CN113939516A - 用于靶向蛋白降解的方法和组合物 - Google Patents
用于靶向蛋白降解的方法和组合物 Download PDFInfo
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- CN113939516A CN113939516A CN202080043111.4A CN202080043111A CN113939516A CN 113939516 A CN113939516 A CN 113939516A CN 202080043111 A CN202080043111 A CN 202080043111A CN 113939516 A CN113939516 A CN 113939516A
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- GDPYNCZCYJBYIN-UHFFFAOYSA-N tert-butyl n-[2-(4-nitrophenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCC1=CC=C([N+]([O-])=O)C=C1 GDPYNCZCYJBYIN-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- 239000001993 wax Substances 0.000 description 1
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- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
提供了式I的化合物:
Description
相关申请
本申请要求于2019年4月9日提交的国际申请号PCT/CN2019/081919的优先权,其全部内容并入本文。
背景技术
蛋白质稳态或蛋白内稳态是指细胞正确调节细胞蛋白质的合成、折叠、运输和降解的能力。正确调节的蛋白质降解是细胞的正常功能(包括其增殖、分化和死亡)所需要的,并且在癌症和其他疾病中常常失调。
泛素-蛋白酶体系统(UPS)是细胞中介导蛋白质的处置和代谢循环的主要途径之一(Yu和Matouschek,Annu Rev Biophys,2017,46:149-173;Navon和Ciechanover,J BiolChem,2009,284:33713-33718)。泛素是一种泛表达的76个氨基酸残基的蛋白质。关于通过UPS实现的蛋白质降解,泛素化的过程在泛素附接至底物蛋白中的赖氨酸氨基酸残基时发生,这涉及一系列酶促步骤。首先,泛素被转移至E1泛素活化酶。其次,活化的泛素从E1转移至E2泛素缀合酶。并且第三,数百种不同的E3泛素连接酶中的一种将泛素连接到底物蛋白中的赖氨酸残基上。这种酶促过程的重复导致用聚泛素链给底物蛋白加标签,然后将其递送至蛋白酶体,一种降解带泛素标签的蛋白质的大型多亚基复合物。一些细胞伴侣蛋白和伴侣复合物朝向UPS引导蛋白质的能力通过它们与E3泛素连接酶的直接相互作用而促进(Amm等人,Biochim Biophys Acta,2014,1843:182-196;Taipale等人,Cell,2012,150:987-1001)。除了蛋白质降解之外,蛋白质的泛素化还可以调节其它过程,诸如底物的亚细胞定位、活性和蛋白质-蛋白质相互作用。
化学诱导的靶向蛋白降解已成为小分子药物开发的一种新方式。小分子可以用于促进一种或多种靶蛋白与各种细胞蛋白降解途径的组分的相互作用,从而诱导一种或多种靶向蛋白的降解,作为治疗疾病的一种方式。
具体地,蛋白水解靶向嵌合体(PROTAC)是此类小分子的一个实例,其通过拉拢UPS而有意地诱导特定蛋白质的蛋白质降解(Burslem和Crews,Cell,2020,181:102-114;Pettersson和Crews,Drug Discov Today Technol,2019,31:15-27)。PROTAC分子是双功能小分子,其同时与一种或多种靶蛋白和E3泛素连接酶结合。一种或多种靶蛋白和E3连接酶的诱导接近导致一种或多种靶蛋白的泛素化以及随后蛋白酶体对所述靶蛋白的降解。尽管掺入混杂地与多种蛋白质结合的靶蛋白结合剂的PROTAC通常可以降解多种蛋白质,但在一些情况下,单个靶标与E3连接酶之间的电荷排斥和空间冲突可以增加观察到的降解选择性(Pettersson和Crews,Drug Discov Today Technol,2019,31:15-27;Bondeson等人,CellChem Biol,2018,25:78-87;Gadd等人,Nat Chem Biol,2017,13:514-521;Zengerle等人,ACS Chem Biol,2015,10:1770-1777)。
AUTAC技术遵循类似的诱导接近原理,但靶向蛋白质以通过自噬进行降解(Daiki等人,Mol Cell,2019,76:797-810)。然而,一些缺点与当前的靶向蛋白降解技术相关联。这些缺点包括许多组织和器官中的靶蛋白混杂降解,而不仅仅是靶蛋白参与疾病过程的组织和器官,预期这会导致治疗的不良副作用。此外,对PROTAC的抗性可以通过UPS组分(诸如E3连接酶)的突变产生(Ottis等人,ACS Chem Biol,2019,14:2215-2223;Zhang等人,MolCancer Ther,2019,18:1302-1311),从而导致丧失治疗功效。因此,需要用于靶向蛋白降解的改进/替代性的方法和组合物。
发明内容
本公开提供了肿瘤靶向蛋白降解嵌合体(T-PEACH),其包含能够结合一种或多种靶蛋白(例如,BRD4)的第一部分和能够结合伴侣蛋白或伴侣复合物的蛋白质组分的第二部分。此类T-PEACH化合物包括具有式I的那些:
以及其药学上可接受的盐,其中X、L和A如本文所定义。
还提供了包含所公开的式I的化合物的组合物以及其制造方法。在一个方面,所公开的化合物以肿瘤选择性方式诱导靶向致癌蛋白降解并且可用于治疗癌症和相关病状。
附图说明
图1示出由化合物074诱导的BRD4降解的蛋白质印迹。
图2示出用化合物074和/或蛋白酶体抑制剂硼替佐米(bortezomib)处理后BRD4的蛋白质印迹。
图3a示出用化合物074处理的小鼠的MV4-11 AML异种移植模型中的平均肿瘤体积。
图3b示出用化合物074处理的小鼠的MV4-11 AML异种移植模型中的平均体重。
图4a示出用化合物074和078处理的小鼠的SU-DHL-4DLCBL异种移植模型中的平均肿瘤体积。
图4b示出用化合物074和078处理的小鼠的SU-DHL-4DLCBL异种移植模型中的平均体重。
具体实施方式
1.化合物综述
本文提供具有式I的T-PEACH化合物:
或其药学上可接受的盐,其中
X是C(O)或(C1-C4)亚烷基;
W是任选地被1至3个选自R2的基团取代的5或6元杂芳基;
V是任选地被1至3个选自R3的基团取代的苯基或5至9元杂芳基;
R1是卤代基、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基或卤代(C1-C4)烷氧基;
R2是(C1-C4)烷基、卤代(C1-C4)烷基、(C2-C6)烯基、卤代(C2-C6)烯基、(C2-C6)炔基、卤代(C2-C6)炔基、CN、-C1-4烷基ORa、-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-C(O)NRa(C1-4亚烷基)ORa、-C(O)NRa(C1-4亚烷基)NRaRb、-C(O)NRa(C1-4亚烷基)OR、-NRaRb、-O(C1-4亚烷基)NRaRb、-C1-4烷基NRaRb、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRaRb、-SO2NRaRb、-NRa(C1-4烷基)ORa、-NRa(C1-4烷基)NRaRb、-C1-6烷基C(O)NRaRb、苯基或5至7元杂芳基,其中所述苯基和5至7元杂芳基各自任选且独立地被1至3个选自R4的基团取代;
Ra和Rb各自独立地选自氢和(C1-C4)烷基,其中所述(C1-C4)烷基任选地被一个或多个卤代基或3至7元杂环基或两者取代;
R3和R4各自独立地为卤代基、-NRaRb、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基或卤代(C1-C4)烷氧基;并且
L是接头。
2.定义
如本文所用,冠词“一个”和“一种”是指冠词的一个/种或多于一个/种(例如,至少一个/种)语法宾语。词语“一个”或“一种”在与术语“包括”在本文结合使用时可表示“一个/种”,但也与“一个/种或多个/种”、“至少一个/种”以及“一个/种或多于一个/种”的含义一致。
如本文所用,“约”和“大约”通常表示给定测量的性质或精度的所测量的量的可接受的误差程度。示例性的误差程度在值的给定范围的百分之20(%)以内,通常在10%以内,并且更通常在5%以内。术语“基本上”是指超过50%,优选超过80%,并且最优选超过90%或95%。
如本文所用,术语“包括”或“包含”在提及给定实施方案中存在的组合物、方法以及其一种或多种相应组分时使用,但对于包括未指明的要素仍然是开放的。
如本文所用,术语“基本上由……组成”是指给定实施方案所需要的那些要素。该术语允许存在不实质影响本发明的那个实施方案的一种或多种基本和新颖或功能特征的另外要素。
术语“由……组成”是指如本文所述的组合物、方法以及其相应组分,其排除在该实施方案的描述中未叙述的任何要素。
如本文所用,术语“烷基”是指具有1至10个碳原子的饱和直链或支链非环烃,例如(C1-C6)烷基或(C1-C4)烷基,除非另外说明。代表性的直链烷基包括甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基和正癸基;而饱和支链烷基包括异丙基、仲丁基、异丁基、叔丁基、异戊基、2-甲基丁基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基、3,3-二乙基己基等。
如本文所用,术语“烯基”是指具有2至10个碳原子(例如,(C2-C6)烯基或(C2-C4)烯基)并且具有至少一个碳-碳双键的饱和直链或支链非环烃,除非另外说明。代表性的直链和支链(C2-C10)烯基包括乙烯基、烯丙基、1-丁烯基、2-丁烯基、异丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、1-己烯基、2-己烯基、3-己烯基、1-庚烯基、2-庚烯基、3-庚烯基、1-辛烯基、2-辛烯基、3-辛烯基、1-壬烯基、2-壬烯基、3-壬烯基、1-癸烯基、2-癸烯基、3-癸烯基等。
如本文所用,术语“炔基”是指具有2至10个碳原子(例如,(C2-C6)炔基或(C2-C4)炔基)并且具有至少一个碳-碳三键的饱和直链或支链非环烃,除非另外说明。代表性的直链和支链炔基包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基、4-戊炔基、1-己炔基、2-己炔基、5-己炔基、1-庚炔基、2-庚炔基、6-庚炔基、1-辛炔基、2-辛炔基、7-辛炔基、1-壬炔基、2-壬炔基、8-壬炔基、1-癸炔基、2-癸炔基、9-癸炔基等。
如本文所用,术语“4至6元环烷基”是指具有4至6个碳原子的饱和单环烷基自由基。代表性环烷基包括环丙基、环丁基、环戊基以及环己基。
如本文所用,术语“卤代烷基”是指其中一个或多个(包括所有)氢自由基被卤代基替代的烷基,其中每个卤代基独立地选自-F、-Cl、-Br和-I。代表性卤代烷基包括三氟甲基、溴甲基、1,2-二氯乙基、4-碘丁基、2-氟戊基等。
如本文所用,“烷氧基”是通过氧接头附接至另一个部分的烷基。
如本文所用,“卤代烷氧基”是通过氧接头附接至另一个部分的卤代烷基。
如本文所用,术语“亚烷基”是指具有两个附接点的烷基。直链亚烷基是优选的。亚烷基的非限制性实例包括亚甲基、亚乙基、正亚丙基、异亚丙基等。亚烷基可任选地被一个或多个取代基取代。
如本文所用,术语“杂环基”是指单环杂环环系,其为饱和环或不饱和非芳族环,在大小和化合价允许时,包括最多至5个独立地选自氮、氧和硫的杂原子。杂环可通过任何杂原子或碳原子附接。代表性杂环包括吗啉基、硫吗啉基、吡咯烷酮基、吡咯烷基、哌啶基、哌嗪基、环氧乙烷基(oxiranyl)、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢氮茚基(tetrahydropyrindinyl)、四氢嘧啶基等。
如本文所用,术语“杂芳族”、“杂芳基”或类似术语在定义的大小允许时是指包括碳原子环成员和一个或多个选自氮、氧和硫的杂原子环成员的单环或多环杂芳族环。代表性杂芳基包括吡啶基、呋喃基、噻吩基、吡咯基、噁唑基、咪唑基、噻唑基、异噁唑基、喹啉基、吡唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、三唑基、噻二唑基、异喹啉基、吲唑基、苯并噁唑基、苯并呋喃基、吲哚嗪基(indolizinyl)、咪唑并吡啶基、四唑基、苯并咪唑基、苯并噻唑基、苯并噻二唑基、苯并噁二唑基、吲哚基、四氢吲哚基、氮杂吲哚基、咪唑并吡啶基、喹唑啉基、嘌呤基、苯丙噻吩基等。杂芳族环或杂芳基环与另一基团的附接点可以在杂芳族环或杂芳基环的碳原子或杂原子处。
如本文所用,术语“卤素”或“卤代基”是指F、Cl、Br或I。
当杂环基或杂芳基含有氮原子时,它可以是取代或未取代的,只要化合价允许。
可互换使用的术语“接头”或“系链”是指接合两个其他部分(例如,第一结合部分和第二结合部分)的化学部分。接头可以共价接合第一结合部分和第二结合部分。在一个方面,接头在体内不可切割。在一个方面,接头包括一个或多个环状环系。在另一方面,接头包括任选地被一个或多个化学基团取代和/或中断的烷基链。在一个方面,接头包括最佳空间和化学特性以实现最佳治疗活性。在一个方面,接头不干扰第一结合部分和第二结合部分结合其相应靶标例如HSP90和BRD4的能力。
当结合使用以描述可具有多个附接点的化学基团时,连字符(-)表示所述基团与定义其的变量的附接点。例如,-NRaRb和-C(O)NRa(C1-4亚烷基)NRaR表示这些基团的附接点分别出现在氮原子和碳原子上。
当所公开化合物的立体化学由结构命名或描述时,所命名或描述的立体异构体相对于所有其它立体异构体具有按重量计至少60%、70%、80%、90%、99%或99.9%的纯度。相对于所有其它立体异构体按重量计的纯度百分比是一种立体异构体的重量与其它立体异构体的重量的比率。例如,当按照结构命名或描述单一对映体时,所描述或命名的对映体具有按重量计至少60%、70%、80%、90%、99%或99.9%的光学纯度。按重量计的光学纯度百分比是对映体的重量与对映体的重量加上其光学异构体的重量之比。
对于医药用途,所公开的化合物的药学上可接受的盐是指无毒的“药学上可接受的盐”。药学上可接受的盐形式包括药学上可接受的酸性/阴离子或碱性/阳离子盐。本文所述化合物的合适的药学上可接受的酸加成盐包括例如无机酸(诸如盐酸、氢溴酸、磷酸、硝酸和硫酸)和有机酸(诸如乙酸、苯磺酸、苯甲酸、甲磺酸和对甲苯磺酸)的盐。具有酸性基团(诸如羧酸)的本教导的化合物可以与一种或多种药学上可接受的碱形成药学上可接受的盐。合适的药学上可接受的碱式盐包括例如铵盐、碱金属盐(诸如钠盐和钾盐)以及碱土金属盐(诸如镁盐和钙盐)。具有季铵基团的化合物还含有抗衡阴离子,诸如氯化物、溴化物、碘化物、乙酸盐、高氯酸盐等。此类盐的其他实例包括盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、硝酸盐、苯甲酸盐以及与氨基酸诸如谷氨酸的盐。
术语“药学上可接受的载剂”是指不破坏与其一起调配的化合物的药理活性的无毒的载剂、佐剂或媒介物。可用于本文所述组合物的药学上可接受的载剂、佐剂或媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质,如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素类物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙二醇-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
本文提供的任何组合物或方法可以与本文提供的任何其他组合物和方法中的一种或多种组合。
如本文所用,术语“受试者”是指人和非人动物,包括兽医学受试者。术语“非人动物”包括所有脊椎动物,例如哺乳动物和非哺乳动物,诸如非人灵长类动物、小鼠、兔子、绵羊、狗、猫、马、牛、鸡、两栖动物和爬行动物。在一个优选实施方案中,受试者是人并且可以被称为患者。
如本文所用,术语“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”优选地是指获得有益的或期望的临床结果的动作,所述临床结果包括但不限于减轻或改善疾病或病状的一种或多种迹象或症状、减轻疾病的程度、疾病状态的稳定性(即,不恶化)、改善或减轻疾病状态、减缓进展的速率或时间,以及缓解(部分或总体),无论可检测还是不可检测。“治疗”还可意味着与不存在治疗的情况下的预期生存相比生存期的延长。治疗不一定是治愈性的。
“治疗有效量”是足以治疗受试者的疾病的量。治疗有效量可以一次或多次施用来施用。在一个方面,治疗有效量是指约0.01至约100mg/kg体重/天的剂量。
术语“施用(administer)”、“施用(administering)”或“施用(administration)”包括将药物组合物或药剂递送到受试者的系统中或递送至受试者体内或体表的特定区域的任何方法。在本发明的某些实施方案中,通过静脉内、肌内、皮下、皮内、鼻内、经口、经皮或经粘膜的方式施用药剂。在一个优选实施方案中,静脉内施用药剂。在另一个优选实施方案中,经口施用药剂。施用药剂可以由许多协同工作的人执行。施用药剂包括,例如,将有待向受试者施用的药剂开处方和/或提供服用特定药剂的说明(直接地或通过另一个),即通过自我递送服用,例如,通过口服递送、皮下递送、通过中心线静脉内递送等服用;或用于由经过训练的专业人员递送,例如,静脉内递送、肌内递送、肿瘤内递送等。
3.化合物
在第一实施方案中,提供了一种式I的化合物:
或其药学上可接受的盐,其中变量如上文所述。
在第二实施方案中,式I的化合物或其药学上可接受的盐中的A是
在第三实施方案中,式I的化合物或其药学上可接受的盐中的R3独立地为(C1-C4)烷基或卤代基,其中其余变量如上文针对式I或第二实施方案所描述。
在第四实施方案中,式I的化合物或其药学上可接受的盐中的A是
其中其余变量如上文针对式I或第二或第三实施方案所描述。可替代地,作为第四实施方案的一部分,式I的化合物或其药学上可接受的盐中的A是
其中其余变量如上文针对式I或第二或第三实施方案所描述。在另一个替代方案中,作为第四实施方案的一部分,式I的化合物或其药学上可接受的盐中的A是
在第五实施方案中,式I的化合物或其药学上可接受的盐中的L是*Het1-X1-、*Het1-X1-Het2-X2-、*Het1-X1-(C1-C4)亚烷基-Het2-X2-、*Het1-X1-Het2-X2(C1-C4)亚烷基-、*-(CH2CH2O)o-(CH2)p-Het1-X1-Het2-(CH2CH2O)n、*-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2、*Het1-X1-Phe-X2-NRc-X3-、*-(CH2CH2O)o-(CH2)p-Het1-X1-Phe-X2-NRc-(CH2CH2O)n-、*-(CH2CH2O)n-(CH2)m-NRc-Phe-X1-、*-(CH2CH2O)o-(CH2)p-NRc-Phe-(CH2CH2O)n-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-、*(CH2CH2O)n-(CH2)m-NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-(CH2CH2O)o、*NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2、*NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-(CH2CH2O)o、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-(CH2CH2O)n-、*-(CH2CH2O)n-(CH2)m-NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p,或*NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2;
*表示与X的附接点;
Het1和Het2各自独立地为苯基、4至6元杂环基、5至7元杂芳基,或4至6元环烷基;
X1、X2和X3各自独立地为C(O)或(CH2)r;
Rc和Rd各自独立地为氢或(C1-C4)烷基;并且
m、n、o、p、q和r各自独立地为选自0、1、2、3、4、5和6的整数,其中其余变量如上文针对式I或第二、第三或第四实施方案所描述。
在第六实施方案中,式I的化合物具有式II:
或其药学上可接受的盐,其中其余变量如上文针对式I或第二、第三、第四或第五实施方案所描述。
在第七实施方案中,式I或II的化合物或其药学上可接受的盐中的R1是卤代基或(C1-C4)烷基,其中其余变量如上文针对式I或第二、第三、第四或第五实施方案所描述。可替代地,作为第七实施方案的一部分,式I或II的化合物或其药学上可接受的盐中的R1是氯、异丙基、甲基、丙基或乙基,其中其余变量如上文针对式I或第二、第三、第四或第五实施方案所描述。在另一个替代方案中,作为第七实施方案的一部分,式I或II的化合物或其药学上可接受的盐中的R1是异丙基或乙基,其中其余变量如上文针对式I或第二、第三、第四或第五实施方案所描述。
在第八实施方案中,式I或II的化合物或其药学上可接受的盐中的R2是-ORa、-SRa、-C(O)NRaRb或-C(O)NRa(C1-4亚烷基)NRaRb,其中其余变量如上文针对式I或第二、第三、第四、第五或第七实施方案所描述。
在第九实施方案中,式I或II的化合物或其药学上可接受的盐中的Ra和Rb各自独立地选自氢和(C1-C4)烷基,其中所述(C1-C4)烷基任选地被1至3个卤代基或6元杂环基取代,其中其余变量如上文针对式I或第二、第三、第四、第五、第七或第八实施方案所描述。
在第十实施方案中,式I或II的化合物或其药学上可接受的盐中的R2是OH、SH、-C(O)NHCH2CF3、-C(O)NHCH2CH3、-C(O)NH(CH2)2N(CH2CH3)2、-C(O)NHCH(CH3)2、C(O)NH2、-C(O)NH(CH2)2哌啶基,其中其余变量如上文针对式I或第二、第三、第四、第五、第七、第八或第九实施方案所描述。可替代地,作为第十实施方案的一部分,式I或II的化合物或其药学上可接受的盐中的R2是-C(O)NHCH2CF3或OH,其中其余变量如上文针对式I或第二、第三、第四、第五、第七、第八或第九实施方案所描述。
在第十一实施方案中,式I的化合物具有式III:
或其药学上可接受的盐,其中其余变量如上文针对式I或第二、第三、第四、第五、第七、第八、第九或第十实施方案所描述。
在第十二实施方案中,如第五和后续实施方案中所定义的Het1和Het2各自独立地为4至6元杂环基,其中其余变量如上文针对式I、II或III或第二、第三、第四、第五、第七、第八、第九或第十实施方案所描述。
在第十三实施方案中,式I、II或III的化合物或其药学上可接受的盐中的L是*Het1-X1-、*Het1-X1-Het2-X2-、*Het1-X1-Het2-(CH2CH2O)n-、*Het1-X1-Phe-X2-NRc-X3-、*Het1-X1-Phe-X2-NRc-(CH2CH2O)n-、*NRc-Phe-X1-、*NRc-Phe-(CH2CH2O)n-、*NRc-(CH2CH2O)n-(CH2)m-、*NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-、*NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-、*NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-、*NRc-(CH2CH2O)n-(CH2)m-Phe-X1-Het1-X2-、*NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-、*NRc-(CH2CH2O)n-(CH2)m-Het1-X1-、*NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p,或*NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2-,其中其余变量如上文针对式I或第二、第三、第四、第五、第七、第八、第九、第十或第十二实施方案所描述。可替代地,式I、II或III的化合物或其药学上可接受的盐中的L是*Het1-X1-(CH2)r、*Het1-X1-Het2-(CH2)r-、*Het1-(CH2)r-Phe-(CH2)r-NRc-(CH2)r-、*NRc-Phe-(CH2)r-、*NRc-(CH2CH2O)n-、*NRc-(CH2)m-、*NRc-(CH2)m-C(O)-NRd-(CH2)p-、*NRc-(CH2)m-C(O)-NRd-(CH2CH2O)o-、*NRc-(CH2)m-Het1-X1-Het2-(CH2)r-、*NRc-(CH2)m-Phe-(CH2)r-Het1-(CH2)r-、*NRc-Phe-NH-C(O)-Het1-(CH2)r-、*NRc-(CH2CH2O)n-(CH2)m-Phe-(CH2)r-NRc-(CH2)p-,或*NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-(CH2)r-,其中其余变量如上文针对式I或第二、第三、第四、第五、第七、第八、第九、第十或第十二实施方案所描述。
