8Hz,0.5H),5.81(dd,J=11.8,5.2Hz,1H),5.28(s,0.5H),5.12–5.03(m,1.5H),4.77(d,J=16.6Hz,1H),4.19(t,J=11.8Hz,1H),4.00–3.43(m,4H),3.11–2.65(m,5H),2.37–1.57(m,21H),1.11–0.99(m,2H)。
实施例十九:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-((5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)吡啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)-5-吗啉吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-19)
化合物TM-19的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=876.93;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.40(s,1H),8.82(d,J=7.9Hz,1H),8.38(s,1H),8.29(s,1H),8.23(dd,J=2.5,0.8Hz,1H),7.80(dd,J=8.5,2.5Hz,1H),7.59(dd,J=8.7,0.8Hz,1H),7.43(dd,J=8.5,7.0Hz,1H),7.25–6.94(m,2H),6.93–6.86(m,2H),5.81(dd,J=11.8,5.2Hz,1H),5.07(dt,J=9.0,4.8Hz,1H),4.25–4.10(m,1H),3.85–3.66(m,8H),3.13–2.66(m,5H),2.34–1.54(m,19H),1.17–0.97(m,2H)。
实施例二十:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-((5-(1-(2,6-二氧哌啶-3-基)-3-甲基-1H-吲唑-4-基)吡啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)-5-(1,4-氧氮杂庚烷-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-20)
化合物4(52mg)加入至乙腈(2mL)中,加入NMI(50mg),TCFH(66mg),室温下搅拌15分钟,随后取样加入一滴四氢吡咯测活化值,随后加入溶于DMF的化合物14(100mg),室温搅拌过夜。LCMS监控,浓缩掉乙腈,加水析出固体,过滤,固体通过高压反相制备得化合物TM19(18.8mg)。LCMS(ESI)m/z:[M+1]=891.56;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.31(s,1H),8.78(d,J=8.0Hz,1H),8.39(s,1H),8.27(s,1H),8.24(dd,J=2.5,0.8Hz,1H),7.80(dd,J=8.5,2.5Hz,1H),7.59(dd,J=8.6,0.9Hz,1H),7.43(dd,J=8.5,7.0Hz,1H),7.28–6.96(m,2H),6.91–6.86(m,1H),6.83(d,J=7.9Hz,1H),5.81(dd,J=11.8,5.1Hz,1H),5.13–5.02(m,1H),4.24–4.12(m,1H),4.10–3.53(m,8H),3.09–2.61(m,5H),2.38–1.51(m,20H),1.32–1.25(m,1H),1.12–0.99(m,2H)。
实施例二十一:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-((5-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)吡啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)5-(1,4-氧氮杂庚烷-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-21)
化合物TM-21的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=907.40;1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.31(s,1H),8.78(d,J=7.9Hz,1H),8.38(s,1H),8.27(s,1H),8.22(d,J=2.5Hz,1H),7.79(dd,J=8.5,2.5Hz,1H),7.44–6.95(m,3H),6.96–6.79(m,3H),5.44(dd,J=12.7,5.5Hz,1H),5.12–5.01(m,1H),4.25–4.14(m,1H),4.12–3.59(m,8H),2.98–2.57(m,8H),2.31–1.54(m,18H),1.14–0.99(m,2H)。
