CN107709322B - 作为抗癌剂的三环化合物 - Google Patents
作为抗癌剂的三环化合物 Download PDFInfo
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- CN107709322B CN107709322B CN201680039269.8A CN201680039269A CN107709322B CN 107709322 B CN107709322 B CN 107709322B CN 201680039269 A CN201680039269 A CN 201680039269A CN 107709322 B CN107709322 B CN 107709322B
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- Prior art keywords
- methyl
- optionally substituted
- triazacyclo
- tridec
- triazol
- Prior art date
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- 238000010626 work up procedure Methods 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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Abstract
本申请涉及其中所有取代基在本申请中定义的式(I)三环化合物及包含本申请化合物的药用组合物及在治疗各种病症中使用所述组合物的方法。
Description
对相关申请的交叉引用
本申请要求2015年5月12日提交的美国临时申请62/159,991的优先权,其公开的内容以全文引用的方式并入本申请。
技术领域
本申请提供新颖的三环化合物、包含所述化合物的药物组合物及使用其例如治疗或预防某些癌症的方法及其在治疗中的用途。
背景技术
真核生物体的基因组高度组织于细胞核中。双螺旋DNA的长链围绕在组蛋白的八聚体周围以形成核小体。此基本单元然后通过核小体的聚集及折叠而进一步压缩以形成高度凝集的染色质结构。可能存在一系列不同的凝集状态且此结构的紧密性在细胞周期中发生变化,其在细胞分裂过程中是最致密的。近来已认识到染色质模板形成一组根本上重要的称为后生调节的基因控制机制。后生调节物通过使组蛋白及DNA具有很多种特异性化学修饰(例如乙酰化、甲基化、磷酸化、泛素化及SUMO化)而对人类基因组的结构、功能及可接近性进行调节,从而对基因表达产生巨大影响。
组蛋白的乙酰化通常与基因转录的活化最相关,这是因为该修饰通过改变静电学而使DNA与组蛋白八聚体的相互作用减弱。除此物理变化外,特异性蛋白与组蛋白中的乙酰化赖氨酸残基结合以读取后生编码。布罗莫结构域(bromodomain)为蛋白质中小的(约110个氨基酸)独特的结构域,其与通常但不限于在组蛋白中的乙酰化赖氨酸残基结合。存在约50种已知含有布罗莫结构域的蛋白质的家族且其在细胞中具有多种功能。含有布罗莫结构域的蛋白质的BET家族包括4种蛋白质(BRD2、BRD3、BRD4及BRD-T),其含有能够与极靠近的两个乙酰化赖氨酸残基结合从而提高相互作用特异性的串联布罗莫结构域。
据报道BRD2及BRD3与伴随积极转录基因的组蛋白相关且可涉及促进转录延长(Leroy等人,Mol.Cell.2008 30(1):51-60),而BRD4似乎涉及将pTEF-I3复合物募集至诱导性基因,从而使RNA聚合酶得以磷酸化及使转录输出得以增加(Hargreaves等人,Cell,2009138(1):1294145)。已报道所有家族成员具有某种控制或执行细胞周期方面的功能且已证实在细胞分裂期间仍保持与染色体的复合物形式,这暗示在维持后生记忆中具有作用。另外,一些病毒利用这些蛋白质以使其基因组与宿主细胞染色质连接作为病毒复制过程的一部分(You等人,Cell,2004 117(3):349-60)。
近来与此靶标相关的论文包括Prinjha等人,Trends in PharmacalogicalSciences,2012年3月,第33卷,第3期,第146-153页;Conway,ACS Med.Chem.Lett.,2012,3,691-694;及Hewings等人,J.Med.Chem.,2012,55,9393-9413。
据报道正在开发的小分子BET抑制剂包括GSK-525762A、OTX-015、TEN-010及来自University of Oxford及Constellation Pharmaceuticals Inc.的其它抑制剂。
已鉴别出数百种后生效应子,其中许多为染色质结合蛋白或染色质修饰酶。这些蛋白质与多种病症相关,例如神经变性病症、代谢疾病、炎症及癌症。因此,抑制布罗莫结构域与其同源乙酰化蛋白结合的这些化合物预示对一系列自身免疫及炎性疾病或病症进行治疗及对各种类型的癌症进行治疗的新措施。
发明内容
本申请提供式(I)化合物和/或其药用盐、互变异构体或立体异构体:
其中
U1、U2、U3及U4独立为-N-或-CH-,条件为其中至少一个为-N-;
W1、W2及W3独立为-N-或-CH-,条件为其中至少一个为-N-;
A为任选经取代的杂环基或任选经取代的杂芳基,其中取代基为一个或多个R;
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基;
R7为氢、任选经取代的(C1-C6)烷基、-OR4、CN或卤素。
在另一个方面,本申请提供药物组合物,其包含本申请化合物或其药用盐及一种或多种药用载体、稀释剂或赋形剂。
在另一个方面,本申请提供本申请化合物或其药用盐,其用于在疗法中使用。具体地,其用于治疗布罗莫结构域抑制剂所针对的疾病或病症。
在另一个方面,本申请提供治疗自身免疫及炎性疾病或病症的方法,其包括向有此需要的个体给药治疗有效量的布罗莫结构域抑制剂。
在另一个方面,本申请提供治疗癌症的方法,其包括向有此需要的个体给药治疗有效量的布罗莫结构域抑制剂。
在本申请另一个方面,本申请提供在有此需要的患者中治疗由含有布罗莫结构域的蛋白质介导的病症的方法,其包括向所述患者给药本申请化合物的步骤。
具体实施方式
在本申请第一个方面,本申请提供式(I)化合物和/或其药用盐、互变异构体或立体异构体:
其中
U1、U2、U3及U4独立为-N-或-CH-,条件为其中至少一个为-N-;
W1、W2及W3独立为-N-或-CH-,条件为其中至少一个为-N-;
A为任选经取代的杂环基或任选经取代的杂芳基,其中取代基为一个或多个R;
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基;
R7为氢、任选经取代的(C1-C6)烷基、-OR4、CN或卤素。
在本申请另一个方面,本申请提供下式化合物和/或其药用盐、互变异构体或立体异构体:
其中
U1、U2、U3及U4独立为-N-或-CH-,条件为其中至少一个为-N-;
A为任选经取代的杂环基或任选经取代的杂芳基,其中取代基为一个或多个R;
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基;
R7为氢、任选经取代的(C1-C6)烷基、-OR4、CN或卤素。
在本申请第二个方面,本申请提供下式化合物和/或其药用盐、互变异构体或立体异构体:
其中
U1、U2、U3及U4独立为-N-或-CH-,条件为其中至少一个为-N-;
A为:
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基。
在前两个方面的范围内的本申请第三个方面,本申请提供式(II)化合物和/或其药用盐、互变异构体或立体异构体:
其中
U1、U2、U3及U4独立为-N-或-CH-,条件为其中至少一个为-N-;
A为:
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R6为氢或任选经取代的(C1-C6)烷基。
在先前方面的范围内的第四个方面,本申请提供下式化合物和/或其药用盐、互变异构体或立体异构体:
其中
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R6为氢或任选经取代的(C1-C6)烷基。
在先前方面的范围内的本申请第五个方面,本申请提供下式化合物和/或其药用盐、互变异构体或立体异构体:
其中
A为:
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R6为氢或任选经取代的(C1-C6)烷基。
在先前方面的范围内的本申请第六个方面,本申请提供下式化合物和/或其药用盐、互变异构体或立体异构体:
其中
A为:
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基
在先前方面的范围内的本申请第七个方面,本申请提供下式化合物:
A为:
在先前方面的范围内的本申请第八个方面,本申请提供下式化合物和/或其药用盐、互变异构体或立体异构体:
其中
A为:
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基。
在先前方面的范围内的本申请另一个方面,本申请提供下式化合物:
其中
A为:
在先前方面的范围内的本申请另一个方面,本申请提供式(V)化合物和/或其药用盐、互变异构体或立体异构体:
其中
A为:
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基。
在先前方面的范围内的本申请另一个方面,本申请提供式(V)化合物,其中A为:
在先前方面的范围内的本申请另一个方面,本申请提供式(VI)化合物和/或其药用盐、互变异构体或立体异构体:
其中
A为:
R独立为一个或多个氢、CD3、卤素、卤代烷基、羟基烷基、CN、CF3、CH2F、CHF2、任选经取代的(C1-C6)烷基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C6)环烷基、任选经取代的杂环基、-OR4、-CONR3R4、-NR3R4、NR3R4(C1-C6)烷基-、-NR6OCOR3、-NR6COR3、NR6COR3(C1-C6)烷基-、-NR6CO2R3、NR6CO2R3(C1-C6)烷基-、-NR6CONR3R4、-SO2NR3R4、SO2(C1-C6)烷基-、-NR6SO2NR3R4、-NR6SO2R4或NR6SO2R4(C1-C6)烷基-;
X及Y独立选自氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的芳基、任选经取代的杂芳基或任选经取代的杂环基;
Z为氢、卤素、-OH、(C1-C6)烷基或(C1-C6)烷氧基;
R1在每次出现时独立为一个或多个氢、卤素、-CN、-OR4、-NR3R4、-CONR3R4、-COOH、-OCONR3R4、-NR6OCOR3、-NR6CONR3R4、-NR6SO2NR3R4、-NR6SO2R4、任选经取代的(C1-C6)烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、任选经取代的(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基、任选经取代的(C3-C8)环烷基(C1-C6)烷基、任选经取代的(C3-C8)环烷基-CO-、任选经取代的(C3-C8)环烷基-SO2-、任选经取代的芳基(C1-C6)烷氧基、任选经取代的(C3-C8)环烷基(C1-C6)烷氧基、任选经取代的杂环基-CO-、任选经取代的杂环基、任选经取代的(C1-C6)烷基-SO2-、-NR6SO2-任选经取代的(C1-C6)烷基、-NR6SO2-任选经取代的杂环基、任选经取代的(C1-C6)烷基-NR6SO2-或任选经取代的杂环基-NR6SO2-;
R2为氢、卤素、-CN、OH、-CONR3R4、-NR6COOR4、-NR6CONR3R4、-NR6COR4、-NR6SO2R5、-SO2NR3R4、-NR6SO2NR3R4、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C1-C6)烷氧基、任选经取代的芳基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的芳基-SO2、任选经取代的杂芳基或任选经取代的杂环基;
R3为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R4为氢、任选经取代的(C1-C6)烷基或任选经取代的(C3-C8)环烷基;
R5为氢、任选经取代的(C1-C6)烷基、任选经取代的(C3-C8)环烷基、任选经取代的(C2-C6)烯基、任选经取代的(C2-C6)炔基、氰基(C1-C6)烷基、羟基(C1-C6)烷基、任选经取代的芳基、任选经取代的芳基(C1-C6)烷基、任选经取代的芳基氧基(C1-C6)烷基、任选经取代的(C1-C6)烷基-SO2-、任选经取代的杂环基、任选经取代的杂环基(C1-C6)烷基、任选经取代的杂芳基或任选经取代的杂芳基(C1-C6)烷基;
R6为氢或任选经取代的(C1-C6)烷基。
在先前方面的范围内的本申请另一个方面,本申请提供式(VI)化合物,其中A为:
在另一个方面,本申请提供选自第一个方面的范围内的示例性实施例的化合物或其药用盐、互变异构体或立体异构体。
在另一个方面,本申请提供选自任何上述方面的范围内的化合物的任何子集的化合物。
在另一个方面,本申请提供选自以下的化合物和/或其药用盐、互变异构体或立体异构体:
5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
13-乙氧基-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
13-(环丙基甲氧基)-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
8-[(S)-(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
13-(环丙基甲氧基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
13-乙氧基-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
13-(环丙基甲氧基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
8-[(S)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[氧杂环己烷-4-基(2,4,6-三氟苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
13-(环丙基甲氧基)-8-[(S)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]环丙磺酰胺;
13-(环丙基甲氧基)-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;
10-甲磺酰基-13-甲氧基-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯;
[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]甲醇;
2-{13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基}丙-2-醇;
13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}甲醇;
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇;
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇;
2-[5-(二甲基-1,2-噁唑-4-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇;
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇;
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇;
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇;
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇;
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基]丙-2-醇;
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇;
2-[5-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇;
4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-1λ6,4-硫吗啉-1,1-二酮;或
2-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇。
本申请一个实施方案提供化合物,其中A为任选经取代的杂环基或任选经取代的杂芳基,其中取代基为一个或多个R。
本申请另一个实施方案提供化合物,其中A为:
R独立为一个或多个氢、CD3、OCD3、CF3、CHF2或(C1-C3)烷基。
本申请另一个实施方案提供化合物,其中A为:
R独立为一个或多个氢、CD3、OCD3、CF3、CHF2或(C1-C3)烷基。
本申请其它实施方案
在另一个实施方案中,本申请提供药物组合物,其包含药用载体及治疗有效量的至少一种本申请化合物或其立体异构体、互变异构体、药用盐或溶剂化物。
在另一个实施方案中,本申请提供制备本申请化合物或其立体异构体、互变异构体、药用盐或溶剂化物的方法。
在另一个实施方案中,本申请涉及本申请化合物、其药用盐、其互变异构体或立体异构体及组合物,其用作药物。
在另一个实施方案中,本申请提供在有此需要的患者中抑制由含有布罗莫结构域的蛋白质介导的病症的活性的方法,其包括向所述患者给药至少一种本申请化合物的步骤。
在另一个实施方案中,本申请提供治疗和/或预防各种类型的癌症的方法,其包括向需要所述治疗和/或预防的患者单独或任选与本申请其它化合物和/或至少一种其它类型的治疗剂组合给药治疗有效量的一种或多种本申请化合物。
在另一个实施方案中,本申请提供治疗和/或预防各种类型的癌症的方法,所述癌症包括但不限于小细胞肺癌、非小细胞肺癌、结肠直肠癌、多发性骨髓瘤、急性髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、胰腺癌、肝癌、肝细胞癌、成神经细胞瘤、其它实体肿瘤或其它血液癌症。
在另一个实施方案中,本申请提供治疗和/或预防各种类型的癌症的方法,所述癌症包括但不限于小细胞肺癌、非小细胞肺癌、结肠直肠癌、多发性骨髓瘤或AML。
在另一个实施方案中,本申请提供本申请化合物,其用于在疗法中使用。
在另一个实施方案中,本申请提供本申请化合物与其它治疗剂的组合制剂,其用于在疗法中同时、分开或依序使用。
在另一个实施方案中,本申请提供抑制含有布罗莫结构域的蛋白质的方法,其包括使所述蛋白质与任何示例性化合物或其药用盐或组合物接触。
治疗性应用
本申请式(I)化合物为布罗莫结构域抑制剂且在治疗布罗莫结构域抑制剂所针对的疾病及病症中具有潜在的实用性。
在一个实施方案中,本申请提供在有此需要的个体中治疗布罗莫结构域抑制剂所针对的疾病或病症的方法,其包括给药治疗有效量的式(I)化合物或其药用盐。
在另一个实施方案中,本申请提供在有此需要的个体中治疗慢性自身免疫和/或炎性病症的方法,其包括给药治疗有效量的一种或多种式(I)化合物或其药用盐。
在另一个实施方案中,本申请提供在有此需要的个体中治疗癌症的方法,其包括给药治疗有效量的一种或多种式(I)化合物或其药用盐。
在一个实施方案中,有此需要的个体为哺乳动物,特别是人类。
据信布罗莫结构域抑制剂可用于治疗与全身或组织炎症、对感染或缺氧的炎性应答、细胞活化及增殖、脂质代谢、纤维变性相关的多种疾病或病症及预防及治疗病毒感染。
布罗莫结构域抑制剂可用于治疗很多种慢性自身免疫及炎性病症例如类风湿性关节炎、骨关节炎、急性痛风、牛皮癣、全身性红斑狼疮、多发性硬化、炎性肠病(克罗恩病及溃疡性结肠炎)、哮喘、慢性阻塞性气道疾病、肺炎、心肌炎、心包炎、肌炎、湿疹、皮炎、脱发、白癜风、大疱性皮肤病、肾炎、血管炎、动脉粥样硬化、阿尔茨海默病、抑郁症、视网膜炎、葡萄膜炎、巩膜炎、肝炎、胰腺炎、原发性胆汁性肝硬化、硬化性胆管炎、阿狄森病、垂体炎、甲状腺炎、I型糖尿病及移植器官急性排斥。
布罗莫结构域抑制剂可用于治疗很多种急性炎性病症例如急性痛风、巨细胞性动脉炎、包括狼疮性肾炎在内的肾炎、累及器官的血管炎例如肾小球肾炎、包括巨细胞性动脉炎在内的血管炎、韦格纳肉芽肿病、结节性多动脉炎、贝切特病、川崎病、高安动脉炎及移植器官急性排斥。
布罗莫结构域抑制剂可用于预防或治疗涉及对细菌、病毒、真菌、寄生虫或其它毒素感染的炎性应答的疾病或病症例如败血病、败血症综合征、败血性休克、内毒素血症、全身性炎性应答综合征(SIRS)、多器官功能障碍综合征、中毒性休克综合征、急性肺损伤、ARDS(成人呼吸窘迫综合征)、急性肾衰竭、暴发型肝炎、灼伤、急性胰腺炎、术后综合征、结节病、赫克斯海默反应、脑炎、脊髓炎、脑膜炎、疟疾、与病毒感染相关的SIRS例如流行性感冒、带状疱疹、单纯疱疹及冠状病毒。
布罗莫结构域抑制剂可用于预防或治疗与缺血-再灌注损伤相关的病症例如心肌梗塞、脑血管缺血(中风)、急性冠状动脉综合征、肾再灌注损伤、器官移植、冠状动脉旁路移植、心肺旁路措施及肺、肾、肝、胃肠或周肢栓塞。
布罗莫结构域抑制剂可用于经由调节APO-A1治疗脂质代谢病症例如高胆固醇血症、动脉粥样硬化及阿尔茨海默病。
布罗莫结构域抑制剂可用于治疗纤维变性病症例如特发性肺纤维变性、肾纤维变性、术后狭窄、瘢痕瘤形成、硬皮病及心脏纤维变性。
布罗莫结构域抑制剂可用于预防及治疗病毒感染例如疱疹病毒、人乳头状瘤病毒、腺病毒、痘病毒及其它DNA病毒。
布罗莫结构域抑制剂也可用于治疗癌症,包括血液学癌瘤、上皮(包括肺、乳腺及结肠)癌瘤、中线癌瘤、间充质肿瘤、肝肿瘤、肾肿瘤及神经学肿瘤。
在一个实施方案中,布罗莫结构域抑制剂所针对的疾病或病症选自与全身性炎性应答综合征相关的疾病例如败血症、灼伤、胰腺炎、严重创伤、出血及缺血。在此实施方案中,布罗莫结构域抑制剂可在诊断点给药以减少SIRS的发生、休克的发作、多器官功能障碍综合征(其包括急性肺损伤、ARDS、急性肾、肝、心及胃肠损伤)及死亡。在另一个实施方案中,布罗莫结构域抑制剂可在与高风险的败血症、出血、大面积组织损伤、SIRS或MODS(多器官功能障碍综合征)相关的手术或其它措施前给药。在具体实施方案中,布罗莫结构域抑制剂所针对的疾病或病症为败血症、败血症综合征、败血性休克及内毒素血症。在另一个实施方案中,布罗莫结构域抑制剂用于治疗急性或急慢性胰腺炎。在另一个实施方案中,布罗莫结构域抑制剂用于治疗灼伤。
在一个实施方案中,布罗莫结构域抑制剂所针对的疾病或病症选自单纯疱疹感染及再活化、唇疱疹、带状疱疹感染及再活化、水痘、带状疱疹、人乳头状瘤病毒、子宫颈瘤形成、包括急性呼吸性疾病在内的腺病毒感染及痘病毒感染例如牛痘及天花及非洲猪瘟病毒。
术语“布罗莫结构域抑制剂所针对的疾病或病症”意欲包括任何或所有以上疾病状态。
在一个实施方案中,本申请提供抑制布罗莫结构域的方法,其包括使所述布罗莫结构域与式(I)化合物或其药用盐接触。
虽然式(I)化合物及其药用盐可按化合物本身形式给药以在疗法中使用,但是更通常以药物组合物形式提供。
药物组合物可按在每个单位剂量中含有预定量的活性成份的单位剂型形式提供。优选的单位剂量组合物为含有每日剂量或其亚剂量或合适分数的活性成份的那些单位剂量组合物。因此,可每天给药上述单位剂量多于一次。优选的单位剂量组合物为包含上述每日剂量或其亚剂量或合适分数(用于每天给药多于一次)的活性成份的那些单位剂量组合物。
可用本申请化合物治疗的癌症类型包括但不限于脑癌、皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、血癌、肺癌及骨癌。上述癌症类型的实例包括成神经细胞瘤、肠癌例如直肠癌、结肠癌、家族性腺瘤性息肉癌及遗传性非息肉结肠直肠癌、食道癌、唇癌、喉癌、咽下癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、子宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、乳腺癌、尿道癌、黑素瘤、脑肿瘤例如成神经细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤及外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、急性髓细胞性白血病(AML)、慢性髓细胞性白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肉瘤、纤维肉瘤、尤因肉瘤及浆细胞瘤。
除在肿瘤中发现的细胞凋亡缺陷外,据信由于细胞凋亡抗性而在清除免疫系统的自身反应性细胞方面的能力缺陷在自身免疫疾病的发病中发挥关键作用。自身免疫疾病的特征在于免疫系统的细胞产生针对其自身器官及分子的抗体或直接攻击组织,从而导致对后者的破坏。上述自身反应性细胞不能经历细胞凋亡,这导致疾病的出现。已在自身免疫疾病例如全身性红斑狼疮或类风湿性关节炎中鉴别出细胞凋亡调节缺陷。
因此,根据另一个实施方案,本申请提供通过向有此需要的患者提供本申请化合物或组合物来治疗自身免疫疾病的方法。上述自身免疫疾病的实例包括但不限于胶原病例如类风湿性关节炎、全身性红斑狼疮、夏普综合征、CREST综合征(钙质沉着症、雷诺综合征、食道运动功能障碍、毛细血管扩张)、皮肌炎、血管炎(韦格纳病)及斯耶格伦综合征、肾病例如古德帕斯彻综合征、急进性肾小球肾炎及II型膜增殖性肾小球肾炎、内分泌疾病例如I型糖尿病、自身免疫多内分泌腺病-念珠菌病-外胚层营养不良(APECED)、自身免疫甲状旁腺病、恶性贫血、性腺功能不全、特发性艾迪生病、甲状腺功能亢进、桥本甲状腺炎及原发性粘液水肿、皮肤病例如寻常天疱疮、大疱性类天疱疮、妊娠疱疹、大疱性表皮松解及重度多形性红斑、肝病例如原发性胆汁性肝硬化、自身免疫胆管炎、1型自身免疫肝炎、2型自身免疫肝炎、原发性硬化性胆管炎、神经元疾病例如多发性硬化、重症肌无力、肌无力性兰伯特-伊顿综合征、获得性肌神经切断、吉兰-巴雷综合征(穆勒-费舍尔综合征)、僵人综合征、小脑变性、共济失调、眼阵挛、感觉神经病变及弛缓不能、血液病例如自身免疫性溶血性贫血、特发性血小板减少性紫癜(韦尔霍夫病)、与自身免疫反应相关的传染病例如AIDS、疟疾及查加斯病。
本申请化合物可单独或与其它治疗剂或放射疗法组合或共同给药用于治疗某些类型的癌症。因此,在一个实施方案中,本申请化合物与放射疗法或具有细胞抑制或抗肿瘤活性的第二治疗剂共同给药。合适的细胞抑制性化学疗法化合物包括但不限于(i)抗代谢剂;(ii)DNA分段剂;(iii)DNA交联剂;(iv)插入剂;(v)蛋白质合成抑制剂;(vi)拓扑异构酶I毒素,例如喜树碱或托泊替康;(vii)拓扑异构酶II毒素;(viii)微管导向剂;(ix)激酶抑制剂;(x)各种研究性药物;(xi)激素;及(xii)激素拮抗剂。本申请化合物意欲可用于与属于以上12类的任何已知药物及当前正在开发的任何未来药物组合。具体地,本申请化合物意欲可用于与当前标准护理及在可预见的未来发展出的任何标准护理组合。具体剂量及给药方案可基于医师不断发展的知识及本领域通用技术。
本申请还提供治疗方法,其中本申请化合物与一种或多种免疫-肿瘤学药物一起给药。本申请使用的免疫-肿瘤学药物(也称为癌症免疫疗法)可在个体中有效增强、刺激和/或上调免疫应答。在一个方面,本申请化合物与免疫-肿瘤学药物的给药在抑制肿瘤生长中具有协同作用。
在一个方面,本申请化合物在给药免疫-肿瘤学药物前依序给药。在另一个方面,本申请化合物与免疫-肿瘤学药物同时给药。在另一个方面,本申请化合物在给药免疫-肿瘤学药物后依序给药。
在另一个方面,本申请化合物可与免疫-肿瘤学药物共同配制。
免疫-肿瘤学药物包括例如小分子药物、抗体或其它生物分子或小分子。生物免疫-肿瘤学药物的实例包括但不限于癌症疫苗、抗体及细胞因子。在一个方面,抗体为单克隆抗体。在另一个方面,单克隆抗体为人化抗体或人抗体。
在一个方面,免疫-肿瘤学药物为(i)刺激性(包括共刺激性)受体的激动剂或(ii)T细胞上抑制性(包括共抑制性)信号的拮抗剂,所述两者均使抗原特异性T细胞应答得以扩大(通常称为免疫检查点调控剂)。
某些刺激性及抑制性分子为免疫球蛋白超家族(IgSF)的成员。与共刺激性或共抑制性受体结合的一个重要膜结合配体家族为B7家族,其包括B7-1、B7-2、B7-H1(PD-L1)、B7-DC(PD-L2)、B7-H2(ICOS-L)、B7-H3、B7-H4、B7-H5(VISTA)及B7-H6。与共刺激性或共抑制性受体结合的另一个膜结合配体家族为与同源TNF受体家族成员结合的TNF家族分子,其包括CD40及CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137(4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LTβR、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素α/TNFβ、TNFR2、TNFα、LTβR、淋巴毒素α1β2、FAS、FASL、RELT、DR6、TROY、NGFR。
在另一个方面,免疫-肿瘤学药物为抑制T细胞活化的细胞因子(例如IL-6、IL-10、TGF-β、VEGF及其它免疫抑制细胞因子)或刺激T细胞活化以刺激免疫应答的细胞因子。
在一个方面,T细胞应答可通过本申请化合物与以下一种或多种药物的组合来刺激:(i)抑制T细胞活化的蛋白质的拮抗剂(例如免疫检查点抑制剂),例如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳凝素-9、CEACAM-1、BTLA、CD69、半乳凝素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1及TIM-4;及(ii)刺激T细胞活化的蛋白质的激动剂,例如B7-1、B7-2、CD28、4-1BB(CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3及CD28H。
可与本申请化合物组合以治疗癌症的其它药物包括NK细胞上抑制性受体的拮抗剂或NK细胞上活化性受体的激动剂。例如,本申请化合物可与KIR的拮抗剂例如lirilumab组合。
用于组合疗法的其它药物包括抑制或消耗巨噬细胞或单核细胞的药物,包括但不限于CSF-1R拮抗剂例如CSF-1R拮抗剂抗体,包括RG7155(WO11/70024、WO11/107553、WO11/131407、WO13/87699、WO13/119716、WO13/132044)或FPA-008(WO11/140249、WO13169264、WO14/036357)。
在另一个方面,本申请化合物可与以下一种或多种药物一起使用:连接阳性共刺激性受体的激动剂、减弱经由抑制性受体的信号传导的阻断剂、拮抗剂及一种或多种全身性提高抗肿瘤T细胞频率的药物、克制肿瘤微环境中独特免疫抑止路径(例如阻断抑制性受体接合(例如PD-L1/PD-1相互作用)、消耗或抑制Treg(例如使用抗CD25单克隆抗体(例如daclizumab)或通过离体抗CD25珠子消耗)、抑制代谢酶例如IDO或逆转/预防T细胞无反应性或耗尽)的药物及在肿瘤部位触发先天免疫活化和/或炎症的药物。
在一个方面,免疫-肿瘤学药物为CTLA-4拮抗剂例如拮抗性CTLA-4抗体。合适的CTLA-4抗体包括例如YERVOY(ipilimumab)或tremelimumab。
在另一个方面,免疫-肿瘤学药物为PD-1拮抗剂例如拮抗性PD-1抗体。合适的PD-1抗体包括例如OPDIVO(nivolumab)、KEYTRUDA(pembrolizumab)或MEDI-0680(AMP-514;WO2012/145493)。免疫-肿瘤学药物还可包括pidilizumab(CT-011),尽管其与PD-1结合的特异性已受到质疑。靶向于PD-1受体的另一种措施为由与IgG1的Fc部分融合的PD-L2(B7-DC)的细胞外结构域构成的称为AMP-224的重组蛋白质。
在另一个方面,免疫-肿瘤学药物为PD-L1拮抗剂例如拮抗性PD-L1抗体。合适的PD-L1抗体包括例如MPDL3280A(RG7446;WO2010/077634)、durvalumab(MEDI4736)、BMS-936559(WO2007/005874)及MSB0010718C(WO2013/79174)。
在另一个方面,免疫-肿瘤学药物为LAG-3拮抗剂例如拮抗性LAG-3抗体。合适的LAG3抗体包括例如BMS-986016(WO10/19570,WO14/08218)或IMP-731或IMP-321(WO08/132601,WO09/44273)。
在另一个方面,免疫-肿瘤学药物为CD137(4-1BB)激动剂例如激动性CD137抗体。合适的CD137抗体包括例如urelumab及PF-05082566(WO12/32433)。