在第十四实施方案中,如第五和后续实施方案中所定义的m、n、o、p、q和r各自独立地为选自0、1、2和3的整数,其中其余变量如上文针对式I、II或III或第二、第三、第四、第五、第七、第八、第九、第十、第十二或第十三实施方案所描述。
在第十五实施方案中,如第五和后续实施方案中所定义的Het1和Het2各自独立地为哌啶基、哌嗪基、氮杂环丁烷基或吡咯烷基,其中其余变量如上文针对式I、II或III或第二、第三、第四、第五、第七、第八、第九、第十、第十二、第十三或第十四实施方案所描述。
在第十六实施方案中,式I、II或III的化合物或其药学上可接受的盐中的L是
在第十七实施方案中,式I的化合物具有式IV:
或其药学上可接受的盐,其中
R1是(C1-C4)烷基;
R2是-C(O)NRaRb或OH;
Ra是氢或(C1-C2)烷基;
Rb是任选地被1至3个卤代基取代的(C1-C4)烷基;并且
L是*Het1-X1-Het2-X2-或*Het1-X1-Phe-X2-NRc-X3,并且其中其余变量如上文针对式I所描述。
在第十八实施方案中,式IV的化合物或其药学上可接受的盐中的Ra是氢,其中其余变量如上文针对式I或第十七实施方案所描述。
在第十九实施方案中,式IV的化合物或其药学上可接受的盐中的Rb是被1至3个卤代基取代的(C1-C4)烷基,其中其余变量如上文针对式I或第十七或第十八实施方案所描述。
在第二十实施方案中,式IV的化合物或其药学上可接受的盐中的L是*Het1-(CH2)r-Het2-X2-或*Het1-(CH2)r-Phe-(CH2)r-NRc-(CH2)r,其中其余变量如上文针对式I或第十七、第十八或第十九实施方案所描述。可替代地,作为第二十实施方案的一部分,式IV的化合物或其药学上可接受的盐中的L是*Het1-(CH2)r-Het2-X2-或*Het1-(CH2)r-Phe-(CH2)r-NRc-(CH2)r;并且每个r独立地为选自1和2的整数,其中其余变量如上文针对式I或第十七、第十八或第十九实施方案所描述。
在第二十一实施方案中,式IV的化合物或其药学上可接受的盐中的Het1和Het2各自独立地为哌啶基或哌嗪基,其中其余变量如上文针对式I或第十七、第十八、第十九或第二十实施方案所描述。
化合物的特定实例在范例部分中提供,并且作为第二十二实施方案的一部分包括在本文中。还包括这些化合物的药学上可接受的盐以及中性形式。
本文还提供了药物组合物,其包含本文所述的化合物的;以及药学上可接受的载剂。
4.用途、调配和施用
本文所述的化合物和组合物通常可用作抗癌疗法。在一个方面,所公开的化合物和组合物表现为肿瘤靶向蛋白降解嵌合体(T-PEACH),其中化合物的一部分负责结合BRD4并且另一部分负责结合HSP90和/或HSP70。其作用机制包括但不限于降解BRD4和/或BET蛋白家族的其它成员,从而阻碍下游信号并导致癌细胞死亡。在一个方面,所公开的化合物实现BRD4的降解。
因此,本文提供治疗对BRD4的降解有响应的病状的方法,其包括向有需要的受试者施用治疗有效量的一种或多种本文所述的化合物或组合物。还提供了本文所述的一种或多种化合物或组合物制造用于治疗对BRD4的降解有响应的病状的药物的用途。还提供了本文所述的化合物或组合物用于治疗对BRD4的降解有响应的病状的用途。
在一个方面,通过本发明化合物和组合物治疗的病状是癌症。术语“癌症”或“肿瘤”是本领域众所周知的,并且是指(例如在受试者中)存在具有致癌细胞的典型特征的细胞,所述特征诸如不受控制的增殖、永生、转移潜力、快速的生长和增殖率、减少的细胞死亡/凋亡,以及某些特征性形态特征。癌细胞通常以实体肿瘤的形式存在。然而,癌症还包括非实体肿瘤,例如血液肿瘤,例如白血病,其中癌细胞源自骨髓。如本文所用,术语“癌症”包括恶变前癌症以及恶性癌症。癌症包括但不限于听神经瘤、急性白血病、急性淋巴细胞白血病、急性髓细胞白血病(单核细胞、成髓细胞、腺癌、血管肉瘤、星形细胞瘤、粒单核细胞和早幼粒细胞)、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞白血病、慢性髓细胞(粒细胞)白血病、慢性骨髓性白血病、结肠癌、结直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、增殖异常性变化(发育异常和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食道癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤文氏瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、重链疾病、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感的前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌、淋巴管内皮肉瘤(lymphagioendotheliosarcoma)、淋巴管肉瘤、成淋巴细胞性白血病、淋巴瘤(霍奇金和非霍奇金)、膀胱、乳房、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增殖(hyperproliferative)病症、T细胞或B细胞起源的淋巴恶性肿瘤、白血病、淋巴瘤、髓样癌、成神经管细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、非小细胞肺癌、少突胶质细胞瘤、口腔癌、成骨肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体肿瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、华氏巨球蛋白血症、睾丸肿瘤、子宫癌和威尔姆氏肿瘤(Wilms'tumor)。其他癌症包括原发癌、转移癌、口咽癌、下咽癌、肝癌、胆囊癌、胆管癌、小肠癌、泌尿道癌、肾癌、尿路上皮癌、女性生殖道癌、子宫癌、妊娠滋养细胞疾病、男性生殖道癌、精囊癌、睾丸癌、生殖细胞肿瘤、内分泌腺肿瘤、甲状腺癌、肾上腺癌、垂体癌、血管瘤、骨和软组织肉瘤、卡波济氏肉瘤、神经癌、眼癌、脑膜癌、成胶质细胞瘤、神经瘤、成神经细胞瘤、神经鞘瘤、由造血系统恶性肿瘤诸如白血病引起的实体肿瘤、转移性黑色素瘤、复发性或持续性卵巢上皮癌、输卵管癌、原发性腹膜癌、胃肠道间质瘤、结直肠癌、胃癌、黑色素瘤、多形性成胶质细胞瘤、非鳞状非小细胞肺癌、恶性胶质瘤、上皮性卵巢癌、原发性浆液性腹膜癌、转移性肝癌、神经内分泌癌、难治性恶性肿瘤、三阴性乳腺癌、HER2扩增乳腺癌、鼻咽癌、口腔癌、胆道癌、肝细胞癌、头颈部鳞状细胞癌(SCCHN)、非髓样甲状腺癌、复发性多形性成胶质细胞瘤、1型神经纤维瘤病、CNS癌、脂肪肉瘤、平滑肌肉瘤、唾液腺癌、粘膜黑色素瘤、肢端/雀斑样黑色素瘤、副神经节瘤、嗜铬细胞瘤、晚期转移癌、实体肿瘤、三阴性乳腺癌、结直肠癌、肉瘤、黑色素瘤、肾癌、子宫内膜癌、甲状腺癌、横纹肌肉瘤、多发性骨髓瘤、卵巢癌、成胶质细胞瘤、胃肠道间质瘤、套细胞淋巴瘤以及难治性恶性肿瘤。
如本文所用,“实体肿瘤”被理解为可以触诊或使用成像方法检测为具有三个维度的异常生长的任何致病性肿瘤。实体肿瘤区别于诸如白血病的血液肿瘤。然而,血液肿瘤的细胞源自骨髓;因此,产生癌细胞的组织是可能缺氧的实体组织。
“肿瘤组织”或“肿瘤性组织”被理解为与实体肿瘤相关联的细胞、细胞外基质以及其它天然存在的组分。
用于任何特定患者的具体剂量和治疗方案将取决于多种因素,包括所采用的具体化合物的活性、年龄、体重、总体健康状况、性别、饮食、施用时间、排泄率、药物组合和治疗医生的判断以及被治疗的特定疾病的严重程度。组合物中本文所述化合物的量还将取决于所述组合物中的具体化合物。
范例
实施例1:化合物039合成
化合物039的代表性合成方案。中间体的具体合成路线在下文示出。
中间体2:
4-硝基苯乙基氨基甲酸叔丁酯
向中间体1(8.00g,39.5mmol)和(Boc)2O(8.60g,39.5mmol)在THF(50mL)和水(50mL)中的溶液中添加NaOH(3.1g,79.0mmol)。然后将反应溶液在室温下搅拌3小时。反应溶液用EtOAc(50mL*3)萃取。合并的有机层用盐水洗涤并经Na2SO4干燥并浓缩,得到为油状物的中间体2(10.0g,收率79.3%)。
中间体3:
4-氨基苯乙基氨基甲酸叔丁酯
将中间体2(10.0g,33.1mmol)和Pd/C(10%,1.5g)在MeOH(150mL)中的溶液在H2气氛下搅拌过夜。过滤混合物,将滤液浓缩,得到为黄色固体的中间体3(8.8g,收率99%)。
中间体4:
4-(2,4-二羟基-5-异丙基苯基硫酰氨基)苯乙基氨基甲酸叔丁酯
将中间体4-1(1.0g,4.38mmol)、ClH2CCOONa(765mg,6.57mmol)和NaHCO3(1.1g,13.14mmol)在DMF(10mL)中的溶液在30℃下搅拌3小时。将中间体3(1.03g,4.38mmol)添加到反应混合物中。将所得混合物在80℃下搅拌4小时后,将混合物倒入冰水中并用EA(20mL*3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并过滤。将滤液浓缩并通过SGC纯化,用PE:EA=1:1洗脱,得到为油状物的中间体4(1.50g,收率79.7%)。
中间体5:
4-(7-羟基-6-异丙基-2-氧代-4-硫代(thioxo)-2H-苯并[e][1,3]噁嗪-3(4H)-基)苯乙基氨基甲酸叔丁酯
将中间体4(1.5g 3.2mmol)和CDI(1.07g,6.57mmol)在THF(3mL)中的溶液在室温下搅拌4小时。将反应溶液倒入盐水(5mL)中并用EA(5mL)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩,得到中间体5(2.5g,粗品),其不经纯化即用于进一步反应。
中间体6:
4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯乙基氨基甲酸叔丁酯
向中间体5(2.5g,粗品)在EtOH(5mL)中的溶液中添加(NH2)2(238mg,7.4mmol)。然后将所得混合物在室温下搅拌过夜。将沉淀的固体过滤并干燥,得到为白色固体的中间体6(500mg,收率20%)。
中间体7:
4-(4-(4-(2-氨基乙基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇
将中间体6(500mg,1.41mmol)在HCl-MeOH(3N,10mL)中的溶液在室温下搅拌16小时。将反应溶液浓缩,得到为白色固体的中间体7(360mg,收率92%)。
化合物039:
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯乙基)乙酰胺
向中间体7-1(50mg,0.125mmol)、HATU(71.3mg,0.188mmol)和DIEA(48.4mg,0.375mmol)在DMF(3mL)中的溶液中添加中间体7(48.8mg,0.125mmol)。所得混合物在室温下搅拌3小时。通过制备型HPLC(Waters 2767/Qda,柱:SunFire 19*250mm 10um,流动相A:0.1%TFA/H2O,B:CAN)纯化混合物,得到为白色固体的化合物039 15mg,收率16.3%)。
1H NMR(400MHz,DMSO-d6):δ11.91(s,1H),9.58(s,1H),9.39(s,1H),8.36-8.30(m,1H),7.45(dd,J=24.9,8.6Hz,4H),7.24(d,J=8.4Hz,2H),7.10(d,J=8.3Hz,2H),6.80(s,1H),6.25(s,1H),4.51(t,J=7.0Hz,1H),3.32-3.27(m,2H),3.23-3.20(m,2H),2.97-2.95(m,1H),2.75-2.70(m,2H),2.59(s,3H),2.41(s,3H),1.62(s,3H),0.97(d,J=6.9Hz,6H)。
LCMS(ESI):RT=1.524min,LCMS-004(LCMS 2020-002)方法:A70B30+-,(A:0.1%FA/H2O B:0.1%FA/ACN柱SunFire C18)C38H37ClN8O4S质量计算值,736.2,m/z实测值737.6[M+H+])。
实施例2:化合物074合成
化合物074的代表性合成方案在下文示出。还示出中间体的具体合成路线。
中间体2:
4-((4-(4-硝基苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
向1-(4-硝基苄基)哌嗪(中间体1)(96g,0.434mol)、4-甲酰基哌啶-1-羧酸叔丁酯(92g,0.434mol)和CH3COOH(26g,0.434mol)在DCE(1L)中的溶液中添加NaBH(OAc)3(138g,0.65mol)。然后将所得混合物在室温下搅拌过夜。将反应溶液倒入NaHCO3水溶液中并用DCM(500mL*3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩,得到为白色固体的中间体2(163g,收率90%)。
中间体3:
4-((4-(4-氨基苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
向中间体2(163g,0.39mol)和NH4Cl(210g,3.9mol)在EtOH(1L)和H2O(100mL)中的溶液中添加Fe粉(109g,1.95mmol)。将所得混合物在80℃下加热3小时。将其冷却至室温并过滤。将滤液倒入NaHCO3水溶液中并用EtOAc(1L*3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩。残余物用PE:EA=10:1研磨,得到为白色固体的中间体3(120g,收率73%)。
中间体4:
4-((4-(4-(2,4-二羟基-5-异丙基苯基硫酰氨基)苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
将中间体3(77.5g,340mmol)、ClCH2CO2Na(49.5g,424.5mmol)和NaHCO3(90g,849mmol)在DMF(500mL)中的溶液在40℃下搅拌3小时。将化合物4(110g,283mmol)添加到反应中。然后将所得混合物在80℃下加热过夜。将反应混合物倒入冰水中,通过过滤收集沉淀的固体,得到为黄色固体的中间体4(132g,80%收率)。
中间体5:
4-((4-(4-(7-羟基-6-异丙基-2-氧代-4-硫代-2H-苯并[e][1,3]噁嗪-3(4H)-基)苄基))哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
将中间体4(132g,226mmol)和CDI(73.4g,452mmol)在THF(1L)中的溶液在室温下搅拌2小时。将反应溶液倒入盐水(1L)中并用EtOAc(500mL*3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩,得到中间体5(138g,粗品),其不经纯化即用于进一步反应。
中间体6:
4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
向中间体5(138g,粗品)在EtOH(1L)中的溶液中添加NH2NH2H2O(22.6g,452mmol)。然后将所得混合物在室温下搅拌过夜。将沉淀的固体过滤并干燥,得到为白色固体的中间体6(62g,2步收率45%)。
中间体7:
4-(5-羟基-4-(4-((4-(哌啶-4-基甲基)哌嗪-1-基)甲基)苯基)-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇
将中间体6(62g,102mmol)在HCl-MeOH(3N,300mL)中的溶液在室温下搅拌16小时。将反应溶液浓缩,得到为白色固体的中间体7(63g,100%收率)。
化合物074:
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮盐酸盐
向中间体7-1(13g,32.5mmol)、BOP(21.55g,48.75mmol)和DIEA(41.86g,325mmol)在DMF(130mL)中的溶液中添加中间体7(20g,32.5mmol)。将所得混合物在室温下搅拌过夜。添加H2O并且通过过滤收集沉淀的固体。将其干燥,然后通过硅胶色谱(梯度,DCM:MeOH=50:1至30:1至20:1)纯化,得到8g白色固体。向该白色固体在MeOH(200mL)中的溶液中添加HCl-MeOH(9mL,3N)并搅拌。在室温下搅拌1小时并浓缩。添加H2O(60mL)并搅拌10min。过滤,用H2O(30mL*2)洗涤滤饼。真空干燥,得到为黄色固体的化合物074(7.5g)。
1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),10.68(m,1H),9.62(s,1H),9.38(s,1H),7.64-7.44(m,6H),7.25(d,J=8.4Hz,2H),6.93(s,1H),6.31(s,1H),4.63(t,J=6.7Hz,1H),4.41-4.15(m,3H),3.79-3.40(m,12H),3.43-3.00(m,4H),2.76-2.55(m,5H),2.42(s,3H),2.05-2.02(m,1H),1.90-1.68(m,2H),1.63(s,3H),0.98(d,J=6.9Hz,6H)。
LCMS(ESI):RT=1.31min,LCMS-004(LCMS 2020-002)方法:A90B10+-,(A:0.1%FA/H2O B:0.1%FA/ACN柱SunFire C18)C47H54Cl2N10O4S质量计算值,924.34m/z实测值889.6[M-HCl+H+])。
实施例3:化合物078合成
化合物078的代表性合成方案在下文示出。还示出中间体的具体合成路线。
中间体2:
4-((4-(4-(5-乙基-2,4-二羟基苯基硫酰氨基)苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
向5-乙基-2,4-二羟基二硫代苯甲酸(3.00g,14.02mmol)和NaHCO3(1.57g,18.70mmol)在DMF(30mL)中的混合物中添加ClCH2CO2Na(1.20g,10.29mmol)。在40℃下搅拌1.5h后,添加在DMF(30mL)中的中间体1(3.64g,9.35mmol)并在80℃下搅拌2h。将其倒入冰水(50mL)中。通过过滤收集沉淀的固体并真空干燥,得到为黄色固体的中间体2(5.0g)。
中间体3:
4-((4-(4-(5-乙基-2,4-二羟基苯并腙酰氨基)苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
向中间体2(5g,5.27mmol)在二噁烷(70mL)中的溶液中添加氢化肼(1.6g,21.08mmol)。将其在室温下搅拌3h并用EtOAc(200mL*2)萃取。合并的有机相用H2O和盐水洗涤,经Na2SO4干燥,过滤并浓缩,得到为棕色固体的中间体3(5.4g)。
中间体4:
4-((4-(4-(3-(5-乙基-2,4-二羟基苯基)-5-((2,2,2-三氟乙基)氨基甲酰基)-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
向中间体3(5.4g,9.5mmol)在i-PrOH(55mL)中的溶液中添加2-氧代-2-((2,2,2-三氟乙基)氨基)乙酸乙酯(3.8g,19.0mmol)和AcOH(0.15mL)。在85℃下搅拌过夜后,将其冷却至室温。过滤收集沉淀的固体并真空干燥,得到为白色固体的中间体4(2.5g)。
中间体5:
5-(5-乙基-2,4-二羟基苯基)-4-(4-((4-(哌啶-4-基甲基)哌嗪-1-基)甲基)苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺
将中间体4(2.5g,3.56mmol)溶解于HCl-二噁烷(3N,10mL)中。将混合物在室温下搅拌过夜并真空浓缩,得到为黄色固体状的标题化合物中间体5(3.0g)。
化合物078:
4-(4-((4-((1-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺盐酸盐
在室温下向中间体5-1(300mg,0.8mmol)和中间体5(530mg,0.8mmol)在DMF(15mL)中的溶液中添加DIEA(4mg,3.8mmol)和HATU(290mg,0.8mmol)。在室温下搅拌过夜后,将反应混合物用水(10mL)稀释并用EtOAc(10mL*3)萃取。合并的有机相用H2O、盐水洗涤,经Na2SO4干燥并浓缩。通过制备型HPLC(Waters 2767/Qda,柱:SunFire19*250mm 10um,流动相A:0.1%TFA/H2O,B:ACN)纯化粗产物,得到白色固体(211mg)。添加饱和NaHCO3(20mL)并用EtOAc(20mL*2)萃取。合并的有机相用H2O和盐水洗涤,经Na2SO4干燥、过滤并浓缩。向残余物中添加H2O(20mL),然后添加HCl(2N,1mL)。将其冻干,得到为黄色固体的化合物078。
1H NMR(400MHz,DMSO-d6):9.75-9.66(m,2H),7.61-7.37(m,8H),6.75(s,1H),6.34(s,1H),4.60-4.57(m,1H),4.37-4.34(m,2H),4.21-4.16(m,2H),3.99-3.95(m,2H),3.66-3.30(m,11H),3.18-3.12(m,3H),2.67-2.57(m,4H),2.44(s,3H),2.33-2.29(m,2H),1.76-1.60(m,4H),1.63(s,3H),1.24(s,1H),0.95-0.91(m,4H)。
LCMS(ESI):Shimadzu LCMS-017RT=1.415min,方法:A90B10,(A:0.1%FA/H2O B:
0.1%FA/CAN柱SunFire C18)C49H54Cl2F3N11O4S化学式质量计算值:1019.34m/z实测值984.4[M-HCl+H]+。
实施例4:化合物016合成
化合物016的代表性合成方案在下文示出。还示出中间体的具体合成路线。
中间体2
5-(2,4-双(苄氧基)-5-异丙基苯基)异噁唑-3-羧酸甲酯
将中间体1(15.5g,33.70mmol)和盐酸羟胺在EtOH(50mL)中的混合物在回流下搅拌4h,然后冷却至室温并浓缩。添加H2O并用DCM(100mL*3)萃取。合并的有机相经Na2SO4干燥,过滤并浓缩。残余物用EtOH/H2O(200mL/200mL)研磨。通过过滤进行收集,得到为黄色固体的中间体2(15g,收率97%)。
中间体3
5-(2,4-双(苄氧基)-5-异丙基苯基)-4-溴异噁唑-3-羧酸甲酯
将甲基中间体2(15g,32.82mmol)、NBS(6.43,36.11mmol)和CAN(9.0g,16.41mmol)在CH3CN(200mL)中的混合物在回流下搅拌14h。冷却至室温后将其浓缩。添加H2O并用EA(100mL*3)萃取。合并的有机相用H2O、盐水洗涤,经Na2SO4干燥并浓缩。通过硅胶色谱(DCM:MeOH=20:1)纯化残余物,得到为黄色固体的化合物中间体3(14.2g,收率81)。
中间体4
5-(2,4-双(苄氧基)-5-异丙基苯基)-4-(4-甲酰基苯基)异噁唑-3-羧酸甲酯
向中间体3(3g,5.6mmol)在DMF/H2O(140mL/28mL)中的溶液中添加(4-甲酰基苯基)硼酸(1.34g,8.4mmol)、NaHCO3(1.4g,16.8mmol)和Pd(PPh3)2Cl2(0.4g,0.56mmol)。将其在Ar气氛下,在80℃下搅拌3h。将所得混合物倒入H2O中并用EtOAc(100mL*3)萃取。合并的有机相用水、盐水洗涤,经Na2SO4干燥并浓缩。残余物通过硅胶色谱(DCM:MeOH=20:1)纯化,得到为黄色固体的中间体4(1.7g,收率54%)。
中间体5
5-(2,4-双(苄氧基)-5-异丙基苯基)-4-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)异噁唑-3-羧酸甲酯
将中间体4(1.7g,3.03mmol)、哌嗪-1-羧酸叔丁酯(0.56g,3.03mmol)在DCE(15mL)中的混合物在室温下搅拌1h。添加NaBH(OAc)3(1.4g,6.4mmol)并搅拌2h。所得混合物用H2O稀释并用EtOAc(20mL*2)萃取。合并的有机相用水、盐水洗涤,经Na2SO4干燥并浓缩,得到为黄色固体的中间体5(1.5g,收率68%)。
中间体6
4-(4-(5-(2,4-双(苄氧基)-5-异丙基苯基)-3-(乙基氨基甲酰基)异噁唑-4-基)苄基)哌嗪-1-羧酸叔丁酯
