CN115246842A - 一类靶向去泛素化酶usp25和usp28的小分子抑制剂 - Google Patents
一类靶向去泛素化酶usp25和usp28的小分子抑制剂 Download PDFInfo
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- CN115246842A CN115246842A CN202210676934.1A CN202210676934A CN115246842A CN 115246842 A CN115246842 A CN 115246842A CN 202210676934 A CN202210676934 A CN 202210676934A CN 115246842 A CN115246842 A CN 115246842A
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Abstract
本申请公开了一类靶向去泛素化酶USP25和USP28的小分子抑制剂。具体公开了如式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,具体取代基如说明书中所定义。该类抑制剂可用于预防或治疗与泛素特异性蛋白酶USP25和/或USP28相关的疾病。
Description
技术领域
本发明涉及化学药物的合成及药理学应用领域,涉及泛素特异性蛋白酶25(USP25)和泛素特异性蛋白酶28(USP28)的抑制剂及其用途。该抑制剂可用于预防或治疗与USP25和/或USP28相关的疾病或紊乱。
具体的说,本发明涉及一类泛素特异性蛋白酶USP25/28抑制剂及其组合物、制备方法和用途,该类抑制剂可以用于预防或治疗与USP25和/或USP28相关的疾病。
背景技术
泛素(Ubiquitin)是一种在生物细胞中广泛存在的小分子调节蛋白(8.5KDa)。泛素化是指泛素蛋白在一系列特殊的酶作用下,对靶蛋白进行特异性修饰的过程。通常情况下,多聚泛素化的蛋白会被蛋白酶体降解,而单泛素化的蛋白会参与细胞通路的调控。泛素化过程可以被一类叫做去泛素化酶(Deubiquitinating Enzymes,DUBs)的蛋白酶逆转,它们通过去除靶蛋白上的泛素蛋白来调节各种细胞过程。
DUBs由大约100个人类基因编码,分为7个家族(USP,UCH,SENP,JAMM,OUT,MJD,MINDY),其中最大的家族是泛素特异性蛋白酶(USP),有50多个蛋白成员。在论文报道中已经指出了一些DUBs在肿瘤细胞或者炎症的发生过程之中产生了作用。Andrew Kovalenkoet al.指出了DUBs家族中的CYLD通过NF-κB通路对肿瘤有负相关作用(Kovalenko,A.etal.Nature 2003,424(6950),801-805.),Lim,Seung-Oe et al.发表了关于DUBs家族中的CSN5对于PD-L1的影响的研究(Lim,S.-O.et al.Cancer Cell 2016,30(6),925-939.)。Junli Liu et al.报道了DUBs家族中的USP10和USP13通过对Vps34复合物中的Beclin1结构进行调节从而对肿瘤的发生产生影响(Liu,J.et al.Cell 2011,147(1),223-234.)。Zhu,Dan et al.报道了DUBs家族中的OTUB1通过泛素化过程可以调控PD-L1在内质网的降解,揭示了OTUB1-PD-L1信号途径在调节肿瘤细胞免疫逃逸中的关键作用(Zhu,D.etal.Cell Death Differ.2021,28(6),1773-1789.)。这些研究表明特异性抑制某个DUBS的活性和功能可能成为肿瘤免疫治疗的潜在靶标,因此开发合适的去泛素化酶抑制剂成为针对这些症状的一种可行性方案。相关的抑制剂研究工作也有报道。Yiwei Wang et al.揭示小分子化合物IU1选择性抑制去泛素化酶USP14的分子机制,并基于结构优化出活性增加10倍的小分子IU1-248(Wang,Y.;Jiang et al.Cell Res.2018,28(12),1186-1194.).
USP28与USP25的结构具有相似性,其氨基酸序列高度同源(Sauer,F.etal.Mol.Cell 2019,74(3),421-435.e10.)。在细胞中,USP25和USP28可以对c-Myc癌蛋白的表达水平和半衰期进行调节,可以抑制一系列癌细胞的活力,最终诱导细胞凋亡(Wrigley,J.D.et al.ACS Chem.Biol.2017,12(12),3113-3125).
USP25是去泛素化酶系统的关键成员之一,USP25的蛋白结构中包含两个肽酶区域,一个可与泛素结合的区域、以及两个可与泛素相互作用的基序。和泛素水解酶活性相关的区域是肽酶区域。USP25在多种细胞生理过程中起到调节的作用。Wnt信号传导通路在多种癌症的发展过程中扮演重要因素(Zhan,T.et al.Oncogene 2017,36(11),1461-1473.),在Wnt/β-catenin信号传导通路中,USP25通过加快Tankyrases的去泛素化过程来使其保持稳定,在此过程中发挥正向调节作用(Xu,D.et al.Genes Dev.2017,31(10),1024-1035.)。在对抗生物体内病毒感染的过程之中,通过同时调控NF-κB和IRF3信号通路,USP25可以对这一过程中进行负向调控。在NF-κB和IRF3的活化过程中,需要利用在K63位有多聚泛素链的活化的TRAF2、TRAF6等。而USP25对β干扰素的表达的负向调节,可以通过下调NF-κB亚基p65和IRF3的磷酸化来来实现;同时,USP25还可以促进RIG-I、TRAF2和TRAF6的去泛素化过程,进一步抑制IRF3和NF-κB的活化,从而对该抗病毒过程进行负向调节(Lin,D.et al.Proc.Natl.Acad.Sci.U.S.A.2015,112(43),E5901.)。此外,也有研究指出了USP25的过量表达与阿尔兹海默症之间的关系(Zheng,Q.et al.Sci.Adv.2021,7(1),1-14.)
表皮生长因子受体EGFR的突变会导致细胞的异常增殖,这往往发生在肿瘤细胞的早期,并在肿瘤的生长和发展中扮演了重要的作用。E3泛素连接酶Cb1在USP25的协助之下,可以与EGFR结合来抑制EGFR的降解。在这一过程中USP25对EGFR的下调过程起负向调节作用。在药物的研发中有希望通过USP25作为目标,对依赖于EGFR的肿瘤的生长发展进行干预(C.A.et al.Biomolecules 2020,10(11),1-16.)。
近些年的研究发现,去泛素化水解酶家族中USP28可以作为潜在的抗肿瘤靶标分子(Chakravorty,D.et al.Comput.Biol.Chem.2020,85(December 2019),107208.)。在肿瘤发展的过程之中,癌蛋白MYC通过对细胞代谢的影响,对肿瘤的发展过程起到重要作用。MYC蛋白家族主要包括C—MYC、N—MYC、L—MYC、R—MYC 4种,进一步的研究发现USP28可以调控MYC和促癌蛋白LSD1(Lysine-specific demethylase1,LSD1)在细胞内的稳定性(Liu,Z.et al.Acta Pharm.Sin.B 2020,10(8),1476-1491.)。因此USP28具有成为针对的癌症的药物靶标的潜力。鳞状细胞癌(SCC)通过表达ΔNp63来促进DNA的修复,这是维持SCC肿瘤生存的关键功能。USP28充当了对ΔNp63蛋白的稳定作用,在小鼠模型中,USP28的抑制剂对肿瘤的生长起到了抑制作用(Prieto-Garcia,C.et al.EMBO Mol.Med.2020,12(4),1-25.)。
在动物实验中已经发现USP28在肠道中能够对抗c-MYC的依赖性降解,使其保持稳定。同时还会抑制另外两种致癌蛋白因子c-JUN和NOTCH1的降解。USP28作为c-MYC的靶基因,在小鼠和人类肠道肿瘤中高表达。由于USP28和c-MYC形成了一个正向反馈回路,USP28的高表达可以维持c-MYC在肿瘤中的高蛋白水平(Wang,H.et al.FEBS J.2020,288,1325-1342.)。
在动物实验中表明,敲除USP28基因并不会在小鼠上出现明显不利的表型,进一步的研究发现其肠道部分的细胞增殖显著降低,部分细胞分化受损。在结直肠癌相关的小鼠模型中,敲除USP28基因的小鼠其肠内肿瘤更少,肿瘤的体积偏小,并且小鼠的寿命得到显著地延长。缺失动物的肠内肿瘤更少。更为重要的是,USP28缺失能够降低肿瘤体积和显著延长小鼠生命。在细胞层面,USP28缺失会促进肿瘤细胞分化以及细胞增殖降低。这些实验表明抑制USP28活性有希望成为结直肠癌的潜在治疗靶点((Diefenbacher,M.E.etal.J.Clin.Invest.2014,124(8),3407-3418.)。
综上所述,靶向USP25和USP28的小分子抑制剂及其在组合物中的使用,有可能成为癌症和其他USP25和USP28相关疾病的治疗方法。
发明内容
本申请的目的之一是提供一类具有USP25和/或USP28抑制活性的化合物。
根据本发明,提供下式I所示的化合物或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药:
其中,
Ar选自取代或未取代的C6-C14芳基,取代或未取代的含有选自N、O、S中的一个或多个杂原子的9-10元双环稠合杂环基,其中用于取代的取代基选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基;
优选地,Ar选自取代或未取代的苯基,取代或未取代的噻吩并吡啶,取代或未取代的呋喃并吡啶,取代或未取代的吡咯并吡啶,取代或未取代的吡唑并吡啶,取代或未取代的吡咯并嘧啶,取代或未取代的噻吩并嘧啶,取代或未取代的苯并吡咯,取代或未取代的苯并呋喃,取代或未取代的苯并噻吩,取代或未取代的苯并噁唑,取代或未取代的苯并噻唑,取代或未取代的苯并吡唑,取代或未取代的苯并三唑,取代或未取代的苯并吡啶,其中用于取代的取代基选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基;
优选地,上述用于取代的取代基可以为选自卤素、氨基、氰基、C1-C6烷基中、卤代C1-C6烷基的1、2或3个,更优选地,选自卤素、氨基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、2,2,2-三氟乙基中的1、2或3个;
例如,Ar可以选自以下结构:
m和n各自独立地为1或2;优选地,m和n相同;
R1选自氢;硝基;卤素;取代或未取代的C1-C6烷氧基,其中,用于取代的取代基选自C1-C6烷基氨基;取代或未取代的C1-C6烷基羰基氨基,其中用于取代的取代基选自卤素、氨基、C1-C6烷基氨基、5-7元杂环基;取代或未取代的5-7元杂环基,其中用于取代的取代基选自氰基、C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、卤素;其中,5-7元杂环基含有选自N、O、S中的一个或多个杂原子;
优选地,R1选自氢;硝基;卤素;取代或未取代的C1-C4烷氧基,其中,用于取代的取代基选自C1-C4烷基氨基;取代或未取代的C1-C4烷基羰基氨基,其中用于取代的取代基选自卤素、氨基、C1-C4烷基氨基、哌嗪基、哌啶基;取代或未取代的哌嗪基;取代或未取代的吗啉基;取代或未取代的呋喃基;取代或未取代的噻吩基;取代或未取代的吡唑基;取代或未取代的吡咯基;取代或未取代的吡啶基;取代或未取代的噁唑基,其中用于取代的取代基分别选自氰基、C1-C4烷基、C1-C4烷基羰基、C1-C4烷氧基羰基、卤素;
