CN116615429A - 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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- CN116615429A CN116615429A CN202180084042.6A CN202180084042A CN116615429A CN 116615429 A CN116615429 A CN 116615429A CN 202180084042 A CN202180084042 A CN 202180084042A CN 116615429 A CN116615429 A CN 116615429A
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本文提供了式I的化合物及其药学上可接受的盐和组合物,它们可用于治疗癌症和相关病症。
Description
相关申请
本申请要求于2020年10月14日提交的PCT/CN2020/120911的优先权权益,其全部内容以引用方式并入本文。
背景技术
蛋白质稳态(Protein homeostasis或proteostasis)是指细胞调节蛋白质合成、折叠、运输和降解的能力。特别地,经适当调节的蛋白质降解是细胞正常功能所必需的,包括它们的增殖、分化和死亡,并且在癌症和其他疾病中经常失调(Van Die,Chin J Cancer,2011年,第30卷:第124-137页)。
泛素-蛋白酶体系统(UPS)是细胞中介导蛋白质处理和代谢循环的主要途径之一(Yu和Matouschek,Annu Rev Biophys,2017年,第46卷:第149-173页;Navon和Ciechanover,J Biol Chem,2009年,第284卷:第33713-33718页)。泛素是广泛表达的具有76个氨基酸残基的蛋白质。关于UPS对蛋白质的降解,当泛素连接到底物蛋白质中的赖氨酸氨基酸残基时,会发生泛素化,这涉及一系列酶促步骤。首先,将泛素转移到E1泛素活化酶。然后,将活化的泛素从E1转移到E2泛素缀合酶。第三步,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质中的赖氨酸残基。这种酶促过程重复进行,使得底物蛋白质被多聚泛素链标记。然后可将此类泛素标记的蛋白质递送到蛋白酶体,蛋白酶体是一种降解蛋白质的大型多亚基复合物。一些细胞伴侣蛋白和伴侣蛋白复合物将蛋白质导向UPS的能力通过它们与E3泛素连接酶的直接相互作用而得到促进(Amm等人,Biochim BiophysActa,2014年,第1843卷:第182-196页;Taipale等人,Cell,2012年,第150卷:第987-1001页)。除了蛋白质降解外,蛋白质的泛素化还可调节其他过程,诸如亚细胞定位、活性和蛋白质-蛋白质相互作用。
化学诱导的靶向蛋白降解(TPD)已成为小分子药物开发的新模式。小分子可用于促进一种或多种靶蛋白与多种细胞蛋白质降解途径中的一种或多种组分的相互作用,从而诱导一种或多种靶蛋白的降解,作为治疗疾病的方式。
特别地,蛋白水解靶向嵌合体(PROTAC)是此类小分子的示例,其通过吸收UPS来故意诱导特定蛋白质的蛋白质降解(Burslem和Crews,Cell,2020年,第181卷:第102-114页;Pettersson和Crews,Drug Discov Today Technol,2019年,第31卷:第15-27页)。PROTAC分子是双功能小分子,其同时结合一种或多种靶蛋白和E3泛素连接酶,从而在细胞中在靶蛋白、PROTAC分子和E3连接酶蛋白之间形成三元复合物。靶蛋白和E3连接酶的诱导接近导致靶蛋白的泛素化,以及随后蛋白酶体对靶蛋白的降解。尽管掺有与多种蛋白质混杂结合的靶蛋白结合剂的PROTAC通常可降解多种蛋白质,但在一些情况下,单个靶标和E3连接酶之间的蛋白质-蛋白质相互作用可增加或减少所观察到的降解效力和选择性,例如通过抑制由于给定靶蛋白和E3连接酶对之间的电荷排斥和空间碰撞而导致的一些三元复合物的形成(Pettersson和Crews,Drug Discov Today Technol,2019年,第31卷:第15-27页;Bondeson等人,Cell Chem Biol,2018年,第25卷:第78-87页;Gadd等人,Nat Chem Biol,2017年,第13卷:第514-521页;Zengerle等人,ACS Chem Biol,2015年,第10卷:第1770-1777页)。
还描述了其他化学诱导TPD的方法,诸如分子胶(Che等人,Bioog Med Chem Lett,2018年,第28卷:第2585-2592页)、AUTAC、ATTEC和LYTAC(Ding等人,Trends PharmacolSci,2020年,第41卷:第464-474页)。例如,AUTAC技术遵循类似的诱导接近原则,但靶向蛋白经由自噬进行降解(Daiki等人,Mol Cell,2019年,第76卷:第797-810页)。
总的来说,TPD技术与常规生化抑制剂相比具有许多优势(Pettersson和Crews,Drug Discov Today Technol,2019年,第31卷:第15-27页;Ding等人,Trends PharmacolSci,2020年,第41卷:第464-474页)。例如,与常规抑制剂不同,TPD试剂以亚化学计量方式起作用,并且通常可介导靶蛋白的多个分子的顺序降解,通常导致比它们掺入的经分离的靶结合部分和其他生化抑制剂更强的效力。此外,由于TPD试剂对靶蛋白功能的抑制主要是由于降解而不是单纯的生化抑制,因此靶蛋白功能的恢复通常比生化抑制剂观察到的要慢。与生化抑制剂相比,TPD试剂还可能具有改善的靶标选择性。最后,TPD试剂可通过与不影响靶标的生物化学活性但仍允许该靶标降解的结合口袋进行相互作用来靶向不受生物化学抑制影响的蛋白质。
然而,一些缺点与当前的TPD技术相关联。这些缺点包括靶蛋白在许多组织和器官中的混杂降解,而不仅仅是靶蛋白参与疾病过程的组织和器官,这预计会导致治疗的不良副作用。此外,对这些技术的抗性可通过UPS组分(诸如E3连接酶)表达的突变或改变而发展(Ottis等人,ACS Chem Biol,2019年,第14卷:第2215-2223页;Zhang等人,Mol CancerTher,2019年,第18卷:第1302-1311页),从而导致疗效丧失。因此,存在对用于TPD的改进/替代方法和组合物的需求。
还期望开发介导与癌症和其他疾病有关的蛋白质降解的改进/替代的TPD试剂。丝裂原激活蛋白质激酶(MAPK)调节细胞功能的许多不同方面,包括癌细胞的生长、存活和死亡。特别地,MEK5信号传导通路的一种组分MAPK7(也称为ERK5)被认为在多种不同类型的癌症中起重要作用(Hoang等人,Cancer Lett,2017年,第392卷:第51-59页;Stecca和Rovida,Int J Mol Sci,2019年,第20卷:第1426页;Pereira和Rodrigues,Trends Mol Med,2020年,第26卷:第394-407页;Tubita等人,Int J Mol Sci,2020年,第21卷:第938页)。例如,在三阴性乳腺癌(TNBC)中,高MAPK7表达与不良预后之间存在相关性(Ortiz-Ruiz等人,Oncotarget,2014年,第5卷:第11308-11318页)。同样,在前列腺癌中,强核MAPK7定位是差疾病特异性存活率的独立预后因素(McCracken等人,Oncogene,2008年,第27卷:第2978-2988页)。重要的是,MAPK7的许多功能不受选择性MAPK7生化抑制剂的影响,因此需要TPD方法来阻断其在癌细胞中的功能(Lin等人,Proc Natl Acad Sci USA,2016年,第113卷:第11865-11870页)。因此,MAPK7代表了有吸引力的药物靶标,并希望开发诱导MAPK7的TPD的药剂。
发明内容
本公开提供了靶向肿瘤的蛋白质降解嵌合体,称为伴侣介导的蛋白质降解物(CHAMP),该降解物包含第一部分和第二部分,该第一部分能够与一种或多种靶蛋白(例如,MAPK7)结合,该第二部分能够结合一种或多种伴侣蛋白或者伴侣复合物的蛋白质组分(例如,HSP90)。此类CHAMP化合物包括具有式I的化合物:
及其药学上可接受的盐,其中W、D、L、A、R10、R12、R16、R17、R18、R19、k和v如本文所定义。
还提供了包含所公开的式I化合物的组合物及其制造方法。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质降解,并且可用于治疗癌症和相关病症。
具体实施方式
1.化合物的一般描述
本文提供了具有式I的CHAMP化合物:
或其药学上可接受的盐,其中,
A是结合HSP90蛋白质的化学部分;
L是接头;
W和D各自独立地为N或CR9;
R10、R16和R19各自独立地选自卤代基、(C1-C6)烷基、(C2-C6)烯基、卤代(C2-C6)烯基、(C2-C6)炔基、-(C1-C6)烷基ORc、-(C1-C6)烷基N(Rd)2、-(C1-C6)烷基C(O)ORd、-(C1-C6)烷基C(O)N(Rd)2、-(C1-C6)烷基O(C1-C6)烷基N(Rd)2、-(C1-C6)烷基SORd、-(C1-C6)烷基S(O)2Rd、-(C1-C6)烷基SON(Rd)2、-(C1-C6)烷基SO2N(Rd)2、-(C1-C6)烷基环烷基、-(C1-C6)烷基杂环基、-(C1-C6)烷基杂芳基、-(C1-C6)烷基芳基、-(C1-C6)烷氧基、卤代(C1-C6)烷氧基、CN、芳基、杂芳基、环烷基、杂环烷基、-C(O)Rd、-C(O)ORd、-C(O)N(Rd)2、N(Rd)2、-C(O)NRd(C1-C6)烷基N(Rd)2、-NRd(C1-C6)烷基N(Rd)2、-NRd(C1-C6)烷基ORd、-SORd、-S(O)2Rd、-SON(Rd)2、-SO2N(Rd)2和CN,其中每个芳基、环烷基、杂环基和杂芳基单独以及与-(C1-C6)烷基环烷基、-(C1-C6)烷基杂环基、-(C1-C6)烷基杂芳基、-(C1-C6)烷基芳基一起任选地被1至3个选自Re的基团取代;
M为O、S或NR11;
R11、R17、R18和R20各自独立地选自氢、(C1-C6)烷基和S(O)2(C1-C6)烷基(另选地,R17或R18各自独立地选自氢、(C1-C6)烷基、C3-C6环烷基和S(O)2(C1-C6)烷基);
R12为氢、(C1-C6)烷基、卤代(C1-C6)烷基、-(C1-C6)烷基ORc、S(O)2(C1-C6)烷基、芳基、杂芳基、环烷基、杂环烷基、C(O)(C1-C6)烷基或-(C1-C6)烷基芳基,其中每个芳基、环烷基、杂环基和杂芳基单独以及与-(C1-C6)烷基芳基一起任选地被1至3个选自Re的基团取代;
Rc和Rd各自独立地选自氢、(C1-C6)烷基和卤代(C1-C6)烷基;
Re选自卤代基、氧代、CN、NO2、-N(Rd)2、-ORd、-C(O)ORd、(C1-C6)烷基、-(C1-C6)烷基ORc、卤代(C1-C6)烷基、(C1-C6)烷氧基、卤代(C1-C6)烷氧基、-(C1-C6)烷基C(O)ORd、-(C1-C6)烷基C(O)N(Rd)2、(C2-C6)烯基、卤代(C2-C6)烯基、(C2-C6)炔基、-(C1-C6)烷基SRd、-(C1-C6)烷基ORc、-(C1-C6)烷基N(Rd)2、-C(O)N(Rd)2、-C(O)NRdC1-6烷基N(Rd)2、-NRdC1-6烷基N(Rd)2、-NRdC1-6烷基ORd、-SORd、-S(O)2Rd、-SON(Rd)2、-SO2N(Rd)2、芳基、杂芳基、环烷基和杂环烷基;并且
k和v各自独立地为0、1、2或3。
2.定义
如本文所用,冠词“a”和“an”指冠词的语法对象中的一个或多个,例如至少一个。当与本文的术语“包括”结合使用时,词语“一个”或“一种”的使用可表示“一个(种)”,但是它也与“一个(种)或多个(种)”、“至少一个(种)”和“一个(种)或一个(种)以上”的含义一致。
如本文所用,“约”和“大约”通常表示在给定测量的性质或精确度的情况下,所测量的量的可接受误差程度。示例性误差程度在给定值范围的百分之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”用于指代存在于给定实施方案中的组合物、方法及其相应组分,但还可包含未指定要素。
如本文所用,术语“基本上由……组成”是指给定实施方案所需的那些元素。该术语允许存在在实质上不影响本公开的该实施方案的基本和新颖或功能特征的附加元素。
术语“由……组成”是指如本文所述的组合物、方法及其相应组分,其不包括在实施方案的描述中未列举的任何要素。
如本文所用,除非另有说明,否则术语“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。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;而饱和的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,除非另有说明,否则术语“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。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,除非另有说明,否则术语“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。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“环烷基”是指具有例如3至10个碳原子(例如4至6个碳原子)的饱和单环烷基基团。代表性的环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基和环癸基。
术语“氧代”是指基团=O。
如本文所用,术语“卤代烷基”是指其中一个或多个(包括所有)氢基团被卤代基团取代的烷基基团,其中每个卤代基团独立地选自-F、-Cl、-Br和-I。代表性的卤代烷基基团包括三氟甲基、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”是经由氧接头连接到另一部分的烷基基团。
如本文所用,“卤代烷氧基”是经由氧接头连接到另一部分的卤代烷基基团。
如本文所用,术语“亚烷基”是指具有两个连接点的烷基基团。直链亚烷基基团是优选的。亚烷基基团的非限制性示例包括亚甲基乙烯、正丙烯、异丙烯等。亚烷基基团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,该单环杂环环系为饱和环或不饱和非芳族环,该单环杂环环系包含在大小和化合价允许的情况下最多5个独立地选自氮、氧和硫的杂原子。杂环可经由任何杂原子或碳原子连接。代表性的杂环包括吗啉基、硫代吗啉基、吡咯烷酮基、吡咯烷基、哌啶基、哌嗪基、环氧乙烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢嘧啶基等。
如本文所用,术语“杂芳基”在定义的大小允许的情况下是指包含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环。代表性的杂芳基基团包括吡啶基、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、咪唑吡啶基、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、苯并噻吩基等。杂芳环(heteroaromatic或heteroaryl ring)与另一基团的连接点可位于杂芳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。
当杂环基或杂芳基基团含有氮原子时,它可在化合价允许的情况下被取代或未被取代。
可互换使用的术语“接头”或“系链”是指连接两个其他部分(例如,第一结合部分和第二结合部分)的化学部分。接头可共价连接第一结合部分和第二结合部分。在一个方面,接头在体内是不可切割的。在一个方面,接头包含一个或多个环状环系。在另一个方面,接头包含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,接头包括实现最佳治疗活性的最佳空间和化学性质。在一个方面,接头不干扰第一结合部分和/或第二结合部分结合它们相应的靶标(例如,HSP90和MAPK7)的能力。在一个方面,接头改变第一结合部分和/或第二结合部分结合它们相应的靶标(例如,HSP90和MAPK7)的能力。
术语“MAPK7”是指丝裂原活化蛋白激酶7基因的蛋白质产物,也称为细胞外信号调节激酶5或ERK5基因。
术语“HSP90”是指热休克蛋白90(90kDa)基因家族成员的蛋白质产物的统称,单独或各种组合,包括:HSP90AA1(HSP90-α或HSP90α)、HSP90AB1(HSP90-β或HSP90β)、HSP90B1(GRP94)和TRAP1。
当用于描述可能具有多个连接点的化学基团时,连字符(-)指定该基团与其定义的变量的连接点。例如,-NRaRb和-C(O)NRa(C1-4亚烷基)NRaR表示这些基团的连接点分别出现在氮原子和碳原子上。
中的哈希键表示所描述的基团连接到所定义的变量的点。
当通过结构来命名或描述所公开的化合物的立体化学时,相对于所有其他立体异构体,所命名或描述的立体异构体至少为60%、70%、80%、90%、99%或99.9%(按重量计)纯。相对于所有其他立体异构体的重量百分比纯是一种立体异构体的重量与其他立体异构体的重量之比。例如,当通过结构来命名或描绘单一对映异构体时,所描绘或命名的对映异构体是至少60%、70%、80%、90%、99%或99.9%(按重量计)光学纯。重量百分比光学纯是对映异构体的重量与对映异构体的重量加上其光学异构体的重量之比。
对于药物用途,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。本文所述的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)的盐和有机酸(诸如乙酸、苯磺酸、苯甲酸、甲磺酸和对甲苯磺酸)的盐。本教导内容的具有酸性基团(诸如羧酸)的化合物可与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性盐包括例如铵盐、碱金属盐(诸如钠盐和钾盐)和碱土金属盐(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,诸如氯离子、溴离子、碘离子、乙酸根、高氯酸根等。此类盐的其他示例包括盐酸盐、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形成的盐。
术语“药学上可接受的载体”是指不破坏与其一起配制的化合物的药理活性的无毒载体、佐剂或媒介物。可用于本文所述的组合物的药学上可接受的载体、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、血清蛋白诸如人血清白蛋白、缓冲物质诸如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质,诸如硫酸鱼精蛋白、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、聚乙烯-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与本文提供的其他组合物和方法中的任何一者或多者组合。
如本文所用,术语“受试者”是指人和非人动物,包括兽医受试者。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、绵羊、狗、猫、马、牛、鸡、两栖动物和爬行动物。在优选实施方案中,受试者是人并且可称为患者。
如本文所用,术语“治疗(treat、treating或treatment)”优选地指获得有益的或期望的临床结果的行为,包括但不限于减轻或改善疾病或病症的一种或多种体征或症状、缩小疾病的范围、稳定疾病的状态(即不恶化)、改善或缓解疾病的状态、降低进展速度或延缓进展时间以及缓解(无论是部分还是全部,无论可检测还是不可检测)。“治疗”还可指与不存在治疗的情况下的预期生存相比,延长生存。治疗不一定是治愈。
“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0.01mg/kg体重/天至约100mg/kg体重/天的剂量。
术语“施用(administer、administering或administration)”包括将药物组合物或药剂递送到受试者的全身或递送到受试者体内或体表的特定区域中的任何方法。在本发明的某些实施方案中,药剂通过静脉内、肌内、皮下、皮内、鼻内、口服、经皮或粘膜施用。在一个优选的实施方案中,药剂通过静脉内施用。在另一个优选的实施方案中,药剂通过口服施用。施用药剂可由许多协同工作的人来执行。施用药剂包括,例如,直接或通过他人开具待施用于受试者的药剂的处方和/或提供服用特定药剂的说明书,通过自我递送,例如通过口服递送、皮下递送、通过中心线等静脉内递送;或由受过训练的专业人员递送,例如静脉内递送、肌内递送、瘤内递送等。
3.化合物
在第一实施方案中,提供了式I的化合物:
或其药学上可接受的盐,其中变量如上所述。
在第二实施方案中,A选自
其中
Q和U各自独立地选自苯基、杂芳基、杂环基和环烷基,它们中的每一者任选地被1至3个选自R2的基团取代;
R13和R14各自独立地选自氢、卤代基、-CN、(C1-C4)烷基、卤代(C1-C4)烷基和-C(O)NRaRb;
R15为氢、(C1-C4)烷基或卤代(C1-C4)烷基;
W为任选地被1至3个选自R2的基团取代的5或6元杂芳基;
V为苯基或任选地被1至3个选自R3的基团取代的5至9元杂芳基;
R1为卤代基、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基或卤代(C1-C4)烷氧基;
R2为(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、-SH、-S(C1-4烷基)、-NRa(C1-4烷基)NRaRb、-C1-6烷基C(O)NRaRb、-O(C1-4亚烯基)NRaC(O)(C1-4亚烷基)NRaRb、苯基或5至7元杂芳基,其中所述苯基和5至7元杂芳基各自任选地且独立地被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元杂环基取代,或两者(另选地,3至7元杂环基可任选地被例如1至3个选自卤代基、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和–OSO2(C1-C3)烷基的基团取代);并且
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,其中剩余的变量如针对式I所述。另选地,作为第二实施方案的一部分,A选自
其中
Q和U各自独立地选自苯基、杂芳基、杂环基和环烷基,它们中的每一者任选地被1至3个选自R2的基团取代;
R13和R14各自独立地选自氢、卤代基、-CN、(C1-C4)烷基、卤代(C1-C4)烷基和-C(O)NRaRb;
R15为氢、(C1-C4)烷基或卤代(C1-C4)烷基;
W为任选地被1至3个选自R2的基团取代的5或6元杂芳基;
V为苯基或任选地被1至3个选自R3的基团取代的5至9元杂芳基;
R1为卤代基、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基或卤代(C1-C4)烷氧基;
R2为(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、-SH、-S(C1-4烷基)、-NRa(C1-4烷基)NRaRb、-C1-6烷基C(O)NRaRb、-O(C1-4亚烯基)NRaC(O)(C1-4亚烷基)NRaRb、苯基或5至7元杂芳基,其中所述苯基和5至7元杂芳基各自任选地且独立地被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元杂环基取代,或两者(另选地,3至7元杂环基可任选地被例如1至3个选自卤代基、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和–OSO2(C1-C3)烷基的基团取代);并且
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,其中剩余的变量如针对式I所述。
在另一个另选方案中,作为第二实施方案的一部分,A是其中剩余的变量如上针对式I所述。在另一个另选方案中,A是/>其中其余变量如上针对式I所述。
在第三实施方案中,式I的化合物具有式:
或其药学上可接受的盐,其中变量如针对式I或第二实施方案所述。
在第四实施方案中,式I的化合物具有式:
或其药学上可接受的盐,其中变量如针对式I或第二实施方案所述。
在第五实施方案中,k为0,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案或第四实施方案所述。
在第六实施方案中,v为0,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案或第五实施方案所述。
在第七实施方案中,R11为氢,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案或第六实施方案所述。
在第八实施方案中,R17为(C1-C6)烷基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案或第七实施方案所述。另选地,作为第八实施方案的一部分,R17为甲基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案或第七实施方案所述。
在第九实施方案中,R12为(C1-C6)烷基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案或第八实施方案所述。另选地,作为第九实施方案的一部分,R12为乙基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案或第八实施方案所述。
在第十实施方案中,R18为(C1-C3)烷基或S(O)2(C1-C3)烷基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案或第九实施方案所述。另选地,作为第十实施方案的一部分,R18为S(O)2Me,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案或第九实施方案所述。
在第十一实施方案中,A选自/> 并且Z为N或CH,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案或第十实施方案所述。另选地,作为第十一实施方案的一部分,A选自以上结构并且Z为CH,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案或第十实施方案所述。
在第十二实施方案中,R3为(C1-C4)烷基或卤代基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案或第十一实施方案所述。
在第十三实施方案中,A选自/> 其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案或第十二实施方案所述。另选地,作为第十三实施方案的一部分,A选自 其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案或第十二实施方案所述。在另一个另选方案中,作为第十三实施方案的一部分,A选自/>其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案或第十二实施方案所述。在另一个另选方案中,作为第十三实施方案的一部分,A为/>其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案或第十二实施方案所述。
在第十四实施方案中,R1为卤代基或(C1-C4)烷基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案或第十三实施方案所述。另选地,作为第十四实施方案的一部分,R1为氯、异丙基、甲基、丙基或乙基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案或第十三实施方案所述。在另一个另选方案中,作为第十四实施方案的一部分,R1为异丙基基或乙基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案或第十三实施方案所述。
在第十五实施方案中,R2为-ORa、-SRa、-C(O)NRaRb或-C(O)NRa(C1-4亚烷基)NRaRb,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案或第十四实施方案所述。
在第十六实施方案中,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,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案或第十五实施方案所述。
在第十七实施方案中,R2为OH、-C(O)NHCH2CF3、-C(O)NHCH2CH3、-C(O)NHCH(CH3)2、-C(O)NH(CH2CH3)2、-C(O)NHCH(CH3)CF3、-C(O)NH环丙基、-C(O)NH甲基环丙基、C(O)NH2或-C(O)NH(CH2)2哌啶基,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案或第十六实施方案所述。另选地,作为第十七实施方案的一部分,R2为-C(O)NHCH2CF3或OH,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案或第十六实施方案所述。在另一个另选方案中,作为第十七实施方案的一部分,R2为OH,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案或第十六实施方案所述。
在第十八实施方案中,L选自-Het1-X1-、-Het1-、-Het1-Het2-X1-、-Het1-Het2-、-NRd-(CH2)m-X3-NRc-(CH2)m-Het1-X1-Het2-X2-、-NRc-(CH2)m-Het1-X1-Het2-X2-、-Het1-X1-Het2-X2-、O-(CH2)m-NRc-X1-(CH2)m-NRd-、-X1-NRc-X2-O-(CH2)m-NRd-、-X1-Het1-X2-Het2-(CH2)mO-、O-Het1-、O-Het1-X1-、-X1(OCH2CH2)n-NRc-、-(CH2)mNRc-、-(CH2)m-、-O-、X1NRc-、-NRc-(CH2)m-X1-Het1-X2-、-NRd-(CH2)m-X3-NRc-(CH2)m-Het1-X1-Het2-X2-、O-Het1-X1-(CH2)m-NRd-、-X1-NRc-X2-(CH2)m-NRd-、X1-Het1-X2-NRc-X3-Het2-(OCH2CH2)n-(CH2)m-NRd-(CH2)m-、-NRd-(CH2)m-X1-NRc-(CH2CH2O)n-、-NRc-(CH2)m-X1-NRc-(CH2)p-、X1-Het1-X2-NRc-X3-Het2-(OCH2CH2)n-NRd-(CH2)m-、-NRc-(CH2)m-X1-Het1-X2-Het2-X3-、O-X1-Het1-、-O(CH2)m-X1-Het1-X2-Het2-X3-、-O(CH2)m-X1-NRc-(CH2)p-Het1-X2-Het2-X3-、O-(CH2)m-NRc-、O-X1-Het1-X2-、-X1-NRc-(CH2)m-Het1-X2-Het2-X3-(CH2)p-NRd-(CH2)p-、-NRc-(CH2)m-X1-(CH)CH3-Het1-X2-Het3-X3-、-NRc-(CH2)m-X1-(CH2)p-Het1-X2-Het2-X3-、-NRc-(CH2)m-X1-NRd-(CH2)p-Het1-X2-Het2-X3-、-NRc-(CH2)m-NRd-X1-Het1-X2-、Het1-X1-Het2-X2-、-Het1-X1-Het2-X2-O-、-O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-、-O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-、-Het1-O-(CH2)m-X1-Het2-X2-、-Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-、-Het1-X1-NRc-(CH2)m-、-Het1-X1-Het2-Het3-X2-、-Het1-X1-NRc-(CH2CH2O)n(CH2)m-、-Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2-、-Het1-X1-NRc-(CH2CH2O)n-、-Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-、-Het1-X1-Het2-(CH2)m-Het3-X2-、-Het1-X1-Het2-、-Het1-X1-NRc-、-Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-、-Het1-X1-Het2-Het3-、-Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-、-Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-、-Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-、-Het1-X1-Het2-(CH2CH2O)n-、-Het1-X1-(CH2)m-Het2-X2-、-(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-、C(O)O-X1-Het1-(CH2CH2O)o-(CH2)m-NRc-、-Het1-(CH2)m-Het2-、-Het1-X1-Het2-(CH2)p-O-(CH2)m-、O(CH2)mC(O)、-OC(O)-NRc-(CH2)m-NRd-、-OC(O)-NRc-(CH2)m-O-(CH2)m-NRd-、OC(O)Het1、-OC(O)-NRc-(CH2CH2O)o-NRd-、OC(O)Het1-Het2-、-OC(O)-NRc-(CH2)mC(O)-Het1-X1-Het2-、O-(CH2)m-Het1-和O-(CH2)m-Het1-X1-Het2;
Het1、Het2和Het3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,它们中的每一者任选地被(C1-C4)烷基取代;
X1、X2和X3各自独立地为C(O)或(CH2)r;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,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案或第十七实施方案所述。另选地,作为第十八实施方案的一部分,L选自Het1-X1-、Het1-X1-Het2-X2-、Het1-O-(CH2)m-X1-Het2-X2-、Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-、Het1-X1-NRc-(CH2)m-、Het1-X1-Het2-Het3-X2-、Het1-X1-NRc-(CH2CH2O)n(CH2)m-、Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2、Het1-X1-NRc-(CH2CH2O)n-、Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-、Het1-X1-Het2-(CH2)m-Het3-X2-、Het1-X1-Het2-、Het1-X1-NRc-、Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-、Het1-X1-Het2-Het3-、Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-、Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-、Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-、Het1-X1-Het2-(CH2CH2O)n-、Het1-X1-(CH2)m-Het2-X2-、-(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和NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案或第十七实施方案所述。另选地,作为第十八实施方案的一部分,L为Het1-X1-*、Het1-X1-Het2-X2-*、Het1-O-(CH2)m-X1-Het2-X2-*、Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-*、Het1-X1-NRc-(CH2)m-*、Het1-X1-Het2-Het3-X2-*、Het1-X1-NRc-(CH2CH2O)n(CH2)m-*、Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2*、Het1-X1-NRc-(CH2CH2O)n-*、Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-X2-*、Het1-X1-Het2-*、Het1-X1-NRc-*、Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-*、Het1-X1-Het2-Het3-*、Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-*、Het1-X1-Het2-(CH2CH2O)n-*、Het1-X1-(CH2)m-Het2-X2-*、-(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*,其中*指示与A的连接点并且其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案或第十七实施方案所述。另选地,作为第十八实施方案的一部分,Het1Het2和Het3各自独立地为苯基、7至9元杂环基、5至7元杂芳基或4至6元环烷基,它们中的每一者任选地被(C1-C4)烷基取代,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案或第十七实施方案所述。