将中间体6(1.5g,2.05mmol)在EtNH2-THF(2N,10mL)中的混合物在回流下搅拌18h。所得混合物用水稀释并用EtOAc(20mL*2)萃取。合并的有机相用H2O、盐水洗涤,经Na2SO4干燥并过滤。将其浓缩,得到为黄色固体的中间体6(1.5g,收率98%)。
中间体7
5-(2,4-双(苄氧基)-5-异丙基苯基)-N-乙基-4-(4-(哌嗪-1-基甲基)苯基)异噁唑-3-甲酰胺
将中间体6(1.5g,2.02mmol)在HCl-MeOH(3N,10mL)中的混合物在室温下搅拌3小时。将所得混合物浓缩,得到为白色固体的中间体7HCl(1.37g)。将其添加到H2O中,然后添加K2CO3,直到pH=10-11。用EtOAc(20mL*3)萃取。合并的有机相用H2O、盐水洗涤,经Na2SO4干燥并浓缩,得到中间体7(1.28g,100%)。
中间体8
4-((4-(4-(5-(2,4-双(苄氧基)-5-异丙基苯基)-3-(乙基氨基甲酰基)异噁唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
将中间体7(1.28g,1.98mmol)、4-甲酰基哌啶-1-羧酸叔丁酯(0.42g,1.98mmol)和AcOH(1mL)在DCE(15mL)中的混合物在室温下搅拌1h。添加NaBH(OAc)3(0.96g,4.34mmol)并搅拌2h。所得混合物用水稀释并用EA(20mL*2)萃取。合并的有机相用H2O、盐水洗涤,经Na2SO4干燥并浓缩,得到为黄色固体的中间体8(1.64g,收率98%)。
中间体9
4-((4-(4-(5-(2,4-二羟基-5-异丙基苯基)-3-(乙基氨基甲酰基)异噁唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯
将中间体8(1.64g,4.51mmol)和Pd/C(10%,600mg)在MeOH(50mL)中的溶液在H2气氛下于室温下搅拌过夜。过滤反应溶液并且真空浓缩滤液,得到为白色固体的中间体9(1.27g,收率100%)。
中间体10
5-(2,4-二羟基-5-异丙基苯基)-N-乙基-4-(4-((4-(哌啶-4-基甲基)哌嗪-1-基)甲基)苯基)异噁唑-3-甲酰胺盐酸盐
将中间体9(1.27g)在HCl-MeOH(3N,20mL)中的混合物在室温下搅拌3小时。将所得混合物浓缩,得到为白色固体的中间体10(1.12g,收率98%)。
化合物16
4-(4-((4-((1-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-乙基异噁唑-3-甲酰胺,三氟乙酸
将中间体10(50mg,0.084mmol)、中间体10-1(33.6mg,0.084mmol)、HATU(48mg,0.126mmol)和DIEA(43mg,0.336mmol)在DMF(2mL)中的混合物在室温下搅拌1h。所得混合物用EtOAc(10mL*3)萃取。合并的有机相用H2O、盐水洗涤,经Na2SO4干燥。将其过滤并浓缩,然后通过制备型HPLC(Waters 2767/Qda,柱:SunFire 19*250mm 10um,流动相A:0.1%TFA/H2O,B:ACN)纯化,得到为黄色固体的化合物016(12.66mg,收率16%)。
1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),9.67(s,1H),8.87(s,1H),7.55-7.19(m,9H),6.76(s,1H),6.44(s,1H),4.57(t,J=6.7Hz,1H),4.35(d,J=11.5Hz,2H),4.15-4.13(m,2H),3.64-3.59(m,7H),3.39-3.33(m,3H),3.26-3.20(m,3H),3.13-3.10(m,4H),3.02-2.95(m,3H),2.60-2.58(m,4H),2.42(s,3H),1.77-1.66(m,2H),1.63(s,3H),1.09(t,J=7.2Hz,3H),0.93(d,J=6.9Hz,6H)。LCMS(ESI):Shimadzu LCMS-009,RT=1.486min,方法:A90B10+-,(A:0.1%FA/H2O B:0.1%FA/ACN柱sunFire C18)C51H58ClN9O5S质量计算值,943.40m/z实测值944.6[M-CF3COOH+H]+。
根据实施例1-4中提到的一般程序和方案制备另外的化合物,包括以下:
化合物001
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮。1H NMR(400MHz,DMSO-d6):δ11.90(s,1H),9.56(s,1H),9.37(s,1H),7.47(m,4H),7.27(d,J=8.1Hz,2H),7.11(d,J=8.2Hz,2H),6.82(s,1H),6.24(s,1H),4.56(t,J=6.8Hz,1H),4.34(m,1H),4.11(m,1H),3.60(s,1H),3.43(s,3H),3.10(s,1H),2.59(s,4H),2.43-2.24(m,11H),2.12(s,2H),1.99(s,1H),1.78(s,2H),1.63(s,4H),1.23(s,2H),1.11(s,1H),0.96(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.083min,m/z实测值875.2[M+H]+。
化合物002
4-(4-(4-((4-((1-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-乙基苯-1,3-二醇,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.60(s,1H),9.36(s,1H),7.51(s,2H),7.40(s,2H),7.22(s,2H),6.87(s,1H),6.24(s,1H),5.32(s,1H),4.29(s,1H),2.85-2.58(m,11H),2.36(m,6H),2.00(m,5H),1.62(s,3H),1.23(s,10H),0.99(t,J=7.5Hz,3H),0.84(d,J=7.0Hz,2H)。LCMS(ESI):RT=1.023min,m/z实测值861.2[M-CF3COOH+H]+。
化合物003
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.61-9.50(m,2H),7.51-7.44(m,4H),7.21(d,J=8.3Hz,2H),7.11(d,J=8.0Hz,2H),6.77(s,1H),6.27(s,1H),4.58(t,J=6.4Hz,2H),4.34(d,J=12.1Hz,2H),4.11(d,J=13.2Hz,1H),3.60-3.59(m,1H),3.38-3.35(m,1H),3.6-2.95(m,2H),2.60-2.57(m,3H),2.52-2.50(m,2H),2.42(s,3H),1.85-1.51(m,6H),1.24-1.00(m,2H),0.96(t,J=6.8Hz,6H)。LCMS(ESI):RT=1.817min,m/z实测值791.2[M-CF3COOH+H]+。
化合物004
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.59-9.50(m,2H),7.50-7.37(m,6H),7.21-7.06(m,3H),6.25-6.17(m,2H),5.20-4.88(m,4H),4.59-4.56(m,2H),4.37-4.34(m,2H),3.98-3.90(m,2H),3.67-3.61(m,2H),3.40-3.33(m,2H),3.17-2.73(m,7H),2.60-2.58(m,4H),2.49(s,3H),1.99(s,1H),1.75-1.69(m,2H),1.63(s,3H)。LCMS(ESI):RT=1.282min,m/z实测值845.7[M-CF3COOH-H]-。
化合物005
2-((6R)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.61(s,1H),9.37(s,1H),7.55-7.15(m,8H),6.82(s,1H),6.26(s,1H),4.59-4.54(m,1H),4.35-4.30(m,1H),4.15-4.10(m,2H),3.75-3.50(m,8H),3.37-3.30(m,2H),3.24-2.90(m,8H),2.63(s,4H),2.42(s,3H),1.77-1.70(m,2H),1.63(s,3H),0.98(d,J=6.9Hz,6H)。LC-MS(ESI):RT=1.235min,m/z实测值889.5[M-CF3COOH+H]+
化合物006
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((R)-1-(4-((1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-基)甲基)苯基)乙基)乙酰胺,三氟乙酸。
1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),10.05-9.15(m,3H),8.76(d,J=7.8Hz,1H),7.55-7.45(m,6H),7.37-7.30(m,2H),7.14-7.09(m,4H),6.77(s,1H),6.27(d,J=4.5Hz,1H),5.04-4.95(m,1H),4.50-4.46(m,1H),4.26-4.24(m,2H),3.43-3.17(m,5H),2.98-2.96(m,1H),2.67-2.60(m,2H),2.61(s,3H),2.39(s,3H),1.71-1.62(m,2H),1.55-1.40(m,3H),1.38-1.28(m,5H),0.94(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.433min,m/z实测值924[M-CF3COOH+H]+。
化合物009
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-甲基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.60(s,1H),9.31(s,1H),7.51-7.42(m,6H),7.22(d,J=8.4Hz,2H),6.95(s,1H),6.24(s,1H),4.58(t,J=6.7Hz,1H),4.35(d,J=12.9Hz,1H),4.15-4.01(m,2H),3.68-3.33(m,3H),3.07-2.85(m,6H),2.60(s,3H),2.55-2.50(m,6H),2.42(s,3H),2.02-1.99(m,1H),1.97(s,3H),1.86-1.75(m,2H),1.63(s,3H),1.35-0.88(m,2H)。LCMS(ESI):RT=1.35min,m/z实测值861.4[M-CF3COOH+H]+。
化合物010
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),11.33(s,1H),9.70-9.40(m,2H),7.65-7.63(m,2H),7.53-7.43(m,4H),7.24(d,J=8.2Hz,2H),6.96(s,1H),6.32(s,1H),4.63(t,J=6.8Hz,1H),4.39-4.33(m,4H),3.79-3.43(s,10H),3.16-3.06(m,3H),2.65-2.60(m,4H),2.43-2.38(m,5H),2.12-1.88(m,4H),1.63(s,3H),0.96(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.07min,m/z实测值875.1[M-HCl+H]+。
化合物011
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),9.70-9.40(m,2H),8.38(s,4H),7.50-7.42(m,6H),7.26(d,J=8.2Hz,2H),7.11(d,J=8.2Hz,2H),6.77(s,1H),6.26(s,1H),4.56(t,J=6.8Hz,1H),4.39-4.20(m,2H),3.33-3.30(m,4H),2.59-2.56(m,5H),250-2.13(m,11H),1.62-1.63(m,8H),1.36-1.00(m,4H),0.76(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.47min,m/z实测值889.3[M-CF3COOH+H]+。
化合物012
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-巯基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ13.92(s,1H),9.66(s,1H),9.43(s,1H),7.51-7.26(m,5H),7.27(d,J=8.0Hz,2H),6.84(s,1H),6.25(s,1H),4.58(t,J=6.7Hz,1H),4.35(d,J=12.9Hz,1H),4.15-4.13(m,1H),3.80-3.30(m,13H),3.15-3.10(m,2H),3.03-2.87(m,2H),2.60-2.58(m,4H),2.42(s,3H),2.24-1.94(m,5H),1.87(s,2H),0.97(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.123min,m/z,实测值905.1[M-CF3COOH+H]+。
化合物013
4-(4-((4-((1-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺。1H NMR(400MHz,DMSO-d6):δ10.45(s,1H),9.75-9.58(m,2H),7.50-7.30(m,6H),6.62(s,1H),6.34(s,1H),4.58-4.55(m,1H),4.36-4.33(m,1H),4.13-4.10(m,1H),3.98-3.94(m,2H),3.60-3.49(m,4H),3.15-3.11(m,1H),2.93-2.90(m,1H),2.60(s,4H),2.41-2.30(m,10H),2.14-2.13(m,2H),1.82-1.79(m,3H),1.63(s,3H),1.23-1.12(m,1H),1.16(t,J=6.8Hz,6H)。LCMS(ESI):RT=1.190min,m/z实测值998.3[M+H]+。
化合物014
4-(4-((4-((1-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ9.71-9.65(m,2H),7.52-7.30(m,8H),6.68(s,1H),6.31(s,1H),5.32-5.30(m,1H),5.00-4.50(m,4H),4.58(t,J=6.8Hz,2H),4.36-4.32(m,2H),4.16-1.10(m,2H),4.03-3.91(m,3H),3.81-3.58(m,3H),3.40-2.90(m,6H),2.64-2.50(m,5H),2.42(s,3H),2.26-2.24(m,2H),2.00-1.98(m,1H),1.87-1.74(m,1H),1.63(s,3H),0.89(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.193min,m/z实测值984.1[M-CF3COOH+H]+。
化合物015
4-(4-((4-((1-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-甲基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ9.70-9.62(m,2H),9.38-9.02(m,1H),7.60-7.20(m,8H),6.72(s,1H),6.28(s,1H),4.58(t,J=6.7Hz,1H),4.36(d,J=12.4Hz,2H),4.15-4.13(m,2H),4.01-3.90(m,10H),3.64-3.63(m,3H),3.37-3.35(m,1H),3.07-2.95(m,7H),2.60-2.58(m,4H),2.42(s,3H),1.87(s,4H),1.73-1.70(m,1H),1.63(s,3H)。LCMS(ESI):RT=1.385min,m/z实测值970.1[M-CF3COOH+H]+。
化合物016
4-(4-((4-((1-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-乙基异噁唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.79(s,1H),9.67(s,1H),8.87(s,1H),7.55-7.19(m,9H),6.76(s,1H),6.44(s,1H),4.57(t,J=6.7Hz,1H),4.35(d,J=11.5Hz,2H),4.15-4.13(m,2H),3.64-3.59(m,7H),3.39-3.33(m,3H),3.26-3.20(m,3H),3.13-3.10(m,4H),3.02-2.95(m,3H),2.60-2.58(m,4H),2.42(s,3H),1.77-1.66(m,2H),1.63(s,3H),1.09(t,J=7.2Hz,3H),0.93(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.486min,m/z实测值944.6[M-CF3COOH+H]+。
化合物017
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)-2-氟苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.00(s,1H),9.64(s,1H),9.39(s,1H),7.51-7.42(m,5H),7.14-7.00(m,2H),6.91(s,1H),6.26(s,1H),4.58-4.55(m,1H),4.36-4.33(m,1H),4.15-4.10(m,1H),3.70-3.35(m,5H),3.10-2.90(m,8H),2.60-2.50(m,6H),2.50-2.48(m,5H),2.33-2.30(m,1H),2.10-2.00(m,1H),1.85-1.80(m,2H),1.63(s,3H),1.23-1.12(m,1H),1.03(t,J=6.8Hz,6H)。LCMS(ESI):RT=1.130min,m/z实测值907.4[M-CF3COOH+H]+。
化合物018
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)-3-氟苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ7.50-7.37(m,5H),7.05-6.95(m,2H),6.46-6.30(m,1H),6.25(s,1H),5.33(s,1H),4.57(t,J=6.7Hz,2H),4.32-4.30(m,2H),4.09-4.07(m,2H),3.60-3.53(m,4H),3.10-3.08(m,1H),2.59-2.58(m,4H),2.450-2.40(m,5H),2.33(s,3H),2.26-2.08(m,5H),2.04-1.94(m,2H),1.77-1.75(m,2H),1.63(s,3H),1.23-1.20(m,3H)。LCMS(ESI):RT=1.073min,m/z实测值893.1[M-CF3COOH+H]+。
化合物019
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((R)-1-(4-((1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-基)甲基)苯基)乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.59(s,2H),7.46-7.33(m,5H),7.35(t,J=8.1Hz,1H),7.03(d,J=11.2Hz,1H),6.95(d,J=7.9Hz,1H),6.88(s,1H),6.24(s,1H),4.56(t,J=6.5Hz,1H),4.33(d,J=12.3Hz,1H),4.10(d,J=11.9Hz,1H),3.60-3.59(s,1H),3.49(s,2H),3.10-3.00(m,1H),2.59-2.58(m,4H),2.41-2.34(m,7H),2.09-2.08(m,3H),1.95(s,3H),1.76-1.75(m,3H),1.63-1.60(m,4H),1.27-0.81(m,4H)。LCMS(ESI):RT=1.355min,m/z实测值877.2[M-H]-。
化合物027
2-((6R)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.62(s,1H),9.38(s,1H),7.50-7.20(m,8H),6.87(s,1H),6.24(s,1H),4.58(t,J=6.7Hz,1H),4.46-4.11(m,8H),3.72-3.63(m,2H),3.40-3.35(m,2H),312-3.04(m,4H),2.42-2.40(m,4H),2.39(s,3H),2.35-2.33(m,2H),1.85-1.72(m,3H),1.63(s,3H),1.20-1.10(m,2H),1.01(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.420min,m/z实测值875.2[M-CF3COOH+H]+。
化合物028
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-巯基-4H-1,2,4-三唑-4-基)苄基)乙酰胺。1HNMR(400MHz,DMSO-d6):δ9.56(s,1H),8.79(s,1H),8.07(s,1H),7.52(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),7.30(d,J=8.0Hz,2H),7.18(d,J=8.4Hz,2H),6.84(s,1H),6.23(s,1H),4.58-4.55(m,1H),4.42-4.32(m,2H),3.35-3.30(m,2H),3.00-2.95(m,1H),2.67(s,3H),2.41(s,3H),1.61(s,3H),0.99-0.95(m,6H)。LCMS(ESI):RT=1.715min,m/z实测值739.2[M+H]+。
化合物029
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯基)哌啶-4-羰基)哌嗪-1-基)乙-1-酮。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),10.14(s,1H),9.89(s,1H),7.51-7.42(m,6H),7.33(s,1H),6.97(d,J=8.8Hz,2H),6.50(s,1H),4.61-4.57(m,1H),3.73-3.40(m,12H),3.15-3.11(m,1H),2.70-2.67(m,2H),2.60(s,3H),2.42(s,3H),2.00-1.95(m,1H),1.73-1.64(m,4H),1.63(s,3H),1.16(t,J=6.8Hz,6H)。LCMS(ESI):RT=1.551min,m/z实测值889.5[M+H]+。
化合物032
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-巯基-4H-1,2,4-三唑-4-基)苯氧基)乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ13.84(s,1H),9.61(s,1H),9.42(s,1H),8.48(t,J=5.6Hz,1H),7.44(dd,J=22.7,8.7Hz,4H),7.15(d,J=8.9Hz,2H),6.95(d,J=9.0Hz,2H),6.87(s,1H),6.24(s,1H),4.52(t,J=7.0Hz,1H),4.01(t,J=5.6Hz,2H),3.49-3.43(m,2H),3.27-3.25(m,2H),2.98-2.91(m,1H),2.59(s,3H),2.41(s,3H),1.61(s,3H),0.99(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.568min,m/z实测值769.1[M+H]+。
化合物033