例如,R1选自氢、甲氨基乙氧基、甲氧基、硝基、氯甲基羰基氨基、甲氨基甲羰基氨基、哌嗪基甲基羰基氨基、哌啶基甲基羰基氨基、哌嗪基、甲羰基哌嗪基、甲基哌嗪基、吗啉基、Br、呋喃基、甲基呋喃基、甲氧基羰基呋喃基、噻吩基、氯噻吩基、甲基噻吩基、氰基噻吩基、吡唑基、叔丁氧羰基吡咯基、噁唑基、吡啶基;
R2选自氢;C1-C6烷基;卤素;C1-C6烷氧基;优选地选自氢;C1-C4烷基;卤素;C1-C4烷氧基;更优选地为氢、甲基、甲氧基、乙氧基或丙氧基;
或者,R1与R2组成一个5-7元杂环基,其中,5-7元杂环基含有选自N、O、S中的一个或多个杂原子,优选地,所述杂原子为O原子。
例如,在一个实施方式中,
Ar为取代或未取代的苯基、噻吩并吡啶、呋喃并吡啶,吡咯并吡啶、吡唑并吡啶、吡咯并嘧啶、噻吩并嘧啶、苯并吡咯、苯并呋喃、苯并噻吩、苯并噁唑、苯并噻唑、苯并吡唑、苯并三唑、苯并吡啶,其中用于取代的取代基选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基;优选地,用于取代的取代基可以为选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基中的1、2或3个;
m和n各自独立地为1或2;
R1选自氢;硝基;卤素;取代或未取代的C1-C4烷氧基,其中,用于取代的取代基选自C1-C4烷基氨基;取代或未取代的C1-C4烷基羰基氨基,其中用于取代的取代基选自卤素、氨基、C1-C4烷基氨基、哌嗪基、哌啶基;取代或未取代的哌嗪基;取代或未取代的吗啉基;取代或未取代的呋喃基;取代或未取代的噻吩基;取代或未取代的吡唑基;取代或未取代的吡咯基;取代或未取代的吡啶基;取代或未取代的噁唑基,其中用于取代的取代基分别选自氰基、C1-C4烷基、C1-C4烷基羰基、C1-C4烷氧基羰基、卤素;
R2选自选自氢;C1-C4烷基;卤素;C1-C4烷氧基。
在另一实施方式中,
Ar选自以下结构:
m和n各自独立地为1或2;
R1选自氢、甲氨基乙氧基、甲氧基、硝基、氯甲基羰基氨基、甲氨基甲羰基氨基、哌嗪基甲基羰基氨基、哌啶基甲基羰基氨基、哌嗪基、甲羰基哌嗪基、甲基哌嗪基、吗啉基、Br、呋喃基、甲基呋喃基、甲氧基羰基呋喃基、噻吩基、氯噻吩基、甲基噻吩基、氰基噻吩基、吡唑基、叔丁氧羰基吡咯基、噁唑基、吡啶基;
R2选自氢、甲基、甲氧基、乙氧基或丙氧基。
在另一实施方式中,
Ar选自取代或未取代的C6-C14芳基,取代或未取代的含有选自N、O、S中的一个或多个杂原子的9-10元双环稠合杂环基,其中用于取代的取代基选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基;
m和n各自独立地为1或2;
R1选自氢;硝基;卤素;取代或未取代的C1-C6烷氧基,其中,用于取代的取代基选自C1-C6烷基氨基;取代或未取代的C1-C6烷基羰基氨基,其中用于取代的取代基选自卤素、氨基、C1-C6烷基氨基、5-7元杂环基;取代或未取代的5-7元杂环基,其中用于取代的取代基选自氰基、C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、卤素;其中,5-7元杂环基含有选自N、O、S中的一个或多个杂原子;
R2选自氢、甲基、甲氧基、乙氧基或丙氧基。
具体地,根据本发明式I所示的化合物可具有以下所示结构:
本发明的另一个目的是提供一种药物组合物,所述药物组合物包含如上所述的式I所示的化合物或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药作为活性成分,及任选的药学上可接受的载体。
本发明的另一个目的是提供如上所述的式I所示的化合物或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药在制备USP25和/或USP28抑制剂的用途。
根据本发明的一方面,提供如上所述的式I所示的化合物或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药在制备用于预防或治疗与USP25和/或USP28相关疾病的药物的用途。
本发明的另一个目的是提供一种预防或治疗与USP25和/或USP28相关的疾病的方法,所述方法包括向受试者施用治疗有效量的如上所述的式I所示的化合物或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,或所述药物组合物。
本发明中,所述与USP25和/或USP28相关的疾病包括癌症(如结直肠癌、)、炎症、自身免疫疾病、以及神经退行性疾病等。
本发明中,“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)即有合理的效益/风险比的物质。
本发明中,“药学上可接受的载体”用于将本发明的活性物质或其生理上可接受的盐传送给动物或人的药学上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
本发明的药物组合物可以是多种形式,如片剂、胶囊、粉末、糖浆、溶液状、悬浮液和气雾剂等。所述组合物可以含有选自甜味剂、着色剂和防腐剂中的一种或多种成分。
本公开的化合物可以用作单一疗法或联合疗法。在一些实施方案中,联合疗法包括用化学治疗剂,治疗性抗体,放射线,细胞疗法或免疫疗法治疗受试者。
定义
如本文所用,术语“烷基”,单独或作为另一基团的一部分使用时,是指直链或支链脂族饱和烃基。在一些实施方式中,烷基可包含1至6个碳原子,即C1-C6烷基,包括C1烷基(如甲基),C2烷基(如乙基),C3烷基(如丙基或异丙基),C4烷基,C5烷基和C6烷基。在一个实施方式中,烷基为直链C1-C4烷基。在另一个实施方式中,烷基为支链C3-6烷基。例如,本文所用的C1-C4烷基是指选自甲基、乙基、丙基(正丙基)、异丙基、丁基(正丁基)、仲丁基、叔丁基和异丁基的基团。任选取代的C1-C4烷基是指所定义的C1-C4烷基,其任选地被如本文所述的一个或多个允许的取代基取代。
如本文所用,术语“烷氧基”,单独或作为另一基团的一部分使用时,是指式-ORa1的基团,其中Ra1为烷基。
如本文所用,术语“烷基氨基”,单独或作为另一基团的一部分使用时,是指式-NHRa1的基团,其中Ra1为烷基。
如本文所用,术语“卤代烷基”,单独或作为另一基团的一部分使用时,是指被一个或多个氟、氯、溴和/或碘原子取代的烷基。
如本文所用,术语“芳基”,单独或作为另一基团的一部分使用时,是指具有在芳香环系统(“C6-14芳基”)中提供的6-14个碳原子和0个杂原子的单环或多环(例如双环)基团。在一些实施方式中,芳基具有6个环碳原子(“C6芳基”;例如,苯基)。在一些实施方式中,芳基具有10个环碳原子(“C10芳基”;例如,萘基,如1-萘基和2-萘基)。在一些实施方式中,芳基具有14个环碳原子(“C14芳基”;例如,蒽基)。
“杂环基”或“杂环”,单独或作为另一基团的一部分使用时,是指具有环碳原子和1-4个环杂原子(其中每个杂原子独立地选自氮、氧、硫)的芳族或非芳族环系统的基团,例如3-10元杂环基是指环碳原子和环杂原子的总数为3至10的芳族或非芳族环系统的基团。杂环基可以是单环的(“单环杂环基”)或稠合环系统,例如双环系统(“双环杂环基”),并且可以是饱和的或可以是部分不饱和的。例如9-10元杂环基表示环碳原子和环杂原子的总数为9至10的芳族或非芳族环系统的基团,包括5元环与6元环稠合的5,6-双环杂环基(9元双环稠合杂环基)以及6元环与6元环稠合的6,6-双环杂环基(10元双环稠合杂环基)。杂环双环系统可在一个或两个环中包含一个或多个杂原子。“杂环基”还包括其中如上所定义的杂环与一个或多个碳环基稠合的,其中连接点在碳环基或杂环上的环系统。
示例性的含有1个杂原子的5元杂环基包括但不限于,呋喃基、噻吩基、吡咯基。示例性的含有2个杂原子的5元杂环基包括但不限于,吡唑基、噁唑基、噻唑基。示例性的含有3个杂原子的5元杂环基包括但不限于,三唑基、噁二唑基和噻二唑基。示例性的含有1个杂原子的6元杂环基包括但不限于,吡啶基、哌啶基。示例性的含有2个杂原子的6元杂环基包括但不限于,吡嗪基、哌嗪基、吗啉基。示例性的5,6-双环杂环基基团(9元杂环基)包括但不限于,噻吩并吡啶、呋喃并吡啶,吡咯并吡啶、吡唑并吡啶、吡咯并嘧啶、噻吩并嘧啶、苯并吡咯、苯并呋喃、苯并噻吩、苯并噁唑、苯并噻唑、苯并吡唑、苯并三唑。示例性的6,6-双环杂环基基团(10元杂环基)包括但不限于苯并吡啶。
在如上所定义的杂环基中,对其连接点不限定,只要其满足价态需求即可。例如,在化合价允许的情况下,在含有一个或多个氮原子的杂环基中,连接点可以是碳或氮原子。例如哌嗪基(哌嗪),其连接点可以是碳原子也可以是氮原子。例如呋喃基,其连接点可在邻位或间位,包括在如上所定义的双环杂环基中,5元和6元环或6元和6元环稠合的位置不限定,只要其满足价态需求即可;另外,双环杂环基的连接点也是不限定的,例如苯并呋喃基(苯并呋喃),其连接点可以在苯环上也可在呋喃环上;再如噻吩并吡啶基(噻吩并吡啶),其连接点可以在苯环上也可在噻吩环上,只要其满足价态需求即可。
如本文所用,术语“卤素”包括氟、氯、溴、碘。
本文中,若取代基为多个基团的组合,例如ABC基,表示ABC-基团,即通过C连接母核的基团,其中A和B连接并通过B连接C。例如甲氧基羰基呋喃基,表示通过呋喃环连接母核的基团,其中甲氧基与羰基相连并通过羰基连接到呋喃环上。
具体实施方式
制备例:示例地,本发明的化合物可以通过如下合成路线制备
实施例中涉及的杂原子芳香基团的制备:
在圆底烧瓶中将2-氯-5-氟烟腈(1eq.)和巯基乙酸甲酯(methyl 2-sulfanylacetate)(1eq.)溶于DMF中,加入DBU(1.5eq.),室温搅拌反应3小时,薄层色谱法监测。反应结束后,加入水打浆,过滤,收集滤饼,烘干得到A1(收率51%)。
取化合物A1(1eq.)溶于甲醇中,加入1M NaOH水溶液,加完后升温至60℃反应3小时,薄层色谱法检测。反应结束后,蒸干甲醇,用10%盐酸水溶液调节pH至4~5,过滤,收集滤饼,烘干得到F1(收率62%)。
以类似于F1合成路线中的方式可合成化合物F2,F3,F4,F5;不同之处是适应改变原料A1,所有原料均可由商业途径购买得到。
反应原料A2可由商业途径购买得到。
将化合物A2(1g,5.68mmol)溶于干燥DMF(26mL)中,冷却到0℃,缓慢加入NaH(0.68g,28.33mmol),0℃下搅拌1h,加入CH3CH2I(11.35mmol,908μL),搅拌反应10h,滴加冰水,停止反应,用3N盐酸调节溶液pH为7,所得混合物用EtOAc萃取,合并有机层,盐水洗涤,无水Na2SO4干燥,过滤,浓缩,通过硅胶柱层析分离得到F6(收率42%)。
将化合物F6(512mg,2.69mmol)溶于DMF(15mL),加入NCS(395.4mg,2.96mmol),20℃反应18h,反应完成后加水淬灭,EtOAc萃取,饱和食盐水反萃,收集有机相,用无水硫酸钠干燥,浓缩,通过硅胶柱层析分离得到F7(收率41%)
将A3(1.0eq.)、4,4-二甲氧基-2-丁酮(1.2eq.)溶于无水甲苯中,80℃搅拌过夜。用薄层色谱法监测反应,反应完毕后,浓缩,进行硅胶柱层析分离得到A4,直接用于下一步。
将A4(1.0eq.)、KOH(5eq.)溶于H2O和乙醇(v∶v=1∶2)中,室温搅拌2h。停止反应后,旋走有机溶剂,缓慢滴加1M HCl直至无沉淀产生,过滤,抽干得到F8(收率35.3%),1HNMR(500MHz,D2O)δ8.60(d,J=6.6Hz,1H),8.26(d,J=3.4Hz,1H),6.91(d,J=6.8Hz,1H),2.53(d,J=3.0Hz,3H).
