CN117586340A - 一类靶向降解mettl3的双功能化合物和药物组合物及应用 - Google Patents
一类靶向降解mettl3的双功能化合物和药物组合物及应用 Download PDFInfo
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- CN117586340A CN117586340A CN202311008297.1A CN202311008297A CN117586340A CN 117586340 A CN117586340 A CN 117586340A CN 202311008297 A CN202311008297 A CN 202311008297A CN 117586340 A CN117586340 A CN 117586340A
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Abstract
本发明公开了一类靶向降解METTL3的双功能化合物和药物组合物及应用,具体地,本发明公开了具有通式(I)的基于靶向抑制和降解METTL3的蛋白水解靶向嵌合(PROTAC)分子、制备方法及用途。本发明化合物在一端上含有结合E3泛素连接酶的配体,另一端含有结合METTL3靶蛋白抑制剂的部分,使得所述靶蛋白被置于所述连接酶附近,以实现所述靶蛋白的泛素化、降解和抑制。本发明化合物展现出与所述靶蛋白的降解或抑制相关的广泛范围的药理活性。用本发明的化合物和组合物治疗或预防起因于所述靶蛋白的融合与过表达的疾病或病症。
Description
技术领域
本发明属于化学医药领域,涉及靶向METTL3的PROTAC双功能化合物和药物组合物及应用。
背景技术
N6-甲基腺嘌呤(N6-methyladenosine,m6A)甲基化修饰是mRNA中最普遍的表观遗传修饰。参与m6A甲基化修饰中的效应器可以分为甲基化转移酶、去甲基化酶和m6A识别蛋白。其中甲基化转移酶的功能主要是由METTL3(Methyltransferase-like 3)、METTL14(Methyltransferase-like 14)和WTAP(Wilms tumor 1-associated protein)共同组成的甲基转移酶复合体来完成,负责将甲基选择性地添加到特定腺嘌呤碱基上(Nature.2012,485,201-206;Mol.Cell.2016,62,335-345;Nature.2018,561,556-560)。去甲基化酶和m6A识别蛋白则分别负责去甲基化和识别甲基化位点,从而发挥一定的调控作用。大多数m6A甲基化修饰位点可以通过METTL3催化过程进行修饰,METTL3在涉及m6A甲基化修饰的RNA生命周期的所有阶段都起着非常重要的作用。这些RNA生命周期包括前mRNA剪接、mRNA衰变、miRNA加工、翻译调节和核输出(Nature.2016,540,301-304;Nature.2014,505,117-120;Nature.2015,519,482-485)。同时,人们发现m6A甲基化修饰调控紊乱与癌症发生和多种人类恶性肿瘤密切相关。已有越来越多的研究发现METTL3参与肿瘤等各种生物学过程的调控,包括上皮-间充质转化、细胞增殖、肿瘤干细胞发育、化疗耐药性、血管生成、衰老、凋亡等。此外,在许多癌症中也发现了METTL3表达的上调。因此,靶向METTL3的治疗在临床上具有重要意义。
目前,已发现了METTL3参与了肿瘤发生发展,此外,大部分肿瘤中METTL3都呈高表达状态,并且与肿瘤患者的不良预后具有相关性,如急性髓系白血病(AML)、肺癌、乳腺癌、肝癌、胃癌、胰腺癌、结直肠癌、大肠癌、膀胱癌、肌肉浸润性肿瘤、前列腺癌、胶质母细胞瘤(GBM)、骨肉瘤、卵巢癌等。
蛋白水解靶向嵌合体(Proteolysis targeting chimeras,PROTAC)是具有两个异功能的配体通过联接链连接的化合物:一个配体靶向于目的蛋白(POI),而另一个配体特异性地募集E3连接酶。当PROTAC结合E3连接酶和目的蛋白时形成了三元复合物,通过劫持E3连接酶,PROTAC使POI呈现出有利的空间位置以促进其泛素化,从而选择性地降低靶蛋白的水平。这种方法的优点是PROTAC可以催化样的多轮降解靶蛋白,这是PROTAC分子与小分子抑制剂最大的不同。而传统的小分子利用拮抗、竞争的关系影响蛋白酶活性,因此极易产生耐药性,同时许多靶蛋白没有催化结构域,成药性差,缺乏相应的小分子药物,PROTAC根本上革新了这一领域,对耐药靶点表现出高特异性,通过敲除而非抑制蛋白避免耐药性产生,同时具有可逆性,且可以靶向非酶支架结构,因此可以更加高效地实现疾病治疗,而且可广泛应用于各类靶标蛋白。
综上所述,本领域迫切需要开发新型的靶向METTL3的蛋白水解靶向嵌合体。
发明内容
本发明的目的是提供一种靶向METTL3的蛋白水解靶向嵌合体。
本发明的第一方面,提供了一种如下式(I)所示的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐或立体异构体,或其前药分子:
其中,METTL3 inhibitors为可以结合METTL3蛋白的抑制剂,其通过基团X与Linker形成共价连接;所述的Linker是连接臂,其通过共价键与X和E3 ligase ligand相连,且所述的Linker选自以下结构:
其中,D、E各自独立地为-C(O)-或化学键;
F、G各自独立地为CH或N;
n、k各自独立地为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15;
j、s和t各自独立地为0、1或2;
且所述的Linker不为化学键;
所述的E3 ligase ligand是ECV(延伸蛋白B/C、Cullen-2、VHL)E3泛素连接酶复合体的底物识别组分VHL的小分子配体,其选自下组:
或所述的E3 ligase ligand是E3泛素连接酶复合体中Cereblon蛋白的小分子配体,其具有下式所示的结构:
W选自下组:CH2、C=O、SO2、NH、或N(C1-C4烷基);
Y1、Y2和Y3各自独立地选自O或S;
R1选自下组:H、D、卤素、硝基、氨基、氰基、羟基、C1-C4烷基、卤代C1-C4烷基、氘代C1-C4烷基;
Z选自下组:化学键、O、NH、C1-C4亚烷基;
所述的基团X选自下组:化学键、-(CH2)p-取代或未取代的苯基、-(CH2)p-取代或未取代的4-6元杂环、-(CH2)p-取代或未取代的5-6元杂芳环;其中,所述的杂环为饱和或部分不饱和(非芳香性)结构,且所述的杂环或杂芳环各自独立地含有1-3个选自N、O或S的杂原子;p为0、1、2、3、4或5。
在另一优选例中,所述的METTL3 inhibitors选自以下结构:
R2、R3为苯环上任意位点的取代基,且所述的R2、R3各自独立地选自下组:H、F、Cl、Br或I。
在另一优选例中,所述的X选自以下结构:
或化学键;
其中,R4为苯环上任意位点的取代基,且所述的R4选自下组:H、F;
A、B各自独立地为CH或N;
m、n各自独立地为1或2。
在另一优选例中,所述的Linker选自以下结构:
其中,D、E各自独立地为-C(O)-或化学键;
F、G各自独立地为CH或N;
n、k各自独立地为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15;j为0、1或2;
且所述的Linker不为化学键。
在另一优选例中,所述的E3 ligase ligand选自以下结构:
其中各基团的定义如上文中所述;
或所述的E3 ligase ligand选自下组:
在另一优选例中,所述的X为化学键,或选自下组的结构:
在另一优选例中,所述的Linker选自如下结构中的一种:
在另一优选例中,所述的化合物为实施例中的化合物M1-M61。
本发明的第二方面,提供了一种药物组合物,其含有治疗有效量的一种或多种如本发明第一方面中任一项所述的具有通式(I)的基于靶向抑制和降解METTL3的蛋白水解靶向嵌合分子,及药学上可接受的载体。
本发明的第三方面,提供了一种药物组合物,其含有治疗有效量的一种或多种如本发明第二方面中任一项所述的具有通式(I)的基于靶向抑制和降解METTL3的蛋白水解靶向嵌合分子,及药学上可接受的辅料。
本发明的第四方面,提供了一种本发明第一方面所述的具有通式(I)的基于靶向抑制和降解METTL3的蛋白水解靶向嵌合分子在制备预防或治疗癌症药物中的用途。
本发明的第五方面,提供了一种如本发明第一方面所述的具有通式(I)的化合物,其药学上可接受的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途,其特征在于,用于制备治疗或预防与METTL3活性或表达量相关的疾病的药物组合物。
其中,所述的疾病选自下组:急性髓细胞白血病、肺癌、乳腺癌、前列腺癌、肝癌、胃癌、胰腺癌、结直肠癌、大肠癌、膀胱癌、脑胶质瘤、卵巢癌等肿瘤疾病或自身免疫性疾病。
附图说明
图1为本发明所述化合物在MOLM13细胞内对METTL3蛋白的降解活性(孵育时间24小时)。
图2为本发明所述化合物中的M2在HL60和SU-DHL-4细胞内对METTL3蛋白的降解时效数据。
图3为本发明所述化合物中的M2在HL60和SU-DHL-4细胞内对METTL3蛋白的降解量效数据(NC为DMSO)。
图4所示为本发明代表化合物的体外抗肿瘤活性测试(IC50,测试时间7天)。
具体实施方式
本发明人经过长期而深入的研究,提供了一种靶向METTL3的蛋白水解靶向嵌合分子,所述的化合物通过泛素蛋白酶体系统直接降解METTL3蛋白,因此可以提高对METTL3甲基化酶活性的抑制作用。基于上述发现,发明人完成了本发明。
术语
本发明所述化学物中,当任何变量(例如R1、R2、R3、R4)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本发明中所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C4烷基”中“C1-C4”的定义包括以直链或支链排列的具有1、2、3、4个碳原子的基团。例如,“C1-C4烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基。
本发明中所用术语“杂环”是指含有1-4个选自O、N和S的杂原子的5元-6元芳香性或非芳香性杂环,且包括双环基团。“杂环基”因此包括上面提及的杂芳基,也包括其二氢化及四氢化类似物。“杂环基”进一步的实施例包括但不限于:咪唑基、吲哚基、异噻唑基、异噁唑基、噁二唑基、噁唑基、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹噁啉基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、l,4-二噁烷基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基和四氢噻吩基,及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。
本发明中所用“卤素”意指氟、氯、溴和碘。
除非另有定义,本发明中的烷基、环烷基、芳基和杂环基取代基可为未被取代的或取代的。例如,(C1-C4)烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。
本发明包括式(I)化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式(Ⅰ)化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
本发明所述的立体异构体包括对映体、非对映体和几何异构体的形式存在。本发明的一些化合物具有环烷基,其可在超过一个碳原子上被取代,在这种情况下,其所有的几何形式,包括顺式和反式,及其混合物,都处在本发明的范围内。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
本发明所述的前药指适于对患者给药的无过分毒性、刺激性和变态反应等的并且对其应用目的有效的式(I)化合物形式,包括缩醛、酯和两性离子形式。前药在体内转化(例如通过在血液中水解)得到上式的母体化合物。
本发明提供一种药物组合物,所述药物组合物包含通式(Ⅰ)的化合物,还包括药剂学上可接受的辅料,所述辅料选自:载体、稀释剂、粘合剂、润滑剂、润湿剂。优选地,所述药物组合物包含治疗有效量的通式(I)的化合物。
本发明的化合物可以配制为以下形式的药物组合物:糖浆剂,酏剂,悬浮剂,粉剂,颗粒剂,片剂,胶囊,锭剂,水溶液,霜剂,膏剂,洗液剂,凝胶剂,乳剂等。
本发明所述的癌症包括急性髓细胞白血病、肺癌、乳腺癌、前列腺癌、肝癌、胃癌、胰腺癌、结直肠癌、大肠癌、膀胱癌、脑胶质瘤、卵巢癌等肿瘤疾病或自身免疫性疾病。
靶向METTL3的蛋白水解靶向嵌合分子
为实现本发明的目的及其他相关目的,本发明提供一种如下式(I)所示的蛋白水解靶向嵌合分子,或其药学上可接受的盐或立体异构体,或其前药分子:
所述的分子包括METTL3 inhibitor和E3泛素酶配体部分,二者通过linker共价连接。其中,METTL3 inhibitors为可以结合METTL3蛋白的抑制剂;所述的METTL3 inhibitors可以通过基团X共价连接Linker,以及E3 ligase ligand共价连接Linker;所述的Linker是连接臂,通过共价键与X和E3 ligase ligand相连,共同构成双功能分子化合物。
在一个优选的实施方式下,所述的分子具有本发明各个实施例中所述的结构。
靶向METTL3的PROTAC类化合物的制备方法
所述的具有通式(I)的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药可以采用本领域常规的方法制备,本发明实施例中所使用的通用合成方法概述如下:
实施例1到10的通用制备方法:
实施例11到14的通用制备方法:
方案2
实施例16到23的通用制备方法:
方案3
实施例24到32的通用制备方法:
方案4
实施例33到41的通用制备方法:
方案5
实施例43到49的通用制备方法:
方案6
实施例50到61的通用制备方法:
方案7
药物组合物和施用方法
由于本发明化合物具有优异的METTL3抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防、治疗和/或缓解METTL3相关疾病,比如治疗癌症。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如 )、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的治疗剂联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的治疗剂。该其他药学上可接受的治疗剂中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于预防、治疗和/或缓解RSK介导的疾病。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1
(2S,4R)-1-[(2S)-2-({3-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基丙-2-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M1)。
合成方法使用通用方案1制备:
步骤1.1 4-氯-6-{[(4-碘苯基)甲基]氨基}嘧啶(3)的制备:
将化合物1(149mg,1.0mmol,1.0equiv)和化合物2(233mg,1.0mmol,1.0equiv)溶解于5mL异丙醇溶液中,再加入三乙胺(303mg,3.0mmol,3.0equiv),室温下搅拌12h。TLC显示反应完成。将反应混合物浓缩并通过硅胶快速柱色谱法用二氯甲烷:甲醇(20:1)纯化,得到呈白色固体状的化合物3(262mg,76%产率)。
1H NMR(400MHz,MeOD)δ8.24(s,1H),7.67(d,J=8.1Hz,2H),7.11(d,J=8.2Hz,2H),6.55(s,1H),4.56(s,2H).