在另一个方面,免疫-肿瘤学药物为GITR激动剂例如激动性GITR抗体。合适的GITR抗体包括例如BMS-986153、BMS-986156、TRX-518(WO06/105021,WO09/009116)及MK-4166(WO11/028683)。
在另一个方面,免疫-肿瘤学药物为IDO拮抗剂。合适的IDO拮抗剂包括例如INCB-024360(WO2006/122150,WO07/75598,WO08/36653,WO08/36642)、indoximod或NLG-919(WO09/73620,WO09/1156652,WO11/56652,WO12/142237)。
在另一个方面,免疫-肿瘤学药物为OX40激动剂例如激动性OX40抗体。合适的OX40抗体包括例如MEDI-6383或MEDI-6469。
在另一个方面,免疫-肿瘤学药物为OX40L拮抗剂例如拮抗性OX40抗体。合适的OX40L拮抗剂包括例如RG-7888(WO06/029879)。
在另一个方面,免疫-肿瘤学药物为CD40激动剂例如激动性CD40抗体。在另一个实施方案中,免疫-肿瘤学药物为CD40拮抗剂例如拮抗性CD40抗体。合适的CD40抗体包括例如lucatumumab或dacetuzumab。
在另一个方面,免疫-肿瘤学药物为CD27激动剂例如激动性CD27抗体。合适的CD27抗体包括例如varlilumab。
在另一个方面,免疫-肿瘤学药物为MGA271(针对B7H3)(WO11/109400)。
组合疗法意欲包括以依序方式给药这些治疗剂即其中每种治疗剂在不同的时间给药及这些治疗剂或所述治疗剂中的至少两种以实质上同时的方式给药。实质上同时给药可例如如下实现:向个体给药具有固定比例的每种治疗剂的单一剂型或多个针对每种治疗剂的单一剂型。依序或实质上同时给药每种治疗剂可通过任何合适的途径来实现,所述途径包括但不限于口服途径、静脉内途径、肌内途径及经由粘膜组织直接吸收。治疗剂可通过相同的途径或通过不同的途径给药。例如,所选组合中的第一治疗剂可通过静脉内注射给药,而所述组合中的其它治疗剂可口服给药。可选择地,例如所有治疗剂均可口服给药或所有治疗剂均可通过静脉内注射给药。组合疗法还可包括将上述治疗剂进一步与其它生物活性成份及非药物疗法(例如手术或放射治疗)组合给药。当组合疗法进一步包括非药物治疗时,非药物治疗可在任何合适的时间进行,只要由治疗剂与非药物治疗的组合的共同作用获得有益的效果。例如,在合适的情况下,当将非药物治疗从治疗剂的给药中暂时除去时,仍将获得有益的效果,其可能历经数日或甚至数周。
可按其它具体形式实施本申请而不脱离其主旨或基本属性。本申请包括在此描述的本申请优选方面的所有组合。应理解的是,本申请任何及所有实施方案可与任何其它实施方案组合以描述额外的实施方案。还应理解的是,实施方案的每个独立要素本身为独立的实施方案。另外,实施方案的任何要素意欲与来自任何实施方案的任何及所有其它要素组合以描述额外的实施方案。
药物组合物及给药
本申请还提供药用组合物,其包含治疗有效量的一种或多种式I化合物,所述式I化合物与一种或多种药用载体(添加剂)和/或稀释剂及任选的一种或多种上述其它治疗剂一起配制。如下所详述,可将本申请药物组合物具体配制成用于以固体或液体形式给药,包括适于以下的那些形式:(1)口服给药,例如灌剂(水性或非水性溶液剂或混悬剂)、片剂(例如靶向于颊、舌下及全身性吸收的那些片剂)、大丸剂、粉末剂、颗粒剂、施用于舌的糊剂;(2)胃肠外给药,例如通过皮下、肌内、静脉内或硬膜外注射,例如以无菌溶液剂或混悬剂或持续释放制剂形式;(3)局部施用,例如以施用于皮肤的乳膏剂、软膏剂或控制释放贴剂或喷雾剂形式;(4)阴道内或直肠内给药,例如以阴道栓剂、乳膏剂或泡沫剂形式;(5)舌下给药;(6)经眼给药;(7)经皮给药;或(8)经鼻给药。
本申请使用的短语“药用”是指在可靠的医药判断范围内适用于与人类及动物的组织接触而不引起过度的毒性、刺激性、变态反应或其它问题或并发症的与合理的益处/风险比例相称的那些化合物、物质、组合物和/或剂型。
本申请使用的短语“药用载体”意指参与将本申请化合物由身体的一个器官或部分携带或运输至身体的另一个器官或部分的药用物质、组合物或媒介物例如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包封物质。每种载体在与制剂的其它成份相容方面必须是“可接受的”且对患者不是有害的。可充当药用载体的物质的一些实例包括:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素;(4)粉末状西黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液;(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酸酐;及(22)用于药物制剂的其它无毒相容物质。
湿润剂、乳化剂及润滑剂例如月桂基硫酸钠及硬脂酸镁及着色剂、释放剂、包衣剂、甜味剂、矫味剂及芳香剂、防腐剂及抗氧化剂也可存在于组合物中。
药用抗氧化剂的实例包括:(1)水溶性抗氧化剂,例如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;及(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本申请制剂包括适于口服、经鼻、局部(包括经颊及舌下)、经直肠、经阴道和/或胃肠外给药的那些制剂。制剂可方便地以单位剂型形式提供且可通过药学领域已知的任何方法来制备。活性成份可与载体物质组合以得到单一剂型的量将随所治疗的患者及特定的给药模式而变化。活性成份可与载体物质组合以得到单一剂型的量通常将为化合物产生疗效的量。此量的范围以百分比计通常将为约0.1%至约99%、优选约5%至约70%、最优选约10%至约30%活性成份。
在某些实施方案中,本申请制剂包含选自环糊精、纤维素、脂质体、胶束形成剂例如胆汁酸及聚合物载体例如聚酯及聚酸酐的赋形剂及本申请化合物。在某些实施方案中,上述制剂使本申请化合物是口服可生物利用的。
制备这些制剂或组合物的方法包括使本申请化合物与载体及任选的一种或多种附属成份组合的步骤。制剂通常如下制备:使本申请化合物与液体载体或微细分散的固体载体或两者均匀且紧密地组合且然后按需使产品成形。
适于口服给药的本申请制剂可呈胶囊剂、扁囊剂、丸剂、片剂、锭剂(使用通常为蔗糖及阿拉伯胶或西黄蓍胶的矫味基质)、粉末剂、颗粒剂形式或呈在水性或非水性液体中的溶液剂或混悬剂形式或呈水包油型或油包水型液体乳剂形式或呈酏剂或糖浆剂形式或呈软锭剂(使用惰性基质例如明胶及甘油或蔗糖及阿拉伯胶)形式和/或呈漱口剂形式等,其各自含有预定量的本申请化合物作为活性成份。本申请化合物也可按大丸剂、药糖剂或糊剂形式给药。
在用于口服给药的本申请固体剂型(胶囊剂、片剂、丸剂、糖锭剂、粉末剂、颗粒剂、锭剂等)中,使活性成份与一种或多种药用载体例如柠檬酸钠或磷酸二钙和/或以下任何一种混合:(1)填充剂或扩容剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐及碳酸钠;(5)溶解阻滞剂,例如石蜡;(6)吸收促进剂,例如季铵化合物及表面活性剂例如泊洛沙姆及月桂基硫酸钠;(7)湿润剂,例如十六烷醇、单硬脂酸甘油酯及非离子型表面活性剂;(8)吸附剂,例如高岭土及膨润土;(9)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠、硬脂酸锌、硬脂酸钠、硬脂酸及其混合物;(10)着色剂;及(11)控制释放剂,例如交聚维酮或乙基纤维素。就胶囊剂、片剂及丸剂而言,药物组合物还可包含缓冲剂。类型相似的固体组合物也可在使用赋形剂例如乳糖及高分子量聚乙二醇等的软壳及硬壳明胶胶囊剂中用作填充剂。
片剂可通过压制或模制任选与一种或多种附属成份一起制备。压制片可使用粘合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如羟乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模制片可如下制备:在合适的机器中对经惰性液体稀释剂湿润的粉末状化合物的混合物进行模制。
本申请药物组合物的片剂及其它固体剂型例如糖锭剂、胶囊剂、丸剂及颗粒剂可任选刻痕或制备有包衣及外壳例如肠溶衣及药物配制领域已知的其它包衣。其还可使用例如羟丙基甲基纤维素(不同比例以提供所需释放分布)、其它聚合物基质、脂质体和/或微球来配制以使其中的活性成份得以缓慢或控制释放。可将其配制成用于快速释放,例如通过冷冻干燥。其可如下灭菌:例如经由细菌截留过滤器过滤或在无菌固体组合物中引入灭菌剂,所述组合物可在使用前即刻溶解于无菌水或一些其它无菌注射用介质中。这些组合物还可任选含有遮光剂且可呈仅或优先在胃肠道的某个部分中任选以延迟方式释放活性成份的组合物形式。可使用的包埋用组合物的实例包括聚合物物质及蜡。活性成份还可按需与一种或多种上述赋形剂一起呈微囊化形式。
本申请化合物用于口服给药的液体剂型包括药用乳剂、微乳剂、溶液剂、混悬剂、糖浆剂及酏剂。液体剂型除活性成份外还可含有本领域常用惰性稀释剂例如水或其它溶剂、增溶剂及乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油及芝麻油)、甘油、四氢呋喃醇、聚乙二醇及脱水山梨醇脂肪酸酯及其混合物。
口服组合物除惰性稀释剂外还可包含辅料例如湿润剂、乳化剂及助悬剂、甜味剂、矫味剂、着色剂、芳香剂及防腐剂。
混悬剂除活性化合物外还可含有助悬剂例如乙氧基化异硬脂醇、聚氧乙烯山梨醇及脱水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及西黄蓍胶及其混合物。
本申请药物组合物用于直肠或阴道给药的制剂可按栓剂形式提供,其可如下制备:将一种或多种本申请化合物与一种或多种合适的无刺激性的赋形剂或载体(包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合且其在室温为固体但在体温为液体且因此将在直肠或阴道腔中融化且释放活性化合物。
适于阴道给药的本申请制剂还包括阴道栓剂、棉塞剂、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾剂,其含有本领域已知的合适载体。
本申请化合物用于局部或经皮给药的剂型包括粉末剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴剂及吸入剂。活性化合物可在无菌条件下与药用载体及可能需要的任何防腐剂、缓冲剂或推进剂混合。
软膏剂、糊剂、乳膏剂及凝胶剂除本申请活性化合物外还可含有赋形剂例如动物及植物脂肪、油、蜡、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石及氧化锌或其混合物。
粉末剂及喷雾剂除本申请化合物外还可含有赋形剂例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末或这些物质的混合物。喷雾剂还可含有常规推进剂例如氯氟烃及挥发性的未经取代的烃如丁烷及丙烷。
经皮贴剂具有可将本申请化合物以控制方式递送至身体的额外优点。上述剂型可通过将化合物溶解或分散于合适的介质中来制备。还可使用吸收促进剂以提高化合物的透皮通量。上述通量的速率可通过提供速率控制膜或将化合物分散于聚合物基质或凝胶中来控制。
眼用制剂、眼膏剂、粉末剂、溶液剂等也包括在本申请范围内。
适于胃肠外给药的本申请药物组合物包含一种或多种本申请化合物与以下一种或多种的组合:药用无菌等渗水性或非水性溶液、分散液、混悬液或乳液或可在使用前即刻复溶成无菌注射用溶液或分散液的无菌粉末,其可含有糖、醇、抗氧化剂、缓冲剂、抑菌剂、使制剂与所预期的接受者的血液等渗的溶质或助悬剂或增稠剂。
可用于本申请药物组合物的合适水性及非水性载体的实例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)及其合适混合物、植物油例如橄榄油及注射用有机酯例如油酸乙酯。合适的流动性可例如如下维持:使用包覆物质例如卵磷脂,在分散液的情况下维持所需要的粒度及使用表面活性剂。
这些组合物还可含有辅料例如防腐剂、湿润剂、乳化剂及分散剂。防止微生物对本申请化合物的作用可通过包含多种抗细菌剂及抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等来确保。还可能需要在组合物中包含等渗剂例如糖、氯化钠等。另外,注射用药物形式的延长吸收可通过包含使吸收得以延迟的物质例如单硬脂酸铝及明胶来实现。
在一些情况下,为了延长药物的作用而需要减缓药物在皮下或肌内注射后的吸收。这可通过使用具有差的水溶性的结晶或无定形物质的液体混悬液来实现。药物的吸收速率然后取决于其溶出速率,而溶出速率可取决于晶体大小及结晶形式。可选择地,胃肠外给药的药物形式的延迟吸收通过将药物溶解或混悬于油媒介物中来实现。
注射用药物储库形式通过形成本申请化合物在生物可降解的聚合物例如聚丙交酯-聚乙交酯中的微囊化基质来制备。取决于药物与聚合物的比例及所用特定聚合物的性质而可控制药物的释放速率。其它生物可降解的聚合物的实例包括聚(原酸酯)及聚(酸酐)。药物储库注射用制剂也通过将药物包埋在与身体组织相容的脂质体或微乳液中来制备。
当本申请化合物作为药物给药于人类及动物时,其可按原样或以含有例如0.1至99%(更优选10至30%)活性成份与药用载体的组合的药物组合物形式给予。
不论选择哪种给药途径,通过本领域技术人员已知的常规方法将本申请化合物(其可按合适的水合形式使用)和/或本申请药物组合物配制成药用剂型。
可改变活性成份在本申请药物组合物中的实际剂量水平以获得活性成份针对特定患者、组合物及给药模式可有效实现所需治疗应答而对患者不具有毒性的量。
所选剂量水平将取决于多种因素,包括所用本申请特定化合物或其酯、盐或酰胺的活性、给药途径、给药时间、所用特定化合物的排泄或代谢速率、吸收速率及程度、治疗持续时间、与所用特定化合物联用的其它药物、化合物和/或物质、所治疗的患者的年龄、性别、体重、状况、一般健康及先前病史及医药领域已知的类似因素。
具有本领域常规技术的医师或兽医可容易地确定及开具所需药物组合物的有效量。例如,医师或兽医可开始于以比实现所需疗效所需要的水平低的水平给药在药物组合物中使用的本申请化合物且逐渐增加剂量直至实现所需效果。
本申请化合物的合适每日剂量通常将为化合物的以下量,其为可有效产生疗效的最低剂量。上述有效剂量通常将取决于上述因素。本申请化合物针对患者的口服、静脉内、脑室内及皮下剂量的范围通常将为约0.01至约50mg/千克体重/日。
活性化合物的有效每日剂量可按需在一整天内以合适的间隔以分开给药的2、3、4、5、6或更多个亚剂量形式任选以单位剂型形式给药。在本申请某些方面,给药为每天给药一次。
虽然本申请化合物可单独给药,但是化合物优选以药物制剂(组合物)形式给药。
定义
除非本申请另有具体说明,否则对单数的提及还可包括复数。例如,“一个”可指一个或一个或多个。
除非另有说明,否则推定任何具有不满足的价数的杂原子具有足够使价数得以满足的氢原子。
在说明书和所附权利要求书通篇中,给定的化学式或名称应包括所有立体和光学异构体及其中存在上述异构体的外消旋体。除非另有说明,否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本申请范围内。在化合物中还可存在C=C双键、C=N双键、环系等的多种几何异构体且所有上述稳定的异构体均包括在本申请中。本申请描述了本申请化合物的顺式和反式(或E-和Z-)几何异构体且可将其分离成异构体的混合物或分开的异构形式。可将本申请化合物分离成光学活性或外消旋形式。光学活性形式可如下制备:拆分外消旋形式或由光学活性原料合成。用于制备本申请化合物的所有方法及其中制备的中间体均视为本申请一部分。当制备对映异构或非对映异构产物时,其可通过常规方法例如色谱或分级结晶来分离。取决于方法条件而以游离(中性)或盐形式获得本申请最终产物。这些最终产物的游离形式和盐均在本申请范围内。可按需将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐;可将盐转化成游离化合物或另一种盐;可将本申请异构化合物的混合物分离成单独的异构体。本申请化合物、其游离形式和盐可按多种互变异构形式存在,其中氢原子转移到分子的其它部分且由此分子中原子之间的化学键发生重排。应理解的是,可存在的所有互变异构形式均包括在本申请中。
除非另有定义,否则当基团被注明为“任选取代”时,取代基选自例如取代基例如烷基、环烷基、芳基、杂芳基、杂环基、卤素、卤代烷基、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、经二取代的其中2个氨基取代基选自烷基、芳基或芳基烷基的氨基、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、经取代的烷酰基氨基、经取代的芳基氨基、经取代的芳烷酰基氨基、巯基、烷基硫基、芳基硫基、芳基烷基硫基、烷基硫羰基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基(例如-SO2NH2)、经取代的磺酰氨基、硝基、氰基、羧基、氨甲酰基(例如-CONH2)、经取代的氨甲酰基(例如-CONH烷基、-CONH芳基、-CONH芳基烷基或其中在氮上存在两个选自烷基、芳基或芳基烷基的取代基的情况)、烷氧基羰基、芳基、经取代的芳基、胍基、杂环基(例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等)及经取代的杂环基。
另外,出于明确的目的,当取代基具有不是在两个字母或符号之间的破折号(-)时,其用于表示取代基的连接点。例如,-CONH2通过碳原子连接。
另外,出于明确的目的,当在实线的末端没有显示取代基时,其表示具有与该键连接的甲基(CH3)。
本申请使用的术语“烷基”或“亚烷基”意欲包括具有指定数目碳原子的支链及直链饱和脂族烃基。例如,“C1-C6烷基”是指具有1至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基及异丙基)、丁基(例如正丁基、异丁基、叔丁基)及戊基(例如正戊基、异戊基、新戊基)。
术语“烯基”是指含有一个或多个双键及长度通常为2至20个碳原子的直链或支链烃基。例如,“C2-C8烯基”含有两个至八个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基、辛烯基等。
术语“炔基”是指含有一个或多个叁键及长度通常为2至20个碳原子的直链或支链烃基。例如,“C2-C8炔基”含有两个至八个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5及C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基及异丙氧基)及叔丁氧基。类似地,“烷基硫基”或“硫代烷氧基”是指通过硫桥连接的如上定义的具有指定数目碳原子的烷基例如甲基-S-及乙基-S-。
单独或作为较大部分例如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的一部分的术语“芳基”是指总共具有5-15个环成员的单环、二环及三环系统,其中该系统中的至少一个环为芳族的及其中该系统中的每个环含有3-7个环成员。在本申请某些实施方案中,“芳基”是指芳族环系,其包括但不限于苯基、联苯、茚满基、1-萘基、2-萘基及四氢萘基。术语“芳烷基”或“芳基烷基”是指与芳基环连接的烷基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环上的合适位置与另一个基团连接。例如:
由环系引出的箭头线表示键可连接至任何合适的环原子。
术语“环烷基”是指环化的烷基。C3-6环烷基意欲包括C3、C4、C5及C6环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基及降莰烷基。支链环烷基例如1-甲基环丙基及2-甲基环丙基包括在“环烷基”的定义中。术语“环烯基”是指环化的烯基。C4-6环烯基意欲包括C4、C5及C6环烯基。环烯基的实例包括但不限于环丁烯基、环戊烯基及环己烯基。
术语“环烷基烷基”是指以下环烷基或经取代的环烷基,其键合至与化合物的核心连接的烷基。
“卤代”或“卤素”包括氟、氯、溴及碘。“卤代烷基”意欲包括经一个或多个卤素取代的具有指定数目碳原子的支链及直链饱和脂族烃基。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基及七氯丙基。卤代烷基的实例还包括“氟代烷基”,其意欲包括经一个或多个氟原子取代的具有指定数目碳原子的支链及直链饱和脂族烃基。
“卤代烷氧基”或“卤代烷基氧基”是指通过氧桥连接的如上定义的具有指定数目碳原子的卤代烷基。例如,“C1-6卤代烷氧基”意欲包括C1、C2、C3、C4、C5及C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基及五氟乙氧基。类似地,“卤代烷基硫基”或“卤代硫代烷氧基”是指通过硫桥连接的如上定义的具有指定数目碳原子的卤代烷基例如三氟甲基-S-及五氟乙基-S-。
本申请使用的术语“苄基”是指其上一个氢原子被苯基代替的甲基。
本申请使用的术语“杂环”、“杂环基”或“杂环基团”意指稳定的3、4、5、6或7元单环或二环或7、8、9、10、11、12、13或14元多环杂环,其为饱和、部分不饱和或完全不饱和的且其含有碳原子及1、2、3或4个独立选自N、O及S的杂原子;及包括其中任何上述杂环与苯环稠合的任何多环基团。氮及硫杂原子可任选氧化(即N→O及其中p为0、1或2的S(O)p)。氮原子可经取代或未经取代(即N或其中R为H或另一种取代基(若定义)的NR)。杂环可在产生稳定结构的任何杂原子或碳原子处与其侧基连接。若所得化合物是稳定的,则本申请所述杂环可在碳或氮原子上经取代。杂环中的氮可任选季铵化。优选地,当杂环中S及O原子的总数超过1时,这些杂原子不彼此相邻。优选地,杂环中S及O原子的总数不大于1。当使用术语“杂环”时,其意欲包括杂芳基。
杂环的实例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、吲哚烯基、吲哚啉基、吲嗪基、吲哚基、3H-吲哚基、靛红基、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、喋啶基、羟吲哚基、嘧啶基、菲啶基、菲啉基、吩嗪基、吩噻嗪基、吩噁噻嗪基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、硫代苯基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基及呫吨基。还包括含有例如上述杂环的稠环及螺环化合物。
本申请使用的术语“二环杂环”或“二环杂环基团”意指含有两个稠合的环且由碳原子及1、2、3或4个独立选自N、O及S的杂原子构成的稳定的9或10元杂环环系。在两个稠合的环中,一个环为5或6元单环芳族环,包括5元杂芳基环、6元杂芳基环或苯并环,其各自与第二个环稠合。第二个环为5或6元单环,其为饱和、部分不饱和或不饱和的且包括5元杂环、6元杂环或碳环(条件是当第二个环为碳环时,第一个环不为苯并环)。
二环杂环基团可在产生稳定结构的任何杂原子或碳原子处与其侧基连接。若所得化合物是稳定的,则本申请所述二环杂环基团可在碳或氮原子上经取代。优选地,当杂环中S及O原子的总数超过1时,这些杂原子不彼此相邻。优选地,杂环中S及O原子的总数不大于1。
二环杂环基团的实例为但不限于喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、吲哚啉基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢喹啉基、2,3-二氢苯并呋喃基、色满基、1,2,3,4-四氢喹喔啉基及1,2,3,4-四氢喹唑啉基。
本申请使用的术语“芳族杂环基团”或“杂芳基”意指包含至少一个杂原子环成员例如硫、氧或氮的稳定的单环及多环芳族烃基。杂芳基包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、嘌呤基、咔唑基、苯并咪唑基、吲哚啉基、苯并二氧杂环戊基及苯并二噁烷基。杂芳基经取代或未经取代。氮原子经取代或未经取代(即N或其中R为H或另一种取代基(若定义)的NR)。氮及硫杂原子可任选氧化(即N→O及其中p为0、1或2的S(O)p)。
桥环也包括在杂环的定义中。当一个或多个(优选一个至三个)原子(即C、O、N或S)连接两个不相邻的碳或氮原子时形成桥环。桥环的实例包括但不限于一个碳原子、两个碳原子、一个氮原子、两个氮原子及碳-氮基团。应注意的是,桥总是将单环转化成三环。当环被桥接时,就该环所描述的取代基也可存在于桥上。
术语“杂环基烷基”是指以下杂环基或经取代的杂环基,其键合至与化合物的核心连接的烷基。
术语“抗衡离子”用于表示带负电荷的物质例如氯离子、溴离子、氢氧根离子、乙酸根离子和硫酸根离子或带正电荷的物质例如钠离子(Na+)、钾离子(K+)、铵根离子(其中n=0-4且m=0-4的RnNHm +)等。
术语“吸电子基团”(EWG)是指使键发生极化的取代基,其向自身吸引电子密度且使电子密度远离其它成键原子。EWG的实例包括但不限于CF3、CF2CF3、CN、卤素、卤代烷基、NO2、砜、亚砜、酯、磺酰胺、甲酰胺、烷氧基、烷氧基醚、烯基、炔基、OH、C(O)烷基、CO2H、苯基、杂芳基、-O-苯基及-O-杂芳基。EWG的优选实例包括但不限于CF3、CF2CF3、CN、卤素、SO2(C1-4烷基)、CONH(C1-4烷基)、CON(C1-4烷基)2及杂芳基。EWG的更优选实例包括但不限于CF3及CN。
本申请使用的术语“胺保护基”意指在有机合成领域中已知用于对胺基团进行保护的任何基团,其对于酯还原剂、经二取代的肼、R4-M和R7-M、亲核试剂、肼还原剂、活化剂、强碱、具有位阻的胺碱和环化剂是稳定的。符合这些标准的上述胺保护基包括Wuts,P.G.M.and Greene,T.W.Protecting Groups in Organic Synthesis,4th Edition,Wiley(2007)和The Peptides:Analysis,Synthesis,Biology,Vol.3,Academic Press,New York(1981)所列出的那些胺保护基,通过引用将其内容并入本申请。胺保护基的实例包括但不限于以下:(1)酰基类,例如甲酰基、三氟乙酰基、邻苯二甲酰基和对甲苯磺酰基;(2)芳族氨基甲酸酯类,例如苄基氧基羰基(Cbz)和取代的苄基氧基羰基、1-(对联苯基)-1-甲基乙氧基羰基和9-芴基甲基氧基羰基(Fmoc);(3)脂族氨基甲酸酯类,例如叔丁基氧基羰基(Boc)、乙氧基羰基、二异丙基甲氧基羰基和烯丙基氧基羰基;(4)环状烷基氨基甲酸酯类,例如环戊基氧基羰基和金刚烷基氧基羰基;(5)烷基类,例如三苯基甲基和苄基;(6)三烷基甲硅烷,例如三甲基甲硅烷;(7)含硫醇类,例如苯基硫基羰基和二硫杂琥珀酰基;和(8)烷基类,例如三苯基甲基、甲基和苄基;和取代的烷基类,例如2,2,2-三氯乙基、2-苯基乙基和叔丁基;和三烷基甲硅烷类,例如三甲基甲硅烷。
本申请使用的术语“取代”意指至少一个氢原子被非氢基团代替,条件是维持正常的化合价且取代得到稳定的化合物。本申请使用的环双键为在两个相邻环原子之间形成的双键(例如C=C、C=N或N=N)。
当在本申请化合物上存在氮原子(例如胺)时,可通过用氧化剂(例如mCPBA和/或过氧化氢)进行处理将这些氮原子转化成N-氧化物以获得本申请其它化合物。因此,所显示和要求保护的氮原子视为包括所显示的氮及其N-氧化物(N→O)衍生物。
当任何变量在化合物的任何组成或结构式中出现大于一次时,其在每次出现时的定义独立于其在每次其它出现时的定义。因此,例如若基团显示取代有0-3个R,则所述基团可任选取代有至多三个R基团且R在每次出现时独立选自R的定义。另外,可允许取代基和/或变量的组合,只要上述组合产生稳定的化合物。
当与取代基连接的键显示为与连接环中两个原子的键交叉时,上述取代基可与环上的任何原子键合。当列出取代基但没有指明上述取代基通过其中哪个原子与具有给定结构式的化合物的其余部分键合时,上述取代基可经由上述取代基中的任何原子来键合。可允许取代基和/或变量的组合,只要上述组合产生稳定的化合物。
本申请意欲包括在本申请化合物中出现的原子的所有同位素。同位素包括原子序数相同但质量数不同的那些原子。例如但不限于此,氢的同位素包括氚及氘。氢的同位素可表示为1H(氢)、2H(氘)及3H(氚)。其还通常表示为D(氘)及T(氚)。在本申请中,CD3表示其中所有氢原子均为氘的甲基。碳的同位素包括13C及14C。本申请经同位素标记的化合物通常可通过本领域技术人员已知的常规技术或通过与本申请所述那些方法类似的方法使用适当的经同位素标记的试剂代替在其它情况下使用的未经标记的试剂来制备。
本申请使用的“药用盐”是指本申请化合物的衍生物,其中母体化合物通过制备其酸或碱盐来改性。药用盐的实例包括但不限于碱性基团例如胺的无机或有机酸盐;及酸性基团例如羧酸的碱金属盐或有机盐。药用盐包括母体化合物的例如由无毒无机或有机酸形成的常规无毒盐或季铵盐。例如,上述常规无毒盐包括衍生自无机酸的那些盐,所述无机酸为例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸;及由有机酸制备的盐,所述有机酸为例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺氨酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸和羟乙磺酸等。
本申请药用盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。通常,上述盐可通过在水或有机溶剂或二者的混合物中使这些化合物的游离酸或碱形式与化学计量量的适当碱或酸反应来制备;通常,非水性介质例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。合适的盐的列表参见Remington:The Science and Practice ofPharmacy,第22版,Allen,L.V.Jr.编辑;Pharmaceutical Press,London,UK(2012),通过引用将其内容并入本申请。
另外,式I化合物可具有前药形式。在体内将发生转化以提供生物活性剂(即式I化合物)的任何化合物为本申请范围和主旨内的前药。前药的各种形式是本领域已知的。上述前药衍生物的实例参见:
a)Bundgaard,H.编辑,Design of Prodrugs,Elsevier(1985)和Widder,K.等人编辑,Methods in Enzymology,112:309 396,Academic Press(1985);
b)Bundgaard,H.,第5章,“Design and Application of Prodrugs”,A Textbookof Drug Design and Development,pp.113 191,Krosgaard Larsen,P.等人编辑,HarwoodAcademic Publishers(1991);
c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1 38(1992);
d)Bundgaard,H.等人,J.Pharm.Sci.,77:285(1988);
e)Kakeya,N.等人,Chem.Pharm.Bull.,32:692(1984);和
f)Rautio,J(编辑).Prodrugs and Targeted Delivery(Methods andPrinciples in Medicinal Chemistry),第47卷,Wiley-VCH,2011。
含有羧基的化合物可形成生理学上可水解的酯,其通过在体内水解以产生式I化合物本身而用作前药。上述前药由于水解在许多情况下主要在消化酶的影响下发生而优选口服给药。当酯本身具有活性或水解在血液中发生时,可使用胃肠外给药。式I化合物的生理学上可水解的酯的实例包括C1-6烷基酯、C1-6烷基苄基酯、4-甲氧基苄基酯、茚满基酯、邻苯二甲酰基酯、甲氧基甲基酯、C1-6烷酰基氧基-C1-6烷基酯(例如乙酰氧基甲基酯、特戊酰基氧基甲基酯或丙酰基氧基甲基酯)、C1-6烷氧基羰基氧基-C1-6烷基酯(例如甲氧基羰基氧基甲基酯或乙氧基羰基氧基甲基酯、甘氨酰基氧基甲基酯、苯基甘氨酰基氧基甲基酯、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯)及其它已知的例如在青霉素和头孢菌素领域中使用的生理学上可水解的酯。上述酯可通过本领域已知的常规技术来制备。前药的制备是本领域已知的且参见例如King,F.D.编辑,Medicinal Chemistry:Principles andPractice,The Royal Society of Chemistry,Cambridge,UK(第2版,复制,2006);Testa,B.等人,Hydrolysis in Drug and Prodrug Metabolism.Chemistry,Biochemistry andEnzymology,VCHA and Wiley-VCH,Zurich,Switzerland(2003);Wermuth,C.G.编辑,ThePractice of Medicinal Chemistry,第3版,Academic Press,San Diego,CA(2008)。