以上片段F9到F32均可由商业途径购买得到。
目标分子通用合成路线1:
将化合物A5(1.0eq.)溶解于DMF中,加入N-Boc-溴乙胺(1.4eq.)和碳酸铯(6eq.),氮气保护下室温反应16小时。用饱和氯化铵淬灭反应,用乙酸乙酯萃取,盐水洗涤3次,有机相用无水硫酸钠进行干燥,过滤、浓缩进行硅胶柱层析分离得到A6(收率81%)。
将化合物A6(1eq.)溶于无水四氢呋喃中,降温至0℃,缓慢加入氢化钠(2.5eq.),搅拌60min,分批加入碘甲烷(2eq.),回到室温反应2小时。加饱和氯化铵水溶液猝灭,用乙酸乙酯萃取。有机相用无水硫酸钠进行干燥,过滤、浓缩进行硅胶柱层析分离得到A7(收率95%)。
将A7(1eq.)、A8(1eq.)、X-Phos(0.2eq.)、醋酸钯(0.1eq.)、碳酸铯(4eq.)和无水甲苯加入反应瓶中,氮气置换15分钟,110℃反应18小时。用薄层色谱法监测反应,结束后,加水淬灭反应,用乙酸乙酯萃取反应液3次。有机相用无水硫酸钠进行干燥,过滤、浓缩进行硅胶柱层析分离得到到A9(收率24%)。
将化合物A9(1eq.)溶于甲醇和四氢呋喃中,加入10%钯碳(0.5eq.)和氢氧化钯(0.5eq.),氢气置换3次以上,在氢气气氛下升温至50℃反应3小时,薄层色谱法检测。反应结束后,过滤,收集滤液,浓缩后进行硅胶柱层析分离得到A10(收率56%)。
将化合物F1(1.0eq.)、A10(1eq.)、EDCl(1.1eq.)、HOBt(1.1eq.)和DIPEA(5eq.)溶解于无水二氯甲烷中,40℃反应16小时后,过滤掉不溶物,浓缩滤液进行分离纯化得到A11(收率75%)。
将化合物A11(1eq.)溶于DCM中,加入TFA(5eq.),室温反应1小时。用10%碳酸氢钠水溶液调节pH至8,用DCM萃取3次以上,用无水硫酸钠干燥,过滤、蒸干溶剂,分离纯化得到化合物I-1(收率70%)。
实施例1:根据通用合成路线1可得。
I-1(20mg,70%产率)。1H NMR(500MHz,MeOD)δ8.52(dd,J=2.7,1.0Hz,1H),8.11(dd,J=9.1,2.7Hz,1H),6.87-6.76(m,2H),6.76-6.61(m,2H),4.56(dq,J=9.3,6.0Hz,1H),4.53-4.44(m,1H),4.23(t,J=7.6Hz,1H),3.99(t,J=5.3Hz,2H),3.30-3.23(m,2H),2.90(t,J=5.2Hz,2H),2.45(s,3H)ppm;质谱:C20H22FN5O2S[M+H]+计算值:416.2,实测值:416.2。
目标分子通用合成路线2:
在圆底烧瓶中将A12(1eq.)和A13(1.05eq.)溶于DMF中,加入碳酸钾(3eq.),65℃搅拌反应4小时,薄层色谱法监测。反应结束后,过滤,收集滤液,加入EA和饱和食盐水萃取,有机相用无水硫酸钠干燥,分离得到A14(收率96%)。
取化合物A14(1eq.)溶于DCM中,加入TFA(10eq.),加完后在室温反应1小时,薄层色谱法检测。反应结束后,用10%碳酸氢钠水溶液调节Ph至8,用DCM萃取3次,有机相用无水硫酸钠干燥,纯化得到A15(收率67%)。
将化合物A15(1.0eq.)、F1(1eq.)、EDCI(1.1eq.)、HOBt(1.1eq.)和DIPEA(5eq.)溶解于无水二氯甲烷中,40℃反应16小时后,过滤,用DCM淋洗滤饼,收集滤饼,烘干得化合物I-2(收率50%)。
将I-2(1eq.)溶于甲醇中(I-2的溶解性极差),加入(Boc)2O(3eq.)到体系中,升温至40℃反应12小时,反应完后,纯化得到A16(收率80%)。
将化合物A16(1.0eq.)溶解于氯仿中,加入锌粉(4eq.),低温下滴加冰乙酸(10eq.),室温反应1小时。过滤掉不溶物,用饱和碳酸氢钠调节pH至8,用二氯甲烷萃取3次,有机相用无水硫酸钠进行干燥,过滤、浓缩进行硅胶柱层析分离得到A17(收率80%)。
将化合物A17(1eq.)溶于DCM中,加入三乙胺(2eq.)和氯乙酰氯(1.2eq.),室温反应2小时。加饱和氯化铵水溶液猝灭,用二氯甲烷萃取。有机相用无水硫酸钠进行干燥,过滤、浓缩进行硅胶柱层析分离得到A18(收率83%)。
将化合物A18(1eq.)溶于DCM中,加入TFA(10eq.),室温反应1小时。用10%碳酸氢钠水溶液调节pH至8,用DCM萃取3次以上,用无水硫酸钠干燥,过滤、蒸干溶剂,纯化分离得到化合物I-3(收率56%)。
将I-3(1eq.)、甲胺水溶液(5eq.)、碳酸钾(3eq.)和乙腈加入反应瓶中,50℃反应2小时。用薄层色谱法监测反应,结束后,加水猝灭反应,用乙酸乙酯萃取反应液3次。有机相用无水硫酸钠进行干燥,过滤、浓缩进行分离得到化合物I-4(收率63%)。
实施例2:
I-2(150mg,50%产率)。1H NMR(500MHz,DMSO)δ8.70(d,J=2.0Hz,1H),8.43(d,J=7.0Hz,1H),8.41(dd,J=9.6,2.8Hz,1H),8.06(d,J=9.2Hz,2H),7.22(s,2H),6.53-6.44(m,2H),4.96-4.76(m,1H),4.36(t,J=8.5Hz,2H),4.05(dd,J=9.2,5.6Hz,2H)ppm;质谱:C17H14FN5O3S[M-H]-计算值:386.2,实测值:386.2。
实施例3:
I-3(11mg,56%产率)。1H NMR(400MHz,DMSO)δ9.97(s,1H),8.71(d,J=2.0Hz,1H),8.45(dd,J=9.5,2.7Hz,1H),7.33(d,J=8.9Hz,2H),6.70(d,J=8.6Hz,2H),4.54(d,J=4.6Hz,2H),4.24(s,1H),4.16(s,2H),3.26(d,J=5.3Hz,2H)ppm;高分辨质谱:C19H17ClFN5O2S[M+H]+计算值:434.08483,实测值:434.08484。
实施例4:
I-4(6.5mg,63%产率)。1H NMR(500MHz,MeOD)δ8.52(dd,J=2.6,1.0Hz,1H),8.11(dd,J=9.1,2.7Hz,1H),7.30(d,J=8.9Hz,2H),6.71(d,J=8.9Hz,2H),4.57(dq,J=9.4,6.0Hz,1H),4.54-4.46(m,1H),4.30-4.19(m,1H),3.66(s,2H),3.40-3.32(m,2H),2.63(s,3H)ppm;质谱:C20H20FN5O3S[M+H]+计算值:429.2,实测值:429.2。
目标分子通用合成路线3:
将化合物A14(1.0eq.)溶解于氯仿中,加入锌粉(4eq.),低温下滴加冰乙酸(10eq.),室温反应1小时。过滤掉不溶物,用饱和碳酸氢钠调节pH至8,用二氯甲烷萃取3次,有机相用无水硫酸钠进行干燥,过滤、浓缩进行硅胶柱层析分离得到A19(收率67%)。
将化合物A19(1eq.)溶于DCM中,加入三乙胺(2eq.)和氯乙酰氯(1.2eq.),室温反应2小时。加饱和氯化铵水溶液猝灭,用二氯甲烷萃取。有机相用无水硫酸钠进行干燥,过滤、浓缩进行硅胶柱层析分离得到A20(收率87%)。
将A20(1eq.)、A21(5eq.)、碳酸钾(3eq.)和乙腈加入反应瓶中,50℃反应2小时。用薄层色谱法监测反应,结束后,加水猝灭反应,用乙酸乙酯萃取反应液3次。有机相用无水硫酸钠进行干燥,过滤、浓缩进行分离得到A22(收率65%)。
将化合物A22(1eq.)溶于DCM中,加入TFA(10eq.),室温反应1小时。用10%碳酸氢钠水溶液调节pH至8,用DCM萃取3次以上,用无水硫酸钠干燥,过滤、蒸干溶剂,纯化分离得到A23(收率82%)。
将化合物A23(1.0eq.)、F1(1eq.)、EDCI(1.1eq.)、HOBt(1.1eq.)和DIPEA(5eq.)溶解于无水二氯甲烷中,40℃反应16小时后,加入饱和氯化铵水溶液淬灭,用DCM萃取3次,有机相用无水硫酸钠干燥,纯化得到A24(收率40%)。
将A24(1eq.)溶于DCM中,低温下加入三溴化硼(5eq.),室温反应1小时,反应完后,加入碳酸氢钠水溶液淬灭,用DCM萃取3次,有机相用无水硫酸钠干燥,用Pre-HPLC纯化得到化合物I-5(收率58%)。
实施例5:
I-5(6mg,58%产率)。1H NMR(500MHz,CD2Cl2)δ8.94(s,1H),8.53(dd,J=2.7,0.9Hz,1H),7.72(dd,J=8.7,2.7Hz,1H),7.38-7.26(m,2H),6.74-6.63(m,2H),6.00(s,2H),4.66(dtd,J=9.6,7.0,5.0Hz,1H),4.52(dd,J=9.5,8.3Hz,1H),4.20(t,J=7.9Hz,1H),4.01(t,J=6.2Hz,1H),3.52-3.45(m,1H),3.30(dt,J=15.6,6.2Hz,1H),3.06(s,2H),2.95-2.89(m,4H),2.55(s,4H)ppm;质谱:C23H26FN7O2S[M+H]+计算值:484.2,实测值:484.2。
实施例6:适应改变原料A21,以类似于合成路线3中的方式可合成化合物I-6。