实施例二十二:N-(3-(二氟甲基)-1-((1r,4r)-4-((4-((5-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)吡啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)5-吗啉吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-22)
化合物TM-22的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=893.39;1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.31(s,1H),8.78(d,J=7.9Hz,1H),8.38(s,1H),8.27(s,1H),8.22(d,J=2.5Hz,1H),7.79(dd,J=8.5,2.5Hz,1H),7.44–6.95(m,3H),6.96–6.79(m,3H),5.44(dd,J=12.7,5.5Hz,1H),5.12–5.01(m,1H),4.25–4.14(m,1H),4.12–3.59(m,8H),2.98–2.57(m,8H),2.31–1.54(m,18H),1.14–0.99(m,2H)。
实施例二十三:5-((1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-N-(3-(二氟甲基)-1-((1r,4R)-4-((4-(5-(1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧-2,3-二氢-1H-苯并[d]咪唑-4-基)吡啶-2-基)氧基)哌啶-1-基)甲基)环己基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(TM-23)
化合物TM-23的制备方法同实施例一TM1的制备方法。LCMS(ESI)m/z:[M+1]=905.39;1H NMR(400MHz,DMSO-d6)δ11.08(br,1H),9.50(d,J=6.3Hz,1H),8.78(d,J=7.7Hz,1H),8.39(d,J=4.3Hz,1H),8.30–8.12(m,2H),7.79(dd,J=8.5,2.5Hz,1H),7.43–6.96(m,3H),6.88(dd,J=15.8,8.0Hz,2.5H),6.45(d,J=7.8Hz,0.5H),5.44(dd,J=12.7,5.5Hz,1H),5.28(s,0.5H),5.11–5.01(m,1.5H),4.77(d,J=16.9Hz,1H),4.25–4.13(m,1H),3.87–3.57(m,4H),3.97–2.89(m,9H),2.30–1.27(m,17H),1.15–0.98(m,2H)。
实施例二十四至实施例四十五:化合物TM24至TM45的制度方法同实施例一TM1的制备方法,化合物编号及结构如表3所示。
表3:本发明化合物TM-24至TM-45的编号与结构
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以下用测试例说明本发明化合物的有益效果。
本发明所用阳性化合物1出自Kymera Therapeutics,Inc.的专利,专利号WO2020113233。结构如下:
测试例一:本发明化合物对人类THP-1细胞TNFα分泌水平的抑制效果
本实验在含10% FBS/1%青霉素/链霉素的RPMI 1640培养基中进行,化合物起始测定浓度为1uM。
取化合物DMSO溶解成储液,并用培养基稀释成3X工作浓度,加入96孔板,每孔100μL;取对数生长期的THP1细胞计数,并稀释成2x 106/mL浓度,加入上述含化合物的96孔板中,每孔100μL,混匀,于37℃,5%CO2培养箱中培养1小时。然后继续加入LPS至最终浓度为1ng/mL,并继续于37℃,5%CO2培养箱中培养5小时。然后1000rpm离心1min,并分别取16uL上清液,按TNFαELISA检测试剂盒进行检测,读取OD450值,根据标准曲线换算成TNFα浓度,并用GraphPad 5.0拟合剂效曲线计算IC50值。
表4化合物对人类THP-1细胞TNFα分泌水平的抑制效果
结果表明:本发明的化合物在100nM-1uM对LPS刺激的TNFα有显著抑制作用。
测试例二:本发明化合物对人类外周血液单核细胞(PBMC)中IL-6分泌水平的抑制效果
(1)实验方法:
本实验在含10% FBS/1%青霉素-链霉素的RPMI 1640培养基中进行,化合物起始测定浓度为1μM。取化合物DMSO溶解成储液,用培养基4倍梯度稀释至4×工作液浓度,加入96孔板,每孔50μL;取PBMC(批号:HPP20062307,四川厚朴生物科技有限公司)细胞计数,并稀释成2×106/mL浓度,加入上述含化合物的96孔板中,每孔150μL,混匀,于37℃,5%CO2培养箱中培养20h。然后继续加入R848至最终浓度为2.5μg/mL,并继续于37℃,5%CO2培养箱中培养24h。然后2000rpm离心4min,取上清液稀释110×,按IL-6ELISA检测试剂盒进行检测,读取OD450值,根据标准曲线换算成IL-6浓度,并用GraphPad 5.0拟合剂效曲线计算IC50值。
(2)实验结果