步骤1.2 4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-9-(6-{[(4-碘苯基)甲基]氨基}嘧啶-4-基)-1,4,9-三氮杂螺[5.5]十一烷-2-酮(5)的制备:
化合物4的合成见参考文献(J.Med.Chem.2021,64,17,12738-12760.)。将化合物3(200mg,0.49mmol,1.0equiv)和化合物4(173mg,0.49mmol,1.0equiv)溶解于5mL异丙醇溶液中,再加入碳酸铯(480mg,1.47mmol,3.0equiv),加热至120℃反应48h。将反应混合物浓缩并通过硅胶快速柱色谱法用二氯甲烷:甲醇(10:1)纯化,得到呈白色固体状的化合物5(74mg,21%产率)。
ESI-MS calcd for C33H40F2IN7O[M+H]+=716.2,found:716.3.
步骤1.3(2S,4R)-1-[(2S)-3,3-二甲基-1-氧亚基-2-[(1-氧亚基丙-2-炔基)氨基]丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(7)的制备:
将丙炔酸(31mg,0.45mmol,1.0equiv)溶于10mL二氯甲烷溶液中,并在室温下搅拌。向搅拌的溶液中依次加入化合物6(200mg,0.45mmol,1.0equiv)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(188mg,0.495mmol,1.1equiv),最后加入N,N-二异丙基乙胺(174mg,1.35mmol,3.0equiv)。将反应混合物在室温下搅拌12h,TLC显示反应完成。加入50mL水稀释,用二氯甲烷(3×25mL)萃取,合并的有机相用无水硫酸钠干燥并浓缩。浓缩物通过硅胶快速柱色谱法用二氯甲烷:甲醇(10:1)纯化,得到呈白色固体状的化合物7(145mg,65%产率)。
ESI-MS calcd for C26H32N4O4S[M+H]+=497.2,found:497.2.
步骤1.4(2S,4R)-1-[(2S)-2-({3-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基丙-2-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M1)的制备:
将化合物5(25mg,0.035mmol,1.0equiv)和化合物7(21mg,0.042mmol,1.2equiv)溶解于2mL的N,N-二甲基甲酰胺溶液中,再加入0.2mL三乙胺。在氩气保护下抽换气三次后加入碘化亚铜(2mg,0.011mmol,0.3equiv)和双三苯基膦二氯化钯(4mg,0.006mmol,0.15equiv),在氩气保护下再次抽换气三次,加热至80℃反应12h。反应结束后,过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到白色固体的化合物M1(15mg,40%产率)。
1H NMR(400MHz,MeOD)δ8.94(s,1H),8.21(s,1H),7.63(d,J=8.2Hz,2H),7.50-7.40(m,6H),7.39-7.31(m,1H),7.02(dd,J=11.4,7.3Hz,1H),5.84(s,1H),5.04-4.98(m,1H),4.80-4.71(m,1H),4.69-4.62(m,1H),4.62-4.56(m,2H),4.48-4.42(m,1H),4.33(s,2H),3.90-3.84(m,1H),3.80(s,2H),3.78-3.72(m,1H),3.71-3.56(m,2H),3.45(s,2H),3.41-3.34(m,2H),3.23-3.12(m,2H),2.48(s,3H),2.42-2.16(m,2H),2.07-1.70(m,6H),1.66(s,3H),1.62-1.40(m,4H),1.08(s,6H),1.04(s,9H).
ESI-MS calcd for C60H71F2N11O5S[M+H]+=1084.5,found:1084.4.
实施例2
(2S,4R)-1-[(2S)-2-({5-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基戊-4-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M2)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ8.95(s,1H),8.19(s,1H),7.43(dd,J=8.2,4.4Hz,4H),7.41-7.33(m,4H),7.32-7.30(m,1H),7.03(dd,J=7.6,3.6Hz,1H),5.82(s,1H),4.99(q,J=6.3Hz,1H),4.70-4.65(m,1H),4.63-4.56(m,1H),4.55-4.52(m,2H),4.45-4.40(m,1H),4.32(s,2H),3.87(d,J=10.8Hz,1H),3.79(s,2H),3.75(dd,J=7.5,3.6Hz,1H),3.70-3.61(m,2H),3.46(s,2H),3.40-3.35(m,2H),3.21-3.14(m,2H),2.71(q,J=6.8Hz,2H),2.67-2.54(m,2H),2.48(s,3H),2.07-1.90(m,4H),1.89-1.68(m,4H),1.65(s,3H),1.60-1.45(m,4H),1.09(s,6H),1.02(s,9H).
13C NMR(200MHz,MeOD)δ173.8,173.1,172.1,169.8,159.6(d,J=244.1Hz),153.1,152.0(d,J=240.7Hz),149.9,148.5,145.7,142.5-142.3(m),137.6,133.6,133.0,131.2,130.4,128.4,127.6,124.5,121.0(d,J=24.2Hz),110.3(dd,J=17.2,7.6Hz),107.5(d,J=27.3Hz),90.0,81.8,70.9,69.0,60.6,59.2,58.4,57.9,55.7(d,J=5.0Hz),54.1,53.6,53.3,50.1,46.0,42.2,41.2,38.8,36.6,36.4,35.7,31.5,28.6,27.1,23.5,22.4,16.6,15.7.
ESI-HRMS calcd for C61H75F2N11O5S[M+H]+=1112.5641,found:1112.5715.
实施例3
(2S,4R)-1-[(2S)-2-({6-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基己-5-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M3)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ9.00(s,1H),8.19(s,1H),7.44(dd,J=8.3,5.0Hz,4H),7.40-7.32(m,4H),7.32-7.28(m,1H),7.02(dd,J=7.2,3.9Hz,1H),5.83(s,1H),5.00(q,J=7.00Hz,1H),4.65-4.60(m,1H),4.59-4.56(m,1H),4.55-4.52(m,2H),4.46-4.40(m,1H),4.32(s,2H),4.20-3.92(m,2H),3.88(d,J=11.1Hz,1H),3.79(s,2H),3.74(dd,J=3.8,11.0Hz,1H),3.70-3.58(m,2H),3.46(s,2H),3.40-3.34(m,2H),3.22-3.12(m,2H),2.49(s,3H),2.48-2.42(m,4H),2.08-1.72(m,8H),1.65(s,3H),1.64-1.45(m,4H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C62H77F2N11O5S[M+H]+=1126.6,found:1126.4.
实施例4
(2S,4R)-1-[(2S)-2-({7-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基庚-6-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M4)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ9.01(s,1H),8.19(s,1H),7.44(dd,J=8.4,5.0Hz,4H),7.39-7.32(m,4H),7.31-7.25(m,1H),7.02(dd,J=7.3,3.9Hz,1H),5.83(s,1H),5.00(q,J=7.0Hz,1H),4.67-4.60(m,1H),4.59-4.56(m,1H),4.55-4.50(m,2H),4.46-4.39(m,1H),4.32(s,2H),4.20-3.92(m,2H),3.88(d,J=11.0Hz,1H),3.79(s,2H),3.75(dd,J=11.0,3.8Hz,1H),3.71-3.59(m,2H),3.46(s,2H),3.40-3.33(m,2H),3.23-3.12(m,2H),2.49(s,3H),2.47-2.40(m,4H),2.24-1.68(m,10H),1.65(s,3H),1.61-1.46(m,4H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C63H79F2N11O5S[M+H]+=1140.6,found:1140.5.
实施例5
(2S,4R)-1-[(2S)-2-({8-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基辛-7-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M5)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ8.96(s,1H),8.19(s,1H),7.43(dd,J=8.2,5.6Hz,4H),7.39-7.31(m,4H),7.31-7.27(m,1H),7.02(dd,J=7.4,4.0Hz,1H),5.83(s,1H),5.00(q,J=7.0Hz,1H),4.64-4.59(m,1H),4.59-4.56(m,1H),4.55-4.52(m,2H),4.46-4.39(m,1H),4.32(s,2H),4.16-3.91(m,2H),3.87(d,J=11.1Hz,1H),3.79(s,2H),3.72(dd,J=11.1,3.9Hz,1H),3.69-3.53(m,2H),3.45(s,2H),3.40-3.33(m,2H),3.22-3.12(m,2H),2.48(s,3H),2.46-2.30(m,4H),2.28-1.65(m,12H),1.65(s,3H),1.52-1.43(m,4H),1.09(s,6H),1.02(s,9H).
ESI-MS calcd for C64H81F2N11O5S[M+H]+=1155.5,found:1155.8.
实施例6
(2S,4R)-1-[(2S)-2-({9-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基壬-8-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M6)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ9.03(s,1H),8.19(s,1H),7.44(dd,J=8.6,5.3Hz,4H),7.39-7.31(m,4H),7.31-7.26(m,1H),7.02(dd,J=11.4,4.1Hz,1H),5.83(s,1H),5.00(q,J=7.0Hz,1H),4.65-4.60(m,1H),4.60-4.56(m,1H),4.55-4.51(m,2H),4.46-4.41(m,1H),4.32(s,2H),4.16-3.91(m,2H),3.91-3.85(m,1H),3.79(s,2H),3.77-3.71(m,1H),3.70-3.59(m,2H),3.46(s,2H),3.40-3.33(m,2H),3.23-3.12(m,2H),2.49(s,3H),2.43-2.25(m,4H),2.23-1.54(m,14H),1.51(s,3H),1.49-1.28(m,4H),1.09(s,6H),1.03(s,9H).
ESI-MS calcd for C65H83F2N11O5S[M+H]+=1169.5,found:1169.6.
实施例7
(2S,4R)-1-[(2S)-2-({10-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基癸-9-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M7)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ8.94(s,1H),8.19(s,1H),7.43(dd,J=8.5,5.4Hz,4H),7.39-7.32(m,4H),7.31-7.27(m,1H),7.02(dd,J=11.4,4.1Hz,1H),5.83(s,1H),5.00(q,J=7.0Hz,1H),4.65-4.60(m,1H),4.60-4.56(m,1H),4.55-4.51(m,2H),4.45-4.40(m,1H),4.32(s,2H),4.16-3.91(m,2H),3.87(d,J=11.1Hz,1H),3.79(s,2H),3.74(dd,J=11.0,3.9Hz,1H),3.70-3.59(m,2H),3.46(s,2H),3.39-3.33(m,2H),3.22-3.12(m,2H),2.48(s,3H),2.44-2.26(m,4H),2.23-1.54(m,16H),1.65(s,3H),1.52-1.47(m,4H),1.09(s,6H),1.03(s,9H).
ESI-MS calcd for C66H85F2N11O5S[M+H]+=1183.5,found:1184.0.
实施例8
(2S,4R)-1-[(2S)-2-({11-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基十一-10-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M8)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ9.04(s,1H),8.19(s,1H),7.44(dd,J=8.4,5.0Hz,4H),7.39-7.32(m,4H),7.31-7.27(m,1H),7.02(dd,J=3.8,11.1Hz,1H),5.83(s,1H),5.00(q,J=7.0Hz,1H),4.64-4.61(m,1H),4.60-4.56(m,1H),4.55-4.50(m,2H),4.46-4.40(m,1H),4.32(s,2H),4.15-3.91(m,2H),3.88(d,J=11.1Hz,1H),3.79(s,2H),3.74(dd,J=11.0,3.8Hz,1H),3.70-3.57(m,2H),3.46(s,2H),3.40-3.33(m,2H),3.22-3.12(m,2H),2.49(s,3H),2.43-2.24(m,4H),2.23-1.49(m,18H),1.48-1.36(m,4H),1.35(s,3H),1.09(s,6H),1.03(s,9H).
ESI-MS calcd for C67H87F2N11O5S[M+H]+=1196.7,found:1196.4.