术语“溶剂化物”意指本申请化合物与一个或多个溶剂分子(无论是有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情况下,例如当一个或多个溶剂分子进入到结晶固体的晶格中时,溶剂化物将能够分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂化物可包含化学计量或非化学计量量的溶剂分子。“溶剂化物”包括溶液相和可分离的溶剂化物。示例性溶剂化物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域已知的。
本申请使用的术语“患者”是指待通过本申请方法治疗的生物体。上述生物体优选包括但不限于哺乳动物(例如鼠类、猿类、马类、牛类、猪类、犬类、猫类等)且最优选是指人类。
本申请使用的术语“有效量”意指药物或活性剂即本申请化合物的以下量,其将引起组织、系统、动物或人类的例如研究人员或医师所正在寻求的生物或医药应答。另外,术语“治疗有效量”意指任何以下量,其与尚未接受上述量的相应个体相比使对疾病、障碍或副作用的处置、治疗、预防或缓解得以改善或使疾病或障碍的进展速率得以降低。有效量可在一次或多次给药、施用或剂量中给予且不意欲限于特定制剂或给药途径。所述术语在其范围内还包括可有效加强正常生理功能的量。
本申请使用的术语“治疗”包括使病症、疾病、障碍等得以改善或使其症状得以缓解的任何作用例如减轻、降低、调节、缓解或消除。
本申请使用的术语“药物组合物”是指活性剂与使组合物特别适于体内或离体诊断或治疗用途的惰性或活性载体的组合。
碱的实例包括但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨及其中W为C1-4烷基的式NW4 +化合物等。
对于治疗用途,本申请化合物的盐为药用的。然而,也发现非药用酸及碱的盐可用于例如制备或纯化药用化合物。
制备方法
本申请化合物可按有机合成领域技术人员已知的多种方法来制备。本申请化合物可使用下述方法及合成有机化学领域已知的合成方法或本领域技术人员所了解的其变化形式来合成。优选的方法包括但不限于下述那些方法。本申请引用的所有参考文献均以全文引用的方式并入本申请。
本申请化合物可使用该章节描述的反应及技术来制备。反应在适于所使用的试剂及物质的溶剂中进行且适于所实施的转化。另外,在对以下合成方法的描述中应理解的是,所提出的所有反应条件(包括对溶剂、反应气氛、反应温度、实验持续时间及后处理操作的选择)均被选择为就该反应而言的标准条件,其应为本领域技术人员容易了解的。有机合成领域技术人员应理解的是,存在于分子的各个部分上的官能团必须与所提出的试剂及反应相容。上述对与反应条件相容的取代基的限制对于本领域技术人员将是显而易见的且然后必须使用代替方法。这有时将需要作出判断以改变合成步骤的顺序或相对于另一种操作方案而选择一种特定操作方案以获得本申请所需化合物。还应了解的是,在本领域中当规划任何合成途径时需要考虑的另一个主要因素为恰当地选择用于对存在于本申请所述化合物中的反应性官能团进行保护的保护基。向本领域技术人员描述多种代替措施的权威报告为Greene和Wuts(Protective Groups In Organic Synthesis,第4版,Wiley and Sons,2007)。
式(I)化合物可通过参考以下方案所说明的方法来制备。如其中所示,最终产物为与式(I)具有相同结构式的化合物。应理解的是,任何式(I)化合物均可通过所述方案且合适地选择具有适当取代情况的试剂来制备。溶剂、温度、压力及其它反应条件可由本领域技术人员容易地选择。原料可商购或由本领域技术人员容易地制备。化合物的组分如本申请或说明书其它处所定义。
用于合成本申请所述化合物的通用途径在方案1-7中说明,其中R1、R2、R7、X、Y、Z、U1、U2、U3、U4及A取代基如上定义或为可转化成所需最终取代基的官能团。取代基L为离去基例如卤素或OH,其可容易地转化成例如三氟甲磺酸酯那样的离去基。如方案1所示,制备本申请化合物的通用程序涉及如方案1所示以合适取代的杂环1及硝基吡啶2为原料。在1(其中M为合适的偶联配体例如硼酸或硼酸酯)与2(例如2,5-二溴-3-硝基吡啶)之间进行的Suzuki反应可得到经官能化的吡啶3。由膦试剂例如1,2-二(二苯基膦基)乙烷(dppe)介导的还原环化可得到三环4。然后如方案1所示,使用合适的催化剂使4与芳族杂环A(其中M为合适的偶联配体例如硼酸、硼酸酯或锡烷的5)偶联得到6。
在最终步骤中,6中的氮可在Mitsunobu条件下使用三苯基膦及偶氮二甲酸二异丙酯(DIAD)用醇7取代。可选择地,6中的氮可如下取代以获得经官能化的三环9:使6中的氮与其中L为离去基例如卤素、甲磺酸酯或三氟甲磺酸酯的烷化剂8在碱例如碳酸钾存在下进行置换反应。
可选择地,中间体4中的氮可首先在Mitsunobu条件下用醇7或其中L为离去基例如卤素、甲磺酸酯或三氟甲磺酸酯的烷化剂8在碱例如碳酸钾存在下取代,得到中间体10。然后使用合适的催化剂使10与芳族杂环A(其中M为合适的偶联配体例如硼酸、硼酸酯或锡烷的5)偶联得到最终三环9。如方案1所示,也可通过由钯介导的C-H活化使中间体10与合适的芳族杂环A(其中M为H的5)直接偶联得到化合物9。
当9为外消旋体时,手性分离可得到对映异构体纯产物。对R1及R2的进一步衍生化可得到本申请其它化合物。例如,当R1为酯时,添加格氏试剂或烷基锂可得到叔醇。相同的R1酯还可使用例如氢氧化钠来水解以得到羧酸(R1=CO2H)作为最终取代基。
方案1
三环9的代替合成可如方案2所概述来实现。10(如方案1制备)中的离去基L可通过钯催化剂的作用而转化成合适的偶联配体M(优选为硼酸酯或硼酸),由此得到11。可使用合适的催化剂使11与芳族杂环A(其中L为合适的离去基例如卤素或三氟甲磺酸酯的5.1)偶联得到三环9。
方案2
羟基甲基吡唑衍生物例如14可根据方案3获得。可通过合适催化剂的作用使中间体11(其中M为合适的偶联配体例如硼酸或硼酸酯)(如方案2制备)与经合适保护的三唑12偶联。三唑12可通过使(叠氮基甲基)三甲基硅烷与经保护的炔丙基醇进行由铜介导的环加成反应而一步获得。然后可使用多种条件对中间体13进行脱保护。例如,当PG为叔丁基二甲基硅烷基时,用四丁基氟化铵处理可得到最终化合物14。通过应用对于本领域技术人员将是显而易见的方法将羟基进一步衍生化(例如烷基化、转化成离去基且置换、氧化成醛或羧酸且然后加工)可得到本申请其它化合物。
方案3
三环4的代替合成可如方案4所概述来实现。可使用Buchwald N-芳基化反应使苯胺15与其中L及L’为两个离去基例如卤素或三氟甲磺酸酯的吡啶16偶联得到中间体17。如方案4所示,使用合适的催化剂例如Pd(OAc)2在酸性介质例如三氟乙酸中进行氧化环合可得到三环4。
方案4
经烷氧基取代的三唑23可如方案5所说明来制备。醛18可通过在酸或脱水剂例如CaCl2存在下用醇19(其中Alk为任选经氘取代的C1-C6烷基或C3-C6环烷基)处理而转化成缩醛20。缩醛20可通过用强碱例如二乙基氨基锂或氨基钠处理而转化成经烷氧基取代的炔烃21。化合物21可通过与叠氮化物22进行由铜催化的3+2环加成反应而转化成三唑23。如方案1所示,三唑23可直接与三环10偶联。在大多数情况下,所述偶联使三甲基硅烷基失去。在没有失去三甲基硅烷基的情况下,其可通过用四丁基氟化铵处理而除去。
方案5
经烷基取代的三唑31可如方案6所说明来制备。乙炔24可在强碱例如n-BuLi作用下用25(其中Alk为任选经氘取代的C1-C6烷基或C3-C6环烷基且其中L为合适的离去基例如碘、溴、氯或磺酸酯)进行烷基化。炔烃26可通过与27进行由铜催化的3+2环加成反应而转化成三唑28。如方案1所说明,三唑28可直接与三环10偶联。可选择地,28中的三甲基硅烷基可在四丁基氟化铵作用下直接除去以得到N-甲基-三唑29。用强碱例如n-BuLi使29发生去质子化,然后与合适的亲电试剂30(其中L为离去基例如卤素或醇化物且M为促进由金属介导的偶联的合适基团例如三丁基锡或硼酸酯;例如M-L=Bu3SnCl或B(OMe)3)反应可得到三唑31,其可如方案1所说明的那样容易地发生偶联。
方案6
如方案7所示,可改变三唑中的取代基。25(其中Alk为任选经氘取代的C1-C6烷基或C3-C6环烷基且其中L为合适的离去基例如碘、溴、氯或磺酸酯)中的离去基可通过用叠氮化钠处理来置换以得到32。炔烃33或34可通过由铜催化的3+2环加成反应与叠氮化物32偶联得到三唑35。如方案1所说明,三唑35可直接与三环偶联。可选择地,用强碱例如n-BuLi使35发生去质子化,然后与合适的亲电试剂30(其中L为离去基例如卤素或醇化物且M为促进由金属介导的偶联的合适基团例如三丁基锡或硼酸酯;例如M-L=Bu3SnCl或B(OMe)3)反应可得到三唑36,其可如方案1所说明的那样容易地发生偶联。
方案7
三环6的代替合成可如方案8所概述来实现。然后使用合适的催化剂使37中的两个离去基(L、L’)中的一个选择性地与芳族杂环A(其中M为合适的偶联配体例如硼酸、硼酸酯或锡烷的5)偶联得到38。可通过SNAr化学反应或Buchwald N-芳基化反应使38中的氨基与39(其中L”为合适的离去基例如卤素)偶联得到40。用合适的催化剂例如二(三苯基膦)氯化钯(II)进行环化可得到三环6,其可如方案1-2所概述的那样进一步加工成三环9。
方案8
三环4的代替合成可如方案9所概述来实现。可在钯催化剂的作用下将41中的两个离去基(L’和L”)中的一个选择性地转化成合适的偶联配体M(优选为硼酸酯或硼酸)以得到42。42接下来可在合适催化剂的作用下与43中的两个离去基(L、L”’)中的一个选择性地偶联得到联芳基化合物44。可使用本领域技术人员已知的方法将44中的硝基还原成相应的胺以得到45。可使用碱(例如NaHMDS或叔丁醇钾)通过分子内SNAr反应或分子内Buchwald N-芳基化反应来环化成三环4。三环4可如方案1-2所概述的那样进一步加工成三环9。
方案9
实施例
本申请在以下实施例中进一步定义。应理解的是,实施例仅出于说明目的而给出。本领域技术人员由上述讨论及实施例可确定本申请基本特征且可在不偏离其主旨及范围的情况下作出各种变化及修改以使本申请适于各种用途及情况。因此,本申请不限于下述说明性实施例,而由所附权利要求书定义。
缩写
实施例1及2
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇
步骤1:2-氯-5-(3,5-二甲基异噁唑-4-基)吡啶-3-胺
5-溴-2-氯吡啶-3-胺(5.11g,24.6mmol)、(3,5-二甲基异噁唑-4-基)硼酸(3.47g,24.6mmol)、PdCl2(dppf)(0.216g,0.296mmol)的混合物用氮气真空净化(3×)。添加磷酸三钾(3M于水中,24.6mL,73.9mmol)及THF(30mL)且混合物再次用氮气真空净化(3×)。使所得混合物升温且在75℃搅拌过夜。冷却混合物至室温,转移至分液漏斗中且除去水层。有机层经无水硫酸钠干燥,过滤且浓缩,得到深色残余物。将残余物混悬于DCM及乙酸乙酯中且浓缩至足够的硅胶上,得到自由流动的粉末。将粉末加载至ISCO固体加载筒中且在ISCO配套色谱系统(120g硅胶筒,用0-100%乙酸乙酯/己烷洗脱,85mL/min)上纯化,得到呈白色固体状的2-氯-5-(3,5-二甲基异噁唑-4-基)吡啶-3-胺(3.82g,17.1mmol,69.3%产率)。1H NMR(400MHz,DMSO-d6)δ7.61(d,J=2.0Hz,1H),7.14(d,J=2.0Hz,1H),5.67(s,2H),2.41(s,3H),2.23(s,3H)。HPLC:RT=0.908min(Waters Acquity BEH C18 1.7μm 2.0×50mm,CH3CN/H2O/0.1%TFA,1.5min梯度,波长=254nm);MS(ES):m/z=224[M+H]+。
步骤2:4-((2-氯-5-(3,5-二甲基异噁唑-4-基)吡啶-3-基)氨基)吡啶-2-甲酸甲酯
在具有Teflon螺帽的厚壁容器中进行反应。用氯化氢(4M于二噁烷中,1.151mL,4.61mmol)处理4-氯吡啶-2-甲酸甲酯(3.95g,23.0mmol)及2-氯-5-(3,5-二甲基异噁唑-4-基)吡啶-3-胺(1.03g,4.61mmol)于MeOH(25mL)中的溶液。在80℃搅拌所得混合物过夜。冷却混合物至室温。LC/MS指示所需产物m/z 359(m+1)与起始苯胺m/z 224(m+1)的比例为54/11。在旋转蒸发器上浓缩反应混合物至干燥。所得残余物用NaHCO3饱和溶液处理直至pH 9,经超声波处理,经由烧结玻璃漏斗过滤且用水洗涤。将产物风干几小时,然后在真空下过夜,得到呈白色固体状的4-((2-氯-5-(3,5-二甲基异噁唑-4-基)吡啶-3-基)氨基)吡啶-2-甲酸甲酯(0.943g,2.63mmol,57.1%产率)。1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.36(d,J=5.5Hz,1H),8.28(d,J=2.2Hz,1H),7.98(d,J=2.2Hz,1H),7.71-7.58(m,1H),7.18-7.07(m,1H),3.84(s,3H),2.47(s,3H),2.33-2.26(m,3H)。HPLC:RT=0.862min(WatersAcquity BEH C18 1.7μm 2.0×50mm,CH3CN/H2O/0.1%TFA,1.5min梯度,波长=254nm);MS(ES):m/z=359[M+H]+。
步骤3:3-(3,5-二甲基异噁唑-4-基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯
4-((2-氯-5-(3,5-二甲基异噁唑-4-基)吡啶-3-基)氨基)吡啶-2-甲酸甲酯(943mg,2.63mmol)、二(三苯基膦)氯化钯(II)(184mg,0.263mmol)及乙酸钠三水合物(539mg,6.57mmol)于DMA(15mL)中的混合物在配备有回流冷凝器及氮气入口的圆底烧瓶中用氮气真空净化(3×)。将所得混合物升温至170℃。1h后,冷却混合物至室温,用氯仿(15mL)稀释,经由硅藻土过滤,用氯仿(3×10mL)洗涤。浓缩所得滤液,得到琥珀色残余物。将残余物溶解于DCM/MeOH的混合物中,浓缩至足够的硅胶上,得到自由流动的粉末。将粉末加载至ISCO固体加载筒中且在ISCO配套色谱系统(40g硅胶筒,先后用0-10%MeOH/DCM和10-30%MeOH/DCM洗脱,40mL/min)上纯化。注意化合物具有差的溶解性且洗脱缓慢。合并类似的级份且浓缩,得到呈淡黄色固体状的3-(3,5-二甲基异噁唑-4-基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯(500mg,1.55mmol,59.0%产率)。1H NMR(400MHz,DMSO-d6)δ12.27(br.s.,1H),9.49(d,J=0.9Hz,1H),8.65(d,J=1.8Hz,1H),8.32(d,J=1.1Hz,1H),8.12(d,J=2.0Hz,1H),3.95(s,3H),2.51(3H,在DMSO峰下),2.30(s,3H)。HPLC:RT=1.118min(Waters Acquity BEH C18 1.7μm 2.0×50mm,CH3CN/H2O/0.1%TFA,1.5min梯度,波长=254nm);MS(ES):m/z=323[M+H]+。
步骤4:3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯
向3-(3,5-二甲基异噁唑-4-基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯(225mg,0.698mmol)、(4-氟苯基)(四氢-2H-吡喃-4-基)甲醇(220mg,1.05mmol)及三苯基膦(275mg,1.05mmol)于二氯甲烷(20mL)中的0℃混悬液中逐滴添加二氮烯-1,2-二甲酸二异丙酯(DIAD)(0.206mL,1.05mmol)。移开冷却浴且在室温搅拌橙色混悬液过夜。真空浓缩反应混合物。将残余物溶解于最少量的DCM中且在ISCO配套色谱系统(40g硅胶筒,先后用0-100%乙酸乙酯/DCM和0-30%MeOH/DCM洗脱,40mL/min)上纯化。合并类似的级份且浓缩,得到琥珀色残余物。将残余物溶解于最少量的DCM中且再次在ISCO配套色谱系统(40g硅胶筒,用0-10%MeOH/DCM,然后0-30%MeOH/DCM洗脱,40mL/min)上纯化。合并类似的级份,得到3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯(225mg,0.437mmol,62.6%产率)。
步骤5:2-[5-(二甲基-1,2-噁唑-4-基)-8-[(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇
向3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯(225mg,0.437mmol)于DCM(10mL)中的-10℃(MeOH/冰)溶液中添加甲基溴化镁(3M于Et2O中,2.186mL,6.56mmol)。约2h后,LC/MS指示原料(SM)m/z 515(m+1)的消耗及产物m/z 515(m+1)的形成。用氯化铵饱和溶液淬灭反应混合物,转移至分液漏斗中且用DCM萃取。合并萃取液,用NH4Cl饱和溶液洗涤,经无水硫酸钠干燥,过滤且浓缩,得到橙色残余物。将残余物溶解于最少量的DCM中且在ISCO配套色谱系统(24g硅胶筒,用0-10%MeOH/DCM洗脱且然后用10-30%MeOH/DCM冲洗,35mL/min)上纯化,得到呈橙色固体状的外消旋2-(3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-基)丙-2-醇(83mg,0.161mmol,36.9%产率)。通过手性SFC分离对映异构体。制备型SFC色谱条件:仪器:Berger SFC MGII,柱:Chiral OD-H 25×3cm ID,5μm,流速:50.0mL/min,流动相:80/20CO2/MeOH,检测器波长:220nm。样品制备及注射体积:3000μL(溶解于7mL MeOH中的86mg),得到实施例1(对映异构体1)25.6mg及实施例2(对映异构体2)26.0mg。每种对映异构体的立体异构体纯度估算为>99%。对于实施例1(对映异构体1):2-[5-(二甲基-1,2-噁唑-4-基)-8-[(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇:1H NMR(400MHz,DMSO-d6)δ9.30(d,J=0.9Hz,1H),8.53(d,J=1.5Hz,1H),8.38-8.29(m,1H),8.28-8.21(m,1H),7.72(d,J=3.3Hz,2H),7.32-7.07(m,2H),5.93-5.79(m,1H),5.41(s,1H),3.99-3.87(m,1H),3.85-3.67(m,1H),3.55-3.42(m,1H),3.41-3.33(m,1H),3.30-3.22(m,1H),2.48(s,3H),2.30(s,3H),1.75-1.63(m,1H),1.59(s,3H),1.57(s,3H),1.39-1.21(m,1H),1.09-1.08(m,1H),1.05-0.90(m,1H)。构成31个H中的30个。其它H可能在溶剂峰下。HPLC:RT=0.996min(Waters Acquity BEH C18 1.7μm 2.0×50mm,CH3CN/H2O/0.1%TFA,1.5min梯度,波长=254nm);MS(ES):m/z=515[M+H]+;HPLC纯度:95/5至5/95H2O/CH3CN/0.05%TFA,流速=0.5mL/min,梯度=15min,Sunfire C18 3.5μm,3.0×150mm:RT=6.12min;220nm的纯度:100%;254nm的纯度:100%,Xbridge Phenyl 3.5μm,3.0×150mm:RT=7.41min;220nm的纯度:100%;254nm的纯度:100%。分析型SFC色谱条件:仪器:Berger分析型SFC,柱:Chiral OD-H 250×4.6mm ID,5μm,流速:2.0mL/min,流动相:80/20CO2/MeOH。对映异构体1RT:8.888min。对于实施例2(对映异构体2):2-[5-(二甲基-1,2-噁唑-4-基)-8-[(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇:1H NMR(400MHz,DMSO-d6)δ9.30(d,J=0.7Hz,1H),8.53(d,J=1.5Hz,1H),8.37-8.28(m,1H),8.25(br.s.,1H),7.72(dd,J=8.7,5.4Hz,2H),7.19(t,J=8.8Hz,2H),5.83(d,J=11.2Hz,1H),5.41(s,1H),3.98-3.86(m,1H),3.82-3.69(m,1H),3.47(s,1H),3.43-3.34(m,1H),3.27(d,J=11.9Hz,1H),2.48(s,3H),2.30(s,3H),1.66(br.s.,1H),1.59(s,3H),1.57(s,3H),1.39-1.19(m,1H),1.05-0.90(m,1H)。构成31个H中的30个。其它H可能在溶剂峰下。HPLC:RT=0.995min(WatersAcquity BEH C18 1.7μm 2.0×50mm,CH3CN/H2O/0.1%TFA,1.5min梯度,波长=254nm);MS(ES):m/z=515[M+H]+;HPLC纯度:95/5至5/95H2O/CH3CN/0.05%TFA,流速=0.5mL/min,梯度=15min,Sunfire C18 3.5μm,3.0×150mm:RT=6.12min;220nm的纯度:100%;254nm的纯度:100%,Xbridge Phenyl 3.5μm,3.0×150mm:RT=7.41min;220nm的纯度:100%;254nm的纯度:98.8%。分析型SFC色谱条件:仪器:Berger分析型SFC,柱:Chiral OD-H 250×4.6mm ID,5μm,流速:2.0mL/min,流动相:80/20CO2/MeOH。对映异构体2RT:13.039min。
实施例3
5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-2’-氟-3-硝基-2,3’-联吡啶
在40mL瓶中将2,5-二溴-3-硝基吡啶(3.00g,10.7mmol)及(2-氟吡啶-3-基)硼酸(1.5g,10.7mmol)于四氢呋喃(20mL)中的混合物在氮气气流下净化且然后用2M磷酸钾水溶液(10.65mL,21.3mmol)处理且然后用PdCl2(dppf)-CH2Cl2加合物(0.435g,0.532mmol)处理。瓶用隔片盖好且抽真空且用氮气净化3次,然后在加热区块中在80℃加热5h。冷却混合物至室温,用水稀释且萃取至乙酸乙酯中。用水及盐水洗涤且浓缩,得到黑色残余物。在ISCO配套80g硅胶柱上对物质进行色谱分离且用EtOAc/己烷梯度(20-100%)洗脱,得到呈灰白色固体状的5-溴-2’-氟-3-硝基-2,3’-联吡啶(1.0g,3.35mmol,31.5%产率)。LCMS:RT=0.86min;(ES):m/z(M+H)+=298.0,300.0(Waters Acquity SDS,柱:BEH C18 2.1×50mm1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。1H NMR(400MHz,CDCl3)δ9.00(d,J=2.0Hz,1H),8.57(s,1H),8.37(dt,J=4.8,1.4Hz,1H),8.15(ddd,J=9.3,7.4,2.0Hz,1H),7.41(ddd,J=7.3,5.1,1.9Hz,1H)。
步骤2:3-溴-9-氟-5H-吡咯并[3,2-b:4,5-c’]二吡啶
在40mL瓶中添加5-溴-2’-氟-3-硝基-2,3’-联吡啶(1g,3.35mmol)及1,2-二(二苯基膦基)乙烷(1.671g,4.19mmol)于1,2-二氯苯(15mL)中的混合物且将瓶盖好且在加热区块中在170℃加热5h。在旋转蒸发器上使用高真空泵浓缩且在ISCO配套40g硅胶柱上对残余物进行色谱分离且用EtOAc/己烷梯度(30-100%)洗脱,得到呈淡茶色固体状的3-溴-9-氟-5H-吡咯并[3,2-b:4,5-c’]二吡啶(460mg,1.73mmol,51.5%产率)。LCMS:RT=0.69min;(ES):m/z(M+H)+=265.9,267.9(Waters Acquity SDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。
步骤3:3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-氟-5H-吡咯并[3,2-b:4,5-c’]二吡啶
在20mL闪烁瓶中添加1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(1001mg,2.59mmol)、3-溴-9-氟-5H-吡咯并[3,2-b:4,5-c’]二吡啶(460mg,1.73mmol)、碘化亚铜(I)(65.9mg,0.346mmol)及Pd(Ph3P)4(200mg,0.173mmol)于DMF(10mL)中的混合物。添加三乙胺(0.482mL,3.46mmol)且瓶用隔片盖好且在加热区块中在90℃加热5h且冷却至室温。用氢氧化铵及水稀释且萃取至乙酸乙酯中且浓缩,得到淡棕色油状物。将物质溶解于DCM中且在ISCO配套40g硅胶柱上进行色谱分离且用MeOH/CH2Cl2梯度(0-10%)洗脱。收集产物级份,得到呈白色固体状的3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-氟-5H-吡咯并[3,2-b:4,5-c’]二吡啶(340mg,1.20mmol,69.7%产率)。LCMS:RT=0.58min;(ES):m/z(M+H)+=283.1(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。1H NMR(400MHz,CDCl3)δ10.13(br.s.,1H),8.69(d,J=1.8Hz,1H),8.26(dd,J=5.8,1.0Hz,1H),7.81(d,J=1.8Hz,1H),7.39(dd,J=5.7,2.4Hz,1H),4.04(s,3H),2.40(s,3H)。
步骤4:5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在圆底(RB)烧瓶中添加3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-氟-5H-吡咯并[3,2-b:4,5-c’]二吡啶(100mg,0.354mmol)、(R)-苯基(四氢-2H-吡喃-4-基)甲醇(136mg,0.709mmol)及Ph3P(186mg,0.709mmol)于二氯甲烷(5mL)中的混合物且在室温搅拌。然后逐滴添加DIAD(0.138mL,0.709mmol)且在室温搅拌所得混合物过夜。在ISCO配套40g硅胶柱上对物质进行色谱分离且首先用乙酸乙酯(100%)洗脱且然后换为10%MeOH/DCM。收集含有产物的级份,得到15mg白色固体,其经由制备型LC/MS在以下条件下进一步纯化:柱:WatersXBridge C18,19×100mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经10分钟0-100%B且然后在100%B保持3分钟;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到1.5mg标题化合物。LCMS:RT=1.52min;(ES):m/z(M+H)+=457.2(Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3分钟0-100%B且然后在100%B保持0.75分钟;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.72(s,1H),8.64(br.s.,1H),8.27(d,J=4.4Hz,1H),8.21(br.s.,1H),7.71(d,J=7.4Hz,2H),7.39-7.33(m,2H),7.32-7.26(m,1H),5.93(d,J=11.4Hz,1H),4.02(br.s.,3H),3.90(d,J=9.4Hz,1H),3.74(d,J=8.8Hz,1H),3.47(t,J=11.1Hz,1H),3.27(t,J=11.3Hz,1H),2.31(s,3H),1.69(d,J=12.8Hz,1H),1.59-1.50(m,1H),1.35-1.26(m,1H),0.98(d,J=12.5Hz,1H)。
实施例4
12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-2’-氯-3-硝基-2,4’-联吡啶
在RB烧瓶中添加2,5-二溴-3-硝基吡啶(8.78g,31.1mmol)及(2-氯吡啶-4-基)硼酸(5g,31.8mmol)于四氢呋喃(60mL)中的混合物且在氮气气流下净化溶液。添加2M磷酸钾水溶液(39.7mL,79mmol)且用氮气继续净化且然后添加PdCl2(dppf)-CH2Cl2加合物(1.297g,1.59mmol)且然后在氮气下加热混合物至回流且保持2.5h。冷却至室温且用水稀释且萃取至乙酸乙酯中。用水洗涤且浓缩。将物质溶解于DCM中且在ISCO配套120g硅胶柱上进行色谱分离且用EtOAc/己烷梯度(20-50%)洗脱,得到5-溴-2’-氯-3-硝基-2,4’-联吡啶(5g,15.9mmol,50.0%产率)。LCMS:RT=0.92min;(ES):m/z(M+H)+=314.0,316.0(WatersAcquity SDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:乙腈-0.1%TFA)。
步骤2:3-溴-8-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶
在两个40mL瓶中各自添加5-溴-2’-氯-3-硝基-2,4’-联吡啶(1g,3.18mmol)及1,2-二(二苯基膦基)乙烷(1.583g,3.97mmol)于1,2-二氯苯(10mL)中的混合物。将瓶盖好且在加热区块中在160℃加热3h。由加热区块取出两个瓶,合并且在高真空下浓缩且将剩余的残余物溶解于DCM中且在ISCO配套40g硅胶柱上进行色谱分离且用EtOAc/己烷梯度(30-60-100%)洗脱,得到两种异构产物。主要异构体提供3-溴-6-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶(420mg,0.779mmol,24.49%产率)。LCMS:RT=0.80min;(ES):m/z(M+H)+=282,284(Waters Acquity SDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.71(d,J=2.0Hz,1H),8.27(d,J=5.3Hz,1H),8.24(d,J=2.0Hz,1H),8.17(d,J=5.3Hz,1H)。次要异构体提供(3-溴-8-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶(100mg,0.177mmol,5.57%产率)。LCMS:RT=0.83min;(ES):m/z(M+H)+=282,284(Waters AcquitySDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。1H NMR(400MHz,DMSO-d6)δ12.09(br.s.,1H),8.85(d,J=1.0Hz,1H),8.67(d,J=2.0Hz,1H),8.37(d,J=2.1Hz,1H),8.18(d,J=1.0Hz,1H)。
步骤3:(S)-3-溴-8-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶
在RB烧瓶中添加3-溴-8-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶(100mg,0.354mmol)、(R)-(2-氟苯基)(四氢-2H-吡喃-4-基)甲醇(149mg,0.708mmol)及三苯基膦(186mg,0.708mmol)于二氯甲烷(5mL)中的混悬液。在室温搅拌混悬液且逐滴用DIAD(0.138mL,0.708mmol)处理且然后在室温搅拌5h。将混合物直接添加至硅胶柱中且在ISCO配套40g硅胶柱上进行色谱分离且用EtOAc/己烷梯度(10-60%)洗脱,得到(S)-3-溴-8-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶(160mg,0.337mmol,95%产率)。LCMS:RT=1.10min;(ES):m/z(M+H)+=474.2,476.2(WatersAcquity SDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。
步骤4:12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯.