在第十九实施方案中,L为Het1-X1-Het2-X2-*、Het1-O-(CH2)m-X1-Het2-X2-*、Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-*、Het1-X1-NRc-(CH2)m-*、Het1-X1-Het2-Het3-X2-*、Het1-X1-NRc-(CH2CH2O)n(CH2)m-*、Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2*、Het1-X1-NRc-(CH2CH2O)n-*、Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-X2-*、Het1-X1-Het2-*、Het1-X1-NRc-*、Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-*、Het1-X1-Het2-Het3-*、Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-*或Het1-X1-Het2-(CH2CH2O)n-*,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案、第十七实施方案或第十八实施方案所述。另选地,作为第十九实施方案的一部分,L为Het1-X1-Het2-X2-*、Het1-X1-NRc-(CH2)m-*、Het1-X1-Het2-Het3-X2-*或Het1-X1-Het2-(CH2)m-Het3-X2-*,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案、第十七实施方案或第十八实施方案所述。在另一个另选方案中,作为第十九实施方案的一部分,L为Het1-X1-NRc-(CH2)m-*或Het1-X1-Het2-(CH2)m-Het3-X2-*,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案、第十七实施方案或第十八实施方案所述。在又一个另选方案中,作为第十九实施方案的一部分,L为Het1-X1-Het2-(CH2)m-Het3-X2-*,其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案、第十七实施方案或第十八实施方案所述。
在第二十实施方案中,如本文所述(例如,如在第十八实施方案或第十九实施方案中)的Het1和Het2各自独立地为苯基或4至6元杂环基。另选地,作为第二十实施方案的一部分,如本文所述(例如,如在第十八实施方案或第十九实施方案中)的Het1和Het2各自独立地为哌啶基、苯基、吡啶基、哌嗪基或吡咯烷基。
在第二十一实施方案中,如本文所述(例如,如在第十八实施方案或第十九实施方案中,或如应用于第二十实施方案)的m、n、o、p、q和r各自独立地为选自0、1、2和3的整数。
在第二十二实施方案中,L选自
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其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案、第十七实施方案、第十八实施方案、第十九实施方案、第二十实施方案或第二十一实施方案所述。另选地,作为第二十二实施方案的一部分,L选自
/> 其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案、第十七实施方案、第十八实施方案、第十九实施方案、第二十实施方案或第二十一实施方案所述。另选地,作为第二十二实施方案的一部分,L选自/> 其中其余变量如上针对式I或第一实施方案、第二实施方案、第三实施方案、第四实施方案、第五实施方案、第六实施方案、第七实施方案、第八实施方案、第九实施方案、第十实施方案、第十一实施方案、第十二实施方案、第十三实施方案、第十四实施方案、第十五实施方案、第十六实施方案、第十七实施方案、第十八实施方案、第十九实施方案、第二十实施方案或第二十一实施方案所述。
具体化合物在下面的范例部分中提供并且作为本发明的一部分包括在内。这些化合物的盐和游离碱也包括在内。
4.用途、配方和施用
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靶向肿瘤的伴侣介导的蛋白质降解物(CHAMP),其中化合物的一部分负责结合MAPK7,而另一部分负责结合至HSP90或其他伴侣蛋白或伴侣复合物的蛋白质组分(例如,HSP70家族的成员)。它们的作用机制包括但不限于降解MAPK7和/或丝裂原激活蛋白质激酶(MAPK)蛋白质家族的其他相关成员,从而阻止可能导致抑制癌细胞生长和/或诱导癌细胞死亡或其他MAPK7或MAPK功能的下游信号。在一个方面,所公开的化合物实现MAPK7的降解。
在一个方面,所公开的化合物和组合物包括具有一系列不同结合亲和力的伴侣或伴侣复合物结合剂。在不同的实施方案中,期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末端ATP结合口袋相互作用的HSP90结合部分可能会抑制HSP90活性并诱导HSP90客户蛋白的降解(Schopf等人,Nat Rev Mol Cell Biol,2017年,第18卷:第345-360页),一些CHAMP分子可能不仅诱导所期望的一种或多种靶蛋白(其可能是也可能不是HSP90客户蛋白)的降解,而且同时诱导HSP90客户蛋白的降解。EGFR和ERBB2(HER2)是两种这样的HSP90客户蛋白(Xu等人,J Biol Chem,2001年,第276卷:第3702-3708页)。相比于针对相同靶标的其他TPD技术,这种降解活性的组合可能会增加CHAMP分子的生物活性,并可能逃避对MAPK7抑制剂和降解剂的抗性机制,诸如由HSP90客户蛋白介导的机制。
在一个方面,所公开的化合物和组合物表现为靶向肿瘤的CHAMP,其中化合物的一部分负责结合MAPK7,而另一部分负责结合至HSP90或其他伴侣蛋白或伴侣复合物的蛋白质组分(例如,HSP70家族的成员)。在一个方面,所公开的化合物和组合物在癌细胞和肿瘤中相对于正常细胞、组织和器官具有延长的药代动力学暴露(Kamal等人,Nature,2003年,第425卷:第407-410页;Vilenchik等人,Chem Biol,2004年,第11卷:第787-797页)。在一个方面,所公开的化合物相对于其他MAPK7抑制剂具有增大的治疗指数。
因此,本文提供了治疗对MAPK7的降解有应答的病症的方法,这些方法包括向有需要的受试者施用治疗有效量的本文所述的一种或多种化合物或组合物。还提供了本文所述的一种或多种化合物或组合物在制备用于治疗对MAPK7的降解有应答的病症的药物中的用途。还提供了本文所述的化合物或组合物用于治疗对MAPK7的降解有应答的病症的用途。
在一个方面,本发明化合物和组合物治疗的病症是癌症。术语“癌症”或“肿瘤”在本领域中是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,诸如不受控制的增殖、永生化、转移潜能、快速生长和增殖率、减少的细胞死亡/凋亡以及某些特征性的形态学特征。癌细胞通常以实体瘤的形式存在。然而,癌症还包括非实体瘤,例如血液肿瘤,例如白血病,其中癌细胞来源于骨髓。如本文所用,术语“癌症”包括癌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、骨髓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、慢性粒细胞(粒细胞)白血病、慢性粒细胞白血病、结肠癌、大肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、异常增生性改变(异型增生和化生)、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、肝细胞瘤、肝细胞癌、激素不敏感前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌、淋巴管内皮肉瘤、淋巴管肉瘤、淋巴细胞白血病、淋巴瘤(霍奇金和非霍奇金);膀胱、乳腺、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性障碍;T细胞或B细胞来源的淋巴恶性肿瘤、白血病、淋巴瘤、髓样癌、髓母细胞瘤、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、神经母细胞瘤、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、子宫癌和肾母细胞瘤。其他癌症包括原发性癌症、转移性癌症、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、妊娠滋养细胞癌疾病、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、垂体腺癌、血管瘤、骨和软组织肉瘤、卡波西肉瘤(Kaposi's sarcoma)、神经癌、眼癌、脑膜癌、胶质母细胞瘤、神经瘤、神经母细胞瘤、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、多形性胶质母细胞瘤、非鳞状非小细胞肺癌、恶性胶质瘤、上皮性卵巢癌、原发性腹膜浆液性癌、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、复发性多形性胶质母细胞瘤、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/雀斑状黑色素瘤、副神经节瘤、嗜铬细胞瘤、晚期转移性癌、实体瘤、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、胶质母细胞瘤、胃肠道间质瘤肿瘤、套细胞淋巴瘤和难治性恶性肿瘤。
如本文所用,“实体瘤”被理解为可使用成像方法触诊或检测为具有三个维度的异常生长的任何致病性肿瘤。实体瘤与血液肿瘤诸如白血病不同。然而,血液肿瘤的细胞来源于骨髓;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“肿瘤的组织”被理解为细胞、细胞外基质和与实体瘤相关的其他天然存在的组分。
针对任何特定患者的特定剂量和治疗方案将取决于多种因素,包括所采用的特定化合物的活性、年龄、体重、一般健康状况、性别、饮食、施用时间、排泄率、药物组合,以及主治医师的判断和所治疗的特定疾病的严重程度。组合物中所述的化合物的量还将取决于组合物中的具体化合物。
范例
实施例1:化合物043合成
用于化合物043的代表性合成方案如下所示。还示出了中间体的具体合成路线。
中间体2:
4-(4-氨基苄基)哌嗪-1-羧酸叔丁酯
向化合物1(2.0g,15.6mmol)的EtOH(15mL)和H2O(5mL)溶液中添加铁粉(1.72g,77.9mmol)和NH4Cl(3.4g,105.5mmol)。将所得混合物加热至80℃达2小时。将反应溶液冷却至室温并过滤。将滤液倒入NaHCO3水溶液,用EtOAc(20mL×3)萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩,得到呈白色固体的中间体2(1.81g,收率100%)。
中间体3:
4-(4-(2,4-二羟基-5-异丙基苯基硫代氨基)苄基)哌嗪-1-羧酸叔丁酯将化合物2-1(1.45g,6.30mmol)、ClCH2COONa(1.09g,9.53mmol)和NaHCO3(1.60g,19.1mmol)的DMF(10mL)溶液在30℃下搅拌3小时。将化合物2(1.85g,6.3mmol)添加到混合物中。将所得混合物在80℃加热4小时后,将反应混合物倒入冰水中并用EtOAc(15mL×3)萃取。将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DCM:MeOH=20:1洗脱,得到呈黄色油状物的中间体3(2.1g,收率70%)。
中间体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-羧酸叔丁酯
将中间体3(2.1g,4.3mmol)和CDI(1.40g,8.6mmol)的THF(15mL)溶液在室温下搅拌4小时。将反应溶液倒入盐水(25mL)中并用EtOAc(25mL×2)萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩,得到中间体4(2.7g,粗品),其无需纯化即可用于进一步反应。
中间体5:
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-羧酸叔丁酯
向中间体4(2.7g,粗品)的EtOH(6mL)溶液中添加NH2NH2-H2O(253mg,7.9mmol)。将所得混合物在室温下搅拌过夜。将所沉淀的固体过滤,得到呈白色固体的中间体5(1.3g,收率48.5%)。
中间体6:
4-(5-羟基-4-(4-(哌嗪-1-基甲基)苯基)-4H-1,2,4-三唑-3-基)-6-异丙基苯基-1,3-二醇,盐酸盐将中间体5(1.3g,2.50mmol)的HCl/MeOH(3N,15mL)溶液在室温下搅拌16小时。将反应溶液浓缩,得到呈白色固体的中间体6(1.02g,收率98%)。
中间体8:
5-(甲基氨基)嘧啶-2,4(1H,3H)-二酮
向装有冷凝器的500mL三颈圆底烧瓶中添加5-溴嘧啶-2,4(1H,3H)-二酮(40g,0.2mol)和甲胺(30%(重量/体积)水溶液,400mL)。搅拌反应混合物并将其在80℃下加热3.5小时。在25℃下,用稀HCl水溶液将反应混合物酸化至pH为约4.5。将产生的淡黄色沉淀物过滤并用水洗涤,然后在真空中干燥以提供呈淡黄色固体的中间体8(25g,收率89%)。
中间体9:
N-(2,4-二氧代-1,2,3,4-四氢嘧啶-5-基)-N-甲基-2-硝基苯甲酰胺在0℃下向中间体8(30g,0.21mol)的四氢呋喃(THF)(300mL)溶液中添加NaOH水溶液(2.5N,300mL,0.75mol)。缓慢地添加2-硝基苯甲酰氯(61g,0.32mol)。将生成的透明棕色溶液在0℃下搅拌40分钟,然后在室温下搅拌4.5小时。将反应混合物用稀HCl水溶液酸化。将产生的淡黄色固体过滤,并用水洗涤滤饼,然后在真空中干燥以提供呈淡黄色固体的中间体9(32g,收率52%)。
中间体10:
N-(2,4-二氯嘧啶-5-基)-N-甲基-2-硝基苯甲酰胺
将中间体9(32g,0.11mol)和N,N-二甲基苯胺(12g,0.1mol)的三氯氧磷(205mL)溶液在100℃下加热过夜。通过旋转蒸发仪去除溶剂,并将残余物真空干燥以提供粗产物中间体10,其无需进一步纯化即可用于下一步反应。
中间体11:
2-氯-5-甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮将粗中间体10(36g,0.11mol)溶解在乙酸(400mL)中,然后在剧烈搅拌下在25℃下添加铁(37g,0.66mol)。将混合物在60℃下加热5小时。添加水(100mL)和乙醇(10mL)并将反应混合物搅拌30分钟。将沉淀物过滤并在EtOAc和水之间萃取。将合并的EtOAc相经硫酸钠干燥,然后浓缩,得到粗中间体11,该粗中间体通过SGC纯化,得到呈白色固体的中间体11(20g,两步收率为70%)。
中间体12:
2-氯-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮将中间体11(5g,19.18mmol)溶解在DMF(50mL)中,然后在搅拌下在0℃下添加NaH(60%的矿物油溶液,1.53g,38mmol)。将混合物在室温下搅拌2小时。添加水并用EtOAc(50mL×3)萃取。将合并的EtOAc相经硫酸钠干燥,然后浓缩,得到粗中间体12,该粗中间体通过SGC纯化,得到呈白色固体的中间体12(4.8g,收率91%)。
中间体13:
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羧酸甲酯向中间体12(5g,18.2mmol)的二噁烷(50mL)溶液中添加1-(4-氨基-3-乙氧基苯基)哌啶-4-羧酸甲酯(5.07g,18.2mmol)、K2CO3(7.55g,54.6mmol)、X-Phos(1.7g)和Pd2(dba)3(1.6g)。将混合物在Ar气氛下回流搅拌过夜。添加水并用EtOAc萃取(50mL×3)。将合并的EtOAc相经硫酸钠干燥,然后浓缩,得到粗中间体13,该粗中间体通过SGC纯化,得到呈白色固体的中间体13(4.0g,收率为43%)。
中间体14:
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羧酸向中间体13(2g,3.87mmol)的H2O/MeOH/THF(10mL/5mL/5mL)溶液中添加LiOH-H2O(0.42g,10mmol)。将混合物在室温下搅拌过夜。添加水并用EtOAc萃取(50mL×3)。添加1N HCl并将pH调节至4。通过过滤收集沉淀的固体并将其干燥,得到呈白色固体的化合物中间体14(1.5g,收率为87.7%)。
化合物043:
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,盐酸盐
向中间体6(340mg,0.7mmol)、HATU(290mg,0.77mmol)和DIEA(450mg,3.48mmol)的DMF(8mL)溶液中添加中间体14(350mg,0.7mmol)。将所得混合物在室温下搅拌2小时。混合物通过制备型HPLC纯化,得到呈白色固体的中间体15(TFA盐)。将其添加到NaHCO3溶液中并添加EtOAc,然后萃取。将有机相干燥并浓缩。将H2O(10mL)和CH3CN(1mL)添加到残余物中,随后添加3N HCl(0.17mL)。将其冻干,得到呈黄色固体的化合物043(230mg)。
1H NMR(400MHz,DMSO-d6):δ13.02(s,1H),11.92(m,2H),9.94-9.24(m,1H),8.49(d,J=28.4Hz,2H),8.26(d,J=8.4Hz,1H),7.72-7.45(m,6H),7.30-7.19(m,4H),6.91(s,1H),6.36(s,1H),4.49-4.16(m,6H),3.76-3.53(m,5H),3.41(s,3H),3.37(s,3H),3.29(d,J=8.4Hz,2H),3.23-3.12(m,2H),3.10-2.89(m,3H),2.29(s,2H),1.94(s,2H),1.40(t,J=7.2Hz,3H),1.03(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.080min,m/z实测值为894.3[M-HCl+H]+。
实施例2:化合物065合成
用于化合物065的代表性合成方案如下所示。还示出了中间体的具体合成路线。
中间体3:
(E)-N'-(3,3-二甲基-5-氧代亚环己基)-4-甲基苯磺酰肼
将1(200g,1426.72mmol)、2(265.71g,1426.7167mmol)和对甲苯磺酸(24.54g,142.67mmol)混合物的甲苯(8L)溶液加热至120℃。1小时后,将混合物冷却,随后添加甲苯(1.2L)。然后将混合物回流1小时。将反应物冷却至环境温度。将所沉淀的固体通过过滤收集,用乙醚洗涤三次并真空干燥得到中间体3(360g,1167.30mmol,81.82%)。LCMS:m/z 309[M+H]+。
中间体4:
6,6-二甲基-3-(三氟甲基)-1,5,6,7-四氢-4H-吲唑-4-酮
在0℃下向3(360g,1167.30mmol)和TEA(486.67mL,3501.33mmol)的THF(3L)悬浮液中添加三氟乙酰基2,2,2-三氟乙酸酯(243.51mL,1750.67mmol)。将所得反应物加热至55℃达3小时,将反应混合物冷却至环境温度。向混合物中添加甲醇(1.4L)和1N NaOH(1.4L)。搅拌3小时后,将反应混合物用饱和氯化铵(3L)稀释,用乙酸乙酯萃取三次,合并有机层,盐水洗涤,经硫酸钠干燥并真空浓缩。残余物通过柱层析纯化,得到中间体4(160g,689.05mmol,59.04%)。LCMS:m/z 233[M+H]+。
中间体6:
2-溴-4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯甲腈在室温下将NaH(15.50g,645.98mmol)添加到4(150g,645.98mmol)的DMSO(2L)溶液中。15分钟后,添加固体2-溴-4-氟苄腈(129.20g,645.98mmol)。将反应混合物在45℃加热过夜。将混合物冷却至室温并用饱和NH4Cl水溶液淬灭。将混合物用水稀释并用EtOAc萃取。将合并的有机层用盐水洗涤,经无水硫酸钠干燥并真空浓缩。残余物通过柱层析纯化,得到中间体6(180g,436.67mmol,67.59%)。LCMS:m/z 412[M+H]+。
中间体8:
2-((4-(苄氧基)苯基)氨基)-4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯甲腈
向6(50g,121.30mmol)的甲苯(500mL)溶液中添加7(24.17g,121.30mmol)和Cs2CO3(79.04g,242.59mmol)。然后在氮气保护下依次添加BINAP(15.10g,24.26mmol)和Pd(OAc)2(2.74g,12.13mmol)。将混合反应物加热至120℃达3小时。在过滤该混合反应物后,将滤液真空浓缩,残余物通过硅胶层析纯化,得到中间体8(40g,75.39mmol,62.16%)。LCMS:m/z531[M+H]+。
中间体9:
2-((4-(苄氧基)苯基)氨基)-4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯甲酰胺
在0℃下,向8(40g,75.39mmol)的EtOH(400mL)和DMSO(100mL)溶液中依次滴加1NNaOH(226.18mL,226.18mmol)和H2O2(25.63g,226.18mmol)。然后将混合物在室温下搅拌2小时,然后用水稀释,将其用EtOAc萃取,用盐水洗涤,经硫酸钠干燥。将有机层真空浓缩,残余物通过硅胶柱纯化,得到中间体9(35g,63.80mmol,84.63%)。LCMS:m/z 549[M+H]+。
中间体10:
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-羟基苯基)氨基)苯甲酰胺
向9(35g,63.80mmol)的MeOH(400mL)溶液中添加Pd/C 10%(6.7g,6.38mmol),将混合物在室温下在H2存在下搅拌过夜。在将其过滤、用EA洗涤、随后用DCM洗涤后,将填料真空浓缩,得到呈固体的中间体10(26g,56.71mmol,88.89%)。LCMS:m/z 459[M+H]+。
中间体12:
2-(2-((叔丁氧基羰基)氨基)乙氧基)乙基甲磺酸酯
在0℃下向11(1g,4.87mmol)的THF(15mL)溶液中添加TEA(2.03mL,14.62mmol),然后将MsCl(0.57mL,7.31mmol)滴加至反应混合物中并将温度控制在5℃以下。然后将其在室温下搅拌2小时,之后用水稀释。然后将其用EA萃取,用饱和盐水洗涤,经硫酸钠干燥,并真空浓缩,得到中间体12(1.3g,4.59mmol,94.17%)。LCMS:m/z 284[M+H]+。
中间体13:
(2-(2-(4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙基)氨基甲酸叔丁酯向12(1.3g,4.59mmol)的DMF(20mL)溶液中添加10(1.89g,4.13mmol)和K2CO3(1.90g,13.76mmol),将混合物在90℃下搅拌过夜。然后添加水,将其用EA萃取,用饱和盐水洗涤,经硫酸钠干燥,并真空浓缩,残余物通过硅胶柱纯化,得到呈固体的中间体(1.6g,2.48mmol,54.01%)。LCMS:646[M+H]+。
中间体14:
2-((4-(2-(2-氨基乙氧基)乙氧基)苯基)氨基)-4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯甲酰胺
向13(1.6g,2.48mmol)的乙腈(25mL)溶液中添加TsOH(1.41g,7.43mmol),将混合物在50℃下搅拌2小时,添加饱和NaHCO3溶液至pH为8~9,然后将其用EA萃取,用饱和盐水洗涤,经硫酸钠干燥,真空浓缩,得到呈黄色固体的中间体14,该中间体无需进一步纯化。LCMS:546[M+H]+。1H NMR(400MHz,DMSO-d6):δ10.08(s,1H),8.16(s,1H),7.88(d,J=8.4Hz,1H),7.57(s,1H),7.21(d,J=8.4Hz,2H),7.01(s,1H),6.94(t,J=9.6Hz,3H),4.07(t,J=4.6Hz,2H),3.70(d,J=9.0Hz,1H),3.41(t,J=5.8Hz,3H),2.89(s,2H),2.65(t,J=5.8Hz,2H),2.41(s,2H),1.02(s,6H)。
化合物065:
N-(2-(2-(4-((2-氨基甲酰基-4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。
向中间体14(340mg,0.7mmol)、HATU(290mg,0.77mmol)和DIEA(450mg,3.48mmol)的DMF(8mL)溶液中添加中间体15(350mg,0.7mmol)。将所得混合物在室温下搅拌2小时。混合物通过制备型HPLC纯化,得到呈白色固体的化合物067(TFA盐)。(230mg)呈黄色固体。1HNMR(400MHz,DMSO-d6):δ10.12(s,1H),8.37(s,1H),8.20-8.05(m,3H),7.90(d,J=8.4Hz,1H),7.69(dd,J=7.6,1.6Hz,1H),7.64-7.47(m,2H),7.26-7.16(m,4H),7.03-6.93(m,5H),4.55-4.28m,4H),4.16-4.08(m,5H),3.74(t,J=4.4Hz,2H),3.64(d,J=12.2Hz,2H),3.51(t,J=5.6Hz,2H),3.39(s,3H),3.32(s,3H),3.26(dd,J=11.4,5.8Hz,2H),2.91(s,2H),2.42(s,3H),1.88(s,3H),1.35(t,J=6.8Hz,3H),1.03(s,6H)。LCMS(ESI):RT=1.500min,m/z实测值为1030.4[M-CF3COOH+H]+。
实施例3:化合物143合成
用于化合物143的代表性合成方案如下所示。还示出了中间体的具体合成路线。
中间体3:
向化合物1(3.0g,16.20mmol)和化合物2(4.6g,17.82mmol)的DMF(50mL)溶液中添加DIEA(8.37g,64.79mmol),随后添加HATU(6.77g,17.82mmol)。将混合物在室温下搅拌过夜。LC-MS指示反应完成。将反应混合物用水(100mL)稀释,用EA(150mL×2)萃取。将合并的有机层用饱和NaHCO3水溶液洗涤,真空浓缩,粗品通过SGC纯化用DCM:MeOH=50:1洗脱,得到呈棕色固体的化合物3(2.7g,收率39%)。
中间体5:
加入化合物3(200mg,0.47mmol)、化合物4(189.2mg,0.94mmol)和PPh3(369.9mg,1.41mmol)的无水THF(9mL)溶液。将混合物在Ar气氛下于室温搅拌15分钟。添加DEAD(245.6mg,1.41mmol)。然后将反应混合物加热至65℃并在Ar气氛下搅拌过夜。LC-MS指示反应完成。将反应混合物用水(30mL)稀释,用EA(50mL×2)萃取。将合并的有机层真空浓缩,并通过SGC纯化用PE:EA=3:1洗脱,得到呈黄色固体的化合物5(152mg,收率53%)。
中间体6:
向化合物3(152mg,0.25mmol)的MeOH(2mL)溶液中添加HCl/二噁烷(2mL)。将混合物在室温下搅拌1小时,LC-MS指示反应完成。将反应混合物真空浓缩,得到呈黄色固体的中间体6(124mg,收率97%)。
化合物143:
N-(4'-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。
向化合物6(35.79mg,0.066mmol)和化合物7(30mg,0.06mmol)的DMF(2mL)溶液中添加DIEA(30.86mg,0.239mmol),随后添加HATU(24.97mg,0.066mmol)。将混合物在室温下搅拌1小时。LC-MS指示反应完成。反应混合物通过制备型HPLC(TFA)纯化,得到呈黄色固体的化合物143(18.92mg,收率32%)。1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),8.39(s,1H),8.25-7.95(m,4H),7.85(d,J=8.4Hz,2H),7.73-7.49(m,6H),7.40-6.95(m,11H),4.75-4.66(m,2H),4.19-4.11(m,2H),3.94-3.78(m,8H),3.71-3.63(m,2H),3.54-3.45(m,1H),3.40(s,4H),3.33(s,4H),3.09-2.95(m,1H),2.10-1.85(m,6H),1.74-1.50(m,2H),1.37(t,J=6.8Hz,3H),1.27-1.21(m,1H)。LCMS(ESI):RT=1.778min,m/z实测值为993.1[M-CF3COOH+H]+。
根据实施例中所述的一般程序和方案制备另外的化合物,这些化合物包括以下:
化合物001
2-((4-(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)-2-氧代乙氧基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6(11H)-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.63(s,1H),9.36(s,1H),8.20-8.19(m,1H),7.66(s,1H),7.51-7.50(m,2H),7.23-7.21(m,5H),6.88(s,1H),6.63-6.62(m,2H),6.25(s,1H),5.33(d,J=4.7Hz,1H),4.34(s,3H),3.99(s,3H),3.26-3.20(m,12H),2.95-2.93(m,5H),1.95-1.93(m,4H),1.49-1.47(m,2H),1.23-1.20(m,5H),0.85(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.047min,m/z实测值为925.3[M-CF3COOH+H]+。
化合物002
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)-2-((1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-基)氧基)乙酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.63(s,1H),9.39(s,1H),8.19(s,1H),7.96(s,1H),7.66(d,J=7.5Hz,1H),7.48(s,1H),7.38-7.10(m,6H),6.87-6.60(m,3H),6.26(s,1H),5.32(d,J=4.7Hz,1H),4.00(s,3H),3.88-3.49(m,8H),3.30(m,11H),3.08-2.77(m,7H),1.96(m,3H),1.51(d,J=47.6Hz,3H),1.19(m,7H),0.97(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.061min,m/z实测值为1012.0[M-CF3COOH+H]+。
化合物003
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)苄基)-1-(3-乙氧基-4-((11-甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.90(s,1H),9.58(s,1H),9.37(s,1H),8.53-8.43(m,2H),8.11-8.00(m,2H),7.77-7.43(m,2H),7.19-7.11(m,6H),6.86(s,1H),6.24(s,1H),4.28(d,J=5.3Hz,2H),4.13(d,J=6.2Hz,2H),3.67-3.50(m,5H),3.39(s,3H),3.32(s,3H),3.00-2.95(m,1H),1.92-1.80(m,3H),1.36-1.34(m,3H),1.19-1.15(m,2H),1.01(d,J=6.9Hz,6H)。LC-MS(ESI):RT=1.161min,m/z实测值为825.5[M-CF3COOH+H]+。
化合物004
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6(11H)-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.60(s,1H),9.41(s,1H),8.31(s,1H),7.87(s,1H),7.78(d,J=8.7Hz,1H),7.67(d,J=7.5Hz,1H),7.49(t,J=7.8Hz,1H),7.20-7.11(m,7H),6.77(s,1H),6.61(s,1H),6.49(d,J=9.5Hz,1H),6.26(s,1H),4.38-4.30(m,1H),4.09-4.03(m,4H),3.67-3.44(m,2H),3.42-4.40(m,2H),3.38-3.35(m,2H),3.28-3.20(m,2H),2.96-2.90(m,2H),2.73-2.63(m,5H),2.33(s,3H),1.79-1.67(m,5H),1.29(t,J=6.9Hz,5H),1.25-1.17(m,2H),0.94(d,J=6.9Hz,6H)。LC-MS(ESI):RT=1.154min,m/z实测值为977.3[M-CF3COOH+H]+。
化合物005
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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,CD3OD):δ8.54(d,J=8.7Hz,1H),8.31(s,1H),7.75(d,J=6.8Hz,1H),7.51(t,J=7.2Hz,1H),7.44(d,J=8.2Hz,2H),7.33-7.13(m,6H),6.74(s,1H),6.25(s,1H),4.56(s,2H),4.24(d,J=6.6Hz,2H),3.81-3.53(m,6H),3.46-3.44(m,8H),3.01(dt,J=13.7,6.8Hz,1H),2.70-2.65(m,1H),2.15-2.08(m,4H),1.51(t,J=6.9Hz,3H),0.92(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.39min,m/z实测值为869.5[M-CF3COOH+H]+。
化合物006
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)哌啶-1-基)乙氧基)甲基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.60(s,1H),9.40(s,1H),9.07(s,1H),8.33(s,1H),7.94-7.80(m,3H),7.68(d,J=7.6Hz,1H),7.48(d,J=6.9Hz,1H),7.16-7.09(m,6H),6.75(s,1H),6.26(s,1H),4.08-4.07(m,3H),3.69-3.56(m,5H),3.40-3.35(m,5H),3.26-3.20(m,9H),2.98-2.87(m,4H),1.75-1.72(m,8H),1.42-1.40(m,2H),1.30-1.28(m,4H),0.92(d,J=6.9Hz,6H)。LC-MS(ESI):RT=1.148min,m/z实测值为981.0[M-CF3COOH+H]+。
化合物007
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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ11.98(s,1H),9.64-9.50(m,2H),8.43-8.09(m,3H),7.68(d,J=7.8Hz,1H),7.62-7.47(m,3H),7.38(t,J=7.8Hz,1H),7.28-7.07(m,8H),6.90(s,1H),6.26(s,1H),4.42-4.00(m,16H),3.64-3.62(m,2H),3.39-3.32(m,8H),3.05-2.92(m,1H),2.31-2.30(m,1H),1.92-1.90(m,4H),1.35-1.30(m,3H),1.01(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.333min,m/z实测值为988.4[M-CF3COOH+H]+。
化合物008
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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.91(s,1H),9.60(s,1H),9.38(s,1H),8.38(s,1H),8.16-8.07(m,2H),7.69(dd,J=7.7,1.4Hz,1H),7.51(t,J=7.0Hz,1H),7.26-7.09(m,7H),6.81(s,1H),6.26(s,1H),4.16-4.12(m,2H),3.66-3.62(m,2H),3.32-3.26(m,9H),3.00-2.98(m,1H),2.74-2.71(m,2H),2.50-2.40(m,2H),1.90-1.85(m,4H),1.36(t,J=6.8Hz,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.513min,m/z实测值为839.8[M-CF3COOH+H]+。
化合物009
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)苯氧基)乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.85(s,1H),9.71-9.43(m,2H),8.35(s 1H),8.15-8.09(m,2H),7.70-7.67(m,1H),7.51-7.42(m,1H),7.30-7.06(m,5H),6.94(d,J=8.9Hz,2H),6.82(s,1H),6.24(s,1H),4.13(q,J=6.8Hz,2H),4.03-3.84(m,2H),3.65(d,J=11.6Hz,2H),3.52-3.18(m,10H),2.98-2.96(m,1H),2.46-2.36(m,2H),1.89-1.80(m,3H),1.36-1.33(m,6H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.39min,m/z实测值为855.5[M-CH3COOH+H]+。
化合物010
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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ11.94(s,1H),9.45(s,2H),8.26-8.25(m,2H),7.91-7.90(m,3H),7.68(s,1H),7.49(s,1H),7.33-7.07(m,5H),6.76(s,1H),6.56-6.53(m,2H),6.27(s,1H),5.32(s,1H),4.08(s,2H),3.64(s,3H),3.38(s,3H),3.28(s,3H),2.79(s,8H),2.33(s,4H),1.93(s,4H),1.66-1.61(m,8H),1.26-1.20(m,7H)。LCMS(ESI):RT=1.018min,m/z实测值为1019.3[M-CF3COOH+H]+。
化合物011