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(2-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-巯基-4H-1,2,4-三唑-4-基)苯氧基)乙氧基)乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ9.58(s,1H),8.31(s,1H),7.49(d,J=8.8Hz,2H),7.43(d,J=8.4Hz,2H),7.13(d,J=8.0Hz,2H),6.94(d,J=8.4Hz,2H),6.24(s,1H),4.58-4.55(m,1H),4.11-4.09(m,2H),3.76-3.74(m,2H),3.53-3.50(m,2H),3.30-3.22(m,4H),3.00-2.95(m,1H),2.67(s,3H),2.41(s,3H),1.62(s,3H),0.99-0.95(m,6H)。LCMS(ESI):RT=1.730min,m/z实测值813.2[M+H]+。
化合物034
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(2-(2-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-巯基-4H-1,2,4-三唑-4-基)苯氧基)乙氧基)乙氧基)乙基)乙酰胺。1H NMR(400MHz,DMSO):δ13.83(s,1H),9.60(s,1H),9.39(s,1H),8.29-8.27(m,1H),7.48(d,J=8.5Hz,2H),7.42(d,J=8.5Hz,2H),7.12(d,J=8.9Hz,2H),6.92(d,J=8.9Hz,2H),6.86(s,1H),6.24(s,1H),4.50(t,J=7.1Hz,1H),4.08-4.07(m,2H),3.73(d,J=4.4Hz,2H),3.58(d,J=8.0Hz,4H),3.46(t,J=5.8Hz,2H),3.28-3.16(m,5H),3.02-2.92(m,1H),2.59(s,3H),2.40(s,3H),2.00-1.99(m,1H),1.62(s,3H),0.99(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.748min,m/z实测值857.7[M+H]+。
化合物037
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(2-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)乙氧基)乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.61(s,1H),9.41(s,1H),9.03-8.98(m,1H),8.31(s,1H),7.49-7.38(m,4H),7.13-7.01(m,4H),6.74(s,1H),6.26(s,1H),4.51(t,J=7.2Hz,2H),3.73(s,2H),3.49(d,J=5.3Hz,4H),3.27(d,J=7.5Hz,6H),2.93-2.85(m,2H),2.67(s,1H),2.59(s,3H),2.39(s,3H),2.33(s,1H),1.71-1.69(m,3H),1.61(s,3H),1.43-1.42(m,1H),0.92(d,J=6.2Hz,6H)。LCMS(ESI):RT=1.120min,m/z实测值878.2[M-CF3COOH+H+])。
化合物038
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.99(s,1H),9.64(s,1H),9.36(s,1H),7.53-7.27(m,8H),6.90(s,1H),6.25(s,1H),4.43(s,2H),4.33(d,J=33.0Hz,4H),3.68-3.60(m,4H),3.20-3.11(m,4H),2.99(s,3H),2.60(s,3H),2.42(s,3H),1.63(s,3H),1.02(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.129min,m/z实测值792.4[M-CF3COOH+H]+。
化合物039
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯乙基)乙酰胺。1HNMR(400MHz,DMSO-d6):δ11.91(s,1H),9.58(s,1H),9.39(s,1H),8.36-8.30(m,1H),7.45(dd,J=24.9,8.6Hz,4H),7.24(d,J=8.4Hz,2H),7.10(d,J=8.3Hz,2H),6.80(s,1H),6.25(s,1H),4.51(t,J=7.0Hz,1H),3.32-3.27(m,2H),3.23-3.20(m,2H),2.97-2.95(m,1H),2.75-2.70(m,2H),2.59(s,3H),2.41(s,3H),1.62(s,3H),0.97(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.524min,m/z实测值737.6[M+H+])。
化合物040
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.62(s,1H),9.38(s,1H),7.58-7.31(m,6H),7.17(t,J=22.5Hz,2H),6.83(s,1H),6.26(s,1H),4.57(t,J=6.7Hz,1H),4.35(d,J=12.9Hz,1H),4.15(s,1H),3.66-3.60(m,8H),3.43-3.31(m,2H),3.21-2.81(m,7H),2.76-2.55(m,5H),2.42(s,3H),2.05-2.02(m,1H),1.90-1.68(m,2H),1.63(s,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.097min,m/z实测值889.3[M-CF3COOH+H]+。
化合物041
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯基)哌嗪-1-基)甲基)哌啶-1-基)乙酮。1H NMR MeOD-d4(400MHz):δ7.46-7.40(m,4H),7.17(m,2H),7.08(m,2H),6.69(s,1H),6.28(s,1H),4.69(d,J=6.6Hz,1H),4.57(m,2H),3.76-3.58(m,4H),3.23(m,7.4Hz,2H),2.99(s,1H),2.70(s,4H),2.45(s,3H),2.18(t,J=3.8Hz,1H),2.02(s,1H),1.70(s,3H),1.60-1.57(m,1H),1.37(d,J=1.3Hz,4H),1.28(s,5H),0.91(s,3H),0.89(s,3H)。LCMS(ESI):RT=1.112min,m/z实测值875.7[M+H]+。
化合物042
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)哌啶-1-基)乙-1-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.61(s,1H),9.38(s,1H),8.44(s,1H),7.51-7.42(m,6H),7.21(d,J=7.6Hz,2H),6.82(s,1H),6.26(s,1H),4.57-4.50(m,2H),4.26-4.20(m,2H),4.00-3.95(m,2H),3.69-3.50(m,6H),3.33-2.95(m,7H),2.67(s,4H),2.55(s,3H),2.36(s,3H),1.62(s,3H),0.97(t,J=6.8Hz,6H)。LCMS(ESI):RT=0.720min,m/z实测值875.3[M-CF3COOH+H]+。
化合物043
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯基)哌嗪-1-基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.88(s,1H),9.61(s,2H),9.43(s,1H),7.62-7.40(m,6H),7.25-6.92(m,5H),6.78(s,1H),6.27(s,1H),4.55-4.53(m,2H),4.36-4.33(m,1H),3.90(d,J=12.6Hz,2H),3.60-3.59(m,4H),3.22-3.18(m,4H),2.99-2.97(m,4H),2.61(s,3H),2.42(s,3H),2.41-2.06(m,4H),1.64(s,3H),0.96(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.371min,m/z实测值861.7[M-CF3COOH+H]+。
化合物044
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(3-(((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)(甲基)氨基)甲基)苯氧基)乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.61(s,1H),9.33(s,2H),8.64(s,1H),7.56-6.83(m,13H),6.23(s,1H),4.27-4.25(m,2H),4.09-4.06(m,2H),3.19-3.10(m,1H),3.02-2.93(m,1H),2.68(s,3H),2.58-2.55(m,4H),2.35(s,3H),1.53-1.50(m,3H),1.25-1.20(m,4H),0.97-0.93(m,6H)。LCMS(ESI):RT=1.381min,m/z实测值886.3[M-CF3COOH+H]+。
化合物045
2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((1-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)吡咯烷-3-基)甲基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.61(s,1H),9.33(s,1H),8.44(s,1H),7.50-7.42(m,6H),7.26(d,J=6.8Hz,2H),6.86(s,1H),6.24(s,1H),4.48-4.45(m,1H),4.26-4.20(m,2H),3.69-3.50(m,6H),3.33-3.10(m,2H),3.02-2.95(m,2H),2.67(s,3H),2.55(s,3H),2.38-2.36(m,4H),2.25(s,3H),1.86-1.82(m,4H),1.61(s,3H),1.01-0.99(m,6H)。LCMS(ESI):RT=1.30min,m/z实测值917.3[M-CF3COOH+H]+。
化合物046
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(((1-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)哌啶-4-基)甲基)氨基)-2-氧代乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.61(s,1H),9.33(s,2H),8.58-8.56(m,1H),7.78-7.65(m,1H),7.53-7.46(m,6H),7.25(d,J=8.0Hz,2H),6.87(s,1H),6.24(s,1H),4.54-4.51(m,1H),4.40-4.30(m,2H),3.98-3.60(m,4H),3.50-3.40(m,6H),3.02-2.85(m,7H),2.61-2.51(m,4H),2.41(s,3H),2.38-2.35(m,1H),1.86-1.60(m,9H),1.01-0.99(m,6H)。LCMS(ESI):RT=1.298min,m/z实测值988.3[M-CF3COOH+H]+。
化合物047
2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(((1-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)吡咯烷-3-基)甲基)氨基)-2-氧代乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.61(s,1H),9.9.34(s,2H),8.58-8.56(m,1H),7.89-7.85(m,1H),7.50-7.46(m,6H),7.28-7.24(m,2H),6.86(s,1H),6.25(s,1H),4.54-4.51(m,1H),4.40-4.30(m,2H),3.98-3.60(m,3H),3.50-3.40(m,5H),3.02-2.85(m,4H),2.61-2.51(m,4H),2.41(s,3H),2.38-2.35(m,2H),1.86-1.60(m,10H),1.01-0.99(m,6H)。LCMS(ESI):RT=1.295min,m/z实测值974.3[M-CF3COOH+H]+。
化合物048
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-((2-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-巯基-4H-1,2,4-三唑-4-基)苯氧基)乙基)氨基)-2-氧代乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ9.58(s,1H),8.59(s 1H),8.07(s,1H),7.50-7.47(m,4H),7.12(d,J=8.4Hz,1H),6.93(d,J=8.4Hz,1H),6.24(s,1H),4.54-4.51(m,1H),4.01-3.98(m,2H),3.83-3.68(m,2H),3.55-3.40(m,2H),3.00-2.95(m,1H),2.67-2.61(m,2H),2.60(s,3H),2.41(s,3H),2.37-2.32(m,2H),1.61(s,3H),0.99-0.95(m,6H)。LCMS(ESI):RT=1.666min,m/z实测值826.2[M+H]+。
化合物049
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(2-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)乙氧基)乙基)乙酰胺,三氟乙酸,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.61(s,1H),9.40(s,1H),8.28(s,1H),7.49-7.38(m,4H),7.27(d,J=8.2Hz,2H),7.12(d,J=8.3Hz,3H),6.76(s,1H),6.27(s,1H),4.49(t,J=6.0Hz,1H),3.43-3.30(m,8H),3.27-3.15(m,4H),2.97-2.92(m,1H),2.59-2.55(m,8H),2.43-2.38(m,6H),1.62(s,3H),0.93(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.074min,m/z实测值879.3[M-CF3COOH+H+])。
化合物050
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(3-(((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)(甲基)氨基)甲基)苯氧基)乙基)乙酰胺,三氟乙酸,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ11.98(s,1H),9.65(s,1H),9.37(s,1H),8.54(s,1H),7.64-6.98(m,13H),6.87(s,1H),6.25(s,1H),4.55-4.48(m,1H),4.40-4.15(m,3H),4.08-4.04(m,2H),3.56-3.53(m,2H),3.23-3.20(m,2H),3.06-2.91(m,1H),2.59(s,3H),2.40(s,3H),2.00-1.95(m,1H),1.59(s,3H),1.25-1.23(m,4H),0.99(d,J=6.0Hz,6H)。LCMS(ESI):RT=1.24min,m/z实测值886.5[M-CF3COOH+H]+。
化合物051
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(3-(((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)(甲基)氨基)甲基)苯氧基)乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.58(s,1H),9.38(s,1H),8.53(s,1H),7.62-6.57(m,14H),6.25(s,1H),4.54-4.47(m,1H),4.05-3.98(m,2H),3.50-3.30(m,5H),2.96-2.91(m,3H),2.67(s,3H),2.40(s,3H),2.33(s,1H),1.62-1.57(m,3H),1.24(s,4H),0.96-0.93(m,6H)。LCMS(ESI):RT=1.355min,m/z实测值886.2[M-CF3COOH+H]+。
化合物052
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)氧基)乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ11.91(s,1H),9.57(s,1H),9.36(s,1H),8.33(t,J=5.4Hz,1H),7.55-7.25(m,6H),7.14(d,J=8.3Hz,2H),6.86(s,1H),6.24(s,1H),4.51-4.48(m,3H),3.52-3.47(m,2H),3.32-3.24(m,4H),3.02-2.93(m,1H),2.59(s,3H),2.41(s,3H),1.61(s,3H),0.99(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.549min,m/z实测值767.2[M+H+])。
化合物053
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((1-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)哌啶-4-基)甲基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),9.62(s,2H),9.35(s,1H),8.24(s,1H),7.51-7.40(m,6H),7.25(d,J=7.6Hz,2H),6.86(s,1H),6.25(s,1H),4.53-4.51(m,1H),4.38-3.92(m,5H),3.19-3.10(m,3H),3.02-2.65(m,7H),2.67(s,3H),2.35(s,3H),1.77-1.62(m,10H),1.25-1.20(m,2H),0.97-0.93(m,8H)。LCMS(ESI):RT=1.392min,m/z实测值931.7[M-CF3COOH+H]+。
化合物054
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-((2-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯氧基)乙基)氨基)-2-氧代乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ11.85(s,1H),9.56(s,1H),9.37(s,1H),8.60(t,J=6.0Hz,1H),8.06(t,J=5.4Hz,1H),7.47(q,J=8.9Hz,4H),7.08(d,J=8.9Hz,2H),6.92(d,J=8.9Hz,2H),6.83(s,1H),6.24(s,1H),4.52(t,J=7.2Hz,1H),3.99(t,J=5.7Hz,2H),3.49-3.43(m,4H),3.36-3.30(m,2H),3.03-2.93(m,1H),2.58(s,3H),2.41(s,3H),1.62(s,3H),0.99(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.645min,m/z实测值810.6[M+H]+。
化合物055
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-((2-(2-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯氧基)乙氧基)乙基)氨基)-2-氧代乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ11.86(s,1H),9.57(s,1H),9.37(s,1H),8.58-8.56(m,1H),7.91-7.89(m,1H),7.50-7.44(m,4H),7.07(d,J=9.0Hz,2H),6.93(t,J=10.4Hz,2H),6.82(s,1H),6.24(s,1H),4.52(t,J=7.3Hz,1H),4.08-4.06(m,3H),3.76-3.64(m,5H),3.30-3.25(m,4H),3.00-2.92(m,1H),2.59(s,3H),2.40(s,3H),1.62(s,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.636min,m/z实测值852.2[M-H]-。
化合物056
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)乙酰胺。1H NMR(400MHz,DMSO):δ8.76(s,1H),7.49(d,J=8.7Hz,2H),7.40(d,J=8.5Hz,2H),7.28(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,2H),6.91(s,1H),6.23(s,1H),4.57-4.51(m,1H),4.34(m,3H),2.60(s,3H),2.41(s,3H),2.38-2.33(m,2H),2.00(d,J=7.7Hz,1H),1.61(s,3H),1.23(s,4H),1.00(t,J=7.5Hz,3H)。
LCMS(ESI):LCMS-010(LCMS 2020-004)RT=1.525min,方法:A70B30+-,(A:
0.1%FA/H2O B:0.1%FA/CAN柱sunFire C18)C36H33ClN8O4S质量计算值708.20,m/z实测值709.6[M+H]+。
化合物057
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)氨基)-2-氧代乙基)乙酰胺。1H NMR(400MHz,DMSO-d6):δ11.90(s,1H),9.55(s,1H),9.36(s,1H),8.74(t,J=5.8Hz,1H),8.29(t,J=6.0Hz,1H),7.54-7.41(m,4H),7.17(d,J=8.3Hz,2H),7.07(t,J=11.9Hz,2H),6.87(s,1H),6.23(s,1H),4.52(t,J=7.4Hz,1H),4.32-4.28(m,2H),3.89-3.84(m,1H),3.76-3.71(m,1H),3.63-3.40(m,3H),3.39-3.35(m,1H),3.30-3.26(m,3H),2.41(s,3H),1.62(s,3H),1.00(dd,J=6.8,1.5Hz,6H)。LCMS(ESI):RT=1.641min,m/z实测值780.6[M+H]+。
化合物058
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(2-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)乙基)哌啶-1-基)乙酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),9.61(s,1H),9.42(s,1H),7.52-7.42(m,4H),7.04(dd,J=30.5,8.8Hz,4H),6.80(s,1H),6.27(s,1H),4.61-4.54(m,1H),4.34-4.30(m,1H),4.15-4.14(m,1H),3.87-3.83(m,2H),3.57-3.50(m,4H),3.24-2.89(m,10H),2.60(s,3H),2.42(s,3H),1.79-1.75(m,1H),1.68-1.63(m,8H),0.97(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.112min,m/z实测值889.4[M-CF3COOH+H+])。