在20mL瓶中添加(S)-3-溴-8-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶(160mg,0.337mmol)、1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(156mg,0.404mmol)、碘化亚铜(I)(12.84mg,0.067mmol)、Pd(Ph3P)4(38.9mg,0.034mmol)及三乙胺(0.141mL,1.01mmol)于DMF(2mL)中的混合物。将瓶盖好且在加热区块中在100℃加热3h。用氢氧化铵及水稀释且萃取至乙酸乙酯中。用水及盐水洗涤且浓缩。在ISCO配套40g硅胶柱上对物质进行色谱分离且首先用乙酸乙酯(100%)洗脱且然后用10%MeOH/DCM洗脱。收集级份,得到65mg呈灰白色固体状的12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯。LCMS:RT=0.90min;(ES):m/z(M+H)+=491.4(WatersAcquity SDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。1H NMR(400MHz,CD3OD)δ9.16(s,1H),8.73-8.64(m,1H),8.56(br.s.,1H),8.31(d,J=0.9Hz,1H),8.16(td,J=7.4,2.1Hz,1H),7.77-7.62(m,1H),7.62-7.51(m,1H),7.18-7.00(m,1H),6.12(d,J=11.5Hz,1H),4.10-4.05(m,3H),4.04-3.96(m,1H),3.84(dd,J=11.6,3.4Hz,1H),3.62(td,J=11.9,2.0Hz,1H),3.45-3.36(m,2H),2.37(s,3H),1.93(d,J=13.3Hz,1H),1.67(td,J=12.3,7.8Hz,1H),1.49(td,J=12.3,7.6Hz,1H),1.03-0.95(m,1H)。
实施例5
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但使用3-溴-6-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶(在步骤2中获得的主要异构体)合成标题化合物。LCMS:RT=0.89min;(ES):m/z(M+H)+=491.1(WatersAcquity SDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。1H NMR(500MHz,DMSO-d6)δ8.70(s,1H),8.38(d,J=5.0Hz,1H),8.33-8.23(m,3H),7.42-7.31(m,2H),7.14(d,J=11.4Hz,1H),7.11-7.04(m,1H),3.92(d,J=9.1Hz,1H),3.86(s,3H),3.79(d,J=9.1Hz,1H),3.62-3.39(m,2H),3.26(t,J=11.3Hz,1H),2.18(s,3H),1.88(d,J=13.5Hz,1H),1.66-1.54(m,1H),1.54-1.43(m,1H),0.93(d,J=12.8Hz,1H)。
实施例6
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:(S)-3-溴-6-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶
向3-溴-6-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶(0.25g,0.885mmol)及(R)-苯基(四氢-2H-吡喃-4-基)甲醇(0.340g,1.77mmol)于THF(2mL)中的混合物中添加三苯基膦(0.464g,1.77mmol)且在25℃历经10min逐滴添加DIAD(0.344mL,1.77mmol)且然后在室温搅拌16h。向硅胶柱中添加混合物且在ISCO配套24g硅胶柱上进行色谱分离且用0至5%DCM/MeOH洗脱,得到呈白色固体状的(S)-3-溴-6-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶(180mg,0.394mmol,44.5%产率)。LCMS:HPLC:RT=1.12min。MS(ES):m/z=458[M+H]+(ACN/H2O及NH4OAc,Acquity BEH C18 1.7μm(50×2.1)mm,梯度=3min,波长=220nm)。
步骤2:10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
通过鼓泡氮气使(S)-3-溴-6-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶(100mg,0.219mmol)、1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(85mg,0.219mmol)及Et3N(0.122mL,0.876mmol)于DMF(2.5mL)中的搅拌的溶液脱气。用Pd(Ph3P)4(25.3mg,0.022mmol)及碘化亚铜(I)(6.25mg,0.033mmol)处理混合物且在95℃加热2小时。用水及氢氧化铵及水淬灭混合物且萃取至乙酸乙酯中。用水及盐水洗涤且浓缩。在ISCO配套12g硅胶柱上对物质进行色谱分离且用CHCl3/MeOH(2%)洗脱。通过制备型HPLC(柱:Sunfire C18(250×30*7μ),流动相A:10mM NH4OAc/水,流动相B:ACN,溶解性:MEOH+THF,流速:15mL/min,T/%B:0/10,11/60)进一步纯化,得到呈白色固体状的标题化合物(35mg,0.072mmol,32.8%产率)。LCMS:HPLC:RT=1.90min(ACN/H2O及HCOONH4,AscentisExpress C8 2.7μm(5×2.1)mm,梯度=4min,波长=220nm);MS(ES):m/z=473[M+H]+。HPLCRT=8.99min,柱:XBridge(150×4.6mm)3.5微米,流动相A:0.05%TFA/水:ACN(95:5),流动相B:ACN:0.05%TFA/水(95:5),流速:1.0mL/min,波长=220nm及254nm;HPLC RT=9.89min,Sunfire C18(4.6×150)mm,3.5微米,流动相A:0.05%TFA/水:ACN(95:5),流动相B:ACN:0.05%TFA/水(95:5),流速:1mL/min,波长=220nm及254nm。1H NMR(400MHz,CD3OD)δ=8.63(d,J=2.0Hz,1H),8.40-8.35(m,2H),8.18(d,J=1.5Hz,1H),7.63(d,J=7.5Hz,2H),7.44-7.36(m,2H),7.34-7.27(m,1H),7.08(d,J=11.0Hz,1H),4.03-3.97(m,1H),3.87(s,3H),3.82(dd,J=3.0,11.5Hz,1H),3.66-3.58(m,1H),3.43-3.34(m,2H),2.22(s,3H),2.12(d,J=12.5Hz,1H),1.68-1.52(m,2H),0.86(d,J=14.1Hz,1H)。
实施例7
5-(二甲基-1H-1,2,3-三唑-5-基)-10-(吗啉-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在微波中在170℃照射10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25mg,0.053mmol)及吗啉(92mg,1.06mmol)的混合物5小时。其通过制备型HPLC(柱:Sunfire C18(250×30mm 7μ),流动相A:10mM NH4OAc/水,流动相B:ACN,梯度:历经30min10-60%B,流速:15mL/min)纯化,得到呈白色固体状的标题化合物(8.0mg,0.014mmol,26.6%产率)。LCMS:RT=1.82min;MS(ES):m/z=524[M+H]+(柱:Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=7.94min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=7.49min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV220nm)。1H NMR(400MHz,CD3OD)δ8.58(d,J=2.01Hz,1H),8.35(s,1H),8.13(d,J=5.52Hz,1H),8.00(d,J=1.51Hz,1H),7.57(d,J=7.03Hz,2H),7.32-7.39(m,2H),7.23-7.31(m,2H),4.11(d,J=10.04Hz,1H),3.95-4.04(m,3H),3.89(s,3H),3.77-3.85(m,2H),3.61(dd,J=12.05,10.04Hz,1H),3.47-3.52(m,1H),3.39(dd,J=11.80,9.79Hz,3H),2.23(s,3H),2.04-2.13(m,1H),1.66(dd,J=12.55,3.51Hz,1H),1.42(dd,J=13.05,4.52Hz,1H),0.93-1.01(m,2H)。
实施例8
5-(二甲基-1H-1,2,3-三唑-5-基)-10-(4-甲基哌嗪-1-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在微波中在170℃照射10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25mg,0.053mmol)及1-甲基哌嗪(106mg,1.06mmol)的混合物3小时。其通过制备型HPLC(柱:Sunfire C18(250×30mm 7μ),流动相A:10mM NH4OAc/水,流动相B:ACN,梯度:历经30min 10-60%B,流速:15mL/min)纯化,得到呈白色固体状的标题化合物(14mg,0.026mmol,34%产率)。LCMS:RT=1.80min;MS(ES):m/z=537[M+H]+(柱:AscentisExpress C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=5.66min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=5.98min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.56-8.60(m,1H),8.30-8.34(m,1H),8.10(d,J=5.02Hz,1H),7.99(d,J=2.01Hz,1H),7.57(d,J=7.53Hz,2H),7.32-7.38(m,2H),7.25-7.31(m,1H),7.16(d,J=10.04Hz,1H),3.99(dd,J=11.55,3.01Hz,1H),3.89(s,3H),3.78-3.83(m,1H),3.60(dd,J=11.80,9.79Hz,1H),3.33-3.52(m,6H),3.11-3.18(m,1H),3.02(d,J=11.04Hz,1H),2.59-2.68(m,1H),2.49(d,J=8.53Hz,1H),2.43(s,3H),2.23(s,3H),2.05(d,J=13.55Hz,3H),1.60-1.71(m,1H),1.43(dd,J=13.05,4.52Hz,1H),0.98(d,J=12.55Hz,1H)。
实施例9
5-(二甲基-1H-1,2,3-三唑-5-基)-N-(2-甲氧基乙基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-胺
在微波中在170℃照射10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25mg,0.053mmol)及2-甲氧基乙胺(79mg,1.06mmol)的混合物3小时。其通过制备型HPLC(柱:Sunfire C18(250×30mm 7μ),流动相A:10mM NH4OAc/水,流动相B:ACN,梯度:历经30min 10-60%B,流速:15mL/min)纯化,得到呈白色固体状的标题化合物(9mg,0.017mmol,27%产率)。LCMS:RT=1.85min;MS(ES):m/z=512[M+H]+(柱:AscentisExpress C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=5.87min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=6.44min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.53(s,1H),8.21(br.s.,1H),8.03(d,J=5.52Hz,1H),7.67(d,J=5.52Hz,1H),7.50(d,J=7.53Hz,2H),7.33-7.41(m,2H),7.27-7.32(m,1H),6.20(d,J=11.04Hz,1H),4.00(d,J=8.53Hz,1H),3.93(s,3H),3.84(d,J=8.53Hz,1H),3.75(br.s.,3H),3.57-3.65(m,1H),3.46(s,3H),3.39-3.44(m,1H),2.27(s,3H),2.05(br.s.,1H),1.66(d,J=10.04Hz,1H),1.39-1.50(m,1H),0.98-1.06(m,1H),0.90(br.s.,1H)。
实施例10
(2-{[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基]氧基}乙基)二甲基胺
在微波中在170℃照射10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25mg,0.053mmol)及2-(二甲基氨基)乙醇(94mg,1.06mmol)的混合物3小时。其通过制备型HPLC(柱:Sunfire C18(250×30mm7μ),流动相A:10mM NH4OAc/水,流动相B:ACN,梯度:历经30min 10-60%B,流速:15mL/min)纯化,得到呈白色固体状的标题化合物(11mg,0.021mmol,32%产率)。LCMS:RT=1.82min;MS(ES):m/z=526[M+H]+(柱:AscentisExpress C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=5.87min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLCRT=6.40min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.54(d,J=1.51Hz,1H),8.16(br.s.,1H),8.06(d,J=5.52Hz,1H),7.90(d,J=5.52Hz,1H),7.64(d,J=7.53Hz,2H),7.36(t,J=7.53Hz,2H),7.24-7.30(m,1H),6.83(br.s.,1H),4.86(br.s.,2H),3.99(d,J=12.05Hz,1H),3.89(s,3H),3.78-3.85(m,1H),3.60(td,J=12.05,2.01Hz,1H),3.35-3.42(m,1H),2.95-3.03(m,2H),2.41(s,6H),2.24(s,3H),2.04(d,J=13.55Hz,1H),1.49-1.64(m,2H),0.89(d,J=14.06Hz,1H)。
实施例11
2-{[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基]氨基}乙-1-醇
在微波中在170℃照射10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25mg,0.053mmol)及2-氨基乙醇(64.6mg,1.06mmol)的混合物3小时。其通过制备型HPLC(柱:Sunfire C18(250×30mm 7μ),流动相A:10mM NH4OAc/水,流动相B:ACN,梯度:历经30min 10-60%B,流速:15mL/min)纯化,得到呈白色固体状的标题化合物(7mg,0.014mmol,26%产率)。LCMS:RT=1.74min;MS(ES):m/z=498[M+H]+(柱:AscentisExpress C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=5.47min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=5.81min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.56(s,1H),8.22(br.s.,1H),8.00(d,J=5.02Hz,1H),7.56(d,J=7.53Hz,2H),7.49(d,J=5.52Hz,1H),7.32(t,J=7.28Hz,2H),7.25(d,J=7.53Hz,1H),6.08(d,J=11.55Hz,1H),4.91(br.s.,1H),3.84-3.96(m,4H),3.73(br.s.,5H),3.50(t,J=11.55Hz,3H),2.21(br.s.,3H),1.86(s,1H),1.64(br.s.,2H),1.23(br.s.,1H)。
实施例12
5-(二甲基-1H-1,2,3-三唑-5-基)-11-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序以(6-甲氧基吡啶-3-基)硼酸为原料合成标题化合物(如方案1所示)。LCMS:HPLC:RT=2.054min(ACN/H2O及NH4HCO2,柱:Ascentis Express C8(50×2.1nm,2.7μm),梯度=4min,波长=254nm);MS(ES):m/z=469.4[M+H]。1H NMR:(400MHz,d4-MeOH)δ8.51(d,J=8.4Hz,1H),8.44(m,1H),8.28(m,1H),7.74(d,J=7.2Hz,2H),7.32(m,2H),7.25(m,1H),6.84(d,J=8.4,1H),5.81(d,J=10.8Hz,1H),4.20(s,3H),4.01-3.96(s+m,4H),3.76(m,1H),3.72(m,1H),3.49(m,1H),3.43(m,1H),2.32(s,3H),1.69(m,1H),1.53-1.41(m,2H),1.39(m,1H)。HPLC RT=9.121min(XBridge Phenyl(4.6×150mm),3.5微米;5/95至95/5H2O/ACN,0.05%TFA;流速=1mL/min;梯度=15min)。HPLC RT=10.043min(Sunfire C18(4.6×150)mm,3.5微米;5/95至95/5H2O/ACN,0.05%TFA;流速=1mL/min;梯度=15min)。
实施例13
5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(2-甲氧基吡啶-4-基)硼酸为原料合成标题化合物(根据方案1)。LCMS:HPLC:RT=1.898min,MS(ES):m/z=469.2[M+H](ACN/H2O及HCOONH4,Ascentis Express C8(50×2.1mm;2.7μ),梯度=4min,波长=220nm)。1H NMR(400MHz,CD3OD)δ8.54(d,J=1.0Hz,1H),8.17(br.s.,1H),8.07(d,J=5.5Hz,1H),7.89(d,J=5.5Hz,1H),7.60(d,J=7.5Hz,2H),7.42-7.32(m,2H),7.30-7.22(m,1H),6.69(br.s.,1H),4.31(s,3H),3.98(dd,J=2.8,11.8Hz,1H),3.89(s,3H),3.81(dd,J=3.0,11.5Hz,1H),3.60(dt,J=2.3,11.9Hz,1H),3.43-3.33(m,2H),2.23(s,3H),2.03(d,J=13.1Hz,1H),1.60-1.39(m,2H),0.92(d,J=14.1Hz,1H)。HPLC:RT=15.331min(Sunfire C18 3.5μm,4.6×150mm,95/5至5/95H2O/CH3CN/0.05%TFA,流速=1mL/min,梯度=25min)。
实施例14
11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-氯吡啶-3-基)硼酸为原料合成标题化合物(根据方案1)。LCMS:HPLC:RT=2.028min,MS(ES):m/z=473.2[M+H](ACN/H2O及HCOONH4,Ascentis Express C8(50×2.1mm;2.7μ),梯度=4min,波长=220nm)。1H NMR(400MHz,CD3OD)δ8.68(d,J=8.53Hz,1H),8.59(d,J=1.51Hz,1H),8.40(d,J=1.51Hz,1H),7.71-7.79(m,2H),7.44-7.51(m,1H),7.32-7.39(m,2H),7.24-7.31(m,1H),5.93(d,J=11.55Hz,1H),3.95-4.04(m,4H),3.82-3.91(m,1H),3.65(d,J=11.55Hz,1H),3.56(dd,J=11.80,9.29Hz,1H),3.43(td,J=11.80,2.51Hz,1H),2.33(s,3H),1.75(d,J=14.05Hz,1H),1.37-1.61(m,2H),1.22(d,J=11.55Hz,1H)。手性HPLC SFC RT=6.90min(柱:Lux Cellulose-2,250×4.6mm,5μm;流动相:60/40CO2/(0.3%DEA/MeOH);流速:4mL/min)。
实施例15
11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-氯吡啶-3-基)硼酸为原料合成标题化合物(根据方案1)。LCMS:HPLC:RT=2.028min,MS(ES):m/z=473.2[M+H](ACN/H2O及HCOONH4,Ascentis Express C8(50×2.1mm;2.7μ),梯度=4min,波长=220nm)。1H NMR(400MHz,CD3OD)δ8.68(d,J=8.53Hz,1H),8.59(d,J=1.51Hz,1H),8.40(d,J=1.51Hz,1H),7.71-7.79(m,2H),7.44-7.51(m,1H),7.32-7.39(m,2H),7.24-7.31(m,1H),5.93(d,J=11.55Hz,1H),3.95-4.04(m,4H),3.82-3.91(m,1H),3.65(d,J=11.55Hz,1H),3.56(dd,J=11.80,9.29Hz,1H),3.43(td,J=11.80,2.51Hz,1H),2.33(s,3H),1.75(d,J=14.05Hz,1H),1.37-1.61(m,2H),1.22(d,J=11.55Hz,1H)。手性HPLC SFC RT=4.59min(柱:Lux Cellulose-2,250×4.6mm,5μm;流动相:60/40CO2/(0.3%DEA/MeOH);流速:4mL/min)。
实施例16
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(3-氟苯基)(氧杂环己烷-4-基)甲基]-11-甲氧基-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(外消旋)
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-甲氧基吡啶-3-基)硼酸为原料及使用外消旋(3-氟苯基)(四氢-2H-吡喃-4-基)甲醇合成标题化合物(根据方案1)。LCMS:HPLC:RT=1.991min,MS(ES):m/z=487.2[M+H](ACN/H2O及HCOONH4,Ascentis Express C8(50×2.1mm;2.7μ),梯度=4min,波长=220nm);HPLCRT=9.874min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.021min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.55(d,J=8.4Hz,1H),8.49(m,1H),8.37(m,1H),7.64(m,1H),7.57(m,1H),7.36(m,1H),7.03(m,1H),6.88(d,J=8.4Hz,1H),5.81(d,J=12.0Hz,1H),4.23(s,3H),4.02(s,3H),4.01(m,1H),3.89(m,1H),3.58(m,1H),3.52(m,1H),2.36(s,3H),1.67(m,1H),1.55(m,1H),1.42(m,1H),1.34(m,2H)。
实施例17
8-[(2,3-二氟苯基)(氧杂环己烷-4-基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-11-甲氧基-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(外消旋)
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-甲氧基吡啶-3-基)硼酸为原料及使用外消旋(2,3-二氟苯基)(四氢-2H-吡喃-4-基)甲醇合成标题化合物(根据方案1)。LCMS:RT=1.983min;MS(ES):m/z=505.2[M+H]+(柱:Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=10.125min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.163min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.51-8.48(m,2H),8.33(m,1H),7.99(m,1H),7.20(m,2H),6.81(d,J=8.4Hz,1H),6.09(d,J=11.2Hz,1H),4.15(s,3H),4.05(s,3H),3.99(m,1H),3.96(m,1H),3.71(M,1H),3.51(M,1H),3.39(M,1H),2.35(s,3H),1.71(m,1H),1.57-1.47(m,2H),1.44(m,1H)。
实施例18
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
对映异构体1
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但使用外消旋(2-氟苯基)-(四氢-2H-吡喃-4-基)甲醇及使用手性制备型SFC(柱:Chiral OD-H,25×2.1cm,5μm;流动相:60/40CO2/(0.25%DEA/MeOH);流速:70mL/min)分离最终对映异构体合成标题化合物。对于对映异构体1:LCMS:RT=1.91min;MS(ES):m/z=487.2[M+H]+(Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=9.806min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=8.666min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δppm 8.56(s,1H),8.16(br.s.,1H),8.03-8.10(m,2H),7.87-7.93(m,1H),7.29-7.41(m,2H),6.92-7.08(m,2H),4.29(br.s.,3H),3.97-4.06(m,1H),3.82-3.96(m,4H),3.57-3.66(m,1H),3.35-3.44(m,2H),2.25(br.s.,3H),2.01(d,J=14.05Hz,1H),1.48-1.68(m,2H),0.88-1.01(m,1H)。手性SFC RT=5.28min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:70/30CO2/(0.25%DEA/MeOH);流速:3mL/min)。
实施例19
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
对映异构体2
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但使用外消旋(2-氟苯基)-(四氢-2H-吡喃-4-基)甲醇及使用手性制备型SFC(柱:Chiral OD-H,25×2.1cm,5μm;流动相:60/40CO2/(0.25%DEA/MeOH);流速:70mL/min)分离最终对映异构体合成标题化合物。对于对映异构体2:LCMS:RT=1.91min;MS(ES):m/z=487.2[M+H]+(Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=9.806min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=8.666min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δppm 8.56(s,1H),8.16(br.s.,1H),8.03-8.10(m,2H),7.87-7.93(m,1H),7.29-7.41(m,2H),6.92-7.08(m,2H),4.29(br.s.,3H),3.97-4.06(m,1H),3.82-3.96(m,4H),3.57-3.66(m,1H),3.35-3.44(m,2H),2.25(br.s.,3H),2.01(d,J=14.05Hz,1H),1.48-1.68(m,2H),0.88-1.01(m,1H)。手性SFC RT=3.88min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:70/30CO2/(0.25%DEA/MeOH);流速:3mL/min)。
实施例20
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(3-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
对映异构体1
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但使用外消旋(3-氟苯基)-(四氢-2H-吡喃-4-基)甲醇及使用手性制备型SFC(柱:Whelk-01(R,R),25×2.1cm,5μm;流动相:65/35CO2/(0.25%DEA/MeOH);流速:75mL/min)分离最终对映异构体合成标题化合物。对于对映异构体1:LCMS:RT=1.91min;MS(ES):m/z=487.2[M+H]+(Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=10.155min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.123min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δppm 8.54-8.61(m,1H),8.26(br.s.,1H),8.10(d,J=5.52Hz,1H),7.92(d,J=5.52Hz,1H),7.34-7.50(m,3H),6.99-7.09(m,1H),6.73(br.s.,1H),4.34(s,3H),3.94-4.04(m,4H),3.80-3.87(m,1H),3.61-3.66(m,1H),3.35-3.44(m,2H),2.25-2.31(m,3H),2.01(d,J=13.55Hz,1H),1.40-1.58(m,2H),0.99(d,J=15.06Hz,1H)。手性SFC RT=4.95min(柱:Whelk-01(R,R),250×4.6mm,5μm;流动相:60/40CO2/(0.25%DEA/MeOH);流速:4mL/min)。
实施例21
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(3-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
对映异构体2
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但使用外消旋(3-氟苯基)-(四氢-2H-吡喃-4-基)甲醇及使用手性制备型SFC(柱:Whelk-01(R,R),25×2.1cm,5μm;流动相:65/35CO2/(0.25%DEA/MeOH);流速:75mL/min)分离最终对映异构体合成标题化合物。对于对映异构体2:LCMS:RT=1.91min;MS(ES):m/z=487.2[M+H]+(Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=10.155min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.123min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δppm 8.54-8.61(m,1H),8.26(br.s.,1H),8.10(d,J=5.52Hz,1H),7.92(d,J=5.52Hz,1H),7.34-7.50(m,3H),6.99-7.09(m,1H),6.73(br.s.,1H),4.34(s,3H),3.94-4.04(m,4H),3.80-3.87(m,1H),3.61-3.66(m,1H),3.35-3.44(m,2H),2.25-2.31(m,3H),2.01(d,J=13.55Hz,1H),1.40-1.58(m,2H),0.99(d,J=15.06Hz,1H)。手性SFC RT=5.76min(柱:Whelk-01(R,R),250×4.6mm,5μm;流动相:60/40CO2/(0.25%DEA/MeOH);流速:4mL/min)。
实施例22
8-[(2,3-二氟苯基)(氧杂环己烷-4-基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
对映异构体1
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但使用外消旋(2,3-二氟苯基)-(四氢-2H-吡喃-4-基)甲醇及使用手性制备型SFC(柱:Chiral OD-H,25×2.1cm,5μm;流动相:65/35CO2/(0.25%DEA/MeOH);流速:70mL/min)分离最终对映异构体合成标题化合物。对于对映异构体1:LCMS:RT=1.94min;MS(ES):m/z=505.2[M+H]+(Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=10.419min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.158min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δppm 8.55-8.62(m,1H),8.18(br.s.,1H),8.08(d,J=5.52Hz,1H),7.82-7.95(m,2H),7.21-7.37(m,2H),6.94-7.08(m,1H),4.30(br.s.,3H),3.80-4.05(m,5H),3.54-3.66(m,1H),3.35-3.44(m,2H),2.26(br.s.,3H),1.93-2.03(m,1H),1.59(br.s.,2H),0.97(d,J=14.06Hz,1H)。手性SFCRT=4.82min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:75/25CO2/(0.25%DEA/MeOH);流速:3mL/min)。
实施例23
8-[(2,3-二氟苯基)(氧杂环己烷-4-基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
对映异构体2
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但使用外消旋(2,3-二氟苯基)-(四氢-2H-吡喃-4-基)甲醇及使用手性制备型SFC(柱:Chiral OD-H,25×2.1cm,5μm;流动相:65/35CO2/(0.25%DEA/MeOH);流速:70mL/min)分离最终对映异构体合成标题化合物。对于对映异构体2:LCMS:RT=1.94min;MS(ES):m/z=505.2[M+H]+(Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=10.419min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.158min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1HNMR(400MHz,CD3OD)δppm 8.55-8.62(m,1H),8.18(br.s.,1H),8.08(d,J=5.52Hz,1H),7.82-7.95(m,2H),7.21-7.37(m,2H),6.94-7.08(m,1H),4.30(br.s.,3H),3.80-4.05(m,5H),3.54-3.66(m,1H),3.35-3.44(m,2H),2.26(br.s.,3H),1.93-2.03(m,1H),1.59(br.s.,2H),0.97(d,J=14.06Hz,1H)。手性SFCRT=7.27min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:75/25CO2/(0.25%DEA/MeOH);流速:3mL/min)。
实施例24
5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲氧基-8-[氧杂环己烷-4-基(2,4,6-三氟苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(外消旋)
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-甲氧基吡啶-3-基)硼酸为原料及使用外消旋(四氢-2H-吡喃-4-基)(2,4,6-三氟苯基)甲醇合成标题化合物(根据方案1)。LCMS:RT=1.935min;MS(ES):m/z=523.2[M+H]+(柱:Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLCRT=9.661min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.216min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.64(d,J=1.51Hz,1H),8.21(br.s.,1H),8.07(d,J=5.52Hz,1H),7.89(d,J=5.52Hz,1H),6.97(t,J=9.04Hz,3H),4.26(br.s.,3H),4.00-4.09(m,4H),3.84(d,J=9.04Hz,1H),3.55(dd,J=11.80,9.79Hz,1H),3.37(br.s.,1H),2.34(s,3H),1.85(br.s.,1H),1.58(br.s.,2H),1.27(d,J=6.02Hz,1H),1.07(br.s.,1H)。
实施例25
8-[(2,4-二氟苯基)(氧杂环己烷-4-基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(外消旋)
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-甲氧基吡啶-3-基)硼酸为原料及使用外消旋(2,4-二氟苯基)(四氢-2H-吡喃-4-基)甲醇合成标题化合物(根据方案1)。LCMS:RT=1.941min;MS(ES):m/z=505.2[M+H]+(柱:Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=9.281min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.041min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δppm 8.58(s,1H),8.04-8.20(m,3H),7.90(d,J=5.52Hz,1H),7.12(t,J=7.28Hz,1H),6.87-7.01(m,2H),4.30(br.s.,3H),3.92-4.05(m,4H),3.85(d,J=9.04Hz,1H),3.61(t,J=11.80Hz,1H),3.36-3.44(m,2H),2.27(br.s.,3H),1.96(br.s.,1H),1.58(br.s.,2H),0.90-1.01(m,1H)。
实施例26
8-[(2,5-二氟苯基)(氧杂环己烷-4-基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(外消旋)
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-甲氧基吡啶-3-基)硼酸为原料及使用外消旋(2,5-二氟苯基)(四氢-2H-吡喃-4-基)甲醇合成标题化合物(根据方案1)。LCMS:RT=1.924min;MS(ES):m/z=505.2[M+H]+(柱:Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLCRT=9.029min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=8.922min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.59(s,1H),8.25(br.s.,1H),8.08(d,J=5.52Hz,1H),7.87-7.99(m,2H),6.90-7.18(m,3H),4.30(br.s.,3H),3.94-4.06(m,4H),3.82-3.91(m,1H),3.62(t,J=10.79Hz,1H),3.35-3.45(m,2H),2.22-2.34(m,3H),1.92-2.01(m,1H),1.47-1.68(m,2H),1.00(d,J=12.05Hz,1H)。
实施例27
8-[(2,6-二氟苯基)(氧杂环己烷-4-基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲氧基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(外消旋)
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-甲氧基吡啶-3-基)硼酸为原料及使用外消旋(2,6-二氟苯基)(四氢-2H-吡喃-4-基)甲醇合成标题化合物(根据方案1)。LCMS:RT=1.915min;MS(ES):m/z=505.2[M+H]+(柱:Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=8.953min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=8.792min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.63(d,J=2.01Hz,1H),8.25(br.s.,1H),8.08(d,J=5.52Hz,1H),7.90(d,J=5.52Hz,1H),7.35-7.48(m,1H),7.05(dd,J=10.04,8.53Hz,2H),4.28(s,3H),4.05(s,4H),3.80-3.91(m,1H),3.49-3.63(m,1H),3.38(d,J=2.51Hz,2H),2.33(s,3H),1.85-1.98(m,1H),1.57(d,J=9.04Hz,2H),1.05(d,J=13.05Hz,1H)。
实施例28
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-甲氧基-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(外消旋)
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(6-甲氧基吡啶-3-基)硼酸为原料及使用外消旋(2-氟苯基)(四氢-2H-吡喃-4-基)甲醇合成标题化合物(根据方案1)。LCMS:RT=1.967min;MS(ES):m/z=487.2[M+H]+(柱:Ascentis Express C8(50×2.1mm;2.7μm),ACN/H2O及NH4OAc,梯度=4min,波长=220nm);HPLC RT=8.983min(柱:Sunfire C18 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=9.053min(柱:XBridge Phenyl 3.5μm,4.6×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ8.51-8.47(m,2H),8.30(m,1H),8.19(m,1H),7.31(m,1H),7.24(m,1H),7.06(m,1H),6.81(d,J=8.4Hz,1H),6.08(d,J=12.0Hz,1H),4.17(s,3H),4.04(s,3H),3.97(m,1H),3.74(m,1H),3.85(m,1H),3.57-3.32(m,2H),2.35(s,3H),1.75(m,1H),1.59-1.40(m,2H),1.19(m,1H)。
实施例29
5-(二甲基-1H-1,2,3-三唑-5-基)-10-氟-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(2-氟吡啶-4-基)硼酸为原料合成标题化合物。LCMS:RT=1.59min;(ES):m/z(M+H)+=475.3(Waters Acquity SDS,柱:BEH C18 2.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。1H NMR(500MHz,DMSO-d6)δ8.72(br.s.,1H),8.43-8.26(m,2H),8.19(br.s.,1H),8.10(br.s.,1H),7.43-7.28(m,2H),7.12(br.s.,1H),6.20(d,J=11.4Hz,1H),3.91(br.s.,3H),3.76(br.s.,2H),3.57-3.37(m,2H),3.26(t,J=11.4Hz,1H),2.22(br.s.,3H),1.83(d,J=12.5Hz,1H),1.39(br.s.,2H),1.00(br.s.,1H)。