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)-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)哌啶-4-基)甲基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO):δ11.98(s,1H),9.60(s,1H),8.38(s,1H),8.22(s,1H),8.06-8.05(m,2H),7.69(d,J=7.1Hz,1H),7.50-7.48(m,3H),7.31-7.15(m,4H),7.04-7.01(m,2H),6.91(s,1H),6.24(s,1H),4.22-4.20(m,8H),3.97(s,1H),3.67(d,J=11.1Hz,2H),3.40(s,3H),3.33(s,3H),3.20-3.18(m,2H),2.97(s,6H),2.38-2.36(m,2H),1.98-1.58(m,12H),1.36(t,J=6.9Hz,3H),1.23(s,3H),1.01(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.005min,m/z实测值为1019.3[M-CF3COOH+H]+。
化合物012
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)-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)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO):δ12.00(s,1H),9.50(m,3H),8.37(s,1H),8.10(m,3H),7.69(dd,J=7.7,1.4Hz,1H),7.50(m,3H),7.30-7.13(m,4H),6.96(d,J=41.6Hz,3H),6.24(s,1H),4.27(s,2H),4.13(d,J=6.9Hz,2H),3.36(m,10H),3.20-2.85(m,8H),2.67(s,1H),2.35-2.32(m,4H),2.04-1.75(m,9H),1.35(t,J=6.8Hz,3H),1.23(s,2H),1.01(dd,J=8.3,6.5Hz,3H)。LCMS(ESI):RT=0.999min,m/z实测值为1005.3[M-CH3COOH+H]+。
化合物013
2-((2-乙氧基-4-(4-(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-羰基)哌啶-1-基)苯基)氨基)-5,11-二甲基-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6(11H)-酮,三氟乙酸。1H NMR(400MHz,DMSO):δ11.96(s,1H),8.39(s,1H),8.20(m,2H),7.69(dd,J=7.7,1.6Hz,1H),7.52(t,J=7.0Hz,1H),7.43(s,1H),7.42(d,J=8.2Hz,2H),7.29-7.14(m,5H),7.03(s,1H),6.89(s,1H),6.25(s,1H),4.40(d,J=12.7Hz,1H),4.23-3.88(m,5H),3.66(d,J=11.0Hz,2H),3.40(s,3H),3.34(s,3H),3.01(m,9H),2.62-2.53(m,1H),2.37(q,J=7.4Hz,3H),1.86(m,8H),1.37(t,J=6.9Hz,3H),1.27-1.11(m,2H),1.00(t,J=7.5Hz,4H)。LCMS(ESI):RT=1.078min,m/z实测值为977.3[M-CF3COOH+H]+。
化合物014
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)-N-(2-(2-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯氧基)乙氧基)乙基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.84(s,1H),9.55(s,1H),9.34(s,1H),8.37(s,1H),8.09-8.06(m,3H),7.69(dd,J=7.8,1.6Hz,1H),7.54-7.48(m,1H),7.25(d,J=8.4Hz,1H),7.18(t,J=7.4Hz,1H),7.08(d,J=8.9Hz,2H),6.92(d,J=9.0Hz,2H),6.85(s,1H),6.24(s,1H),4.17-4.04(m,4H),3.76-3.69(m,2H),3.65(d,J=11.6Hz,2H),3.49(t,J=5.7Hz,2H),3.39(s,3H),3.32(s,3H),3.28-3.22(m,2H),2.35(m,3H),2.00-1.99(m,1H),1.88(s,4H),1.35(t,J=6.7Hz,3H),1.23(s,3H),0.99(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.157min,m/z实测值为885.2[M-CF3COOH+H]+。
化合物015
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)乙氧基)乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO):δ11.86(s,1H),9.58(s,1H),9.38(s,1H),8.37(s,1H),8.09(m,3H),7.69(dd,J=7.7,1.6Hz,1H),7.50(d,J=6.9Hz,1H),7.25(d,J=8.3Hz,1H),7.18(t,J=7.3Hz,1H),7.10(d,J=8.9Hz,2H),6.93(d,J=9.0Hz,2H),6.81(s,1H),6.25(s,1H),4.10-4.08(m,5H),3.72(s,2H),3.65(d,J=11.2Hz,2H),3.49(t,J=5.8Hz,2H),3.39(s,3H),3.32(s,3H),3.25(d,J=5.8Hz,2H),3.01-2.96(m,1H),2.00(d,J=7.5Hz,1H),1.87(s,4H),1.35(t,J=6.9Hz,3H),1.24(s,3H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.192min,m/z实测值为899.3[M-CF3COOH+H]+。
化合物016
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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)乙氧基)乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.86(s,1H),9.58(s,1H),9.38(s,1H),8.37(s,1H),8.09-8.06(m,3H),7.69(d,J=7.7Hz,1H),7.51(t,J=7.1Hz,1H),7.28-7.15(m,3H),7.09(d,J=8.9Hz,2H),6.93(d,J=8.8Hz,2H),6.81(s,1H),6.25(s,1H),4.10-4.09(m,4H),3.63-3.61(m,9H),3.42-3.40(m,5H),3.32(s,3H),3.23(d,J=5.5Hz,2H),3.01-2.95(m,1H),2.04-1.81(m,5H),1.35(t,J=6.9Hz,3H),1.24(s,2H),0.98(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.186min,m/z实测值为943.2[M-CF3COOH+H]+。
化合物017
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)-N-(2-(2-(2-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯氧基)乙氧基)乙氧基)乙基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.83(s,1H),9.54(s,1H),9.33(s,1H),8.37(s,1H),8.01(s,2H),7.69(dd,J=7.7,1.6Hz,1H),7.51(t,J=6.9Hz,1H),7.25(d,J=8.4Hz,1H),7.18(t,J=7.4Hz,1H),7.07(d,J=8.9Hz,2H),6.91(d,J=9.0Hz,2H),6.85(s,1H),6.24(s,1H),4.13(d,J=6.8Hz,2H),4.08-4.04(m,2H),3.75-3.52(m,9H),3.45-3.38(m,5H),3.32(s,3H),3.22(d,J=5.7Hz,2H),2.35(q,J=7.6Hz,2H),2.02 -1.84(m,4H),1.38-1.22(m,8H),0.99(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.159min,m/z实测值为929.2[M-CF3COOH+H]+。
化合物018
5-(2,4-二羟基-5-甲基苯基)-4-(4-((4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)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,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.71-9.63(m,3H),8.36(s,1H),8.09-8.01(m,2H),7.69(dd,J=1.2Hz,1H),7.53-7.16(m,8H),6.72(s,2H),6.29(s,1H),4.42-4.39(m,1H),4.13-4.11(m,3H),4.01-3.92(m,6H),3.68-3.65(m,2H),3.39(s,4H),3.31(s,4H),3.10-2.86(m,7H),2.67-2.50(m,2H),2.05-1.96(m,2H),1.87(s,3H),1.78(s,6H),1.34(t,J=6.8Hz,3H),1.23(s,2H),1.17-0.98(m,2H)。LCMS(ESI):RT=1.123min,m/z实测值为1072.3[M-CF3COOH+H]+。
化合物019
2-((2-乙氧基-4-(4-(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)-2-氟苄基)哌嗪-1-基)甲基)哌啶-1-羰基)哌啶-1-基)苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.00(s,1H),9.64-9.40(m,2H),8.37(s,1H),8.15-8.05(m,2H),7.69(d,J=7.6Hz,1H),7.53-7.49(m,1H),7.44-7.40(m,1H),7.26-6.94(m,6H),6.26(s,1H),4.57-4.37(m,5H),4.16-4.11(m,3H),4.01-3.98(m,1H),3.76-3.64(m,3H),3.39(s,4H),3.32(s,4H),3.07-2.94(m,7H),2.42-2.33(s,4H),2.02-1.77(m,8H),1.37-1.33(m,3H),1.23-1.08(m,2H),1.05-1.01(m,4H)。LCMS(ESI):RT=1.033min,m/z实测值为995.3[M-CF3COOH+H]+。
化合物020
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,CD3OD):δ8.23(s,1H),8.10(d,J=8.8Hz,1H),7.76-7.70(m,1H),7.53-7.48(m,1H),7.42(d,J=8.4Hz,2H),7.26-7.14(m,4H),6.72-6.59(m,3H),6.23(s,1H),5.36-5.31(m,1H),4.12(m,6.9Hz,2H),3.65(m,4H),3.47(s,3H),3.41(s,3H),3.13(s,1H),2.81-2.58(m,10H),2.32(m,6.9Hz,4H),2.18(d,J=7.7Hz,1H),2.03(d,J=5.9Hz,1H),1.94-1.85(m,4H),1.81(d,J=11.5Hz,2H),1.60(s,2H),1.45-1.37(m,6H),0.90(t,J=6.7Hz,3H),0.79(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.033min,m/z实测值为991.3[M-CF3COOH+H]+。
化合物021
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,CD3OD):δ8.56(d,J=8.7Hz,1H),8.33(s,1H),7.76(m,1.5Hz,1H),7.56-7.50(m,1H),7.46(d,J=8.4Hz,2H),7.30-7.19(m,6H),7.03(d,J=8.5Hz,1H),6.26(m,1H),6.17(d,J=2.2Hz,1H),4.57(m,1H),4.25(m,6.8Hz,2H),4.14(m,1H),3.97(s,2H),3.82-3.66(m,5H),3.47(m,6H),3.13(m,12H),2.80(m,2H),2.71(m,1H),2.15(m,6H),1.90(m,2H),1.51(t,J=7.0Hz,3H)。LCMS(ESI):RT=0.973min,m/z实测值为949.2[M-CF3COOH+H]+。
化合物022
4-(4-((4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)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。1H NMR(400MHz,DMSO-d6):δ9.67(m,2H),8.37(s,1H),8.09(m,2H),7.69(m,1.5Hz,1H),7.51(m,1H),7.39(m,7.8Hz,4H),7.27-7.14(m,2H),6.98(s,1H),6.68(s,1H),6.31(s,1H),4.40(m,1H),4.13(m,2H),4.05-3.88(m,4H),3.66(m,2H),3.39(s,3H),3.32(s,3H),3.14-2.72(m,9H),2.58(s,1H),2.34-2.22(m,3H),1.90(m,9H),1.35(t,J=6.9Hz,3H),1.25-0.98(m,4H),0.89(m,4H)。LCMS(ESI):RT=1.083min,m/z实测值为1086.3[M-CF3COOH+H]+。
化合物023
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.66(s,1H),9.51(s,1H),8.44(s,1H),8.23(s,1H),8.18(s,1H),7.76-7.74(m,1H),7.60-7.55(m,1H),7.32(d,J=8.4Hz,1H),7.27-7.22(m,1H),7.13-7.01(m,5H),6.85(s,1H),6.33(s,1H),4.24-4.18(m,2H),3.85-3.68(m,9H),3.46(s,4H),3.39(s,4H),3.32-3.27(m,4H),3.09-3.02(m,2H),1.97(s,3H),1.42(t,J=6.8Hz,3H),1.02(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.268min,m/z实测值为880.2[M-CF3COOH+H]+。
化合物024
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.11(s,1H),9.66(s,1H),9.37(s,1H),8.35(s,1H),8.09(s,1H),7.95(s,1H),7.69(m,1.5Hz,1H),7.51(t,J=8.5Hz,3H),7.33-7.13(m,4H),6.89(s,1H),6.76(s,1H),6.26(s,1H),4.34(m,3H),4.11(m,6.7Hz,3H),3.73(s,3H),3.35(m,8H),3.15-2.85(m,7H),1.81(s,4H),1.33(t,J=6.9Hz,3H),1.02(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.083min,m/z实测值为894.2[M-CF3COOH+H]+。
化合物025
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.62(s,1H),9.41(s,1H),8.87(s,1H),8.35(s,1H),8.16-7.85(m,2H),7.68(d,J=7.6Hz,1H),7.56-7.46(m,1H),7.28-7.09(m,7H),6.76(s,1H),6.27(s,1H),4.44-4.34(m,2H),4.16-3.93(m,6H),3.70-3.61(m,2H),3.54-3.44(m,2H),3.39(s,3H),3.30(s,3H),3.22-2.64(m,10H),2.12-1.91(m,2H),1.81-1.70(m,8H),1.53-1.40(m,2H),1.36-1.29(m,3H),0.94(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.009min,m/z实测值为990.4[M-CF3COOH+H]+。
化合物026
N-(4-(3-(2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.59(s,2H),8.49-8.37(m,2H),8.13-8.02(m,2H),7.69(dd,J=7.6,1.3Hz,1H),7.53-7.49(m,1H),7.26-7.04(m,8H),6.24-6.17(m,2H),4.32(s,4H),4.28(d,J=5.1Hz,2H),4.13(dd,J=12.1,8.6Hz,2H),3.67(d,J=12.2Hz,2H),3.39(s,3H),3.32(s,3H),1.93(s,4H),1.35(t,J=6.8Hz,3H)。LCMS(ESI):RT=1.063min,m/z实测值为783.3[M-CF3COOH+H]+。
化合物027
N-(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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.86(s,1H),9.64-9.24(m,2H),8.54-8.32(m,2H),8.19-7.99(m,1H),7.74-7.63(m,1H),7.57-7.46(m,1H),7.28-7.09(m,6H),6.93(s,1H),6.23(s,1H),5.35-4.45(m,3H),4.28(d,J=5.2Hz,2H),4.19-4.09(m,2H),3.71-3.62(m,2H),3.39(s,3H),3.32(s,3H),2.02-1.76(m,8H),1.40-1.29(m,3H)。LCMS(ESI):RT=1.094min,m/z实测值为797.4[M-CF3COOH+H]+。
化合物028
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)-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)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.96-11.84(m,1H),9.58(s,1H),9.39(s,1H),8.51(s,1H),8.43-7.32(m,1H),8.13(s,2H),7.72(s,1H),7.53(s,1H),7.36-7.08(m,7H),6.97-6.87(m,1H),6.31-6.21(m,1H),4.32(s,3H),4.15(s,3H),3.69(s,2H),3.48-3.27(m,7H),2.44-2.33(m,3H),1.93(s,4H),1.37(s,3H),1.12-0.96(m,3H)。LCMS(ESI):RT=1.137min,m/z实测值为811.7[M-CF3COOH+H]+。
化合物029
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N-(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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),9.60-9.25(m,2H),8.56-8.32(m,2H),8.12(s,1H),7.68(d,J=8.0Hz,1H),7.55-7.47(m,1H),7.30-7.06(m 7H),6.86(s,1H),6.24(s,1H),4.92-4.35(m,5H),4.28(d,J=5.2Hz,2H),4.17-4.08(m,2H),3.72-3.61(m,2H),3.44-3.26(m,6H),2.35-2.28(m,3H),1.93(s,4H),1.49-1.30(m,5H),0.80(t,J=7.2Hz,3H)。LCMS(ESI):RT=1.174min,m/z实测值为825.3[M-CF3COOH+H]+。
化合物030
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)-2-(三氟甲基)苄基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),9.61-6.37(m,2H),8.58(s,1H),8.37(s,1H),8.15-8.05(m,2H),7.69(d,J=7.6Hz,1H),7.51-7.46(m,4H),7.26-7.16(m,2H),6.99(s,2H),6.24(s,1H),5.04-4.51(m,4H),4.44(d,J=4.4Hz,2H),4.14(dd,J=11.9,5.4Hz,2H),3.68(d,J=11.2Hz,2H),3.39(s,3H),3.32(s,3H),3.07-3.01(m,1H),2.10-1.76(m,4H),1.35(t,J=6.5Hz,3H),1.06(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.253min,m/z实测值为893.7[M-CF3COOH+H]+。
化合物031
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)-N-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)-2-(三氟甲基)苄基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.01(s,1H),9.59(s,1H),9.37(s,1H),8.54(s,1H),8.36(s,1H),8.17-7.96(m,2H),7.69(d,J=7.2Hz,1H),7.54-7.43(m,4H),7.26-7.16(m,2H),7.01(s,1H),6.24(s,1H),4.71-4.27(m,6H),4.12(dd,J=14.0,6.7Hz,2H),3.68(d,J=12.0Hz,2H),3.35(d,J=30.0Hz,6H),2.44-2.33(m,4H),2.05-1.76(m,3H),1.34(t,J=6.4Hz,3H),1.26-1.14(m,1H),1.05(t,J=7.6Hz,3H)。LCMS(ESI):RT=1.167min,m/z实测值为879.7[M-CF3COOH+H]+。
化合物032
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.50(d,J=95.9Hz,2H),8.36(s,1H),8.20-7.94(m,2H),7.69(d,J=7.6Hz,1H),7.51-7.38(m,3H),7.26-7.16(m,4H),7.10-6.87(m,1H),6.82(s,1H),6.26(s,1H),5.29-4.66(m,4H),4.39(d,J=12.0Hz,1H),4.13(q,J=6.8Hz,2H),3.99(d,J=9.6Hz,1H),3.66(d,J=12.0Hz,2H),3.39(s,3H),3.32(s,4H),3.18-2.81(m,8H),2.45-2.30(m,2H),2.06-1.92(m,1H),1.90-1.64(m,7H),1.34(t,J=6.7Hz,3H),1.27-1.20(m,1H),1.17-1.06(m,1H),0.98(d,J=6.8Hz,9H)。LCMS(ESI):RT=1.060min,m/z实测值为991.4[M-HCl+H]+。
化合物033
2-((4-(4-(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)哌啶-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.99(s,1H),9.64(s,1H),9.39(s,1H),8.36(s,1H),8.09(s,3H),7.69(d,J=7.5Hz,1H),7.54-7.48(m,1H),7.47-7.39(m,1H),7.28-7.09(m,4H),7.01(d,J=9.1Hz,1H),6.91(s,1H),6.26(s,1H),4.52(s,1H),4.12(d,J=6.3Hz,4H),3.67(m,6H),3.39(s,6H),3.31(s,3H),3.16-2.92(m,8H),2.08(m,2H),1.80(s,4H),1.51(s,2H),1.34(m,4H),1.02(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.180min,m/z实测值为996.0[M-CF3COOH+H]+。
化合物034
4-(4-((4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)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):δ9.64(s,1H),8.36-8.32(m,2H),8.09-8.08(m,2H),7.68-7.73(m,2H),7.53-7.16(m,8H),6.91-6.75(m,1H),6.62(s,1H),6.31(s,1H),4.39-4.38(m,1H),4.15-4.10(m,2H),4.05-3.95(m,1H),3.68-3.65(m,2H),3.39(s,4H),3.32(s,4H),3.11-2.89(m,6H),2.53-2.35(m,5H),2.41-2.22(m,3H),1.80-1.73(m,8H),1.34(m,4H),1.02(m,2H),0.85-0.84(m,4H)。LCMS(ESI):RT=1.060min,m/z实测值为1004.4[M-CF3COOH+H]+。
化合物035
N-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-((2,2,2-三氟乙基)氨基甲酰基)-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)苯乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),9.61(m,1H),8.33(s,1H),7.95(s,3H),7.68-7.67(d,J=7.5Hz,1H),7.50-7.17(m,13H),6.59(s,1H),6.34(s,1H),4.24-4.23(m,2H),4.11-4.07(m,4H),3.99-3.90(m,4H),3.65-3.62(m,3H),3.38-3.29(m,9H),2.91-2.74(m,5H),2.55-2.54(m,1H),2.33(m,1H),2.01(m,1H),1.77-1.70(m,5H),1.33-1.24(m,5H),0.82-0.81(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.230min,m/z实测值为1135.3[M-CF3COOH+H]+。
化合物036
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)-2-氟苄基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.96(s,1H),9.61(s,1H),9.42(s,1H),8.49(s,1H),8.37(s,1H),8.28-7.99(m,2H),7.70-7.67(m,1H),7.53-7.49(m,1H),7.29-6.93(m,9H),6.25(s,1H),4.31(d,J=4.4Hz,2H),4.16-4.11(m,2H),3.67(d,J=12Hz,2H),3.39(s,3H),3.32(s,3H),3.04-3.00(m,2H),1.99-1.78(m,4H),1.35(t,J=7.2Hz,3H),1.24(s,2H),1.04(d,J=7.2Hz,6H)。LCMS(ESI):RT=1.366min,m/z实测值为843.8[M-CF3COOH+H]+。
化合物037
1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)-N-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)-2-氟苄基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.59(s,1H),9.42(s,1H),8.47(s,1H),8.37(s,1H),8.20-8.01(m,2H),7.70-7.67(m,1H),7.53-7.49(m,1H),7.27-6.95(m,8H),6.25(s,1H),4.30(d,J=5.2Hz,2H),4.16-4.11(m,2H),3.67(d,J=12Hz,2H),3.39(s,3H),3.32(s,3H),2.43-2.37(m,3H),1.96-1.73(m,4H),1.35(t,J=6.8Hz,3H),1.24(s,2H),1.04(d,J=7.6Hz,4H)。LCMS(ESI):RT=1.327min,m/z实测值为829.8[M-CF3COOH+H]+。
化合物038
2-((4-(4-(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-(三氟甲基)苄基)哌嗪-1-基)哌啶-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),9.60(s,1H),9.36(s,1H),8.31(s,1H),7.86-7.65(m,5H),7.49-7.42(m,3H),7.24-7.14(m,2H),6.90(s,1H),6.61(d,J=2.8Hz,1H),6.51-6.47(m,1H),6.25(s,1H),4.42-4.38(m,1H),4.08-3.98(m,3H),3.67-3.55(m,5H),3.78(s,3H),3.26(s,3H),3.03-2.99(m,2H),2.73-2.54(m,4H),2.51(s,2H),2.39-2.35(m,4H),1.85-1.62(m,6H),1.29(t,J=6.8Hz,4H),1.24-1.15(m,3H),1.01(d,J=7.2Hz,6H)。LCMS(ESI):RT=1.367min,m/z实测值为1046.0[M-CF3COOH+H]+。
化合物039
N-(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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),9.58-9.26(m,2H),8.56-8.34(m,2H),8.30-7.95(m,2H),7.69(dd,J=7.6Hz,1.2Hz,1H),7.55-7.47(m,1H),7.28-7.08(m,7H),6.86(s,1H),6.24(s,1H),4.31-4.24(m,4H),4.18-4.11(m,4H),3.71-3.61(m,2H),3.44-3.26(m,7H),2.37-2.29(m,2H),1.97(s,4H),1.48-1.32(m,5H),0.83-0.77(m,3H)。LCMS(ESI):RT=1.240min,m/z实测值为825.3[M-CF3COOH+H]+。
化合物040
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),9.74-9.36(m,3H),8.35(s,1H),8.14-7.84(m,2H),7.68(dd,J=7.6Hz,1.6Hz,1H),7.54-7.47(m,1H),7.26-7.00(m,6H),6.90-6.65(m,2H),6.27(s,1H),4.67-4.47(m,3H),4.24-4.08(m,4H),3.94-3.84(m,2H),3.74-3.50(m,6H),3.39(s,3H),3.31(s,3H),3.23-3.09(m,3H),3.02-2.91(m,4H),2.22-2.08(m,2H),1.79(s,4H),1.66-1.43(m,2H),1.37-1.30(m,3H),0.96(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.206min,m/z实测值为964.0[M-CF3COOH+H]+。
化合物041
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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.91(s,1H),9.59(s,1H),9.41(s,1H),8.31(s,1H),7.89-7.77(m,3H),7.70-7.64(m,1H),7.54-7.45(m,1H),7.29(d,J=8.0Hz,2H),7.23(d,J=8.4Hz,1H),7.19-7.10(m,3H),6.75(s,1H),6.63-6.59(m,1H),6.52-6.47(m,1H),6.26(s,1H),4.41-4.32(m,1H),4.12-4.02(m,2H),3.96-3.85(m,1H),3.71-3.60(m,2H),3.42(s,2H),3.38(s,3H),3.28(s,3H),3.02-2.89(m,4H),2.84-2.74(m,2H),2.71-2.56(m,3H),2.29-2.21(m,1H),2.03-1.93(m,2H),1.85-1.41(m,14H),1.29(t,J=6.8Hz,3H),0.93(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.035min,m/z实测值为1033.4[M-CF3COOH+H]+。
化合物042
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6(11H)-酮,盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.70(s,1H),9.29(s,1H),8.44(s,1H),8.36(s,1H),8.26(s,1H),7.74-7.58(m,4H),7.55-7.49(m,1H),7.44(s,1H),7.31-7.17(m,4H),6.93(s,1H),6.34(s,1H),4.59-4.53(m,1H),4.45-4.33(m,2H),4.23-4.12(m,3H),3.80-3.45(m,12H),3.40(s,3H),3.36(s,3H),3.20-3.08(m,2H),3.05-2.99(m,1H),2.70-2.54(m,2H),2.35-2.10(m,4H),1.98-1.82(m,2H),1.76-1.64(m,1H),1.61-1.49(m,1H),1.40(t,J=6.8Hz,3H),1.04(d,J=6.8Hz,6H)。LC-MS(ESI):RT=1.031min,m/z实测值为977.3[M-HCl+H]+。
化合物043
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,盐酸盐。1H NMR(400MHz,DMSO-d6):δ13.02(s,1H),11.92(d,J=50.0Hz,2H),9.94-9.24(m,1H),8.49(d,J=28.4Hz,2H),8.26(d,J=8.4Hz,1H),7.72-7.45(m,6H),7.30-7.19(m,4H),6.91(s,1H),6.36(s,1H),4.49-4.16(m,6H),3.76-3.53(m,5H),3.41(s,3H),3.37(s,3H),3.29(d,J=8.4Hz,2H),3.23-3.12(m,2H),3.10-2.89(m,3H),2.29(s,2H),1.94(s,2H),1.40(t,J=7.2Hz,3H),1.03(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.080min,m/z实测值为894.3[M-HCl+H]+。
化合物044
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.64(m,3H),8.42(s,1H),8.28(s,2H),7.70(d,J=7.7Hz,1H),7.52(t,J=7.5Hz,2H),7.27(d,J=8.3Hz,1H),7.19(t,J=7.8Hz,3H),7.12(d,J=8.3Hz,2H),6.77(d,J=4.5Hz,1H),6.31(s,1H),4.37(s,2H),4.21-4.15(m,4H),3.99(s,1H),3.59(s,3H),3.45(s,2H),3.40(s,3H),3.35(s,3H),3.10(s,3H),3.01-2.89(m,3H),2.81(s,2H),2.68-2.54(m,3H),2.10(s,2H),1.87(m,3H),1.69(s,3H),1.39(t,J=6.8Hz,3H),1.24(s,1H),1.17(s,1H),1.04(s,1H),0.97-0.93(m,6H)。LCMS(ESI):RT=1.100min,m/z实测值为990.4[M-HCl+H]+。
化合物045
(R)-N-(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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ11.92(s,1H),9.62(s,1H),9.39(s,1H),8.42-8.35(m,2H),8.07-7.95(m,2H),7.68(dd,J=8.0,1.2Hz,1H),7.55-7.34(m,5H),7.25-7.09(m,6H),6.92-6.67(m,2H),6.26(d,J=3.6Hz,1H),4.97-4.93(m,1H),4.37-4.08(m,4H),3.70-3.65(m,2H),3.39(s,3H),3.35-3.31(m,5H),3.14-2.66(m,4H),2.48-2.30(s,4H),2.02-1.63(m,7H),1.41-1.24(m,9H),0.94(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.345min,m/z实测值为1027.0[M-CF3COOH+H]+。
化合物046