I-6(10mg,42%产率)。1H NMR(400MHz,MeOD)δ8.57(dd,J=2.7,1.0Hz,1H),8.14(dd,J=9.1,2.7Hz,1H),7.38(d,J=8.8Hz,2H),6.52(d,J=8.8Hz,2H),4.91(d,J=6.4Hz,1H),4.23(t,J=7.5Hz,2H),3.95-3.72(m,2H),3.08(s,2H),2.55(s,4H),1.72-1.64(m,4H),1.49(t,J=12.2Hz,2H)ppm;质谱:C24H27FN6O2S[M+H]+计算值:483.2,实测值:483.2。
目标分子通用合成路线4:
称量化合物A21(1eq.),4-溴苯硼酸(2eq.),4AMS(2eq.),Cu(OAc)2(0.4eq.),抽真空,充氧气,氧气氛下加入Et3N(3eq.),溶剂干燥的CH2Cl2,35℃反应12h,反应完成后,过滤除去固体,CH2Cl2和水萃取,收集有机相,干燥,浓缩,通过硅胶柱层析分离得到A25(收率62%)。
称量化合物A25(1eq.),A13(2eq.),Pd(OAc)2(0.1eq.),XPHOS(0.2eq.),Cs2CO3(3eq.),抽真空,充氮气,氮气氛下加入溶剂干燥的甲苯,110℃反应12h,反应完成后,过滤,CH2Cl2和水萃取,收集有机相,干燥,浓缩,通过硅胶柱层析分离得到A26(收率69%)。
称量化合物A26(1eq.),溶于干燥的CH2Cl2,滴加TFA(3eq.),25℃反应2h,反应完成后,CH2Cl2和水萃取,饱和碳酸氢钠溶液调节溶液pH为7-8,收集有机相,干燥,浓缩,通过硅胶柱层析分离得到A27(收率75%)。
称量化合物A27(1eq.),F13(1eq.),EDCl(1.1eq.),HOBt(1.1eq.),DIPEA(3eq.),溶于干燥的CH2Cl2,40℃反应12h,反应完成后,CH2Cl2和水萃取,收集有机相,干燥,浓缩,通过硅胶薄层层析分离得到A28(收率34%)。
称量化合物A28(1eq.),溶于干燥的CH2Cl2,滴加BBr3的CH2Cl2溶液,25℃反应1h,反应完成后,滴加CH3OH淬灭反应,旋干溶剂,通过反相半制备HPLC纯化得到化合物I-20(收率28%)。
实施例7:适应改变原料F13为F6,以类似于合成路线4中的方式合成化合物I-7
I-7,收率:41.38%。1H NMR(300MHz,DMSO)δ9.00(d,J=7.0Hz,1H),8.77(d,J=1.9Hz,1H),8.48(d,J=2.0Hz,1H),7.69(d,J=3.5Hz,1H),6.83(d,J=8.8Hz,2H),6.59(d,J=3.5Hz,1H),6.43(d,J=8.8Hz,2H),4.85(dd,J=13.5,6.7Hz,1H),4.32(q,J=7.2Hz,2H),4.12(t,J=7.3Hz,2H),3.69(t,J=6.6Hz,2H),2.84(d,J=7.9Hz,8H),1.39(t,J=7.2Hz,3H).质谱:C23H29N6O[M+H]+计算值:405.2,实测值:405.2。
实施例8:适应改变原料A13,以类似于合成路线I-7中的方式合成化合物I-8。
I-8,39.30%产率。1H NMR(500MHz,CDCl3)δ8.73(d,J=2.0Hz,1H),8.33(d,J=2.1Hz,1H),7.31(d,J=3.7Hz,1H),6.94(d,J=9.1Hz,2H),6.91-6.88(m,2H),6.54(d,J=3.5Hz,1H),4.38(q,J=7.3Hz,2H),4.27(dd,J=14.2,7.1Hz,1H),3.54(d,J=12.6Hz,4H),3.06(d,J=3.4Hz,8H),2.89(t,J=10.6Hz,4H),1.49(t,J=7.3Hz,3H).质谱:C25H33N6O[M+H]+计算值:433.5,实测值:433.2。
实施例9:适应改变原料F13为F2,以类似于合成路线4中的方式合成化合物I-9。
I-9,收率:35.82%。1H NMR(500MHz,CDCl3)δ7.81(d,J=8.3Hz,1H),7.18(d,J=8.3Hz,1H),6.89-6.83(m,2H),6.70-6.64(m,2H),4.64(dt,J=13.5,5.9Hz,1H),4.48(dd,J=9.4,8.2Hz,1H),4.20(t,J=7.9Hz,1H),3.38(dd,J=12.1,5.3Hz,1H),3.27(dd,J=12.1,6.2Hz,1H),3.02(dq,J=4.4,2.6Hz,8H),2.69(s,3H).
质谱:C22H27N6OS[M+H]+计算值:423.2,实测值:423.2。
实施例10:适应改变原料F13为F8,以类似于合成路线4中的方式合成化合物I-10。
I-10,35.30%产率。1H NMR(300MHz,D2O)δ8.64(d,J=7.2Hz,1H),8.20(s,1H),6.98(d,J=7.2Hz,1H),6.83(d,J=8.8Hz,2H),6.74(d,J=8.8Hz,2H),4.73(s,1H),4.44(dd,J=15.3,8.5Hz,2H),4.28(t,J=5.6Hz,2H),3.26-3.17(m,4H),3.08(d,J=5.0Hz,4H),2.53(s,3H).质谱:C21H25N7O[M+H]+计算值:392.2,实测值:392.1。
实施例11:采用F8并适应改变A13,以类似于合成路线4中的方式可合成化合物I-11。
I-11,收率:42.23%。1H NMR(300MHz,CD3CN)δ8.74(d,J=7.2Hz,1H),8.44(s,1H),7.00(d,J=7.2Hz,1H),6.97-6.85(m,4H),4.17-4.00(m,1H),3.54-3.38(m,2H),2.97(dd,J=6.5,2.7Hz,4H),2.93-2.85(m,4H),2.67(s,3H),2.15-2.03(m,4H),1.76(dtd,J=13.4,9.9,3.8Hz,2H).质谱:C23H30N7O[M+H]+计算值:420.2,实测值:420.2。
实施例12:适应改变原料F13,A13和A21,以类似于合成路线4中的方式合成化合物I-12。
I-12,收率:38.78%。1H NMR(500MHz,CDCl3)δ7.96(s,1H),7.84(d,J=8.3Hz,1H),6.90(dd,J=23.1,9.1Hz,4H),4.03-3.90(m,1H),3.88-3.81(m,4H),3.52(d,J=12.9Hz,2H),3.12-3.03(m,4H),2.82(dd,J=17.2,6.8Hz,2H),2.72(s,3H),2.10(d,J=12.0Hz,2H),1.71(dd,J=16.0,7.3Hz,2H).
质谱:C25H31N4O2S[M+H]+计算值:452.2,实测值:452.2。
实施例13:适应改变F13、A13和A21,以类似于合成路线4中的方式合成化合物I-13。
I-13,收率42.10%。1H NMR(400MHz,CDCl3)δ7.80(d,J=8.2Hz,2H),7.18(d,J=8.3Hz,1H),6.97(d,J=8.0Hz,2H),6.86(t,J=6.9Hz,1H),4.12(d,J=7.6Hz,1H),3.69(d,J=12.5Hz,4H),2.93(t,J=11.6Hz,4H),2.67(s,3H),2.13(d,J=12.0Hz,4H),1.71(d,J=10.9Hz,2H),1.46(d,J=31.7Hz,2H),0.87(d,J=6.8Hz,2H).
质谱:C23H29N6O2[M+H]+计算值:421.2,实测值:421.2。
适应改变原料化合物,以类似于合成路线4中的方式合成以下化合物。
实施例14:
I-14,收率38.10%。1H NMR(500MHz,CDCl3)δ9.21(s,1H),9.02(s,1H),7.03-6.83(m,4H),4.24(s,1H),3.92-3.81(m,4H),3.46(dd,J=37.3,10.8Hz,2H),3.09(m,4H),2.98(t,J=10.2Hz,2H),2.25-2.16(m,2H),2.02(d,J=5.8Hz,2H),1.89(d,J=9.6Hz,2H),1.63(dd,J=15.1,7.3Hz,2H).
质谱:C22H24N5O2SCl[M+H]+计算值:458.1,实测值:458.1。
实施例15:
I-15,收率:43.20%。1H NMR(500MHz,CDCl3)δ8.33(d,J=1.9Hz,1H),8.27(s,J=1.9Hz,1H),6.97-6.82(m,4H),6.23(s,1H),3.91(s,1H),3.87-3.81(m,4H),3.48(d,J=11.9Hz,2H),3.15-3.08(m,2H),3.07(s,4H),2.80(t,J=10.9Hz,2H),2.67(dd,J=11.4,8.9Hz,2H),2.05(d,J=10.7Hz,2H),1.99(s,3H).
质谱:C25H32N5O2[M+H]+计算值:434.3,实测值:434.2。
实施例16:
I-16,收率:40.23%。1H NMR(400MHz,CD3CN)δ9.41(s,1H),8.12-8.07(m,1H),7.65(d,J=4.8Hz,1H),7.56(d,J=2.7Hz,1H),7.21(d,J=2.7Hz,1H),6.82(d,J=8.8Hz,2H),6.67(d,J=8.7Hz,2H),4.52-4.46(m,1H),4.19(d,J=5.7Hz,2H),3.29(d,J=2.6Hz,2H),2.26-2.16(m,4H),2.02(d,J=6.0Hz,4H).