实施例30
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
使用针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(2-甲氧基吡啶-3-基)硼酸为原料合成标题化合物。LCMS:RT=1.45min;(ES):m/z(M+H)+=487.3(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.62(br.s.,1H),8.23(t,J=7.1Hz,3H),7.95(s,1H),7.43-7.27(m,2H),7.12(t,J=9.3Hz,1H),6.03(d,J=11.1Hz,1H),4.09(s,3H),3.98(br.s.,3H),3.89(d,J=11.8Hz,1H),3.71(d,J=9.4Hz,1H),3.52-3.35(m,2H),3.21(t,J=11.4Hz,1H),2.28(br.s.,3H),1.73(d,J=13.5Hz,1H),1.66-1.52(m,1H),1.32(d,J=12.5Hz,1H),0.76(d,J=12.5Hz,1H)。
实施例31
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-(甲基硫基)-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在2打兰瓶中添加10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(50mg,0.102mmol)及硫代甲醇钠(28.6mg,0.407mmol)于DMSO(2mL)中的混合物且将瓶盖好且在加热区块中在80℃加热3h。用甲醇稀释混合物且经由制备型LC/MS(柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 37-77%B且然后在100%B保持5min;流速:20mL/min)纯化,得到产率为59%的标题化合物。LCMS:RT=1.847min;(ES):m/z(M+H)+=503.10(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.61(s,1H),8.46(d,J=5.0Hz,1H),8.21(t,J=6.6Hz,1H),8.10(s,1H),8.00(d,J=5.0Hz,1H),7.40-7.28(m,2H),7.11-7.02(m,1H),6.90(d,J=11.3Hz,1H),3.96-3.88(m,1H),3.82(s,3H),3.77(d,J=9.0Hz,1H),3.63-3.46(m,2H),3.25(t,J=11.4Hz,1H),2.81(s,3H),2.14(s,3H),1.88(d,J=12.6Hz,1H),1.79-1.67(m,1H),1.58-1.45(m,1H),0.79(d,J=11.8Hz,1H)。
实施例32
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-12-甲磺酰基-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在2打兰瓶中添加12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(40mg,0.081mmol)、甲亚磺酸钠(41.6mg,0.407mmol)、碘化亚铜(I)(7.76mg,0.041mmol)、脯氨酸(9.38mg,0.081mmol)及Cs2CO3(26.5mg,0.081mmol)于DMSO(1mL)中的混合物且将瓶盖好且在加热区块中在95℃加热7天。用甲醇稀释混合物且经由制备型LC/MS(柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 37-77%B且然后在100%B保持5min;流速:20mL/min)纯化,得到标题化合物(18mg,0.033mmol,53%产率)。LCMS:RT=1.324min;(ES):m/z(M+H)+=535.0(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.84(m.,2H),8.79-8.70(m,2H),8.36(br.s.,1H),7.44-7.31(m,2H),7.21-7.07(m,1H),6.31(d,J=11.1Hz,1H),4.05(br.s.,3H),3.92(d,J=12.1Hz,1H),3.72(d,J=8.8Hz,1H),3.47(br.s.,2H),3.34(s,3H),3.24(t,J=11.3Hz,1H),2.33(br.s.,3H),1.78(d,J=12.5Hz,1H),1.65(d,J=10.1Hz,1H),1.40(br.s.,1H),0.81(d,J=12.5Hz,1H)。
实施例33
5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序合成标题化合物。LCMS:RT=1.366min;(ES):m/z(M+H)+=517.15(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.84(s,1H),8.75(br.s.,1H),8.60(br.s.,1H),7.95(s,1H),7.70(d,J=7.7Hz,2H),7.39-7.33(m,2H),7.32-7.25(m,1H),6.03(d,J=11.4Hz,1H),4.03(br.s.,3H),3.94-3.87(m,1H),3.76-3.68(m,4H),3.55-3.42(m,2H),3.27(t,J=11.4Hz,1H),2.31(br.s.,3H),1.74(d,J=12.8Hz,1H),1.63-1.53(m,1H),1.32(m,1H),0.94(d,J=12.5Hz,1H)。
实施例34
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序合成标题化合物。LCMS:RT=2.05min;(ES):m/z(M+H)+=473.3(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.78(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.66(s,1H),8.62(br.s.,1H),7.79(d,J=7.4Hz,2H),7.35-7.28(m,2H),7.27-7.21(m,1H),5.91(br.s.,1H),4.03(s,3H),3.87(d,J=10.8Hz,1H),3.74(d,J=10.4Hz,1H),3.54-3.36(m,2H),3.25(t,J=11.3Hz,1H),2.31(s,3H),1.52(d,J=10.1Hz,1H),1.45-1.33(m,1H),1.32-1.19(m,1H),1.11(d,J=12.1Hz,1H)。
实施例35
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序合成标题化合物。LCMS:RT=1.71min;(ES):m/z(M+H)+=439.3(柱:WatersAcquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.76(d,J=3.7Hz,1H),8.66(d,J=7.1Hz,1H),8.62(s,1H),8.57(br.s.,1H),7.81(d,J=7.4Hz,2H),7.45(dd,J=7.6,4.9Hz,1H),7.34-7.28(m,2H),7.27-7.20(m,1H),5.96(br.s.,1H),4.03(s,3H),3.88(d,J=9.4Hz,1H),3.74(d,J=11.4Hz,1H),3.57-3.35(m,2H),3.26(t,J=11.3Hz,1H),2.31(s,3H),1.54(dd,J=11.1,2.4Hz,1H),1.46-1.35(m,1H),1.32-1.20(m,1H),1.11(d,J=11.8Hz,1H)。
实施例36
10,13-二氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(2,5-二氯吡啶-3-基)硼酸为原料合成标题化合物。LCMS:RT=1.85min;(ES):m/z(M+H)+=507.3(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.58(bs,1H),8.40(s,1H),8.04(bs,1H),7.46(d,J=7.7Hz,2H),7.23-7.15(m,2H),7.13-7.07(m,J=7.4Hz,1H),6.68(d,J=11.1Hz,1H),3.74-3.68(m,1H),3.66(s,3H),3.53(d,J=8.8Hz,1H),3.38-3.26(m,2H),3.04(t,J=11.3Hz,1H),1.96(s,3H),1.72(d,J=12.8Hz,1H),1.30-1.11(m,2H),0.67(d,J=12.5Hz,1H)。
实施例37
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(5-氯-2-氟吡啶-3-基)硼酸为原料合成标题化合物。LCMS:RT=1.78min;(ES):m/z(M+H)+=491.3(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.49(s,1H),8.18(s,1H),8.02(s,1H),7.44(d,J=7.7Hz,2H),7.20-7.10(m,2H),7.10-7.02(m,1H),6.63(d,J=11.1Hz,1H),3.66(d,J=9.8Hz,1H),3.62(s,3H),3.50(d,J=10.4Hz,1H),3.36-3.22(m,2H),3.00(t,J=11.3Hz,1H),1.92(s,3H),1.67(d,J=12.8Hz,1H),1.27-1.06(m,2H),0.65(d,J=11.8Hz,1H)。
实施例38
10-溴-5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(5-溴-2-甲氧基吡啶-3-基)硼酸为原料合成标题化合物。LCMS:RT=1.82min;(ES):m/z(M+H)+=547.3(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1HNMR(500MHz,DMSO-d6)δ8.42(s,1H),8.22(s,1H),7.90(s,1H),7.41(d,J=7.7Hz,2H),7.15(t,J=7.6Hz,2H),7.09-7.04(m,J=7.1Hz,1H),6.86(d,J=11.1Hz,1H),3.89(s,3H),3.72-3.65(m,1H),3.61(s,3H),3.30(m,2H),3.51(d,J=11.4Hz,1H),3.06-2.97(m,1H),1.93(s,3H),1.71(d,J=11.8Hz,1H),1.30-1.13(m,2H),0.58(d,J=12.1Hz,1H)。
实施例39
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(2-氯-5-甲氧基吡啶-3-基)硼酸为原料合成标题化合物。LCMS:RT=1.62min;(ES):m/z(M+H)+=503.3(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),7.95(s,1H),7.89(s,1H),7.38(d,J=7.7Hz,2H),7.18-7.07(m,2H),7.06-6.98(m,1H),6.71(d,J=10.8Hz,1H),3.89(s,3H),3.71-3.63(m,1H),3.61(s,3H),3.45-3.34(m,1H),3.30-3.20(m,J=11.4Hz,1H),3.00(t,J=11.4Hz,1H),1.92(s,3H),1.68(d,J=12.1Hz,1H),1.27-1.10(m,2H),0.58(d,J=11.8Hz,1H)。
实施例40
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序但以(5-氯-2-甲氧基吡啶-3-基)硼酸为原料合成标题化合物。LCMS:RT=1.85min;(ES):m/z(M+H)+=503.2(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.67(br.s.,1H),8.35(s,1H),8.18(s,1H),7.67(d,J=7.4Hz,2H),7.38(t,J=7.6Hz,2H),7.32-7.24(m,1H),6.87(d,J=11.1Hz,1H),4.13(s,3H),3.94-3.83(m,4H),3.75(d,J=8.8Hz,1H),3.52(d,J=11.8Hz,1H),3.46-3.33(m,1H),3.25(t,J=11.4Hz,1H),2.18(s,3H),1.92(d,J=13.1Hz,1H),1.51-1.32(m,2H),0.86(d,J=13.1Hz,1H)。
实施例41
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-N,N-二甲基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
在2打兰瓶中添加10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.041mmol)于2M二甲胺/THF溶液(1mL,2.00mmol)中的溶液且在室温搅拌溶液2小时。用甲醇稀释且经由制备型LC/MS(柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min37-77%B且然后在100%B保持5min;流速:20mL/min)纯化,得到标题化合物(14.5mg,0.028mmol,69.0%产率)。LCMS:RT=2.04min;(ES):m/z(M+H)+=516(柱:Waters AcquityUPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.63(s,1H),8.27(s,1H),8.07(s,1H),7.64(d,J=7.4Hz,2H),7.37(t,J=7.6Hz,2H),7.31-7.23(m,1H),6.93(d,J=11.1Hz,1H),3.88(d,J=8.8Hz,1H),3.84(s,3H),3.74(d,J=10.4Hz,1H),3.62-3.45(m,2H),3.30-3.23(m,1H),3.21(s,6H),2.15(s,3H),1.92(d,J=12.1Hz,1H),1.50-1.33(m,2H),0.84(d,J=12.8Hz,1H)。
实施例42
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在2打兰瓶中添加10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.041mmol)及甲亚磺酸钠(20.79mg,0.204mmol)于DMSO(1mL)中的溶液且在加热区块中在75℃加热溶液过夜。添加额外的甲亚磺酸钠(20.79mg,0.204mmol)且再在95℃加热4h。用甲醇稀释且经由制备型LC/MS(柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min37-77%B且然后在100%B保持5min;流速:20mL/min)纯化,得到标题化合物(6.9mg,0.012mmol,30%产率)。LCMS:RT=1.61min;(ES):m/z(M+H)+=551.0(柱:Waters AcquityUPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.90(s,1H),8.85(s,1H),8.29(s,1H),7.67(d,J=7.4Hz,2H),7.43-7.35(m,2H),7.34-7.28(m,1H),7.01(d,J=11.1Hz,1H),3.91(d,J=11.8Hz,1H),3.87(s,3H),3.74(d,J=9.1Hz,1H),3.70(s,3H),3.61-3.46(m,2H),3.25(t,J=11.4Hz,1H),2.16(s,3H),1.95(d,J=12.5Hz,1H),1.54-1.33(m,2H),0.86(d,J=12.5Hz,1H)。
实施例43
10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在2打兰瓶中添加10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.061mmol)及KOtBu(41.1mg,0.367mmol)于乙醇(1ml,17.1mmol)中的溶液且在室温搅拌所得溶液过夜。混合物用1N HCl淬灭且用甲醇稀释且经由制备型LC/MS(柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 37-77%B且然后在100%B保持5min;流速:20mL/min)纯化,得到标题化合物(5.8mg,0.010mmol,16%产率)。LCMS:RT=2.02min;(ES):m/z(M+H)+=517.0(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.65(s,1H),8.31(s,1H),8.13(s,1H),7.64(d,J=7.7Hz,2H),7.42-7.33(m,2H),7.32-7.24(m,1H),6.86(d,J=11.1Hz,1H),4.61(q,J=6.5Hz,2H),3.89(d,J=7.4Hz,1H),3.85(s,3H),3.74(d,J=9.8Hz,1H),3.65-3.45(m,2H),3.30-3.18(m,1H),2.16(s,3H),1.91(d,J=13.1Hz,1H),1.49-1.35(m,5H),0.85(d,J=10.8Hz,1H)。
实施例44
10-氯-N-(环丙基甲基)-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
在2打兰瓶中添加10-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.061mmol)及环丙胺(44mg,0.631mmol)于DMSO(1mL)中的溶液且在室温搅拌所得溶液过夜。用甲醇稀释混合物且经由制备型LC/MS(柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 37-77%B且然后在100%B保持5min;流速:20mL/min)纯化,得到标题化合物(18mg,0.033mmol,53%产率)。LCMS:RT=2.37min;(ES):m/z(M+H)+=542.1(柱:WatersAcquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.60(bs,1H),8.15(bs,1H),8.13(bs,1H),7.65(d,J=7.7Hz,2H),7.44(t,J=5.6Hz,1H),7.37(t,J=7.6Hz,2H),7.32-7.22(m,1H),6.73(d,J=11.1Hz,1H),3.92-3.83(m,4H),3.75(d,J=9.4Hz,1H),3.62(d,J=14.1Hz,2H),3.55-3.40(m,2H),3.25(t,J=11.6Hz,1H),2.16(s,3H),1.87(d,J=12.1Hz,1H),1.46-1.32(m,2H),1.23-1.13(m,1H),0.91(d,J=12.1Hz,1H),0.48(d,J=7.1Hz,2H),0.30(d,J=4.0Hz,2H)。
实施例45
5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-2-(5-甲磺酰基-2-甲氧基吡啶-3-基)-3-硝基吡啶
向含有5-甲磺酰基-2-甲氧基-3-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶(664mg,2.12mmol)及2,5-二溴-3-硝基吡啶(598mg,2.12mmol)/THF(12mL)的100mL圆底烧瓶中添加磷酸三钾(2M水溶液,3.18mL,6.36mmol)及Pd(dppf)Cl2-CH2Cl2(87mg,0.106mmol)。使氮气鼓泡通过反应混合物2min,然后加热至回流且保持1h。冷却反应混合物至室温且然后浓缩。添加水且混合物用CHCl3萃取两次。合并的有机层经MgSO4干燥,过滤且然后浓缩。残余物在用CH2Cl2至20%EtOAc/CH2Cl2梯度洗脱的80g硅胶柱上纯化。收集含有产物的管且浓缩,得到呈浅黄色固体状的标题化合物(405mg,49.2%)。1H NMR(500MHz,CDCl3)δ8.97(d,J=2.0Hz,1H),8.84(d,J=2.4Hz,1H),8.49(d,J=2.0Hz,1H),8.47(d,J=2.4Hz,1H),3.97(s,3H),3.18(s,3H);LCMS(M+H)=388;HPLC RT=2.033min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
步骤2:5-溴-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-溴-2-(5-甲磺酰基-2-甲氧基吡啶-3-基)-3-硝基吡啶(405mg,1.04mmol)/1,2-二氯苯(10mL)的50mL圆底烧瓶中添加Ph3P(821mg,3.13mmol)且加热反应混合物至170℃且保持1.5h。冷却至室温后,反应混合物直接在用CH2Cl2至60%EtOAc/CH2Cl2梯度洗脱的80g硅胶柱上纯化。浓缩含有产物的管且所得固体用Et2O研磨。过滤固体,得到呈奶油色固体状的标题化合物(148.9mg,40.1%),1H NMR(500MHz,DMSO-d6)δ12.22(br.s.,1H),8.69(br.s.,1H),8.59(s,1H),8.26(s,1H),4.19(s,3H),3.40(s,3H);LCMS(M+H)=356;HPLC RT=1.880min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
步骤3:5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向在冰/水浴中冷却的含有5-溴-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(100mg,0.281mmol)及(R)-氧杂环己烷-4-基(苯基)甲醇(108mg,0.561mmol)/甲苯(2mL)的20mL瓶中添加Ph3P(147mg,0.561mmol)及DIAD(0.109mL,0.561mmol)。由冰/水浴取出反应混合物且在室温搅拌1h且然后直接在用CH2Cl2至EtOAc梯度洗脱的80g硅胶柱上纯化。收集含有产物的管且浓缩,得到标题化合物(147mg,99%)。1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.76(d,J=1.8Hz,1H),7.77(d,J=2.0Hz,1H),7.51-7.48(m,2H),7.43-7.38(m,2H),7.37-7.32(m,1H),6.89(d,J=10.1Hz,1H),4.39(s,3H),4.06(dd,J=11.5,2.8Hz,1H),3.78(dd,J=11.7,3.1Hz,1H),3.54(td,J=11.9,1.9Hz,1H),3.31-3.22(m,4H),3.00-2.88(m,1H),2.13(d,J=13.4Hz,1H),1.96-1.85(m,1H),1.54-1.48(m,1H),0.36(d,J=12.4Hz,1H);LCMS(M+H)=530;HPLC RT=2.783min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
步骤4:5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(50mg,0.094mmol)及(二甲基-1,2-噁唑-4-基)硼酸(19.9mg,0.141mmol)/THF(1mL)的8mL瓶中添加磷酸三钾(2M水溶液,0.141mL,0.283mmol)及Pd(dppf)Cl2-CH2Cl2(7.7mg,0.009mmol)。使氮气鼓泡通过反应混合物30秒,然后在氮气下密封且在80℃加热区块上加热1h。冷却反应混合物至室温且然后浓缩。残余物在用CH2Cl2至3%MeOH/CH2Cl2梯度洗脱的40g硅胶柱上纯化。收集含有产物的管且浓缩,得到呈灰白色固体状的标题化合物(36.4mg,70.6%)。1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.64(d,J=1.7Hz,1H),7.50(d,J=7.9Hz,2H),7.42-7.36(m,3H),7.36-7.30(m,1H),6.91(d,J=9.9Hz,1H),4.42(s,3H),4.07(dd,J=11.6,2.7Hz,1H),3.80-3.76(m,1H),3.53(td,J=11.9,1.9Hz,1H),3.36(s,3H),3.21(td,J=11.9,1.9Hz,1H),3.00-2.89(m,1H),2.24(s,3H),2.21-2.15(m,1H),2.06(s,3H),2.01-1.91(m,1H),1.64-1.57(m,1H),0.37(d,J=12.5Hz,1H);LCMS(M+H)=547;HPLC RT=2.632min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例46
5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(50mg,0.094mmol)/DMF(1mL)的8mL瓶中添加1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(54.6mg,0.141mmol)、CuI(2.69mg,0.014mmol)、Et3N(0.026mL,0.189mmol)及Pd(Ph3P)4(8.17mg,0.007mmol)。使氮气鼓泡通过反应混合物30秒,然后在氮气下密封且在100℃加热区块上加热30min。冷却反应混合物至室温且然后用水稀释。通过过滤收集所得析出物且在用CH2Cl2至4%MeOH/CH2Cl2梯度洗脱的硅胶柱(40g)上纯化。浓缩含有所需化合物的管且真空干燥,得到标题化合物(33.6mg,64%)。1H NMR(500MHz,CDCl3)δ9.02(s,1H),8.69(d,J=1.8Hz,1H),7.49(d,J=7.8Hz,2H),7.46(d,J=1.8Hz,1H),7.43-7.38(m,2H),7.37-7.32(m,1H),6.93(d,J=9.9Hz,1H),4.43(s,3H),4.07(dd,J=11.6,2.7Hz,1H),3.79(dd,J=11.7,3.2Hz,1H),3.71(s,3H),3.54(td,J=11.9,1.9Hz,1H),3.39(s,3H),3.22(td,J=12.0,2.0Hz,1H),3.00-2.90(m,1H),2.19(d,J=13.7Hz,1H),2.16(s,3H),2.02-1.91(m,1H),1.67-1.57(m,1H),0.37(d,J=12.2Hz,1H);LCMS(M+H)=547;HPLCRT=2.400min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例47
10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(35mg,0.066mmol)/NMP(0.13mL)的4mL瓶中添加4-(2H3)甲基-1-[(三甲基硅烷基)甲基]-1H-1,2,3-三唑(22.7mg,0.132mmol)、四丁基乙酸铵(39.8mg,0.132mmol)及Pd(dppf)Cl2-CH2Cl2(6.8mg,0.006mmol)。在氮气下将瓶密封且在100℃加热区块上加热2小时。冷却反应混合物至室温且然后添加TBAF(1M于THF中,0.66mL,0.66mmol),在室温搅拌15min,然后用氢氧化铵饱和水溶液稀释。浓缩反应混合物且在制备型HPLC(柱:Phen Luna C18,30×100mm,5μm粒子;流动相A:5:95ACN:水及0.1%TFA;流动相B:95:5ACN:水及0.1%TFA;梯度:历经12min 10-100%B且然后在100%B保持3min;流速:40mL/min)上纯化残余物。用K2CO3饱和水溶液中和含有所需化合物的管且浓缩以除去CH3CN。形成白色析出物,其用水稀释,过滤且真空干燥,得到标题化合物(12.2mg,33%)。1H NMR(500MHz,CDCl3)δ9.02(s,1H),8.69(d,J=1.8Hz,1H),7.49(d,J=7.9Hz,2H),7.46(d,J=1.8Hz,1H),7.43-7.37(m,2H),7.37-7.32(m,1H),6.93(d,J=9.9Hz,1H),4.43(s,3H),4.07(dd,J=11.7,2.7Hz,1H),3.79(dd,J=11.8,3.1Hz,1H),3.71(s,3H),3.54(t,J=11.9Hz,1H),3.39(s,3H),3.22(td,J=11.9,1.9Hz,1H),3.00-2.90(m,1H),2.19(d,J=13.4Hz,1H),2.02-1.91(m,1H),1.67-1.58(m,1H),0.37(d,J=12.8Hz,1H);LCMS(M+H)=550;HPLC RT=2.387min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例48
5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(75mg,0.211mmol)及(R)-(2-氟苯基)(氧杂环己烷-4-基)甲醇(89mg,0.421mmol)转化成标题化合物(85.5mg,74%)。1H NMR(500MHz,CDCl3)δ9.07(s,1H),8.72(d,J=1.8Hz,1H),7.82-7.77(m,1H),7.75(d,J=1.8Hz,1H),7.42-7.32(m,2H),7.15(d,J=10.2Hz,1H),6.98(ddd,J=11.6,7.7,1.6Hz,1H),4.38(s,3H),4.08(d,J=11.3Hz,1H),3.86(dd,J=11.5,3.0Hz,1H),3.57(td,J=11.7,2.2Hz,1H),3.39(s,3H),3.32(td,J=11.9,1.8Hz,1H),3.04(q,J=11.0Hz,1H),2.11-1.85(m,3H),0.51(d,J=13.0Hz,1H);LCMS(M+H)=548;HPLC RT=2.703min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
步骤2:5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.055mmol)转化成标题化合物(22.5mg,72%)。1H NMR(500MHz,CDCl3)δ9.09(s,1H),8.62(d,J=1.8Hz,1H),7.77(t,J=7.5Hz,1H),7.46(d,J=1.7Hz,1H),7.40-7.30(m,2H),7.19(d,J=10.1Hz,1H),7.00(ddd,J=11.6,8.0,1.2Hz,1H),4.41(s,3H),4.08(dd,J=11.3,2.4Hz,1H),3.85(dd,J=11.6,3.4Hz,1H),3.54(td,J=11.8,2.1Hz,1H),3.41(s,3H),3.27(td,J=11.9,1.9Hz,1H),3.04(q,J=10.9Hz,1H),2.25(s,3H),2.13-2.02(m,4H),2.01-1.89(m,2H),0.51(d,J=13.0Hz,1H);LCMS(M+H)=565;HPLCRT=2.532min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例49
5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(75mg,0.211mmol)及(R)-(4-氟苯基)(氧杂环己烷-4-基)甲醇(89mg,0.421mmol)转化成标题化合物(91.4mg,79%)。1HNMR(500MHz,CDCl3)δ8.95(s,1H),8.77(d,J=1.8Hz,1H),7.75(d,J=1.8Hz,1H),7.53(dd,J=8.5,5.2Hz,2H),7.10(t,J=8.5Hz,2H),6.83(d,J=10.1Hz,1H),4.38(s,3H),4.06(dd,J=11.4,2.7Hz,1H),3.77(dd,J=11.5,3.0Hz,1H),3.53(td,J=11.9,1.7Hz,1H),3.34(s,3H),3.25(td,J=11.9,1.7Hz,1H),2.96-2.85(m,1H),2.08(d,J=13.4Hz,1H),1.90-1.80(m,1H),1.54-1.44(m,1H),0.34(d,J=12.8Hz,1H);LCMS(M+H)=548;HPLC RT=2.873min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
步骤2:5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.055mmol)转化成标题化合物(21mg,66%)。1H NMR(500MHz,CDCl3)δ8.95(s,1H),8.66(d,J=1.7Hz,1H),7.53(dd,J=8.5,5.2Hz,2H),7.41(d,J=1.8Hz,1H),7.09(t,J=8.5Hz,2H),6.87(d,J=9.9Hz,1H),4.41(s,3H),4.07(dd,J=11.7,2.6Hz,1H),3.77(dd,J=11.5,3.1Hz,1H),3.51(t,J=11.1Hz,1H),3.39(s,3H),3.20(td,J=11.9,1.8Hz,1H),2.97-2.85(m,1H),2.29(s,3H),2.16-2.09(m,4H),1.96-1.85(m,1H),1.54-1.47(m,1H),0.35(d,J=13.1Hz,1H);LCMS(M+H)=565;HPLC RT=2.686min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例50
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.055mmol)转化成标题化合物(15.9mg,51%)。1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.66(d,J=1.8Hz,1H),7.78(t,J=7.4Hz,1H),7.52(d,J=1.8Hz,1H),7.41-7.36(m,1H),7.35-7.31(m,1H),7.21(d,J=10.2Hz,1H),7.00(ddd,J=11.7,8.0,1.3Hz,1H),4.42(s,3H),4.08(dd,J=11.5,2.5Hz,1H),3.86(dd,J=11.7,3.1Hz,1H),3.76(s,3H),3.54(td,J=11.9,2.1Hz,1H),3.43(s,3H),3.27(td,J=12.0,2.0Hz,1H),3.08-2.97(m,1H),2.14(s,3H),2.12-1.93(m,3H),0.53(d,J=11.9Hz,1H);LCMS(M+H)=565;HPLCRT=2.345min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例51
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(24mg,0.044mmol)转化成标题化合物(9mg,35%)。1H NMR(500MHz,CDCl3)δ9.12(s,1H),8.66(d,J=1.8Hz,1H),7.77(t,J=7.6Hz,1H),7.52(d,J=1.8Hz,1H),7.42-7.36(m,1H),7.35-7.31(m,1H),7.21(d,J=10.1Hz,1H),7.04-6.95(m,1H),4.42(s,3H),4.08(d,J=9.0Hz,1H),3.86(dd,J=11.7,3.4Hz,1H),3.76(s,3H),3.59-3.51(m,1H),3.43(s,3H),3.31-3.22(m,1H),3.08-2.96(m,1H),2.13-1.93(m,3H),0.53(d,J=11.3Hz,1H);LCMS(M+H)=568;HPLC RT=2.348min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例52
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.055mmol)转化成标题化合物(21.4mg,68%)。1H NMR(500MHz,CDCl3)δ8.98(s,1H),8.70(d,J=1.7Hz,1H),7.53(dd,J=8.5,5.2Hz,2H),7.47(d,J=1.7Hz,1H),7.10(t,J=8.5Hz,2H),6.89(d,J=10.1Hz,1H),4.42(s,3H),4.07(dd,J=11.7,2.7Hz,1H),3.83-3.75(m,4H),3.56-3.48(m,1H),3.42(s,3H),3.20(td,J=12.0,1.8Hz,1H),2.97-2.85(m,1H),2.19(s,3H),2.13(d,J=13.6Hz,1H),1.98-1.85(m,1H),1.63-1.56(m,1H),0.35(d,J=12.5Hz,1H);LCMS(M+H)=565;HPLC RT=2.477min(柱:Chromolith ODSS5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例53
5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(16mg,0.029mmol)/EtOH(0.75mL)的4mL瓶中添加KOtBu(23mg,0.205mmol)且在室温搅拌反应混合物15h。反应混合物用0.15mL NMP稀释且再在室温搅拌3h且然后添加1M柠檬酸水溶液(0.073mL,0.073mmol)。浓缩反应混合物,然后用水稀释且通过过滤收集所得析出物且真空干燥,得到标题化合物(10.7mg,61%)。1H NMR(500MHz,CDCl3)δ9.00(s,1H),8.68(d,J=1.7Hz,1H),7.48(d,J=7.6Hz,2H),7.44(d,J=1.7Hz,1H),7.42-7.36(m,2H),7.36-7.31(m,1H),6.92(d,J=9.9Hz,1H),4.95(q,J=7.0Hz,2H),4.07(dd,J=11.0,3.2Hz,1H),3.79(dd,J=11.9,2.9Hz,1H),3.69(s,3H),3.53(td,J=11.8,1.3Hz,1H),3.39(s,3H),3.27-3.17(m,J=10.5Hz,1H),2.99-2.89(m,J=11.3,11.3,11.3Hz,1H),2.20(br.s.,1H),2.15(s,3H),2.02-1.91(m,J=4.9Hz,1H),1.64(s,4H),0.39(d,J=13.3Hz,1H);LCMS(M+H)=561;HPLCRT=2.587min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min0-100%B;流速:4mL/min)。
实施例54
10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(23.4mg,0.043mmol)/CD3OD(1.5mL)的4mL瓶中添加KOtBu(22.1mg,0.197mmol)且在80℃加热区块上加热反应混合物17h。冷却反应混合物至室温且添加1M柠檬酸水溶液(0.043mL,0.043mmol)。浓缩反应混合物,然后用水稀释且通过过滤收集所得析出物且真空干燥。将粗固体溶解于MeOH(1mL)中且添加KOtBu(22.1mg,0.197mmol)且在室温搅拌反应混合物20min。然后用NaHCO3饱和水溶液稀释反应混合物,然后通过蒸发除去MeOH且用水稀释,得到白色析出物。通过过滤收集白色析出物且真空干燥,得到标题化合物(15.5mg,61%)。1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.64(d,J=1.5Hz,1H),7.49(d,J=7.6Hz,2H),7.44-7.36(m,3H),7.36-7.31(m,1H),6.91(d,J=9.9Hz,1H),4.11-3.99(m,1H),3.78(dd,J=11.6,2.9Hz,1H),3.53(t,J=11.2Hz,1H),3.36(s,3H),3.25-3.17(m,1H),3.02-2.89(m,1H),2.18(d,J=13.4Hz,1H),2.06(s,3H),2.01-1.90(m,1H),1.64-1.58(m,1H),0.37(d,J=12.7Hz,1H);LCMS(M+H)=553;HPLC RT=2.636min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例55
8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(15mg,0.027mmol)转化成标题化合物(3.4mg,21%)。1H NMR(500MHz,CDCl3)δ8.95(s,1H),8.66(d,J=1.7Hz,1H),7.53(dd,J=8.5,5.1Hz,2H),7.41(d,J=1.7Hz,1H),7.09(t,J=8.5Hz,2H),6.87(d,J=9.9Hz,1H),4.07(d,J=8.9Hz,1H),3.77(dd,J=11.8,3.0Hz,1H),3.51(t,J=11.1Hz,1H),3.39(s,3H),3.20(t,J=11.1Hz,1H),2.96-2.82(m,1H),2.12(s,4H),1.96-1.86(m,1H),1.53-1.48(m,1H),0.35(d,J=12.5Hz,1H);LCMS(M+H)=571;HPLC RT=2.700min(柱:ChromolithODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例56
13-乙氧基-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(31mg,0.056mmol)转化成标题化合物(6.4mg,19.9%)。1H NMR(500MHz,CDCl3)δ9.00(s,1H),8.68(d,J=1.8Hz,1H),7.48(d,J=7.9Hz,2H),7.44(d,J=1.8Hz,1H),7.42-7.37(m,2H),7.36-7.31(m,J=7.3Hz,1H),6.92(d,J=9.9Hz,1H),4.95(qd,J=7.0,1.0Hz,2H),4.07(dd,J=11.6,2.7Hz,1H),3.79(dd,J=11.5,3.0Hz,1H),3.69(s,3H),3.53(td,J=11.9,1.8Hz,1H),3.39(s,3H),3.22(td,J=11.9,1.9Hz,1H),3.01-2.89(m,1H),2.19(d,J=13.4Hz,1H),2.03-1.91(m,J=4.4Hz,1H),1.70-1.59(m,J=7.1,7.1Hz,4H),0.39(d,J=12.8Hz,1H);LCMS(M+H)=564;HPLC RT=2.590min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例57
5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.037mmol)/iPrOH(0.75mL)转化成标题化合物(18.7mg,84%)。1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.65(d,J=1.8Hz,1H),7.47(d,J=8.5Hz,2H),7.41(s,1H),7.40-7.36(m,2H),7.35-7.30(m,J=7.2Hz,1H),6.91(d,J=9.9Hz,1H),5.84(spt,J=6.2Hz,1H),4.07(dd,J=11.8,2.7Hz,1H),3.79(dd,J=12.0,3.3Hz,1H),3.68(s,3H),3.53(td,J=11.9,1.7Hz,1H),3.38(s,3H),3.21(td,J=12.0,1.8Hz,1H),3.00-2.88(m,1H),2.19(d,J=13.4Hz,1H),2.14(s,3H),2.02-1.89(m,1H),1.67-1.59(m,J=11.4,6.3Hz,7H),0.40(d,J=12.8Hz,1H);LCMS(M+H)=575;HPLC RT=2.745min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例58
10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.055mmol)/iPrOH(1mL)转化成标题化合物(16.9mg,50%)。1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.65(d,J=1.8Hz,1H),7.49-7.45(m,2H),7.42(d,J=1.8Hz,1H),7.38(s,3H),6.92(d,J=9.8Hz,1H),5.84(spt,J=6.2Hz,1H),4.07(dd,J=11.6,2.9Hz,1H),3.79(dd,J=11.3,3.9Hz,1H),3.68(s,3H),3.53(td,J=11.9,1.8Hz,1H),3.37(s,3H),3.21(td,J=11.9,1.8Hz,1H),3.01-2.87(m,1H),2.18(d,J=13.0Hz,1H),2.03-1.90(m,J=4.3Hz,1H),1.63(dd,J=9.0,6.2Hz,7H),0.41(d,J=12.7Hz,1H);LCMS(M+H)=578;HPLC RT=2.741min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例59