2-((4-(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-(三氟甲基)苄基)哌嗪-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.07(s,1H),9.65(s,1H),9.38(s,1H),8.36(s,1H),8.23-7.95(m,2H),7.85(d,J=7.6Hz,1H),7.71-7.49(m,4H),7.26-7.16(m,2H),7.01-6.89(m,2H),6.25(s,1H),4.72-4.54(m,4H),4.13(q,J=6.8Hz,4H),3.67(d,J=10.8Hz,4H),3.36(d,J=29.2Hz,8H),3.12-2.81(m,4H),1.85(s,4H),1.35(t,J=6.8Hz,3H),1.04(d,J=6.8Hz,7H)。LCMS(ESI):RT=1.320min,m/z实测值为962.3[M-CF3COOH+H]+。
化合物047
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)(甲基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,CD3OD):δ7.96(s,1H),7.79-7.76(m,2H),7.60-7.55(m,3H),7.40(d,J=8.4Hz,2H),7.26-7.21(m,4H),6.89-6.76(m,3H),6.22(s,1H),4.39(m,3H),4.08-4.03(m,3H),3.96-3.80(m,4H),3.49-3.43(m,9H),3.11-3.05(m,4H),1.99-1.91(s,4H),1.32-1.41(m,5H),1.21(t,J=7.6Hz,3H),1.02(d,J=7.6Hz,6H)。LCMS(ESI):RT=1.043min,m/z实测值为908.5[M-CF3COOH+H]+。
化合物048
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.57(s,1H),9.32(s,1H),8.31(s,1H),7.86(s,1H),7.78(d,J=8.8Hz,1H),7.68-7.65(m,1H),7.51-7.46(m,1H),7.30-7.11(m,6H),6.90(s,1H),6.61(d,J=2.0Hz,1H),6.50-6.47(m,1H),6.23(s,1H),4.09-4.03(m,2H),3.67-3.64(m,2H),3.53-3.47(m,6H),3.38(s,3H),3.31(s,1H),3.28(s,3H),2.73-2.67(m,3H),2.37-2.28(m,4H),1.95(s,3H),1.67-1.71(m,4H),1.29(t,J=7.2Hz,3H)。LCMS(ESI):RT=1.041min,m/z实测值为866.3[M-CF3COOH+H]+。
化合物049
2-((2-乙氧基-4-(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-羰基)哌啶-1-基)苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),10.05(s,1H),9.62(d,J=3.2Hz,1H),9.34(d,J=4.0Hz,1H),8.35(s,1H),8.10-8.18(m,2H),7.70-7.67(m,1H),7.53-7.47(m,3H),7.29-7.10(m,5H),6.98-6.68(m,3H),6.24(s,1H),4.34(s,1H),4.30(s,2H),4.14-4.08(m,3H),3.70-3.66(m,2H),3.39(s,4H),3.31(s,4H),3.13-2.90(m,5H),2.45-2.33(m,2H),1.82(s,5H),1.33(t,J=7.6Hz,3H),1.02(t,J=7.8Hz,4H)。LCMS(ESI):RT=1.076min,m/z实测值为880.3[M-CF3COOH+H]+。
化合物050
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.52(s,1H),9.35(s,1H),8.31(s,1H),7.86(s,1H),7.79(d,J=8.8Hz,1H),7.67(dd,J=7.6,1.6Hz,1H),7.52-7.46(m,1H),7.31-7.10(m,6H),6.79(s,1H),6.61(d,J=2.0Hz,1H),6.49(dd,J=8.8,2.0Hz,1H),6.25(s,1H),4.11-4.03(m,2H),3.70-3.62(m,2H),3.53(s,2H),3.47(s,3H),3.38(s,3H),3.31-3.25(m,4H),2.79-2.62(m,3H),2.41-2.25(m,7H),1.72-1.63(m,4H),1.44-1.35(m,2H),1.32-1.26(m,3H),0.80-0.74(m,3H)。LCMS(ESI):RT=1.198min,m/z实测值为894.9[M-CF3COOH+H]+。
化合物051
(R)-2-((4-(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)-3-甲基哌嗪-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.62(s,1H),9.34(s,1H),8.33(s,1H),8.05-7.82(m,1H),7.71-7.65(m,1H),7.59-7.43(m,3H),7.33-6.85(m,6H),6.78-6.54(m,1H),6.25(s,1H),4.13-4.05(m,5H),3.73-3.63(m,4H),3.41-3.27(m,9H),3.10-2.75(m,7H),1.83-1.66(m,4H),1.52-1.28(m,7H),1.06-0.97(m,7H)。LCMS(ESI):RT=1.042min,m/z实测值为908.3[M-CF3COOH+H]+。
化合物052
2-((2-乙氧基-4-(4-(4-((4-(4-(3-羟基-5-(4-羟基-5-异丙基-2-甲氧基苯基)-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-羰基)哌啶-1-基)苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,CD3OD):δ8.23(s,1H),8.10(d,J=8.8Hz,1H),7.75-7.71(m,1H),7.53-7.47(m,1H),7.35(d,J=8.0Hz,2H),7.25-7.11(m,5H),6.69-6.59(m,2H),6.24(s,1H),5.36-5.31(m,1H),4.60(s,3H),4.57-4.50(m,1H),4.16-4.04(m,3H),3.67-3.56(m,4H),3.47(s,3H),3.40(s,3H),3.21-3.11(m,3H),2.83-2.72(m,3H),2.63-2.48(m,7H),2.33-2.26(m,2H),2.21-2.15(m,1H),2.06-1.99(m,1H),1.82-1.78(m,7H),1.43(t,J=6.8Hz,3H),1.16(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.163min,m/z实测值为1005.4[M-CF3COOH+H]+。
化合物053
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)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,盐酸盐。1H NMR(400MHz,DMSO):δ11.92(s,1H),9.60(s,1H),9.36(d,J=2.4Hz,1H),8.41(d,J=4.8Hz,1H),8.20-8.13(m,2H),7.70-7.68(m,1H),7.52-7.50(m,1H),7.34-7.14(m,7H),6.85(s,1H),6.25(s,1H),4.47(d,J=6.0Hz,2H),4.18-4.13(m,2H),3.64-3.55(m,8H),3.54-3.45(m,3H),3.43(s,3H),3.40(s,3H),3.31-3.27(m,2H),3.01-2.97(m,1H),2.04-1.92(m,2H),1.38-1.33(m,4H),0.98(d,J=7.6Hz,6H)。LCMS(ESI):RT=1.341min,m/z实测值为870.0[M-HCl+H]+。
化合物054
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)(甲基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),11.33-10.48(m,1H),9.64(s,1H),9.41(s,1H),8.20(s,1H),7.68-7.47(m,5H),7.28-7.14(m,6H),6.89(s,2H),6.28(s,1H),4.48-4.46(m,1H),4.33-4.30(m,2H),4.20(d,J=3.2Hz,1H),4.06-3.91(m,4H),3.64-3.48(m,3H),3.34-3.31(m,9H),3.23-2.85(m,5H),1.88-1.80(m,4H),1.09-0.97(m,10H)。LCMS(ESI):RT=1.084min,m/z实测值为908.4[M-HCl+H]+。
化合物055
(S)-2-((4-(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)-3-甲基哌嗪-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.60(s,1H),9.41(s,1H),8.31(s,1H),7.87-7.13(m,11H),6.78-6.48(m,3H),6.27(s,1H),4.07(q,J=6.8Hz,2H),3.92-3.62(m,5H),3.38(s,3H),3.33(s,3H),3.28(s,1H),3.10-2.91(m,2H),2.87-2.61(m,3H),2.45-2.32(m,1H),2.15-1.94(m,1H),1.77-1.59(m,4H),1.31-1.23(m,5H),1.07(dd,J=31.7,5.4Hz,2H),0.95(d,J=6.0Hz,6H)。LCMS(ESI):RT=1.060min,m/z实测值为908.4[M-CF3COOH+H]+。
化合物056
N-(4-((4-(4-(3-(2,4-二羟基-5-异丙基苯基)-5-(异丙基氨基甲酰基)-4H-1,2,4-三唑-4-基)苄基)哌啶-1-基)甲基)苄基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ10.62(d,J=24Hz,1H),9.79(d,J=15.6Hz,1H),8.76(d,J=8.8Hz,1H),8.40-8.32(m,2H),7.87(s,1H),7.80(d,J=8.8Hz,1H),7.67(dd,J=7.7,1.6Hz,1H),7.51-7.4(m,1H),7.35-7.14(m,10H),6.63-6.37(m,2H),6.51(dd,J=8.8,1.9Hz,1H),6.35(s,1H),4.27-4.05(m,5H),3.95-3.86(m,1H),3.68(d,J=12.0Hz,2H),3.38(s,3H),3.28(s,3H),2.96-2.72(m,3H),2.70-2.59(m,2H),2.58-2.52(m,2H),2.39-2.27(m,2H),2.04-1.92(m,1H),1.85-1.66(m,5H),1.65-1.52(m,3H),1.31-1.23(m,6H),1.11-1.06(m,5H),0.80(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.330min,m/z实测值为1082.2[M-CF3COOH+H]+。
化合物057
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((((6-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)吡啶-3-基)甲基)(甲基)氨基)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。1H NMR(400MHz,DMSO-d6):δ10.03(s,1H),9.87-9.64(m,2H),8.64(s,1H),8.36(s,1H),8.12-7.87(m,3H),7.6(dd,J=7.8,1.5Hz,1H),7.67-7.40(m,7H),7.27-7.16(m,2H),6.99-6.76(m,2H),6.29(s,1H),4.56-4.36(m,6H),4.12(dd,J=13.7,6.0Hz,3H),4.01-3.92(m,4H),3.66(d,J=11.2Hz,2H),3.39(s,3H),3.31(s,3H),3.09-2.86(m,3H),2.81-2.86(m,2H),2.57-2.51(m,3H),2.11-1.97(m,1H),1.94-1.80(m,4H),1.72-1.55(m,2H),1.34(t,J=6.4Hz,3H),1.26-1.01(m,2H),0.91(d,J=6.6Hz,6H)。LCMS(ESI):RT=1.140min,m/z实测值为1136.4[M-CF3COOH+H]+。
化合物058
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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。1H NMR(400MHz,DMSO-d6):δ9.67-9.63(m,2H),8.85(s,1H),8.64(s,1H),7.76-7.74(d,J=7.7Hz,1H),7.60-7.59(d,J=6.9Hz,2H),7.48-7.34(m,6H),6.87-6.68(m,3H),6.31(s,1H),4.42-4.27(m,3H),4.14-4.10(m,8H),3.69(m,6H),3.46(s,3H),3.09-2.86(m,9H),2.57-2.47(m,2H),2.30-2.24(m,2H),2.01(s,1H),1.77-1.71(m,6H),1.19(t,J=6.9Hz,3H),1.18-0.90(m,2H),0.89(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.200min,m/z实测值为1149.9[M-CF3COOH+H]+。
化合物059
2-((4-(4-(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)哌啶-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.00(s,1H),9.70(s,1H),9.14(s,1H),8.84(s,1H),8.63(s,1H),7.76-7.74(m,1H),7.60(m,2H),7.59-7.40(m,3H),7.14-7.11(m,1H),7.02-6.99(m,1H),6.91(s,1H),6.26(s,1H),4.55-4.52(m,2H),4.05-4.02(m,3H),3.69-3.60(m,8H),3.46-3.41(m,3H),3.16-2.84(m,9H),2.06(m,2H),1.74(s,3H),1.28-1.17(m,8H),1.20(t,J=6.4Hz,3H),1.01(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.210min,m/z实测值为1058.9[M-CF3COOH+H]+。
化合物060
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.88(s,1H),9.62(m,2H),9.43(s,1H),8.82(s,1H),8.62(s,1H),7.76-7.74(m,1H),7.59-7.58(m,2H),7.47-7.45(m,2H),7.10-7.00(m,4H),6.78-6.52(m,2H),6.27(s,1H),4.60-4.50(m,1H),4.25-3.54(m,15H),3.46(s,3H),3.21-2.75(m,8H),2.15(m,2H),1.73-1.45(m,6H),1.19(t,J=6.4Hz,3H),0.94(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.150min,m/z实测值为1028.1[M-CF3COOH+H]+。
化合物061
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),9.62(s,1H),9.43(s,1H),8.88(s,1H),8.64(s,1H),7.76(d,J=7.8Hz,1H),7.60-7.20(m,8H),6.78-6.68(m,3H),6.26(s,1H),4.43-4.31(m,1H),4.07-3.99(m,4H),3.90-3.80(s,3H),3.70(s,8H),3.46(s,4H),3.06-2.81(m,11H),2.02-1.90(m,1H),1.88-1.72(m,6H),1.23-1.18(m,4H),0.98(d,J=7.6Hz,7H)。LCMS(ESI):RT=1.043min,m/z实测值为1054.9[M-CF3COOH+H]+。
化合物062
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)乙氧基)乙基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.88(s,1H),9.66(s,1H),9.43(s,1H),8.88(s,1H),8.65(s,1H),8.01-7.96(m,1H),7.76(d,J=7.8Hz,1H),7.60(d,J=3.6Hz,2H),7.48-7.45(m,2H),7.09(d,J=9.2Hz,1H),6.95-6.72(m,5H),6.26(s,1H),4.08-4.03(m,4H),3.74-3.66(m,9H),3.47-3.40(m,10H),3.23-3.17(m,4H),3.00-2.96(m,2H),2.42-2.33(m,1H),1.82(s,4H),1.23-1.18(m,4H),0.98(d,J=6.8Hz,7H)。LCMS(ESI):RT=1.253min,m/z实测值为1006.9[M-CF3COOH+H]+。
化合物063
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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):δ10.39(s,1H),9.71(s,1H),8.76(s,1H),8.60(s,1H),8.28(s,1H),7.74(d,J=7.2Hz,2H),7.59-7.57(m,2H),7.47-7.43(m,1H),7.35-7.25(m,5H),6.59-6.47(m,3H),6.32(s,1H),4.41-4.37(m,1H),4.03-3.96(m,3H),3.72-3.63(m,5H),3.49-3.45(m,6H),3.03-2.94(m,1H),2.77-2.70(m,4H),2.39-2.27(m,7H),2.24-2.08(m,5H),1.78-1.67(m,7H),1.17-1.13(m,3H),1.03-0.95(m,1H),0.83(t,J=7.2Hz,4H)。LCMS(ESI):RT=1.118min,m/z实测值为1069.2[M-CF3COOH+H]+。
化合物064
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.60(s,1H),9.41(s,1H),8.76(s,1H),8.60(s,1H),7.74(d,J=7.2Hz,1H),7.64-7.55(m,2H),7.47-7.43(m,1H),7.29-7.24(m,3H),7.12(d,J=8.4Hz,2H),6.77(s,1H),6.59-6.47(m,2H),6.26(s,1H),4.39(d,J=12.8Hz,1H),4.06-3.97(m,3H),3.70(d,J=11.6Hz,5H),3.44(d,J=12.4Hz,6H),3.34-3.30(m,4H),3.05-2.93(m,2H),2.82-2.66(m,4H),2.46-2.23(m,4H),1.86-1.58(m,6H),1.38-1.13(m,5H),0.94(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.150min,m/z实测值为1042.2[M-CF3COOH+H]+。
化合物065
N-(2-(2-(4-((2-氨基甲酰基-4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.12(s,1H),8.37(s,1H),8.20-8.05(m,3H),7.90(d,J=8.4Hz,1H),7.69(dd,J=7.6,1.6Hz,1H),7.64-7.47(m,2H),7.26-7.16(m,4H),7.03-6.93(m,5H),4.55-4.28m,4H),4.16-4.08(m,5H),3.74(t,J=4.4Hz,2H),3.64(d,J=12.2Hz,2H),3.51(t,J=5.6Hz,2H),3.39(s,3H),3.32(s,3H),3.26(dd,J=11.4,5.8Hz,2H),2.91(s,2H),2.42(s,3H),1.88(s,3H),1.35(t,J=6.8Hz,3H),1.03(s,6H)。LCMS(ESI):RT=1.500min,m/z实测值为1030.4[M-CF3COOH+H]+。
化合物066
5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-(3-(4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)丙氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.13(s,1H),8.36(s,1H),8.21(s,1H),8.16-8.07(m,1H),7.91(d,J=8.4Hz,1H),7.70-7.49(m,3H),7.26-7.16(m,4H),7.04-6.94(m,5H),4.41(d,J=16.4Hz,2H),4.22-3.83(m,18H),3.67(d,J=10.4Hz,3H),3.39(s,3H),3.32(s,3H),2.92(s,3H),2.43(s,3H),2.15-2.04(m,2H),1.97-1.67(m,8H),1.34(t,J=6.9Hz,3H),1.13-0.93(m,9H)。LCMS(ESI):RT=1.180min,m/z实测值为1166.5[M-CF3COOH+H]+。
化合物067
N-(2-(2-(4-((2-氨基甲酰基-4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.12(s,1H),8.85(s,1H),8.64(s,1H),8.19(s,1H),8.01(s,1H),7.91-7.89(m,1H),7.76-7.74(m,1H),7.59-7.58(m,3H),7.49-7.44(m,2H),7.25-7.22(m,2H),7.03-6.93(m,5H),4.10-3.96(m,5H),3.75-3.65(m,8H),3.51-3.46(m,6H),3.28-3.23(m,2H),2.91(s,3H),2.43(s,3H),1.85-1.72(m,4H),1.21-1.18(m,3H),1.03(s,6H)。LCMS(ESI):RT=1.500min,m/z实测值为1094.3[M-CF3COOH+H]+。
化合物068
5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-(3-(4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)丙氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.13(s,1H),8.85(s,1H),8.63(s,1H),8.21(s,1H),7.91(d,J=8.5Hz,1H),7.75(d,J=7.8Hz,1H),7.59(d,J=3.8Hz,3H),7.50-7.43(m,1H),7.25(d,J=8.9Hz,2H),7.04(d,J=2.0Hz,1H),7.00-6.91(m,3H),4.41(m,2H),4.11-3.95(m,13H),3.70(s,6H),3.46(s,3H),3.11(m,8H),2.92(s,3H),2.89-2.79(m,2H),2.43(s,2H),2.00(m,4H),1.76(s,6H),1.19(t,J=6.7Hz,3H),1.04(s,6H)。LCMS(ESI):RT=1.160min,m/z实测值为616.1[1/2M-CF3COOH+H]+。
化合物069
2-((4-(4-(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-(三氟甲基)苄基)哌嗪-1-基)哌啶-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.04(s,1H),9.69-9.35(m,3H),8.84(s,1H),8.63(s,1H),7.75(d,J=7.5Hz,2H),7.62-7.43(m,5H),6.93(s,1H),6.72(m,2H),6.25(s,1H),4.55(m,1H),4.14-4.02(m,8H),3.70(s,6H),3.46(s,6H),3.15-2.83(m,9H),2.10(s,2H),1.76(s,4H),1.19(t,J=6.7Hz,3H),1.02(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.100min,m/z实测值为1109.3[M-CF3COOH+H]+。
化合物070
2-((2-乙氧基-4-(4-(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-羰基)哌啶-1-基)苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.94(s,1H),9.62-9.33(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.60-7.20(m,8H),6.87(d,J=4.4Hz,1H),6.86-6.64(m,1H),6.24(s,1H),4.44-4.34(m,4H),4.13-3.98(m,5H),3.72-3.65(m,6H),3.46-3.42(m,5H),3.16-2.81(m,8H),2.43-2.31(m,4H),1.97-1.93(m,1H),1.78-1.68(m,6H),1.19(d,J=6.8Hz,4H),0.98(d,J=7.6Hz,5H)。LCMS(ESI):RT=1.004min,m/z实测值为1041.4[M-CF3COOH+H]+。
化合物071
1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)-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)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.55(s,1H),9.35(d,J=2.4Hz,1H),8.85(s,1H),8.64(s,1H),8.45(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.43(m,2H),7.22-7.10(m,4H),6.90(s,1H),7.84-6.70(m,1H),6.23(s,1H),4.27(d,J=5.6Hz,2H),4.07-4.00(m,2H),3.84-5.54(m,7H),3.46(s,3H),3.05-3.78(m,2H),2.45-2.34(m,3H),1.87-1.79(m,4H),1.19(d,J=6.4Hz,3H),1.01(d,J=7.2Hz,3H)。LCMS(ESI):RT=1.205min,m/z实测值为875.2[M-CF3COOH+H]+。
化合物072
2-((4-(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-(三氟甲基)苄基)哌嗪-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.08(s,1H),9.66(s,1H),9.39(s,1H),8.85(s,1H),8.63(s,1H),7.86-7.74(m,2H),7.60-7.44(s,6H),6.97(s,1H),6.78-6.63(m,2H),6.25(s,1H),4.08-4.00(m,2H),3.73-3.65(m,7H),3.46-3.36(m,10H),3.07-2.73(m,5H),1.76(s,4H),1.23-1.16(m,4H),1.04(d,J=7.2Hz,6H)。LCMS(ESI):RT=1.314min,m/z实测值为1025.9[M-CF3COOH+H]+。
化合物073
N-(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)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),9.57(s,1H),9.33(s,1H),8.84(s,1H),8.63(s,1H),8.48-8.40(m,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=4.0Hz,2H),7.52-7.39(m,2H),7.23-7.09(m,4H),6.94(s,1H),6.85-6.60m,2H),6.23(s,1H),4.30-4.24(m,2H),4.10-3.99(m,2H),3.75-3.64(m,6H),3.46(s,3H),3.02-2.82(m,2H),2.44-2.38(m,1H),1.97(s,3H),1.92-1.74(m,4H),1.22-1.15(m,3H)。LCMS(ESI):RT=1.063min,m/z实测值为861.7[M-CF3COOH+H]+。
化合物074
N-(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)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.88(s,1H),9.60-9.30(m,2H),8.84(s,1H),8.64(s,1H),8.48-8.39(m,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.50-7.39(m,2H),7.25-7.07(m,5H),6.89-6.61(m,3H),6.23(s,1H),4.27(d,J=5.7Hz,2H),4.10-4.00(m,2H),3.70(s,5H),3.46(s,4H),2.36-2.29(m,2H),2.04-1.76(m,5H),1.47-1.38(m,2H),1.24-1.16(m,6H),0.82-0.77(m,3H)。LCMS(ESI):RT=1.157min,m/z实测值为889.6[M-CF3COOH+H]+。
化合物075
N-环丙基-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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):δ9.72(s,1H),9.07(d,J=4.8Hz,1H),8.86(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.62-7.56(m,3H),7.50-7.30(m,6H),6.92-6.60(m,3H),6.30(s,1H),4.44-4.36(m,3H),4.09-3.97(m,7H),3.73-3.64(m,7H),3.46(s,5H),3.04-2.88(m,6H),2.77-2.65(m,3H),2.61-2.54(m,2H),2.30-2.23(m,2H),2.06-1.94(m,1H),1.84-1.69(m,7H),1.26-1.16(m,4H),1.14-0.96(m,2H),0.91-0.85(m,3H),0.67-0.55(m,4H)。LCMS(ESI):RT=1.032min,m/z实测值为1108.3[M-CF3COOH+H]+。
化合物076
5-(2,4-二羟基-5-异丙基苯基)-4-(4-(((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)苄基)(甲基)氨基)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。1H NMR(400MHz,DMSO-d6):δ10.03-9.65(m,4H),8.83(s,1H),8.63(s,1H),7.75(d,J=7.2Hz,1H),7.64-7.26(m,13H),6.84-6.54(m,3H),6.30(s,1H),4.53-4.44(m,1H),4.38(d,J=14.1Hz,2H),4.27-4.16(m,3H),4.00-3.94(m,6H),3.69(s,6H),3.46(s,3H),3.03-2.83(m,4H),2.59-2.55(m,2H),1.83-1.64(m,6H),1.23-1.16(m,5H),1.05-0.97(m,1H),0.91(d,J=6.4Hz,6H)。LCMS(ESI):RT=1.200min,m/z实测值为600.5[M/2-CF3COOH+H]+。
化合物077
(R)-N-(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)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.61(s,1H),9.47-9.30(m,2H),8.81(s,1H),8.62(s,1H),8.37(d,J=7.6Hz,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.37(m,7H),7.24-7.09(m,4H),6.84-6.51(m,3H),6.26(d,J=3.2Hz,1H),4.98-4.91(m,1H),4.22(d,J=2.9Hz,2H),4.05-4.01(m,2H),3.71-3.67(m,6H),3.46(s,3H),3.33(d,J=13.3Hz,1H),3.18-3.07(m,1H),3.00–2.79(m,4H),1.81-1.67(m,8H),1.42-1.34(m,5H),1.17(t,J=6.8Hz,3H),0.94(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.140min,m/z实测值为1089.8[M-CF3COOH+H]+。
化合物078
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,盐酸盐。1H NMR(400MHz,DMSO-d6):δ9.73-9.61(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.49-7.32(m,6H),6.84-6.63(m,2H),6.30(s,1H),4.68-4.60(m,1H),4.44-4.36(m,2H),4.33-4.14(m,6H),4.08-.399(m,4H),3.69(s,5H),3.46(s,3H),3.20-2.77(m,10H),2.61-2.56(m,1H),2.28(q,J=7.6Hz,2H),2.08-1.95(m,1H),1.85-1.67(m,6H),1.34(d,J=7.0Hz,3H),1.19(t,J=6.8Hz,3H),1.14-0.98(m,2H),0.90(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.100min,m/z实测值为1164.3[M-HCl+H]+。
化合物079
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1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)-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)哌啶-4-基)甲基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),9.60(s,1H),9.46(s,1H),9.32(s,1H),8.80(s,1H),8.62(s,1H),7.89(s,1H),7.75(d,J=8.0Hz,1H),7.60-7.44(m,4H),7.38-7.16(m,3H),6.91(s,1H),6.67(s,2H),6.23(s,1H),4.30(m,3H),4.07-4.00(m,2H),3.70(m,7H),3.46(s,3H),3.28(m,4H),2.93(s,7H),2.37(m,7.3Hz,3H),1.87-1.56(m,10H),1.29-1.08(m,5H),1.01(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.000min,m/z实测值为1083.3[M-CF3COOH+H]+。
化合物080
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)苄基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.90(s,1H),9.58-9.36(m,2H),8.86(s,1H),8.64(s,1H),8.46(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.44(m,2H),7.24-7.11(m,4H),6.88-6.69(m,3H),6.24(s,1H),4.28(d,J=5.6Hz,2H),4.23-3.97(m,5H),3.70(s,4H),3.46(s,3H),3.03-2.96(m,2H),1.88(s,4H),1.20(t,J=6.8Hz,3H),1.01(d,J=6.8Hz,7H)。LCMS(ESI):RT=1.225min,m/z实测值为889.2[M-CF3COOH+H]+。
化合物081
5-(2,4-二羟基-5-甲基苯基)-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.93-9.50(m,3H),8.86(s,1H),8.64(s,1H),7.76(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.52-7.32(m,6H),6.97-6.59(m,3H),6.29(s,1H),4.49-4.36(m,6H),4.05-3.93(m,6H),3.70(s,5H),3.46(s,3H),3.14-2.83(m,8H),2.06-1.96(m,1H),1.87(s,3H),1.84-1.71(m,6H),1.25-1.10(m,6H),1.05-0.95(m,1H),0.85-0.71(m,1H)。LCMS(ESI):RT=1.060min,m/z实测值为1136.3[M-CF3COOH+H]+。