实施例9
(2S,4R)-1-[(2S)-2-({12-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基十二-11-炔基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M9)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ8.93(s,1H),8.19(s,1H),7.43(dd,J=8.5,5.3Hz,4H),7.38-7.31(m,4H),7.31-7.27(m,1H),7.03(dd,J=11.3,4.0Hz,1H),5.84(s,1H),5.00(q,J=7.0Hz,1H),4.65-4.61(m,1H),4.60-4.56(m,1H),4.55-4.51(m,2H),4.45-4.41(m,1H),4.32(s,2H),4.13-3.92(m,2H),3.88(d,J=11.2Hz,1H),3.80(s,2H),3.74(dd,J=11.0,3.9Hz,1H),3.71-3.61(m,2H),3.46(s,2H),3.40-3.34(m,2H),3.22-3.13(m,2H),2.48(s,3H),2.43-2.25(m,4H),2.24-1.50(m,20H),1.49-1.36(m,4H),1.34(s,3H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C68H89F2N11O5S[M+H]+=1211.6,found:1212.0.
实施例10
(2S,4R)-1-[(15S)-1-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-15-(2-甲基丙-2-基)-13,16-二氧亚基-14-氮杂-4,7,10-三氧杂十六-1-炔-16-基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M10)。
合成方法使用通用方案1制备,参考实施例1。
1H NMR(400MHz,MeOD)δ9.05(s,1H),8.19(s,1H),7.48-7.46(m,1H),7.44(dd,J=8.0,4.6Hz,4H),7.42-7.30(m,4H),7.02(dd,J=7.3,4.1Hz,1H),5.84(s,1H),4.99(q,J=7.0Hz,1H),4.66-4.61(m,1H),4.59-4.54(m,3H),4.44-4.40(m,3H),4.32(s,2H),4.14-3.90(m,2H),3.86(d,J=11.2Hz,1H),3.79(s,2H),3.77-3.58(m,14H),3.45(s,2H),3.40-3.33(m,2H),3.22-3.12(m,2H),2.62-2.54(m,1H),2.49(s,3H),2.48-2.42(m,1H),2.24-2.16(m,1H),2.05-1.80(m,5H),1.65(s,3H),1.52-1.48(m,2H),1.09(s,6H),1.03(s,9H).
ESI-MS calcd for C66H85F2N11O8S[M+H]+=1231.5,found:1232.0.
实施例11
4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)-N-[(2S)-1-[(2S,4R)-4-羟基-2-({[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]氨基}羰基)四氢-1H-吡咯-1-基]-3,3-二甲基-1-氧亚基丁-2-基]苯甲酰胺(M11)。
合成方法使用通用方案2制备,参考实施例12。
1H NMR(400MHz,MeOD)δ8.90(s,1H),8.21(s,1H),7.87-7.86(m,3H),7.50(d,J=8.0,2H),7.47-7.40(m,4H),7.38-7.32(m,1H),7.06-7.01(m,1H),5.84(s,1H),5.04-5.00(m,1H),4.64(s,2H),4.61-4.57(m,1H),4.49-4.44(m,1H),4.32(s,2H),3.96-3.93(m,1H),3.80-3.78(m,2H),3.72-3.63(m,2H),3.48-3.44(m,2H),3.35(s,2H),3.22-3.13(m,2H),2.48-2.46(m,3H),2.25-2.17(m,1H),2.04-1.94(m,3H),1.86-1.79(m,2H),1.69-1.63(m,4H),1.53-1.51(m,3H),1.37-1.30(m,4H),1.09(s,6H),0.99(s,9H).
ESI-MS calcd for C57H71F2N11O5S[M+H]+=1060.3,found:1060.8.
实施例12
(2S,4R)-1-[(2S)-2-({2-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]乙酰基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M12)。
合成方法使用方案2制备:
步骤2.1[4-(氨基甲基)苯基]乙酸甲酯(11)的合成:
将化合物10(250mg,1.43mmol,1equiv)溶解于10mL的甲醇中,通入氢气抽换气三次,再加入钯碳(15mg,0.143mmol,0.1equiv),室温下反应3h,TLC显示反应完全。过滤除去反应中的固体,将反应混合物浓缩并通过硅胶快速柱色谱法用石油醚:乙酸乙酯(10:1)纯化,得到化合物11(200mg,78%产率)。
步骤2.2(4-{[(6-氯嘧啶-4-基)氨基]甲基}苯基)乙酸甲酯(12)的合成:
将化合物11(200mg,1.12mmol,1.0equiv)和化合物1(167mg,1.12mmol,1.0equiv)溶解于5mL异丙醇溶液中,再加入三乙胺(340mg,3.36mmol,3.0equiv),室温下搅拌12h。TLC显示反应完成。将反应混合物浓缩并通过硅胶快速柱色谱法用二氯甲烷:甲醇(20:1)纯化,得到呈白色固体状的化合物12(203mg,62%产率)。
步骤2.3[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]乙酸(13)的合成:
化合物4的合成见参考文献(J.Med.Chem.2021,64,17,12738-12760.)。将化合物12(30mg,0.10mmol,1.0equiv)和化合物4(41mg,0.10mmol,1.0equiv)溶解于5mL异丙醇溶液中,再加入碳酸铯(98mg,0.30mmol,3.0equiv),加热至120℃反应48h。反应结束后,过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到白色固体的化合物13(11mg,17%产率)。
ESI-MS calcd for C35H43F2N7O3[M+H]+=648.3,found:648.3.
步骤2.4(2S,4R)-1-[(2S)-2-({2-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]乙酰基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M12)的合成:
将化合物13(11mg,0.017mmol,1.0equiv)溶于2mL二氯甲烷溶液中,并在室温下搅拌。向搅拌的溶液中依次加入化合物6(8mg,0.017mmol,1.0equiv)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(7mg,0.019mmol,1.1equiv),最后加入N,N-二异丙基乙胺(7mg,0.051mmol,3.0equiv)。将反应混合物在室温下搅拌1h,TLC显示反应完成。过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到呈白色固体状的化合物M12(4mg,22%产率)。
1H NMR(400MHz,MeOD)δ8.93(s,1H),8.19(s,1H),7.43(dd,J=8.5,5.5Hz,4H),7.39-7.36(m,1H),7.35-7.30(m,4H),7.03(dd,J=7.1,4.1Hz,1H),5.84(s,1H),5.00-4.97(m,1H),4.64-4.60(m,1H),4.59-4.56(m,1H),4.54(s,2H),4.43-4.38(m,1H),4.32(s,2H),3.79(s,2H),3.75-3.67(m,2H),3.65-3.60(m,2H),3.47(s,2H),3.40-3.35(m,2H),3.21-3.13(m,2H),2.48(s,3H),2.25-1.59(m,14H),1.54-1.47(m,3H),1.09(s,6H),0.99(s,9H).
ESI-MS calcd for C58H73F2N11O5S[M+H]+=1074.6,found:1074.6.
实施例13
(2S,4R)-1-[(2S)-2-({3-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]丙酰基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M13)。
合成方法使用通用方案2制备,参考实施例12。
1H NMR(400MHz,MeOD)δ8.94(s,1H),8.19(s,1H),7.43(dd,J=8.5,5.5Hz,4H),7.39-7.36(m,1H),7.35-7.30(m,4H),7.03(dd,J=7.1,4.1Hz,1H),5.84(s,1H),5.00-4.97(m,1H),4.64-4.60(m,1H),4.59-4.56(m,1H),4.54(s,2H),4.43-4.38(m,1H),4.32(s,2H),3.79(s,2H),3.75-3.67(m,2H),3.65-3.60(m,2H),3.47(s,2H),3.40-3.35(m,2H),3.33-3.23(m,2H),3.21-3.13(m,2H),2.48(s,3H),2.25-1.59(m,14H),1.54-1.47(m,3H),1.09(s,6H),0.99(s,9H).
ESI-MS calcd for C59H75F2N11O5S[M+H]+=1088.6,found:1088.6.
实施例14
(2S,4R)-1-[(2S)-2-({4-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基丁基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M14)。
ESI-MS calcd for C60H77F2N11O5S[M+H]+=1102.6,found:1102.6.
合成方法使用通用方案2制备,参考实施例12。
实施例15
(2S,4R)-1-[(2S)-2-({5-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-1-氧亚基戊基}氨3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M15)的制备:
化合物M2的合成见实施例2。将化合物M2(20mg,0.018mmol,1.0equiv)溶于2mL甲醇溶液中,通入氢气充换气三次,再加入5mg钯碳,室温下反应10h。反应结束后,过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到白色固体的化合物M15(8mg,40%产率)。
1H NMR(400MHz,MeOD)δ8.93(s,1H),8.19(s,1H),7.43(dd,J=8.5,5.5Hz,4H),7.39-7.36(m,1H),7.35-7.30(m,4H),7.03(dd,J=7.1,4.1Hz,1H),5.84(s,1H),5.04-5.00(m,1H),4.63-4.53(m,3H),4.43-4.40(m,1H),4.32(s,2H),3.80-3.78(m,3H),3.70-3.60(m,2H),3.46(s,2H),3.38-3.35(m,2H),3.22-3.13(m,2H),2.66-2.60(m,2H),2.48-2.46(m,3H),2.31-2.17(m,3H),2.05-1.90(m,3H),1.88-1.77(m,2H),1.68-1.63(m,8H),1.52-1.50(m,4H),1.33-1.30(m,3H),1.09(s,6H),0.99(s,9H).
ESI-MS calcd for C61H79F2N11O5S[M+H]+=1116.6,found:1116.8.
实施例16
(2S,4R)-1-[(2S)-2-[(5-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基戊基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M16)。
合成方法使用通用方案3制备,参考实施例21。
1H NMR(400MHz,MeOD)δ8.90(s,1H),8.17(s,1H),7.43(dd,J=8.1,4.5Hz,4H),7.37-7.32(m,1H),7.04(dd,J=7.0,4.3Hz,1H),5.87(s,1H),5.05-4.95(m,1H),4.63-4.61(m,1H),4.57-4.55(m,1H),4.45-4.43(m,1H),4.32(s,2H),3.81(s,2H),3.78-3.63(m,4H),3.48(s,2H),3.39-3.34(m,2H),3.20-3.14(m,2H),2.48(s,3H),2.39-2.17(m,4H),2.10-1.84(m,6H),1.77-1.61(m,9H),1.59-1.45(m,4H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C54H73F2N11O5S[M+H]+=1026.6,found:1026.6.
实施例17
(2S,4R)-1-[(2S)-2-[(6-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基己基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M17)。
合成方法使用通用方案3制备,参考实施例21。
1H NMR(400MHz,MeOD)δ8.90(s,1H),8.17(s,1H),7.42(dd,J=8.2,4.9Hz,4H),7.38-7.33(m,1H),7.04(dd,J=7.0,4.3Hz,1H),5.87(s,1H),5.05-4.95(m,1H),4.63-4.61(m,1H),4.57-4.55(m,1H),4.45-4.43(m,1H),4.31(s,2H),3.81(s,2H),3.78-3.63(m,4H),3.50(s,2H),3.39-3.34(m,2H),3.20-3.14(m,2H),2.48(s,3H),2.39-2.17(m,4H),2.28-2.16(m,2H),2.10-1.84(m,6H),1.77-1.61(m,9H),1.59-1.45(m,4H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C55H75F2N11O5S[M+H]+=1040.6,found:1040.5.
实施例18
(2S,4R)-1-[(2S)-2-[(7-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基庚基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M18)。
合成方法使用通用方案3制备,参考实施例21。
1H NMR(400MHz,MeOD)δ8.90(s,1H),8.17(s,1H),7.43(dd,J=8.2,5.0Hz,4H),7.37-7.31(m,1H),7.04(dd,J=7.6,3.4Hz,1H),5.84(s,1H),5.01-4.98(m,1H),4.65-4.61(m,1H),4.60-4.54(m,1H),4.45-4.42(m,1H),4.32(s,2H),3.80(s,2H),3.78-3.60(m,4H),3.48(s,2H),3.39-3.34(m,2H),3.21-3.13(m,2H),2.48(s,3H),2.35-2.15(m,4H),2.10-1.84(m,6H),1.73-1.56(m,9H),1.53-1.31(m,8H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C56H77F2N11O5S[M+H]+=1054.6,found:1054.6.
实施例19
(2S,4R)-1-[(2S)-2-[(8-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基辛基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M19)。
合成方法使用通用方案3制备,参考实施例21。
1H NMR(400MHz,MeOD)δ8.91(s,1H),8.17(s,1H),7.44(dd,J=8.3,4.9Hz,4H),7.36-7.30(m,1H),7.04(dd,J=7.6,3.4Hz,1H),5.85(s,1H),5.01-4.98(m,1H),4.64-4.60(m,1H),4.59-4.54(m,1H),4.48-4.45(m,1H),4.32(s,2H),3.81(s,2H),3.79-3.63(m,4H),3.48(s,2H),3.42-3.35(m,2H),3.22-3.13(m,2H),2.50(s,3H),2.38-2.20(m,4H),2.19-2.14(m,2H),2.10-1.84(m,6H),1.72-1.56(m,9H),1.53-1.31(m,8H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C57H79F2N11O5S[M+H]+=1068.6,found:1068.6.