质谱:C21H25N6O[M+H]+计算值:377.2,实测值:377.1。
实施例17:
I-17,收率:17.54%。质谱:C22H27N6O2[M+H]+计算值:407.48,实测值:407.4。
质谱:C21H25N6O[M+H]+计算值:377.2,实测值:377.1
实施例18:
I-18,收率:43.20%。1H NMR(300MHz,CDCl3)δ8.62(s,1H),8.36(d,J=7.3Hz,1H),6.93(d,J=6.3Hz,2H),6.86(d,J=7.1Hz,1H),6.56(d,J=6.3Hz,2H),5.13(d,J=6.5Hz,1H),4.40-4.30(m,2H),3.88(d,J=4.1Hz,4H),3.77(s,2H),3.07(s,4H),2.71(s,3H).
质谱:C21H25N7O[M+H]+计算值:393.2,实测值:392.1。
实施例19:
I-19,(4.5mg,收率35.10%)。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.41(d,J=6.9Hz,1H),8.27(s,1H),8.19(d,J=7.9Hz,1H),7.23(d,J=7.9Hz,1H),6.80(d,J=8.9Hz,1H),6.37(d,J=8.8Hz,1H),4.51(dd,J=13.2,6.1Hz,1H),3.98(t,J=7.4Hz,1H),3.72-3.64(m,2H),3.46-3.39(m,1H),3.26(m,4H),2.94-2.85(m,2H),2.52(m,4H).
质谱:C23H27N5O2SF[M+H]+计算值:456.4,实测值:456.0。
实施例20:
I-20(2.3mg,28%产率).1H NMR(500MHz,CDCl3)δ9.11(s,1H),8.60(s,1H),8.16(d,J=7.2Hz,1H),7.47(s,1H),6.85(d,J=8.2Hz,2H),6.66(d,J=9.3Hz,2H),4.61(d,J=6.7Hz,1H),4.29(s,1H),3.65(s,2H),3.40(s,6H),3.34(s,4H)ppm.
质谱:C21H24N5OS[M+H]+理论值:394.2,实测值:394.2。
实施例21:
I-21,收率36.35%。1H NMR(400MHz,CDCl3)δ8.81(d,J=2.1Hz,1H),8.31(d,J=2.1Hz,1H),7.28(s,1H),7.25(s,1H),6.88(d,J=8.8Hz,2H),6.49(d,J=8.8Hz,2H),5.02(dd,J=12.0,4.8Hz,1H),4.34(q,J=7.3Hz,2H),4.28(t,J=7.4Hz,2H),3.88-3.80(m,4H),3.74(dd,J=7.6,4.9Hz,2H),3.07-2.96(m,4H),1.47(t,J=7.3Hz,3H).
质谱:C23H28N5O2[M+H]+计算值:406.2,实测值:406.2。
实施例22:
I-22,收率:41.20%。1HNMR(400MHz,CDCl3)δ8.81(d,J=2.1Hz,1H),8.31(d,J=2.1Hz,1H),7.28(s,1H),6.88(d,J=8.8Hz,2H),6.49(d,J=8.8Hz,2H),5.02(dt,J=12.0,5.9Hz,1H),4.34(q,J=7.3Hz,2H),4.28(t,J=7.4Hz,2H),3.89-3.81(m,4H),3.74(dd,J=7.6,4.9Hz,2H),3.06-2.98(m,4H),1.47(t,J=7.3Hz,3H).
质谱:C23H27N5O2Cl[M+H]+计算值:440.1,实测值:440.2
实施例23:
I-23(9.1mg,45%产率).1H NMR(400MHz,CDCl3)δ8.83(d,J=2.0Hz,1H),8.33(d,J=2.0Hz,1H),7.39(s,1H),7.28(s,1H),6.84(d,J=8.9Hz,2H),6.48(d,J=8.9Hz,2H),5.03(dd,J=12.1,4.9Hz,1H),4.35(q,J=7.3Hz,2H),4.27(t,J=7.4Hz,2H),3.79-3.73(m,5H),1.48(t,J=7.3Hz,3H)ppm.
质谱:C20H22ClN4O2[M+H]+理论值:385.1,实测值:385.1。
实施例24:
I-24(4.7mg,36%产率).1H NMR(500MHz,CDCl3)δ8.84(d,J=1.8Hz,1H),8.34(d,J=1.9Hz,1H),7.29(s,1H),6.87(s,1H),6.81(d,J=8.5Hz,1H),6.16(s,1H),6.09(d,J=7.0Hz,1H),5.05(d,J=7.1Hz,1H),4.34(dd,J=14.2,7.4Hz,4H),3.87(s,3H),3.82(s,3H),3.11(s,2H),1.48(dd,J=7.3,5.0Hz,3H).ppm.
质谱:C21H24ClN4O3[M+H]+理论值:415.1,实测值:415.1。
实施例25:
I-25(6.3mg,54%产率).1H NMR(500MHz,CDCl3)δ8.86(s,1H),8.37(s,1H),7.27(s,1H),6.88(s,2H),6.48(s,2H),5.06(s,1H),4.34(d,J=7.2Hz,4H),3.70(s,4H),3.58(s,2H),3.18-2.82(m,4H),2.11(s,3H),1.47(t,J=7.2Hz,3H)ppm.
质谱:C25H30ClN6O2[M+H]+理论值:481.2,实测值:481.2。
实施例26:
I-26(5.2mg,51%产率).1H NMR(300MHz,CDCl3)δ8.94(s,1H),8.47(s,1H),7.93(d,J=6.4Hz,1H),7.32(s,1H),6.83(d,J=7.8Hz,2H),6.42(d,J=8.1Hz,2H),5.00(d,J=5.6Hz,1H),4.43-4.11(m,4H),3.88(s,2H),3.34(s,4H),3.20(s,4H),2.77(s,3H),1.53(d,J=7.4Hz,3H)ppm.
质谱:C24H30ClN6O[M+H]+理论值:453.2,实测值:453.2。
实施例27:以类似于合成路线4中的方式合成化合物I-27
I-27(6.5mg,39%产率).1H NMR(300MHz,CDCl3)δ8.82(d,J=2.1Hz,1H),8.31(d,J=2.1Hz,1H),7.30(t,J=2.3Hz,2H),7.01(d,J=7.3Hz,1H),6.33(d,J=8.7Hz,2H),5.04(ddd,J=12.3,7.2,2.1Hz,1H),4.31(dt,J=21.5,7.4Hz,4H),3.77(dd,J=7.8,5.1Hz,2H),1.47(t,J=7.3Hz,3H)ppm.
质谱:C19H19BrClN4O[M+H]+理论值:433.0,实测值:433.0。
目标分子通用合成路线5
称量化合物I-27,1eq.,3-硼酸呋喃(2eq.),K2CO3(3eq.),Pd(dppf)2Cl2(0.2eq.),抽真空,充氮气,氮气氛下加入二氧六环(dioxane)和水,90℃反应12h,反应完成后,CH2Cl2和水萃取,收集有机相,干燥,浓缩,通过硅胶薄层层析分离得到化合物I-32(收率42%)。
目标分子通用合成路线6
称量化合物A13(1eq.),4-溴苯硼酸(2eq.),4AMS(2eq.),Cu(OAc)2(0.4eq.),抽真空,充氧气,氧气氛下加入Et3N(3eq.),溶剂干燥的CH2Cl2,35℃反应12h,反应完成后,过滤除去固体,CH2Cl2和水萃取,收集有机相,干燥,浓缩,通过硅胶柱层析分离得到A26(收率34%)。
称量化合物A26(1eq.),呋喃-2-硼酸(2eq.),K2CO3(3eq.),Pd(dppf)2Cl2(0.2eq.),抽真空,充氮气,氮气氛下加入溶剂1,4-二氧六环和水,90℃反应12h,反应完成后,CH2Cl2和水萃取,收集有机相,干燥,浓缩,通过硅胶柱层析分离得到A27(收率59%)
称量化合物A27(1eq.),溶于干燥的CH2Cl2,滴加TFA(3eq.),25℃反应2h,反应完成后,CH2Cl2和水萃取,饱和碳酸氢钠溶液调节溶液pH为7-8,收集有机相,干燥,浓缩,通过硅胶柱层析分离得到A28(收率71%)。
称量化合物F14(1eq.),A28(1.1eq.),EDCI(1.1eq.),HOBt(1.1eq.),DIPEA(3eq.),溶于干燥的CH2Cl2,40℃反应12h,反应完成后,CH2Cl2和水萃取,收集有机相,干燥,浓缩,通过硅胶薄层层析分离得到I-44(收率35%)。
实施例28:
I-28(2.1mg,23%产率).1H NMR(500MHz,CDCl3)δ7.86(d,J=5.6Hz,2H),7.49-7.45(m,3H),7.39(d,J=6.4Hz,2H),7.07-7.03(m,2H),6.51(d,J=8.0Hz,1H),6.47(s,1H),6.43(d,J=3.9Hz,1H),5.30(s,1H),4.40(dd,J=1.9,0.7Hz,2H),4.17(d,J=0.8Hz,2H)ppm.
质谱:C23H19N4O2[M+H]+理论值:383.1,实测值:383.1。
实施例29:
I-29(3.7mg,42%产率).1H NMR(300MHz,CDCl3)δ8.58(d,J=2.0Hz,1H),7.64(dd,J=8.2,2.7Hz,2H),7.46(t,J=1.6Hz,1H),7.39(d,J=8.6Hz,2H),6.66(d,J=0.9Hz,1H),6.55(d,J=8.4Hz,2H),5.00(dt,J=12.4,6.2Hz,1H),4.35(t,J=7.6Hz,2H),3.88-3.77(m,2H)ppm.
质谱:C21H18FN4O2S[M+H]+理论值:409.1,实测值:409.1。
实施例30:
I-30(7.5mg,59%产率).1H NMR(400MHz,CDCl3)δ8.83(d,J=2.0Hz,1H),8.32(d,J=2.1Hz,1H),7.48(d,J=8.6Hz,2H),7.27(s,1H),7.17(t,J=4.8Hz,2H),7.04(dd,J=5.0,3.6Hz,1H),6.83(s,1H),6.49(d,J=8.4Hz,2H),5.12-5.02(m,1H),4.44--4.29(m,4H),3.83(dd,J=7.4,5.1Hz,2H),1.47(t,J=7.3Hz,3H)ppm.