化合物082
2-((2-乙氧基-4-(4-(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)-2-氟苄基)哌嗪-1-基)甲基)哌啶-1-羰基)哌啶-1-基)苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ11.96(s,1H),9.59(s,1H),9.37(s,1H),8.74(s,1H),8.60(s,1H),7.74(d,J=7.2Hz,1H),7.58(d,J=3.2Hz,2H),7.47-7.25(s,3H),7.05-6.89(m,3H),6.59-6.47(m,2H),6.25(s,1H),4.38-4.29(m,1H),4.03-3.96(m,3H),3.68-3.65(m,5H),3.47-3.45(m,6H),3.08-2.96(m,1H),2.81-2.66(m,3H),2.65-2.55(m,3H),2.40-2.32(m,8H),2.10(d,J=6.8Hz,2H),1.75-1.66(m,7H),1.15(t,J=7.2Hz,3H),1.01(t,J=7.6Hz,4H),0.96-0.85(m,1H)。LCMS(ESI):RT=1.000min,m/z实测值为1059.3[M-CF3COOH+H]+。
化合物083
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1-甲基环丙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.72(s,1H),9.14(s,1H),8.83(s,1H),8.63(s,1H),7.75(d,J=8.0Hz,2H),7.62-7.30(m,10H),6.81-6.62(m,3H),6.30(s,1H),4.47-4.45(m,2H),4.13-4.01(m,5H),3.69(s,7H),3.50-3.42(m,7H),3.14-3.06(m,3H),2.96-2.80(m,2H),2.29-2.23(s,2H),2.11-1.98(m,1H),1.85-1.70(m,8H),1.25-1.23(m,3H),1.19-1.13(m,3H),1.03-0.98(m,1H),0.87(t,J=7.2Hz,4H),0.67(s,2H),0.53(s,2H)。LCMS(ESI):RT=1.058min,m/z实测值为1122.3[M-CF3COOH+H]+。
化合物084
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(戊-3-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.72(s,1H),8.85(s,1H),8.66-8.63(m,2H),7.75(d,J=8.0Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.31(m,6H),6.81-6.55(m,3H),6.31(s,1H),4.42-4.40(m,2H),4.33-4.25(m,4H),4.17-4.00(m,6H),3.69(s,5H),3.57-3.55(m,1H),3.46(s,5H),3.06-2.87(m,9H),2.30-2.24(m,2H),2.05-1.96(m,1H),1.88-1.76(m,6H),1.46-1.40(m,4H),1.21(t,J=6.8Hz,3H),1.15-0.97(m,2H),0.90(t,J=7.6Hz,3H),0.79(t,J=6.8Hz,6H)。LCMS(ESI):RT=1.099min,m/z实测值为1138.4[M-CF3COOH+H]+。
化合物085
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.96(s,1H),9.94(s,1H),9.61(s,1H),9.30(s,1H),8.78(s,1H),8.61(s,1H),7.75(d,J=7.6Hz,1H),7.61-7.43(m,5H),7.37-7.25(m,3H),6.97(s,1H),6.71-6.51(m,2H),6.23(s,1H),4.54-4.19(m,4H),4.10-3.97(m,4H),3.74-3.66(m,7H),3.46(s,4H),3.37-3.26(m,2H),3.12-2.78(m,5H),1.98(s,3H),1.80-1.65(m,4H),1.17(t,J=6.8Hz,3H)。LCMS(ESI):RT=1.000min,m/z实测值为930.3[M-CF3COOH+H]+。
化合物086
2-((2-乙氧基-4-(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-羰基)哌啶-1-基)苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.90(s,1H),9.55(s,1H),9.35(s,1H),8.74(s,1H),8.60(s,1H),7.74(d,J=7.6Hz,1H),7.62-7.54(m,2H),7.48-7.41(m,1H),7.33-7.11(m,5H),6.83(s,1H),6.62-6.45(m,2H),6.25(s,1H),4.08-3.95(m,2H),3.74-3.62(m,5H),3.56-3.44(m,9H),2.82-2.68(m,3H),2.41-2.27(m,6H),1.72-1.63(m,4H),1.17-1.12(m,3H),1.00-0.94(m,3H)。LCMS(ESI):RT=1.036min,m/z实测值为944.2[M-CF3COOH+H]+。
化合物087
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.54-9.33(m,2H),8.76-8.58(m,2H),7.74(d,J=7.6Hz,1H),7.61-7.42(m,3H),7.31-7.10(m,5H),6.79(s,1H),6.62-6.46(m,2H),6.25(s,1H),4.08-3.96(m,2H),3.75-3.64(m,5H),3.57-3.44(m,9H),2.82-2.66(m,3H),2.42-2.27(m,6H),1.73-1.62(m,4H),1.43-1.33(m,2H),1.15(t,J=6.8Hz,3H),0.77(t,J=7.2Hz,3H)。LCMS(ESI):RT=1.069min,m/z实测值为958.3[M-CF3COOH+H]+。
化合物088
1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)-N-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)-2-氟苄基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.96(s,1H),9.59(s,1H),9.39(s,1H),8.85(s,1H),8.64(s,1H),8.44(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=4.0Hz,2H),7.48-7.44(m,2H),7.25(t,J=8.4Hz,1H),7.06(dd,J=10.8,1.5Hz,1H),6.99-6.92(m,2H),6.91-6.66(m,2H),6.25(s,1H),4.30(d,J=5.4Hz,2H),4.09-4.01(m,3H),3.70(s,4H),3.46(s,3H),2.97(s,2H),2.40(q,J=7.6Hz,3H),1.94-1.74(m,4H),1.20(t,J=6.7Hz,3H),1.04(t,J=7.6Hz,3H)。LCMS(ESI):RT=1.290min,m/z实测值为892.8[M-CF3COOH+H]+。
化合物089
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1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)-N-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)-2-(三氟甲基)苄基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),9.60(s,1H),9.38(s,1H),8.86(s,1H),8.64(s,1H),8.54(s,1H),7.76(d,J=7.6Hz,1H),7.63-7.39(m,7H),7.01(s,1H),6.96-6.64(m,2H),6.24(s,1H),4.44(d,J=5.2Hz,2H),4.08-4.03(m,3H),3.70(s,5H),3.47(s,3H),3.17-2.85(m,2H),2.41(q,J=7.6Hz,2H),2.00-1.75(m,4H),1.20(t,J=6.8Hz,3H),1.05(t,J=7.6Hz,3H)。LCMS(ESI):RT=1.370min,m/z实测值为942.7[M-CF3COOH+H]+。
化合物090
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.59(d,J=24.4Hz,2H),8.67(d,J=56.0Hz,2H),7.74(d,J=7.6Hz,1H),7.63-7.54(m,2H),7.50-7.41(m,1H),7.32-7.18(m,3H),7.15-6.97(m,3H),6.64-6.43(m,2H),6.30-6.11(m,2H),4.37(d,J=12.7Hz,1H),4.08-3.92(m,3H),3.80-3.59(m,5H),3.43(d,J=14.0Hz,5H),3.37-3.34(m,2H),3.11-2.94(m,1H),2.84-2.64(m,3H),2.44-2.24(m,7H),2.11(d,J=6.8Hz,2H),1.82-1.57(m,7H),1.15(t,J=6.8Hz,3H),1.06-0.79(m,2H)。LCMS(ESI):RT=1.040min,m/z实测值为1012.8[M-CF3COOH+H]+。
化合物091
1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)-N-(2-(2-(4-(3-(5-乙基-2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苯氧基)乙氧基)乙基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.84(s,1H),9.57-9.33(m,2H),8.85(s,1H),8.64(s,1H),7.98(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.48-7.44(m,2H),7.08(d,J=7.2Hz,2H),6.93-6.68(m,5H),6.25(s,1H),4.16-3.99(m,5H),3.77-3.66(m,7H),3.50-3.41(m,5H),3.25-3.22(m,2H),3.04-2.88(m,2H),2.38-2.32(m,3H),1.78(s,4H),1.24-1.17(m,3H),1.00(d,J=7.2Hz,3H)。LCMS(ESI):RT=1.223min,m/z实测值为948.8[M-CF3COOH+H]+。
化合物092
N-(4-(3-(2,4-二羟基苯基)-5-羟基-4H-1,2,4-三唑-4-基)苄基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),9.62-9.58(m,2H),8.83(d,J=4.8Hz,1H),8.63(s,1H),8.42(d,J=3.6Hz,1H),7.75(d,J=8.0Hz,1H),7.59(d,J=4.0Hz,2H),7.48-7.43(m,2H),7.21-7.03(m,5H),6.87-6.55(m,1H),6.24-6.16(m,2H),4.27(d,J=6.0Hz,2H),4.08-4.00(m,2H),3.95-3.55(m,8H),3.46(s,3H),3.12-2.64(m,2H),1.86-1.77(m,4H),1.19(d,J=6.8Hz,3H)。LCMS(ESI):RT=1.108min,m/z实测值为847.2[M-CF3COOH+H]+。
化合物093
5-(2,4-二羟基-5-丙基苯基)-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)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):δ9.25(s,1H),9.28-9.21(m,1H),9.08(s,1H),8.84(s,1H),8.63(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=4.0Hz,2H),7.47-7.30(m,6H),6.72-6.65(m,2H),6.30(s,1H),4.44-4.33(m,3H),4.07-4.02(m,4H),3.69(s,6H),3.56-3.49(m,5H),3.46(s,4H),3.20(d,J=5.2Hz,2H),3.06-2.83(m,12H),2.61-2.53(m,1H),2.24(t,J=7.2Hz,2H),2.11-1.92(m,1H),1.83-1.55(m,12H),1.35-1.29(m,1H),1.20-0.99(m,5H),0.74(t,J=7.2Hz,6H)。LCMS(ESI):RT=0.936min,m/z实测值为597.6[M/2-CF3COOH+H]+。
化合物094
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4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-(2-(4-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌嗪-1-基)乙氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.16(s,2H),8.82(s,1H),8.63(s,1H),8.21(s,1H),7.91(d,J=8.4Hz,1H),7.75(d,J=7.6Hz,1H),7.65-7.56(m,3H),7.51-7.36(m,2H),7.29(d,J=8.8Hz,2H),7.09-7.02(m,3H),6.99-6.94(m,1H),6.80-6.56(m 2H),4.58-4.43(m,1H),4.41-4.34(m,2H),4.09-4.02(m,5H),3.75-3.67(m,6H),3.64-3.56(m,4H),3.46(s,4H),2.98-2.86(m,5H),2.43(s,2H),1.84-1.70(m,4H),1.19(t,J=6.8Hz,3H),1.04(s,6H)。LCMS(ESI):RT=1.276min,m/z实测值为1118.8[M-CF3COOH+H]+。
化合物095
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(3-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺基)丙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.64(s,1H),8.43(s,1H),7.99(s,1H),7.86(s,1H),7.81-7.73(m,2H),7.59(d,J=4.0Hz,2H),7.50-7.35(m,2H),7.10-6.70(m,5H),4.57-4.48(m,1H),4.09-4.02(m,3H),3.73-3.63(m,7H),3.49-3.42(m,4H),3.09-3.03(m,2H),3.00-2.95(m,4H),2.45(s,2H),2.36-2.31(m,1H),2.06-1.78(m,8H),1.54-1.19(m,9H),1.03(s,6H)。LCMS(ESI):RT=1.509min,m/z实测值为1112.9[M-CF3COOH+H]+。
化合物096
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-乙基-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,DMSO-d6):δ10.39(s,1H),9.73(s,1H),8.99-8.93(m,1H),8.75(s,1H),8.60(s,1H),7.74(d,J=7.6Hz,1H),7.58(d,J=3.6Hz,2H),7.45-7.25(m,8H),6.60-6.47(m,3H),6.32(s,1H),5.05-5.01(m,1H),4.42-4.33(m,1H),4.05-3.96(m,3H),3.71-3.60(m,6H),3.49(s,2H),3.45(s,3H),3.19-3.15(m,2H),3.05-2.99(m,1H),2.79-2.71(m,3H),2.42-2.31(m,7H),2.24-2.11(m,4H),2.03-1.95(m,1H),1.77-1.66(m,6H),1.28-1.14(m,8H),1.07-1.01(m,4H),0.86-0.81(m,4H)。LCMS(ESI):RT=1.134min,m/z实测值为1095.8[M-HCl+H]+。
化合物097
4-(4-(((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)苄基)(甲基)氨基)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。1H NMR(400MHz,DMSO-d6):δ10.03-9.65(m,3H),8.88(s,1H),8.65(s,1H),7.76(d,J=7.6Hz,1H),7.76-7.29(m,12H),6.96-6.72(m,3H),6.29(s,1H),4.52-4.18(m,5H),4.11-3.92(m,5H),3.76-3.67(m,5H),3.47(s,4H),3.16-2.79(m,4H),2.61-2.55(m,4H),2.29(q,J=7.4Hz,2H),1.91-1.71(m,5H),1.70-1.53(m,2H),1.32-1.08(m,5H),1.04-0.90(m,4H)。LCMS(ESI):RT=1.255min,m/z实测值为1184.7[M-CF3COOH+H]+。
化合物098
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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):δ10.34(d,J=20.0Hz,1H),9.73(s,1H),8.77(d,J=11.6Hz,2H),8.60(s,1H),7.74(d,J=8.0Hz,1H),7.59-7.24(m,8H),6.59-6.47(m,3H),6.32(s,1H),4.38(d,J=12.0Hz,1H),4.19(q,J=6.8Hz,1H),4.07-3.87(m,4H),3.69(d,J=10.0Hz,5H),3.53-3.47(m,2H),3.45(s,4H),3.10-2.95(m,1H),2.81-2.68(m,3H),2.43-2.28(m,6H),2.22(q,J=7.4Hz,2H),2.12(d,J=6.8Hz,2H),2.04-1.94(m,1H),1.81-1.62(m,7H),1.23-1.07(m,10H),0.89-0.80(m,4H)。LCMS(ESI):RT=1.155min,m/z实测值为1109.8[M-CF3COOH+H]+。
化合物099
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)(乙基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.62(s,1H),9.38(s,1H),8.79-8.37(m,1H),7.20(s,1H),7.56-7.35(m,4H),7.21(d,J=8.8Hz,2H),7.13-6.97(m,1H),6.82(s,1H),6.73-6.47(m,2H),6.26(s,1H),4.43-4.36(m,1H),4.09-3.93(m,12H),3.68-3.64(m,3H),3.44(s,4H),3.21(s,3H),3.09-2.83(m,9H),2.63-2.54(m,2H),2.06-1.89(m,1H),1.82-1.61(m,6H),1.19-1.04(m,6H),0.98(d,J=6.8Hz,7H)。LCMS(ESI):RT=5.067min,m/z实测值为1083.3[M-CF3COOH+H]+。
化合物100
5-(2,4-二羟基-5-甲基苯基)-4-(4-(((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)苄基)(甲基)氨基)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。1H NMR(400MHz,DMSO-d6):δ10.04(s,1H),9.70-9.58(m,2H),8.74(s,1H),8.60(s,1H),7.74(d,J=7.6Hz,1H),7.59-7.13(m,13H),6.65-6.46(m,3H),6.30(s,1H),5.45-5.11(m,1H),4.46-4.36(m,1H),4.00-3.93(m,5H),3.71-3.61(m,4H),3.68(s,2H),3.51-3.45(m,4H),2.99-2.92(m,1H),2.75-2.67(m,3H),2.07-1.97(m,4H),1.80-1.52(m,10H),1.24(s,3H),1.19-1.13(m,3H),0.97-0.83(m,2H)。LCMS(ESI):RT=1.245min,m/z实测值为1172.1[M-CF3COOH+H]+。
化合物101
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-(2-(4-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌嗪-1-基)乙氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.16(s,1H),8.38(s,1H),8.27-8.20(m,2H),8.12-8.04(m,1H),7.92(d,J=8.8Hz,1H),7.71-7.50(m,3H),7.31-6.96(m,10H),4.37(s,2H),4.17-4.11(m,3H),3.86-3.76(m,7H),3.65-3.55(m,6H),3.40(s,3H),3.33(s,3H),3.22-3.11(m,2H),3.00-2.94(m,3H),2.43(s,2H),1.89(s,3H),1.35(t,J=6.8Hz,3H),1.04(s,6H)。LCMS(ESI):RT=1.302min,m/z实测值为1154.8[M-CF3COOH+H]+。
化合物102
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(3-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺基)丙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.39(s,2H),8.22-7.96(m,4H),7.81-7.68(m,2H),7.54-7.50(m,1H),7.37-7.07(m,6H),6.90(s,1H),6.75-6.72(m,1H),4.53(s,1H),4.18-4.12(m,2H),3.69-3.65(m,3H),3.58-3.40(m,5H),3.34-3.24(m,5H),3.11-2.98(m,6H),2.45(s,3H),2.06-1.93(m,7H),1.57-1.48(m,4H),1.38-1.23(m,5H),1.04(s,6H)。LCMS(ESI):RT=1.519min,m/z实测值为1048.9[M-CF3COOH+H]+。
化合物103
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(2-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺基)乙氧基)乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.54-8.33(m,2H),8.24-7.96(m,4H),7.83-7.67(m,2H),7.55-6.87(m,8H),6.76-6.69(m,1H),4.59-4.49(m,1H),4.18-4.09(m,2H),3.67(s,3H),3.44-3.38(m,8H),3.32(s,3H),3.27-3.20(m,3H),3.17-3.09(m,3H),2.97(s,2H),2.44(s,3H),2.08-1.87(m,8H),1.56-1.43(m,2H),1.38-1.21(m,7H),1.03(s,6H)。LCMS(ESI):RT=1.506min,m/z实测值为1078.8[M-CF3COOH+H]+。
化合物104
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(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基4-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌嗪-1-羧酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.36-8.34(m,2H),8.29-7.96(m,3H),7.85-7.67(m,2H),7.56-7.48(m,1H),7.37(s,1H),7.29-7.17(m,2H),7.15-6.95(m,2H),6.89(d,J=2.0Hz 1H),6.74(dd,J=8.4,1.6Hz,1H),4.68-4.58(m,1H),4.20-4.12(m,2H),3.68(s,4H),3.52-3.48(m,5H),3.46-3.43(m,2H),3.41-3.37(m,5H),3.33(s,4H),2.99(s,3H),2.45(s,2H),2.06-1.88(m,8H),1.61-1.51(m,2H),1.42-1.33(m,5H),1.04(s,6H)。LCMS(ESI):RT=1.594min,m/z实测值为1060.9[M-CF3COOH+H]+。
化合物105
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(2-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺基)乙氧基)乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.83(s,1H),8.64(s,1H),8.43(s,1H),8.05-7.89(m,2H),7.82-7.72(m,2H),7.59(d,J=3.6Hz,2H),7.52-7.31(m,3H),7.11-7.04(m,1H),6.95-6.67(m,4H),4.58-4.49(m,1H),4.10-4.01(m,3H),3.72-3.65(m,6H),3.48-3.37(m,9H),3.25-3.09(m,4H),3.03-2.85(m,4H),2.44(s,3H),2.08-1.79(m,8H),1.55-1.17(m,8H),1.03(s,6H)。LCMS(ESI):RT=1.508min,m/z实测值为1142.9[M-CF3COOH+H]+。
化合物106
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基4-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌嗪-1-羧酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.89(s,1H),8.66(s,1H),8.49(s,1H),8.00(s,1H),7.81-7.75(m,2H),7.60-7.31(m,5H),6.95-6.73(m,4H),4.65-4.60(m,1H),4.10-4.04(m,3H),3.69(d,J=8.8Hz,4H),3.60-3.33(m,13H),3.25-3.09(m,1H),3.02-2.87(m,3H),2.45(s,2H),2.07-1.78(m,8H),1.56(dd,J=20.6,10.3Hz,2H),1.37(dd,J=21.2,10.7Hz,2H),1.22(t,J=6.8Hz,3H),1.04(s,6H)。LCMS(ESI):RT=1.590min,m/z实测值为1124.9[M-CF3COOH+H]+。
化合物107
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,盐酸盐。1H NMR(400MHz,DMSO-d6):δ11.58(s,1H),9.80(s,1H),9.66(d,J=9.0Hz,1H),9.09(s,1H),8.72(s,1H),7.99-7.27(m,12H),6.80(s,1H),6.37(s,1H),4.66(m,1H),4.40(m,2H),4.17-4.12(m,4H),3.72(s,7H),3.60(s,4H),3.48(s,5H),3.11(s,4H),2.61(t,J=11.6Hz,1H),2.20(m,10H),1.40-1.24(m,6H),1.22-1.03(m,2H),0.95(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.140min,m/z实测值为1164.3[M-HCl+H]+。
化合物108
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.10(s,1H),8.40(s,1H),8.30-8.11(m,3H),7.91(d,J=8.4Hz,1H),7.71-7.50(m,3H),7.27-6.93(m,10H),4.47(d,J=12.4Hz,1H),4.17(q,J=6.8Hz,2H),4.04(d,J=12.4Hz,1H),3.86(d,J=6.0Hz,2H),3.70-3.64(m,2H),3.40(s,3H),3.34(s,3H),3.16-2.02(m,2H),2.91(s,2H),2.69-2.56(m,1H),2.52-2.43(m,4H),2.08-1.79(m,7H),1.38(t,J=6.8Hz,3H),1.29-1.14(m,2H),1.04(s,6H)。LCMS(ESI):RT=1.493min,m/z实测值为1040.5[M-CF3COOH+H]+。
化合物109
(1R,4R)-4-((2-氰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(2-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺基)乙氧基)乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.37(s,1H),8.17-8.01(m,3H),7.69(dd,J=7.9,2.0Hz,2H),7.54-7.49(m,1H),7.26-6.86(m,7H),6.18(d,J=7.6Hz,1H),4.52-4.43(m,1H),4.14(q,J=6.8Hz,2H),3.67-3.64(m,3H),3.42-3.39(m,6H),3.33(s,3H),3.23(dd,J=11.2,5.6Hz,3H),3.14(dd,J=11.6,6.0Hz,2H),2.98(s,2H),2.55-2.38(m,5H),2.08-1.80(m,8H),1.59-1.41(m,4H),1.35(t,J=6.8Hz,3H),1.03(s,6H)。LCMS(ESI):RT=1.458min,m/z实测值为1061.5[M-CF3COOH+H]+。
化合物110
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.09(s,1H),8.92(s,1H),8.67(s,1H),8.20(s,1H),7.90(d,J=8.4Hz,1H),7.76(d,J=7.6Hz,1H),7.61-7.45(m,5H),7.23(d,J=8.8Hz,2H),7.03-6.83(m,6H),4.48-4.44(m,1H),4.12-4.01(m,3H),3.86(d,J=6.0Hz,2H),3.71-3.64(m,5H),3.30-3.08(m,2H),2.96-2.90(m,3H),2.64-2.57(m,1H),2.51-2.43(m,5H),2.08-1.84(m,8H),1.27-1.15(m,6H),1.03(s,6H)。LCMS(ESI):RT=1.497min,m/z实测值为1104.4[M-CF3COOH+H]+。
化合物111
(1R,4R)-4-((2-((l2-亚氮烷基)-l3-甲基)-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(2-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺基)乙氧基)乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.86(s,1H),8.64(s,1H),7.97(d,J=5.2Hz,1H),7.77-7.44(m,6H),7.10-6.86(m,5H),6.18(s,1H),4.47(s,1H),4.08-4.01(m,2H),3.70-3.63(m,6H),3.41-3.40(m,4H),3.29-3.20(m,2H),3.15-3.11(m,2H),3.02-2.98(m,4H),2.51-2.34(m,6H),2.08-1.83(m,8H),1.52-1.43(m,4H),1.24-1.18(m,4H),1.03(s,6H)。LCMS(ESI):RT=1.492min,m/z实测值为1125.5[M-CF3COOH+H]+。
化合物112
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4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-((1-(1-(3-乙氧基-4-(乙基(5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.10(s,1H),8.86(s,1H),8.19(s,1H),7.90(d,J=8.4Hz,1H),7.71-7.41(m,5H),7.23(d,J=8.8Hz,2H),7.03-6.93(m,5H),6.62-6.45(m,2H),4.44(s,1H),4.06-3.74(m,11H),3.45-3.40(m,3H),3.22(s,2H),3.12-3.00(m,1H),2.90-2.73(m,5H),2.59-2.50(m,1H),2.43(s,2H),2.03-1.95(m,1H),1.86-1.68(m,6H),1.23-1.10(m,8H),1.08(s,6H)。LCMS(ESI):RT=1.907min,m/z实测值为1132.3[M-CF3COOH+H]+。
化合物113
(1R,4R)-4-((2-((l2-亚氮烷基)-l3-甲基)-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(2-(1-(3-乙氧基-4-(乙基(5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺基)乙氧基)乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.65(s,1H),8.45(s,1H),7.88-7.87(m,1H),7.71-7.68(m,3H),7.48-7.42(m,3H),7.08-6.87(m,4H),6.62-6.60(m,2H),6.19-6.17(m,1H),4.48-4.46(m,1H),4.00-3.71(m,6H),3.53-3.38(m,8H),3.22-2.98(m,8H),2.72-2.70(m,2H),2.44(s,2H),2.33-2.32(m,1H),1.96-1.95(m,4H),1.71-1.44(m,9H),1.23-1.08(m,5H),1.02(s,6H)。LCMS(ESI):RT=1.860min,m/z实测值为1153.3[M-CF3COOH+H]+。
化合物114
4-(4-((4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.70(s,1H),9.58-9.56(m,1H),8.31(s,1H),7.86(s,1H),7.80-7.78(m,1H),7.68-7.66(m,1H),7.51-7.47(m,1H),7.34-7.14(m,6H),6.61(s,2H),6.51-6.48(m,1H),6.31(s,1H),4.66-4.64(m,1H),4.39-4.36(m,1H),4.10-3.95(m,3H),3.67-3.64(m,2H),3.48(s,2H),3.38(s,3H),3.30-3.28(m,5H),3.02-2.98(m,1H),2.87-2.68(m,3H),2.38-2.33(m,6H),2.25-2.21(m,2H),2.12-2.11(m,2H),1.77-1.68(m,7H),1.33-1.28(m,7H),0.88-0.84(m,5H)。LCMS(ESI):RT=1.140min,m/z实测值为1100.3[M-CF3COOH+H]+。
化合物115
4-(4-((4-((1-(1-(3-乙氧基-4-(乙基(5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),9.70(s,1H),9.58-9.56(m,1H),8.66(s,1H),7.72-7.68(m,2H),7.49-7.41(m,3H),7.32-7.25(m,4H),7.05-6.98(m,1H),6.62-6.59(m,3H),6.31(s,1H),4.66-4.64(m,1H),4.37-4.36(m,1H),3.97-3.75(m,9H),3.48-3.41(m,6H),3.30-3.22(m,2H),3.05-2.95(m,1H),2.82-2.76(m,3H),2.45-2.38(m,5H),2.27-2.21(m,5H),1.77-1.71(m,8H),1.14-1.07(m,5H),0.88-0.73(m,5H)。LCMS(ESI):RT=1.229min,m/z实测值为1190.1[M-CF3COOH-H]-。
化合物116