13-(环丙基甲氧基)-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(27mg,0.049mmol)/环丙基甲醇(0.4mL)转化成标题化合物(14.2mg,48.5%)。1H NMR(500MHz,CDCl3)δ8.98(s,1H),8.69(d,J=1.7Hz,1H),7.51-7.46(m,2H),7.44(d,J=1.8Hz,1H),7.42-7.36(m,2H),7.36-7.31(m,1H),6.92(d,J=9.8Hz,1H),4.79-4.67(m,2H),4.12-4.03(m,1H),3.79(dd,J=11.9,3.1Hz,1H),3.69(s,3H),3.57-3.50(m,1H),3.38(s,3H),3.22(t,J=11.1Hz,1H),3.00-2.89(m,1H),2.19(d,J=13.1Hz,1H),2.04-1.92(m,1H),1.69-1.58(m,2H),0.75-0.64(m,2H),0.60-0.51(m,2H),0.41(d,J=12.8Hz,1H);LCMS(M+H)=590;HPLC RT=2.793min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例60
10-甲磺酰基-13-甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.037mmol)/CH3OD(1.5mL)转化成标题化合物(9mg,44%)。1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.64(d,J=1.7Hz,1H),7.52-7.46(m,2H),7.43-7.33(m,4H),6.92(d,J=9.8Hz,1H),4.42(s,3H),4.07(dd,J=11.8,3.4Hz,1H),3.78(dd,J=12.2,3.2Hz,1H),3.53(td,J=11.9,1.8Hz,1H),3.36(s,3H),3.21(td,J=12.0,2.0Hz,1H),3.01-2.88(m,1H),2.18(d,J=14.1Hz,1H),2.06(s,3H),2.02-1.90(m,J=4.3Hz,1H),1.65-1.59(m,1H),0.37(d,J=11.9Hz,1H);LCMS(M+H)=550;HPLCRT=2.631min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例61
2-({10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}氧基)乙-1-醇
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(14mg,0.025mmol)/乙二醇(0.6mL)转化成标题化合物(9.3mg,61%)。1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.64(d,J=1.7Hz,1H),7.52-7.44(m,3H),7.40(t,J=7.5Hz,2H),7.38-7.32(m,1H),6.93(d,J=9.9Hz,1H),5.02-4.90(m,J=3.5Hz,2H),4.16(br.s.,2H),4.07(dd,J=11.6,2.6Hz,1H),3.89(br.s.,1H),3.80(dd,J=11.7,3.1Hz,1H),3.70(s,3H),3.54(td,J=11.9,1.3Hz,1H),3.40(s,3H),3.23(td,J=11.9,1.7Hz,1H),3.02-2.89(m,1H),2.20(d,J=13.3Hz,1H),2.03-1.91(m,J=4.3Hz,1H),1.68-1.62(m,J=4.3Hz,1H),0.39(d,J=12.5Hz,1H);LCMS(M+H)=580;HPLCRT=2.285min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例62
13-乙氧基-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.035mmol)转化成标题化合物(13.9mg,66%)。1H NMR(500MHz,CDCl3)δ9.09(s,1H),8.65(d,J=1.7Hz,1H),7.77(t,J=7.5Hz,1H),7.50(d,J=1.8Hz,1H),7.40-7.29(m,2H),7.19(d,J=10.2Hz,1H),6.99(ddd,J=11.6,8.0,1.1Hz,1H),4.94(q,J=7.0Hz,2H),4.08(br dd,J=11.4,2.4Hz,1H),3.86(brdd,J=11.7,3.2Hz,1H),3.75(s,3H),3.54(td,J=11.9,1.9Hz,1H),3.42(s,3H),3.27(td,J=12.0,1.8Hz,1H),3.03(q,J=11.1Hz,1H),2.13-1.94(m,3H),1.63(t,J=7.0Hz,3H),0.54(br d,J=12.4Hz,1H);LCMS(M+H)=582;HPLC RT=2.538min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例63
2-({8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}氧基)乙-1-醇
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25.6mg,0.045mmol)/乙二醇(1mL)转化成标题化合物(16mg,58.8%)。1H NMR(500MHz,CDCl3)δ9.08(s,1H),8.60(d,J=1.7Hz,1H),7.78(br t,J=7.5Hz,1H),7.52(d,J=1.7Hz,1H),7.43-7.32(m,2H),7.20(br d,J=10.2Hz,1H),7.00(ddd,J=11.6,8.0,1.2Hz,1H),5.02-4.88(m,2H),4.14(br s,2H),4.08(br dd,J=11.8,2.2Hz,2H),3.87(br dd,J=12.1,3.5Hz,1H),3.75(s,3H),3.58-3.50(m,1H),3.43(s,3H),3.27(td,J=11.9,1.8Hz,1H),3.03(q,J=10.9Hz,1H),2.14-1.93(m,3H),0.53(br d,J=13.1Hz,1H);LCMS(M+H)=598;HPLC RT=2.247min(柱:ChromolithODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
实施例64及65
8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(150mg,0.421mmol)及外消旋(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲醇(178mg,0.842mmol)转化成标题化合物(154.9mg,66.9%)。1H NMR(500MHz,CDCl3)δ9.04(s,1H),8.73(d,J=1.8Hz,1H),8.57(br d,J=2.7Hz,1H),8.18(d,J=1.8Hz,1H),7.39-7.33(m,2H),7.25(s,1H),4.37(s,3H),4.03(br dd,J=11.5,2.5Hz,1H),3.83(brdd,J=11.4,3.3Hz,1H),3.55(td,J=11.7,2.3Hz,1H),3.48-3.37(m,4H),3.35-3.28(m,1H),1.95-1.76(m,3H),0.49(br d,J=11.7Hz,1H);LCMS(M+H)=549;HPLC RT=2.615min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min)。
步骤2:8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-溴-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(154.9mg,0.282mmol)/DMF(4mL)的20mL瓶中添加4-(2H3)甲基-5-(三丁基锡烷基)-1-[(三甲基硅烷基)甲基]-1H-1,2,3-三唑(195mg,0.423mmol)、CuI(8.0mg,0.042mmol)、Et3N(0.079mL,0.564mmol)及Pd(Ph3P)4(24.4mg,0.021mmol)。使氮气鼓泡通过反应混合物30秒,然后在氮气下密封且在95℃加热区块上加热1h。冷却反应混合物至室温且用1M TBAF/THF(0.564mL,0.564mmol)稀释。在室温搅拌25min后,浓缩反应混合物。用水稀释残余物且通过过滤收集所得析出物且在用CH2Cl2至6%MeOH/CH2Cl2梯度洗脱的硅胶柱(40g)上纯化。收集含有产物的管且浓缩,得到外消旋标题化合物(125.2mg,78%)。在手性制备型SFC上对外消旋化合物(41mg,0.072mmol)进行手性分离,得到对映异构体A(18.2mg,44%)及对映异构体B(18.6mg,45%)。对映异构体A:1H NMR(500MHz,CDCl3)δ9.08(s,1H),8.69(d,J=1.8Hz,1H),8.51(dt,J=3.8,1.9Hz,1H),8.01(d,J=1.8Hz,1H),7.40-7.35(m,2H),7.34-7.30(m,1H),4.41(s,3H),4.06-4.00(m,1H),3.92(s,3H),3.84(br dd,J=11.4,3.4Hz,1H),3.50(td,J=11.3,3.1Hz,1H),3.45(s,3H),3.43-3.36(m,1H),3.24(td,J=11.8,1.8Hz,1H),1.91-1.80(m,3H),0.52(br dd,J=13.1,1.5Hz,1H);LCMS(M+H)=569;HPLC RT=2.173min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=11.1min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。对映异构体B:1H NMR(500MHz,CDCl3)δ9.11(s,1H),8.78(br s,1H),8.51(d,J=4.1Hz,1H),8.19(br s,1H),7.44-7.33(m,3H),4.45(s,3H),4.07-4.00(m,1H),3.96(s,3H),3.85(br dd,J=11.6,3.4Hz,1H),3.54-3.46(m,1H),3.45(s,3H),3.37(br s,1H),3.24(td,J=11.9,1.8Hz,1H),1.91-1.84(m,3H),0.51(br d,J=11.6Hz,1H);LCMS(M+H)=569;HPLC RT=2.163min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=15.6min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。
实施例66及67
8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-(2H3)甲磺酰基-13-甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-13-甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-(二甲基-1,2-噁唑-4-基)-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(76mg,0.134mmol)转化成外消旋标题化合物。在手性制备型SFC上对外消旋化合物进行手性分离,得到对映异构体A(29.1mg,37.9%)及对映异构体B(28.8mg,37.5%)。对映异构体A:1H NMR(500MHz,CDCl3)δ9.05(s,1H),8.64(d,J=1.8Hz,1H),8.52(dd,J=4.7,1.4Hz,1H),7.87(d,J=1.8Hz,1H),7.39-7.33(m,1H),7.32-7.28(m,2H),4.40(s,3H),4.03(br dd,J=11.5,2.7Hz,1H),3.84(brdd,J=11.6,3.2Hz,1H),3.52(td,J=11.7,2.4Hz,1H),3.44-3.39(m,1H),3.25(td,J=11.9,2.1Hz,1H),2.21(s,3H),1.97-1.91(m,1H),1.85(quind,J=12.5,4.5Hz,2H),0.58-0.46(m,1H);LCMS(M+H)=572;HPLC RT=2.380min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=9.1min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。对映异构体B:1H NMR(500MHz,CDCl3)δ9.05(s,1H),8.64(s,1H),8.52(br s,1H),7.87(s,1H),7.39-7.28(m,3H),4.40(s,3H),4.03(br d,J=11.1Hz,1H),3.84(br d,J=11.1Hz,1H),3.52(br t,J=11.7Hz,1H),3.44(br d,J=8.1Hz,1H),3.26(br t,J=11.7Hz,1H),2.21(s,3H),1.98-1.91(m,1H),1.91-1.77(m,2H),0.51(br d,J=12.7Hz,1H);LCMS(M+H)=572;HPLC RT=2.383min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=11.7min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)
实施例68及69
13-乙氧基-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(42mg,0.074mmol)转化成外消旋标题化合物。在手性制备型SFC上对外消旋化合物进行手性分离,得到对映异构体A(15.3mg,35.6%)及对映异构体B(15.8mg,36%)。对映异构体A:1H NMR(500MHz,CDCl3)δ9.05(s,1H),8.68(d,J=1.7Hz,1H),8.53-8.48(m,1H),7.98(d,J=1.8Hz,1H),7.40-7.29(m,3H),4.94(q,J=7.0Hz,2H),4.05-4.00(m,1H),3.91(s,3H),3.84(br dd,J=11.4,3.1Hz,1H),3.50(td,J=11.4,3.2Hz,1H),3.45(s,3H),3.41(br d,J=12.2Hz,1H),3.24(td,J=11.9,2.1Hz,1H),1.92-1.80(m,3H),1.63(t,J=7.0Hz,3H),0.53(br d,J=11.3Hz,1H);LCMS(M+H)=583;HPLC RT=2.352min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=10.8min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。对映异构体B:1H NMR(500MHz,CDCl3)δ9.05(s,1H),8.68(d,J=1.8Hz,1H),8.52-8.48(m,1H),7.98(d,J=1.8Hz,1H),7.40-7.29(m,3H),4.94(q,J=7.0Hz,2H),4.02(br d,J=11.1Hz,1H),3.91(s,3H),3.84(br dd,J=11.4,3.2Hz,1H),3.50(td,J=11.4,3.2Hz,1H),3.45(s,3H),3.43-3.36(m,1H),3.24(td,J=11.9,2.1Hz,1H),1.93-1.80(m,3H),1.63(t,J=7.0Hz,3H),0.53(br d,J=13.0Hz,1H);LCMS(M+H)=583;HPLC RT=2.353min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=11.2min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)
实施例70及71
8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(42mg,0.074mmol)转化成外消旋标题化合物。在手性制备型SFC上对外消旋化合物进行手性分离,得到对映异构体A(9.0mg,20.4%)及对映异构体B(11.2mg,25.5%)。对映异构体A:1H NMR(500MHz,CDCl3)δ9.04(s,1H),8.65(d,J=1.7Hz,1H),8.53-8.47(m,1H),7.94(d,J=1.8Hz,1H),7.38-7.29(m,3H),5.83(spt,J=6.3Hz,1H),4.06-3.99(m,1H),3.90(s,3H),3.84(br dd,J=11.5,3.0Hz,1H),3.50(td,J=11.4,3.1Hz,1H),3.44(s,3H),3.43-3.35(m,1H),3.24(td,J=11.9,2.0Hz,1H),1.93-1.80(m,3H),1.62(dd,J=9.5,6.3Hz,6H),0.54(br d,J=11.3Hz,1H);LCMS(M+H)=597;HPLCRT=2.532min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=10.0min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。对映异构体B:1H NMR(500MHz,CDCl3)δ9.04(s,1H),8.65(d,J=1.8Hz,1H),8.52-8.48(m,1H),7.94(d,J=1.8Hz,1H),7.38-7.30(m,3H),5.83(spt,J=6.3Hz,1H),4.06-3.98(m,1H),3.90(s,3H),3.84(br dd,J=11.2,3.0Hz,1H),3.50(td,J=11.4,3.1Hz,1H),3.44(s,3H),3.42-3.35(m,1H),3.24(td,J=12.0,2.0Hz,1H),1.92-1.83(m,3H),1.62(dd,J=9.6,6.3Hz,6H),0.54(br d,J=12.8Hz,1H);LCMS(M+H)=597;HPLC RT=2.537min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=12.5min(柱:Chiral OD-H,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)
实施例72及73
8-[(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-8-[(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(100mg,0.281mmol)及外消旋(4,4-二氟环己基)(3-氟吡啶-2-基)甲醇(138mg,0.561mmol)转化成标题化合物。
步骤2:8-[(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将5-溴-8-[(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(164mg,0.281mmol)转化成外消旋标题化合物(92.1mg,54.4%)。在手性制备型SFC上对外消旋化合物(46mg,0.076mmol)进行手性分离,得到对映异构体A(23mg,49.5%)及对映异构体B(21.6mg,47%)。对映异构体A:1H NMR(400MHz,CDCl3)δ9.08(s,1H),8.68(d,J=1.8Hz,1H),8.52(dt,J=3.9,1.8Hz,1H),7.90(d,J=1.8Hz,1H),7.39-7.34(m,2H),7.33-7.28(m,2H),4.42(s,3H),3.90(s,3H),3.45(s,3H),3.36-3.24(m,1H),2.17(br s,1H),2.07(br d,J=6.0Hz,1H),2.03-1.81(m,4H),0.79(brd,J=13.2Hz,1H);LCMS(M+H)=603;HPLC RT=2.690min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=7.0min(柱:Chiral AS,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。对映异构体B:1H NMR(400MHz,CDCl3)δ9.08(s,1H),8.68(d,J=1.8Hz,1H),8.52(dt,J=3.9,1.8Hz,1H),7.90(d,J=1.8Hz,1H),7.39-7.34(m,2H),7.33-7.28(m,2H),4.42(s,3H),3.90(s,3H),3.45(s,3H),3.36-3.23(m,1H),2.18(br s,1H),2.07(br d,J=6.0Hz,1H),2.02-1.80(m,4H),0.79(br d,J=16.1Hz,1H);LCMS(M+H)=603;HPLC RT=2.690min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=10.9min(柱:Chiral AS,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)
实施例74及75
8-[(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-13-乙氧基-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯所描述的程序类似的程序将8-[(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(46mg,0.076mmol)转化成外消旋标题化合物。在手性制备型SFC上对外消旋化合物进行手性分离,得到对映异构体A(18.6mg,39%)及对映异构体B(21.4mg,45.5%)。对映异构体A:1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.67(d,J=1.7Hz,1H),8.55-8.50(m,1H),7.88(d,J=1.8Hz,1H),7.38-7.34(m,2H),7.31-7.29(m,1H),4.94(q,J=7.1Hz,2H),3.89(s,3H),3.45(s,3H),3.29(br d,J=12.8Hz,1H),2.17(br s,1H),2.07(br d,J=6.0Hz,1H),2.03-1.80(m,4H),1.63(t,J=7.0Hz,4H),0.79(brd,J=13.3Hz,1H);LCMS(M+H)=617;HPLCRT=2.831min(柱:Chromolith ODS S5 4.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=7.5min(柱:Chiral AS,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。对映异构体B:1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.68(d,J=1.8Hz,1H),8.54-8.49(m,1H),7.88(d,J=1.7Hz,1H),7.38-7.34(m,2H),7.30(dd,J=1.9,1.0Hz,1H),4.94(q,J=7.0Hz,2H),3.89(s,3H),3.45(s,3H),3.35-3.23(m,1H),2.17(br s,1H),2.11-2.05(m,1H),2.03-1.81(m,4H),1.63(t,J=7.0Hz,4H),0.80(br d,J=14.3Hz,1H);LCMS(M+H)=617;HPLC RT=2.840min(柱:Chromolith ODS S54.6×50mm;流动相A:10:90MeOH:水及0.1%TFA;流动相B:90:10MeOH:水及0.1%TFA;温度:40℃;梯度:历经4min 0-100%B;流速:4mL/min);SFC RT=14.2min(柱:Chiral AS,250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。
使用针对实施例45、46、47及56的合成所描述的程序合成实施例76至96。
实施例76
13-(环丙基甲氧基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=1.736min;(ES):m/z(M+H)+=608.15(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1HNMR(500MHz,DMSO-d6)δ8.91(s,1H),8.71(s,1H),8.20-8.10(m,1H),7.96(s,1H),7.42-7.31(m,2H),7.12-7.01(m,1H),6.92(d,J=10.4Hz,1H),4.59-4.52(m,2H),3.89(d,J=8.1Hz,1H),3.81-3.69(m,4H),3.59(s,3H),3.55-3.43(m,2H),3.32-3.21(m,1H),1.85(d,J=12.1Hz,1H),1.75(m,2H),1.51-1.38(m,1H),0.67(d,J=11.1Hz,1H),0.61(d,J=6.7Hz,2H),0.46(d,J=3.7Hz,2H)。
实施例77
13-乙氧基-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=1.615min;(ES):m/z(M+H)+=582.25.(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.90(s,1H),8.73(s,1H),7.89(s,1H),7.73-7.63(m,2H),7.19(t,J=8.8Hz,2H),6.68(d,J=10.4Hz,1H),4.75(q,J=6.7Hz,2H),3.88(d,J=12.5Hz,1H),3.82(s,3H),3.72(s,3H),3.66(d,J=8.4Hz,1H),3.56-3.40(m,2H),3.19(t,J=11.3Hz,1H),1.94(d,J=13.1Hz,1H),1.72-1.53(m,2H),1.49(t,J=7.1Hz,3H),0.44(d,J=12.5Hz,1H)。
实施例78
13-(环丙基甲氧基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=1.551min;(ES):m/z(M+H)+=608.00(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1HNMR(500MHz,DMSO-d6)δ8.88(s,1H),8.75(d,J=1.2Hz,1H),7.89(d,J=1.5Hz,1H),7.69(dd,J=8.4,5.3Hz,2H),7.19(t,J=8.7Hz,2H),6.69(d,J=10.1Hz,1H),4.55(d,J=7.0Hz,2H),3.88(d,J=8.5Hz,1H),3.82(s,3H),3.71(s,3H),3.66(dd,J=11.6,3.4Hz,1H),3.55-3.50(m,2H),3.23-3.14(m,1H),1.94(d,J=12.8Hz,1H),1.70-1.52(m,2H),1.50-1.39(m,1H),0.65-0.57(m,2H),0.49-0.42(m,J=4.6Hz,3H)。
实施例79
8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=1.544min;(ES):m/z(M+H)+=596.1(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.88(s,1H),8.73(d,J=1.5Hz,1H),7.86(d,J=1.5Hz,1H),7.68(dd,J=8.2,5.5Hz,2H),7.19(t,J=8.7Hz,2H),6.68(d,J=10.1Hz,1H),5.80-5.68(m,1H),3.92-3.85(m,1H),3.82(s,3H),3.70(s,3H),3.66(d,J=11.0Hz,2H),3.57-3.50(m,2H),3.23-3.15(m,1H),1.94(d,J=13.1Hz,1H),1.69-1.53(m,2H),1.48(t,J=5.5Hz,6H),0.49-0.41(m,1H)。
实施例80
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=1.739min;(ES):m/z(M+H)+=596.1(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.92(s,1H),8.70(d,J=0.9Hz,1H),8.18-8.12(m,1H),7.95(s,1H),7.41-7.33(m,2H),7.06(dd,J=11.6,9.2Hz,1H),6.91(d,J=10.1Hz,1H),5.76(quin,J=6.2Hz,1H),3.93-3.86(m,1H),3.76(s,3H),3.73(d,J=7.6Hz,1H),3.59(s,3H),3.57-3.51(m,2H),3.27(t,J=11.1Hz,1H),1.85(d,J=12.8Hz,2H),1.76(d,J=10.4Hz,1H),1.48(d,J=6.1Hz,6H),0.71-0.63(m,1H)。
实施例81
8-[(S)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=0.89min;(ES):m/z(M+H)+=584.2(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。HPLC RT=11.87min(柱:Sunfire C18 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=11.67min(柱:XBridge Phenyl 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CD3OD)δ9.01(s,1H),8.70(d,J=1.7Hz,1H),7.52-7.46(m,2H),7.45-7.34(m,4H),6.94(d,J=9.9Hz,1H),4.44(s,3H),3.70(s,3H),3.43(s,3H),2.80(d,J=10.5Hz,1H),2.43-2.21(m,2H),2.05-1.84(m,3H),1.72-1.19(m,3H)。手性SFC RT=6.389min(柱:Chiral OD-H 250×4.6mm ID,5mm;流速:2.0mL/min;流动相:70/30CO2/MeOH)。
实施例82
8-[(R)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=0.89min;(ES):m/z(M+H)+=584.2(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。HPLC RT=11.87min(柱:Sunfire C18 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=11.67min(柱:XBridge Phenyl 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1HNMR(400MHz,CD3OD)δ9.01(s,1H),8.70(d,J=1.7Hz,1H),7.52-7.46(m,2H),7.45-7.34(m,4H),6.94(d,J=9.9Hz,1H),4.44(s,3H),3.70(s,3H),3.43(s,3H),2.80(d,J=10.5Hz,1H),2.43-2.21(m,2H),2.05-1.84(m,3H),1.72-1.19(m,3H)。手性SFC RT=11.069min(柱:Chiral OD-H 250×4.6mm ID,5mm;流速:2.0mL/min;流动相:70/30CO2/MeOH)。
实施例83
10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[氧杂环己烷-4-基(2,4,6-三氟苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体1
LCMS:RT=1.515min;(ES):m/z(M+H)+=604.1(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ9.00(s,1H),8.77(s,1H),8.04(s,1H),7.38(d,J=11.1Hz,1H),7.26(t,J=9.9Hz,2H),4.23(s,3H),4.01-3.86(m,4H),3.72(d,J=10.4Hz,1H),3.57(s,1H),3.52-3.36(m,2H),3.31-3.19(m,1H),1.82-1.49(m,3H),0.82(d,J=12.5Hz,1H)。手性HPLC RT=7.53min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:45%乙醇/庚烷(0.1%DEA);流速:1mL/min)。
实施例84
10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[氧杂环己烷-4-基(2,4,6-三氟苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体2
LCMS:RT=1.515min;(ES):m/z(M+H)+=604.1(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ9.00(s,1H),8.77(s,1H),8.04(s,1H),7.38(d,J=11.1Hz,1H),7.26(t,J=9.9Hz,2H),4.23(s,3H),4.01-3.86(m,4H),3.72(d,J=10.4Hz,1H),3.57(s,1H),3.52-3.36(m,2H),3.31-3.19(m,1H),1.82-1.49(m,3H),0.82(d,J=12.5Hz,1H)。手性HPLC RT=9.34min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:45%乙醇/庚烷(0.1%DEA);流速:1mL/min)。
实施例85
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-13-(3-氟丙氧基)-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=1.457min;(ES):m/z(M+H)+=614.1(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.92(s,1H),8.67(s,1H),8.13(br.s.,1H),7.95(s,1H),7.36(br.s.,2H),7.11-6.99(m,1H),6.91(d,J=10.4Hz,1H),4.84-4.73(m,3H),4.69(t,J=5.7Hz,1H),3.89(d,J=7.1Hz,1H),3.74(s,3H),3.70-3.61(m,2H),3.58(s,3H),3.51(t,J=11.3Hz,1H),3.26(t,J=11.4Hz,1H),2.34-2.21(m,2H),1.89-1.69(m,3H),0.66(d,J=12.1Hz,1H)。
实施例86
8-[(3-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体1
LCMS:RT=0.79min;(ES):m/z(M+H)+=568.2(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。HPLC RT=10.576min(柱:Sunfire C18 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=10.563min(柱:XBridge Phenyl 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.73(d,J=1.8Hz,1H),7.51(d,J=1.8Hz,1H),7.44-7.36(m,1H),7.35-7.21(m,2H),7.11-7.04(m,1H),6.95(d,J=9.9Hz,1H),4.44(s,3H),4.08(dd,J=11.0,3.1Hz,1H),3.84-3.76(m,4H),3.59-3.48(m,1H),3.42(s,3H),3.29-3.16(m,1H),2.93(m,1H),2.16(d,J=13.6Hz,1H),1.95(dd,J=12.9,4.1Hz,1H),1.68-1.54(m,1H),0.40(d,J=12.8Hz,1H)。手性SFCRT=8.378min(柱:Chiral OD-H 250×4.6mm ID,5mm;流速:2.0mL/min;流动相:70/30CO2/MeOH)。
实施例87
8-[(3-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体2
LCMS:RT=0.79min;(ES):m/z(M+H)+=568.2(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。HPLC RT=10.576min(柱:Sunfire C18 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=10.563min(柱:XBridge Phenyl 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.73(d,J=1.8Hz,1H),7.51(d,J=1.8Hz,1H),7.44-7.36(m,1H),7.35-7.21(m,2H),7.11-7.04(m,1H),6.95(d,J=9.9Hz,1H),4.44(s,3H),4.08(dd,J=11.0,3.1Hz,1H),3.84-3.76(m,4H),3.59-3.48(m,1H),3.42(s,3H),3.29-3.16(m,1H),2.93(m,1H),2.16(d,J=13.6Hz,1H),1.95(dd,J=12.9,4.1Hz,1H),1.68-1.54(m,1H),0.40(d,J=12.8Hz,1H)。手性SFCRT=10.680min(柱:Chiral OD-H 250×4.6mm ID,5mm;流速:2.0mL/min;流动相:70/30CO2/MeOH)。
实施例88
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体1
LCMS:RT=1.95min;(ES):m/z(M+H)+=581.1(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.89(s,1H),8.63(s,1H),7.71(s,1H),7.61(d,J=7.8Hz,2H),7.43-7.33(m,2H),7.32-7.25(m,1H),6.70(d,J=10.4Hz,1H),4.23(s,3H),3.71(s,3H),2.26(s,3H),2.13(d,J=12.8Hz,3H),2.06(s,4H),1.84(br.s.,1H),1.65(d,J=19.3Hz,3H),0.66(br.s.,1H)。手性HPLC RT=18.1min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:14%乙醇/庚烷(0.1%DEA);流速:1mL/min)。
实施例89
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体2
LCMS:RT=1.95min;(ES):m/z(M+H)+=581.1(柱:Waters Acquity UPLCBEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:历经3min0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.89(s,1H),8.63(s,1H),7.71(s,1H),7.61(d,J=7.8Hz,2H),7.43-7.33(m,2H),7.32-7.25(m,1H),6.70(d,J=10.4Hz,1H),4.23(s,3H),3.71(s,3H),2.26(s,3H),2.13(d,J=12.8Hz,3H),2.06(s,4H),1.84(br.s.,1H),1.65(d,J=19.3Hz,3H),0.66(br.s.,1H)。手性HPLC RT=20.2min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:14%乙醇/庚烷(0.1%DEA);流速:1mL/min)。
实施例90
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体1
LCMS:RT=1.749min;(ES):m/z(M+H)+=581.15(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1HNMR(500MHz,DMSO-d6)δ8.92(s,1H),8.71(s,1H),7.86(s,1H),7.60(d,J=7.7Hz,2H),7.40-7.34(m,2H),7.32-7.26(m,1H),6.71(d,J=10.4Hz,1H),4.24(s,3H),3.77(s,3H),3.72(s,3H),2.17-2.04(m,7H),1.85(br.s.,1H),1.67(d,J=17.8Hz,3H),0.71(d,J=8.6Hz,1H)。手性SFC RT=4.58min(柱:Chiralpak IB,250×4.6mm,5μm;流动相:70/30CO2/MeOH;流速:2mL/min)。
实施例91
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯对映异构体2
LCMS:RT=1.749min;(ES):m/z(M+H)+=581.15(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.92(s,1H),8.71(s,1H),7.86(s,1H),7.60(d,J=7.7Hz,2H),7.40-7.34(m,2H),7.32-7.26(m,1H),6.71(d,J=10.4Hz,1H),4.24(s,3H),3.77(s,3H),3.72(s,3H),2.17-2.04(m,7H),1.85(br.s.,1H),1.67(d,J=17.8Hz,3H),0.71(d,J=8.6Hz,1H)。手性SFC RT=5.45min(柱:Chiralpak IB,250×4.6mm,5μm;流动相:70/30CO2/MeOH;流速:2mL/min)。
实施例92
8-[(S)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-醇
LCMS:RT=1.542min;(ES):m/z(M+H)+=570.2(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1H NMR(500MHz,DMSO-d6)δ8.60(s,1H),8.28(br.s.,1H),7.73(s,1H),7.58(d,J=7.7Hz,3H),7.38(t,J=7.6Hz,3H),7.33-7.28(m,1H),6.54(d,J=10.3Hz,1H),3.74(s,3H),3.58(s,3H),3.32(d,J=11.4Hz,1H),2.22-1.99(m,4H),1.94-1.82(m,1H),1.77-1.56(m,4H),0.74(br.s.,1H)。
实施例93
5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-醇
LCMS:RT=1.13min;(ES):m/z(M+H)+=533.2(柱:Waters Acquity UPLCBEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:历经3min0-100%B且然后在100%B保持0.75min;流速:1.11mL/min)。1HNMR(500MHz,DMSO-d6)δ8.60(s,1H),8.28(s,1H),7.78(s,1H),7.61(d,J=7.7Hz,2H),7.42-7.35(m,2H),7.33-7.27(m,1H),6.56(d,J=10.1Hz,1H),3.88(d,J=9.8Hz,1H),3.75-3.67(m,4H),3.59(s,3H),3.52(t,J=11.4Hz,1H),3.42-3.34(m,1H),3.22(t,J=11.3Hz,1H),2.06(s,3H),1.98(d,J=13.1Hz,1H),1.92(s,1H),1.74-1.53(m,2H),0.48(d,J=11.8Hz,1H)。
实施例94
13-(环丙基甲氧基)-8-[(S)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=0.98min;(ES):m/z(M+H)+=624.3(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。HPLC RT=13.529min(柱:Sunfire C18 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=13.169min(柱:XBridge Phenyl 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.70(d,J=1.8Hz,1H),7.52-7.45(m,2H),7.43-7.33(m,4H),6.93(d,J=9.9Hz,1H),4.81-4.67(m,2H),3.69(s,3H),3.42(s,3H),2.80(d,J=10.3Hz,1H),2.37(d,J=9.8Hz,1H),2.26(br.s.,1H),2.02-1.90(m,3H),1.69-1.53(m,2H),0.95-0.84(m,1H),0.76-0.61(m,3H),0.60-0.52(m,2H)。
实施例95