实施例20
(2S,4R)-1-[(2S)-2-[(9-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基壬基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M20)。
合成方法使用通用方案3制备,参考实施例21。
1H NMR(400MHz,MeOD)δ8.92(s,1H),8.16(s,1H),7.43(dd,J=8.4,4.2Hz,4H),7.37-7.31(m,1H),7.03(dd,J=7.3,4.0Hz,1H),5.84(s,1H),5.03-4.97(m,1H),4.65-4.61(m,1H),4.57-4.55(m,1H),4.45-4.42(m,1H),4.32(s,2H),3.80(s,2H),3.78-3.61(m,4H),3.48(s,2H),3.40-3.35(m,2H),3.21-3.13(m,2H),2.48(s,3H),2.33-2.17(m,4H),2.08-1.85(m,6H),1.71-1.57(m,10H),1.46-1.32(m,11H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C58H81F2N11O5S[M+H]+=1082.8,found:1082.6.
实施例21
(2S,4R)-1-[(2S)-2-[(10-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基癸基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M21)。
合成方法使用通用方案3制备:
步骤3.1[(10-{[(2S)-1-[(2S,4R)-4-羟基-2-({[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]氨基}羰基)四氢-1H-吡咯-1-基]-3,3-二甲基-1-氧亚基丁-2-基]氨基}-10-氧亚基癸基)氨基]甲烷酸-2-甲基丙-2-基酯(15)的合成:
将化合物14(129mg,0.45mmol,1.0equiv)溶于10mL二氯甲烷溶液中,并在室温下搅拌。向搅拌的溶液中依次加入化合物6(200mg,0.45mmol,1.0equiv)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(188mg,0.495mmol,1.1equiv),最后加入N,N-二异丙基乙胺(174mg,1.35mmol,3.0equiv)。将反应混合物在室温下搅拌12h,TLC显示反应完成。加入50mL水稀释,用二氯甲烷(3×25mL)萃取,合并的有机相用无水硫酸钠干燥并浓缩。浓缩物通过硅胶快速柱色谱法用二氯甲烷:甲醇(10:1)纯化,得到呈白色固体状的化合物15(160mg,50%产率)。
步骤3.2(2S,4R)-1-[(2S)-2-[(10-氨基-1-氧亚基癸基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(16)的合成:
将化合物15(160mg,0.22mmol,1.0equiv)溶解于10mL甲醇溶液中,再加入5mL的盐酸二氧六环溶液(4mol/L),室温下搅拌2h。TLC显示反应完成。将反应混合物浓缩得到化合物16(138mg,100%产率)。
步骤3.3(2S,4R)-1-[(2S)-2-({10-[(6-氯嘧啶-4-基)氨基]-1-氧亚基癸基}氨基)-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(17)的合成:
将化合物16(148mg,0.24mmol,1.0equiv)和化合物1(36mg,0.24mmol,1.0equiv)溶解于5mL异丙醇溶液中,再加入三乙胺(73mg,0.72mmol,3.0equiv),加热至60℃反应12h。将反应混合物浓缩并通过硅胶快速柱色谱法用二氯甲烷:甲醇(10:1)纯化,得到呈白色固体状的化合物17(70mg,40%产率)。
ESI-MS calcd for C37H52ClN7O4S[M+H]+=726.4,found:726.4.
步骤3.4(2S,4R)-1-[(2S)-2-[(10-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基癸基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M21)的制备:
化合物4的合成见参考文献(J.Med.Chem.2021,64,17,12738-12760.)。将化合物17(15mg,0.02mmol,1.0equiv)和化合物4(10mg,0.024mmol,1.2equiv)溶解于2mL1,4-二氧六环溶液中,再加入碳酸铯(16mg,0.05mmol,2.5equiv)。在氩气保护下抽换气三次后加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(3mg,0.003mmol,0.15equiv),在氩气保护下再次抽换气三次,加热至105℃反应12h。反应结束后,过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到白色固体的化合物M21(3mg,14%产率)。
1H NMR(400MHz,MeOD)δ8.94(s,1H),8.16(s,1H),7.43(dd,J=8.5,5.0Hz,4H),7.37-7.30(m,1H),7.04(dd,J=7.2,4.2Hz,1H),5.84(s,1H),5.02-4.97(m,1H),4.65-4.60(m,1H),4.58-4.54(m,1H),4.45-4.41(m,1H),4.32(s,2H),3.81(s,2H),3.78-3.54(m,4H),3.48(s,2H),3.39-3.34(m,2H),3.22-3.14(m,2H),2.49(s,3H),2.35-2.16(m,4H),2.10-1.83(m,6H),1.70-1.49(m,12H),1.45-1.30(m,11H),1.09(s,6H),0.99(s,9H).
ESI-MS calcd for C59H83F2N11O5S[M+H]+=1096.6,found:1096.5.
实施例22
(2S,4R)-1-[(2S)-2-[(11-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基十一烷基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M22)。
合成方法使用通用方案3制备,参考实施例21。
1H NMR(400MHz,MeOD)δ8.88(s,1H),8.16(s,1H),7.43(dd,J=8.4,4.4Hz,4H),7.37-7.30(m,1H),7.04(dd,J=7.4,4.0Hz,1H),5.84(s,1H),5.02-5.00(m,1H),4.72-4.61(m,1H),4.61-4.53(m,1H),4.47-4.41(m,1H),4.32(s,2H),3.81(s,2H),3.78-3.58(m,4H),3.48(s,2H),3.39-3.35(m,2H),3.21-3.13(m,2H),2.48(s,3H),2.38-2.15(m,4H),2.12-1.80(m,6H),1.73-1.42(m,12H),1.41-1.15(m,13H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C60H85F2N11O5S[M+H]+=1110.6,found:1110.8.
实施例23
(2S,4R)-1-[(2S)-2-[(12-{[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}-1-氧亚基十二烷基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M23)。
合成方法使用通用方案3制备,参考实施例21。
1H NMR(400MHz,MeOD)δ8.91(s,1H),8.16(s,1H),7.43(dd,J=8.4,4.2Hz,4H),7.38-7.31(m,1H),7.03(dd,J=7.2,4.1Hz,1H),5.84(s,1H),5.03-4.98(m,1H),4.65-4.61(m,1H),4.60-4.53(m,1H),4.46-4.41(m,1H),4.32(s,2H),3.81(s,2H),3.78-3.52(m,4H),3.48(s,2H),3.40-3.34(m,2H),3.22-3.12(m,2H),2.48(s,3H),2.35-2.15(m,4H),2.11-1.81(m,6H),1.75-1.47(m,12H),1.44-1.29(m,15H),1.09(s,6H),1.04(s,9H).
ESI-MS calcd for C61H87F2N11O5S[M+H]+=1124.7,found:1124.7.
实施例24
5-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]戊-4-炔酰胺(M24)。
合成方法使用通用方案4制备:
步骤4.1,4.2同实施例1反应步骤1.1,1.2.
步骤4.3N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]戊-4-炔酰胺(9)的制备:
将4-戊炔酸(118mg,1.2mmol,1.2equiv)溶于4mL二氯甲烷溶液中,并在冰浴下加入二氯亚砜(143mg,1.2mmol,1.2equiv),在无水条件下室温搅拌4小时。旋干反应液,向旋干的混合物中依次加入化合物8(300mg,1.1mmol,1.1equiv)和6mL四氢呋喃溶液,反应混合物在室温下搅拌12h,TLC显示反应完成。加入20mL水稀释,用乙酸乙酯(3×20mL)萃取,合并的有机相用无水硫酸钠干燥并浓缩。浓缩物通过硅胶快速柱色谱法用二氯甲烷:甲醇(10:1)纯化,得到呈无色油状化合物9(100mg,25.7%产率)。
1H NMR(400MHz,DMSO)δ11.16(s,1H),9.79(s,1H),8.45-8.43(m,1H),7.85-7.81(m,1H),7.63-7.61(m,1H),5.16-5.13(m,1H),2.93-2.77(m,2H),2.69-2.21(m,4H),2.54-2.51(m,1H),2.89-2.67(m,7H),2.41-2.35(m,1H),2.07(brs,1H),.
步骤4.4 5-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]戊-4-炔酰胺(M24)制备:
将化合物5(46mg,0.064mmol,1.0equiv)和化合物9(30mg,0.077mmol,1.2equiv)溶解于2mL N,N-二甲基甲酰胺溶液中,再加入0.2mL三乙胺。在氩气保护下抽换气三次后加入碘化亚铜(2.5mg,0.013mmol,0.2equiv)和双三苯基膦二氯化钯(5mg,0.006mmol,0.1equiv),在氩气保护下再次抽换气三次,加热至80℃反应12h。反应结束后,过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到白色固体的化合物M24(15mg,25%产率)。
1H NMR(400MHz,MeOD)δ8.67(d,J=8.4Hz,1H),8.18(s,1H),7.78(t,J=8.0Hz,1H),7.59(d,J=7.2Hz,1H),7.35-7.31(m,3H),7.29-7.27(m,2H),7.03(dd,J=11.2,7.2Hz,1H),5.79(s,1H),5.15-5.10(m,1H),4.52(s,2H),4.32(s,2H),3.97(brs,2H),3.80(s,2H),3.66(brs,2H),3.45(s,2H),3.38-3.35(m,2H),3.21-3.14(m,2H),2.89-2.67(m,7H),2.14-2.10(m,1H),2.05-1.94(m,2H),1.89-1.80(m,2H),1.68-1.65(m,4H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C51H54F2N10O6[M+H]+=941.0,found:941.4.
实施例25
6-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]己-5-炔酰胺(M25)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.63(d,J=8.4Hz,1H),8.20(s,1H),7.73(t,J=7.6Hz,1H),7.52(d,J=7.2Hz,1H),7.36-7.31(m,3H),7.26-7.24(m,2H),7.02(dd,J=11.6,7.2Hz,1H),5.82(s,1H),5.15-5.10(m,1H),4.51(s,2H),4.32(s,2H),3.99(brs,2H),3.79(s,2H),3.67(brs,2H),3.46(s,2H),3.37-3.34(m,2H),3.21-3.14(m,2H),2.92-2.83(m.1H),2.78-2.67(m,4H),2.55(t,J=6.8Hz,2H),2.21-2.12(m,1H),2.07-2.00(m,4H),1.87-1.81(m,2H),1.68-1.65(m,4H),1.09(s,3H),l.04(s,3H).
ESI-MS calcd for C52H56F2N10O6[M+H]+=955.1,found:955.4.
实施例26
7-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]庚-6-炔酰胺(M26)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.64(d,J=8.64Hz,1H),8.19(s,1H),7.79-7.75(m,1H),7.57(d,J=7.2Hz,1H),7.38-7.28(m,5H),7.05-7.00(m,1H),5.82(s,1H),5.15-5.10(m,1H),4.53(s,2H),4.32(s,2H),3.99(brs,2H),3.79(s,2H),3.66(brs,2H),3.45(s,2H),3.37-3.34(m,2H),3.22-3.13(m,2H),2.93-2.82(m,1H),2.76-2.66(m,2H),2.58(t,J=7.6Hz,2H),2.49(t,J=6.8Hz,2H),2.16-2.12(m,1H),2.03-1.96(m,2H),1.95-1.89(m,2H),1.86-1.81(m,2H),1.73-1.65(m,6H),1.09(s,3H),l.04(s,3H).
ESI-MS calcd for C53H58F2N10O6[M+H]+=969.1,found:969.4.
实施例27
8-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]辛-7-炔酰胺(M27)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.63(d,J=8.4Hz,1H),8.20(s,1H),7.74(t,J=7.6Hz,1H),7.53-7.52(m,1H),7.36-7.22(m,5H),7.02(dd,J=11.6,7.2Hz,1H),5.82(s,1H),5.14-5.10(m,1H),4.52(s,2H),4.32(s,2H),4.00(brs,2H),3.79(s,2H),3.67(brs,2H),3.46(s,2H),3.37-3.34(m,2H),3.21-3.13(m,2H),2.91-2.82(m,1H),2.77-2.64(m,1H),2.55(t,J=7.2Hz,2H),2.44(t,J=6.0Hz,2H),2.15-2.09(m,1H),2.04-1.99(m,2H),1.87-1.78(m,4H),1.71-1.59(m,8H),1.09(s,3H),l.04(s,3H).
ESI-MS calcd for C54H60F2N10O6[M+H]+=983.4,found:983.4.
实施例28
9-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]壬-8-炔酰胺(M28)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.63(d,J=8.4Hz,1H),8.19(s,1H),7.78-7.74(m,1H),7.57(d,J=7.2Hz,1H),7.36-7.32(m,3H),7.31-7.28(m,2H),7.05-7.00(m,1H),5.82(s,1H),5.15-5.11(m,1H),4.53(s,2H),4.32(s,2H),4.00(brs,2H),3.79(s,2H),3.65(brs,2H),3.46(s,2H),3.37-3.34(m,2H),3.21-3.13(m,2H),2.87-2.81(m,1H),2.76-2.70(m,2H),2.53(t,J=7.2Hz,2H),2.42(t,J=6.8Hz,2H),2.19-2.13(m,1H),2.03-2.00(m,2H),1.87-1.74(m,4H),1.65-1.61(m,6H),1.57-1.48(m,4H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C55H62F2N10O6[M+H]+=997.4,found:997.4.