质谱:C23H22ClN4OS[M+H]+理论值:437.1,实测值:437.1。
实施例31:
I-31(8.2mg,64%产率).1H NMR(400MHz,CDCl3)δ8.83(d,J=2.0Hz,1H),8.32(d,J=2.1Hz,1H),7.54(d,J=8.7Hz,2H),7.40(d,J=1.1Hz,1H),7.27(s,1H),6.85(d,J=7.3Hz,1H),6.52-6.42(m,4H),5.13-4.98(m,1H),4.40-4.30(m,4H),3.83(dd,J=7.8,5.0Hz,2H),1.47(t,J=7.3Hz,3H)ppm.
质谱:C23H22ClN4O2[M+H]+理论值:421.1,实测值:421.1。
实施例32:
I-32(7.3mg,66%产率).1H NMR(300MHz,CDCl3)δ8.83(d,J=2.0Hz,1H),8.33(d,J=2.1Hz,1H),7.64(s,1H),7.45(t,J=1.7Hz,1H),7.36(d,J=8.6Hz,2H),7.28(s,1H),6.85(d,J=7.4Hz,1H),6.64(dd,J=1.8,0.8Hz,1H),6.52(d,J=8.5Hz,2H),5.07(ddd,J=12.2,7.2,2.3Hz,1H),4.34(q,J=7.2Hz,4H),3.83(dd,J=7.8,5.0Hz,2H),1.48(t,J=7.3Hz,3H)ppm.
质谱:C23H22ClN4O2[M+H]+理论值:421.1,实测值:421.1。
实施例33:
I-33(3.9mg,39%产率).1H NMR(300MHz,CDCl3)δ8.92(s,1H),8.45(s,1H),7.97(s,1H),7.65(s,1H),7.46(d,J=6.4Hz,2H),7.24(s,1H),6.41(d,J=7.0Hz,3H),5.05(s,1H),4.35-4.22(m,4H),3.85(s,2H),1.45(t,J=7.2Hz,3H)ppm.
质谱:C22H22ClN6O[M+H]+理论值:421.1,实测值:421.1。
实施例34:
I-34(7.9mg,72%产率).1H NMR(500MHz,CDCl3)δ8.56(d,J=2.2Hz,1H),7.73(dd,J=8.4,2.6Hz,1H),7.49(d,J=8.5Hz,2H),7.18-7.15(m,2H),7.04(dd,J=4.9,3.7Hz,1H),6.50(d,J=8.5Hz,2H),6.16-6.04(m,3H),5.03-4.95(m,1H),4.34(t,J=7.5Hz,2H),3.83(dd,J=7.6,5.2Hz,2H)ppm.
质谱:C21H18FN4OS2[M+H]+理论值:425.1,实测值:425.1。
实施例35:
I-35(8.1mg,70%产率).1H NMR(500MHz,CDCl3)δ8.56(d,J=2.1Hz,1H),7.69(dd,J=8.4,2.7Hz,1H),7.54(d,J=8.6Hz,2H),7.40(d,J=1.1Hz,1H),6.50(d,J=8.6Hz,2H),6.47-6.41(m,2H),6.10(d,J=7.2Hz,3H),5.03-4.95(m,1H),4.33(t,J=7.5Hz,2H),3.82(dd,J=7.8,5.2Hz,2H)ppm.
质谱:C21H18FN4O2S[M+H]+理论值:409.1,实测值:409.1。
实施例36:
I-36(2.3mg,31%产率).1H NMR(500MHz,CDCl3)δ8.56(s,1H),7.80(d,J=8.4Hz,1H),7.60(s,2H),7.48(s,1H),7.40(s,2H),6.53(d,J=8.1Hz,2H),6.18(d,J=18.2Hz,3H),5.00(s,1H),4.35(t,J=7.5Hz,2H),3.90-3.81(m,2H)ppm.
质谱:C20H18FN6OS[M+H]+理论值:409.1,实测值:409.1。
实施例37:
I-37(6.1mg,50%产率).1H NMR(400MHz,CDCl3)δ8.57(d,J=2.1Hz,1H),7.69(dd,J=8.4,2.6Hz,1H),7.53-7.46(m,2H),7.37-7.31(m,3H),6.54(d,J=8.5Hz,2H),6.19-5.97(m,3H),5.00(d,J=7.3Hz,1H),4.35(t,J=7.5Hz,2H),3.82(dd,J=7.8,5.2Hz,2H)ppm.
质谱:C21H18FN4OS2[M+H]+理论值:425.1,实测值:425.1。
实施例38:
I-38(9.7mg,48%产率).1H NMR(500MHz,CDCl3)δ8.83(d,J=1.9Hz,1H),8.33(d,J=2.0Hz,1H),7.48(d,J=8.5Hz,2H),7.34(qd,J=5.0,2.1Hz,2H),7.31-7.27(m,2H),6.79(d,J=7.4Hz,1H),6.53(d,J=8.5Hz,2H),5.12-5.03(m,1H),4.35(dt,J=14.5,7.4Hz,4H),3.84(dd,J=7.8,5.0Hz,2H),1.48(t,J=7.3Hz,3H)ppm.
质谱:C23H22ClN4OS[M+H]+理论值:437.1,实测值:437.1。
实施例39:
I-39(9.7mg,48%产率).1H NMR(400MHz,CDCl3)δ8.56(d,J=2.0Hz,1H),7.72(dd,J=8.5,2.7Hz,1H),7.30(dd,J=3.3,1.8Hz,1H),7.22(d,J=8.5Hz,2H),6.43(d,J=8.6Hz,2H),6.20(t,J=3.3Hz,1H),6.18-6.04(m,4H),4.97(dd,J=12.4,5.2Hz,1H),4.29(t,J=7.5Hz,2H),3.72(dd,J=7.4,4.9Hz,2H),1.42(s,9H)ppm.
质谱:C26H27FN5O3S[M+H]+理论值:508.2,实测值:508.2。
实施例40:
I-40(4.2mg,38%产率).1H NMR(500MHz,CDCl3)δ8.55(d,J=2.6Hz,1H),7.84(dd,J=8.5,2.7Hz,1H),7.48(s,1H),7.17(d,J=8.5Hz,1H),6.48(d,J=8.5Hz,2H),6.24(s,2H),6.12(d,J=6.9Hz,1H),4.99(d,J=7.0Hz,1H),4.31(t,J=7.5Hz,2H),3.81(dd,J=7.8,5.2Hz,2H)ppm.
质谱:C20H17FN5O2S[M+H]+理论值:410.1,实测值:410.1。
实施例41:
I-41(8.1mg,52%产率).1H NMR(400MHz,CDCl3)δ8.54(d,J=2.1Hz,1H),7.91(dd,J=8.5,2.6Hz,1H),7.32(s,2H),6.50-6.26(m,4H),6.22(d,J=6.8Hz,1H),4.97(dd,J=12.5,5.4Hz,1H),4.28(t,J=7.5Hz,2H),3.80(dd,J=7.6,5.4Hz,2H)ppm.
质谱:C21H17ClFN4OS2[M+H]+理论值:459.0,实测值:459.0。
实施例42:
I-42(9.2mg,81%产率).1H NMR(400MHz,CDCl3)δ8.55(d,J=1.9Hz,1H),7.83(dd,J=8.5,2.7Hz,1H),7.66(d,J=8.7Hz,2H),7.23(d,J=3.6Hz,1H),6.55(d,J=3.6Hz,1H),6.50(d,J=8.7Hz,2H),6.33-6.07(m,3H),5.00(dt,J=12.6,6.4Hz,1H),4.37(t,J=7.7Hz,2H),3.97-3.80(m,5H)ppm.
质谱:C23H20FN4O4S[M+H]+理论值:467.1,实测值:467.1。
实施例43:
I-43(5.1mg,61%产率).1H NMR(500MHz,CDCl3)δ8.51(d,J=2.1Hz,1H),7.87(dd,J=8.5,2.5Hz,1H),7.47(d,J=8.5Hz,2H),6.46(d,J=8.5Hz,2H),6.39-6.24(m,3H),6.21(d,J=7.2Hz,1H),5.98(d,J=2.1Hz,1H),4.96(dd,J=12.3,5.3Hz,1H),4.30(t,J=7.5Hz,2H),3.81(dd,J=7.5,5.4Hz,2H),2.32(s,3H)ppm.
质谱::C22H20FN4O2S[M+H]+理论值:423.1,实测值:423.1。
实施例44:
I-44(4.2mg,35%产率).1H NMR(400MHz,CDCl3)δ8.45(d,J=1.2Hz,1H),8.04(dd,J=8.6,1.6Hz,1H),7.95(d,J=8.5Hz,1H),7.80(d,J=7.2Hz,1H),7.52(d,J=8.6Hz,2H),7.40(s,1H),6.52-6.36(m,4H),5.13-4.97(m,1H),4.32(t,J=7.5Hz,2H),3.94(dd,J=7.5,5.4Hz,2H)ppm.
质谱:C21H17ClN3O2S[M+H]+理论值:410.1,实测值:410.1。
实施例45:
I-45(7.4mg,54%产率).1H NMR(500MHz,CDCl3)δ8.09(s,1H),7.85(d,J=8.2Hz,1H),7.66(d,J=8.4Hz,1H),7.58-7.31(m,4H),6.58-6.31(m,4H),5.11-4.99(m,1H),4.33(t,J=7.4Hz,2H),3.94-3.84(m,2H),2.66(s,3H)ppm.
质谱:C22H20N3O3[M+H]+理论值:374.1,实测值:374.1。
实施例46:
I-46(4.0mg,43%产率).1H NMR(400MHz,CDCl3)δ8.27(d,J=6.0Hz,1H),7.79(d,J=2.2Hz,1H),7.56(d,J=8.7Hz,2H),7.41(d,J=1.2Hz,1H),7.33(d,J=12.2Hz,2H),6.80(dd,J=2.1,0.9Hz,1H),6.53(d,J=8.5Hz,2H),6.48-6.39(m,2H),5.09(td,J=7.2,5.2Hz,1H),4.38(t,J=7.6Hz,2H),3.83(dd,J=7.6,5.4Hz,2H)ppm.
质谱:C22H18FN2O3[M+H]+理论值:377.1,实测值:377.1。
实施例47:
I-47(3.2mg,29%产率).1H NMR(400MHz,CDCl3)δ9.17(d,J=1.7Hz,1H),7.91-7.77(m,2H),7.67(dd,J=8.7,1.8Hz,1H),7.56(d,J=8.7Hz,2H),7.41(d,J=1.1Hz,1H),6.52(d,J=8.6Hz,2H),6.48-6.37(m,2H),5.08(tt,J=12.6,6.3Hz,1H),4.39(t,J=7.5Hz,2H),3.87(dd,J=7.7,5.3Hz,2H)ppm.