8-[(S)-(4,4-二氟环己基)(4-氟苯基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=0.90min;(ES):m/z(M+H)+602.2(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。HPLC RT=10.849min(柱:Sunfire C18 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=10.483min(柱:XBridge Phenyl 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.72(d,J=1.8Hz,1H),7.53(dd,J=8.5,5.1Hz,2H),7.46(d,J=1.8Hz,1H),7.12(t,J=8.6Hz,2H),6.91(d,J=10.0Hz,1H),4.44(s,3H),3.79(s,3H),3.46(s,3H),2.78(d,J=9.7Hz,1H),2.37-2.19(m,2H),2.06-1.82(m,3H),1.36-1.23(m,2H),0.60(d,J=9.7Hz,1H)。手性SFC RT=12.40min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。
实施例96
8-[(R)-(4,4-二氟环己基)(4-氟苯基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
LCMS:RT=0.90min;(ES):m/z(M+H)+602.2(Waters Acquity SDS,柱:BEH C182.1×50mm 1.7μ,(1.6min梯度)2-98%B,流速=0.8mL/min,溶剂A:H2O-0.1%TFA,溶剂B:ACN-0.1%TFA)。HPLC RT=10.849min(柱:Sunfire C18 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。HPLC RT=10.483min(柱:XBridge Phenyl 3.5μm,3.0×150mm;流动相A:5:95ACN:水及0.05%TFA;流动相B:95:5ACN:水及0.05%TFA;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm)。1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.72(d,J=1.8Hz,1H),7.53(dd,J=8.5,5.1Hz,2H),7.46(d,J=1.8Hz,1H),7.12(t,J=8.6Hz,2H),6.91(d,J=10.0Hz,1H),4.44(s,3H),3.79(s,3H),3.46(s,3H),2.78(d,J=9.7Hz,1H),2.37-2.19(m,2H),2.06-1.82(m,3H),1.36-1.23(m,2H),0.60(d,J=9.7Hz,1H)。手性SFC RT=14.75min(柱:Chiralcel OD-H 250×4.6mm,5μm;流动相:80/20CO2/MeOH;流速:2mL/min)。
实施例97
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]环丙磺酰胺
向5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(40.0mg,0.073mmol)及环丙磺酰胺(35.5mg,0.293mmol)于NMP(0.50mL)中的搅拌的溶液中添加t-BuOK(20.5mg,0.183mmol)。在95℃加热反应混合物5.5h且然后冷却至室温。用NH4Cl饱和溶液稀释混合物且用EtOAc萃取。合并的EtOAc萃取液经MgSO4干燥,过滤且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:Waters XBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 15-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]环丙磺酰胺(12.2mg,26.2%)。1H NMR(500MHz,DMSO-d6)δ8.97(s,1H),8.76(s,1H),7.98(s,1H),7.63(br d,J=7.4Hz,2H),7.39-7.32(m,2H),7.31-7.24(m,1H),6.68(brd,J=10.1Hz,1H),3.87(br d,J=7.1Hz,1H),3.76(s,3H),3.70(s,1H),3.61(br d,J=10.4Hz,1H),3.53-3.44(m,1H),3.42(br d,J=12.1Hz,1H),3.20(br t,J=11.9Hz,1H),2.54(s,3H),2.06(s,3H),1.96(br d,J=12.5Hz,1H),1.66-1.52(m,3H),1.32(br s,2H),1.17(br d,J=6.7Hz,2H),0.50(br d,J=11.8Hz,1H);LCMS:RT=1.588min;(ES):m/z(M+H)+=636.0;LCMS:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:100%。
实施例98
N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]环丙磺酰胺
向5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(23.0mg,0.042mmol)及乙磺酰胺(90.4mg,0.579mmol)于NMP(1.20mL)中的搅拌的溶液中添加t-BuOK(55.6mg,0.496mmol)。在95℃加热反应混合物14.5h且冷却至室温。用EtOAc稀释混合物且用10%LiCl溶液洗涤。有机层经MgSO4干燥,过滤且浓缩,得到粗物质。其通过快速色谱(Teledyne ISCO CombiFlash,0%至100%溶剂A/B=DCM/(10%MeOH/DCM),RediSepSiO2 24g,在254nm检测且在220nm监测)纯化。浓缩合适的级份,得到不纯的化合物。其通过制备型HPLC进一步纯化(3-LUNA C18 100×30mm;40mL/min;12min 30至80%梯度,在100%保持6min;A:90%水-10%MeOH-0.1%TFA;B:90%MeOH-10%水-0.1%TFA;在220nm检测)。浓缩所需级份且冻干成TFA盐。通过用NaHCO3饱和溶液洗涤将EtOAc中的此TFA盐释放成游离胺碱。浓缩EtOAc层,得到油状物且然后经由制备型LC/MS在以下条件下纯化:柱:WatersXBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 15-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]环丙磺酰胺(6.5mg,6.1%)。1HNMR(500MHz,DMSO-d6)δ8.95(br s,1H),8.69(br s,1H),7.85(br s,1H),7.66(br d,J=7.4Hz,2H),7.36(br t,J=7.6Hz,2H),7.27(br s,1H),6.69(br d,J=10.1Hz,1H),3.90(s,1H),3.87(br s,1H),3.70(br s,1H),3.67(br d,J=11.1Hz,1H),3.55-3.45(m,1H),3.20(br t,J=11.8Hz,1H),2.54(s,3H),2.48-2.46(m,1H),2.27(s,3H),2.07(s,3H),1.98(br d,J=12.5Hz,1H),1.69-1.51(m,2H),1.31(br s,2H),1.15(br s,2H),0.46(br d,J=11.8Hz,1H);LCMS:RT=1.878min;(ES):m/z(M+H)+=636.5;LCMS:柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:98%。
实施例99
N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]乙烷-1-磺酰胺
向5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(23.0mg,0.042mmol)及乙磺酰胺(16.1mg,0.147mmol)于DMF(0.25mL)(注意:若使用NMP代替DMF,则可避免由于在碱中加热由DMF产生副产物)中的搅拌的溶液中添加叔丁醇钾。在95℃加热反应混合物14h且冷却至室温。用盐水稀释混合物且用EtOAc萃取。EtOAc萃取液经MgSO4干燥,过滤且浓缩,得到粗物质。其经由制备型LC/MS在以下条件下纯化:柱:WatersXBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 15-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]乙烷-1-磺酰胺(2.8mg,10.7%)。1H NMR(500MHz,DMSO-d6)δ8.93(br s,1H),8.68(s,1H),7.82(br s,1H),7.64(br d,J=7.4Hz,2H),7.40-7.32(m,2H),7.30-7.24(m,1H),7.23(br s,1H),6.66(br d,J=10.1Hz,1H),3.86(br d,J=6.7Hz,1H),3.65(br s,1H),3.50(br t,J=11.6Hz,1H),3.37(br d,J=11.4Hz,1H),3.19(br t,J=11.6Hz,1H),2.54(s,3H),2.51-2.50(m,2H),2.24(s,3H),2.04(s,3H),1.97(br d,J=12.5Hz,1H),1.66-1.49(m,2H),1.33(t,J=7.2Hz,3H),0.43(br d,J=12.5Hz,1H);LCMS:RT=1.596min;(ES):m/z(M+H)+=625.0;LCMS:柱:Waters AcquityUPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:100%。
实施例100
N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]丙烷-2-磺酰胺
遵循与在N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]乙烷-1-磺酰胺的制备中描述的程序类似的程序将5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯(23.0mg,0.042mmol)及丙烷-2-磺酰胺(18.1mg,0.147mmol)转化成N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]丙烷-2-磺酰胺(2.2mg,7.5%)。1HNMR(500MHz,DMSO-d6)δ8.93(br s,1H),8.69(s,1H),7.83(br s,1H),7.65(br d,J=7.7Hz,2H),7.38-7.32(m,2H),7.31-7.25(m,1H),6.67(brd,J=10.4Hz,1H),3.87(br d,J=8.4Hz,1H),3.65(br d,J=12.8Hz,1H),3.57(br s,1H),3.38(br s,1H),3.19(br t,J=11.1Hz,2H),2.54(s,3H),2.56-2.52(m,1H),2.25(s,3H),2.05(s,3H),1.97(br d,J=11.8Hz,1H),1.60(br t,J=12.5Hz,2H),1.40(br t,J=5.9Hz,6H),0.43(br s,1H);LCMS:RT=1.940min;(ES):m/z(M+H)+=638;LCMS:柱:WatersAcquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:91%。
实施例101
13-(环丙基甲氧基)-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-13-(环丙基甲氧基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(50.0mg,0.094mmol)于环丙基醇(1.20mL,16.8mmol)中的搅拌的溶液中添加t-BuOK(22.0mg,0.196mmol)。在室温搅拌反应混合物21.5h且用EtOAc稀释。用10%LiCl溶液洗涤所得混合物。EtOAc层经MgSO4干燥,过滤且浓缩。粗物质通过快速色谱(Teledyne ISCO CombiFlash,0%至100%溶剂A/B=己烷/EtOAc,RediSep SiO2 12g,在254nm检测且在220nm监测)纯化。浓缩合适的级份,得到5-溴-13-(环丙基甲氧基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(53.4mg,99%)。1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.75(d,J=1.8Hz,1H),7.75(d,J=1.8Hz,1H),7.51-7.45(m,2H),7.43-7.30(m,4H),6.88(d,J=10.0Hz,1H),4.67(s,1H),4.06(dd,J=11.6,2.9Hz,1H),3.78(dd,J=11.7,3.1Hz,1H),3.53(td,J=11.9,1.9Hz,1H),3.27(s,3H),3.26-3.19(m,1H),2.98-2.81(m,1H),2.12(d,J=13.6Hz,1H),1.97-1.83(m,1H),1.58-1.48(m,2H),0.70-0.62(m,2H),0.57-0.49(m,2H),0.39(d,J=12.5Hz,1H);HPLC:RT=3.145min(Chromolith ODS 4.6×50mm,(4min梯度)历经4min用含有0.%TFA的10-90%MeOH水溶液洗脱,4mL/min,在220nm监测);MS(ES):m/z=570.4[M+H]+。
步骤2:13-(环丙基甲氧基)-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯:
用氮气净化5-溴-13-(环丙基甲氧基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25.0mg,0.044mmol)、1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(30.5mg,0.079mmol)及四(三苯基膦)钯(0)(3.8mg,3.29μmol)于DMF(1.0mL)中的搅拌的混合物。在净化时添加碘化亚铜(1.25mg,6.57μmol)及Et3N(0.013mL,0.096mmol)。继续氮气净化5min。在85℃加热混合物4h且冷却至室温。在氮气净化下添加另一批1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(30.5mg,0.079mmol)、Et3N(0.013mL,0.096mmol)、碘化亚铜(1.25mg,6.57μmol)及四(三苯基膦)钯(0)(3.8mg,3.29μmol)。在95℃加热混合物14h且冷却至室温。用1:1MeOH/DCM(10mL)稀释混合物,过滤且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:Waters XBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 15-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到13-(环丙基甲氧基)-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(10.9mg,42.4%)。1H NMR(500MHz,DMSO-d6)δ8.87(s,1H),8.72(s,1H),7.86(s,1H),7.61(br d,J=7.7Hz,2H),7.39-7.31(m,2H),7.31-7.22(m,1H),6.70(br d,J=10.4Hz,1H),4.54(d,J=7.1Hz,2H),3.87(br d,J=9.8Hz,1H),3.64(br s,1H),3.46(br s,1H),3.19(br t,J=11.6Hz,1H),2.54(s,6H),2.06(s,3H),1.97(br d,J=12.8Hz,1H),1.72-1.52(m,2H),1.44(br s,1H),0.60(br d,J=6.7Hz,2H),0.45(br d,J=3.7Hz,3H),0.31-0.30(m,1H);LCMS:RT=1.70min;(ES):m/z(M+H)+=587.4;LCMS:柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:97%。
实施例102
N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺
步骤1:N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}甲磺酰胺
向5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(45.0mg,0.085mmol)及甲磺酰胺(72.6mg,0.764mmol)于DMF(1.00mL)中的搅拌的溶液中添加t-BuOK(60.0mg,0.535mmol)。在95℃加热反应混合物13.5h且冷却至室温。用EtOAc稀释混合物,用10%LiCl溶液洗涤,经MgSO4干燥,过滤且浓缩。通过快速色谱(Teledyne ISCO CombiFlash,0%至100%溶剂A/B=DCM/(10%MeOH/DCM),RediSep SiO2 24g,在254nm检测且在220nm监测)纯化粗物质。浓缩合适的级份,得到N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}甲磺酰胺(24.0mg,47.7%)。1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.64(d,J=1.7Hz,1H),7.82(d,J=1.7Hz,1H),7.56-7.45(m,2H),7.41-7.27(m,3H),6.85(d,J=10.3Hz,1H),6.02(br.s.,1H),4.11-4.00(m,1H),3.87-3.77(m,2H),3.59-3.51(m,1H),3.36(s,3H),3.28(d,J=3.5Hz,1H),2.13(d,J=13.2Hz,1H),1.95-1.79(m,1H),1.60(qd,J=12.4,4.5Hz,1H),0.41(d,J=12.7Hz,1H);HPLC:RT=2.780min(Chromolith ODS 4.6×50mm,(4min梯度)历经4min用含有0.%TFA的10-90%MeOH水溶液洗脱,4mL/min,在220nm监测);MS(ES):m/z=593;595[M+H]+。
步骤2:N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺
向N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}甲磺酰胺(12.0mg,0.020mmol)及(3,5-二甲基异噁唑-4-基)硼酸(5.7mg,0.040mmol)于二噁烷(0.50mL)中的搅拌的溶液中添加2M K3PO4溶液(0.025mL,0.051mmol)。用氮气净化混合物且添加PdCl2(dppf)-CH2Cl2加合物(5.33mg,6.53μmol)且然后加热至95℃且保持1h。冷却的混合物用1:1MeOH/DCM(10mL)稀释,过滤且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:Waters XBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 15-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺(3.5mg,28.4%)。1HNMR(500MHz,DMSO-d6)δ8.93(br s,1H),8.66(br s,1H),7.80(br s,1H),7.65(br d,J=7.4Hz,2H),7.37(br t,J=7.6Hz,2H),7.29(br t,J=7.2Hz,1H),6.68(br d,J=10.1Hz,1H),3.89(s,1H),3.87(br s,1H),3.68(br s,1H),3.58(br s,2H),3.38(br s,1H),3.21(br t,J=11.4Hz,2H),2.58-2.54(m,3H),2.26(s,3H),2.06(s,3H),1.99(br d,J=12.8Hz,1H),1.71-1.55(m,2H),0.44(br d,J=12.5Hz,1H);LCMS:RT=1.75min;(ES):m/z(M+H)+=610.3;LCMS:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:96%。
实施例103
13-(环丙基甲氧基)-5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与在N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺的步骤2的制备中描述的程序类似的程序将5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(25.0mg,0.044mmol)及(3,5-二甲基异噁唑-4-基)硼酸(12.4mg,0.088mmol)转化成13-(环丙基甲氧基)-5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(15.7mg,61.1%)。1H NMR(500MHz,DMSO-d6)δ8.84(s,1H),8.64(s,1H),7.69(s,1H),7.61(br d,J=7.7Hz,2H),7.37-7.31(m,2H),7.29-7.23(m,1H),6.69(br d,J=10.4Hz,1H),4.53(d,J=7.1Hz,2H),3.87(br d,J=14.1Hz,1H),3.67(s,3H),3.19(brt,J=11.4Hz,1H),2.54(s,3H),2.24(s,3H),2.04(s,3H),1.98(br s,1H),1.67(br d,J=10.1Hz,1H),1.56(br d,J=8.4Hz,1H),1.44(br s,1H),0.60(br d,J=6.7Hz,2H),0.45(br d,J=4.4Hz,2H),0.38(br d,J=12.1Hz,1H);LCMS:RT=1.84min;(ES):m/z(M+H)+=587.2;LCMS:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:100%。
实施例104
1-环丙基-N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺
步骤1:N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}-1-环丙基甲磺酰胺
遵循与在N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}甲磺酰胺的制备中描述的程序类似的程序将5-溴-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(40.0mg,0.075mmol)及环丙基甲磺酰胺(88.0mg,0.651mmol)转化成N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}-1-环丙基甲磺酰胺(50.0mg,定量产量)。1H NMR(400MHz,CDCl3)δ10.15(br s,1H),9.05(s,1H),8.63(d,J=1.7Hz,1H),7.80(d,J=1.8Hz,1H),7.52-7.43(m,2H),7.43-7.30(m,3H),6.84(d,J=10.0Hz,1H),4.08-3.99(m,1H),3.81(br dd,J=11.7,3.2Hz,1H),3.74(d,J=7.2Hz,1H),3.60-3.48(m,1H),3.33(s,3H),3.04(d,J=7.2Hz,2H),2.11(br d,J=13.4Hz,1H),1.92-1.81(m,1H),1.57(qd,J=12.4,4.4Hz,1H),1.34-1.22(m,1H),1.21-1.12(m,1H),0.76-0.64(m,2H),0.45-0.37(m,2H);HPLC:RT=3.058min(Chromolith ODS 4.6×50mm,(4min梯度)历经4min用含有0.%TFA的10-90%MeOH水溶液洗脱,4mL/min,在220nm监测);MS(ES):m/z=633;635[M+H]+。
步骤2:1-环丙基-N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺
遵循与在13-(环丙基甲氧基)-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的步骤2的制备中描述的程序类似的程序将N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}-1-环丙基甲磺酰胺(25.0mg,0.039mmol)及1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(27.4mg,0.071mmol)转化成1-环丙基-N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺(2.9mg,11.3%)。1HNMR(500MHz,DMSO-d6)δ8.97(br s,1H),8.79(br s,1H),8.03(br s,1H),7.66(br d,J=7.4Hz,2H),7.38-7.32(m,3H),7.30-7.25(m,1H),6.69(br d,J=10.1Hz,1H),3.89(s,1H),3.87(br s,1H),3.78(s,3H),3.72(br s,2H),3.67(br d,J=8.8Hz,1H),3.47(br s,1H),3.20(br t,J=11.4Hz,1H),2.54(s,3H),2.08(s,3H),1.95(br d,J=12.5Hz,1H),1.62(brd,J=8.4Hz,2H),1.15(br s,1H),0.57(br d,J=6.1Hz,2H),0.50(br d,J=12.1Hz,1H),0.35(br d,J=4.0Hz,2H);LCMS:RT=1.698min;(ES):m/z(M+H)+=650.2;LCMS:柱:WatersAcquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:100%。
实施例105
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺
遵循与在1-环丙基-N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺的制备中描述的程序类似的程序将N-{5-溴-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}甲磺酰胺(12.0mg,0.020mmol)及1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(14.5mg,0.036mmol)转化成N-[5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]甲磺酰胺(3.2mg,26.0%)。1H NMR(500MHz,DMSO-d6)δ8.98(br s,1H),8.77(br s,1H),7.99(br s,1H),7.64(br d,J=7.7Hz,2H),7.40-7.32(m,2H),7.31-7.22(m,1H),6.69(br d,J=10.1Hz,1H),3.89(s,1H),3.86(br s,1H),3.77(s,3H),3.72-3.61(m,2H),3.20(br t,J=11.3Hz,1H),2.54(s,1H),2.07(s,6H),1.96(br d,J=12.5Hz,1H),1.62(br s,2H),0.49(br d,J=12.5Hz,1H);LCMS:RT=1.418min;(ES):m/z(M+H)+=610.05;LCMS:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:100%。
实施例106
3-({[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基]磺酰基}甲基)氧杂环丁烷-3-醇
在氮气下在室温向5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(24.0mg,0.044mmol)于THF(1.50mL)中的搅拌的溶液中添加1M KHMDS/THF(0.077mL,0.077mmol)。在室温搅拌混合物15min且添加氧杂环丁烷-3-酮(11.2mg,0.155mmol)。将所得混合物在室温再搅拌10min且倾入MeOH(10mL)中。浓缩混合物且经由制备型LC/MS在以下条件下纯化:柱:Waters XBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 15-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到3-({[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基]磺酰基}甲基)氧杂环丁烷-3-醇(11.3mg,41.6%)。1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.68(s,1H),7.79(s,1H),7.59(d,J=7.7Hz,2H),7.38-7.32(m,2H),7.31-7.23(m,1H),6.70(d,J=10.1Hz,1H),6.37(s,1H),4.75(d,J=6.7Hz,1H),4.59(d,J=6.7Hz,1H),4.48(d,J=7.1Hz,1H),4.42(d,J=6.7Hz,1H),4.27(s,1H),4.23(s,3H),4.13(d,J=14.5Hz,1H),3.91-3.84(m,1H),3.72(s,3H),3.64(d,J=8.4Hz,1H),3.18(t,J=11.8Hz,1H),2.54(s,5H),1.98(br.s.,1H),1.78-1.66(m,1H),1.60-1.47(m,1H),0.42(d,J=12.1Hz,1H);LCMS:RT=1.25min;(ES):m/z(M+H)+=619.3;LCMS:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.11mL/min。在220nm的HPLC纯度:98%。
实施例107
10-甲磺酰基-13-甲氧基-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向干燥的经氮气冲洗的1打兰瓶中装入四甲基乙酸铵(30.1mg,0.226mmol)、二(三苯基膦)二氯化钯(II)(7.94mg,0.011mmol)及(S)-3-溴-9-甲氧基-6-(甲磺酰基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(60.0mg,0.113mmol)。向其中添加4-甲氧基-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑(41.9mg,0.226mmol)。瓶再次用氮气冲洗。向其中添加N-甲基-2-吡咯烷酮(0.8ml)。在氮气气流下剧烈搅拌所得混合物10min。将瓶置于在95℃预加热的油浴中且加热过夜。添加四甲基乙酸铵(30.1mg,0.226mmol)且在95℃再加热反应混合物30min。冷却反应混合物至室温,用乙酸乙酯稀释,先后用饱和氯化铵、水和盐水洗涤,经硫酸镁干燥,过滤且浓缩。通过制备型HPLC(柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经30min 20-50%B且然后在100%B保持5min;流速:20mL/min)纯化残余物,得到39.4mg(62%)。1H NMR(500MHz,DMSO-d6)δ8.91(s,1H),8.74(s,1H),7.94(brs,1H),7.65(d,c,2H),7.38(m,2H),7.31(m,1H),6.72(d,3.92(d,J=10.3Hz,1H),4.24(s,3H),3.97(s,3H),3.89(d,J=9.2Hz,1H),3.8(s,3H),3.71(s,3H),3.64(d,J=10.3Hz,1H),3.54-3.33(m,2H),3.18(t,J=11.2Hz,1H),2.0(d,J=13.6Hz,1H),1.61(m,2H),0.35(d,J=12.8Hz,1H);LCMS(M+H)+=365.5。
实施例108
10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-13-(2-甲基丙氧基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向2打兰压力瓶中装入10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.036mmol)及KOtBu(20.41mg,0.182mmol)。在室温向该混合物中添加2-甲基-1-丙醇(500μl,5.40mmol)。2.5h后,用几滴1.0N HCl淬灭反应混合物且通过制备型HPLC纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。收集级份,得到7.2mg(33%产率)产物。1H NMR(500MHz,DMSO-d6)δ8.89(s,1H),8.74(s,1H),7.87(s,1H),7.63(d,J=7.7Hz,2H),7.39-7.32(m,2H),7.32-7.25(m,1H),6.72(d,J=10.6Hz,1H),4.47(d,J=3.7Hz,2H),3.88(d,J=11.4Hz,1H),3.76(s,3H),3.72-3.62(m,4H),3.56-3.47(m,1H),3.43(d,J=11.4Hz,1H),3.21(t,J=12.5Hz,1H),2.23(dt,J=13.0,6.7Hz,1H),1.98(d,J=11.7Hz,1H),1.76-1.55(m,2H),1.09(d,J=6.2Hz,6H),0.46(d,J=11.7Hz,1H)。质谱实测值:592(M+H)+。
实施例109
10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-[(2R)-氧杂环戊烷-2-基甲氧基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-13-(2-甲基丙氧基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由(R)-(-)-四氢糠醇制备标题化合物,得到8.6mg(38%产率)产物。1HNMR(400MHz,CDCl3)δ8.98(s,1H),8.65(d,J=1.8Hz,1H),7.51-7.44(m,2H),7.44-7.30(m,4H),6.91(d,J=9.8Hz,1H),4.90-4.81(m,2H),4.61-4.53(m,1H),4.11-3.99(m,2H),3.92-3.84(m,1H),3.83-3.74(m,1H),3.69(s,3H),3.54(t,J=11.2Hz,1H),3.38(s,3H),3.27-3.16(m,1H),3.01-2.88(m,1H),2.26-2.08(m,1H),2.05-1.83(m,1H),1.62(qd,J=12.4,4.3Hz,2H),0.94-0.79(m,3H),0.40(d,J=12.8Hz,1H)。手性HPLC:Chiralpak ID柱,60%MeOH,2mL/min,150巴,温度:35℃,流速:40mL/min持续17min,在UV 252nm监测,注射:0.25mL约6mg/mL于MeOH中(12mg通过堆迭注射纯化)。SFC RT:11min。质谱实测值:620(M+H)+。
实施例110
10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-[(2S)-氧杂环戊烷-2-基甲氧基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-13-(2-甲基丙氧基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由四氢糠醇制备标题化合物,得到5.9mg(26%产率)产物。在最后步骤中产生的非对映异构体通过手性SFC分离。Chiralpak ID制备型柱,21×250mm,5μm粒径,流动相:60%MeOH/CO2,130巴,温度:35℃,流速:40mL/min持续17min,在UV 252nm监测,注射:0.25mL约6mg/mL于MeOH中。1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.66(d,J=1.8Hz,1H),7.50-7.45(m,2H),7.43-7.31(m,4H),6.91(d,J=9.8Hz,1H),4.91(dd,J=11.3,3.8Hz,1H),4.81-4.74(m,1H),4.58(qd,J=6.8,3.8Hz,1H),4.13-3.98(m,2H),3.93-3.83(m,1H),3.82-3.74(m,2H),3.69(s,3H),3.60-3.48(m,1H),3.38(s,3H),3.21(t,J=11.0Hz,1H),3.02-2.87(m,1H),2.27-2.08(m,2H),2.05-1.88(m,1H),1.71-1.51(m,2H),0.95-0.77(m,3H),0.39(d,J=13.3Hz,1H)。手性SFC RT:13.5min。质谱实测值:620(M+H)+。
实施例111
10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(氧杂环丁烷-3-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:13-氯-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向24/40-50mL圆底烧瓶中装入10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(336mg,0.611mmol)及溶解于DMF(6113μl)中。向该溶液中添加POCl3(570μl,6.11mmol)。将烧瓶置于预加热至80℃的油浴中且排气于部分填充有氮气的气囊中。1.5h后,将反应混合物倾至冰上且用乙酸乙酯稀释。用固体碳酸氢钠缓慢淬灭反应混合物。将溶液转移至分液漏斗中且分离各层且用水洗涤有机相。用乙酸乙酯萃取水相且弃去水相。用盐水洗涤合并的有机相,经硫酸镁干燥,过滤,减压浓缩且通过快速色谱纯化:24g ISCO RediSep Rf,在DCM中/用DCM加载且干燥,级份大小:9mL13×100mm且用丙酮/DCM 0%[75mL]、0-25%[250mL]、25%[200mL]、25-100%[400mL]洗脱。收集级份,得到282mg(83%产率)。1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.77(d,J=1.8Hz,1H),7.55-7.52(m,1H),7.52-7.47(m,2H),7.46-7.34(m,3H),6.97(d,J=10.0Hz,1H),4.11-4.04(m,1H),3.85-3.77(m,1H),3.72(s,3H),3.59-3.50(m,1H),3.48(s,3H),3.29-3.18(m,1H),3.04-2.89(m,1H),2.26-2.13(m,1H),2.06-1.92(m,1H),1.71-1.59(m,1H),0.37(d,J=13.3Hz,1H)。质谱实测值:555(M+H)+。
步骤2:10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(氧杂环丁烷-3-基氧基)-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯
向2打兰压力瓶中装入13-氯-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(38mg,0.069mmol)及KOtBu(38.5mg,0.343mmol)。向该混合物中添加氧杂环丁烷-3-醇(750μl,11.82mmol)。2h后,用氮气气流蒸发挥发物。用2mL甲醇稀释混合物,经由0.45μ针筒头过滤器过滤且通过制备型HPLC纯化:柱:Waters XBridgeC18 100×30mm 5μ,溶剂A:95:5水/ACN,B:95:5ACN/水,缓冲剂:10mM NH4OAc,%B:33%等度(10min),流速:30mL/min,4次注射,在254nm监测。在Speed Vacuum上浓缩含有产物的级份过夜。经由用DCM洗涤的小硅胶塞过滤产物且用丙酮洗脱,得到18.5mg(45%产率)产物。1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.67(d,J=1.8Hz,1H),7.52-7.46(m,3H),7.43-7.31(m,3H),6.93(d,J=9.8Hz,1H),6.02(quin,J=6.0Hz,1H),5.19-5.11(m,2H),5.04(ddd,J=9.8,7.5,5.8Hz,2H),4.07(dd,J=11.9,2.6Hz,1H),3.79(dd,J=11.8,3.0Hz,1H),3.71(s,3H),3.53(t,J=11.0Hz,1H),3.38(s,3H),3.22(td,J=11.9,2.0Hz,1H),3.03-2.88(m,1H),2.24-2.12(m,1H),2.06-1.90(m,1H),1.69-1.60(m,1H),0.38(d,J=12.3Hz,1H)。质谱实测值:592(M+H)+。
实施例112
13-(2,2-二氟乙氧基)-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:13-(2,2-二氟乙氧基)-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(氧杂环丁烷-3-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由2,2-二氟乙醇制备标题化合物,得到5.7mg(23%产率)产物。1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.70(d,J=1.8Hz,1H),7.51-7.45(m,3H),7.44-7.33(m,3H),6.93(d,J=10.0Hz,1H),6.59-6.25(m,1H),5.17-4.97(m,2H),4.08(d,J=9.0Hz,1H),3.85-3.75(m,1H),3.70(s,3H),3.54(t,J=11.0Hz,1H),3.41(s,3H),3.28-3.16(m,1H),3.03-2.90(m,1H),2.27-2.14(m,1H),2.08-1.91(m,1H),1.71-1.54(m,1H),0.39(d,J=12.8Hz,1H)。质谱实测值:600(M+H)+。
实施例113
N-[(1S)-1-环丙基乙基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
向1打兰压力瓶中装入13-氯-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(17.3mg,0.031mmol)且溶解于DMSO(250μL)中。向该溶液中添加(S)-1-环丙基乙胺(53.2mg,0.624mmol)。2h后,用500μL甲醇稀释混合物,经由0.45μ针筒头过滤器过滤且通过制备型HPLC纯化:柱:Waters XBridge C18 100×30mm 5μ,溶剂A:95:5水/ACN,B:95:5ACN/水,缓冲剂:10mM NH4OAc,%B梯度52%(15min),流速:30mL/min,1次注射,在254nm监测。在Speed Vacuum上浓缩含有产物的级份过夜。经由用DCM洗涤的小硅胶塞过滤产物且用丙酮洗脱,得到17.2mg(91%产率)。1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.47(d,J=1.8Hz,1H),8.16(d,J=8.3Hz,1H),7.49(d,J=7.8Hz,2H),7.42-7.30(m,4H),6.89(d,J=10.0Hz,1H),4.14-4.00(m,2H),3.83(dd,J=11.5,3.3Hz,1H),3.70(s,3H),3.59-3.48(m,1H),3.32(s,3H),3.24(td,J=11.9,1.8Hz,1H),3.01-2.87(m,1H),2.22-2.12(m,1H),2.07-1.85(m,1H),1.75-1.58(m,1H),1.48(d,J=6.8Hz,3H),0.69-0.46(m,5H),0.41(dq,J=9.1,4.7Hz,1H)。质谱实测值:603(M+H)+。
实施例114
N-[(1R)-1-环丙基乙基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对N-[(1S)-1-环丙基乙基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺的合成所描述的程序类似的程序由(R)-1-环丙基乙胺半硫酸盐制备标题化合物,得到6.8mg(52%产率)产物。1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.48(d,J=1.8Hz,1H),8.15(d,J=8.3Hz,1H),7.50(d,J=7.8Hz,2H),7.42-7.29(m,4H),6.89(d,J=10.0Hz,1H),4.16-4.02(m,2H),3.86-3.77(m,1H),3.69(s,3H),3.53(td,J=11.9,1.8Hz,1H),3.32(s,3H),3.28-3.19(m,1H),3.00-2.87(m,1H),2.21-2.13(m,1H),2.02-1.87(m,1H),1.73-1.62(m,1H),1.50(d,J=6.5Hz,3H),0.66-0.44(m,5H),0.42-0.34(m,1H)。质谱实测值:603(M+H)+。