实施例29
10-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]癸-9-炔酰胺(M29)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.63(d,J=8.0Hz,1H),8.19(s,1H),7.79-7.75(m,1H),7.56(d,J=7.2Hz,1H),7.36-7.27(m,5H),7.05-7.00(m,1H),5.81(s,1H),5.15-5.11(m,1H),4.52(s,2H),4.32(s,2H),4.00(brs,2H),3.79(s,2H),3.66(brs,2H),3.46(s,2H),3.38-3.34(m,2H),3.21-3.17(m,2H),2.91-2.82(m,1H),2.77-2.66(m,2H),2.51(t,J=7.2Hz,2H),2.41(t,J=6.8Hz,2H),2.19-2.11(m,1H),2.04-1.99(m,2H),1.87-1.81(m,2H),1.78-1.75(m,2H),1.68-1.64(m,4H),1.62-1.57(m,2H),1.52-1.43(m,6H),1.09(s,3H),l.04(s,3H).
ESI-MS calcd for C56H64F2N10O6[M+H]+=1011.4,found:1011.4.
实施例30
11-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]十一-10-炔酰胺(M30)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.63(d,J=8.4Hz,1H),8.19(s,1H),7.76(t,J=7.6Hz,1H),7.56(d,J=7.2Hz,1H),7.36-7.29(m,5H),7.03-6.99(m,1H),5.82(s,1H),5.13(dd,J=12.8,5.6Hz,1H),4.52(s,2H),4.32(s,2H),4.00(brs,2H),3.79(s,2H),3.65(brs,2H),3.45(s,2H),3.37-3.34(m,2H),3.19-3.13(m,2H),2.90-2.82(m,1H),2.78-2.70(m,2H),2.49(t,J=7.2Hz,2H),2.39(t,J=6.8Hz,2H),2.18-2.12(m,1H),2.04-2.00(m,2H),1.87-1.81(m,2H),1.76-1.73(m,2H),1.69-1.65(m,4H),1.61-1.55(m,2H),1.50-1.46(m,2H),1.45-1.41(m,6H),1.09(s,3H),l.03(s,3H).
ESI-MS calcd for C57H66F2N10O6[M+H]+=1025.4,found:1025.4.
实施例31
12-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]十二-11-炔酰胺(M31)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.63(d,J=8.4Hz,1H),8.18(s,1H),7.79-7.75(m,1H),7.57(d,J=7.2Hz,1H),7.37-7.29(m,5H),7.04-7.00(m,1H),5.82(s,1H),5.16-5.11(m,1H),4.52(s,2H),4.32(s,2H),4.00(brs,2H),3.79(s,2H),3.66(brs,2H),3.46(s,2H),3.38-3.34(m,2H),3.21-3.14(m,2H),2.92-2.82(m,1H),2.78-2.68(m,2H),2.48(t,J=7.6Hz,2H),2.39(t,J=6.8Hz,2H),2.21-2.12(m,1H),2.04-2.00(m,2H),1.87-1.82(m,2H),1.75-1.71(m,2H),1.69-1.65(m,4H),1.62-1.56(m,2H),1.55-1.47(m,2H),1.39-1.37(m,8H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C58H68F2N10O6[M+H]+=1039.4,found:1039.4.
实施例32
3-({9-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-3,6-二氧杂壬-8-炔-1-基}氧基)-N-[2-(2,6-二氧亚基六氢吡啶-3-基)-1,3-二氧亚基-2,3-二氢-1H-异吲哚-4-基]丙酰胺(M32)。
合成方法使用通用方案4制备,参考实施例24。
1H NMR(400MHz,MeOD)δ8.70(d,J=8.0Hz,1H),8.19(s,1H),7.75-7.71(m,1H),7.52(d,J=7.2Hz,1H),7.43-7.40(m,2H),7.35-7.30(m,3H),5.82(s,1H),5.12(dd,J=12.8,5.6Hz,1H),4.55(s,2H),4.33-4.32(m,4H),3.99(brs,2H),3.84(t,J=5.6Hz,2H),3.79(s,2H),2.90-2.81(m,1H),2.76-2.69(m,4H),2.19-2.11(m,1H),2.03-1.99(m,2H),1.87-1.82(m,2H),1.68-1.64(m,4H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C56H64F2N10O9[M+H]+=1059.4,found:1059.4.
实施例33
1-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[(2S)-1-[(2S,4R)-4-羟基-2-({[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]氨基}羰基)四氢-1H-吡咯-1-基]-3,3-二甲基-1-氧亚基丁-2-基]六氢吡啶-4-甲酰胺(M33)。
合成方法使用通用方案5制备:
步骤5.1 1-[4-(2,2-二甲基-4-氧亚基-5-氮杂-3-氧杂己-6-基)苯基]六氢吡啶-4-甲酸甲酯(20)的合成:
将化合物18(1g,3.5mmol,1.0equiv)和化合物19(750mg,5.2mmol,1.5equiv)溶解于25mL的甲苯溶液中,再加入碳酸铯(2.28g,7mmol,2equiv)。在氩气保护下抽换气三次后加入醋酸钯(80mg,0.35mmol,0.1equiv)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(410mg,0.7mmol,0.2equiv)。在氩气保护下再次抽换气三次,加热至100℃反应12小时。TLC显示反应完成,将反应混合物过滤浓缩并通过硅胶快速柱色谱法用石油醚:乙酸乙酯(5:1)纯化,得到无色油状液体20(770mg,63%产率)。
1H NMR(400MHz,CDCl3)δ7.14(d,J=8.4Hz,2H),6.86(d,J=8.6Hz,2H),4.26-4.11(m,2H),3.68(s,3H),3.64-3.53(m,2H),2.74(td,J=12.2,2.4Hz,2H),2.48-2.37(m,1H),2.03-1.96(m,2H),1.90-1.78(m,2H),1.43(s,9H).
步骤5.2 1-[4-(氨基甲基)苯基]六氢吡啶-4-甲酸甲酯(21)的合成:
将化合物20(770mg,2.21mmol,1.0equiv)溶解于10mL甲醇溶液中,再加入3mL的盐酸二氧六环溶液(4mol/L),室温下搅拌2h。TLC显示反应完成,将反应混合物浓缩得到化合物21(549mg,100%产率)。
步骤5.3 1-(4-{[(6-氯嘧啶-4-基)氨基]甲基}苯基)六氢吡啶-4-甲酸甲酯(22)的合成:
将化合物21(549mg,2.21mmol,1.0equiv)和化合物1(329mg,2.21mmol,1.0equiv)溶解于5mL异丙醇溶液中,再加入三乙胺(671mg,6.63mmol,3.0equiv),加热至60℃反应12h。TLC显示反应完成,将反应混合物浓缩并通过硅胶快速柱色谱法用二氯甲烷:甲醇(20:1)纯化,得到黄褐色固体22(600mg,75%产率)。
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.15(d,J=8.4Hz,2H),6.86(d,J=8.5Hz,2H),6.31(s,1H),4.34(s,2H),3.67(s,3H),3.64-3.53(m,2H),2.75(td,J=12.2,2.4Hz,2H),2.47-2.37(m,1H),2.03-1.92(m,2H),1.90-1.72(m,2H),1.43(s,9H).
步骤5.4 1-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]六氢吡啶-4-甲酸(23)的合成:
化合物4的合成见参考文献(J.Med.Chem.2021,64,17,12738-12760.)。将化合物22(89mg,0.25mmol,1.0equiv)和化合物4(100mg,0.25mmol,1.0equiv)溶解于2mL异丙醇溶液中,再加入碳酸铯(240mg,0.74mmol,3.0equiv),加热至130℃反应48h。将反应混合物浓缩并通过硅胶快速柱色谱法用二氯甲烷:甲醇(10:1)纯化,得到呈白色固体状的化合物23(71mg,40%产率)。
ESI-MS calcd for C39H50F2N8O3[M+H]+=717.4,found:717.3.
步骤5.5 1-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[(2S)-1-[(2S,4R)-4-羟基-2-({[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]氨基}羰基)四氢-1H-吡咯-1-基]-3,3-二甲基-1-氧亚基丁-2-基]六氢吡啶-4-甲酰胺(M33)的制备:
将化合物23(19mg,0.03mmol,1.0equiv)溶于1mL二氯甲烷溶液中,并在室温下搅拌。向搅拌的溶液中依次加入化合物6(12mg,0.03mmol,1.0equiv)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(10mg,0.03mmol,1.0equiv),最后加入N,N-二异丙基乙胺(10mg,0.09mmol,3.0equiv)。将反应混合物在室温下搅拌1h,TLC显示反应完成。过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到呈白色固体状的化合物M33(8mg,26%产率)。
1H NMR(400MHz,MeOD)δ8.95(s,1H),8.20(s,1H),7.59-7.49(m,4H),7.44(dd,J=8.6,3.6Hz,4H),7.37-7.31(m,1H),7.02(dd,J=7.3,4.1Hz,1H),5.88(s,1H),5.01(q,J=6.9Hz,1H),4.67-4.62(m,1H),4.62-4.60(m,1H),4.60-4.55(m,2H),4.49-4.41(m,1H),4.32(s,2H),4.19-3.92(m,2H),4.91-3.86(m,1H),3.84-3.76(m,4H),3.76-3.49(m,4H),3.46(s,2H),3.45-3.32(m,4H),3.22-3.12(m,2H),2.49(s,3H),2.25-1.93(m,8H),1.89-1.80(m,2H),1.75-1.62(m,4H),1.60-1.48(m,3H),1.09(s,6H),1.07(s,9H).
ESI-MS calcd for C62H80F2N12O5S[M+H]+=1143.6,found:1143.4.
实施例34
(2S,4R)-1-[(2S)-2-[(2-{1-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]六氢吡啶-4-基}乙酰基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M34)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(400MHz,MeOD)δ8.92(s,1H),8.20(s,1H),7.60-7.52(m,4H),7.43(dd,J=8.6,3.8Hz,4H),7.37-7.31(m,1H),7.02(dd,J=7.2,4.0Hz,1H),5.88(s,1H),5.01(q,J=6.9Hz,1H),4.68-4.62(m,1H),4.62-4.58(m,2H),4.58-4.53(m,1H),4.48-4.40(m,1H),4.32(s,2H),4.16-3.94(m,2H),4.92-3.86(m,1H),3.84-3.69(m,4H),3.68-3.52(m,4H),3.46(s,2H),3.46-3.32(m,4H),3.23-3.12(m,2H),2.48(s,3H),2.40-2.31(m,2H),2.24-2.15(m,2H),2.10-1.99(m,4H),1.90-1.72(m,4H),1.71-1.60(m,4H),1.60-1.49(m,3H),1.09(s,6H),1.06(s,9H).
ESI-MS calcd for C63H82F2N12O5S[M+H]+=1157.6,found:1157.4.
实施例35
(2S,4R)-1-[(2S)-2-{[2-(1-{[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]甲基}六氢吡啶-4-基)乙酰基]氨基}-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M35)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(400MHz,MeOD)δ8.93(s,1H),8.20(s,1H),7.51(dd,J=8.6,3.2Hz,4H),7.43(dd,J=8.4,4.4Hz,4H),7.38-7.32(m,1H),7.02(dd,J=7.3,4.1Hz,1H),5.87(s,1H),5.00(q,J=7.0Hz,1H),4.67-4.61(m,1H),4.61-4.55(m,2H),4.46-4.40(m,1H),4.48-4.40(m,1H),4.32(s,2H),4.30-4.28(m,1H),4.17-3.93(m,2H),3.80(s,2H),3.79-3.57(m,4H),3.57-3.39(m,4H),3.38-3.33(m,2H),3.21-3.13(m,2H),3.06-2.92(m,2H),2.48(s,3H),2.34-2.20(m,2H),2.20-1.85(m,8H),1.85-1.52(m,8H),1.52-1.44(m,3H),1.09(s,6H),1.03(s,9H).
ESI-MS calcd for C64H84F2N12O5S[M+H]+=1171.6,found:1171.8.
实施例36
(2S,4R)-1-[(2S)-2-[(3-{1-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]六氢吡啶-4-基}丙酰基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M36)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(400MHz,MeOD)δ8.95(s,1H),8.20(s,1H),7.60-7.52(m,4H),7.43(dd,J=8.6,3.8Hz,4H),7.37-7.31(m,1H),7.02(dd,J=7.2,4.0Hz,1H),5.88(s,1H),5.01(q,J=6.9Hz,1H),4.68-4.62(m,1H),4.62-4.58(m,2H),4.58-4.53(m,1H),4.48-4.40(m,1H),4.32(s,2H),4.16-3.94(m,2H),4.92-3.86(m,1H),3.84-3.69(m,4H),3.68-3.52(m,4H),3.46(s,2H),3.46-3.32(m,4H),3.23-3.12(m,2H),2.48(s,3H),2.40-2.31(m,2H),2.24-2.15(m,2H),2.10-1.99(m,4H),1.90-1.72(m,4H),1.71-1.60(m,4H),1.60-1.49(m,3H),1.09(s,6H),1.06(s,9H).