质谱:C21H17BrN3O2S[M+H]+理论值:454.0,实测值:454.0。
实施例48:
I-48(3.7mg,33%产率).1H NMR(500MHz,CDCl3)δ9.01(d,J=2.7Hz,1H),8.35(s,1H),8.27(d,J=8.4Hz,1H),8.20(d,J=8.8Hz,1H),8.09(dd,J=8.8,1.9Hz,1H),7.57(d,J=8.6Hz,2H),7.50(dd,J=8.3,4.2Hz,1H),7.41(s,1H),6.84(d,J=6.7Hz,1H),6.53(d,J=8.6Hz,2H),6.47(d,J=3.3Hz,1H),6.44(dd,J=3.3,1.8Hz,1H),5.10(d,J=7.4Hz,1H),4.40(t,J=7.5Hz,2H),3.86(dd,J=7.9,4.8Hz,2H)ppm.
质谱:C23H20N3O2[M+H]+理论值:370.1,实测值:370.2。
实施例49:
I-49(5.5mg,34%产率).1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.02-7.98(m,1H),7.55(t,J=9.1Hz,3H),7.40(d,J=0.9Hz,1H),6.54-6.39(m,4H),5.07(dd,J=12.4,5.1Hz,1H),4.34(t,J=7.6Hz,2H),3.92(dd,J=7.7,5.2Hz,2H)ppm.
质谱:C21H17BrN3O2S[M+H]+理论值:454.0,实测值:454.0。
实施例50:
I-50(2.4mg,27%产率).1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.59(d,J=1.3Hz,1H),8.17(d,J=8.5Hz,1H),8.01(dd,J=8.6,1.6Hz,1H),7.54(d,J=8.6Hz,2H),7.40(s,2H),6.50(d,J=8.6Hz,2H),6.47-6.36(m,3H),5.11-5.04(m,1H),4.35(t,J=7.5Hz,2H),3.91(dd,J=7.7,5.2Hz,2H)ppm.
质谱:C21H19N4O2[M+H]+理论值:359.1,实测值:359.2。
实施例51:
I-51(8.3mg,49%产率).1H NMR(400MHz,DMSO)δ11.59(s,1H),8.45(d,J=7.3Hz,1H),8.09(d,J=2.9Hz,1H),7.96(d,J=7.8Hz,1H),7.60(d,J=1.2Hz,1H),7.51(d,J=8.6Hz,2H),7.03-6.88(m,2H),6.64(d,J=3.2Hz,1H),6.57-6.41(m,3H),4.95-4.81(m,1H),4.21(t,J=7.5Hz,2H),3.84-3.70(m,2H),2.45(s,3H)ppm.
质谱:C23H22N3O2[M+H]+理论值:372.2,实测值:372.2。
实施例52:
I-52(2.3mg,26%产率).1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.90(d,J=8.5Hz,1H),7.83(d,J=8.4Hz,1H),7.54(d,J=11.6Hz,1H),7.25-7.22(m,2H),7.00(s,1H),6.87-6.74(m,2H),6.53(d,J=7.5Hz,2H),5.06(dd,J=11.1,5.0Hz,1H),4.35(t,J=7.6Hz,2H),3.84-3.77(m,2H),2.87(s,3H)ppm.
质谱:C22H20N3O2S[M+H]+理论值:390.1,实测值:390.1。
实施例53:
I-53(7.2mg,33%产率).1H NMR(500MHz,CDCl3)δ9.70(s,1H),9.62(d,J=5.8Hz,1H),9.09(s,1H),8.02(d,J=9.5Hz,1H),7.67(d,J=9.4Hz,1H),7.45(d,J=8.6Hz,2H),7.39(s,1H),6.43(d,J=13.1Hz,4H),5.02(d,J=6.2Hz,1H),4.28(t,J=7.0Hz,2H),4.14(t,J=6.1Hz,2H)ppm.
质谱:C20H18N5O2[M+H]+理论值:360.1,实测值:360.1。
实施例54:
I-54(6.4mg,38%产率).1H NMR(500MHz,CDCl3)δ9.47(s,1H),9.23(d,J=5.8Hz,1H),7.97(d,J=9.4Hz,1H),7.75(s,1H),7.62(d,J=13.7Hz,2H),7.48(d,J=8.3Hz,2H),7.39(s,1H),6.46(d,J=8.3Hz,2H),6.43(s,2H),5.04(dd,J=12.8,6.4Hz,1H),4.30(t,J=7.3Hz,2H),4.14(t,J=6.5Hz,2H)ppm.
质谱:C21H19N4O2[M+H]+理论值:359.1,实测值:359.1。
实施例55:
I-55(5.1mg,36%产率).1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.04(d,J=8.4Hz,1H),7.91(d,J=8.2Hz,1H),7.82(t,J=7.1Hz,1H),7.63(t,J=7.1Hz,1H),7.54(t,J=6.1Hz,3H),7.40(s,1H),6.51(d,J=8.7Hz,2H),6.48-6.38(m,2H),5.09(dd,J=12.4,5.1Hz,1H),4.38(t,J=7.5Hz,2H),3.91(dd,J=7.8,5.1Hz,2H)ppm.
质谱:C23H19ClN3O2[M+H]+理论值:404.1,实测值:404.1。
实施例56:
I-56(3.2mg,30%产率).1H NMR(400MHz,CDCl3)δ8.65-8.58(m,1H),8.56(s,1H),8.29(d,J=3.5Hz,1H),8.18(d,J=6.6Hz,1H),7.51(d,J=8.6Hz,2H),7.39(s,1H),7.17(dd,J=7.9,4.8Hz,1H),6.49(d,J=8.6Hz,2H),6.43(s,2H),5.06(dd,J=13.0,6.0Hz,1H),4.33(t,J=7.5Hz,2H),4.10-3.97(m,2H)ppm.
质谱:C21H19N4O2[M+H]+理论值:359.1,实测值:359.1。
实施例57:
I-57(6.2mg,40%产率).1H NMR(500MHz,CDCl3)δ9.81(s,1H),8.45(d,J=7.4Hz,1H),7.57(d,J=1.7Hz,1H),7.52(d,J=8.7Hz,2H),7.41(dd,J=6.6,1.3Hz,2H),7.32(d,J=1.6Hz,1H),6.49(d,J=8.7Hz,2H),6.46-6.40(m,2H),5.12-5.04(m,1H),4.32(t,J=7.5Hz,2H),4.01(dd,J=7.6,5.4Hz,2H)ppm.
质谱:C22H18BrClN3O2[M+H]+理论值:470.0,实测值:470.0。
实施例58:
I-58(9.4mg,47%产率).1H NMR(500MHz,CDCl3)δ9.52(d,J=7.6Hz,1H),8.43(dd,J=4.7,1.0Hz,1H),8.19(s,1H),7.97(d,J=8.0Hz,1H),7.54(d,J=8.5Hz,2H),7.40(d,J=1.1Hz,1H),7.14(dd,J=8.2,4.8Hz,1H),6.52(d,J=8.6Hz,2H),6.47-6.41(m,2H),5.16(dd,J=13.3,6.1Hz,1H),4.40-4.30(m,2H),3.99-3.86(m,2H)ppm.
质谱:C21H19N4O2[M+H]+理论值:359.1,实测值:359.1。
实施例59:
I-59(8.2mg,51%产率).1H NMR(400MHz,CDCl3)δ8.33(d,J=8.1Hz,1H),7.60(d,J=8.4Hz,2H),7.53(d,J=8.7Hz,2H),7.38(t,J=7.3Hz,2H),7.24(s,1H),6.50(d,J=8.6Hz,2H),6.43(dd,J=9.3,2.5Hz,2H),5.10(d,J=7.3Hz,1H),4.36(t,J=7.5Hz,2H),3.83(dd,J=7.6,5.3Hz,2H)ppm.
质谱:C21H19N4O2[M+H]+理论值:359.1,实测值:359.1。
实施例60:
I-60(7.2mg,44%产率).1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.62(d,J=1.4Hz,1H),8.16(d,J=8.5Hz,1H),8.04(dd,J=8.6,1.7Hz,1H),7.62(d,J=7.2Hz,1H),7.53(d,J=8.7Hz,2H),7.40(d,J=1.0Hz,1H),6.49(d,J=8.7Hz,2H),6.45-6.38(m,2H),5.14-5.01(m,1H),4.35(t,J=7.5Hz,2H),3.93(dd,J=7.7,5.3Hz,2H)ppm.
质谱:C21H18N3O2S[M+H]+理论值:376.1,实测值:376.1。
实施例61:
I-61(5.2mg,33%产率).1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.35(d,J=5.5Hz,1H),7.96(d,J=8.7Hz,1H),7.85(d,J=6.1Hz,1H),7.44(d,J=8.2Hz,2H),7.33(s,1H),6.42(d,J=8.3Hz,2H),6.37(s,2H),4.98(d,J=5.3Hz,1H),4.26(t,J=7.0Hz,2H),4.01-3.92(m,2H)ppm.
质谱:C20H18N5O2[M+H]+理论值:360.1,实测值:360.1。
实施例I-62:
I-62:收率:15.00%。1H NMR(500MHz,CDCl3)δ8.08-7.77(m,1H),7.21-7.10(m,1H),6.96-6.83(m,4H),3.91(s,1H),3.89-3.81(m,4H),3.48(d,J=11.9Hz,2H),3.07(s,4H),2.80(t,J=10.9Hz,2H),2.05(d,J=10.7Hz,3H),1.99(s,4H),1.42(dd,J=11.8,4.4Hz,2H).质谱:C24H28N5O3[M-1]-计算值:433.2,实测值:433.1。
实施例I-63:
I-63:收率42.10%。1H NMR(500MHz,CDCl3)δ7.86(s,1H),6.94-6.81(m,4H),4.03-3.89(m,1H),3.89-3.81(m,2H),3.55-3.46(m,2H),3.19(s,1H),3.07(d,J=4.8Hz,4H),2.87-2.81(m,2H),2.62(s,3H),2.58(s,3H),2.51(d,J=21.5Hz,2H),2.08(d,J=12.8Hz,4H).质谱:C25H31N5O2S[M+H]+计算值:466.2,实测值:466.2。
实施例1-64:
I-64:收率:14.86%。质谱:C23H29N6SO[M+H]+计算值:437.28,实测值:437.2。
实施例I-65:
I-65:收率:18.11%。1H NMR(500MHz,CDCl3)δ8.57(s,1H),7.64(d,J=5.9Hz,1H),6.90(d,J=8.5Hz,2H),6.50(d,J=8.5Hz,2H),6.02(s,3H),5.05-4.90(m,1H),4.28(t,J=5.0Hz,2H),3.87-3.79(m,4H),3.73(t,J=5.0Hz,2H),3.05(m,4H).质谱:C21H23N5O2SF[M+H]+计算值:428.1,实测值:428.1。
实施例I-66:BR-003006-NX-1
I-66,收率:33.91%。质谱:C21H24FN6OS[M+H]+计算值:476.28,实测值:476.2。
实施例I-67:BR-003517-NX-1
I-67,(1.1mg,15%产率)质谱:C22H26N5OS[M+H]+理论值:408.2,实测值:408.2。
实施例I-68:BR-003519-NX-1
I-68:(2.1mg,32%产率)质谱:C22H19FN5OS[M+H]+理论值:420.1,实测值:420.1。
实施例I-69:BR-003693-NX-1
I-69:(5.0mg,15.18%产率)1H NMR(500MHz,Chloroform-d)δ7.46(s,1H),7.24(d,J=8.6Hz,2H),6.84-6.77(m,1H),6.60-6.47(m,4H),5.98(d,J=7.4Hz,1H),4.99(qt,J=7.3,5.0Hz,1H),4.32(t,J=7.5Hz,2H),3.78(dd,J=7.8,5.0Hz,2H),2.74(s,3H).