实验结果见下表1,其中各化合物的EC50值按照以下说明分类:
“+”表示IC50值大于1μM;
“++”表示IC50值小于1μM大于300nM;
“+++”表示IC50值小于300nM大于100nM;
“++++”表示IC50值小于100nM。
表5化合物对PBMC细胞IL-6分泌水平的抑制效果
化合物 | IC50(三次平均值,nM) |
阳性化合物1 | 9.58 |
TM-9 | 3.9 |
TM-10 | 1.43 |
TM-12 | 1.37 |
TM-21 | 0.34 |
结果表明:本发明的化合物对PBMC细胞IL-6分泌有显著抑制作用。
测试例三:本发明化合物对人类外周血液单核细胞(PBMC)中IRAK4降解水平的研究
本实验在含10% FBS/1%青霉素/链霉素的RPMI 1640培养基中进行,化合物起始测定浓度为1uM。
将冷冻人类PBMC解冻到培养基中。以最少2.5×106c/mL培养细胞。在37℃/5%CO2下培育PBMC并且使其静置隔夜。在隔夜回收之后,通过锥虫蓝排除法进行细胞计数/存活率评估。将细胞密度调节到2.5×106/mL。再将其加到96孔板中,每孔90uL。取化合物DMSO溶解成储液,并用培养基稀释成3X工作浓度,加入上述96孔板,每孔10μL。于37℃,5%CO2培养箱中培养20小时。在处理结束时,收集细胞并且在1800rpm离心5分钟。1×PBS洗涤并且在1800rpm下离心5分钟。冷冻细胞集结粒并且储存在-80℃下直到进一步加工。通过在溶解缓冲剂中再悬浮来产生溶解物。用BCA试剂盒进行蛋白质定量。每道装载20μg蛋白质并且在26孔4-12%Bis-Tris SDS-page凝胶上操作。使用伯乐混合MW turbo程序(BioRad Mixed MWturbo program)对PVDF膜进行转印7分钟。在室温下将膜在摇荡器上阻断一小时。将初级抗体在4℃下在摇荡器上培育隔夜。膜3×TBST洗涤,各5分钟。添加二级抗体且在室温下在摇荡器上培育一小时。膜3×TBST洗涤,各5分钟,并且用去离子H2O充分冲洗。使用利科奥德赛CLx扫描膜,且使用Image Studio简化版本5.2软件对波段进行定量。
表6化合物对PBMC中IRAK4的降解效果
化合物 | DC50(nM) |
阳性化合物1 | 3.19 |
TM-9 | 2.34 |
TM-10 | 1.05 |
TM-12 | 0.69 |
TM-21 | 1.58 |
结果表明:本发明化合物对PBMC中IRAK4有显著降解效果,并能取得90%以上的降解。
测试例四:化合物在THP1细胞中对IRAK4蛋白降解效果
将THP-1细胞种到96孔细胞培养板中,每孔5×104个细胞,100μL培养基。细胞培养板在37℃,5%CO2培养箱中培养过夜。每孔细胞中加入100nl制备好的化合物储液,以及无化合物的DMSO储液。细胞培养板在37℃,5% CO2培养箱中处理24小时。向20mL细胞裂解缓冲液中,加入一片蛋白酶抑制剂,以及一片磷酸酶抑制剂,轻轻混匀至完全溶解。向4x制样缓冲液中加入终浓度200mM DTT,配置成4x制样工作液。用超纯水稀释20x电泳缓冲液至1x。用超纯水稀释20x转膜缓冲液至1x,并加入20%甲醇。用超纯水稀释10x电泳缓冲液至1x。IRAK4蛋白一抗工作液:在20mL封闭液中加入IRAK4抗体20μl;β-Actin一抗工作液:在20mL封闭液中加入beta-actin(13E5)Rabbit mAb抗体2μl。IRAK4蛋白二抗工作液:DonkeyAnti-Goat IgG H&L(HRP)在封闭液中进行1/5000稀释;β-Actin二抗工作液:Anti-rabbitIgG,HRP-linked antibody在封闭液中进行1/10000稀释。细胞培养板3000rpm,离心3min,小心吸掉大部分培养基,细胞板倒置,300rpm,离心30s;每孔加入45μL lysis buffer 300转震荡30s,冰上静置30min,20min时吹打30下;18μL蛋白上清加4x制样工作液6μL进行样品制备,70℃加热10min。剩余蛋白样品-80℃保存。在预制胶中,每孔上样8μl,恒压120V进行电泳,约60min。使用PVDF膜进行转膜,恒流300mA,1小时。转膜后,用封闭液室温封闭1小时。一抗工作液4℃孵育过夜。用1×TBST缓冲液洗膜,3×10min。二抗工作液室温孵育1小时。用1×TBST缓冲液洗膜,3×10min,用显色液进行曝光显色。使用ImagJ软件,计算各个条带的灰度值,进行半定量分析并用GraphPad Prism8.0计算DC50。
“+”表示DC50值大于等于1μM;
“++”表示DC50值小于1μM大于等于100nM;
“+++”表示DC50值小于100nM;
表7化合物在THP1细胞中对IRAK4蛋白降解效果
化合物 | DC50(nM) |
阳性化合物1 | 5.78 |
TM-2 | 24.28 |
TM-3 | 22.43 |
TM-6 | 17.43 |
TM-9 | 2.10 |
TM-12 | 1.27 |
TM-14 | 2.90 |
TM-17 | 16.88 |
TM-18 | 34.24 |
TM-20 | 27.58 |
TM-21 | 6.21 |
结果表明:本发明化合物在THP1细胞中对IRAK4有显著降解效果,并能取得90%以上的降解。