ESI-MS calcd for C64H84F2N12O5S[M+H]+=1171.6,found:1171.8.
实施例37
1-{[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]甲基}-N-[(2S)-1-[(2S,4R)-4-羟基-2-({[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]氨基}羰基)四氢-1H-吡咯-1-基]-3,3-二甲基-1-氧亚基丁-2-基]六氢吡啶-4-甲酰胺(M37)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(400MHz,MeOD)δ8.93(s,1H),8.21(s,1H),7.52(dd,J=11.7,3.3Hz,4H),7.43(dd,J=12.9,4.4Hz,4H),7.35(q,J=6.3Hz,1H),7.02(dd,J=11.4,4.1Hz,1H),5.89(s,1H),5.00(q,J=6.9Hz,1H),4.62(s,2H),4.59(s,1H),4.56-4.49(m,1H),4.4(s,1H),4.37-4.33(m,1H),4.32(s,2H),4.12-3.92(m,2H),3.80(s,2H),3.76-3.65(m,4H),3.54-3.45(m,4H),3.38-3.34(m,2H),3.20-3.13(m,2H),3.07-3.01(m,2H),2.48(s,3H),2.38-1.94(m,8H),1.88-1.65(m,8H),1.52-1.49(m,3H),1.09(s,6H),1.04(s,9H).LRMS(ESI)m/zcalcd for C63H82F2N12O5S[M+H]+=1157.6,found:1157.6.
ESI-MS calcd for C63H82F2N12O5S[M+H]+=1157.6,found:1157.6.
实施例38
(2S,4R)-1-[(2S)-2-[(2-{4-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]哌嗪-1-基}乙酰基)氨基]-3,3-二甲基-1-氧亚基丁基]-4-羟基-N-[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]四氢吡咯-2-甲酰胺(M38)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(400MHz,MeOD)δ8.92(s,1H),8.18(s,1H),7.43(dd,J=12.0,3.6Hz,4H),7.38-7.35(m,1H),7.34-7.31(m,2H),7.06-7.03(m,2H),7.01-6.98(m,1H),5.85(s,1H),5.03-4.98(m,1H),4.66(s,1H),4.60-4.55(m,1H),4.47(s,2H),4.38(s,1H),4.32(s,2H),4.16-4.01(m,4H),3.92-3.78(m,4H),3.73-3.50(m,8H),3.48-3.35(m,8H),3.21-3.14(m,2H),2.48(s,3H),2.04-1.85(m,4H),1.81-1.64(m,4H),1.53-1.49(m,3H),1.08(s,9H),1.06-1.03(m,6H).
ESI-MS calcd for C62H81F2N13O5S[M+H]+=1158.6,found:1158.5.
实施例39
1-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[(2S)-1-[(2S,4R)-4-羟基-2-({[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]氨基}羰基)四氢-1H-吡咯-1-基]-3,3-二甲基-1-氧亚基丁-2-基]氮杂环丁烷-3-甲酰胺(M39)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(400MHz,MeOD)δ8.91(s,1H),8.17(s,1H),7.43(dd,J=13.3,5.2Hz,4H),7.37-7.31(m,1H),7.20-7.17(m,2H),7.03(dd,J=11.2,3.8Hz,1H),6.78-6.74(m,2H),5.85(s,1H),5.00-4.98(m,1H),4.69(s,1H),4.61-4.56(m,1H),4.45(s,1H),4.40(s,2H),4.32(s,2H),4.02(s,2H),4.93-3.88(m,1H),3.82-3.58(m,6H),3.47(s,2H),3.40-3.32(m,4H),3.21-3.13(m,2H),2.48(s,3H),2.30-2.16(m,2H),2.05-1.83(m,6H),1.67-1.58(m,4H),1.51-1.48(m,3H),1.09-1.03(m,6H),1.00(s,9H).
ESI-MS calcd for C60H76F2N12O5S[M+H]+=1115.6,found:1115.6.
实施例40
4-[4-({[6-(4-{4-[(4,4-二甲基六氢吡啶-1-基)甲基]-2,5-二氟苯基}-2-氧亚基-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基]氨基}甲基)苯基]-N-[(2S)-1-[(2S,4R)-4-羟基-2-({[(1S)-1-[4-(4-甲基-1,3-硫杂氮杂环戊熳-5-基)苯基]乙基]氨基}羰基)四氢-1H-吡咯-1-基]-3,3-二甲基-1-氧亚基丁-2-基]哌嗪-1-甲酰胺(M40)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(400MHz,MeOD)δ9.02(s,1H),8.19(s,1H),7.47-7.42(m,4H),7.38-7.34(m,1H),7.33-7.30(m,2H),7.09-7.06(m,2H),7.03-6.98(m,1H),5.84(s,1H),5.03-4.99(m,1H),4.61-4.58(m,1H),4.57-4.52(m,1H),4.47(s,2H),4.45-4.41(m,1H),4.32(s,2H),4.23-3.95(m,2H),3.80-3.77(m,4H),3.75-3.55(m,6H),3.46(s,2H),3.38-3.33(m,2H),3.23-3.17(m,4H),2.50(s,3H),2.24-2.18(m,1H),2.00-1.64(m,10H),1.53-1.49(m,3H),1.39-1.36(m,1H),1.09(s,6H),1.06(s,9H).
ESI-MS calcd for C61H79F2N13O5S[M+H]+=1144.6,found:1144.6.
实施例41
(2S,4R)-1-((S)-2-(2-(1-(4-(6-(4-(4-(4-[4-(4-二甲基哌嗪杂乙基)-1-甲基甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺-5.5-茚-9-基嘧啶-4-基甲基甲基甲基甲基苯基苯基氮杂环丁烷-3-乙酰氨基)-3,3-二甲基丁烯杂乙基-4-羟基-1-(4-4-甲基噻唑偶氮)偶氮唑偶氮唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M41)。
合成方法使用通用方案5制备,参考实施例33。
1H NMR(600MHz,MeOD)δ8.91(s,1H),8.19(s,1H),7.43(dd,J=11.4,5.9Hz,4H),7.37-7.33(m,1H),7.32-7.29(m,2H),7.05-7.02(m,1H),7.00-6.97(m,2H),5.84(s,1H),5.00(q,J=4.7Hz,1H),4.60(s,1H),4.59-4.54(m,1H),4.47(s,2H),4.42(s,1H),4.32(s,2H),4.23-3.87(m,2H),3.80(s,2H),3.74-3.57(m,4H),3.47(s,2H),3.38-3.34(m,2H),3.30-3.28(m,2H),3.24-3.21(m,2H),3.20-3.15(m,2H),2.48(s,3H),2.22-2.17(m,1H),2.05-2.02(m,2H),1.98-1.92(m,1H),1.87-1.82(m,2H),1.79-1.74(m,1H),1.71-1.64(m,4H),1.63-1.56(m,2H),1.52-1.49(m,3H),1.09-1.03(m,6H),1.02(s,9H).
ESI-MS calcd for C61H78F2N12O5S[M+H]+=1129.6,found:1129.6.
实施例42
5-(4-(4-(((6-(4-(-4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)甲基)苯基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮(M42)。
1H NMR(400MHz,MeOD)δ8.18(s,1H),7.70(d,J=8.5Hz,1H),7.40(s,1H),7.37-7.27(m,4H),7.07(d,J=8.5Hz,2H),7.03-6.99(m,,1H),5.82(s,1H),5.08(dd,J=12.6,5.4Hz,1H),4.47(s,2H),4.30(s,2H),3.99(brs,2H),3.79(s,2H),3.72-3.60(m,6H),3.45(s,2H),3.38-3.34(m,6H),3.20-3.13(m,2H),2.91-2.82(m,1H),2.76-2.66(m,2H),2.14-2.09(m,1H),2.02-1.98(m,2H),1.86-1.80(m,2H),1.73-1.61(m,4H),1.08(s,3H),1.03(s,3H).
ESI-MS calcd for C50H57F2N11O5[M+H]+=931.1,found:931.5.
实施例43
(2S,4R)-1-((S)-2-(2-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M43)。
合成方法使用通用方案6制备:
步骤6.1 2-(4-(2-((6-氯嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙酸甲酯(25)的合成:
将化合物24(425mg,2.11mmol,1.0equiv)和化合物1(314mg,2.11mmol,1.0equiv)溶解于10mL异丙醇溶液中,再加入三乙胺(700mg,6.63mmol,3.0equiv),加热至50℃反应4h。TLC显示反应完成,将反应混合物浓缩并通过硅胶快速柱色谱法用二氯甲烷:甲醇(20:1)纯化,得无色透明液体25(600mg,80%产率)。
1H NMR(400MHz,CDCl3)δ8.27(s,1H),6.32(s,2H),5.91(s,1H),4.40(t,J=8.0Hz,2H),3.68(s,3H),3.59(t,J=8.0Hz,2H),3.19(s,2H),2.59-2.52(m,8H).
步骤6.2 2-(4-(2-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙酸(26)的合成:
将化合物4(100mg,0.25mmol,1.0equiv)和化合物25(85mg,0.27mmol,1.1equiv)溶解于2mL异丙醇溶液中,再加入碳酸铯(240mg,0.74mmol,3.0equiv),加热至120℃反应24h。过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得化合物26(30mg,16%产率)。
步骤6.3(2S,4R)-1-((S)-2-(2-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M43)的合成:
将化合物26(30mg,0.045mmol,1.0equiv)溶于2mL二氯甲烷溶液中,并在室温下搅拌。向搅拌的溶液中依次加入化合物6(20mg,0.045mmol,1.0equiv)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(17mg,0.045mmol,1.0equiv),最后加入N,N-二异丙基乙胺(18mg,0.14mmol,3.0equiv)。将反应混合物在室温下搅拌1h,TLC显示反应完成。过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到呈白色固体状的化合物M43(8mg,16%产率)。
1H NMR(400MHz,MeOD)δ8.98(s,1H),8.23(s,1H),7.47-7.44(m,2H),7.43-7.40(m,2H),7.37-7.32(m,1H),7.02(dd,J=11.3,7.3Hz,1H),5.97(s,1H),5.04-4.97(m,1H),4.65(s,1H),4.59-4.54(m,1H),4.51-4.44(m,1H),4.32(s,2H),4.10-3.97(m,2H),3.81(s,2H),3.75-3.50(m,8H),3.48(s,2H),3.44-3.39(m,4H),3.29-3.18(m,6H),3.16-3.10(m,4H),2.49(s,3H),2.24-1.86(m,6H),1.73-1.62(m,4H),1.53-1.49(m,3H),1.09(s,6H),1.06(s,9H).
ESI-MS calcd for C57H79F2N13O5S[M+H]+=1096.6,found:1096.5.
实施例44
(2S,4R)-1-((S)-2-(2-(4-(3-(6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)丙基)哌嗪-1-基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M44)。
合成方法使用通用方案6制备,参考实施例43。
1H NMR(400MHz,MeOD)δ8.99(s,1H),8.20(s,1H),7.47-7.44(m,2H),7.43-7.40(m,2H),7.37-7.32(m,1H),7.02(dd,J=11.4,7.3Hz,1H),5.91(s,1H),5.04-4.98(m,1H),4.65(s,1H),4.59-4.54(m,1H),4.48-4.44(m,1H),4.32(s,2H),4.10-3.97(m,2H),3.81(s,2H),3.76-3.54(m,4H),3.48(s,2H),3.44-3.34(m,8H),3.29-3.15(m,6H),3.05-2.91(m,4H),2.49(s,3H),2.16-1.87(m,8H),1.70-1.63(m,4H),1.53-1.49(m,3H),1.09(s,6H),1.05(s,9H).
ESI-MS calcd for C58H81F2N13O5S[M+H]+=1110.6,found:1110.8.
实施例45
(2S,4R)-1-((S)-2-(2-(4-(4-(6-(4-((4-(4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)丁基)哌嗪-1-基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M45)。
合成方法使用通用方案6制备,参考实施例43。
1H NMR(400MHz,MeOD)δ8.97(s,1H),8.18(s,1H),7.47-7.44(m,2H),7.43-7.39(m,2H),7.37-7.31(m,1H),7.02(dd,J=11.4,4.0Hz,1H),5.88(s,1H),5.04-4.98(m,1H),4.65(s,1H),4.59-4.54(m,1H),4.47-4.43(m,1H),4.32(s,2H),4.10-3.98(m,2H),3.80(s,2H),3.75-3.52(m,4H),3.48(s,2H),3.43-3.34(m,8H),3.28-3.13(m,6H),3.08-2.82(m,4H),2.49(s,3H),2.23-1.88(m,8H),1.76-1.64(m,6H),1.53-1.49(m,3H),1.09(s,6H),1.05(s,9H).
ESI-MS calcd for C59H83F2N13O5S[M+H]+=1124.6,found:1124.5.