质谱:C21H22N4OF3S[M+H]+理论值:435.1,实测值:435.2。
实施例I-70:BR-003694-NX-1
I-70:(11.0mg,2.72%产率)1H NMR(500MHz,Chloroform-d)δ7.46(s,1H),7.24(d,J=8.6Hz,2H),6.84-6.77(m,1H),6.60-6.47(m,4H),5.98(d,J=7.4Hz,1H),4.99(qt,J=7.3,5.0Hz,1H),4.32(t,J=7.5Hz,2H),3.78(dd,J=7.8,5.0Hz,2H),2.74(s,3H).
质谱:C21H23N4OF3S[M+H]+理论值:407.1,实测值:407.0。
实施例I-71:BR-003891-NX-1
I-71:(11.0mg,22.4%产率)1H NMR(500MHz,Chloroform-d)δ8.82(d,J=2.1Hz,1H),8.33(d,J=2.2Hz,1H),7.29(s,1H),6.70(d,J=8.4Hz,1H),6.47(d,J=4.2Hz,1H),6.32(s,1H),5.04(q,J=5.6,5.0Hz,1H),4.52(t,J=8.6Hz,2H),4.36(q,J=7.3Hz,2H),4.27(t,J=7.4Hz,2H),3.75(s,2H),3.18(t,J=8.6Hz,2H),1.48(d,J=7.3Hz,3H).
质谱:C21H22N4O2Cl[M+H]+理论值:397.1,实测值:397.0。
实施例I-72:BR-003892-NX-1
I-72:质谱:C23H20N4O2F3S[M+H]+理论值:472.2,实测值:473.0。
实施例I-73:BR-003893-NX-1
I-73:质谱:C21H17N2O2F4[M+H]+理论值:405.11,实测值:405.0。
实施例I-74:BR-003894-NX-1
I-74:(43.0mg,25.03%产率)1H NMR(500MHz,Chloroform-d)δ8.07(dd,J=6.7,2.3Hz,1H),8.02(ddd,J=8.6,4.6,2.4Hz,1H),7.30(t,J=9.2Hz,1H),7.25-7.22(m,2H),6.82(tt,J=7.4,1.1Hz,1H),6.63(d,J=5.5Hz,1H),6.54-6.49(m,2H),4.99(tdd,J=7.3,4.6,2.6Hz,1H),4.32(ddd,J=7.9,7.2,0.7Hz,2H),3.78(ddd,J=7.9,4.7,0.8Hz,2H).
质谱:C17H15N2OF4[M+H]+理论值:339.10,实测值:339.0。
实施例I-75:BR-008207-NX-1
I-75:(3.9mg,35%产率).1H NMR(400MHz,CDCl3)δ8.83(d,J=2.0Hz,1H),8.33(d,J=2.1Hz,1H),7.43(d,J=8.6Hz,2H),7.29(s,1H),6.95(d,J=3.5Hz,1H),6.74(d,J=7.6Hz,1H),6.68(dd,J=3.5,1.1Hz,1H),6.49(d,J=8.6Hz,2H),5.12-5.02(m,1H),4.35(q,J=7.3Hz,4H),3.83(dd,J=7.8,5.0Hz,2H),2.48(d,J=0.7Hz,3H),1.48(t,J=7.3Hz,3H)ppm.
质谱:C24H24ClN4OS[M+H]+理论值:451.1,实测值:451.1。
实施例I-76:BR-008208-NX-1
I-76:(2.4mg,25%产率).1H NMR(400MHz,CDCl3)δ8.85(d,J=2.1Hz,1H),8.35(d,J=2.1Hz,1H),7.59-7.53(m,1H),7.50(d,J=8.7Hz,2H),7.32(s,1H),7.14(d,J=3.9Hz,1H),6.70(s,1H),6.58-6.46(m,2H),5.15-5.10(m,1H),4.46-4.33(m,4H),3.96-3.88(m,2H),1.50(d,J=7.3Hz,3H)ppm.
质谱:C24H21ClN5OS[M+H]+理论值:462.1,实测值:462.1。
试验例
酶活性抑制测试方法:
USP25酶活性抑制测试方法:反应体系溶液为50mM Tris(pH 7.5),150mM NaCl,1mM DTT,0.05%Tween-20。室温下将10ul 20nM USP25(50mM Tris pH 7.5,150mM NaCl,1mM DTT,20%glycerol)移液到96孔板中;加入10ul不同浓度的化合物,共同孵育20分钟;最后加入10ul 20uM底物Ub-AMC反应30分钟。反应体系中USP25蛋白终浓度为4nM,底物Ub-AMC终浓度为4uM,DMSO终浓度为1%。在多功能酶标仪Synergy Neo2(BioTek)上以动力学模式检测荧光信号(激发波长360nm和发射波长460nm);使用前30分钟内的荧光信号变化计算反应速率,该变化在该测定的线性区间内。为了验证化合物不干扰检测系统,在上述反应中不加入蛋白作为对照来测试化合物对反应的影响。
Ki,化合物处理的USP25反应30分钟荧光信号变化值;K0,对照DMSO处理的USP25反应30分钟荧光信号变化值.
USP28酶活性抑制测试方法:
反应体系溶液为50mM Tris(pH 7.5),150mM NaCl,1mM DTT,0.05%Tween-20。室温下将10ul 10nM USP28(50mM Tris pH 7.5,150mM NaCl,1mM DTT,20%glycerol)移液到96孔板中;加入10ul不同浓度的化合物,共同孵育20分钟;最后加入10ul 5uM底物Ub-AMC反应15分钟。反应体系中USP28蛋白终浓度为2nM,底物Ub-AMC终浓度为1uM,DMSO终浓度为1%。在多功能酶标仪Synergy Neo2(BioTek)上以动力学模式检测荧光信号(激发波长360nm和发射波长460nm);使用前15分钟内的荧光信号变化计算反应速率,该变化在该测定的线性区间内。为了验证化合物不干扰检测系统,在上述反应中不加入蛋白作为对照来测试化合物对反应的影响。
Ki,化合物处理的USP28反应30分钟荧光信号变化值;K0,对照DMSO处理的USP28反应30分钟荧光信号变化值.
化合物活性抑制测试结果:
化合物100uM单点浓度活性抑制测试结果
部分化合物梯度活性抑制测试结果:
表格中符号对应IC50的结果如下:
“+++++”:1uM-10uM;“+++”:10uM-30uM;“++”:30uM-50uM;“+”:50uM-100uM;“-”:>100uM
Claims (10)
1.式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药:
其中,
Ar选自取代或未取代的C6-C14芳基,取代或未取代的含有选自N、O、S中的一个或多个杂原子的9-10元双环稠合杂环基,其中用于取代的取代基选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基;
m和n各自独立地为1或2;
R1选自氢;硝基;卤素;取代或未取代的C1-C6烷氧基,其中,用于取代的取代基选自C1-C6烷基氨基;取代或未取代的C1-C6烷基羰基氨基,其中用于取代的取代基选自卤素、氨基、C1-C6烷基氨基、5-7元杂环基;取代或未取代的5-7元杂环基,其中用于取代的取代基选自氰基、C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、卤素;其中,5-7元杂环基含有选自N、O、S中的一个或多个杂原子;
R2选自氢;C1-C6烷基;卤素;C1-C6烷氧基;
或者,R1与R2组成一个5-7元杂环基,其中,5-7元杂环基含有选自N、O、S中的一个或多个杂原子,优选地,所述杂原子为O原子。
2.根据权利要求1所述的式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,其中,Ar选自取代或未取代的苯基,取代或未取代的噻吩并吡啶、取代或未取代的呋喃并吡啶,取代或未取代的吡咯并吡啶、取代或未取代的吡唑并吡啶、取代或未取代的吡咯并嘧啶、取代或未取代的噻吩并嘧啶、取代或未取代的苯并吡咯、取代或未取代的苯并呋喃、取代或未取代的苯并噻吩、取代或未取代的苯并噁唑、取代或未取代的苯并噻唑、取代或未取代的苯并吡唑、取代或未取代的苯并三唑、取代或未取代的苯并吡啶,其中用于取代的取代基各自独立地选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基;优选地,用于取代的取代基为选自卤素、氨基、氰基、C1-C6烷基、卤代C1-C6烷基中的1、2或3个。
4.根据权利要求1至3中任一项所述的式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,其中,
R1选自氢;硝基;卤素;取代或未取代的C1-C4烷氧基,其中,用于取代的取代基选自C1-C4烷基氨基;取代或未取代的C1-C4烷基羰基氨基,其中用于取代的取代基选自卤素、氨基、C1-C4烷基氨基、哌嗪基、哌啶基;取代或未取代的哌嗪基;取代或未取代的吗啉基;取代或未取代的呋喃基;取代或未取代的噻吩基;取代或未取代的吡唑基;取代或未取代的吡咯基;取代或未取代的吡啶基;取代或未取代的噁唑基,其中用于取代的取代基分别选自氰基、C1-C4烷基、C1-C4烷基羰基、C1-C4烷氧基羰基、卤素。
5.根据权利要求1至3中任一项所述的式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,其中,R1选自氢、甲氨基乙氧基、甲氧基、硝基、氯甲基羰基氨基、甲氨基甲羰基氨基、哌嗪基甲基羰基氨基、哌啶基甲基羰基氨基、哌嗪基、甲羰基哌嗪基、甲基哌嗪基、吗啉基、Br、呋喃基、甲基呋喃基、甲氧基羰基呋喃基、噻吩基、氯噻吩基、甲基噻吩基、氰基噻吩基、吡唑基、叔丁氧羰基吡咯基、噁唑基、吡啶基。
6.根据权利要求1至5中任一项所述的式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,其中,R2选自氢;C1-C4烷基;卤素;C1-C4烷氧基。
7.根据权利要求1至5中任一项所述的式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,其中,R2为氢、甲基、甲氧基、乙氧基或丙氧基。
9.根据权利要求1至8中任一项所述的式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,在制备USP25和/或USP28抑制剂的用途。
10.根据权利要求1至8中任一项所述的式I所示的化合物,或其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物、药学上可接受的盐或前药,在制备用于预防或治疗与USP25和/或USP28相关疾病的药物的用途,
优选地,所述与USP25和/或USP28相关的疾病包括癌症、炎症、自身免疫疾病、以及神经退行性疾病。
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