化合物059
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((1-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)氮杂环丁烷-3-基)甲基)乙酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.55(d,J=8.1Hz,2H),7.52-7.24(m,6H),6.87(s,1H),6.20(s,1H),4.64(s,1H),4.33(s,3H),4.05(s,2H),3.74(s,1H),3.58-3.33(m,6H),3.01(m,4H),2.69(d,J=3.2Hz,3H),2.45(s,3H),1.97(m,5H),1.69(s,3H),1.29(s,4H),1.05-0.92(m,6H)。LCMS(ESI):RT=1.039min,m/z实测值903.4[M-CF3COOH+H]+。
化合物060
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(((1-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)氮杂环丁烷-3-基)甲基)氨基)-2-氧代乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.45(m,8H),6.87(s,1H),6.20(s,1H),4.65(t,J=6.6Hz,1H),4.31(s,3H),3.99(m,3H),3.81–3.64(m,2H),3.47(s,5H),3.05(m,3H),2.86(s,1H),2.69(s,3H),2.58(s,1H),2.44(s,3H),2.20(m,1H),1.95(m,5H),1.69(d,J=2.2Hz,3H),1.30(s,4H),1.01(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.063min,m/z实测值960.3[M-CF3COOH+H]+。
化合物061
4-(4-(4-((2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)氨基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.60(s,1H),9.31(s,1H),8.89-8.80(m,2H),7.51-7.46(m,6H),7.24-7.22(m,2H),6.95(s,1H),6.24(s,1H),4.35-4.24(m,3H),3.75-3.33(m,3H),3.07(d,J=47.4Hz,6H),2.76-2.66(m,3H),2.60(s,3H),2.42(s,3H),1.97(s,3H),1.63(s,3H),1.01-0.88(m,6H)。LCMS(ESI):RT=1.347min,m/z实测值709.2[M-CF3COOH+H]+。
化合物062
(S)-4-(4-(4-(2-((2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)氨基)乙氧基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),9.58(s,1H),9.37(s,1H),8.84-8.81(m,2H),7.49(s,4H),7.14(d,J=8.9Hz,2H),6.98(d,J=9.0Hz,2H),6.84(s,1H),6.25(s,1H),4.33(d,J=7.6Hz,1H),4.26-4.23(m,2H),3.72-3.60(m,2H),3.03-2.93(m,1H),2.72-2.69(m,3H),2.61(s,3H),2.40(s,3H),2.35-2.33(m,1H),1.62(s,3H),0.99(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.358min,m/z实测值739.2[M-CF3COOH+H]+。
化合物063
(S)-4-(4-(4-(2-(2-((2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)氨基)乙氧基)乙氧基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),9.59(s,1H),9.38(s,1H),8.68-8.50(m,2H),7.50(s,4H),7.09(d,J=8.9Hz,2H),6.91(d,J=9.0Hz,2H),6.82(s,1H),6.25(s,1H),4.33-4.28(m,1H),4.12-4.11(m,2H),3.80-3.70(m,5H),3.44-3.40(m,1H),3.30-3.25(m,2H),3.02-2.93(m,1H),2.68-2.55(m,2H),2.60(s,3H),2.40(s,3H),1.61(s,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.385min,m/z实测值783.5[M-CF3COOH+H]+。
化合物064
(4-(((2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)氨基)甲基)哌啶-1-基)(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-基)甲酮,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.57(d,J=8.3Hz,2H),7.51(d,J=8.5Hz,2H),7.42(m,4H),6.87(s,1H),6.22(s,1H),4.42(s,1H),4.34(s,2H),3.58(m,6H),3.06(d,J=8.3Hz,6H),2.77(d,J=6.5Hz,2H),2.71(s,3H),2.44(s,3H),2.21–2.15(m,1H),1.99(m,7H),1.70(s,3H),1.30(s,7H),1.01(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.042min,m/z实测值917.3[M-CF3COOH+H]+。
化合物065
(S)-4-(4-(4-(2-((2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)(甲基)氨基)乙氧基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇。1H NMR(400MHz,DMSO-d6):δ7.49(s,4H),7.14(d,J=8.9Hz,2H),6.79-6.77(m,3H),6.25(s,1H),4.33(t,J=7.6Hz,1H),3.96-3.94(m,2H),3.03-2.93(m,1H),2.78-2.75(m,4H),2.61(s,3H),2.40(s,3H),2.33(s,1H),1.62(s,3H),0.99(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.417min,m/z实测值753.7[M+H]+。
化合物066
(3-(((2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)氨基)甲基)吡咯烷-1-基)(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-基)甲酮,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.48(m,7.9Hz,8H),6.88(s,1H),6.21(s,1H),4.38(m,3H),3.88(m,2H),3.56(m,5H),3.22(d,J=5.6Hz,2H),3.06(d,J=7.3Hz,3H),2.79(s,3H),2.71(s,3H),2.60(s,1H),2.44(s,3H),2.34-2.11(m,2H),2.07-1.81(m,5H),1.70(s,3H),1.27(m,4H),1.02(d,J=6.9Hz,6H)。LCMS(ESI):RT=0.978min,m/z实测值903.3[M-CF3COOH+H]+。
化合物067
(3-(((2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)氨基)甲基)吡咯烷-1-基)(1-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-基)甲酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.99(s,1H),9.64(s,2H),9.36(s,1H),8.68-8.65(m,2H),7.52-7.49(m,6H),7.26(d,J=8.3Hz,2H),6.91(s,1H),6.24(s,1H),4.31-4.29(m,3H),3.47-3.25(m,7H),3.10-2.80(m,4H),2.64-2.60(m,5H),2.43-2.29(m,5H),2.05-1.78(m,6H),1.62(s,3H),1.23-1.20(m,3H),1.01(t,J=7.5Hz,3H)。LCMS(ESI):RT=0.946min,m/z实测值889.3[M-CF3COOH+H]+。
化合物068
(4-(((2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)氨基)甲基)哌啶-1-基)(1-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-基)甲酮,三氟乙酸。1H NMR(400MHz,DMSO):δ11.98(s,1H),9.63(s,2H),9.35(s,1H),8.56(s,2H),7.49(m,5H),7.27(d,J=8.2Hz,2H),6.91(s,1H),6.23(s,1H),4.30(m,4H),2.96(s,5H),2.64(m,8H),2.43-2.34(m,4H),1.99(s,3H),1.80(s,4H),1.62(s,3H),1.51-1.42(m,1H),1.23(s,5H),1.01(t,J=7.5Hz,3H)。LCMS(ESI):RT=0.958min,m/z实测值903.3[M-CF3COOH+H]+。
化合物070
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((R)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)苯基)乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.61(s,1H),9.34(s,1H),8.73(s,1H),7.56-7.31(m,10H),7.19(s,2H),6.84(s,1H),6.27(s,1H),4.99(s,1H),4.47(d,J=8.6Hz,1H),4.30(s,1H),3.36-3.30(m,7H),3.23-3.20(m,2H),2.98-2.96(m,2H),2.65-2.58(m,7H),2.39(s,3H),1.56(s,3H),1.39(d,J=6.6Hz,3H),0.98(d,J=6.7Hz,6H)。LCMS(ESI):RT=1.081min,m/z实测值925.5[M-CF3COOH+H]+。
化合物071
(S)-4-(4-(4-(2-(2-((2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)(甲基)氨基)乙氧基)乙氧基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ7.55-7.37(m,4H),7.11-7.09(m,1H),6.88(d,J=8.1Hz,2H),6.69(s,1H),6.26(s,1H),4.37-4.35(m,1H),4.06-3.67(m,9H),3.11-2.96(m,4H),2.79-2.70(m,2H),2.66(d,J=8.6Hz,3H),2.43(s,3H),1.67(s,3H),1.29-1.25(m,3H),0.90-0.89(m,6H)。LCMS(ESI):RT=1.347min,m/z实测值797.3[M-CF3COOH+H]+。
化合物072
N-(4-(2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰氨基)苯基)-1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.64-7.31(m,13H),6.89(s,1H),6.21(s,1H),4.71(dd,J=8.6,5.5Hz,1H),4.36-4.33(m,2H),3.64-3.47(m,6H),3.13-3.09(m,3H),2.71(s,3H),2.45(s,3H),2.19-1.95(m,3H),1.70(s,3H),1.02(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.748min,m/z实测值925.9[M-CF3COOH+H]+。
化合物073
2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((1-(1-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)吡咯烷-3-基)甲基)乙酰胺盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.99(s,1H),10.20(s,1H),9.61(s,1H),9.33(s,2H),8.44(s,1H),7.55-7.41(m,6H),7.25(d,J=6.8Hz,2H),6.87(s,1H),6.28(s,1H),4.27-4.25(m,1H),4.09-4.06(m,2H),3.69-3.20(m,11H),3.02-2.85(m,4H),2.61-2.51(m,4H),2.41(s,3H),1.86-1.82(m,5H),1.61(m,3H),1.01-0.99(m,6H)。LCMS(ESI):RT=1.305min,m/z实测值917.4[M-HCl+H]+。
化合物074
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙酮盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),10.68(m,1H),9.62(s,1H),9.38(s,1H),7.64-7.44(m,6H),7.25(d,J=8.4Hz,2H),6.93(s,1H),6.31(s,1H),4.63(t,J=6.7Hz,1H),4.41-4.15(m,3H),3.79-3.40(m,12H),3.43-3.00(m,4H),2.76-2.55(m,5H),2.42(s,3H),2.05-2.02(m,1H),1.90-1.68(m,2H),1.63(s,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.31min,m/z实测值889.6[M-HCl+H]+。
化合物076
4-(4-(4-((4-((1-(2-((6S)-4-(4-氯苯基))-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙基)哌啶-4-基)甲基)哌啶-1-基)甲基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-6-异丙基苯-1,3-二醇,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.58-7.45(m,8H),6.83(s,1H),6.23(s,1H),4.38(t,J=6.1Hz,1H),4.16(s,2H),3.75-3.70(m,4H),3.21-2.95(m,12H),2.71(s,3H),2.65-2.61(m,2H),2.44(s,3H),2.17-2.04(m,3H),1.70(s,3H),1.55-1.50(m,2H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.224min,m/z实测值875.5[M-CF3COOH+H]+。
化合物077
2-((6S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((1-(1-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-4-羰基)吡咯烷-3-基)甲基)乙酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.46(m,8H),6.89(s,1H),6.18(s,1H),4.64(s,1H),4.32(s,2H),3.51(s,7H),3.06(s,2H),2.85(s,2H),2.70(s,3H),2.44(s,6H),1.96(m,6H),1.69(s,4H),1.30(s,5H),1.03(s,3H)。LCMS(ESI):RT=1.054min,m/z实测值903.1[M-CF3COOH+H]+。
化合物078
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺盐酸盐。1HNMR(400MHz,DMSO-d6):9.75-9.66(m,2H),7.61-7.37(m,8H),6.75(s,1H),6.34(s,1H),4.60-4.57(m,1H),4.37-4.34(m,2H),4.21-4.16(m,2H),3.99-3.95(m,2H),3.66-3.30(m,11H),3.18-3.12(m,3H),2.67-2.57(m,4H),2.44(s,3H),2.33-2.29(m,2H),1.76-1.60(m,4H),1.63(s,3H),1.24(s,1H),0.95-0.91(m,4H)。LCMS(ESI):RT=1.415min,m/z实测值984.4[M-HCl+H]+。
化合物079
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯基)哌嗪-1-基)乙-1-酮。1H NMR(400MHz,DMSO-d6):δ11.85(s,1H),9.59(s,2H),7.50-7.43(m,4H),7.07-6.96(m,4H),6.80(s,1H),6.27(s,1H),4.62-4.59(t,1H),3.81-3.77(m,2H),3.70-3.66(m,2H),3.48-3.40(m,2H),3.29-3.26(m,2H),3.00-2.97(m,1H),2.63(s,3H),2.45(s,3H),1.64(s,3H),0.98-0.97(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.573min,m/z实测值778.1[M+H]+。
化合物080
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(2-(4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)乙基)哌啶-1-基)乙-1-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.63(s,1H),9.42(s,1H),7.51-7.43(m,4H),7.22-7.12(m,4H),6.77(s,1H),6.27(s,1H),4.59-4.56(t,J=13.2Hz,1H),4.36-4.33(m,1H),4.13-4.10(m,1H),3.70-3.33(m,3H),3.22-2.96(m,7H),2.60(s,3H),1.99-2.01(m,1H),1.78-1.59(m,10H),1.39-1.24(m,6H),1.01(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.193min,m/z实测值902.2[M-CF3COOH+H]+。
化合物081
2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((R)-1-(3-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)苯基)乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.91(s,1H),9.60-9.40(m,3H),8.73-8.71(m,2H),7.52-7.10(m,12H),6.76(s,1H),6.26(s,1H),4.02-4.00(m,1H),4.48-4.46(m,1H),4.27-4.26(m,2H),4.94-3.59(m,4H),3.43-3.33(m,3H),2.98-2.86(m,3H),2.68-2.66(m,4H),2.40(s,3H),1.76-1.72(m,2H),1.56(s,3H),1.43-1.24(m,3H),0.94(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.410min,m/z实测值924.3[M-CF3COOH+H]+。
化合物082
2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((R)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)苯基)乙基)乙酰胺盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.83(s,1H),9.62(s,1H),9.40(s,1H),8.78-8.76(m,2H),7.57-7.44(m,6H),7.37-7.32(m,2H),7.20-7.09(m,4H),6.77(s,1H),6.28(s,1H),5.00(t,J=6.7Hz,1H),4.49-4.46(m,1H),4.25-4.24(m,2H),3.40-3.12(m,5H),2.98-2.96(m,1H),2.86-2.82(m,2H),2.67-2.60(m,4H),2.39(s,3H),1.71-1.68(m,4H),1.55(s,3H),1.46-1.39(m,4H),0.95(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.285min,m/z实测值924.6[M-HCl+H]+。
化合物083
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-(4-(((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)(甲基)氨基)甲基)苄基)哌啶-1-基)乙-1-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),9.81(s,1H),9.80(s,1H),9.61(s,1H),7.52-7.26(m,12H),6.90(s,1H),6.24(s,1H),4.57(t,J=6.7Hz,1H),4.45-4.11(m,8H),3.59(s,1H),3.39-3.35(s,1H),3.06-2.98(m,2H),2.60-2.58(m,5H),2.52-2.49(m,2H),2.41(s,3H),1.83(s,1H),1.68-1.63(m,5H),1.02(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.203min,m/z实测值924.2[M-CF3COOH+H]+。
化合物084
(S)-4-(4-(((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)苄基)(甲基)氨基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):9.70-9.64(m,3H),7.57-7.31(m,12H),6.77(s,1H),6.29(s,1H),4.59-3.94(m,11H),3.72-3.63(m,1H),3.40-3.33(m,1H),2.96-2.92(m,2H),2.60-2.49(m,8H),2.42(s,3H),2.09(m,1H),2.01(m,1H),1.66-1.63(m,5H),1.01(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.293min,m/z实测值1033.1[M-CF3COOH+H]+。
化合物085