实施例46
(2S,4R)-1-((S)-2-(5-(3-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)戊酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M46)。
合成方法使用通用方案6制备,参考实施例43。
1H NMR(400MHz,MeOD)δ8.92(s,1H),8.20-8.14(m,1H),7.47-7.41(m,4H),7.34(dd,J=13.0,6.8Hz,1H),7.03(dd,J=10.7,7.8Hz,1H),5.88(s,1H),5.04-4.97(m,1H),4.60-4.59(m,1H),4.56-4.53(m,1H),4.49-4.44(m,1H),4.38-4.32(m,3H),4.18-3.86(m,4H),3.80(s,2H),3.77-3.60(m,6H),3.47(s,2H),3.18-3.35(m,2H),3.25-3.13(m,5H),2.48(s,3H),2.42-2.30(m,2H),2.24-2.18(m,1H),2.07-1.81(m,5H),1.78-1.57(m,8H),1.53-1.50(m,3H),1.33-1.29(m,1H),1.14-1.05(m,15H).
ESI-MS calcd for C58H80F2N12O5S[M+H]+=1095.4,found:1095.5.
实施例47
(2S,4R)-1-((S)-2-(3-(4-(((6-(4-(4-(4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)甲基)哌啶-1-基丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M47)。
合成方法使用通用方案6制备,参考实施例43。
1H NMR(400MHz,MeOD)δ8.91(s,1H),8.19(s,1H),7.46-7.44(m,2H),7.43-7.39(m,2H),7.37-7.31(m,1H),7.03(dd,J=11.4,7.3Hz,1H),5.91(s,1H),5.04-4.98(m,1H),4.58(s,1H),4.54-4.50(m,1H),4.46-4.44(m,1H),4.32(s,2H),4.10-3.92(m,2H),3.81(s,2H),3.76-3.54(m,6H),3.48(s,2H),3.41-3.34(m,4H),3.21-3.12(m,3H),3.05-2.94(m,2H),2.85-2.80(m,2H),2.48(s,3H),2.21-1.87(m,10H),1.72-1.58(m,6H),1.52-1.48(m,3H),1.09(s,6H),1.06(s,9H).
ESI-MS calcd for C58H80F2N12O5S[M+H]+=1095.6,found:1095.6.
实施例48
(2S,4R)-1-((S)-2-(4-(((6-(4-(4-(4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)甲基)哌啶-1-基丁酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M48)。
合成方法使用通用方案6制备,参考实施例43。
1H NMR(600MHz,MeOD)δ8.91(s,1H),8.19(s,1H),7.46-7.44(m,2H),7.43-7.41(m,2H),7.36-7.32(m,1H),7.03(dd,J=11.3,7.3Hz,1H),5.91(s,1H),5.03-4.99(m,1H),4.59-4.51(m,2H),4.45(s,1H),4.32(s,2H),4.07-3.89(m,2H),3.80(s,2H),3.76-3.60(m,6H),3.48(s,2H),3.43-3.34(m,4H),3.24-3.16(m,3H),3.15-3.11(m,2H),2.98-2.92(m,2H),2.48(s,3H),2.22-1.85(m,12H),1.68-1.56(m,6H),1.52-1.49(m,3H),1.09(s,6H),1.06(s,9H).
ESI-MS calcd for C59H82F2N12O5S[M+H]+=1109.4,found:1109.4.
实施例49
(2S,4R)-1-((S)-2-(2-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)乙氧基)乙氧基乙氧基乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M49)。
合成方法使用通用方案6制备,参考实施例43。
1H NMR(400MHz,MeOD)δ8.97(s,1H),8.21(s,1H),7.46-7.37(m,4H),7.34(dd,J=12.9,6.7Hz,1H),7.02(dd,J=11.5,7.3Hz,1H),5.95(s,1H),5.03-4.94(m,1H),4.77(s,1H),4.60-4.55(m,1H),4.47(s,1H),4.32(s,2H),4.08-4.01(m,3H),3.90-3.87(m,1H),3.83-3.77(m,3H),3.72-3.69(m,8H),3.61-3.55(m,2H),3.47-3.44(m,2H),3.38-3.35(m,3H),3.20-3.13(m,2H),2.48(s,3H),2.30-2.25(m,1H),2.09-1.97(m,3H),1.91-1.82(m,2H),1.74-1.61(m,4H),1.46(d,J=7.0Hz,3H),1.09(s,3H),1.05(s,9H),1.03(s,3H).
ESI-MS calcd for C55H75F2N11O7S[M+H]+=1072.3,found:1072.5.
实施例50
5-((2-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)乙基)氨基)-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M50)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.17(s,1H),7.45(d,J=10.1Hz,1H),7.36(dd,J=12.9,6.7Hz,1H),7.27(d,J=7.2Hz,1H),7.03(dd,J=11.4,7.3Hz,1H),5.79(s,1H),5.06(dd,J=12.6,5.4Hz,1H),4.34(s,2H),4.00-3.83(m,2H),3.68-3.59(m,6H),3.59-3.50(m,2H),3.48-3.43(m,2H),3.22-3.16(m,2H),2.91-2.82(m,2H),2.76-2.67(m,2H),2.14-2.09(m,2H),2.04-2.02(m,2H),1.91-1.85(m,2H),1.75-1.64(m,4H),1.11(s,3H),1.06(s,3H).
ESI-MS calcd for C41H47F3N10O5[M+H]+=817.4,found:817.4.
实施例51
5-((3-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)丙基)氨基)-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M51)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.12(s,1H),7.43(d,J=10.2Hz,1H),7.35(dd,J=12.8,6.7Hz,1H),7.12(d,J=7.2Hz,1H),7.02(dd,J=11.4,7.3Hz,1H),5.74(s,1H),5.04(dd,J=12.6,5.5Hz,1H),4.32(s,2H),3.98-3.80(m,4H),3.71-3.55(m,2H),3.49-3.43(m,6H),3.39-3.36(m,2H),3.21-3.14(m,2H),2.90-2.81(m,1H),2.77-2.64(m,2H),2.13-1.97(m,5H),1.88-1.81(m,2H),1.73-1.62(m,4H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C42H49F3N10O5[M+H]+=831.4,found:831.4.
实施例52
5-((4-((6-(4-(4-(4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)丁基)氨基)-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M52)。
合成方法使用通用方案7制备:
步骤7.1(4-((6-氯嘧啶-4-基)氨基)丁基)氨基甲酸叔丁酯(25)的合成:
将化合物24(217mg,1.46mmol,1.0equiv)和化合物1(275mg,1.46mmol,1.0equiv)溶解于5mL异丙醇溶液中,再加入三乙胺(442mg,4.38mmol,3.0equiv),加热至60℃反应12h。TLC显示反应完成,将反应混合物浓缩并通过硅胶快速柱色谱法用石油醚:乙酸乙酯(1:1)纯化,得到无色透明油状固体25(447mg,86%产率)。
1H NMR(400MHz,CDCl3)δ8.22(s,1H),6.29(s,1H),6.20(s,1H),4.97(s,1H),3.29-3.07(m,4H),1.57-1.49(m,4H).
步骤7.2(2-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)乙基)氨基甲酸叔丁酯(26)的合成:
将化合物4(100mg,0.25mmol,1.0equiv)和化合物25(82mg,0.27mmol,1.1equiv)溶解于2mL异丙醇溶液中,再加入碳酸铯(326mg,0.74mmol,3.0equiv),加热至125℃反应48h,TLC显示反应完成。过滤除去反应液中的固体,粗品通过反相HPLC纯化,冻干后得到呈白色固体状的化合物26(20mg,11%产率)。
ESI-MS calcd for C35.H52F2N8O3[M+H]+=671.4,found:671.3.
步骤7.3 9-(6-((4-氨基丁基)氨基)嘧啶-4-基)-4-(4-(((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-1,4,9-三氮杂螺[5.5]十一烷-2-酮(27)的合成:
将化合物26(20mg)溶解于1mL甲醇溶液中,再加入0.5mL的盐酸二氧六环溶液(4mol/L),室温下搅拌2h。TLC显示反应完成,将反应混合物浓缩得到化合物27(20mg,100%产率)。
ESI-MS calcd for C30H44F2N8O[M+H]+=571.4,found:571.3.
步骤7.4 5-((4-((6-(4-(4-(4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)丁基)氨基)-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M52)的合成:
将化合物27(7mg,0.012mmol,1.0equiv)和化合物28(3.6mg,0.012mmol,1.0equiv)溶于1mL DMSO溶液中,再加入DIPEA(4.6mg,0.036mmol,3.0equiv)。加热至80℃反应24h,粗品通过反相HPLC纯化,冻干后得到呈白色固体状的化合物M52(3mg,28%产率)。
1H NMR(400MHz,MeOD)δ8.15(s,1H),7.41(d,J=10.2Hz,1H),7.33(dd,J=12.8,6.7Hz,1H),7.14(d,J=7.2Hz,1H),7.04(dd,J=11.5,7.3Hz,1H),5.78(s,1H),5.05(dd,J=12.4,5.5Hz,1H),4.32(s,2H),4.15-3.88(m,4H),3.81(s,2H),3.73-3.60(m,2H),3.46(s,2H),3.40-3.35(m,4H),3.22-3.14(m,2H),2.89-2.80(m,1H),2.76-2.66(m,2H),2.14-2.00(m,4H),1.90-1.79(m,5H),1.68-1.65(m,4H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C43.H51F3N10O5[M+H]+=835.4,found:845.3.
实施例53
5-((5-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)戊基)氨基-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M53)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.14(s,1H),7.40(d,J=10.2Hz,1H),7.33(dd,J=12.8,6.7Hz,1H),7.12(d,J=7.2Hz,1H),7.04(dd,J=11.4,7.3Hz,1H),5.78(s,1H),5.05(dd,J=12.6,5.5Hz,1H),4.32(s,2H),4.12-3.94(m,2H),3.81(s,2H),3.76-3.65(m,2H),3.46(s,2H),3.42-3.35(m,6H),3.25-3.13(m,2H),2.89-2.81(m,1H),2.77-2.66(m,2H),2.13-2.01(m,4H),1.94-1.82(m,2H),1.79-1.53(m,9H),1.09(s,3H),1.05(s,3H).
ESI-MS calcd for C44H53F3N10O5[M+H]+=859.4,found:859.4
实施例54
5-((6-(6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)己基)氨基)-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M54)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.15(s,1H),7.40-7.34(m,2H),7.10(d,J=7.2Hz,1H),7.01(dd,J=11.3,7.2Hz,1H),5.82(s,1H),5.05(dd,J=12.6,5.5Hz,1H),4.32(s,2H),4.14-3.93(m,2H),3.80(s,2H),3.74-3.62(m,2H),3.46(s,2H),3.40-3.34(m,5H),3.24-3.13(m,3H),2.91-2.81(m,1H),2.76-2.65(m,2H),2.14-2.01(m,3H),1.92-1.84(m,2H),1.76-1.61(m,8H),1.55-1.46(m,4H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C45H55F3N10O5[M+H]+=873.4,found:873.4.
实施例55
5-(((7-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)庚基)氨基-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M55)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.15(s,1H),7.40(d,J=10.2Hz,1H),7.33(dd,J=12.7,6.7Hz,1H),7.10(d,J=7.1Hz,1H),7.03(dd,J=11.4,7.3Hz,1H),5.82(s,1H),5.04(dd,J=12.6,5.5Hz,1H),4.32(s,2H),4.13-3.90(m,2H),3.80(s,2H),3.76-3.65(m,2H),3.46(s,2H),3.37-3.33(m,6H),3.24-3.11(m,2H),2.89-2.81(m,1H),2.76-2.67(m,2H),2.12-1.99(m,4H),1.92-1.84(m,2H),1.72-1.62(m,7H),1.49-1.42(m,6H),1.09(s,3H),1.04(s,3H)
ESI-MS calcd for C46H57F3N10O5[M+H]+=887.4,found:887.5.
实施例56
5-((8-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)辛基)氨基-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M56)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.16(s,1H),7.40(d,J=10.3Hz,1H),7.33(dd,J=12.8,6.7Hz,1H),7.10(d,J=7.2Hz,1H),7.03(dd,J=11.4,7.3Hz,1H),5.82(s,1H),5.04(dd,J=12.6,5.5Hz,1H),4.32(s,2H),4.14-3.96(m,2H),3.80(s,2H),3.76-3.64(m,2H),3.47(s,2H),3.38-3.35(m,2H),3.30-3.28(m,4H),3.22-3.13(m,2H),2.90-2.81(m,1H),2.76-2.68(m,2H),2.13-2.02(m,3H),1.91-1.85(m,2H),1.70-1.63(m,8H),1.49-1.36(m,8H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C47H59F3N10O5[M+H]+=901.5,found:901.6.
实施例57
5-((9-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)壬基)氨基-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M57)。
合成方法使用通用方案7制备,参考实施例52。
ESI-MS calcd for C48H61F3N10O5[M+H]+=915.5,found:916.5.