测试例五:代谢稳定性测试
预热空的孵化板T60和NCF60 10分钟;在100mM磷酸盐缓冲液中将肝微粒体(人源)稀释至0.56mg/mL,将445uL微粒体工作溶液(0.56mg/mL)转移到预热的“孵化”板T60和NCF60中,然后将孵化板T60和NCF60在37℃下持续摇动预孵育10分钟。将54μL肝微粒体转移到空白板,然后将6μL NAPDH辅因子添加到空白板中,然后将180μL淬灭溶液添加到空白板中;将5μL复合工作溶液(100μM)添加到含有微粒的孵化板(T60和NCF60)中,并彻底混合3次;对于NCF60板,添加50uL缓冲液并彻底混合3次。开始计时;板将在37℃振荡孵育60分钟;在淬灭板T0中,添加180μL淬灭溶液和6μL NAPDH辅因子。确保板已冷却以防止蒸发,对于T60板,彻底混合3次,并在0分钟时间点立即将54μL混合物移至淬灭板。然后将44μL NAPDH辅因子添加到孵化板(T60)中。开始计时;板将在37℃振荡孵育60分钟。在5、15、30、45和60分钟时,将180μL淬火溶液添加到淬灭板中,混合一次,然后将每个时间点的60μL样品从T60板连续转移到淬灭板。
就NCF60而言,混合一次,并在60分钟的时间点将60μL样品从NCF60孵化转移到包含淬灭溶液的淬灭板。将所有采样板振摇10分钟,然后在4℃下以4000rpm的速度离心20分钟,将80μL上清液转移到240μL HPLC水中,并通过板振动器混合10分钟;在LC-MS/MS分析之前,将每个生物分析板密封并振摇10分钟。
表8化合物在人肝微粒体中的代谢稳定性
化合物 | 半衰期(t1/2,min) |
阳性化合物1 | 39 |
TM-10 | 54 |
TM-12 | 65 |
结果表明:本发明化合物在肝微粒体中有相当的稳定性,半衰期t1/2能够达到60分钟以上。
测试例六:本发明化合物对银屑病模型的治疗作用
雄性BALB/c小鼠,6-8周龄,适应性饲养1周后随机分为9组,即空白组、咪喹莫特模型组(即IMQ组)、IRAK4小分子抑制剂PF-06650833组(30mg/kg和100mg/kg)、IRAK4蛋白降解剂阳性化合物1组(30mg/kg和100mg/kg)和本发明化合物(10mg/kg、30mg/kg、100mg/kg),每组6到7只。第0天在小鼠背部用脱毛膏脱毛,脱毛面积为2×2cm2。第一天开始用IMQ乳膏造模,并灌胃相应的药物治疗。IRAK4小分子抑制剂PF-06650833组(30mg/kg和100mg/kg)、和本发明化合物(15mg/kg、30mg/kg、100mg/kg)每日早晚两次灌胃相应药物,两次灌胃间隔8h,在当天首次灌胃2h后在小鼠背部脱毛部位及左耳涂抹IMQ乳膏,背部脱毛部位及左耳IMQ乳膏给药剂量分别为80mg和10mg。阳性化合物1组在当天首次灌胃4h后在小鼠背部脱毛部位及左耳涂抹IMQ乳膏。空白组和IMQ组每日早晚两次灌胃溶媒,两次灌胃间隔8h,在当天首次灌胃间隔2h后于当天分别在小鼠背部脱毛部位及耳朵涂抹凡士林和IMQ乳膏,连续给药7天。
参考银屑病面积与严重性指数(PASI)评分标准。从造模第1d开始,每日上午对背部皮肤皮损处银屑、红斑和厚度按0~4评分,评分标准见表1。将3项得分相加得到总分,即为PASI总分。实验第7d,对各组小鼠典型皮肤如下银屑造模第七天图片所示。第0d开始,每日上午使用数显游标卡尺测量小鼠左耳耳厚,测量三次,取平均值。
表9银屑病面积与严重性指数(PASI)评分标准
结果显示本发明化合物对IMQ诱发的银屑病包括银屑、耳后、皮肤厚度及红斑有显著抑制作用。并对脾脏及皮肤里的蛋白降解能够达到75%以上的清除。
综上,本发明公开了式I所示化合物,该类化合物能够有效降解IRAK4或者以其他方式抑制IRAK4的活性。在IRAK4介导的疾病包括免疫性疾病(如银屑病、化脓性汗腺炎、特异性皮炎、类风湿性关节炎和系统性红斑狼疮等)、肿瘤(如多发性骨髓瘤、淋巴细胞性白血病和淋巴瘤等)、阿尔茨海默病和纤维化疾病等疾病中具有非常好的应用前景,为临床上筛选和/或制备与IRAK4活性相关的疾病的药物提供了一种新的选择。
Claims (10)
1.式I所示的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐:
其中,
R1选自-NR1aR1b、4~10元杂环基、5~12元桥杂环基或5~12元螺杂环基,其中所述杂环基、桥杂环基、螺杂环基可任选被一个、两个或三个R11取代;
R1a、R1b分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
每个R11分别独立选自氢、卤素、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-OR12、-C0~2亚烷基-NR12R13、-C0~2亚烷基-C(O)R12、-C0~2亚烷基-NR12C(O)R13、-C0~2亚烷基-C(O)NR12R13、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
R12、R13分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
n1、n2分别独立选自0、1或2;
U选自N或CRU;
RU选自氢或C1~6烷基;