(S)-4-(4-((1-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌啶-4-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,甲酸。1HNMR(400MHz,DMSO-d6):δ10.56(s,1H),9.57(s,1H),9.38(s,1H),8.33(s,1H),7.50-7.42(m,4H),7.29-7.23(m,4H),6.61(s,1H),6.35(s,1H),4.58(m,1H),4.33(m,1H),4.15(m,1H),3.98-3.94(m,2H),3.42-3.38(m,2H),3.11(m,2H),2.93-2.89(m,1H),2.60(s,3H),2.65-2.55(m,3H),2.44(s,3H),2.11-2.10(m,2H),1.79(m,4H),1.63-1.54(m,7H),1.24-1.21(m,2H),0.81(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.460min,m/z实测值997.3[M-CF3COOH+H]+。
化合物086
(S)-4-(4-((1-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌啶-4-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ9.73-9.59(m,2H),8.82(s,1H),9.38(s,1H),7.51-7.43(m,4H),7.29-7.24(m,4H),6.61(s,1H),6.33(s,1H),4.60-4.56(m,1H),4.38-4.34(m,1H),4.23-4.21(m,1H),3.98-3.94(m,2H),3.64-3.52(m,3H),3.40-3.15(m,3H),2.98-2.86(m,3H),2.62-2.58(m,5H),2.42(s,3H),2.27-2.21(m,3H),1.87-1.73(m,6H),1.63(s,4H),1.38-1.10(m,2H),0.84-0.88(m,3H)。LCMS(ESI):RT=1.534min,m/z实测值983.4[M-CF3COOH+H]+。
化合物087
(S)-4-(4-((1-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌啶-4-基)甲基)苯基)-N-乙基-5-(5-乙基-2,4-二羟基苯基)-1H-1,2,4l4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.25(s,1H),8.98(s,1H),7.51-7.43(m,4H),7.26(s,4H),6.56(s,1H),6.33(s,1H),4.58(t,J=6.7Hz,1H),4.38-4.35(m,1H),4.19-4.08(m,1H),3.78-3.36(m,5H),3.19-3.16(m,4H),2.98-2.81(m,3H),2.67-2.60(m,6H),2.42(s,3H),2.26-2.22(m,3H),1.89-1.74(m,5H),1.63(s,3H),1.60-1.24(m,4H),1.06-1.03(m,3H),0.86-0.83(m,3H)。LCMS(ESI):RT=1.409min,m/z实测值929.3[M-CF3COOH+H]+。
化合物088
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)哌啶-1-基)乙-1-酮,甲酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.56(s,1H),9.37(s,1H),8.15(s,1H),7.51-7.42(m,4H),7.18-7.08(m,4H),6.80(s,1H),6.26(s,1H),4.59-4.15(m,3H),3.70-3.59(m,1H),3.40-3.38(m,3H),3.12-2.99(m,3H),2.60(s,3H),2.42(s,3H),2.39-2.30(m,4H),2.29-1.98(m,2H),1.83-1.80(m,2H),1.64-1.57(m,7H),1.29-1.25(m,2H),0.98-0.94(m,4H)。LCMS(ESI):RT=1.337min,m/z实测值874.1[M-HCOOH+H]+。
化合物089
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)苄基)乙酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.50-7.22(m,12H),6.69(s,1H),6.26(s,1H),4.66-4.65(m,1H),4.51-4.49(m,2H),4.28-4.26(m,2H),3.45-3.35(m,4H),2.99-2.91(m,3H),2.68(s,3H),2.64-2.62(m,2H),2.35(s,3H),1.89-1.85(m,3H),1.68(s,3H),1.48-1.44(m,2H),0.89(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.153min,m/z实测值910.2[M-CF3COOH+H]+。
化合物090
(S)-4-(4-((1-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌啶-4-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-乙基-4H-1,2,4-三唑-3-甲酰胺。1H NMR(400MHz,DMSO-d6):δ10.69(d,J=1.2Hz,1H),9.77(s,1H),8.95(t,J=1.6Hz,1H),7.50-7.41(m,4H),7.26-7.25(m,4H),6.75(s,1H),6.35(s,1H),4.58(t,J=6.8Hz,1H),4.32-4.32(m,1H),4.25-4.20(m,1H),3.65-3.60(m,1H),3.16-3.14(m,4H),2.91-2.88(m,3H),2.59(s,3H),2.54-2.50(m,3H),2.41(s,3H),2.40-2.38(m,1H),2.11-2.01(m,2H),1.98-1.97(m,2H),1.79-1.66(m,4H),1.57(s,3H),1.57-1.45(m,5H),1.03(t,J=6.8Hz,3H),0.83(d,J=6.8Hz,6H)。LCMS(ESI):RT=2.294min,m/z实测值943.0[M+H]+。
化合物091
(S)-4-(4-((1-(4-((2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰氨基)甲基)苄基)哌啶-4-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):9.74-9.62(m,2H),8.81(t,J=6.7Hz,1H),7.50-7.40(m,8H),7.27-7.24(m,4H),6.60(s,1H),6.32(s,1H),4.57-4.27(m,5H),3.98-3.94(m,2H),3.37-3.32(m,4H),2.90-2.85(m,2H),2.60(s,3H),2.54-2.50(m,2H),2.41(s,3H),2.24-2.20(m,2H),1.75-1.61(m,6H),1.40-1.25(m,3H),0.86-0.83(m,3H)。LCMS(ESI):RT=1.383min,m/z实测值1005.2[M-CF3COOH+H]+。
化合物092
2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((R)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)苯基)乙基)-N-甲基乙酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):7.50-7.31(m,12H),7.30-7.29(m,2H),6.76(s,1H),6.24(s,1H),5.98(s,1H),4.78-4.75(m,3H),3.48-3.37(m,8H),3.18-2.89(m,8H),2.71-2.55(m,5H),2.46(s,3H),1.74-1.29(m,5H),0.93-0.92(m,6H)。LCMS(ESI):RT=1.172min,m/z实测值939.3[M-CF3COOH+H]+。
化合物093
2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-((R)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)苯基)乙基)-N-甲基乙酰胺,三氟乙酸。1HNMR(400MHz,CD3OD):δ7.50-7.41(m,8H),7.30-7.20(m,4H),6.87(d,J=3.2Hz,1H),6.26(s,1H),4.78(t,J=6.7Hz,1H),4.30-4.29(m,2H),3.35-3.33(m,2H),3.10(s,3H),3.10-3.09(m,1H),2.71(s,3H),2.65(s,3H),2.65-2.63(m,3H),2.45(s,3H),1.93-1.90(m,3H),1.70(s,3H),1.59-1.57(m,2H),1.38-1.30(m,4H),0.86(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.203min,m/z实测值938.3[M-CF3COOH+H]+。
化合物094
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)哌啶-1-基)乙-1-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.94(s,1H),9.62(s,1H),9.48(s,1H),8.38(s,1H),7.51(d,J=7.6Hz,2H),7.44(d,J=7.6Hz,2H),7.22(d,J=7.6Hz,2H),7.13(d,J=7.6Hz,2H),6.77(s,1H),6.27(s,1H),4.58(t,J=6.7Hz,1H),4.37-4.34(m,1H),4.18-4.16(m,1H),3.66-3.60(m,2H),3.20-3.10(m,1H),2.99-2.84(m,4H),2.56(s,3H),2.52-2.50(m,3H),2.40(s,3H),2.10-2.00(m,1H),1.83-1.73(m,5H),1.63(s,3H),1.48-1.44(m,2H),1.25-1.20(m,3H),0.96(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.174min,m/z实测值888.2[M-CF3COOH+H]+。
化合物095
(S)-4-(4-((1-(4-(2-(2-(4-(4-氯苯基))-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰氨基)乙基)苄基)哌啶-4-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.82(s,1H),9.62(s,1H),9.38(s,1H),7.50-7.20(m,12H),6.60(s,1H),6.33(s,1H),4.52(t,J=6.7Hz,1H),4.46-4.11(m,1H),3.95-3.90(m,2H),3.40-3.55(m,10H),3.30-3.22(m,4H),2.90-2.79(m,2H),2.67-2.61(m,2H),2.55(s,3H),2.41(s,3H),1.85-1.72(m,3H),1.63(s,3H),1.30-1.20(m,2H),0.82(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.253min,m/z实测值1033.3[M-CF3COOH+H]+。
化合物096
(S)-4-(4-((1-(4-((2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰氨基)甲基)苄基)哌啶-4-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ9.62-9.50(m,2H),8.88(s,1H),7.50-7.42(m,8H),7.28-7.26(m,4H),6.77(s,1H),6.34(s,1H),4.58(t,J=6.7Hz,1H),4.39-4.38(m,3H),4.32-4.25(m,3H),3.98-3.95(m,5H),3.70-3.65(m,2H),3.25-3.20(m,1H),1.85-2.83(m,3H),2.42-2.40(m,4H),2.39(s,3H),1.85-1.72(m,3H),1.63(s,3H),1.20-1.10(m,2H),0.82(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.255min,m/z实测值1019.3[M-CF3COOH+H]+。
化合物097
4-(4-((1-(3-((R)-1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰氨基)乙基)苄基)哌啶-4-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),9.60-9.50(m,2H),8.73(d,J=7.6Hz,1H),7.52-7.40(m,7H),7.31-7.24(m,6H),6.59(s,1H),6.34(s,1H),5.00(t,J=6.7Hz,1H),4.49-4.46(m,1H),4.28-4.26(m,2H),3.99-3.97(m,2H),3.38-3.35(m,2H),3.32-3.24(m,2H),3.13-3.10(m,3H),2.59(s,3H),2.50-2.48(m,2H),2.41(s,1H),1.75-1.72(m,3H),1.63(s,3H),1.44-1.41(m,4H),1.22(t,J=6.8Hz,3H),0.98(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.455min,m/z实测值1033.3[M-CF3COOH+H]+。
化合物098
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)苯乙基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.91(s,1H),9.62-9.38(m,3H),8.31(d,J=2.4Hz,1H),7.50-7.33(m,8H),7.19-7.09(m,4H),6.76-6.75(m,1H),6.26-6.24(m,1H),4.51-4.49(m,1H),4.21-3.92(m,2H),3.44-3.25(m,2H),2.98-2.82(m,7H),2.68-2.66(m,4H),2.41(s,3H),1.73-1.71(m,3H),1.68-1.66(m,3H),1.35-1.33(m,2H),0.94(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.172min,m/z实测值924.3[M-CF3COOH+H]+。
化合物099
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(2-(4-(((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)(甲基)氨基)甲基)苯氧基)乙基)-N-甲基乙酰胺,甲酸。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.75-9.30(m,2H),8.37(s,3H),7.43-7.12(m,11H),6.95-6.90(m,2H),6.76(s,1H),6.26(s,1H),4.58-4.55(m,1H),4.31-4.24(m,1H),4.06-4.04(m,1H),3.45(s,3H),3.42(s,3H),3.27(s,2H),2.95-2.92(m,2H),2.59(s,3H),2.42-2.41(m,3H),2.04(s,3H),1.62(d,J=9.2Hz,3H),0.91(d,J=7.2Hz,6H)。LCMS(ESI):RT=1.403min,m/z实测值900.2[M-HCOOH+H]+。
化合物100
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-(3-(4-(((4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)(乙基)氨基)甲基)苯氧基)丙基)乙酰胺,甲酸。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.81-9.32(m,2H),8.44-8.29(m,4H),7.42-7.33(m,7H),7.22-7.12(m,4H),6.85(d,J=8.4Hz,2H),6.74(s,1H),6.27(s,1H),4.52-4.49(m,1H),3.99-3.96(m,2H),3.49(s,2H),3.45(s,2H),3.20-3.14(m,1H),2.95-2.91(m,1H),2.59(s,3H),2.42-2.33(m,6H),1.91-1.97(m,2H),1.59(s,3H),0.96(t,J=7.2Hz,3H),0.89(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.398min,m/z实测值914.2[M-HCOOH+H]+。
化合物101
(S)-4-(4-(((4-(2-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-N-甲基乙酰氨基)乙氧基)苄基)(甲基)氨基)甲基)苯基)-5-(2,4-二羟基)-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,甲酸。1H NMR(400MHz,CD3OD):δ7.54-7.42(m,2H),7.41-7.29(m,8H),7.08-7.02(m,2H),6.74(s,1H),6.26(d,J=1.6Hz,1H),4.76-4.72(m,1H),4.57(s,3H),4.22-4.21(m,1H),4.08-3.96(m,6H),3.40(s,2H),3.13(s,2H),3.01-2.89(m,1H),2.68(s,3H),2.55(s,3H),2.44(s,4H),1.68(d,J=6.4Hz,3H),0.89(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.457min,m/z实测值1009.2[M-HCOOH+H]+。
化合物102
(S)-4-(4-(((4-(3-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰氨基)丙氧基)苄基)(乙基)氨基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2,2,2-三氟乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.71-9.63(m,3H),8.32-8.31(m,1H),7.57-7.45(m,2H),7.43-7.37(m,8H),7.02(d,J=8.4Hz,2H),6.77(s,1H),6.29(s,1H),4.52-4.49(m,1H),4.32-4.23(m,4H),4.06-3.94(m,4H),3.31-3.24(m,4H),2.96-2.91(m,3H),2.59(s,3H),2.40(s,3H),1.93-1.90(m,2H),1.61(s,3H),1.24(t,J=7.2Hz,3H),0.90(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.456min,m/z实测值1023.2[M-CF3COOH+H]+。
化合物103
(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮乙酸酯。
1H NMR(400MHz,DMSO-d6):δ11.92(s,2H),9.58(s,1H),9.40(s,1H),7.50-7.42(m,4H),7.30(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),6.77(s,1H),6.27(s,1H),4.59-4.55(m,1H),4.36-4.32(m,1.H),4.13-4.10(m,1H),3.60-3.58(m,1H),3.46(s,1H),3.38-3.32(m,6H),3.11-2.95(m,2H),2.51-2.50(m,4H),2.41-2.33(m,8H),2.15(s,2H),1.91(s,3H),1.81-1.68(m,3H),1.63(s,3H),1.24-1.22(m,1H),0.94(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.512min,m/z实测值889.3[M-CH3COOH+H]+。
化合物104
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-(2-(二乙基氨基)乙基)-5-(5-乙基-2,4-二羟基苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.72(s,1H),9.22-9.10(m,2H),7.51-7.30(m,8H),6.77(s,1H),6.34(s,1H),4.58(t,J=6.7Hz,1H),4.46-4.35(m,1H),4.20-4.10(m,1H),3.70-3.65(m,3H),3.35-3.16(m,8H),3.10-2.80(m,7H),2.67(s,3H),2.42(s,3H),2.34-2.23(m,6H),1.85-1.70(m,3H),1.63(s,3H),1.18(d,J=6.9Hz,6H),0.89(t,J=6.9Hz,6H)。LCMS(ESI):RT=1.275min,m/z实测值1001.2[M-CF3COOH+H]+。
化合物105
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-N-异丙基-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.69(s,1H),7.51-7.28(m,8H),6.62(s,1H),6.31(s,1H),4.59-3.92(m,4H),3.77-3.61(m,13H),3.26-2.88(m,8H),2.67(s,3H),2.38(s,3H),2.33-2.22(m,2H),1.87-1.72(m,2H),1.63(s,3H),1.13-1.06(m,6H),0.89-0.85(m,3H)。LCMS(ESI):RT=1.200min,m/z实测值944.2[M-CF3COOH+H]+。
化合物106
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.62(s,1H),8.29(s,1H),7.71(s,1H),7.51-7.32(m,9H),6.61(s,1H),6.36(s,3H),4.58(t,J=6.7Hz,1H),4.46-4.33(m,1H),4.22-4.10(m,1H),3.68-3.55(m,6H),3.20-2.80(m,6H),2.75-2.67(m,2H),2.67(s,3H),2.41(s,3H),2.32-2.24(m,3H),2.05-1.98(m,1H),1.75-1.65(m,3H),1.63(s,3H),1.20-1.10(m,3H),0.86(t,J=6.9Hz,6H)。LCMS(ESI):RT=1.117min,m/z实测值902.2[M-CF3COOH+H]+。
化合物107
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-(2-(哌啶-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ7.55-7.40(m,8H),6.70(s,1H),6.31(s,1H),5.11-5.00(m,6H),4.75-4.20(m,2H),3.88-3.39(m,12H),2.97-2.91(m,8H),2.74-2.70(m,3H),2.45-2.44(m,3H),1.94-1.68(m,11H),1.63-1.20(m,3H),0.92-0.90(m,2H)。LCMS(ESI):RT=0.915min,m/z实测值1027.6[M-CF3COOH+H]+。
化合物108