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(2-(2-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺基)乙氧基)乙氧基)乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.76(s,1H),8.60(s,1H),8.43(d,J=7.2Hz,1H),8.07-7.70(m,4H),7.62-7.54(m,2H),7.48-7.22(m,3H),7.13-7.06(m,1H),6.89(d,J=1.6Hz,1H),6.73(dd,J=8.4,1.6Hz,1H),6.59(d,J=2.0Hz,1H),6.51-6.45(m,1H),4.58-4.48(m,1H),4.07-3.94(m,2H),3.75-3.63(m,5H),3.50(s,4H),3.45(s,3H),3.42-3.38(m,4H),3.32-3.30(m,1H),3.25-3.17(m,2H),3.14-3.08(m,2H),2.98(s,2H),2.69-2.59(m,2H),2.44(s,2H),2.34-2.22(m,1H),2.07-1.87(m,4H),1.78-1.60(m,4H),1.54-1.43(m,2H),1.38-1.25(m,2H),1.15(t,J=6.8Hz,3H),1.03(s,6H)。LCMS(ESI):RT=1.415min,m/z实测值为1187.0[M-CF3COOH+H]+。
化合物117
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-羧酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.47(s,1H),8.85(s,1H),8.63(s,1H),8.50(s,1H),8.03(s,1H),7.83-7.73(m,2H),7.59(d,J=3.6Hz,2H),7.51-7.30(m,3H),6.89(d,J=1.6Hz,1H),6.78-6.62(m,2H),4.68-4.60(m,1H),4.45-4.37(m,1H),4.07-4.00(m,6H),3.74-3.66(m,6H),3.54-3.44(m,7H),3.30-3.18(m,2H),3.06-2.97(m,6H),2.93-2.81(m,2H),2.64-2.54(m,1H),2.45(s,2H),2.08-1.91(m,5H),1.82-1.68(m,6H),1.61-1.51(m,2H),1.44-1.33(m,2H),1.21-1.15(m,3H),1.04(s,6H)。LCMS(ESI):RT=1.345min,m/z实测值为1222.6[M-CF3COOH+H]+。
化合物118
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基4-(1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)哌嗪-1-羧酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.76(s,1H),8.60(s,1H),8.48(d,J=7.6Hz,1H),8.00(s,1H),7.82-7.72(m,2H),7.617-.54(m,2H),7.50-7.23(m,3H),6.88(d,J=2.0Hz,1H),6.73(dd,J=8.4,1.6Hz,1H),6.59(d,J=1.6Hz,1H),6.48(dd,J=8.8,2.0Hz,1H),4.63-4.53(m,1H),4.46-4.37(m,1H),4.09-3.96(m,3H),3.75-3.63(m,5H),3.45(s,4H),3.33-3.31(m,6H),3.08-2.92(m,3H),2.84-2.68(m,3H),2.45(s,7H),2.06-1.88(m,4H),1.84-1.62(m,6H),1.57-1.47(m,2H),1.40-1.28(m,3H),1.15(t,J=6.8Hz,3H),1.03(s,6H)。LCMS(ESI):RT=1.318min,m/z实测值为1208.6[M-CF3COOH+H]+。
化合物119
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)-2-氧代乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.70(s,1H),8.60(s,1H),8.42(d,J=7.6Hz,1H),7.97(s,1H),7.82-7.72(m,2H),7.58(d,J=4.0Hz,2H),7.48-7.42(m,1H),7.36-7.22(m,2H),7.03-6.96(m,1H),6.89(s,1H),6.72(d,J=8.0Hz,1H),6.59(s,1H),6.49(d,J=8.4Hz,1H),4.58-4.50(m,1H),4.43-4.33(m,1H),4.07-3.94(m,3H),3.85-3.78(m,2H),3.73-3.62(m,5H),3.50-3.36(m,8H),3.08-2.94(m,3H),2.82-2.68(m,3H),2.59-2.52(m,1H),2.45(s,2H),2.38-2.26(m,4H),2.17-1.90(m,6H),1.81-1.64(m,7H),1.56-1.46(m,2H),1.39-1.29(m,2H),1.18-1.13(m,3H),1.04(s,6H),0.98-0.80(m,2H)。LCMS(ESI):RT=1.298min,m/z实测值为1279.6[M-CF3COOH+H]+。
化合物120
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(2-(2-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺基)乙氧基)乙氧基)乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.42(d,J=7.2Hz,1H),8.30(s,1H),7.97(s,1H),7.85-7.66(m,4H),7.67(d,J=8.6Hz,1H),7.48(t,J=8.4Hz,1H),7.31(s,1H),7.23-7.13(m,2H),7.04(t,J=6.0Hz,1H),6.88(s,1H),6.75-6.69(m,1H),6.61(d,J=2.0Hz,1H),6.53-6.46(m,1H),4.53(s,1H),4.07(q,J=7.2Hz,2H),3.69-3.60(m,2H),3.50(s,4H),3.44-3.36(m,8H),3.28(s,3H),3.23-3.18(m,2H),3.15-3.09(m,2H),2.97(s,2H),2.68-2.57(m,2H),2.44(s,2H),2.30-2.21(m,1H),2.09-1.88(m,4H),1.80-1.62(m,4H),1.54-1.42(m,2H),1.36-1.27(m,5H),1.03(s,6H)。LCMS(ESI):RT=1.450min,m/z实测值为1123.4[M-CF3COOH+H]+。
化合物121
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-羧酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.44(s,1H),8.49(s,1H),8.35(s,1H),8.02(d,J=30.8Hz,3H),7.80(d,J=8.4Hz,1H),7.69(d,J=8.8Hz,1H),7.54-7.48(m,1H),7.34(s,1H),7.25-7.16(m,2H),6.92-6.71(m,3H),4.64(s,1H),4.41(d,J=12.8Hz,1H),4.14-4.09(m,2H),4.05-4.00(m,2H),3.70-3.67(m,3H),3.49(s,3H),3.39(s,3H),3.31-3.20(m,6H),3.15-2.88(m,10H),2.65-2.55(m,1H),2.45(s,2H),2.16-1.93(m,6H),1.79(s,6H),1.62-1.53(m,2H),1.43-1.24(m,5H),1.04(s,6H)。LCMS(ESI):RT=1.250min,m/z实测值为1158.3[M-CF3COOH+H]+。
化合物122
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基(2-(4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)-2-氧代乙基)氨基甲酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.43(d,J=7.2Hz,1H),8.32(s,1H),8.00(s,1H),7.86(s,1H),7.79(d,J=8.4Hz,2H),7.67(dd,J=7.7,1.6Hz,1H),7.51-7.45(m,1H),7.35(s,1H),7.24-7.14(m,2H),7.04(t,J=5.6Hz,1H),6.90(s,1H),6.73(dd,J=9.2,1.6Hz,1H),6.61(d,J=2.2Hz,1H),6.50(dd,J=8.8,2.4Hz,1H),4.59-4.48(m,1H),4.39(d,J=13.6Hz,1H),4.10-3.94(m,3H),3.81(d,J=5.2Hz,2H),3.66(d,J=12.0Hz,2H),3.47-3.38(m,8H),3.28(s,4H),3.07-2.96(m,3H),2.79-2.67(m,3H),2.45(s,2H),2.31(d,J=16.4Hz,4H),2.17-1.90(m,6H),1.82-1.63(m,8H),1.57-1.47(m,2H),1.37-1.28(m,5H),1.04(s,7H)。LCMS(ESI):RT=1.330min,m/z实测值为1215.7[M-CF3COOH+H]+。
化合物123
(R)-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.73-9.61(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.49-7.32(m,6H),6.84-6.63(m,2H),6.30(s,1H),4.68-4.60(m,1H),4.44-4.36(m,2H),4.33-4.14(m,6H),4.08-.399(m,4H),3.69(s,5H),3.46(s,3H),3.20-2.77(m,10H),2.61-2.56(m,1H),2.28(q,J=7.6Hz,2H),2.08-1.95(m,1H),1.85-1.67(m,6H),1.34(d,J=7.0Hz,3H),1.19(t,J=6.8Hz,3H),1.14-0.98(m,2H),0.90(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.100min,m/z实测值为1164.3[M-CF3COOH+H]+。
化合物124
(S)-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.73-9.61(m,2H),8.85(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.49-7.32(m,6H),6.84-6.63(m,2H),6.30(s,1H),4.68-4.60(m,1H),4.44-4.36(m,2H),4.33-4.14(m,6H),4.08-.399(m,4H),3.69(s,5H),3.46(s,3H),3.20-2.77(m,10H),2.61-2.56(m,1H),2.28(q,J=7.6Hz,2H),2.08-1.95(m,1H),1.85-1.67(m,6H),1.34(d,J=7.0Hz,3H),1.19(t,J=6.8Hz,3H),1.14-0.98(m,2H),0.90(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.100min,m/z实测值为1164.3[M-CF3COOH+H]+。
化合物125
(1R,4R)-4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)环己基4-(1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)哌嗪-1-羧酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.48(d,J=8.0Hz,1H),8.32(s,1H),8.00(s,1H),7.87-7.77(m,3H),7.67(dd,J=7.8,2.0Hz,1H),7.51-7.47m,1H),7.35(s,1H),7.24-7.14(m,2H),6.88(d,J=1.6Hz,1H),6.73(dd,J=8.4,1.6Hz,1H),6.61(d,J=2.4Hz,1H),6.49(dd,J=8.8,2.0Hz,1H),4.58(s,1H),4.42(d,J=13.0Hz,1H),4.13-3.99(m,3H),3.66(d,J=12.4Hz,2H),3.52-3.43(m,1H),3.38(s,4H),3.30(s,2H),3.28(s,4H),3.03-2.93(m,3H),2.81-2.65(m,3H),2.45(s,7H),2.02-1.87(m,4H),1.84-1.62(m,6H),1.58-1.47(m,2H),1.38-1.18(m,7H),1.03(s,6H),0.98 -0.91(m,1H)。LCMS(ESI):RT=1.180min,m/z实测值为1144.4[M-CF3COOH+H]+。
化合物126
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2-((4-(4-(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)苯甲酰基)哌嗪-1-基)甲基)哌啶-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),9.60(s,1H),9.37(s,1H),8.31(s,1H),7.86-7.78(m,2H),7.78-7.66(m,1H),7.49-7.38(m,3H),7.24-7.14(m,4H),6.88(s,1H),6.61-6.60(m,1H),6.50-6.48(m,1H),6.26(s,1H),4.40-4.37(m,1H),4.08-4.05(m,3H),3.67-3.61(m,4H),3.28(m,4H),3.02-2.99(m,2H),2.74-2.70(m,3H),2.51-2.31(m,4H),2.16(m,2H),1.79-1.64(m,7H),1.31-1.24(m,4H),1.01-1.00(m,7H),0.98-0.85(m,1H)。LCMS(ESI):RT=1.040min,m/z实测值为1005.3[M-CF3COOH+H]+。
化合物127
2-((4-(4-(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)苯甲酰基)哌嗪-1-基)甲基)哌啶-1-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),9.60(s,1H),9.37(s,1H),8.74(s,1H),8.60(s,1H),7.74(d,J=7.7Hz,1H),7.58(d,J=3.5Hz,2H),7.49-7.33(m,3H),7.24(m,8.7Hz,3H),6.87(s,1H),6.59(s,1H),6.48(d,J=8.6Hz,1H),6.25(s,1H),4.37(s,1H),4.07-3.92(m,3H),3.68(s,7H),3.45(s,3H),3.31-3.23(m,3H),3.07-2.96(m,2H),2.75(s,3H),2.33(s,4H),2.16(s,2H),1.71(m,7H),1.15(t,J=6.9Hz,3H),1.00(d,J=6.9Hz,6H),0.96-0.78(m,2H)。LCMS(ESI):RT=1.020min,m/z实测值为1069.3[M-CF3COOH+H]+。
化合物128
2-((2-乙氧基-4-(4-(4-((4-(4-(3-羟基-5-(4-羟基-5-异丙基-2-甲氧基苯基)-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-羰基)哌啶-1-基)苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.95(s,1H),9.83(s,1H),8.82(s,1H),8.63(s,1H),7.75(d,J=7.8Hz,1H),7.59(d,J=3.7Hz,2H),7.51-7.31(m,4H),7.11(d,J=6.1Hz,3H),6.69(m,2H),6.30(s,1H),4.39(d,J=12.4Hz,1H),4.10-4.00(m,8H),3.69(s,7H),3.46(s,3H),3.21(s,3H),3.12-2.84(m,10H),1.95(s,1H),1.74(d,J=8.7Hz,6H),1.28-1.03(m,12H)。LCMS(ESI):RT=1.040min,m/z实测值为1069.3[M-CF3COOH+H]+。
化合物129
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-((1-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌啶-4-基)甲氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.11(s,1H),9.02(s,1H),8.37(s,1H),8.21-8.02(m,3H),7.91(d,J=8.8Hz,1H),7.70-7.49(m,3H),7.26-7.16(m,4H),7.03-6.93(m,5H),4.52-4.36(m,2H),4.16-4.10(m,3H),4.05-3.97(m,2H),3.87(d,J=5.2Hz,2H),3.69-3.56(m,4H),3.39-3.32(m,7H),3.15-3.03(m,2H),3.01-2.87(m,6H),2.61-2.53(m,1H),2.43(s,2H),2.17-1.95(m,3H),1.94-1.70(m,6H),1.68-1.57(m,2H),1.35(t,J=6.8Hz,3H),1.03(s,8H)。LCMS(ESI):RT=1.176min,m/z实测值为1137.3[M-CF3COOH+H]+。
化合物130
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-(2-(4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)乙氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.14(s,1H),8.37(s,1H),8.25-8.00(m,3H),7.91(d,J=8.8Hz,1H),7.70-7.49(m,3H),7.28-7.16(m,4H),7.06-6.94(m,7H),4.82-4.51(m,5H),4.42-4.39(m,2H),4.25(s,2H),4.16-4.11(m,2H),3.99(d,J=2.0Hz,1H),3.68-3.64(m,2H),3.40-3.32(m,10H),3.24-3.03(m,3H),2.97-2.89(m,4H),2.61-2.54(m,1H),2.43(s,3H),2.02-1.63(m,8H),1.35(t,J=6.8Hz,3H),1.04(s,7H)。LCMS(ESI):RT=1.151min,m/z实测值为1152.3[M-CF3COOH+H]+。
化合物131
N-(2-(2-(2-(4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙氧基)乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.12(s,1H),8.38(s,1H),8.20-8.06(m,4H),7.90(d,J=8.4Hz,1H),7.70-7.49(m,3H),7.26-6.93(m,10H),4.16-4.07(m,4H),3.76-3.55(m,8H),3.46-3.22(m,12H),2.90(s,2H),2.42(s,3H),1.91(s,4H),1.35(t,J=6.8Hz,3H),1.03(s,7H)。LCMS(ESI):RT=1.443min,m/z实测值为1074.3[M-CF3COOH+H]+。
化合物132
N-(2-(2-(2-(2-(4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙氧基)乙氧基)乙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.12(s,1H),8.37(s,1H),8.20-8.05(m,4H),7.90(d,J=8.4Hz,1H),7.70-7.49(m,3H),7.26-6.93(m,10H),4.16-4.08(m,4H),3.75-3.53(m,12H),3.44-3.21(m,12H),2.90(s,2H),2.42(s,3H),1.91(s,4H),1.35(t,J=6.8Hz,3H),1.03(s,7H)。LCMS(ESI):RT=1.443min,m/z实测值为1118.3[M-CF3COOH+H]+。
化合物133
2-((4-(4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)(乙基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.12(s,1H),7.65(d,J=6.8Hz,1H),7.48(s,1H),7.36-7.24(m,3H),7.19-7.09(m,4H),6.93(s,1H),6.69-6.55(m,2H),6.48(s,1H),6.25(s,1H),4.42-4.34(m,1H),4.05-3.86(m,5H),3.78-3.68(m,3H),3.48-3.39(m,7H),3.08-2.88(m,2H),2.82-2.70(m,4H),2.44-2.25(m,7H),2.16-2.07(m,2H),1.82-1.60(m,8H),1.23-0.96(m,8H),0.87(d,J=6.8Hz,8H)。LCMS(ESI):RT=1.266min,m/z实测值为1019.9[M-CF3COOH+H]+。
化合物134
4-(4-((4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-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。1HNMR(400MHz,DMSO-d6):δ10.38(s,1H),9.70(s,1H),8.99-8.92(m,1H),8.31(s,1H),7.86(s,1H),7.79(d,J=8.8Hz,1H),7.67(dd,J=8.0,1.6Hz,1H),7.53-7.46(m,1H),7.34(d,J=8.0Hz,2H),7.29-7.21(m,3H),7.19-7.12(m,1H),6.61(d,J=2.4Hz,1H),6.54(s,1H),6.52-6.47(m,1H),6.32(s,1H),4.42-4.34(m,1H),4.11-4.04(m,2H),4.01-3.93(m,1H),3.70-3.61(m,2H),3.49(s,2H),3.38(s,3H),3.30-3.25(m,5H),3.21-3.13(m,2H),3.08-2.95(m,1H),2.78-2.65(m,3H),2.59-2.51(m,2H),2.44-2.29(m,7H),2.24-2.18(m,2H),2.16-2.09(m,2H),1.80-1.64(m,7H),1.32-1.27(m,3H),1.04(t,J=7.2Hz,3H),0.85-0.81(m,3H)。LCMS(ESI):RT=1.051min,m/z实测值为1032.3[M-CF3COOH+H]+。
化合物135
4-(4-((4-((1-(1-(3-乙氧基-4-(乙基(5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-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):δ9.71(s,1H),9.04-8.96(m,1H),8.74-8.44(m,1H),7.72(s,1H),7.65-7.20(m,8H),7.16-6.94(m,1H),6.72-6.52(m,3H),6.31(s,1H),4.42-4.38(m,1H),4.02-3.74(m,10H),3.44(s,5H),3.24-3.13(m,5H),3.12-2.76(m,11H),2.63-2.53(m,2H),2.29-2.22(m,2H),2.11-1.91(m,1H),1.82-1.62(m,7H),1.14-1.03(m,9H),0.90-0.84(m,3H)。LCMS(ESI):RT=1.138min,m/z实测值为1124.3[M-CF3COOH+H]+。
化合物136
4-(4-((4-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)(乙基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-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):δ9.73(s,1H),9.00(t,J=5.6Hz,1H),8.17(s,1H),7.67(d,J=7.2Hz,1H),7.59-7.33(m,6H),7.27-7.13(m,2H),7.06(d,J=7.2Hz,1H),6.74(s,1H),6.63(s,2H),6.31(s,1H),4.40(d,J=13.6Hz,1H),4.13-3.66(m,11H),3.34(s,5H),3.21-3.14(m,3H),3.12-2.80(m,12H),2.63-2.54(m,2H),2.26(q,J=7.4Hz,2H),2.00(s,1H),1.85-1.68(m,7H),1.18-1.04(m,9H),0.87(t,J=7.4Hz,3H)。LCMS(ESI):RT=1.160min,m/z实测值为1060.4[M-CF3COOH+H]+。
化合物137
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-((1-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌啶-4-基)甲氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.12(s,1H),9.01(s,1H),8.85(s,1H),8.64(s,1H),8.21(s,1H),7.91(d,J=8.4Hz,1H),7.76(d,J=7.8Hz,1H),7.65-7.53(m,3H),7.51-7.38(m,2H),7.25(d,J=8.8Hz,2H),7.05-6.93(m,4H),6.83-6.59(m,2H),4.42(d,J=14.0Hz,1H),4.09-3.99(m,4H),3.87(d,J=5.6Hz,2H),3.70(s,4H),3.57(s,2H),3.46(s,3H),3.32-3.21(m,1H),3.16-3.03(m,2H),3.04-2.96(m,3H),2.92(s,3H),2.68-2.55(m,1H),2.43(s,4H),2.15-1.94(m,4H),1.86-1.70(m,5H),1.67-1.56(m,2H),1.23-1.13(m,4H),1.03(s,6H)。LCMS(ESI):RT=1.300min,m/z实测值为1201.6[M-CF3COOH+H]+。
化合物138
4-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)-2-((4-(2-(4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)乙氧基)苯基)氨基)苯甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.15(s,1H),8.90(s,1H),8.65(s,1H),8.22(s,1H),7.91(d,J=8.5Hz,1H),7.76(d,J=7.7Hz,1H),7.69-7.39(m,5H),7.27(d,J=8.8Hz,2H),7.08-6.72(m,6H),4.41(d,J=12.6Hz,1H),4.26(s,2H),4.05(m,4H),3.70(s,5H),3.47(s,3H),3.34(s,5H),3.09(m,5H),2.93(s,7H),2.57(t,J=12.3Hz,1H),2.43(s,2H),1.99(s,1H),1.79(s,6H),1.26-1.09(m,4H),1.04(s,7H)。LCMS(ESI):RT=1.270min,m/z实测值为1216.6[M-CF3COOH+H]+。
化合物139
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N-(2-(2-(2-(4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙氧基)乙基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.11(s,1H),8.86(s,1H),8.64(s,1H),8.20(s,1H),7.99(s,1H),7.90(d,J=8.5Hz,1H),7.76(d,J=7.7Hz,1H),7.59(d,J=3.8Hz,3H),7.47(m,1H),7.23(d,J=8.8Hz,2H),7.05-6.92(m,4H),6.86-6.71(m,1H),4.11-4.00(m,7H),3.79-3.63(m,8H),3.62-3.53(m,4H),3.48-3.40(m,5H),3.26-3.20(m,2H),2.90(s,2H),2.42(s,3H),1.83(s,4H),1.21(m,3H),1.03(s,6H)。LCMS(ESI):RT=1.555min,m/z实测值为1138.6[M-CF3COOH+H]+。
化合物140
N-(2-(2-(2-(2-(4-((2-氨基甲酰基-5-(6,6-二甲基-4-氧代-3-(三氟甲基)-4,5,6,7-四氢-1H-吲唑-1-基)苯基)氨基)苯氧基)乙氧基)乙氧基)乙氧基)乙基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.11(s,1H),8.88(s,1H),8.65(s,1H),8.20(s,1H),7.99(s,1H),7.90(d,J=8.5Hz,1H),7.76(d,J=7.7Hz,1H),7.68-7.40(m,5H),7.23(d,J=8.8Hz,2H),7.05-6.69(m,6H),4.11-4.03(m,4H),3.79-3.64(m,7H),3.62-3.37(m,14H),3.29-3.19(m,2H),3.02(s,1H),2.91(s,2H),2.42(s,3H),1.83(s,4H),1.20(t,J=6.7Hz,3H),1.03(s,6H)。LCMS(ESI):RT=1.555min,m/z实测值为1182.5[M-CF3COOH+H]+。
化合物141
2-((2-乙氧基-4-(4-(4-((4-(4-(3-羟基-5-(4-羟基-5-异丙基-2-甲氧基苯基)-4H-1,2,4-三唑-4-基)苄基)哌嗪-1-基)甲基)哌啶-1-羰基)哌啶-1-基)苯基)(乙基)氨基)-5,11-二甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1HNMR(400MHz,DMSO-d6):δ11.90(s,1H),9.76(s,1H),8.08(s,1H),7.65(d,J=7.6Hz,1H),7.52-7.39(m,1H),7.26-6.89(m,8H),6.57-6.46(m,2H),6.28(s,1H),4.39-4.35(m,1H),4.01-3.71(m,6H),3.41(s,2H),3.32-3.23(m,5H),3.17(s,3H),3.11-2.97(m,2H),2.82-2.76(m,4H),2.67-2.51(m,4H),2.33(s,7H),2.25-2.10(m,2H),2.02-1.92(m,1H),1.75-1.67(m,7H),1.09-1.00(m,10H),0.98-0.87(m,3H)。LCMS(ESI):RT=5.062min,m/z实测值为1033.3[M-CF3COOH+H]+。
化合物142
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-(5-乙基-4-羟基-2-甲氧基苯基)-N-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.87(s,1H),9.64(d,J=8.8Hz,1H),8.86(s,1H),8.64(s,1H),7.75(d,J=7.6Hz,1H),7.60(d,J=3.6Hz,2H),7.47-7.45(m,2H),7.35(s,2H),7.20-7.00(m,4H),6.82-6.68(m,1H),6.31(s,1H),4.62-4.55(m,2H),4.38-4.26(m,2H),4.06-3.96(m,3H),3.70(s,6H),3.46(s,3H),3.30(s,3H),3.21-2.58(m,11H),2.45-2.41(m,5H),2.11-1.52(m,8H),1.35(d,J=7.2Hz,3H),1.21-1.17(m,5H),1.08-1.04(m,3H)。LCMS(ESI):RT=1.085min,m/z实测值为1178.3[M-CF3COOH+H]+。
化合物143
N-(4'-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),8.39(s,1H),8.25-7.95(m,4H),7.85(d,J=8.4Hz,2H),7.73-7.49(m,6H),7.40-6.95(m,11H),4.75-4.66(m,2H),4.19-4.11(m,2H),3.94-3.78(m,8H),3.71-3.63(m,2H),3.54-3.45(m,1H),3.40(s,4H),3.33(s,4H),3.09-2.95(m,1H),2.10-1.85(m,6H),1.74-1.50(m,2H),1.37(t,J=6.8Hz,3H),1.27-1.21(m,1H)。LCMS(ESI):RT=1.778min,m/z实测值为993.1[M-CF3COOH+H]+。
化合物144
N-(4'-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),8.88(s,1H),8.65(s,1H),8.05-7.96(m,2H),7.88-7.73(m,3H),7.65-7.58(m,6H),7.49-6.94(m,9H),4.74-4.66(m,1H),4.08-4.03(m,2H),3.91-3.78(m,14H),3.73-3.67(m,5H),3.52-3.43(m,4H),3.34-3.26(m,1H),2.98-2.88(m,1H),2.10-1.51(m,8H),1.25-1.15(m,3H)。LCMS(ESI):RT=1.752min,m/z实测值为1057.1[M-CF3COOH+H]+。
化合物145
N-(4'-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),8.37(s,1H),8.14(s,1H),8.04-7.97(m,2H),7.84(d,J=8.8Hz,2H),7.70-7.49(m,6H),7.42-6.90(m,11H),4.51-4.43(m,1H),4.20-4.10(m,4H),4.10-4.00(m,3H),3.94-3.89(m,3H),3.87(s,3H),3.80(s,3H),3.71-3.63(m,3H),3.39(s,3H),3.32(s,3H),3.16-2.95(m,2H),2.68-2.57(m,1H),2.12-2.00(m,1H),1.96-1.76(m,5H),1.40-1.32(m,3H),1.27-1.13(m,2H)。LCMS(ESI):RT=1.858min,m/z实测值为1008.1[M-CF3COOH+H]+。
化合物146
N-(4'-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),8.89(s,1H),8.65(s,1H),8.06-7.97(m,2H),7.87-7.74(m,3H),7.64-7.57(m,6H),7.53-6.88(m,10H),4.52-4.44(m,1H),4.11-4.03(m,3H),3.93-3.89(m,2H),3.87(s,4H),3.80(s,5H),3.71(s,5H),3.47(s,3H),3.17-3.07(m,1H),2.96-2.89(m,1H),2.65-2.57(m,1H),2.11-2.02(m,1H),1.93-1.74(m,6H),1.27-1.14(m,6H)。LCMS(ESI):RT=1.763min,m/z实测值为1071.2[M-CF3COOH+H]+。
化合物147
N-(3-((4'-(3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺基)-[1,1'-联苯]-4-基)氧基)丙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.37(s,1H),8.23-7.92(m,5H),7.84(d,J=8.6Hz,2H),7.68(d,J=7.8Hz,1H),7.61(d,J=8.6Hz,4H),7.51(t,J=7.7Hz,1H),7.37(t,J=7.9Hz,1H),7.26(dd,J=8.6,5.0Hz,2H),7.21-7.05(m,4H),7.04-6.91(m,4H),5.17-4.24(m,3H),4.18-4.07(m,2H),4.07-3.98(m,2H),3.83(d,J=24.8Hz,6H),3.67(d,J=11.7Hz,2H),3.39(s,3H),3.32(s,3H),3.29-3.20(m,3H),1.98-1.77(m,6H),1.35(t,J=6.8Hz,3H)。LCMS(ESI):RT=1.637min,m/z实测值为967.2[M-CF3COOH+H]+。
化合物148
N-(3-((4'-(3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺基)-[1,1'-联苯]-4-基)氧基)丙基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.92(s,1H),8.66(s,1H),8.11-7.96(m,3H),7.84(d,J=8.6Hz,2H),7.76(d,J=7.9Hz,1H),7.61(d,J=8.4Hz,7H),7.54-7.41(m,2H),7.37(t,J=8.1Hz,1H),7.26(d,J=8.5Hz,1H),7.16-6.92(m,6H),4.18-4.01(m,9H),3.83(d,J=24.8Hz,6H),3.73-3.66(m,4H),3.47(s,3H),3.29-3.23(m,2H),1.99-1.77(m,6H),1.27-1.17(m,3H)。LCMS(ESI):RT=1.750min,m/z实测值为1032.0[M-CF3COOH+H]+。