V选自化学键、O、S或CRV1RV2;
RV1、RV2分别独立选自氢或C1~6烷基;
A环选自5元芳杂环或6元芳杂环,其中所述芳杂环可任选被一个、两个或三个RA取代;
每个RA分别独立选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
表示单键或双键;
X选自CRX或NRX;
Y选自N或C(O);
Z选自N或C;
Q选自N或CRQ;
RX选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-ORX1、-C0~2亚烷基-NRX1RX2、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
RX1、RX2分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
RQ选自氢、卤素、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基。
2.根据权利要求1所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,其特征在于:
R1选自-NR1aR1b、5元含氮杂环基、6元含氮杂环基、7元含氮杂环基、8元含氮杂环基、6元含氮桥杂环基、7元含氮桥杂环基、8元含氮桥杂环基、9元含氮桥杂环基、10元含氮桥杂环基、6元含氮螺杂环基、7元含氮螺杂环基、8元含氮螺杂环基、9元含氮螺杂环基或10元含氮螺杂环基,其中所述杂环基、桥杂环基、螺杂环基可任选被一个、两个或三个R11取代。
3.根据权利要求2所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,其特征在于:
R1选自
4.根据权利要求1所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,其特征在于:
n1选自0,n2选自1;或n1选自1,n2选自0;或n1选自1,n2选自1;或n1选自2,n2选自1;或n1选自1,n2选自2;
U选自N或CH;
V选自化学键、O或CH2;
Q选自N或CH。
5.根据权利要求1~4中任一项所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,其特征在于:式I所示的化合物具有式IIa或式IIb所示的结构:
其中,
A环选自6元芳杂环,其中所述芳杂环可任选被一个、两个或三个RA取代;
每个RA分别独立选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
RX选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-ORX1、-C0~2亚烷基-NRX1RX2、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
RX1、RX2分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基。
6.根据权利要求1~4中任一项所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,其特征在于:式I所示的化合物具有式III所示的结构:
其中,
A环选自5元芳杂环或6元芳杂环,其中所述芳杂环可任选被一个、两个或三个RA取代;
每个RA分别独立选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基;
RX选自氢、卤素、氰基、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基、卤素取代的C2~6炔基、-C0~2亚烷基-ORX1、-C0~2亚烷基-NRX1RX2、-C0~2亚烷基-3~10元碳环基或-C0~2亚烷基-4~10元杂环基;
RX1、RX2分别独立选自氢、C1~6烷基、C2~6烯基、C2~6炔基、卤素取代的C1~6烷基、卤素取代的C2~6烯基或卤素取代的C2~6炔基。
7.根据权利要求1~6任一项所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,其特征在于:所述化合物具体包括:
8.权利要求1-7任一项所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗和预防白介素-1受体相关激酶4(IRAK4)信号转导通路相关或介导的疾病,白细胞介素-6(IL-6)受体和/或肿瘤坏死因子α(TNFα)相关或介导的疾病。
9.根据权利要求8所述的用途,其特征在于:所述的疾病包括癌症、神经退行性疾病、病毒性疾病、自身免疫性疾病、炎性疾病、遗传性疾病、激素相关疾病、代谢紊乱性疾病、与器官移植有关的疾病、免疫缺陷疾病、骨破坏性疾病、增生性疾病、传染病、凝血酶诱导的血小板聚集、肝病、T细胞活化导致的病变、心血管疾病。
10.一种药物组合物,包括权利要求1-7任一项所述的化合物、或其立体异构体、或其氘代化合物、或其药学上可接受的盐,加上药学上可接受的辅料制备而成的制剂。
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