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-异丙基-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.76(s,1H),8.93-8.75(m,1H),7.50-7.31(m,9H),6.60(s,1H),6.34(s,1H),4.70-3.85(m,4H),3.62-3.45(m,2H),3.20-2.92(m,9H),2.78-2.57(m,5H),2.42-2.00(m,7H),1.87-1.60(m,8H),1.11-1.07(m,6H),0.95-0.75(m,6H)。LCMS(ESI):RT=1.196min,m/z实测值958.2[M-CF3COOH+H]+。
化合物109
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.81(s,1H),8.32(s,1H),7.72(s,1H),7.51-7.37(m,8H),6.20(s,1H),6.34(s,1H),4.60-4.12(m,3H),3.17-2.93(m,11H),2.67-2.50(m,4H),2.41-2.33(m,4H),2.05-2.02(m,6H),1.63(s,3H),1.23-0.84(m,10H)。LCMS(ESI):RT=1.136min,m/z实测值916.2[M-CF3COOH+H]+。
化合物110
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基苯基)-N-(2-(哌啶-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ9.27-9.25(m,2H),7.51-7.29(m,9H),6.92-6.90(m,2H),6.21-6.18(m,2H),4.60-4.56(m,1H),4.41-4.35(m,1H),4.22-4.18(m,1H),3.57-3.50(m,5H),3.42-3.19(m,3H),2.94-2.86(m,5H),2.60(s,3H),2.44-2.33(m,8H),2.23-2.05(m,2H),1.87-1.56(m,12H),1.26-0.99(m,5H)。LCMS(ESI):RT=1.131min,m/z实测值985.5[M-CF3COOH+H]+。
化合物111
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-(2-(二乙基氨基)乙基)-5-(2,4-二羟基苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ9.24-9.22(m,3H),7.52-7.29(m,9H),6.91(d,J=8.4Hz,1H),6.22-6.17(m,2H),4.60-4.55(m,1H),4.38-4.33(m,2H),4.21-4.13(m,2H),3.69-3.51(m,4H),3.42-3.32(m,1H),3.25-2.80(m,15H),2.60(s,4H),2.42(s,5H),2.04(s,1H),1.89-1.69(m,2H),1.63(s,3H),1.21-1.16(m,6H)。LCMS(ESI):RT=0.946min,m/z实测值973.3[M-CF3COOH+H]+。
化合物112
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.15-9.51(m,1H),8.84(s,1H),8.31(s,1H),7.51-7.26(m,9H),7.01-6.83(m,1H),6.29-6.14(m,2H),4.60-4.55(m,1H),4.39-4.33(m,1H),4.20-4.14(m,2H),3.67-3.61m,6H),3.42-3.33(m,2H),3.15-2.92(m,6H),2.68-2.58(m,5H),2.42(s,4H),2.05(s,1H),1.88-1.71(m,2H),1.63(s,3H),1.31-0.96(m,2H)。LCMS(ESI):RT=1.190min,m/z实测值874.2[M-CF3COOH+H]+。
化合物117
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-N-(2-(哌啶-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.72(s,1H),9.62-9.60(m,1H),9.00(s,1H),7.51-7.33(m,10H),6.77(s,1H),6.30(s,1H),4.58(t,J=6.7Hz,2H),4.30-4.20(m,2H),4.15-4.10(m,2H),3.63-3.50(m,7H),3.20-3.17(m,2H),2.91-2.88(m,4H),2.60(s,3H),2.42(s,3H),2.33-2.27(m,4H),1.83-1.60(m,14H),1.20-1.10(m,2H),0.91-0.87(m,4H)。LCMS(ESI):RT=0.996min,m/z实测值1013.2[M-CF3COOH+H]+。
化合物118
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-(2-(二乙基氨基)乙基)-5-(2,4-二羟基-5-异丙基苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.55-7.38(m,8H),6.70(s,1H),6.31(s,1H),4.76-4.68(m,5H),4.30-4.20(m,1H),3.86-3.50(m,11H),3.12-2.96(m,10H),2.71(s,3H),2.45(s,3H),2.20-2.10(m,1H),1.98-1.90(m,2H),1.70(s,3H),1.40-1.38(m,1H),1.31(t,J=6.8Hz,6H),0.90(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.005min,m/z实测值1015.2[M-CF3COOH+H]+。
化合物119
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基苯基)-N-异丙基-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.46-7.26(m,9H),6.87(d,J=8.8Hz,1H),6.22(d,J=2.4Hz,1H),6.18(dd,J1=8.4Hz,J2=2.4Hz,1H),4.70-4.50(m,3H),4.28-4.26(m,2H),4.04-4.02(m,1H),3.65-3.58(m,4H),3.30-3.23(m,1H),2.72-2.62(m,12H),2.44-2.39(m,5H),1.94-1.91(m,3H),1.69(s,3H),1.20(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.411min,m/z实测值916.2[M-CF3COOH+H]+。
化合物120
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-4H-1,2,4-三唑-3-甲酰胺盐酸盐。1H NMR(400MHz,CD3OD):δ7.89-7.87(m,2H),7.67-7.60(m,6H),6.83-6.81(m,1H),6.46-6.43(m,1H),5.13-5.11(m,1H),4.65-4.59(m,3H),4.22-4.21(m,1H),3.93-3.71(m,9H),3.31-3.28(m,8H),3.01(s,3H),2.87-2.82(m,1H),2.36-2.32(m,3H),2.13-2.01(m,2H),1.72(s,3H),1.55-1.29(m,2H),0.93-0.91(m,3H)。LCMS(ESI):RT=1.130min,m/z实测值902.2[M-HCl+H]+。
化合物121
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-2,4-二羟基苯基)-4H-1,2,4-三唑-3-甲酰胺盐酸盐。1H NMR(400MHz,CD3OD):δ7.89-7.87(m,2H),7.67-7.60(m,6H),6.83-6.81(m,1H),6.46-6.43(m,1H),5.13-5.11(m,1H),4.65-4.59(m,3H),4.22-4.21(m,1H),3.93-3.71(m,9H),3.31-3.28(m,8H),3.01(s,3H),2.87-2.82(m,1H),2.36-2.32(m,3H),2.13-2.01(m,2H),1.72(s,3H),1.55-1.29(m,2H),0.93-0.91(m,3H)。LCMS(ESI):RT=1.130min,937.34m/z实测值902.2[M-HCl+H]+。
化合物123
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-丙基苯基)-N-(2-(哌啶-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.70(s,1H),9.25(s,1H),9.05(s,1H),7.51-7.32(m,8H),6.66(s,1H),6.30(s,1H),4.59-4.56(m,1H),4.35-4.33(m,4H),4.17-4.15(m,4H),3.55-3.53(m,2H),3.50-3.49(m,6H),3.30-3.28(m,2H),3.18-3.16(m,2H),3.11-2.95(m,6H),2.60(s,3H),2.50(s,3H),2.25-2.23(m,2H),1.63-1.60(m,6H),1.58(s,3H),1.33-1.31(m,4H),1.10-1.08(m,2H),0.75-0.72(m,3H)。LCMS(ESI):RT=1.066min,m/z实测值1027.5[M-CF3COOH+H]+。
化合物124
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-甲基苯基)-N-(2-(哌啶-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.73(s,1H),9.25(s,1H),9.02(s,1H),7.52-7.47(m,2H),7.46-7.41(m,2H),7.40-7.35(m,2H),7.33-7.28(m,2H),6.72(s,1H),6.28(s,1H),4.60-4.54(m,1H),4.40-4.32(m,1H),4.22-4.13(m,1H),3.25-3.09(m,10H),3.05-2.78(m,12H),2.59(s,3H),2.41(s,3H),2.11-1.94(m,3H),1.88(s,4H),1.83-1.62(m,12H)。LCMS(ESI):RT=1.017min,m/z实测值999.4[M-CF3COOH+H]+。
化合物125
(R)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)-1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),11.26(s,1H),9.62(s,1H),9.31(s,1H),7.64-7.44(m,6H),7.25(d,J=8.4Hz,2H),6.93(s,1H),6.31(s,1H),4.63(t,J=6.7Hz,1H),4.41-4.15(m,3H),3.79-3.40(m,12H),3.43-3.00(m,4H),2.76-2.55(m,5H),2.42(s,3H),2.05-2.02(m,1H),1.90-1.68(m,2H),1.63(s,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):Rt=1.088min,m/z实测值889.6[M-HCl+H+]。
化合物126
(S)-4-(4-((4-((1-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(2,4-二羟基-5-异丙基苯基)-N-乙基异噁唑-3-甲酰胺盐酸盐。1H NMR(400MHz,DMSO-d6):9.85(s,1H),9.67(s,1H),8.93-8.90(m,1H)7.52-7.31(m,8H),6.82(s,1H),6.48(s,1H),4.60(t,J=6.7Hz,1H),4.37-4.23(m,2H),4.17-4.02(m,2H),3.74-2.98(m,19H),2.67-2.65(m,4H),2.42(s,3H),2.16-2.14(m,1H),1.94-1.92(m,2H),1.63(s,3H),1.23-1.11(m,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.420min,m/z实测值944.6[M-HCl+H]+。
实施例5:各种T-PEACH分子的测试
材料和方法
HSP90α结合荧光偏振(FP)测定
使用测定缓冲液、BSA和FITC-格尔德霉素制备主混合物(master mix)。在96孔板中,制备各化合物的连续3倍稀释液,范围从40μM直到低至2.0nM。同样在96孔板中,将重组HSP90α蛋白稀释至28μg/ml。然后,在384孔板中,向重复孔中每孔添加10μl主混合物和5μl化合物稀释液,并通过短暂振荡混合。然后每孔添加5μl稀释的HSP90α蛋白,通过短暂振荡混合,在25℃下孵育30、60和120min,并在EnVision读板机上测量荧光。由EnVision原始数据计算减去背景的mP值,并使用GraphPad Prism 7.0拟合四参数“log[抑制剂]相对于响应”曲线。
溴结构域结合测定
展示不同的人溴结构域蛋白的T7噬菌体菌株在源自BL21菌株的大肠杆菌宿主中在24孔块(24-well block)中平行生长。大肠杆菌生长至对数期并用来自冷冻储备液的T7噬菌体感染(感染复数=0.4),并且在32℃下振荡孵育直至裂解(90-150min)。裂解物以5,000xg离心并0.2μm过滤以去除细胞碎片。链霉亲和素包被的磁珠在室温下用生物素化的小分子或乙酰化的肽配体处理30min,以产生用于溴结构域测定的亲和树脂。带配体的珠粒用过量生物素封闭,并用具有1%BSA、0.05%Tween 20和1mM DTT的SEA BLOCK封闭缓冲液(Pierce Scientific)洗涤,以去除未结合的配体并减少非特异性噬菌体结合。通过将溴结构域、带配体的亲和珠粒和测试化合物合并在1X结合缓冲液(16%SEA BLOCK、0.32XPBS、0.02%BSA、0.04%Tween 20、0.004%叠氮化钠和7.9mM DTT)中来组装结合反应。测试化合物制备为在100%DMSO中的1000X储备液,并且随后在单乙二醇(MEG)中按1:25稀释。然后将化合物直接稀释到测定液中,使得DMSO和MEG的最终浓度分别为0.1%和2.4%。所有反应均在聚丙烯384孔板中进行,最终体积为0.02mL。将测定板在室温下振荡孵育1hr,并用洗涤缓冲液(1X PBS、0.05%Tween 20)洗涤亲和珠粒。然后将珠粒重悬于洗脱缓冲液(1X PBS、0.05%Tween 20、2μM非生物素化的亲和配体)中,并在室温下振荡孵育30min。通过qPCR测量洗脱液中的溴结构域浓度。化合物的对照百分比(Percent control)通过以下等式确定:
%对照=(信号化合物-信号PC)/(信号NC-信号PC)
BRD4结合均相时间分辨荧光荧光(HTRF)测定
使用测定缓冲液、1.8μg/ml重组BRD4(BD1+BD2结构域)蛋白以及Tb标记供体和染料标记受体的200倍稀释液制备主混合物。在1X BRD TR-FRET测定缓冲液中制备乙酰化和非乙酰化配体的40倍稀释液。此外,制备各化合物的连续3倍稀释液,范围从40μM直到低至2.0nM。在384孔板中,向重复孔中每孔添加5μl稀释配体和5μl化合物稀释液,并通过短暂振荡混合。然后每孔添加10μl主混合物,通过短暂振荡混合,在25℃下孵育2hr,并在EnVision读板机上测量荧光。665nm/615nm比由EnVision原始数据计算得出。使用“正”和“负”读数的整板平均值对数据进行归一化。使用GraphPad Prism7.0拟合四参数“log[抑制剂]相对于响应”曲线。
蛋白质降解流式细胞术
将MV4-11细胞以350,000个细胞/450μL/孔的密度涂板在24孔组织培养板中,并在37℃/5%CO2下孵育1hr。然后用各种浓度的化合物处理细胞,并在37℃/5%CO2下孵育24hr。收获细胞,洗涤一次,计数并添加200μL的1%多聚甲醛/PBS,并且在室温下孵育15min。添加200μL的1X PBS/0.4%Triton X-100并在4℃下孵育15min。将细胞洗涤3次并重悬于50μL的1X PBS/0.2%Triton X-100中。添加2μL/106细胞的抗BRD4抗体(ABCAM,#128874)并通过上下吹打混合。将细胞在室温下在黑暗中孵育30min,洗涤3次并重悬于50μL的1X PBS/0.2%Triton X-100中。添加山羊抗兔IgG H&L抗体(1:2000稀释),通过上下吹打混合并且在室温下在黑暗中孵育30min。最后,将细胞洗涤3次并重悬于200μL PBS中以用于流式细胞术分析。化合物的抑制效率通过以下等式确定并使用GraphPad Prism 7.0进行分析:
%抑制=100-(D-B)/(S-B)*100%。
S:使用抗体的情况下MV4-11的荧光强度
D:存在不同化合物稀释液与抗体的情况下的荧光强度
B:仅MV4-11的荧光强度
使用抗ERBB2(R&D,#FAB1129P)、抗IGF1R(Cell Signaling Technology,#9750)、抗EGFR(Cell Signaling Technology,#139690)和抗RAF1(ABCAM,#ab181115)抗体对BT-474人乳腺癌细胞(ATCC,#HTB-20)中的ERBB2以及HEK-293人胚胎肾(ATCC,#CRL-1573)中的IGF1R、EGFR和RAF1进行类似的流式细胞术实验。
蛋白质印迹
将MV4-11人急性髓性白血病细胞(ATCC,#CRL-9591)接种在6孔组织培养板中,并且在1hr后,以各种浓度添加化合物,并在37℃/5%CO2下孵育24hr。然后通过离心收集细胞,用冷PBS洗涤一次,吸出上清液,并用含有蛋白酶/磷酸酶抑制剂混合物的4℃RIPA裂解缓冲液裂解细胞沉淀。细胞裂解物的总蛋白质浓度通过BCA蛋白测定试剂盒(BCA ProteinAssay kit)确定。将样品针对当量蛋白质浓度(equivalent protein concentration)归一化,添加5X上样缓冲液并加热至100℃,持续10min,并且冷却至室温。将20l各样品/孔上样到SDS-PAGE凝胶上并在80V下电泳20min,然后在120V下电泳1.5hr。接着使用湿转移方法在250mA下将凝胶电印迹到硝酸纤维素膜上,持续2.5hr。膜用封闭缓冲液孵育1hr,并用TBST洗涤3次,每次5min。然后将膜与按照制造商的建议稀释于封闭缓冲液中的抗BRD4(CellSignaling Technology,#13440)和抗β-肌动蛋白(Cell Signaling Technology,#3700)抗体一起在4℃下孵育过夜。洗涤3次后,将印迹与适当的标记二抗一起在室温下孵育1hr并再次洗涤。在LI-COR上读取图像,并通过ImageJ软件确定条带的光密度值。使用GraphPadPrism 7.0分析数据。
使用抗BRD2(Cell Signaling Technology,#139690)和抗BRD3(Cell SignalingTechnology,#50818)在MV4-11细胞中针对BRD2和BRD3进行类似的蛋白质印迹实验。
MYC HTRF测定
使用基于人c-Myc细胞的测定试剂盒(Human c-Myc Cell-based Assay Kit,Cisbio,#63ADK053PEG)测量MYC蛋白表达,这是一种均相时间分辨荧光(HTRF)测定。将MV4-11细胞以100,000个细胞/90μL/孔的密度涂板在96孔组织培养板中,并在37℃/5%CO2下孵育1hr,接着用各种浓度的化合物(从10μM开始的10点3倍连续稀释系列)处理,然后在37℃/5%CO2下孵育24hr。通过离心收集细胞,通过吸取移除上清液,添加10μL裂解缓冲液并且在振荡的同时在室温下孵育45min。在384孔板中,将10μL细胞裂解物/孔与10μL在检测缓冲液中制备的含有抗人MYC-Eu3+Cryptate的预混抗体溶液合并,并在室温下孵育过夜,然后测量信号。计算每个单独孔的受体和供体发射信号的比率(比率=665nm/620nm x 104)。各化合物的抑制效率通过以下等式确定并使用GraphPad Prism 7.0进行分析:
%抑制=100-(D-B)/(S-B)*100%。
S:比率最大值(阳性对照)
D:存在不同稀释度化合物与细胞的情况下的比率
B:比率最小值(空白对照)
细胞毒性测定
将MV4-11细胞以4,500个细胞/90μL/孔的密度涂板在96孔组织培养板中,并在37℃/5%CO2下孵育24hr。接着用各种浓度的化合物(从20μM开始的10点3倍连续稀释系列)处理细胞,最终浓度为0.5%DMSO/孔,并且接着在37℃/5%CO2下孵育72hr。将10μL细胞增殖试剂CCK-8(WST-8)添加到每个孔中,并在37℃/5%CO2下孵育3-4hr,并使用EnVision读板机测量450nm处的吸光度。化合物的抑制效率通过以下等式确定并使用GraphPad Prism7.0进行分析:
%抑制=100-(D-B)/(S-B)*100%。
S:吸光度最大值(含DMSO的细胞)
D:存在不同稀释度化合物与细胞的情况下的吸光度
B:吸光度最小值(含DMSO的培养基)
小鼠的肿瘤异种移植研究
MV4-11急性髓性白血病和SU-DHL-4弥漫性大B细胞淋巴瘤(ATCC,#CRL-2957)细胞在补充有10%胎牛血清的培养基中在37℃/5%CO2下培养。收集5x 106个MV-4-11或1x 107个SU-DHL-4细胞并将其重悬于0.1mL含Matrigel(1:1v/v)的无血清培养基中,以用于分别在异氟醚麻醉的雄性BALB/c裸鼠或CB-17scid小鼠(根据AAALAC动物福利指南进行处理)中进行每只小鼠的皮下接种。当平均肿瘤体积达到100-200mm3时,去除肿瘤体积异常值并且将其余动物随机分成6-8的组,每组平均肿瘤体积相似。在45%PEG300和55%生理盐水中制备化合物074和化合物078的溶液,并用0.15M碳酸氢钠溶液调整至pH 3.0-7.0。动物以25mg/kg、50mg/kg或100mg/kg 1X/周静脉内给药,持续3或4周。每天观察并记录每只小鼠的外观和行为。每2-4天测量并记录体重和肿瘤体积,结果表示为组平均值±SEM。组间配对统计比较通过单因素方差分析进行,并且p<0.05被视为统计上显著的。
药代动力学和组织分布
在30%PEG300和70%生理盐水中制备化合物074的溶液,并用0.15M碳酸氢钠溶液调整至pH 3.0-7.0。对15只雌性CB-17SCID小鼠(根据AAALAC动物福利指南处理)称重,并通过单次静脉内注射施用5mg/kg的化合物074。通过下颌下静脉从每只小鼠中收集0.10mL血液并添加肝素钠作为抗凝剂。在化合物施用前和施用后1hr、6hr、24hr和48hr时间点收集样品,每个时间点对3只小鼠采样。收集后,将样品置于冰上并将动物处死以收集肿瘤和正常组织。所有样品的方法开发和分析均由上海美迪西公司(Shanghai Medicilon Inc.)的分析实验室进行。在样品分析期间进行样品的日内准确度评估以用于质量控制,并且要求超过66.7%的样品的质量控制准确度介于80-120%之间。使用Phoenix WinNonlin 7.0软件计算药代动力学参数。
结果
已经开发了许多合成方案来构建各种T-PEACH分子。代表性实例如下在HSP90结合剂与BET结合剂(+)-JQ1之间示出。类似化学可以应用于其他T-PEACH分子,不限于HSP90结合剂和(+)-JQ1。
应用测量与FTIC-格尔德霉素的竞争的HSP90α荧光偏振(FP)结合测定来评估T-PEACH分子与HSP90的结合能力。如表1所示,文献中记载的含有HSP90结合部分的T-PEACH分子通常与所公开的结构活性关系(SAR)一致。
在此测定中,将分子量与HSP90α结合剂相似的(+)-JQ1 BET结合剂掺入T-PEACH中对T-PEACH分子与HSP90的结合仅有很小影响。存在多种原因:首先,这些部分与其相应蛋白质的共晶结构是可获得的,并且允许基于结构的精确分子设计;其次,系链被构造成以合适的长度提供刚性。
表1:HSP90α结合FP测定
*A.IC50<100nM;B.IC50=100-1000nM;C.IC50>1000nM
存在超过40种含有一个或多个溴结构域基序的人蛋白质,其中BET家族的每个成员含有两个独立的溴结构域,称为BD1和BD2,它们可以独立地结合乙酰化赖氨酸。为了评估化合物074结合多种重组溴结构域蛋白的能力,采用了配体结合定点竞争测定。如表2所示,10μM化合物074能够有效地竞争配体结合BRD2、BRD3、BRD4和BRD4蛋白中的每一个中存在的两个溴结构域。然而,化合物074表现出与多种其他溴结构域蛋白很少或没有结合。
表2:使用10μM化合物074进行的溴结构域结合测定
*A.<10%;B.11-75%;C.>75%