化合物149
N-(4'-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)氧基)-2'-(3-(二甲基氨基)丙氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6)δ10.21(s,1H),9.40(s,1H),8.36(s,1H),8.17-7.94(m,4H),7.80(d,J=7.9Hz,2H),7.69(d,J=7.6Hz,1H),7.55-7.09(m,11H),6.97(d,J=8.7Hz,1H),6.78-6.67(m,2H),4.71(s,1H),4.16-4.03(m,7H),3.84(d,J=25.2Hz,9H),3.71-3.65(m,2H),3.53-3.45(m,1H),3.39(s,3H),3.31(s,4H),3.15-3.09(m,2H),2.99-2.90(m,1H),2.77(d,J=4.1Hz,6H),2.11-2.01(m,3H),1.98-1.92(m,1H),1.83(s,3H),1.72-1.63(m,1H),1.56(s,1H),1.39-1.31(m,3H)。LCMS(ESI):RT=1.390min,m/z实测值为1095.1[M-CF3COOH+H]+。
化合物150
N-(2'-(3-(二甲基氨基)丙氧基)-4'-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.43(s,1H),8.85(s,1H),8.63(s,1H),8.05-7.94(m,2H),7.78(dd,J=18.6,7.7Hz,3H),7.60(s,2H),7.46(d,J=8.2Hz,3H),7.38(t,J=7.7Hz,2H),7.29-7.24(m,2H),7.14-7.08(m,2H),6.96(d,J=8.4Hz,1H),6.80-6.59(m,4H),4.71(s,1H),4.09-3.99(m,5H),3.84(d,J=25.2Hz,8H),3.75-3.64(m,6H),3.46(s,4H),3.31(s,1H),3.16-3.07(m,2H),2.91(s,1H),2.77(d,J=4.3Hz,6H),2.09-1.91(m,5H),1.78(s,4H),1.70-1.63(m,1H),1.56(s,1H),1.22-1.15(m,3H)。LCMS(ESI):RT=1.390min,m/z实测值为1158.8[M-CF3COOH+H]+。
化合物151
N-(4'-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲氧基)-2'-(3-(二甲基氨基)丙氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6)δ10.21(s,1H),9.44(s,1H),8.38(s,1H),8.19(s,2H),8.02(dd,J=8.6,2.2Hz,1H),7.97(d,J=2.3Hz,1H),7.80(d,J=8.7Hz,2H),7.69(dd,J=7.8,1.6Hz,1H),7.55-7.49(m,1H),7.45(d,J=8.6Hz,2H),7.38(t,J=7.9Hz,1H),7.29-7.23(m,3H),7.19(t,J=7.4Hz,1H),7.15-7.06(m,3H),6.98-6.94(m,1H),6.69-6.62(m,2H),4.48(d,J=12.7Hz,1H),4.15(q,J=6.9Hz,2H),4.05(t,J=5.8Hz,3H),3.91(d,J=6.1Hz,2H),3.87(s,3H),3.81(s,3H),3.67(d,J=10.7Hz,2H),3.40(s,3H),3.33(s,3H),3.16-3.07(m,3H),3.00(s,1H),2.77(d,J=4.9Hz,6H),2.63(t,J=12.8Hz,1H),2.11-2.01(m,3H),1.95-1.78(m,6H),1.42-1.05(m,7H)。LCMS(ESI):RT=1.280min,m/z实测值为1108.4[M-CF3COOH+H]+。
化合物152
N-(3-((4'-(3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺基)-2-(3-(二甲基氨基)丙氧基)-[1,1'-联苯]-4-基)氧基)丙基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6)δ10.21(s,1H),9.44(s,1H),8.37(s,1H),8.21-7.93(m,5H),7.80(d,J=8.7Hz,2H),7.69(dd,J=7.7,1.6Hz,1H),7.54-7.08(m,11H),7.02-6.82(m,2H),6.69-6.61(m,2H),4.17-4.00(m,6H),3.84(d,J=25.1Hz,6H),3.67(d,J=11.7Hz,2H),3.39(s,3H),3.32(s,3H),3.28-3.24(m,2H),3.17-3.03(m,3H),2.76(d,J=4.8Hz,6H),2.43-2.35(m,1H),2.10-2.02(m,2H),1.95-1.79(m,6H),1.38-1.21(m,4H)。LCMS(ESI):RT=1.240min,m/z实测值为1068.4[M+CF3COOH+H]+。
化合物153
N-(4'-((1-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌啶-4-基)氧基)-2'-(3-(二甲基氨基)丙氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),10.23(s,1H),9.57(s,1H),8.92(s,1H),8.35(s,1H),8.07-7.95(m,3H),7.82(d,J=8.7Hz,2H),7.68(dd,J=7.7,1.6Hz,1H),7.54-7.34(m,5H),7.29-7.07(m,5H),6.96(dd,J=8.2,2.0Hz,1H),6.85-6.64(m,2H),5.76(s,1H),5.21-5.12(m,2H),4.43-4.26(m,5H),4.13-4.00(m,7H),3.86(s,3H),3.80(s,3H),3.70-3.60(m,2H),3.39(s,3H),3.30(s,3H),3.19-3.02(m,7H),2.95-2.85(m,1H),2.78(d,J=4.7Hz,6H),2.66-2.50(m,2H),2.22-2.02(m,3H),1.94-1.68(m,6H),1.32(t,J=6.8Hz,3H)。LCMS(ESI):RT=1.330min,m/z实测值为1192.2[M+CF3COOH+H]+。
化合物154
N-(4'-((1-((1-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌啶-4-基)氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,CD3OD)δ8.56(d,J=8.8Hz,1H),8.33(s,1H),8.03-7.91(m,2H),7.76(d,J=8.1Hz,3H),7.63-7.48(m,6H),7.37-7.04(m,12H),6.91(d,J=9.2Hz,1H),4.62(d,J=12.9Hz,1H),4.30-4.16(m,3H),3.90(s,3H),3.83(s,4H),3.78-3.66(m,5H),3.52-3.31(m,8H),3.25-3.09(m,6H),2.80-2.69(m,1H),2.31-1.90(m,13H),1.52(t,J=6.8Hz,3H)。LCMS(ESI):RT=1.340min,m/z实测值为1090.4[M+CF3COOH+H]+。
化合物155
N-(2'-(3-(二甲基氨基)丙氧基)-4'-((1-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌啶-4-基)氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,CD3OD)δ8.56(d,J=8.8Hz,1H),8.33(s,1H),8.03-7.91(m,2H),7.76(d,J=8.1Hz,3H),7.63-7.48(m,6H),7.37-7.04(m,12H),6.91(d,J=9.2Hz,1H),4.62(d,J=12.9Hz,1H),4.30-4.16(m,3H),3.90(s,3H),3.83(s,4H),3.78-3.66(m,5H),3.52-3.31(m,8H),3.25-3.09(m,6H),2.80-2.69(m,1H),2.31-1.90(m,13H),1.52(t,J=6.8Hz,3H)。LCMS(ESI):RT=1.304min,m/z实测值为1254.0[M+CF3COOH+H]+。
化合物156
N-(4'-((1-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌啶-4-基)氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),10.22(s,1H),9.57(s,1H),8.86(d,J=40.0Hz,2H),8.62(s,1H),8.05-7.95(m,2H),7.83-7.74(m,3H),7.60 -7.24(m,9H),7.15-7.07(m,2H),6.97-6.05(m,1H),6.71-6.56(m,2H),5.76(s,1H),5.21-5.12(m,2H),4.45-4.29(m,4H),4.06-3.99(m,7H),3.86(s,3H),3.80(s,3H),3.69(s,4H),3.46(s,3H),3.19-3.01(m,7H),2.88-2.74(m,9H),2.62-2.50(m,2H),2.20-2.04(m,3H),1.95-1.67(m,6H),1.17(t,J=6.8Hz,3H)。LCMS(ESI):RT=1.285min,m/z实测值为1256.5[M+CF3COOH+H]+。
化合物157
N-(3-((4'-(3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺基)-2-(3-(二甲基氨基)丙氧基)-[1,1'-联苯]-4-基)氧基)丙基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),9.42(s,1H),8.79(s,1H),8.62(s,1H),8.04-7.94(m,3H),7.83-7.72(m,3H),7.58(d,J=3.4Hz,2H),7.45(d,J=8.8Hz,3H),7.25(t,J=7.6Hz,7H),7.19-7.15(m,6H),7.00-6.94(m,1H),6.70-6.63(m,3H),4.09-3.99(m,6H),3.87(s,3H),3.80(s,3H),3.72-3.66(m,5H),3.27-3.22(m,2H),3.14-3.06(m,2H),2.76(d,J=4.7Hz,6H),2.30(s,6H),2.12-2.04(m,2H),1.92-1.85(m,2H),1.81-1.75(m,2H),1.23(s,1H),1.20-1.12(m,3H)。LCMS(ESI):RT=1.350min,m/z实测值为1132.7[M-CF3COOH+H]+。
化合物158
N-(2'-(3-(二甲基氨基)丙氧基)-4'-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲氧基)-[1,1'-联苯]-4-基)-3',6-二甲氧基-[1,1'-联苯]-3-甲酰胺,三氟乙酸。1H NMR(400MHz,CD3OD)δ8.68(s,1H),8.37(d,J=8.7Hz,1H),7.98(dd,J=8.6,2.3Hz,1H),7.93(d,J=2.3Hz,1H),7.85(d,J=6.5Hz,1H),7.75(d,J=8.6Hz,2H),7.66-7.55(m,6H),7.50(t,J=7.5Hz,1H),7.35-7.02(m,8H),6.92(d,J=1.7Hz,1H),4.61(d,J=13.8Hz,1H),4.27-4.13(m,3H),3.90(s,3H),3.83(s,3H),3.80-3.62(m,5H),3.61-3.50(m,7H),3.44-3.33(m,2H),3.25-3.10(m,4H),2.74(t,J=11.9Hz,1H),2.45-1.84(m,12H),1.47(t,J=7.0Hz,3H),1.38-1.18(m,4H)。LCMS(ESI):RT=1.420min,m/z实测值为1171.2[M-CF3COOH+H]+。
化合物159
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,CD3OD)δ8.53(s,1H),7.81(dd,1H),7.67-7.56(m,2H),7.54-7.37(m,4H),7.25(d,J=8.3Hz,2H),6.74(s,1H),6.65(d,J=2.2Hz,1H),6.58(dd,J=8.7,2.4Hz,1H),6.27(s,1H),4.13-3.97(m,2H),3.73-3.54(m,13H),3.09-2.98(m,1H),2.86-2.74(m,3H),2.58-2.39(m,4H),2.25-2.12(m,1H),1.92-1.74(m,4H),1.33-1.28(m,7H),0.98-0.89(m,6H)。LCMS(ESI):RT=1.160min,m/z实测值为958.5[M-CF3COOH+H]+。
化合物160
2-((4-(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-羰基)哌啶-1-基)-2-乙氧基苯基)(乙基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,CD3OD)δ8.53(s,1H),7.81(dd,1H),7.67-7.56(m,2H),7.54-7.37(m,4H),7.25(d,J=8.3Hz,2H),6.74(s,1H),6.65(d,J=2.2Hz,1H),6.58(dd,J=8.7,2.4Hz,1H),6.27(s,1H),4.13-3.97(m,2H),3.73-3.54(m,13H),3.09-2.98(m,1H),2.86-2.74(m,3H),2.58-2.39(m,4H),2.25-2.12(m,1H),1.92-1.74(m,4H),1.33-1.28(m,7H),0.98-0.89(m,6H)。LCMS(ESI):RT=1.160min,m/z实测值为985.5[M-CF3COOH+H]+。
化合物161
4-(4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-((1,1,1-三氟丙-2-基)氨基甲酰基)-4H-1,2,4-三唑-3-基)-2-乙基-5-羟基苯基异丁酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.68(s,1H),8.34(d,J=8.2Hz,1H),7.86(d,J=6.4Hz,1H),7.65-7.60(m,1H),7.56(d,J=7.3Hz,1H),7.52-7.45(m,3H),7.36(d,J=8.3Hz,2H),7.19(s,1H),7.14(d,J=8.5Hz,1H),7.08(s,1H),6.46(s,1H),4.73-4.63(m,1H),4.58(d,J=12.4Hz,1H),4.32-4.03(m,4H),3.92(s,2H),3.76(s,3H),3.59(d,J=13.9Hz,9H),3.20(d,J=14.0Hz,5H),2.96(s,4H),2.86-2.80(m,3H),2.71(t,J=11.8Hz,2H),2.34(q,J=7.5Hz,2H),2.14-2.10(M,6H),2.01-1.80(m,3H),1.47-1.41(m,6H),1.28(d,J=7.0Hz,6H),0.99(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.360min,m/z实测值为618.3[M/2-CF3COOH+H]+。
化合物162
2-(4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-5-((1,1,1-三氟丙-2-基)氨基甲酰基)-4H-1,2,4-三唑-3-基)-4-乙基-5-羟基苯基异丁酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ8.68(s,1H),8.34(d,J=8.2Hz,1H),7.86(d,J=6.4Hz,1H),7.65-7.60(m,1H),7.56(d,J=7.3Hz,1H),7.52-7.45(m,3H),7.36(d,J=8.3Hz,2H),7.19(s,1H),7.14(d,J=8.5Hz,1H),7.08(s,1H),6.46(s,1H),4.73-4.63(m,1H),4.58(d,J=12.4Hz,1H),4.32-4.03(m,4H),3.92(s,2H),3.76(s,3H),3.59(d,J=13.9Hz,9H),3.20(d,J=14.0Hz,5H),2.96(s,4H),2.86-2.80(m,3H),2.71(t,J=11.8Hz,2H),2.34(q,J=7.5Hz,2H),2.14-2.10(M,6H),2.01-1.80(m,3H),1.47-1.41(m,6H),1.28(d,J=7.0Hz,6H),0.99(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.360min,m/z实测值为618.3[M/2-CF3COOH+H]+。
化合物163
N-(2-(二乙基氨基)乙基)-5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.77(s,1H),9.24(t,J=6.0Hz,2H),8.34(s,1H),8.03(s,1H),7.92-7.90(m,1H),7.68(dd,J=8.0,4.0Hz,1H),7.54-7.47(m,3H),7.44(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,1H),7.18(t,J=6.0Hz,1H),6.80(s,1H),6.73(s,1H),6.31(s,1H),4.35(s,1H),4.10(q,J=16.0Hz,1H),3.70-3.67(m,8H),3.56-3.52(m,4H),3.39(s,3H),3.30(s,3H),3.22-3.17(m,8H),3.00–2.85(m,5H),1.79(s,4H),1.32(t,J=6.0Hz,3H),1.19(t,J=6.0Hz,6H),0.92(d,J=8.0Hz,6H)。LCMS(ESI):RT=1.120min,m/z实测值为1021.2[M-CF3COOH+H]+。
化合物164
N-(2-(二乙基氨基)乙基)-5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),9.24(t,J=5.9Hz,2H),8.78(s,1H),8.62(s,1H),7.75(d,J=8.0Hz,1H),7.59(d,J=4.0Hz,2H),7.52(d,J=8.3Hz,2H),7.45-7.43(m,2H),7.33(d,J=8.0Hz,1H),6.73(s,1H),6.67(s,1H),6.56(d,J=8.0Hz,1H),6.31(s,1H),4.34(s,1H),4.07-3.99(m,1H),3.73-3.68(m,6H),3.54(s,6H),3.49(s,3H),3.46(s,3H),3.24-3.16(m,8H),3.00-2.93(m,1H),2.84(s,4H),1.74(s,4H),1.22–1.14(m,9H),0.92(d,J=8.0Hz,6H)。LCMS(ESI):RT=1.090min,m/z实测值为1085.3[M-CF3COOH+H]+。
化合物165
N-(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)苄基)-1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),9.83(s,1H),9.67(s,1H),9.37(s,1H),8.56(t,J=5.8Hz,1H),8.37(s,1H),8.15(s,1H),8.02(s,1H),7.69(dd,J=7.7,1.6Hz,1H),7.53-7.49(m,3H),7.45(d,J=8.1Hz,2H),7.34(d,J=8.1Hz,2H),7.27-7.24(m,3H),7.18(t,J=7.5Hz,1H),7.03-6.96(m,1H),6.90(s,2H),6.25(s,1H),4.31(dd,J=20.5,8.4Hz,6H),4.14-4.12(m,3H),3.68(d,J=12.0Hz,2H),3.39(s,3H),3.32(s,3H),3.13(s,1H),3.04-2.91(m,3H),1.94(s,4H),1.35(t,J=6.9Hz,3H),1.25(t,J=7.1Hz,4H),1.01(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.250min,m/z实测值为972.5[M-CF3COOH+H]+。
化合物166
N-(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)苄基)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),9.70(d,J=39.7Hz,2H),9.36(s,1H),8.84(s,1H),8.63(s,1H),8.50(t,J=6.0Hz,1H),7.75(d,J=7.8Hz,1H),7.59(d,J=3.7Hz,2H),7.52-7.42(m,5H),7.33(d,J=8.0Hz,2H),7.26(d,J=8.2Hz,2H),6.90(s,1H),6.83-6.57(m,2H),6.24(s,1H),4.34-4.26(m,5H),4.06-4.02(m,2H),3.74-3.68(m,5H),3.46(s,3H),3.03-2.84(m,5H),2.45-2.39(m,1H),1.90-1.75(m,4H),1.26-1.23(m,4H),1.18(t,J=6.7Hz,3H),1.01(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.240min,m/z实测值为1036.4[M-CF3COOH+H]+。
化合物167
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-N-(2-(4-甲基哌嗪-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.99-8.96(m,1H),8.34(s,1H),8.06(s,1H),7.93(d,J=8.6Hz,1H),7.69(dd,J=7.8,1.6Hz,1H),7.59-7.47(m,4H),7.44(d,J=8.4Hz,2H),7.24(d,J=8.1Hz,1H),7.18(t,J=7.4Hz,1H),6.84(s,1H),6.76-6.71(m,1H),6.69(s,1H),6.32(s,1H),4.37(s,2H),4.14-4.08(m,3H),3.70-3.67(m,8H),3.40-3.34(m,11H),3.31(s,5H),2.99-2.92(m,4H),2.78(s,3H),2.75-2.67(m,3H),1.81(s,4H),1.33(t,J=6.9Hz,3H),0.90(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.240min,m/z实测值为1048.2[M-CF3COOH+H]+。
化合物168
2-((4-(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)-2-氧代乙氧基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6(11H)-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.86(s,1H),9.07-9.04(m,1H),8.88(s,1H),8.69(s,1H),7.82(d,J=8.0Hz,1H),7.66-7.60(m,4H),7.55-7.49(m,3H),7.44(d,J=12.0Hz,1H),6.79-6.76(m,2H),6.68(d,J=8.0Hz,1H),6.38(s,1H),4.44(s,2H),4.13-4.08(m,2H),3.80-3.75(m,8H),3.52(s,3H),3.46-3.42(m,4H),3.30-3.21(m,4H),3.05-3.01(m,1H),3.00-2.92(m,4H),2.85(s,3H),2.80-2.72(m,3H),1.83-1.80(m,4H),1.25(t,J=6.0Hz,3H),0.97(d,J=8.0Hz,6H)。LCMS(ESI):RT=1.135min,m/z实测值为1112.2[M-CF3COOH+H]+。
化合物169
2-((4-(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)-2-氧代乙氧基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6(11H)-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.93(s,1H),9.63(s,1H),9.34(s,1H),8.53(s,1H),8.36(s,1H),8.05(d,J=45.0Hz,2H),7.68(d,J=7.7Hz,1H),7.48(dd,J=22.0,8.1Hz,5H),7.34(d,J=8.0Hz,2H),7.26(t,J=8.8Hz,3H),7.18(t,J=7.5Hz,1H),6.90(s,2H),6.24(s,1H),4.73-4.52(m,3H),4.37(dd,J=23.7,9.2Hz,6H),4.15(dd,J=19.2,12.3Hz,5H),3.68(d,J=11.8Hz,2H),3.39(s,3H),3.32(s,3H),3.01(dd,J=13.8,6.9Hz,1H),1.91(s,4H),1.34(t,J=6.9Hz,3H),1.01(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.420min,m/z实测值为958.6[M-CF3COOH+H]+。
化合物170
N-(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)-1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),9.88-9.73(m,1H),9.61(s,1H),9.32(s,1H),8.79(s,1H),8.62(s,1H),8.54-8.38(m,1H),7.75(d,J=7.8Hz,1H),7.58(d,J=3.9Hz,2H),7.52-7.43(m,5H),7.30(dd,J=27.8,8.2Hz,5H),6.90(s,1H),6.72-6.53(m,2H),6.24(s,1H),4.46-4.30(m,5H),4.26-4.13(m,4H),4.07-3.98(m,3H),3.71(d,J=17.5Hz,5H),3.46(s,3H),3.06-2.95(m,1H),2.84-2.71(m,1H),2.43-2.35(m,1H),1.88-1.72(m,4H),1.17(t,J=6.9Hz,3H),1.01(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.040min,m/z实测值为1022.3[M-CF3COOH+H]+。
化合物171
4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-乙基-5-(5-乙基-4-羟基-2-甲氧基苯基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),9.07-9.00(m,1H),8.82(s,1H),8.62(s,1H),7.75(d,J=7.8Hz,1H),7.59(d,J=4.0Hz,2H),7.51-7.44(m,2H),7.33(s,3H),7.22-7.06(m,3H),6.77-6.51m,1H),6.28(s,1H),4.44-4.37(m,2H),4.10-3.97(m,6H),3.74-3.64(m,6H),3.46(s,3H),3.30(s,3H),3.23-3.14(m,3H),3.11-2.77(m,9H),2.44-2.33(m,4H),1.82-1.63(m,7H),1.21-1.14(m,3H),1.08-1.03(m,8H)。LCMS(ESI):RT=1.040min,m/z实测值为1110.3[M-CF3COOH+H]+。
化合物172
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-N-(2-(4-甲基磺酰基)哌嗪-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ10.72-10.22(m,1H),9.79(s,1H),9.37-9.23(m,1H),8.36(s,1H),8.11(s,1H),8.03-7.90(m,1H),7.69(dd,J=7.7,1.7Hz,1H),7.57-7.42(m,5H),7.28-7.14(m,2H),7.00-6.74(m,2H),6.72(s,1H),6.32(s,1H),4.53-4.28(m,3H),4.12(q,J=6.9Hz,2H),3.85-3.44(m,9H),3.39(s,4H),3.36-3.07(m,13H),3.06-2.88(m,8H),1.83(s,4H),1.34(t,J=6.9Hz,3H),0.92(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.000min,m/z实测值为1111.2[M-CF3COOH+H]+。
化合物173
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5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-N-(2,2,3,3,3-五氟丙基-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1HNMR(400MHz,DMSO-d6)δ10.43-9.99(m,1H),9.76(s,1H),9.66(t,J=6.5Hz,1H),8.36(s,1H),8.12(s,1H),7.97(s,1H),7.69(dd,J=7.7,1.6Hz,1H),7.59-7.43(m,5H),7.28-7.14(m,2H),7.04-6.68(m,3H),6.31(s,1H),4.57-4.32(m,3H),4.29-3.94(m,5H),3.69(d,J=11.7Hz,2H),3.55-3.43(m,1H),3.39(s,3H),3.31(s,5H),3.20-2.85(m,7H),1.83(s,4H),1.34(t,J=6.9Hz,3H),0.92(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.260min,m/z实测值为1053.2[M-CF3COOH+H]+。
化合物174
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-N-(2-(4-甲基磺酰基)哌嗪-1-基)乙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.77(s,1H),9.28(s,1H),8.81(s,1H),8.62(s,1H),7.75(d,J=7.9Hz,1H),7.51(m,8H),7.36(s,1H),6.65-6.63(m,3H),6.31(s,1H),4.38(s,4H),4.11-3.95(m,3H),3.69(s,7H),3.55(s,3H),3.46(s,4H),3.20(d,J=66.1Hz,8H),3.03(s,4H),2.98-2.87(m,6H),1.75(s,4H),1.18(t,J=6.8Hz,3H),0.92(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.033min,m/z实测值为1175.2[M-CF3COOH+H]+。
化合物175
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-N-(2,2,3,3,3-五氟丙基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ10.13(s,1H),9.76-9.65(m,2H),8.83(s,1H),8.63(s,1H),7.75(d,J=7.7Hz,1H),7.57(dd,J=17.9,6.0Hz,4H),7.44(dd,J=19.4,14.1Hz,4H),6.69-6.66(m,3H),6.31(s,1H),4.39(s,3H),4.31-4.17(m,1H),4.02-3.98(m,4H),3.69(s,5H),3.39(d,J=56.6Hz,6H),3.13(s,1H),3.06–2.79(m,6H),1.77(s,4H),1.19(t,J=6.8Hz,3H),0.92(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.260min,m/z实测值为1117.1[M-CF3COOH+H]+。
化合物176
(R)-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ9.83-9.54(m,2H),8.86(s,1H),8.65(s,1H),7.76(d,J=7.6Hz,1H),7.59(d,J=3.6Hz,2H),7.55-7.38(m,4H),7.34(d,J=8.2Hz,2H),6.88(s,1H),6.76(s,1H),6.69(s,1H),6.31(s,1H),4.69-4.59(m,2H),4.40(d,J=13.2Hz,1H),4.13-3.80(m,5H),3.69(s,5H),3.47(s,3H),3.23-2.74(m,11H),2.63-2.50(m,4H),2.28(q,J=7.5Hz,2H),2.01(s,1H),1.90-1.71(m,6H),1.34(d,J=7.0Hz,3H),1.21(t,J=6.9Hz,3H),1.17-0.97(m,2H),0.90(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.180min,m/z实测值为1164.3[M-CF3COOH+H]+。
化合物177
(S)-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.60(d,J=9.1Hz,1H),8.98(s,1H),8.70(s,1H),7.78-7.74(m,1H),7.74-7.29(m,10H),6.77(s,1H),6.47(s,1H),4.71-4.61(m,2H),4.38(d,J=12.0Hz,2H),4.14-4.07(m,4H),3.71(s,5H),3.65-3.55(m,4H),3.48(s,4H),3.45-3.25(m,5H),3.16-3.02(m,3H),2.71-2.55(m,2H),2.32(q,J=7.4Hz,2H),2.17-1.98(m,3H),1.95-1.79(m,3H),1.39-1.19(m,10H),1.11-1.01(m,1H),0.95(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.180min,m/z实测值为1164.3[M-CF3COOH+H]+。
化合物178
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-((1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)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。1H NMR(400MHz,DMSO-d6):δ9.57(s,1H),8.72(s,1H),8.60(s,1H),7.74(d,J=7.3Hz,1H),7.61-7.53(m,2H),7.49-7.17(m,7H),6.63-6.44(m,3H),6.24(s,1H),4.04-3.91(m,4H),3.66(d,J=19.0Hz,4H),3.48(d,J=19.5Hz,6H),2.95-2.89(m,1H),2.68-2.60(m,2H),2.41(s,5H),2.17(d,J=7.1Hz,2H),2.05-1.94(m,1H),1.78(d,J=11.7Hz,2H),1.65(s,1H),1.24(s,4H),1.15(t,J=6.9Hz,4H),0.93(d,J=6.7Hz,1H),0.79(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.210min,m/z实测值为1053.5[M+H]+。
化合物179
4-(4-((4-((1-((1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-基)甲基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺2,2,2-三氟乙酸酯,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.80-9.56(m,2H),9.19(s,1H),8.79(s,1H),8.62(s,1H),7.75(d,J=7.7Hz,1H),7.64-7.28(m,9H),6.64(d,J=32.5Hz,3H),6.31(s,1H),4.63(dd,J=15.6,7.5Hz,1H),4.11-3.94(m,3H),3.69(s,6H),3.57(s,2H),3.46(s,3H),3.17(s,2H),3.02(s,4H),2.94-2.62(m,8H),2.28(q,J=7.4Hz,3H),1.89(dd,J=27.5,12.1Hz,7H),1.40-1.31(m,8H),1.18(t,J=6.8Hz,3H),0.89(t,J=7.5Hz,3H)。LCMS(ESI):RT=1.090min,m/z实测值为1150.6[M-CF3COOH+H]+。
化合物180