实施例58
5-((10-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)癸基)氨基-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M58)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.16(s,1H),7.40(d,J=10.3Hz,1H),7.33(dd,J=12.9,6.7Hz,1H),7.10(d,J=7.2Hz,1H),7.03(dd,J=11.4,7.3Hz,1H),5.83(s,1H),5.04(dd,J=12.6,5.5Hz,1H),4.32(s,2H),4.18-3.91(m,2H),3.80(s,2H),3.78-3.67(m,2H),3.47(s,2H),3.38-3.35(m,6H),3.21-3.13(m,2H),2.90-2.81(m,1H),2.77-2.63(m,2H),2.12-2.02(m,4H),1.94-1.85(m,2H),1.68-1.63(m,9H),1.42-1.36(m,10H),1.09(s,3H),1.04(s,3H).
ESI-MS calcd for C49H63F3N10O5[M+H]+=929.5,found:930.5.
实施例59
5-((12-((6-(4-(4-((4,4-二甲基哌啶-1-基)甲基)-2,5-二氟苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)十二烷基)氨基)-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚啉-1,3-二酮(M59)。
合成方法使用通用方案7制备,参考实施例52。
1H NMR(400MHz,MeOD)δ8.13(s,1H),7.40(d,J=10.3Hz,1H),7.33(dd,J=12.8,6.7Hz,1H),7.10(d,J=7.1Hz,1H),7.03(dd,J=11.2,7.3Hz,1H),5.79(s,1H),5.04(dd,J=12.5,5.5Hz,1H),4.31(s,2H),4.08-3.93(m,2H),3.80(s,2H),3.71-3.61(m,2H),3.47(s,2H),3.28-3.26(m,6H),3.23-3.15(m,2H),2.90-2.81(m,1H),2.76-2.67(m,2H),2.13-1.99(m,4H),1.92-1.82(m,2H),1.69-1.60(m,8H),1.38-1.30(m,15H),1.14-1.01(m,6H).
ESI-MS calcd for C51H67F3N10O5[M+H]+=957.5,found:957.5.
实施例60
(2S,4R)-1-((S)-2-(5-(4-(((6-(4-(4-(4,4-二甲基哌啶-1-基)甲基)苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)甲基)苯基)戊基-4-酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M60)。
1H NMR(400MHz,MeOD)δ8.98(s,1H),8.19(s,1H),7.46-7.37(m,8H),7.31(d,J=8.1,2H),7.03(d,J=8.6,2H),5.82(s,1H),5.02-4.99(m,1H),4.67(s,1H),4.61-4.54(m,3H),4.42(s,1H),4.22(s,2H),3.98-3.73(m,8H),3.54(s,2H),3.31(s,1H),3.12-3.05(m,2H),2.73-2.68(m,H),2.65-2.58(m,1H),2.54-2.50(m,1H),2.48(s,3H),2.22-2.17(m,1H),1.97-1.90(m,3H),1.84-1.80(m,2H),1.70-1.57(m,5H),1.50(d,J=7.0,3H),1.07-1.01(m,15H).
ESI-MS calcd for C61H77N11O5S[M+H]+=1076.6,found:1076.3.
实施例61
(2S,4R)-1-((S)-2-(5-(4-(((6-(4-(4-(4,4-二甲基哌啶-1-基)甲基)苯基)-2-氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基)嘧啶-4-基)氨基)甲基)苯基)戊基-4-酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(M61)。
1H NMR(400MHz,MeOD)δ8.95(s,1H),8.20(s,1H),7.46-7.32(m,9H),7.02(dd,J=11.4,7.3Hz,1H),5.85(s,1H),5.03-4.97(m,1H),4.68-4.66(m,1H),4.53-4.42(m,3H),4.42(s,1H),4.32(s,2H),4.10-3.95(m,2H),3.88-3.85(m,1H),3.80(s,2H),3.77-3.73(m,1H),3.72-3.62(m,2H),3.46(s,2H),3.35(s,2H),3.23-3.13(m,2H),2.76-2.51(m,4H),2.48(s,3H),2.21-2.16(m,1H),2.04-1.82(m,5H),1.73-1.62(m,4H),1.51(d,J=7.0,3H),1.09-1.00(m,15H).
ESI-MS calcd for C61H75F2N11O5S[M+H]+=1111.6,found:1111.8.
实施例62METTL3靶蛋白降解活性测试
本发明化合物对METTL3靶蛋白降解活性的测试方法如下:
BCA法总蛋白定量
BCA法总蛋白定量采用赛默飞公司的BCA蛋白定量试剂盒,首先配置蛋白质标准品:在96孔板中,加入50μL初浓度为2μg/μL的蛋白标准品及同等体积的ddH2O,充分吹打均匀稀释,从中吸出50μL液体,加入第二个含有50μL ddH2O孔中,继续吹打稀释,同样操作总共得到梯度稀释的标准品,其中第9个孔为纯ddH2O。依次从低浓度到高浓度加入96孔板另一列中,每孔20μL液体,设置重复组;配置待测蛋白样品:每孔各自依次加入18μL ddH2O和待测蛋白样品2μL;BCA试剂A液与B液以50:1的比例现用现配,每孔加入200μL试剂,37℃下孵育25分钟,待第三孔颜色由绿色变成紫色,于酶标仪562nm波长下进行读数,根据线性响应曲线计算蛋白浓度。
根据定量结果,以每组蛋白样品中浓度最低的样品为标准,用2%SDS稀释其他样品,最后按照35:65(v/v)体积比加入4×上样缓冲液(200mM pH6.8的Tris-HCL溶液,8%SDS,0.4%溴酚蓝染料,40%甘油,1M DTT),均匀混合,100℃金属浴加热30分钟。
蛋白免疫印迹实验(Western blot)
安装配胶板,采用雅酶公司的预制胶液按照1:1比例配置7.5%、10%、12.5%浓度的SDS-聚丙烯酰胺(SDS-PAGE)凝胶。将样品按照10μL-15μL每孔加入安装在电泳槽的胶板孔隙中,电泳缓冲液为25mM Tris,250mM甘氨酸,0.1%SDS,电泳条件为:90V 20-30分钟,120V1-2小时。电泳结束后,用金斯瑞快速转膜仪转膜将蛋白转至硝酸纤维素膜,根据蛋白marker的大小确定目的蛋白的大概位置,对目的蛋白进行裁剪,将条带置于3%的BSA中封闭1小时。
按10μL-15μL每孔取样品进行SDS-PAGE电泳。电泳结束后,用半干电转系统转膜1.5小时-2小时将蛋白转至硝酸纤维素膜,根据marker的大小来确定目的蛋白的大概位置并将膜裁成适合大小,并将条带在3%的BSA的TBST溶液中封闭1小时后,置于一抗缓冲液中4℃孵育过夜,一抗浓度根据抗体说明书稀释,用3%BSA的TBST溶液配制。后用TBST溶液室温摇床洗涤三次,每次10分钟。最后弃去TBST,将印有蛋白的纤维素膜与配制好的二抗溶液(兔抗加鼠抗)室温孵育1小时;TBST溶液室温摇床洗涤三次,每次10分钟。最后选取各种发色液试剂,滴加在蛋白条带上,使用Imagequant成像系统进行显影成像。
表1
结果如表1中所示,表1为本发明化合物在MOLM13细胞内对METTL3蛋白的降解测试(图1)的定量结果(孵育时间24小时)。结果显示,本发明多数化合物在MOLM13细胞系中对于METTL3蛋白有良好的降解效果。
实施例63 CCK-8法检测细胞增殖实验
Cell Counting Kit-8(CCK-8)是一种主要成分为WST-8的应用于细胞增殖检测的试剂。WST-8可被活细胞中线粒体内的脱氢酶还原为橙黄色甲瓒。细胞越少,颜色越浅,细胞数量越多,则颜色越深。即活细胞的数量与颜色的深浅成正比。使用CCK-8法可以检测悬浮细胞增殖抑制情况。
具体操作如下:将生长处于对数期的悬浮细胞,按照3000细胞/180μL/孔的密度接种于96孔细胞板中,在CO2培养箱培养24小时。根据实验要求在96孔板中以1:2的比例梯度稀释化合物,浓度为终浓度的20倍,一共设定8个浓度梯度。然后各取20μL化合物加入96孔板中,每个浓度三复孔。同时加入相应体积的DMSO设定溶剂对照组及无细胞空白孔。化合物作用6天后,每孔加入10μL的CCK-8试剂,再将96孔板放入细胞培养箱中,孵育30分钟以上,一般1-4小时,期间注意颜色变化,如果发现橙色明显变深之后,用酶标仪在450nm波长下检测吸光度OD值,OD值在0.8-1.2之间最好。
细胞增殖抑制率的计算公式:抑制率(IR)(%)=(OD对照组-OD加药组)/OD对照组×100%。根据给药浓度的对应抑制率,采用SoftmaxPro 5.4.1软件中的四参数法计算待测化合物的IC50。每个实验重复两次,结果用平均值±S.D。
本发明化合物M2的体外抗肿瘤活性测试(IC50)结果如图4所示,测试时间7天,对照化合物为已报道的METTL3抑制剂UZH2(J.Med.Chem.2021,64,17,12738-12760.)和STM2457(Nature.2021,593(7860):597.),显示出本发明化合物M2在所测细胞系的体外活性优于已报道的METTL3抑制剂UZH2和STM2457。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (12)
1.一种如下式(I)所示的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐或立体异构体,或其前药分子:
其中,METTL3 inhibitors为可以结合METTL3蛋白的抑制剂,其通过基团X与Linker形成共价连接;所述的Linker是连接臂,其通过共价键与X和E3 ligase ligand相连,且所述的Linker选自以下结构:
其中,D、E各自独立地为-C(O)-或化学键;
F、G各自独立地为CH或N;
n、k各自独立地为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15;
j、s和t各自独立地为0、1或2;
且所述的Linker不为化学键;
所述的E3 ligase ligand是ECV(延伸蛋白B/C、Cullen-2、VHL)E3泛素连接酶复合体的底物识别组分VHL的小分子配体,其选自下组:
或所述的E3 ligase ligand是E3泛素连接酶复合体中Cereblon蛋白的小分子配体,其具有下式所示的结构:
W选自下组:CH2、C=O、SO2、NH、或N(C1-C4烷基);
Y1、Y2和Y3各自独立地选自O或S;
R1选自下组:H、D、卤素、硝基、氨基、氰基、羟基、C1-C4烷基、卤代C1-C4烷基、氘代C1-C4烷基;
Z选自下组:化学键、O、NH、C1-C4亚烷基;
所述的基团X选自下组:化学键、-(CH2)p-取代或未取代的苯基、-(CH2)p-取代或未取代的4-6元杂环、-(CH2)p-取代或未取代的5-6元杂芳环;其中,所述的杂环为饱和或部分不饱和(非芳香性)结构,且所述的杂环或杂芳环各自独立地含有1-3个选自N、O或S的杂原子;p为0、1、2、3、4或5。
2.如权利要求1所述的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药,其特征在于,所述的METTL3 inhibitors选自以下结构:
R2、R3为苯环上任意位点的取代基,且所述的R2、R3各自独立地选自下组:H、F、Cl、Br或I。
3.如权利要求1所述的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药,其特征在于,所述的X选自以下结构:
或化学键;
其中,R4为苯环上任意位点的取代基,且所述的R4选自下组:H、F;
A、B各自独立地为CH或N;
m、n各自独立地为1或2。
4.如权利要求1所述的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药,其中,所述的Linker选自以下结构:
其中,D、E各自独立地为-C(O)-或化学键;
F、G各自独立地为CH或N;
n、k各自独立地为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15;j为0、1或2;
且所述的Linker不为化学键。
5.根据权利要求1所述的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药;其特征在于,所述的E3 ligase ligand选自以下结构:
其中各基团的定义如权利要求1中所述;
或所述的E3 ligase ligand选自下组:
6.根据权利要求1和3所述的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药,其中,所述的X为化学键,或选自下组的结构:
7.根据权利要求1和4所述的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药,其特征在于,所述的Linker选自如下结构中的一种:
8.根据权利要求1所述的靶向METTL3的PROTAC类化合物,或其药学上可接受的盐、水合物或前药,其特征在于,所述的化合物选自下组:
9.一种药物组合物,其含有治疗有效量的一种或多种如权利要求1-8中任一项所述的具有通式(I)的基于靶向抑制和降解METTL3的蛋白水解靶向嵌合分子,及药学上可接受的载体。
10.一种药物组合物,其含有治疗有效量的一种或多种如权利要求1-8中任一项所述的具有通式(I)的基于靶向抑制和降解METTL3的蛋白水解靶向嵌合分子,及药学上可接受的辅料。
11.权利要求1所述的具有通式(I)的基于靶向抑制和降解METTL3的蛋白水解靶向嵌合分子在制备预防或治疗癌症药物中的用途。
12.如权利要求1-8任一项所述的具有通式(I)的化合物,其药学上可接受的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途,其特征在于,用于制备治疗或预防与METTL3活性或表达量相关的疾病的药物组合物。
其中,所述的疾病选自下组:急性髓细胞白血病、肺癌、乳腺癌、前列腺癌、肝癌、胃癌、胰腺癌、结直肠癌、大肠癌、膀胱癌、脑胶质瘤、卵巢癌等肿瘤疾病或自身免疫性疾病。
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