还使用HTRF测定评估了多种T-PEACH分子对BRD4(BD1+BD2)蛋白与其底物的结合的抑制,如表3所示。文献中记载的含有BRD4结合部分的T-PEACH分子通常与所公开的SAR分析一致。那些BRD4结合部分包括基于(+)-JQ1的支架,尤其是携带与OTX-15和(+)-JQ1相似结构的化合物。
在此测定中,掺入伴侣结合部分,诸如HSP90结合剂,对T-PEACH分子与BRD4的结合仅有最小影响。存在多种原因:首先,这些部分与其相应蛋白质的共晶结构是可获得的,并且允许基于结构的精确分子设计;其次,系链被构造成以合适的长度提供刚性。
表3:BRD4(BD1+BD2)结合HTRF测定
*A.IC50<100nM;B.IC50=100-1000nM;C.IC50>1000nM
T-PEACH嵌合分子被设计成诱导靶向蛋白降解。如表4所示,对于用其中BET结合部分和HSP90结合部分共价连接的T-PEACH分子处理的MV4-11细胞,50%或更多的细胞BRD4蛋白在24hr内降解,如在流式细胞术测定中所测量的。相比之下,当用醚BET抑制剂(+)-JQ1或HSP90结合剂(1-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-基)乙-1-酮)处理MV4-11细胞时,未观察到明显的BRD4降解。化合物005是含有非BET结合(-)-JQ1部分的对照T-PEACH分子并且不降解BRD4。此外,当细胞用HSP90结合剂和(+)-JQ1的组合预处理时,化合物40降解BRD4的能力显著降低。这表明需要将两个结合部分共价连接于T-PEACH构建体中。
表4:BRD4降解流式细胞术测定
*A.降解>50%;B.10%<降解=10-50%;C.降解<10%
#在40-1000nM之间的浓度下观察到最高降解百分比
&在添加化合物40之前,将细胞用HSP90结合剂和(+)-JQ1的组合预处理30分钟
为了进一步评估BRD4降解,将MV4-11细胞用各种浓度的T-PEACH化合物处理24hr,并通过蛋白质印迹评估BRD4表达。如图1所示,在100和300nM的化合物074浓度下观察到BRD4降解。重要的是,当MV-411细胞用化合物074和蛋白酶体抑制剂硼替佐米处理时,BRD4降解被阻断(图2)。这表明T-PEACH分子诱导通过UPS实现的靶向蛋白降解。
尽管(+)-JQ1是泛BET蛋白家族结合剂,但由于单个BET家族成员靶标与伴侣或伴侣复合物之间的电荷排斥和/或空间冲突,掺入(+)-JQ1部分的T-PEACH分子可在蛋白质降解中表现出更大的选择性是有可能的。为了检查这一点,将MV4-11细胞用基于(+)-JQ1的PROTAC dBET1(Winter等人,Science,2015,348:1376-1381)和化合物047处理24hr,并且通过流式细胞术评估BRD2、BRD3和BRD4的表达。如表5所示,dBET1以相似的效力诱导BRD2、BRD3和BRD4的降解。相比之下,化合物047仅诱导BRD4的显著降解。这表明使用T-PEACH技术可将混杂的靶结合剂转化为选择性降解剂。
表5:BET蛋白家族降解流式细胞术测定
已知BRD4调节MYC基因的表达。如表6所示,发现选定的T-PEACH分子在24hr处理后降低MV4-11细胞中的MYC蛋白表达,如通过HTRF测定所评估的。
表6:MYC蛋白表达HTRF测定
化合物 | MYC蛋白表达* |
005 | A |
040 | A |
*A.IC50<100nM;B.IC50=100-1000nM;C.IC50>1000nM
T-PEACH分子可包括伴侣和伴侣复合物结合剂,其具有一系列不同的结合亲和力。在不同的实施方案中,希望使用高亲和力结合剂、中等亲和力结合剂或低亲和力结合剂。由于与HSP90的N端ATP结合袋相互作用的HSP90结合部分可抑制HSP90活性并诱导HSP90客户蛋白的降解,因此一些T-PEACH分子将不仅诱导一种或多种期望靶蛋白(可以是或可以不是HSP90客户蛋白)的降解,而且还同时诱导HSP90客户蛋白的降解。相比于针对一种或多种相同靶标的其他靶向蛋白降解技术,降解活性的这种组合可增加T-PEACH分子的活性。如表1所示,化合物074在与HSP90的结合中具有中等效力。为了评估化合物074相对于已知的敏感性HSP90客户蛋白对BRD4(它不是敏感性HSP90客户蛋白)的选择性,对表达HSP90客户蛋白的各种细胞系进行流式细胞术测定:HER2乳腺癌细胞中的ERBB2)以及HEK-293胚胎肾细胞中的IGF1R、EGFR和RAF1。如表7所示,对于这些HSP90客户蛋白的降解,化合物074表现出介于339-1055nM之间的IC50值,比在MV4-11细胞中通过蛋白质印迹确定的针对BRD4降解的IC50值59nM高6至18倍。这表明相对于其它已知的HSP90客户蛋白,具有中等亲和力HSP90结合部分的T-PEACH分子表现出针对预期降解靶标BRD4的选择性。
表7:使用化合物074进行的HSP90客户蛋白降解流式细胞术测定
HSP90客户蛋白 | ERBB2* | IGF1R** | EGFR** | RAF1** |
IC<sub>50</sub>(nM) | 340 | 1055 | 405 | 762 |
*BT-474细胞;**HEK-293细胞
如表8所示,在细胞毒性测定中,用各种T-PEACH分子进行处理有效地抑制了MV4-11细胞的生长和存活。
表8:MV4-11细胞毒性测定
*A.IC50<100nM;B.IC50=100-1000nM;C.IC50>1000nM
选择化合物074和078来测试在小鼠荷瘤异种移植模型中的体内功效。在MV4-11异种移植模型中,25mk/kg、50mg/kg和100mg/kg的化合物074以1X/周静脉内给药。如图3a所示,给药3周后,100mg/kg组表现出显著的肿瘤生长抑制,其中在研究结束时,6只动物中有4只没有肿瘤。50mg/kg组也表现出显著的肿瘤生长抑制,其中在研究结束时,6只动物中有1只没有肿瘤。相比之下,BET抑制剂(+)-JQ1的25mg/kg腹膜内给药1X/天得到中等肿瘤生长抑制。在任一组中均未观察到动物死亡或对体重的显著影响(图3b)。
在SU-DHL-4异种移植小鼠模型中,50mg/kg和100mg/kg的化合物074和078以1X/周静脉内给药。如图4a所示,给药4周后,两种化合物的100mg/kg组均表现出显著的肿瘤生长抑制,其中化合物074和078的肿瘤相对于对照(T/C)值分别为41%和28%。相比之下,临床阶段BET抑制剂OTX-015的100mg/kg口服给药1X/天(Boi,Clin Cancer Res,2015,21:1628-38)表现出45%的T/C值。在任一剂量水平下均未观察到动物死亡或对体重的显著影响(图4b)。
为了检查T-PEACH分子的肿瘤选择性保留,在小鼠的MV4-11异种移植肿瘤模型中进行药代动力学和组织分布研究。5mg/kg的化合物074通过单次静脉内剂量给予,并在48hr内的不同时间点处死动物以评估该化合物在血浆、心脏、肝脏、肺和肿瘤组织中的药代动力学。如表9所示,尽管与在肿瘤中观察到的相比,化合物074在心脏、肝脏和肺中的初始浓度更高,但其在肿瘤中的32.10hr半衰期是血浆和其它器官中的4.6-9.5倍,证明了这种T-PEACH分子的肿瘤选择性保留。
表9:化合物074在小鼠的MV4-11异种移植模型中的药代动力学和分布
在不脱离本公开的范围和精神的情况下,本公开的所述方法和组合物的修改和变化对于本领域技术人员将是显而易见的。尽管已经结合具体实施方案描述了本公开,但是应当理解,所要求保护的公开内容不应过度地限于此类具体实施方案。实际上,本公开所属相关领域的技术人员预期和理解用于执行本公开的所述模式的各种修改落入由以下权利要求表示的本公开的范围内。
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Claims (31)
1.一种式I的化合物:
或其药学上可接受的盐,其中
X是C(O)或(C1-C4)亚烷基;
W是任选地被1至3个选自R2的基团取代的5或6元杂芳基;
V是任选地被1至3个选自R3的基团取代的苯基或5至9元杂芳基;
R1是卤代基、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基或卤代(C1-C4)烷氧基;
R2是(C1-C4)烷基、卤代(C1-C4)烷基、(C2-C6)烯基、卤代(C2-C6)烯基、(C2-C6)炔基、卤代(C2-C6)炔基、CN、-C1-4烷基ORa、-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-C(O)NRa(C1-4亚烷基)ORa、-C(O)NRa(C1-4亚烷基)NRaRb、-C(O)NRa(C1-4亚烷基)OR、-NRaRb、-O(C1-4亚烷基)NRaRb、-C1-4烷基NRaRb、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRaRb、-SO2NRaRb、-NRa(C1-4烷基)ORa、-NRa(C1-4烷基)NRaRb、-C1-6烷基C(O)NRaRb、苯基或5至7元杂芳基,其中所述苯基和5至7元杂芳基各自任选且独立地被1至3个选自R4的基团取代;
Ra和Rb各自独立地选自氢和(C1-C4)烷基,其中所述(C1-C4)烷基任选地被一个或多个卤代基或3至7元杂环基或两者取代;
R3和R4各自独立地为卤代基、-NRaRb、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基或卤代(C1-C4)烷氧基;并且
L是接头。
3.根据权利要求2所述的化合物,或其药学上可接受的盐,
其中Z是CH。
4.根据权利要求1至3中任一项所述的化合物,其中各R3独立地为(C1-C4)烷基或卤代基。
8.根据权利要求1至7中任一项所述的化合物,或其药学上可接受的盐,其中
L是*Het1-X1-、*Het1-X1-Het2-X2-、*Het1-X1-(C1-C4)亚烷基-Het2-X2-、*Het1-X1-Het2-X2(C1-C4)亚烷基-、*-(CH2CH2O)o-(CH2)p-Het1-X1-Het2-(CH2CH2O)n、*-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2、*Het1-X1-Phe-X2-NRc-X3-、*-(CH2CH2O)o-(CH2)p-Het1-X1-Phe-X2-NRc-(CH2CH2O)n-、*-(CH2CH2O)n-(CH2)m-NRc-Phe-X1-、*-(CH2CH2O)o-(CH2)p-NRc-Phe-(CH2CH2O)n-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-、*(CH2CH2O)n-(CH2)m-NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-(CH2CH2O)o、*NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2、*NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-(CH2CH2O)o、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-、*-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-(CH2CH2O)n-、*-(CH2CH2O)n-(CH2)m-NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p,或*NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2;
*表示与X的附接点;
Het1和Het2各自独立地为苯基、4至6元杂环基、5至7元杂芳基,或4至6元环烷基;
X1、X2和X3各自独立地为C(O)或(CH2)r;
Rc和Rd各自独立地为氢或(C1-C4)烷基;并且
m、n、o、p、q和r各自独立地为选自0、1、2、3、4、5和6的整数。
10.根据权利要求1至9中任一项所述的化合物,或其药学上可接受的盐,其中R1是卤代基或(C1-C4)烷基。
11.根据权利要求1至10中任一项所述的化合物,或其药学上可接受的盐,其中R1是氯、异丙基、甲基、丙基或乙基。
12.根据权利要求1至11中任一项所述的化合物,或其药学上可接受的盐,其中R1是异丙基或乙基。
13.根据权利要求1至12中任一项所述的化合物,或其药学上可接受的盐,其中R2是-ORa、-SRa、-C(O)NRaRb,或-C(O)NRa(C1-4亚烷基)NRaRb。
14.根据权利要求1至13中任一项所述的化合物,或其药学上可接受的盐,其中Ra和Rb各自独立地选自氢和(C1-C4)烷基,其中所述(C1-C4)烷基任选地被1至3个卤代基或6元杂环基取代。
15.根据权利要求1至14中任一项所述的化合物,或其药学上可接受的盐,其中R2是OH、SH、-C(O)NHCH2CF3、-C(O)NHCH2CH3、-C(O)NH(CH2)2N(CH2CH3)2、-C(O)NHCH(CH3)2、C(O)NH2、-C(O)NH(CH2)2哌啶基。
16.根据权利要求1至15中任一项所述的化合物,或其药学上可接受的盐,其中R2是-C(O)NHCH2CF3或OH。
18.根据权利要求8至17中任一项所述的化合物,或其药学上可接受的盐,其中Het1和Het2各自独立地为4至6元杂环基。
19.根据权利要求1至18中任一项所述的化合物,或其药学上可接受的盐,其中L是*Het1-X1-、*Het1-X1-Het2-X2-、*Het1-X1-Het2-(CH2CH2O)n-、*Het1-X1-Phe-X2-NRc-X3-、*Het1-X1-Phe-X2-NRc-(CH2CH2O)n-、*NRc-Phe-X1-、*NRc-Phe-(CH2CH2O)n-、*NRc-(CH2CH2O)n-(CH2)m-、*NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-、*NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-、*NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-、*NRc-(CH2CH2O)n-(CH2)m-Phe-X1-Het1-X2-、*NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-、*NRc-(CH2CH2O)n-(CH2)m-Het1-X1-、*NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p,或*NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2-。
20.根据权利要求1至19中任一项所述的化合物,或其药学上可接受的盐,其中L是*Het1-X1-(CH2)r、*Het1-X1-Het2-(CH2)r-、*Het1-(CH2)r-Phe-(CH2)r-NRc-(CH2)r-、*NRc-Phe-(CH2)r-、*NRc-(CH2CH2O)n-、*NRc-(CH2)m-、*NRc-(CH2)m-C(O)-NRd-(CH2)p-、*NRc-(CH2)m-C(O)-NRd-(CH2CH2O)o-、*NRc-(CH2)m-Het1-X1-Het2-(CH2)r-、*NRc-(CH2)m-Phe-(CH2)r-Het1-(CH2)r-、*NRc-Phe-NH-C(O)-Het1-(CH2)r-、*NRc-(CH2CH2O)n-(CH2)m-Phe-(CH2)r-NRc-(CH2)p-,或*NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-(CH2)r-。
21.根据权利要求8至20中任一项所述的化合物,或其药学上可接受的盐,其中m、n、o、p、q和r各自独立地为选自0、1、2和3的整数。
22.根据权利要求8至21中任一项所述的化合物,或其药学上可接受的盐,其中Het1和Het2各自独立地为哌啶基、哌嗪基、氮杂环丁烷基或吡咯烷基。
25.根据权利要求24所述的化合物,或其药学上可接受的盐,其中Ra是氢。
26.根据权利要求24或25所述的化合物,或其药学上可接受的盐,其中Rb是被1至3个卤代基取代的(C1-C4)烷基。
27.根据权利要求24至25中任一项所述的化合物,或其药学上可接受的盐,其中L是*Het1-(CH2)r-Het2-X2-或*Het1-(CH2)r-Phe-(CH2)r-NRc-(CH2)r。
28.根据权利要求24至26中任一项所述的化合物,或其药学上可接受的盐,其中每个r独立地为选自1和2的整数。
29.根据权利要求24至29中任一项所述的化合物,或其药学上可接受的盐,其中Het1和Het2各自独立地为哌啶基或哌嗪基。
30.一种药物组合物,其包含根据权利要求1至29中任一项所述的化合物,或其药学上可接受的盐;以及药学上可接受的载剂。
31.一种治疗癌症的方法,其包括向受试者施用治疗有效量的根据权利要求1至29中任一项所述的化合物,或其药学上可接受的盐,或根据权利要求30所述的组合物。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018051107A1 (en) * | 2016-09-14 | 2018-03-22 | University Of Dundee | Fluorohydroxyproline derivatives useful in the preparation of proteolysis targeted chimeras |
CN108084193A (zh) * | 2017-12-19 | 2018-05-29 | 郭守东 | 一种brd4蛋白抑制剂 |
CN108129484A (zh) * | 2017-12-19 | 2018-06-08 | 郭守东 | 杂芳环衍生物 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012075456A1 (en) * | 2010-12-02 | 2012-06-07 | Constellation Pharmaceuticals | Bromodomain inhibitors and uses thereof |
KR102204989B1 (ko) * | 2012-01-12 | 2021-01-20 | 예일 유니버시티 | E3 유비퀴틴 리가아제에 의한 표적 단백질 및 다른 폴리펩티드의 증진된 분해를 위한 화합물 및 방법 |
US20140079636A1 (en) * | 2012-04-16 | 2014-03-20 | Dinesh U. Chimmanamada | Targeted therapeutics |
US20160009725A1 (en) * | 2013-02-22 | 2016-01-14 | Bayer Pharma Aktiengesellschaft | Pyrrolo- and pyrazolo-triazolodiazepines as bet-protein inhibitors for treating hyperproliferative diseases |
EP2958923A1 (de) * | 2013-02-22 | 2015-12-30 | Bayer Pharma Aktiengesellschaft | 4-substituierte pyrrolo- und pyrazolo-diazepine |
WO2015038649A1 (en) * | 2013-09-10 | 2015-03-19 | Synta Pharmaceuticals Corp. | Targeted therapeutics |
WO2015143004A1 (en) * | 2014-03-18 | 2015-09-24 | Synta Pharmaceuticals Corp. | Targeted therapeutics |
US20170136085A1 (en) * | 2014-05-29 | 2017-05-18 | Synta Pharmaceuticals Corp. | Targeted therapeutics |
PL3458101T3 (pl) * | 2016-05-20 | 2021-05-31 | F. Hoffmann-La Roche Ag | Koniugaty PROTAC-przeciwciało i sposoby ich stosowania |
-
2019
- 2019-04-09 WO PCT/CN2019/081919 patent/WO2020206608A1/en active Application Filing
-
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- 2020-04-08 CN CN202080043111.4A patent/CN113939516A/zh active Pending
- 2020-04-08 EP EP20786761.5A patent/EP3952914A4/en not_active Withdrawn
- 2020-04-08 JP JP2021560608A patent/JP2022528767A/ja active Pending
- 2020-04-08 KR KR1020217036443A patent/KR20220007055A/ko unknown
- 2020-04-08 US US17/602,345 patent/US20220162228A1/en active Pending
- 2020-04-08 WO PCT/CN2020/083648 patent/WO2020207396A1/en unknown
- 2020-04-08 EP EP20787651.7A patent/EP3953359A4/en active Pending
- 2020-04-08 BR BR112021020285A patent/BR112021020285A2/pt unknown
- 2020-04-08 CA CA3136372A patent/CA3136372A1/en active Pending
- 2020-04-08 MX MX2021012423A patent/MX2021012423A/es unknown
- 2020-04-08 WO PCT/CN2020/083647 patent/WO2020207395A1/en unknown
- 2020-04-08 SG SG11202111193UA patent/SG11202111193UA/en unknown
- 2020-04-08 CN CN202080042019.6A patent/CN113924123A/zh active Pending
- 2020-04-08 AU AU2020256600A patent/AU2020256600A1/en not_active Abandoned
- 2020-04-08 US US17/602,335 patent/US20220168427A1/en active Pending
- 2020-04-08 AU AU2020256814A patent/AU2020256814A1/en active Pending
-
2021
- 2021-10-07 IL IL287082A patent/IL287082A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018051107A1 (en) * | 2016-09-14 | 2018-03-22 | University Of Dundee | Fluorohydroxyproline derivatives useful in the preparation of proteolysis targeted chimeras |
CN108084193A (zh) * | 2017-12-19 | 2018-05-29 | 郭守东 | 一种brd4蛋白抑制剂 |
CN108129484A (zh) * | 2017-12-19 | 2018-06-08 | 郭守东 | 杂芳环衍生物 |
Non-Patent Citations (1)
Title |
---|
IAN COLLINS等: "Chemical approaches to targeted protein degradation through modulation of the ubiquitin–proteasome pathway", BIOCHEMICAL JOURNAL, vol. 474, no. 7, pages 1127, XP055531205, DOI: 10.1042/BCJ20160762 * |
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MX2021012423A (es) | 2022-01-19 |
KR20220007055A (ko) | 2022-01-18 |
SG11202111193UA (en) | 2021-11-29 |
EP3953359A4 (en) | 2023-07-19 |
JP2022528767A (ja) | 2022-06-15 |
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