4-(4-(4-((4-(1-(4-((5,11-二甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌啶-4-羰基)哌嗪-1-基)甲基)苯基)-5-羟基-4H-1,2,4-三唑-3-基)-5-羟基-2-异丙基苯基磷酸二氢酯。1H NMR(400MHz,DMSO-d6):δ8.53(s,1H),8.33(s,1H),7.75(d,J=7.9Hz,1H),7.55-7.41(m,3H),7.31-7.24(m,3H),7.22-7.13(m,4H),6.86(s,1H),4.34(s,2H),4.26(d,J=7.0Hz,2H),3.70(s,2H),3.63-3.56(m,2H),3.52-3.44(m,8H),3.21-3.16(m,2H),3.13-3.11(m,1H),2.98(s,2H),2.05(s,5H),1.52(t,J=6.9Hz,3H),1.16(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.040min,m/z实测值为974.2[M+H]+。
化合物181
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-((1-((1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.61(d,J=8.9Hz,1H),9.20-9.05(m,1H),8.77(s,1H),8.61(s,1H),7.75(d,J=7.8Hz,1H),7.58(s,2H),7.48-7.32(m,5H),6.66(d,J=6.4Hz,2H),6.56(d,J=7.8Hz,1H),6.33(s,1H),5.32(t,J=4.6Hz,1H),4.70-4.59(m,1H),4.11-3.98(m,4H),3.68(s,8H),3.46(s,4H),3.07-2.73(m,12H),2.02-1.81(m,7H),1.34(d,J=7.0Hz,4H),1.24(s,5H),1.18(t,J=6.7Hz,3H),0.87(d,J=6.0Hz,6H)。LCMS(ESI):RT=1.105min,m/z实测值为1164.7[M-CF3COOH+H]+。
化合物182
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-((1-(1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)哌啶-4-羰基)哌啶-4-基)甲基)哌嗪-1-基)甲基)苯基)-N-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.62(s,1H),9.59(s,1H),8.83(s,1H),8.63(s,1H),7.75(d,J=7.8Hz,1H),7.59(d,J=3.7Hz,3H),7.54-7.32(m,8H),6.83-6.60(m,3H),6.33(s,1H),4.68-4.59(m,1H),4.40(d,J=11.9Hz,1H),4.11-3.93(m,4H),3.69(s,7H),3.46(s,5H),2.96-2.88(m,4H),2.04-1.92(m,2H),1.75(s,8H),1.34(d,J=7.0Hz,4H),1.24(s,3H),1.19(t,J=6.7Hz,5H),0.87(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.210min,m/z实测值为1178.7[M-CF3COOH+H]+。
化合物183
2-((4-(4-((7-(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)-2,7-二氮杂螺[3.5]壬-2-基)甲基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1HNMR(400MHz,DMSO-d6)δ11.98(s,1H),10.03(s,1H),9.80-9.60(m,2H),9.37(s,1H),8.74(s,1H),8.60(s,1H),7.75(d,J=8.2Hz,1H),7.58(s,2H),7.47(d,J=8.0Hz,2H),7.29(t,J=9.6Hz,2H),6.84(s,1H),6.62(s,1H),6.52(d,J=8.3Hz,1H),6.26(s,1H),4.24(s,1H),4.15(s,1H),4.09–3.89(m,5H),3.68(s,3H),3.46(s,3H),3.29-3.17(m,4H),3.07-2.85(m,3H),2.65(d,J=11.1Hz,2H),2.35-2.16(m,3H),2.09-1.94(m,1H),1.80(dd,J=42.0,11.6Hz,4H),1.37-1.21(m,4H),1.17(t,J=6.9Hz,3H),1.00(dd,J=6.6,3.6Hz,6H)。LCMS(ESI):RT=0.940min,m/z实测值为984.3[M-CF3COOH+H]+。
化合物184
2-((4-(4-((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)-2,7-二氮杂螺[3.5]壬-7-基)甲基)哌啶-1-基)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1HNMR(400MHz,CD3OD)δ8.61(s,1H),7.96(d,J=8.8Hz,1H),7.84(dd,J=7.7,1.5Hz,1H),7.64-7.45(m,6H),7.38(d,J=8.4Hz,2H),6.89(d,J=4.9Hz,2H),6.83(d,J=8.2Hz,1H),6.21(s,1H),4.46(s,2H),4.17-4.07(m,5H),3.74-3.67(m,2H),3.56(d,J=4.3Hz,6H),3.14-3.06(m,5H),2.24-2.14(m,3H),2.06-1.98(m,3H),1.67-1.57(m,2H),1.40-1.27(m,9H),1.03(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.150min,m/z实测值为984.5[M-CF3COOH+H]+。
化合物185
4-(4-((4-((1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苯基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.60(d,J=9.0Hz,1H),8.77(s,1H),8.62(s,1H),7.75(d,J=7.4Hz,1H),7.60-7.57(m,2H),7.49-7.29(m,7H),6.68(s,2H),6.59(s,1H),6.31(s,1H),4.67-4.61(m,1H),4.07-3.99(m,4H),3.68(s,5H),3.46(s,3H),2.99(s,4H),2.77(s,2H),2.34-2.24(m,3H),2.03-1.97(m,1H),1.84(d,J=12.5Hz,2H),1.34(d,J=7.0Hz,5H),1.24(s,3H),1.18(t,J=6.9Hz,4H),0.92-0.84(m,4H)。LCMS(ESI):RT=1.210min,m/z实测值为1053.3[M-CF3COOH+H]+。
化合物186
4-(4-((4-((1-(4-((11-环戊基-5-甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)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-(1,1,1-三氟丙-2-基)-4H-1,2,4-三唑-3-甲酰胺,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ9.69(s,1H),9.60(d,J=9.2Hz,1H),8.35(s,1H),7.93(s,1H),7.87-7.73(m,1H),7.57(d,J=7.7Hz,1H),7.48-7.24(m,7H),7.16(t,J=7.2Hz,1H),6.68(s,3H),6.31(s,1H),4.63(s,2H),4.07(d,J=7.5Hz,3H),3.41(s,6H),3.07(s,8H),2.28(d,J=7.6Hz,5H),2.06(s,2H),1.84(s,2H),1.57(s,6H),1.36-1.26(m,9H),0.89(t,J=7.5Hz,4H)。LCMS(ESI):RT=1.330min,m/z实测值为1043.3[M-CF3COOH+H]+。
化合物187
2-((4-(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)-2-乙氧基苯基)氨基)-5-甲基-11-(甲基磺酰基)-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮。1H NMR(400MHz,DMSO-d6):δ11.92(s,1H),9.60(s,1H),9.41(s,1H),8.72(s,1H),8.60(s,1H),7.74(d,J=7.5Hz,1H),7.58(d,J=3.7Hz,2H),7.48-7.41(m,1H),7.27(dd,J=16.9,8.5Hz,3H),7.13(d,J=8.3Hz,2H),6.76(s,1H),6.57(s,1H),6.47(d,J=8.7Hz,1H),6.27(s,1H),4.07-3.91(m,3H),3.65(d,J=20.0Hz,5H),3.45(d,J=4.4Hz,6H),3.03-2.90(m,1H),2.63(t,J=11.4Hz,2H),2.37(s,6H),2.16(d,J=6.4Hz,2H),2.03-1.95(m,1H),1.76(d,J=11.0Hz,2H),1.62(s,1H),1.32(d,J=15.0Hz,2H),1.15(t,J=6.9Hz,3H),0.94(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.150min,m/z实测值为944.3[M+H]+。
化合物188
11-环戊基-2-((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)-2-乙氧基苯基)氨基)-5-甲基-5,11-二氢-6H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),9.62(s,1H),8.47(s,1H),8.33(s,1H),7.85(s,1H),7.75(d,J=8.9Hz,1H),7.56(d,J=6.0Hz,1H),7.43(d,J=7.4Hz,1H),7.34(d,J=8.0Hz,1H),7.26(d,J=8.6Hz,1H),7.15(d,J=7.8Hz,3H),6.78(s,1H),6.60(s,1H),6.49(s,1H),6.27(s,1H),4.05(d,J=5.6Hz,2H),3.52(s,2H),3.40(s,3H),2.33(s,1H),2.08(s,4H),1.56(s,5H),1.29-1.23(m,8H),1.17-1.09(m,3H),0.96(d,J=6.8Hz,6H)。LCMS(ESI):RT=1.117min,m/z实测值为837.5[M-CF3COOH+H]+。
化合物189
2-((4-(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)-2-氧代乙氧基)哌啶-1-基)-2-乙氧基苯基)氨基)-5,11-二甲基-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-6(11H)-酮,三氟乙酸。1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),9.59(s,1H),9.40(s,1H),8.32(s,1H),7.93(s,1H),7.69(d,J=8.8Hz,1H),7.55(dd,J=7.7,1.6Hz,1H),7.43(ddd,J=12.2,4.9Hz,1H),7.34(d,J=8.3Hz,2H),7.26(d,J=8.3Hz,1H),7.15(t,J=7.6Hz,3H),6.78(s,1H),6.61(d,J=2.2Hz,1H),6.51-6.45(m,1H),6.28(s,1H),3.78(s,3H),3.52(s,2H),3.40(s,3H),3.12(s,4H),2.99-2.95(m,1H),1.56(s,5H),1.28-1.17(m,8H),0.96(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.097min,m/z实测值为823.4[M-CF3COOH+H]+。
化合物190
4-(4-((4-(4-((11-环戊基-5-甲基-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)-3-乙氧基苯基)哌嗪-1-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)δ8.95(t,J=5.8Hz,1H),8.34(s,1H),7.86(s,1H),7.76(d,J=8.7Hz,1H),7.56(dd,J=7.7,1.6Hz,1H),7.44(dd,J=13.4,5.0Hz,3H),7.29(dd,J=24.1,8.3Hz,3H),7.15(t,J=7.5Hz,1H),6.65-6.57(m,2H),6.50(dd,J=8.8,2.2Hz,1H),6.33(s,1H),4.65-4.54(m,1H),4.12-4.00(m,2H),3.58(s,2H),3.40(s,4H),3.23-3.08(m,7H),3.00-2.87(m,1H),2.56(s,4H),2.32-2.22(m,1H),2.12-2.00(m,1H),1.65-1.46(m,5H),1.44-1.33(m,1H),1.27(t,J=6.9Hz,3H),1.05(t,J=7.2Hz,3H),0.83(d,J=6.9Hz,6H)。LCMS(ESI):RT=1.437min,m/z实测值为892.5[M+H]+。
化合物191
5-(2,4-二羟基-5-异丙基苯基)-4-(4-((4-((1-(3-乙氧基-4-((5-甲基-11-(甲基磺酰基)-6-氧代-6,11-二氢-5H-苯并[e]嘧啶[5,4-b][1,4]二氮杂-2-基)氨基)苄基)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。1H NMR(400MHz,DMSO-d6):δ10.45(s,1H),9.83(s,1H),9.68-9.54(m,1H),8.92(s,1H),8.69(s,1H),7.76(d,J=7.5Hz,2H),7.70-7.55(m,3H),7.53-7.25(m,6H),6.61(s,1H),6.38(s,1H),4.22-3.89(m,6H),3.70(s,4H),3.48(s,7H),2.98-2.81(m,2H),2.45-2.06(m,9H),1.24(s,8H),0.82(d,J=6.8Hz,7H)。LCMS(ESI):RT=1.367min,m/z实测值为1067.5[M+H]+。
实施例2:测试各种CHAMP分子
材料和方法
细胞系
采用以下癌细胞系:A549人肺癌(ATCC,#CCL-185);BT-474人乳腺癌(ATCC,#HTB-20);MDA-MB-231人乳腺腺癌(ATCC,#CRM-HTB-26);MDA-MB-468人乳腺腺癌(ATCC,#HTB-132);MV-4-11人急性髓性白血病(ATCC,#CRL-9591);和U-87MG人胶质母细胞瘤(ATCC,#HTB-14)。细胞系基本上根据ATCC推荐进行培养。
HSP90α结合荧光偏振(FP)测定
除非另有说明,否则使用HSP90α(N末端)测定试剂盒(BPS Bioscience,#50298)遵循制造商的说明书通过荧光偏振(FP)来测量测试化合物与HSP90α蛋白的结合。使用荧光标记的HSP90结合化合物(即提供的FITC-格尔德霉素)(5nM最终浓度)或RNK04010(一种基于三唑酮的HSP90结合小分子),通过哌嗪-苯基接头(5nM最终浓度)用BODIPY标记。测定每种测试化合物的2.5倍连续稀释(范围为20μM至5.2nM),用于与HSP90α结合。在将HSP90α蛋白添加到每个测定孔的最后一步后,通过短暂摇动来混合板,在25℃下温育FITC-格尔德霉素达120分钟或温育RNK04010达300分钟,并使用PerkinElmer EnVision读板器测量荧光。从原始数据计算扣除背景的mP值,并拟合四参数“log[抑制剂]与响应”曲线,并使用GraphPadPrism 7软件计算IC50值(发生最大抑制的50%时的浓度)。
MAPK7激酶测定
除非另有说明,否则遵循制造商的说明书通过ADP-Glo激酶测定(Promega,#V6930)来测量测试化合物对MAPK7激酶活性的抑制。制备50μM至2.54nM范围内的每种测试化合物的3倍系列稀释液。此外,作为阳性对照,制备了10μM至0.04nM范围内的MAPK7抑制剂XMD17-109(MedChemExpress,#HY-15665)的4倍系列稀释液。简而言之,在384孔板中,将测试化合物添加至含有重组MAPK7蛋白质(Carna Biosciences,#04-146;20nM最终浓度)、髓鞘碱性蛋白质(SignalChem Biotech,#M42-54G;0.1mg/mL最终浓度)和ATP(340μM最终浓度)的激酶反应混合物中,然后通过摇动而混合并与ADP-Glo试剂和激酶检测试剂一起温育。在BioTek读板器上测量发光。使用以下等式计算抑制%并作图,并使用GraphPad Prism7软件计算IC50值(发生最大抑制的50%时的浓度):
整个板上10孔阳性对照(10μM XMD17-109)的平均比。
整个板上10孔阴性对照(0.5%DMSO)的平均比。
MAPK7蛋白质印迹蛋白质降解测定
将U-87MG人胶质母细胞瘤细胞接种在6孔或12孔组织培养板中,1小时后,添加各种浓度的测试化合物并在37℃/5%CO2下温育达48小时。然后将细胞用冷PBS洗涤,吸出,并添加含有蛋白酶/磷酸酶抑制剂混合物的冷RIPA缓冲液以裂解细胞。离心后,使用BCA蛋白质测定法来确定细胞裂解物的总蛋白质浓度。针对等效蛋白质浓度将样品标准化,添加5XSDS-PAGE上样缓冲液并使其在100℃下变性达10分钟。将20μL每个样品/孔装载在SDS-PAGE凝胶上,并在80V下电泳达20分钟,然后在120V下电泳达1.5小时。然后使用湿转移法在250mA下将凝胶电印迹至硝酸纤维素膜达2.5小时。将膜与封闭缓冲液一起温育达1小时,并用TBST洗涤3次达5分钟。然后根据制造商的推荐,将膜与稀释在封闭缓冲液中的抗MAPK7(抗ERK5;Cell Signaling Technology,#12950)和抗β肌动蛋白(Cell SignalingTechnology,#3700)单克隆抗体在4℃下一起温育过夜。洗涤3次后,将印迹与适当标记的二抗在室温下一起温育达1小时,然后再次洗涤。使用LI-COR Odyssey进行荧光成像和定量。使用GraphPad Prism 7软件分析结果。ERBB2(HER2)流式细胞术蛋白质降解测定
将BT-474人乳腺癌细胞以250,000个细胞/孔的密度接种在24孔组织培养板中,并在37℃/5%CO2下温育达24小时。然后用各种浓度的测试化合物处理细胞,并在37℃/5%CO2下温育达24小时。为了通过流式细胞术分析总ERBB2表达,用胰蛋白酶分离细胞,将其洗涤、计数并用10μL/106个细胞PE缀合的抗ERBB2单克隆抗体(R&D Systems,#FAB1129P)在25℃下黑暗中处理达30分钟。然后洗涤细胞,将其重悬于200μL 1%多聚甲醛中并通过流式细胞术分析。通过以下等式确定化合物抑制并使用GraphPad Prism 7软件计算DC50值(发生ERBB2的最大降解的50%时的浓度):
抑制%=100-(D-B)/(S-B)*100%。
S:细胞与抗体的荧光强度
D:经化合物处理的细胞与抗体的荧光强度
B:不含抗体的细胞的荧光强度
癌细胞系增殖(CCK-8)测定
将细胞以4,000个细胞/孔的密度接种在96孔组织培养板中,并在37℃/5%CO2下温育达24小时。制备20μM至1.02nM范围内的每种测试化合物的3倍系列稀释液。然后用各种浓度的测试化合物处理细胞,其中最终浓度为0.5%DMSO/孔,然后在37℃/5%CO2下温育达72小时。将10μL细胞增殖检测试剂CCK-8(Dojindo Molecular Technologies,#CK04)添加至每个孔并在37℃/5%CO2下温育达3-4小时,并使用Perkin Elmer EnVision读板器测量450nm处的吸光度。通过以下等式确定化合物抑制并使用GraphPad Prism 7软件计算EC50值(发生最大抑制的50%时的浓度):
抑制%=100-(D-B)/(S-B)*100%。
S:经DMSO处理的细胞的吸光度
D:经化合物处理的细胞的吸光度
B:含DMSO但不含细胞的培养基的吸光度
结果
已经开发了许多合成方案来构建设计用于降解MAPK7的各种CHAMP分子(被称为MAPK7-CHAMP分子)。示出了代表性示例,每个示例都由与MAPK7结合剂连接的HSP90结合剂组成。类似的化学反应可应用于其他CHAMP分子而不限于这些特定的HSP90结合部分和MAPK7结合部分。
应用HSP90α结合荧光偏振(FP)测定测量了与荧光标记的HSP90结合剂、FITC-格尔德霉素或RNK04010(BODIPY标记)的竞争,以评估CHAMP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CHAMP分子与已发表的构效关系(SAR)大体一致。
在该测定中,将与HSP90结合剂具有相似分子量的MAPK7结合剂掺入CHAMP中通常对CHAMP分子与HSP90α结合的影响很小(表1)。原因有很多:首先,这些部分及其相应蛋白质的共晶结构是可用的,并且允许进行精确的基于结构的分子设计;其次,接头被构造为提供具有合适长度的刚性。
在生化激酶测定中,通过测量MAPK7磷酸化活性的抑制来评估多种CHAMP分子与MAPK7的结合,如表1所示。文献中记载的含有MAPK7结合部分的CHAMP分子与已发表的SAR大体一致。
伴侣结合部分(诸如HSP90结合剂)的掺入通常对CHAMP分子与MAPK7结合的影响很小,如通过该测定所测量的。原因有很多:首先,这些部分及其相应蛋白质的共晶结构是可用的,并且允许进行精确的基于结构的分子设计;其次,接头被构造为提供具有合适长度的刚性。
具有MAPK7结合部分和HSP90结合部分两者的异双功能CHAMP分子旨在诱导MAPK7的靶向蛋白质降解(TPD)。如表2所示,用各种浓度的CHAMP化合物将表达MAPK7的U-87MG人胶质母细胞瘤细胞处理48小时,并通过蛋白质印迹观察MAPK7的降解。
CHAMP分子可包括具有一系列不同结合亲和力的伴侣或伴侣复合物结合剂。在不同的实施方案中,期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末端ATP结合口袋相互作用的HSP90结合部分可能会抑制HSP90活性并诱导HSP90客户蛋白的降解,一些CHAMP分子可能不仅诱导期望的一种靶蛋白或多种靶蛋白(其可能是或可能不是HSP90客户蛋白)的降解,而且同时也诱导HSP90客户蛋白的降解。如表1所示,CHAMP化合物还表现出对HSP90客户蛋白ERBB2的不同程度的降解,如通过流式细胞术在表达ERBB2的BT-474人乳腺癌细胞中评估的。
如表1所示,各种MAPK7 CHAMP分子也抑制一组癌细胞系的生长和/或存活,如通过CCK-8细胞系增殖测定所测量的。
表1:化合物的生化测定和基于细胞的测定
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1HSP90α结合FP(BODIPY)测定:A.IC50<100nM;B.IC50=100nM至1000nM;C.IC50>1000nM;
2HSP90α结合FP(FITC)测定:A.IC50<100nM;B.IC50=100nM至1000nM;C.IC50>1000nM;
3MAPK7激酶测定:A.IC50<100nM;B.IC50=100nM至1000nM;C.IC50>1000nM;4BT-474细胞中的ERBB2流式细胞术蛋白质降解测定:A.DC50<100nM;B.DC50=100nM至1000nM;C.
DC50>1000nM;5A549 CCK-8增殖测定:A.EC50<100nM;B.EC50=100nM至1000nM;C.
EC50>1000nM;6MDA-MB-231CCK-8增殖测定:A.EC50<100nM;B.EC50=100nM至1000nM;C.
EC50>1000nM;7MDA-MB-468CCK-8增殖测定:A.EC50<100nM;B.EC50=100nM至1000nM;C.
EC50>1000nM;8MV-4-11CCK-8增殖测定:A.EC50<100nM;B.EC50=100nM至1000nM;C.
EC50>1000nM;9U87 MG CCK-8增殖测定:A.EC50<100nM;B.EC50=100nM至1000nM;C.
EC50>1000nM
表2:化合物的MAPK7降解
-1U-87MG细胞中的MAPK7蛋白质印迹蛋白质降解测定:
A.>66%降解;B.33%-66%降解;C.<33%降解
在不脱离本公开的范围和实质的情况下,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来说将是显而易见的。尽管已结合特定实施方案描述了本公开,但应理解,所要求保护的本公开不应不适当地局限于此类特定实施方案。实际上,用于执行本公开的所述模式的各种修改旨在并且被本公开所在的相关领域的技术人员理解为在如所附权利要求所表示的本公开的范围内。
以引用方式并入
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Claims (43)
1.一种式I的化合物:
或其药学上可接受的盐,其中,
A是结合HSP90蛋白质的化学部分;
L是接头;
W和D各自独立地为N或CR9;
R10、R16和R19各自独立地选自卤代基、(C1-C6)烷基、(C2-C6)烯基、卤代(C2-C6)烯基、(C2-C6)炔基、-(C1-C6)烷基ORc、-(C1-C6)烷基N(Rd)2、-(C1-C6)烷基C(O)ORd、-(C1-C6)烷基C(O)N(Rd)2、-(C1-C6)烷基O(C1-C6)烷基N(Rd)2、-(C1-C6)烷基SORd、-(C1-C6)烷基S(O)2Rd、-(C1-C6)烷基SON(Rd)2、-(C1-C6)烷基SO2N(Rd)2、-(C1-C6)烷基环烷基、-(C1-C6)烷基杂环基、-(C1-C6)烷基杂芳基、-(C1-C6)烷基芳基、-(C1-C6)烷氧基、卤代(C1-C6)烷氧基、CN、芳基、杂芳基、环烷基、杂环烷基、-C(O)Rd、-C(O)ORd、-C(O)N(Rd)2、N(Rd)2、-C(O)NRd(C1-C6)烷基N(Rd)2、-NRd(C1-C6)烷基N(Rd)2、-NRd(C1-C6)烷基ORd、-SORd、-S(O)2Rd、-SON(Rd)2、-SO2N(Rd)2和CN,其中每个芳基、环烷基、杂环基和杂芳基单独以及与-(C1-C6)烷基环烷基、-(C1-C6)烷基杂环基、-(C1-C6)烷基杂芳基、-(C1-C6)烷基芳基一起任选地被1至3个选自Re的基团取代;
M为O、S或NR11;
R11、R17、R18和R20各自独立地选自氢、(C1-C6)烷基和S(O)2(C1-C6)烷基;
R12为氢、(C1-C6)烷基、卤代(C1-C6)烷基、-(C1-C6)烷基ORc、S(O)2(C1-C6)烷基、芳基、杂芳基、环烷基、杂环烷基、C(O)(C1-C6)烷基或-(C1-C6)烷基芳基,其中每个芳基、环烷基、杂环基和杂芳基单独以及与-(C1-C6)烷基芳基一起任选地被1至3个选自Re的基团取代;
Rc和Rd各自独立地选自氢、(C1-C6)烷基和卤代(C1-C6)烷基;
Re选自卤代基、氧代、CN、NO2、-N(Rd)2、-ORd、-C(O)ORd、(C1-C6)烷基、-(C1-C6)烷基ORc、卤代(C1-C6)烷基、(C1-C6)烷氧基、卤代(C1-C6)烷氧基、-(C1-C6)烷基C(O)ORd、-(C1-C6)烷基C(O)N(Rd)2、(C2-C6)烯基、卤代(C2-C6)烯基、(C2-C6)炔基、-(C1-C6)烷基SRd、-(C1-C6)烷基ORc、-(C1-C6)烷基N(Rd)2、-C(O)N(Rd)2、-C(O)NRdC1-6烷基N(Rd)2、-NRdC1-6烷基N(Rd)2、-NRdC1-6烷基ORd、-SORd、-S(O)2Rd、-SON(Rd)2、-SO2N(Rd)2、芳基、杂芳基、环烷基和杂环烷基;并且
k和v各自独立地为0、1、2或3。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中A选自
其中
Q和U各自独立地选自苯基、杂芳基、杂环基和环烷基,它们中的每一者任选地被1至3个选自R2的基团取代;
R13和R14各自独立地选自氢、卤代基、-CN、(C1-C4)烷基、卤代(C1-C4)烷基和-C(O)NRaRb;
R15为氢、(C1-C4)烷基或卤代(C1-C4)烷基;
W为任选地被1至3个选自R2的基团取代的5或6元杂芳基;
V为苯基或任选地被1至3个选自R3的基团取代的5至9元杂芳基;
R1为卤代基、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基或卤代(C1-C4)烷氧基;
R2为(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、-SH、-S(C1-4烷基)、-NRa(C1-4烷基)NRaRb、-C1-6烷基C(O)NRaRb、-O(C1-4亚烯基)NRaC(O)(C1-4亚烷基)NRaRb、苯基或5至7元杂芳基,其中所述苯基和5至7元杂芳基各自任选地且独立地被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元杂环基取代,或被两者取代;并且
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。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐,其中A是
4.根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐,其中所述化合物具有下式:
5.根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐,其中所述化合物具有下式:
6.根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐,其中k为0。
7.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中v为0。
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R11是氢。
9.根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐,其中R17是(C1-C6)烷基。
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R17是甲基。
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R12为(C1-C6)烷基。
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R12是乙基。
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R18是(C1-C3)烷基或S(O)2(C1-C3)烷基。
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R18是S(O)2Me。
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A选自 并且
Z为N或CH。
16.根据权利要求15所述的化合物或其药学上可接受的盐,其中Z为CH。
17.根据权利要求1至16中任一项所述的化合物,其中每个R3为(C1-C4)烷基或卤代基。
18.根据权利要求1至17中任一项所述的化合物或其药学上可接受的盐,其中A为
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A为
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A为
21.根据权利要求1至20中任一项所述的化合物或其药学上可接受的盐,其中A为
22.根据权利要求1至21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。
23.根据权利要求1至22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。
24.根据权利要求1至23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。
25.根据权利要求1至24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。
26.根据权利要求1至25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。
27.根据权利要求1至26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、-C(O)NHCH2CF3、-C(O)NHCH2CH3、-C(O)NHCH(CH3)2、-C(O)NH(CH2CH3)2、-C(O)NHCH(CH3)CF3、-C(O)NH环丙基、-C(O)NH甲基环丙基、C(O)NH2或-C(O)NH(CH2)2哌啶基。
28.根据权利要求1至27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。
29.根据权利要求1至28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。
30.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,其中
L是Het1-X1-*、Het1-X1-Het2-X2-*、Het1-O-(CH2)m-X1-Het2-X2-*、Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-*、Het1-X1-NRc-(CH2)m-*、Het1-X1-Het2-Het3-X2-*、Het1-X1-NRc-(CH2CH2O)n(CH2)m-*、Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2*、Het1-X1-NRc-(CH2CH2O)n-*、Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-X2-*、Het1-X1-Het2-*、Het1-X1-NRc-*、Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-*、Het1-X1-Het2-Het3-*、Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-*、Het1-X1-Het2-(CH2CH2O)n-*、Het1-X1-(CH2)m-Het2-X2-*、-(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A的连接点;
Het1、Het2和Het3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,它们中的每一者任选地被(C1-C4)烷基取代;
X1、X2和X3各自独立地为C(O)或(CH2)r;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。
31.根据权利要求1至30中任一项所述的化合物或其药学上可接受的盐,其中L为Het1-X1-Het2-X2-*、Het1-O-(CH2)m-X1-Het2-X2-*、Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-*、Het1-X1-NRc-(CH2)m-*、Het1-X1-Het2-Het3-X2-*、Het1-X1-NRc-(CH2CH2O)n(CH2)m-*、Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2*、Het1-X1-NRc-(CH2CH2O)n-*、Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-X2-*、Het1-X1-Het2-*、Het1-X1-NRc-*、Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-*、Het1-X1-Het2-Het3-*、Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-*、Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-*或Het1-X1-Het2-(CH2CH2O)n-*。
32.根据权利要求1至31中任一项所述的化合物或其药学上可接受的盐,其中L为Het1-X1-Het2-X2-*、Het1-X1-NRc-(CH2)m-*、Het1-X1-Het2-Het3-X2-*或Het1-X1-Het2-(CH2)m-Het3-X2-*。
33.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,其中L为Het1-X1-NRc-(CH2)m-*或Het1-X1-Het2-(CH2)m-Het3-X2-*。
34.根据权利要求1至33中任一项所述的化合物或其药学上可接受的盐,其中L为Het1-X1-Het2-(CH2)m-Het3-X2-*。
35.根据权利要求30至34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各自独立地为苯基或4至6元杂环基。
36.根据权利要求30至35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、苯基、吡啶基、哌嗪基或吡咯烷基。
37.根据权利要求30至36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。
38.根据权利要求1至31中任一项所述的化合物或其药学上可接受的盐,其中L选自
39.根据权利要求1至31中任一项所述的化合物或其药学上可接受的盐,其中L选自
40.根据权利要求1所述的化合物,其中所述化合物选自以下结构式:
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或前述化合物中任一者的药学上可接受的盐。
41.根据权利要求1所述的化合物,其中所述化合物选自以下结构式:
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或前述化合物中任一者的药学上可接受的盐。
42.一种药物组合物,所述药物组合物包含根据权利要求1至41中任一项所述的化合物或其药学上可接受的盐;和药学上可接受的载体。
43.一种治疗癌症的方法,所述方法包括向受试者施用治疗有效量的根据权利要求1至41中任一项所述的化合物或其药学上可接受的盐或者根据权利要求42所述的组合物。
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