实施例115
N-乙基-10-甲磺酰基-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对N-[(1S)-1-环丙基乙基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺的合成所描述的程序类似的程序由N-乙基甲胺制备标题化合物,得到14.8mg(93%产率)产物。1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.51(d,J=2.0Hz,1H),7.49(d,J=7.8Hz,2H),7.41-7.30(m,4H),6.93(d,J=9.8Hz,1H),4.11-3.98(m,3H),3.84-3.76(m,1H),3.68(s,3H),3.53(td,J=11.9,1.8Hz,1H),3.46(s,3H),3.34(s,3H),3.23(td,J=11.9,1.9Hz,1H),3.01-2.89(m,1H),2.24-2.12(m,1H),2.06-1.88(m,1H),1.73-1.59(m,1H),1.38(t,J=7.0Hz,3H),0.46(d,J=12.8Hz,1H)。质谱实测值:577(M+H)+。
实施例116
10-甲磺酰基-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-N-(丙-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对N-[(1S)-1-环丙基乙基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺的合成所描述的程序类似的程序由N-异丙基甲胺制备标题化合物,得到15.7mg(96%产率)产物。1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.51(d,J=2.0Hz,1H),7.48(d,J=7.8Hz,2H),7.41-7.29(m,4H),6.91(d,J=9.8Hz,1H),5.13(spt,J=6.7Hz,1H),4.06(dd,J=11.5,2.8Hz,1H),3.85-3.76(m,1H),3.67(s,3H),3.53(td,J=11.9,1.6Hz,1H),3.35(s,3H),3.29(s,3H),3.23(td,J=11.9,2.0Hz,1H),3.02-2.89(m,1H),2.23-2.13(m,1H),2.06-1.89(m,1H),1.73-1.59(m,1H),1.41(dd,J=6.5,2.8Hz,6H),0.46(d,J=13.1Hz,1H)。质谱实测值:591(M+H)+。
实施例117
N-(2,2-二氟乙基)-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对N-[(1S)-1-环丙基乙基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺的合成所描述的程序类似的程序由2,2-二氟乙胺制备标题化合物,得到18.4mg(56%产率)产物。1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.49(d,J=1.8Hz,1H),8.25(t,J=6.4Hz,1H),7.53-7.46(m,2H),7.44-7.30(m,4H),6.90(d,J=10.0Hz,1H),6.32-5.96(m,1H),4.25(tdd,J=14.5,6.3,4.0Hz,2H),4.07(dd,J=11.7,2.6Hz,1H),3.82(dd,J=11.7,3.1Hz,1H),3.70(s,3H),3.58-3.49(m,1H),3.34(s,3H),3.24(td,J=11.9,1.8Hz,1H),3.01-2.87(m,1H),2.21-2.13(m,1H),2.00-1.86(m,1H),1.73-1.56(m,1H),0.45(d,J=12.5Hz,1H)。质谱实测值:599(M+H)+。
实施例118及119
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶
向10-20mL微波瓶中装入1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(650mg,1.68mmol)且用DMF(7019μl)稀释。向该溶液中添加3-溴-9-甲氧基-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(500mg,1.40mmol)、碘化亚铜(I)(40.1mg,0.211mmol)、三乙胺(293μl,2.11mmol)及Pd(Ph3P)4(122mg,0.105mmol)。将瓶密封且使用超纯氩气及超声波处理脱气2分钟。将瓶置于预加热至80℃的油浴中。1.5h后,经由硅藻土垫过滤温热的反应混合物且减压浓缩。将所得固体混悬于DCM中且通过过滤收集。先后用少量DCM和几倍体积的己烷洗涤滤饼,得到165mg所需产物。将上清液直接加载至柱上且通过快速色谱纯化:24gISCO RediSep Rf,在DCM中/用DCM加载且干燥,级份大小:9mL 13×100mm且用甲醇/DCM0%[75mL]、0-4%[201mL]、4%[201mL]、4-10%[200mL]洗脱。减压浓缩含有产物的级份且与先前过滤的物质合并,得到370mg(71%产率)。1H NMR(400MHz,CDCl3)δ9.88(s,1H),8.75(d,J=2.0Hz,1H),8.72(s,1H),7.83(d,J=2.0Hz,1H),4.41(s,3H),4.04(s,3H),3.27(s,3H),2.40(s,3H)。质谱实测值:373(M+H)+。
步骤2:5-((4,4-二氟环己基)(苯基)甲基)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶
向24/40-50mL圆底烧瓶中装入三苯基膦(423mg,1.61mmol)且溶解于THF(4028μl)中。冷却混合物至0℃且一次性添加偶氮二甲酸二叔丁酯(371mg,1.61mmol)。30min后,形成粘稠乳状固体且添加(4,4-二氟环己基)(苯基)甲醇(365mg,1.61mmol)。20min后,添加呈固体状的3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(300mg,0.806mmol)。使用4mL THF将剩余的咔啉洗涤至反应混合物中。1h后,添加TFA(621μl,8.06mmol)且搅拌混合物30min且减压浓缩。用乙酸乙酯稀释黄色油状物且用1.5M磷酸三钾溶液淬灭且转移至分液漏斗中。分离各层。粘稠乳液存留且通过过滤收集,得到65mg所需产物。用水及盐水洗涤有机相,经硫酸镁干燥,过滤,减压浓缩且通过快速色谱纯化:40g ISCO RediSep Rf,在DCM中/用DCM加载且干燥,级份大小:21mL 16×150mm且用丙酮/DCM 0%[102mL]、0-30%[400mL]、30%[400mL]、30-100%[400mL]洗脱。收集级份且合并多批,得到343mg(73.3%产率)产物。1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.69(d,J=2.0Hz,1H),7.51-7.45(m,2H),7.44-7.34(m,4H),6.92(d,J=10.0Hz,1H),4.43(s,3H),3.68(s,3H),3.42(s,3H),2.77(br.s.,1H),2.35(br.s.,1H),2.30-2.18(m,1H),2.14(s,3H),2.00-1.83(m,3H),1.71-1.42(m,2H),0.57(br.s.,1H)。质谱实测值:581(M+H)+。
步骤3:9-氯-5-((4,4-二氟环己基)(苯基)甲基)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶
向24/40-100mL圆底烧瓶中装入(S)-5-((4,4-二氟环己基)(苯基)甲基)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(343mg,0.591mmol)且溶解于DMF(1737μL)中且添加POCl3(50μL,0.536mmol)。将烧瓶置于预加热至80℃的反应区块中。2h后,将混合物倾至冰上且用乙酸乙酯稀释。用固体碳酸氢钠缓慢淬灭反应混合物。将经淬灭的溶液转移至分液漏斗中且分离各层。用水洗涤有机相。用乙酸乙酯萃取水相且弃去水相。用盐水洗涤合并的有机相,经硫酸镁干燥,过滤且减压浓缩。在试图将产物溶解于DCM中以加载至柱上时,白色固体存留。通过过滤收集固体且NMR显示其为所需产物。浓缩上清液且再重复研磨过程三次,得到合并产量的197mg纯产物。通过快速色谱纯化上清液:24g ISCO RediSep Rf,在DCM中/用DCM加载且干燥,级份大小:9mL13×100mm且用乙酸乙酯/DCM 0%[102mL]、0-30%[252mL]、30%[300mL]、30-100%[252mL]洗脱。收集级份,得到70mg所需产物,将其与先前收集的批料合并,得到267mg(77%产率)产物。1H NMR(400MHz,CDCl3)δ9.10(s,1H),8.77(d,J=1.8Hz,1H),7.52-7.46(m,3H),7.46-7.33(m,3H),6.96(d,J=10.0Hz,1H),3.70(s,3H),3.50(s,3H),2.79(br.s.,1H),2.36(br.s.,1H),2.26(br.s.,1H),2.15(s,3H),2.01-1.88(m,3H),1.75-1.56(m,2H),0.59(d,J=14.3Hz,1H)。质谱实测值:585(M+H)+。
步骤4:8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向1打兰压力瓶中装入2-丙醇(500μl,6.49mmol)。添加KOtBu(96mg,0.855mmol)且搅拌30min。添加9-氯-5-((4,4-二氟环己基)(苯基)甲基)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(50mg,0.085mmol),然后添加NMP(500μL)。10min后,用碳酸氢钠饱和溶液淬灭混合物且用DCM稀释。分离各层且用水及盐水洗涤有机相且弃去水相。用盐水洗涤合并的有机相,经硫酸镁干燥,过滤,在高真空压力下浓缩且通过制备型HPLC纯化。粗物质质量:44mg。将粗物质溶解于2mL NMP中。柱:WatersXBridge C18 100×30mm 5μ,溶剂A:95:5水/ACN,B:95:5ACN/水,缓冲剂:10mM NH4OAc,%B梯度50%(13min),流速:30mL/min,产物RT:10.45min,4次注射,在254nm监测。在SpeedVacuum上浓缩含有产物的级份过夜,得到36mg外消旋产物。通过手性SFC分离外消旋混合物:Chiralcel OD-H制备型柱,30×250mm,5μm粒径,流动相:20%MeOH/CO2,130巴,温度:35℃,流速:70mL/min持续15min,在UV 220nm监测,注射:0.35mL约7mg/mL于1:1CHCl3:MeOH中(36mg通过堆迭注射纯化),得到对映异构体A(15.2mg,29%产率)及对映异构体B(13.5mg,26%产率)。对映异构体A:1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.65(d,J=2.0Hz,1H),7.50-7.43(m,2H),7.42-7.31(m,4H),6.90(d,J=9.8Hz,1H),5.84(spt,J=6.3Hz,1H),3.65(s,3H),3.40(s,3H),2.85-2.72(m,1H),2.40-2.32(m,1H),2.29-2.21(m,1H),2.12(s,3H),2.03-1.87(m,3H),1.72-1.60(m,4H),0.67-0.58(m,1H)。SFC RT:10.95min。质谱实测值:609(M+H)+。对映异构体B:1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.65(d,J=1.8Hz,1H),7.49-7.43(m,2H),7.42-7.31(m,4H),6.90(d,J=10.0Hz,1H),5.84(spt,J=6.2Hz,1H),3.69-3.63(m,3H),3.40(s,3H),2.85-2.71(m,1H),2.36(d,J=10.0Hz,1H),2.29-2.21(m,1H),2.12(s,3H),2.02-1.84(m,3H),1.69-1.62(m,4H),0.68-0.58(m,1H)。SFC RT:13min。质谱实测值:609(M+H)+。
实施例120及121
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(3-甲氧基氮杂环丁烷-1-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由3-甲氧基氮杂环丁烷HCl制备标题化合物,得到33mg外消旋产物。通过手性SFC分离对映异构体:Chiralcel OD-H制备型柱,30×250mm,5μm粒径,流动相:20%MeOH/CO2,150巴,温度:35℃,流速:70mL/min持续39min,在UV 220nm监测,注射:0.75mL约8mg/mL于1:1CHCl3:MeOH中(33mg通过堆迭注射纯化),得到对映异构体A(13.2mg,40%产率)及对映异构体B(13mg,39%产率)。对映异构体A:1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.44(d,J=1.8Hz,1H),7.49-7.43(m,2H),7.42-7.28(m,4H),6.91(d,J=9.8Hz,1H),5.23-4.75(m,2H),4.72-4.46(m,2H),4.42(tt,J=6.3,4.2Hz,1H),3.65(s,3H),3.41(s,3H),3.34(s,3H),2.83-2.71(m,J=9.8Hz,1H),2.34(d,J=9.8Hz,1H),2.22(d,J=13.6Hz,1H),2.16(s,3H),2.04-1.79(m,3H),1.75-1.57(m,2H),0.65(d,J=10.5Hz,1H)。SFC RT:25min。质谱实测值:636(M+H)+。对映异构体B:1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.44(d,J=1.8Hz,1H),7.49-7.43(m,2H),7.42-7.28(m,4H),6.91(d,J=9.8Hz,1H),5.23-4.75(m,2H),4.75-4.45(m,2H),4.42(tt,J=6.3,4.1Hz,1H),3.65(s,3H),3.41(s,3H),3.34(s,3H),2.84-2.69(m,J=9.5Hz,1H),2.39-2.29(m,1H),2.28-2.18(m,1H),2.16(s,3H),2.02-1.80(m,3H),1.74-1.61(m,2H),0.65(d,J=10.8Hz,1H)。SFC RT:33.75min。质谱实测值:636(M+H)+。
实施例122及123
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-N-(丙-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由异丙胺制备标题化合物,得到30mg外消旋产物。通过手性SFC分离对映异构体:Chiralcel OD-H制备型柱,30×250mm,5μm粒径,流动相:20%MeOH/CO2,130巴,温度:35℃,流速:70mL/min持续19min,在UV 220nm监测,注射:0.35mL约11mg/mL于1:1CHCl3:MeOH中(23mg通过堆迭注射纯化),得到对映异构体A(11.6mg,31%产率)及对映异构体B(11.8mg,31%产率)。对映异构体A:1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.46(d,J=1.5Hz,1H),8.00(d,J=7.8Hz,1H),7.51-7.45(m,2H),7.43-7.30(m,4H),6.88(d,J=9.8Hz,1H),4.75-4.65(m,1H),3.67(s,3H),3.33(s,3H),2.77(d,J=10.5Hz,1H),2.33(d,J=9.3Hz,1H),2.27-2.13(m,4H),2.04-1.81(m,3H),1.77-1.63(m,2H),1.46(dd,J=8.5,6.5Hz,6H),0.73-0.62(m,1H)。SFC RT:12.6min。质谱实测值:608(M+H)+。对映异构体B:1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.46(d,J=1.8Hz,1H),8.00(d,J=8.0Hz,1H),7.51-7.45(m,2H),7.42-7.29(m,4H),6.88(d,J=10.0Hz,1H),4.75-4.64(m,1H),3.67(s,3H),3.33(s,3H),2.77(d,J=10.5Hz,1H),2.33(d,J=9.5Hz,1H),2.28-2.13(m,4H),2.05-1.80(m,3H),1.76-1.62(m,2H),1.46(dd,J=8.5,6.5Hz,6H),0.74-0.63(m,1H)。SFC RT:15.5min。质谱实测值:608(M+H)+。
实施例124及125
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-N-(2-甲基丙基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由异丁胺制备标题化合物,得到19.6mg外消旋产物。通过手性SFC分离对映异构体:Chiralcel OD-H制备型柱,30×250mm,5μm粒径,流动相:20%MeOH/CO2,150巴,温度:35℃,流速:70mL/min持续18min,在UV 220nm监测,注射:0.25mL约7mg/mL于MeOH中(20mg通过堆迭注射纯化),得到对映异构体A(7.8mg,20.6%产率)及对映异构体B(9.8mg,26%产率)。对映异构体A:1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.46(d,J=1.8Hz,1H),8.22(t,J=5.9Hz,1H),7.51-7.45(m,2H),7.43-7.36(m,2H),7.36-7.30(m,2H),6.89(d,J=9.8Hz,1H),3.70-3.65(m,5H),3.34(s,3H),2.84-2.71(m,J=9.8Hz,1H),2.33(d,J=8.0Hz,1H),2.23(d,J=11.0Hz,1H),2.17(s,3H),2.05-1.82(m,4H),1.77-1.60(m,2H),1.12(d,J=6.5Hz,6H),0.73-0.64(m,1H)。SFC RT:12.9min。质谱实测值:622(M+H)+。对映异构体B:1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.46(d,J=1.5Hz,1H),8.22(t,J=5.9Hz,1H),7.52-7.46(m,2H),7.42-7.36(m,2H),7.36-7.30(m,2H),6.89(d,J=10.3Hz,1H),3.70-3.65(m,5H),3.34(s,3H),2.84-2.71(m,J=9.0Hz,1H),2.38-2.30(m,1H),2.29-2.22(m,1H),2.17(s,3H),2.05-1.83(m,4H),1.76-1.63(m,2H),1.12(d,J=6.5Hz,6H),0.76-0.66(m,1H)。SFC RT:14.5min。质谱实测值:622(M+H)+。
实施例126及127
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-N-甲基-N-(丙-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由N-异丙基甲胺制备标题化合物,得到30.3mg外消旋产物。通过手性SFC分离对映异构体:Chiralcel OD-H制备型柱,30×250mm,5μm粒径,流动相:35%MeOH/CO2,150巴,温度:35℃,流速:70mL/min持续12min,在UV220nm监测,注射:0.5mL约10mg/mL于MeOH中(30mg通过堆迭注射纯化),得到对映异构体A(14.4mg,44.5%产率)及对映异构体B(14.5mg,44.8%产率)。对映异构体A:1H NMR(400MHz,CDCl3)δ8.88(s,1H),8.51(d,J=2.0Hz,1H),7.50-7.43(m,2H),7.41-7.35(m,2H),7.35-7.31(m,2H),6.90(d,J=9.8Hz,1H),5.13(spt,J=6.6Hz,1H),3.65(s,3H),3.37(s,3H),3.29(s,3H),2.85-2.72(m,1H),2.40-2.30(m,1H),2.28-2.20(m,1H),2.16(s,3H),2.05-1.91(m,3H),1.77-1.61(m,2H),1.41(t,J=6.3Hz,6H),0.67(d,J=13.3Hz,1H)。SFCRT:16.1min。质谱实测值:622(M+H)+。对映异构体B:1H NMR(400MHz,CDCl3)δ8.88(s,1H),8.51(d,J=1.8Hz,1H),7.50-7.43(m,2H),7.41-7.35(m,2H),7.35-7.30(m,2H),6.90(d,J=9.8Hz,1H),5.13(spt,J=6.6Hz,1H),3.67-3.62(m,3H),3.37(s,3H),3.29(s,3H),2.78(s,1H),2.40-2.30(m,1H),2.24(br.s.,1H),2.16(s,3H),2.05-1.89(m,3H),1.76-1.62(m,2H),1.41(t,J=6.4Hz,6H),0.67(s,1H)。SFC RT:18.6min。质谱实测值:622(M+H)+。
实施例128
13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-2’-甲氧基-3-硝基-2,3’-联吡啶
向24/40-200mL圆底烧瓶中装入2,5-二溴-3-硝基吡啶(3.54g,12.6mmol)、(2-甲氧基吡啶-3-基)硼酸(2.017g,13.2mmol)及PdCl2(dppf)-CH2Cl2加合物(0.513g,0.628mmol)。将混合物溶解于THF(50.2mL)中且添加2M磷酸三钾(18.84ml,37.7mmol)。使用超声波处理及超纯氩气将混合物脱气5min。加热混合物至80℃。4.5h后,冷却混合物,浓缩以除去大部分THF,然后用乙酸乙酯稀释且用水及盐水洗涤。经MgSO4干燥有机相,过滤且浓缩,得到棕色固体。该物质在SiO2(40g)上纯化,其中以DCM加载于干燥柱上,吹干且使用己烷(96mL)、50%DCM/己烷(480mL)、50至100%DCM/己烷(384mL,线性梯度)、DCM(240mL)、0至10%乙酸乙酯/DCM(384mL,线性梯度)、10%乙酸乙酯/DCM(360mL)洗脱,得到2.6g(67%产率)产物。1H NMR(400MHz,CDCl3)δ8.94(d,J=2.0Hz,1H),8.42(d,J=2.0Hz,1H),8.30(dd,J=5.0,2.0Hz,1H),7.99(dd,J=7.4,1.9Hz,1H),7.11(dd,J=7.3,5.0Hz,1H),3.87(s,3H)。质谱实测值:310(M+H)+。
步骤2:3-溴-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶
在40mL额定压力瓶中向5-溴-2’-甲氧基-3-硝基-2,3’-联吡啶(2.6g,8.38mmol)及DPPE(5.01g,12.6mmol)的混合物中添加1,2-二氯苯(20mL)。将瓶密封且加热至165℃。3h后,使瓶冷却至环境温度,然后用乙醚稀释溶液且过滤。浓缩滤液,用DCM研磨且过滤。该固体由DCM再次研磨且过滤,得到1.02g(44%产率)产物。1H NMR(400MHz,CDCl3)δ8.76(d,J=2.0Hz,1H),8.41(br.s.,1H),8.20(d,J=5.8Hz,1H),7.92(d,J=2.0Hz,1H),7.06(d,J=5.8Hz,1H),4.29(s,3H)。质谱实测值:279(M+H)+。
步骤3:13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向经烘箱干燥的2-5mL微波瓶中装入4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(420mg,1.08mmol)且用DMF(4495μl)稀释。向该溶液中添加3-溴-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶(250mg,0.899mmol)、碘化亚铜(I)(25.7mg,0.135mmol)、三乙胺(188μl,1.35mmol)及Pd(Ph3P)4(78mg,0.067mmol)。将瓶密封且使用超纯氩气及超声波处理脱气2分钟。将瓶密封且置于预加热至80℃的油浴中。35min后,冷却混合物至室温且经由硅藻土垫过滤。减压浓缩溶液且通过快速色谱纯化:24g ISCO RediSep Rf,在DCM中/用DCM加载且干燥,级份大小:9mL 13×100mm且用甲醇/DCM0%[100mL]、0-5%[175mL]、5%[125mL]、5-7%[201mL]、7%[150mL]洗脱。收集级份,得到260mg(97%产率)产物。1H NMR(400MHz,CDCl3)δ8.73(br.s.,1H),8.68(d,J=1.8Hz,1H),8.25(d,J=6.0Hz,1H),7.72(d,J=2.0Hz,1H),7.13(d,J=5.8Hz,1H),4.33(s,3H),4.03(s,3H)。质谱实测值:298(M+H)+。
步骤4:13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向24/40-50mL圆底烧瓶中装入三苯基膦(459mg,1.75mmol)且溶解于THF(4372μl)中。冷却混合物至0℃且一次性添加偶氮二甲酸二叔丁酯(403mg,1.75mmol)。30min后,黄色溶液变成粘稠乳状浆液。添加(R)-苯基(四氢-2H-吡喃-4-基)甲醇(336mg,1.75mmol)且在10min后添加呈固体状的13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(260mg,0.874mmol)且添加额外量的THF(4372μl)以溶解剩余的咔啉且将其添加至反应混合物中。移开冰浴。45min后,添加TFA(674μl,8.74mmol)以淬灭反应混合物且搅拌混合物10min且减压浓缩。用乙酸乙酯稀释黄色油状物且用1.5M磷酸三钾溶液淬灭且转移至分液漏斗中。分离各层且用水、盐水洗涤有机相,过滤,经硫酸镁干燥,减压浓缩且通过快速色谱纯化:40g ISCO RediSepRf,在DCM中/用DCM加载且干燥,级份大小:9mL 13×100mm且用丙酮/DCM 0%[130mL]、0-30%[250mL]、30%[250mL]、30-50%[250mL]、50%[250mL]、50-70%[250mL]洗脱。收集级份,得到194mg(47.0%产率)产物。用1mL甲醇稀释10mg经纯化的产物且通过制备型HPLC纯化:Waters XBridge C18 100×30mm 5μ,溶剂A:95:5水/ACN,B:95:5ACN/水,缓冲剂:10mMNH4OAc,%B梯度30%(15min),流速:30mL/min。减压浓缩含有产物的级份。经由硅胶塞过滤所得固体,用丙酮洗脱产物。1H NMR(400MHz,CDCl3)δ8.62(d,J=2.0Hz,1H),8.29(d,J=6.3Hz,1H),7.60(d,J=1.8Hz,1H),7.46-7.41(m,2H),7.40-7.28(m,4H),5.46(d,J=10.8Hz,1H),4.32(s,3H),4.06(dd,J=11.7,2.9Hz,1H),3.91-3.83(m,4H),3.54(td,J=11.9,1.9Hz,1H),3.36(td,J=11.9,2.0Hz,1H),3.07(qt,J=11.1,3.6Hz,1H),2.07-1.98(m,1H),1.66-1.52(m,1H),1.45-1.32(m,1H),1.06(d,J=12.8Hz,1H)。质谱实测值:472(M+H)+。
实施例129
13-乙氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向2.0-5.0mL微波瓶中装入13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(196mg,0.416mmol)且溶解于DMF(4156μl)中。向该溶液中添加POCl3(387μl,4.16mmol)。将瓶密封且置于预加热至80℃的反应区块中。4h后,将反应混合物倾入冰水中且用固体碳酸氢钠中和。用乙酸乙酯稀释粗混合物且转移至分液漏斗中,其中各层分离。有机相用盐水(×3)洗涤。用乙酸乙酯萃取合并的水相且弃去水相。用盐水洗涤合并的有机相,经硫酸镁干燥,过滤,减压浓缩且通过快速色谱纯化:24g ISCO RediSepRf,在DCM中/用DCM加载且干燥,级份大小:9mL 13×100mm且用丙酮/DCM0%[125mL]、0-35%[333mL]、35%[165mL]、35-100%[201mL]洗脱。收集级份,得到133mg(67.2%产率)产物。1H NMR(400MHz,CDCl3)δ8.72(d,J=1.8Hz,1H),8.51(d,J=6.0Hz,1H),7.67(d,J=1.5Hz,1H),7.60(d,J=6.0Hz,1H),7.45-7.33(m,5H),5.52(d,J=10.8Hz,1H),4.11-4.05(m,1H),3.92-3.86(m,4H),3.60-3.51(m,1H),3.36(td,J=11.8,2.0Hz,1H),3.08(s,1H),2.05(d,J=13.3Hz,1H),1.66-1.52(m,1H),1.45-1.32(m,1H),1.06(d,J=12.5Hz,1H)。质谱实测值:476(M+H)+。
步骤2:13-乙氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向1打兰压力瓶中装入乙醇(250μL,4.28mmol)且一次性添加KOtBu(23.57mg,0.210mmol)。10min后,添加溶解于NMP(150μL)中的13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(10mg,0.021mmol)。将瓶置于预加热至55℃的反应区块中。2h后,用碳酸氢钠饱和溶液淬灭混合物且用甲醇稀释。经由0.45μ针筒头过滤器过滤出无机固体且通过制备型HPLC纯化澄清溶液:柱:Waters XBridge C18 100×30mm 5μ,溶剂A:95:5水/ACN,B:95:5ACN/水,缓冲剂:10mM NH4OAc,%B:32%(20min),流速:30mL/min,1次注射,在254nm监测。收集含有产物的级份且减压浓缩。经由硅胶塞过滤所得固体,用丙酮洗脱产物,得到5.1mg(49.5%产率)产物。1H NMR(400MHz,CDCl3)δ8.62(d,J=1.8Hz,1H),8.27(d,J=6.0Hz,1H),7.57(d,J=1.8Hz,1H),7.45-7.39(m,2H),7.39-7.29(m,3H),7.26(d,J=6.3Hz,1H),5.46(d,J=10.8Hz,1H),4.84(q,J=7.1Hz,2H),4.06(dd,J=11.8,2.8Hz,1H),3.91-3.83(m,4H),3.54(td,J=11.9,2.0Hz,1H),3.35(td,J=11.9,2.0Hz,1H),3.13-3.00(m,1H),2.03(d,J=13.1Hz,1H),1.66-1.52(m,4H),1.46-1.32(m,1H),1.07(d,J=13.3Hz,1H)。质谱实测值:486(M+H)+。
实施例130
13-(环丙基甲氧基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对13-乙氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由环丙烷甲醇制备标题化合物,得到5.8mg(53.4%产率)产物。1H NMR(400MHz,CDCl3)δ8.62(d,J=1.8Hz,1H),8.25(d,J=6.0Hz,1H),7.57(d,J=1.8Hz,1H),7.45-7.40(m,2H),7.38-7.30(m,3H),7.26(d,J=6.0Hz,1H),5.46(d,J=10.5Hz,1H),4.66-4.54(m,2H),4.06(dd,J=11.8,3.0Hz,1H),3.91-3.82(m,4H),3.54(td,J=11.9,2.0Hz,1H),3.35(td,J=11.9,1.9Hz,1H),3.13-3.00(m,1H),2.03(d,J=12.8Hz,1H),1.62-1.51(m,2H),1.46-1.32(m,1H),1.08(d,J=13.1Hz,1H),0.68-0.61(m,2H),0.54-0.48(m,2H)。质谱实测值:512(M+H)+。
实施例131
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
遵循与针对13-乙氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯的合成所描述的程序类似的程序由2-丙醇制备标题化合物,得到5.6mg(52.8%产率)产物。1H NMR(400MHz,CDCl3)δ8.60(d,J=2.0Hz,1H),8.26(d,J=6.0Hz,1H),7.54(d,J=1.8Hz,1H),7.44-7.39(m,2H),7.39-7.30(m,3H),7.23(d,J=6.0Hz,1H),5.73(spt,J=6.3Hz,1H),5.45(d,J=10.8Hz,1H),4.05(dd,J=11.8,2.8Hz,1H),3.92-3.81(m,4H),3.54(td,J=11.9,2.0Hz,1H),3.35(td,J=11.9,2.0Hz,1H),3.13-2.99(m,1H),2.03(d,J=14.1Hz,1H),1.59(dd,J=6.3,4.3Hz,7H),1.46-1.32(m,1H),1.11-1.02(m,1H)。质谱实测值:500(M+H)+。
实施例132
N-乙基-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
向1打兰压力瓶中装入13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(10mg,0.021mmol)且溶解于NMP(150μL)中。添加N-乙基甲胺(150μl,1.73mmol)且将反应混合物置于预加热至90℃的加热区块中。4h后,所得反应混合物通过制备型HPLC直接纯化:柱:Waters XBridge C18 100×30mm 5μ,溶剂A:95:5水/ACN,B:95:5ACN/水,缓冲剂:10mM NH4OAc,%B:43%(10min),流速:30mL/min,1次注射,在254nm监测。减压浓缩含有产物的级份。经由硅胶塞洗涤所得固体,用丙酮洗脱产物,得到7.5mg(69.4%产率)产物。1H NMR(400MHz,CDCl3)δ8.51(d,J=2.0Hz,1H),8.32(d,J=6.0Hz,1H),7.52(d,J=2.0Hz,1H),7.46-7.40(m,2H),7.39-7.28(m,3H),7.09(d,J=6.0Hz,1H),5.47(d,J=10.5Hz,1H),4.09-3.96(m,3H),3.90-3.84(m,4H),3.54(td,J=11.9,1.9Hz,1H),3.40-3.30(m,4H),3.14-3.00(m,1H),2.04(d,J=13.6Hz,1H),1.68-1.52(m,1H),1.48-1.34(m,1H),1.33-1.28(m,3H),1.10-1.03(m,1H)。质谱实测值:499(M+H)+。
实施例133
N-(2,2-二氟乙基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对N-乙基-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺的合成所描述的程序类似的程序由2,2-二氟乙胺制备标题化合物,得到12.4mg(89%产率)产物。1H NMR(400MHz,CDCl3)δ8.43(d,J=1.8Hz,1H),8.23(d,J=6.0Hz,1H),7.54(d,J=1.8Hz,1H),7.46-7.41(m,2H),7.39-7.29(m,3H),7.25(t,J=6.4Hz,1H),7.01(d,J=6.0Hz,1H),6.32-5.97(m,1H),5.38(d,J=10.5Hz,1H),4.23-4.09(m,2H),4.05(dd,J=11.7,2.6Hz,1H),3.93-3.85(m,4H),3.53(td,J=11.9,2.0Hz,1H),3.37(td,J=11.9,2.0Hz,1H),3.11-2.99(m,1H),1.96(d,J=13.1Hz,1H),1.62-1.50(m,1H),1.47-1.34(m,1H),1.12(d,J=12.8Hz,1H)。质谱实测值:521(M+H)+。
实施例134
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-N-(2,2,2-三氟乙基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
遵循与针对N-乙基-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺的合成所描述的程序类似的程序由2,2,2-三氟乙胺制备标题化合物,得到6.3mg(55%产率)产物。1H NMR(400MHz,CDCl3)δ8.43(d,J=1.8Hz,1H),8.26(d,J=6.0Hz,1H),7.55(d,J=1.5Hz,1H),7.46-7.41(m,2H),7.39-7.28(m,4H),7.04(d,J=6.3Hz,1H),5.38(d,J=10.5Hz,1H),4.51(qd,J=9.1,6.8Hz,2H),4.08-4.01(m,1H),3.93-3.84(m,4H),3.53(td,J=11.9,2.0Hz,1H),3.37(td,J=11.9,2.0Hz,1H),3.12-2.99(m,1H),1.96(d,J=12.8Hz,1H),1.59-1.49(m,1H),1.47-1.33(m,1H),1.16(d,J=13.6Hz,1H)。质谱实测值:539(M+H)+。
实施例135
5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯
步骤1:6-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-甲酸甲酯
向250mL圆底烧瓶中装入5-溴-6-甲氧基吡啶-3-甲酸甲酯(3.77g,15.3mmol)且溶解于二噁烷(61.3ml)中。向该搅拌的溶液中添加乙酸钾(3.01g,30.6mmol)、联硼酸二频那醇酯(4.47g,17.6mmol)及PdCl2(dppf)(0.112g,0.153mmol)。将烧瓶密封且通过超声波处理同时使氩气鼓泡通过溶液5min脱气。将反应烧瓶置于预加热至80℃的油浴中且搅拌过夜。17.5h后,冷却混合物至室温且添加额外量的联硼酸二频那醇酯(2.0g,7.87mmol)及PdCl2(dppf)(450mg,0.615mmol)。将烧瓶密封且如上所述脱气且继续加热4h,然后冷却混合物且减压浓缩,得到黑色固体。将该固体溶解于乙酸乙酯中。添加水且经由硅藻土垫过滤混合物。将滤液转移至分液漏斗中且分离各层。用水(×1)及盐水(×2)洗涤有机相,经硫酸镁干燥,过滤且减压浓缩。通过快速色谱纯化粗残余物:40g ISCO RediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用0%-50%乙酸乙酯/己烷洗脱,得到呈结晶白色固体状的标题化合物(3.52g,12.0mmol,78%产率)。1H NMR(400MHz,CDCl3)δ8.89(d,J=2.5Hz,1H),8.56(d,J=2.5Hz,1H),4.04(s,3H),3.92(s,3H),1.37(s,12H)。LCMS:Rt=0.97min;(ES):m/z(M+H)+294(Waters Acquity SDS柱:BEH C18 2.1×50mm 1.7μm;(1.5min梯度)2-98%B;流速=0.8mL/min;溶剂A:H2O-0.1%TFA;溶剂B:ACN-0.1%TFA)。
步骤2:5-溴-2’-甲氧基-3-硝基-[2,3’-联吡啶]-5’-甲酸甲酯
向含有6-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-甲酸甲酯(3.52g,12.0mmol)的250mL圆底烧瓶中添加THF(100mL)。向该溶液中添加2,5-二溴-3-硝基吡啶(4.06g,14.4mmol)、2.0M磷酸三钾(12.01mL,24.0mmol)及PdCl2(dppf)(0.300g,0.410mmol)。将烧瓶密封且通过超声波处理同时使氩气鼓泡通过溶液脱气。然后将烧瓶置于预加热至65℃的油浴中。1h后,冷却混合物且减压浓缩。将所得棕色固体溶解于乙酸乙酯中且用水稀释。经由硅藻土垫过滤两相混合物且转移至分液漏斗中,其中各层分离。用水(×1)及盐水(×2)洗涤有机层,经硫酸镁干燥,过滤且浓缩。通过快速色谱纯化粗产物:40g ISCO RediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用0-15%乙酸乙酯/己烷洗脱,得到呈固体状的标题化合物(1.67g,4.54mmol,37.8%产率)。1H NMR(400MHz,CDCl3)δ8.97(d,J=2.0Hz,1H),8.94(d,J=2.5Hz,1H),8.57(d,J=2.3Hz,1H),8.46(d,J=2.0Hz,1H),3.97-3.95(m,3H),3.94(s,3H)。LCMS:Rt=1.24min;(ES):m/z(M+H)+369(Waters Acquity SDS柱:BEH C18 2.1×50mm 1.7μm;(1.5min梯度)2-98%B;流速=0.8mL/min;溶剂A:H2O-0.1%TFA;溶剂B:ACN-0.1%TFA)。
步骤3:3-溴-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯
向100mL圆底烧瓶中装入5-溴-2’-甲氧基-3-硝基-[2,3’-联吡啶]-5’-甲酸甲酯(2.42g,6.57mmol)及1,2-二(二苯基膦基)乙烷(3.93g,9.86mmol)。将混合物混悬于1,2-二氯苯(21.9ml)中,在氮气气囊气氛下密封且置于预加热至160℃的油浴中。30min后,冷却混合物至室温且添加乙醚,形成析出物,其通过过滤收集。用DCM研磨粗物质,得到250mg呈茶色固体状的所需产物,其通过过滤收集且通过1H NMR表征。减压浓缩上清液且通过快速色谱纯化:40g ISCO RediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用乙酸乙酯/DCM 0%[150mL]、0-15%[500mL]、15%[600mL]洗脱。浓缩含有产物的级份,得到棕色不纯固体。用DCM研磨该固体且通过过滤收集所需产物。以此方式多次重复研磨滤液及合并多批,得到呈淡棕色固体状的标题化合物(950mg,2.83mmol,43.0%产率)。1H NMR(400MHz,CDCl3)δ10.04(br.s.,1H),8.86(s,1H),8.78(d,J=2.0Hz,1H),8.00(d,J=1.8Hz,1H),4.36(s,3H),4.05(s,3H)。
步骤4:(S)-3-溴-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯
向100mL圆底烧瓶中装入三苯基膦(624mg,2.38mmol)且溶解于THF(5mL)中。用冰浴冷却溶液且逐滴添加溶解于THF(1mL)中的偶氮二甲酸二叔丁酯(548mg,2.38mmol),得到黄色溶液,其在30min后变成粘稠白色混悬液。然后一次性添加(R)-苯基(四氢-2H-吡喃-4-基)甲醇(458mg,2.38mmol)且搅拌混合物45min。将3-溴-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(400mg,1.19mmol)部分混悬于THF(20mL)中且历经10min逐滴添加至反应混合物中。移开冰浴且将反应混合物升温至室温。2.5h后,添加三氟乙酸(0.917mL,11.9mmol)且搅拌混合物20min且然后减压浓缩。用乙酸乙酯稀释混合物且用1.5M磷酸钾水溶液淬灭。将烧瓶的内含物转移至分液漏斗中且分离各层。用水(×2)及盐水(×1)洗涤有机相。用乙酸乙酯(×2)反萃取合并的水相且弃去。用盐水(×1)洗涤合并的有机相,经硫酸镁干燥,减压浓缩且通过快速色谱纯化:40g ISCO RediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用乙酸乙酯/DCM 0%[102mL]、0-15%[352mL]、15%[552mL]、15-50%[1000mL]洗脱。含有产物的级份得到呈无定形白色固体状的(S)-3-溴-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(581mg,1.14mmol,96%产率),其含有28%3-溴-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯作为杂质。物质按原样使用。1H NMR(400MHz,CDCl3)δ8.81(s,1H),8.69(d,J=1.8Hz,1H),7.80(d,J=2.0Hz,1H),7.57(d,J=7.5Hz,2H),7.42-7.36(m,2H),7.33(d,J=7.3Hz,1H),6.55-6.48(m,1H),4.35(s,3H),4.04(s,3H),4.05-4.00(m,1H),3.83-3.76(m,J=4.0Hz,1H),3.59-3.51(m,J=1.8Hz,1H),3.30(td,J=11.9,2.3Hz,1H),3.00-2.88(m,1H),2.06(d,J=13.8Hz,1H),1.64-1.50(m,1H),1.44-1.30(m,J=4.8Hz,1H),0.53(d,J=12.8Hz,1H)。LCMS:Rt=1.02min;(ES):m/z(M+H)+512(Waters Acquity SDS柱:BEH C18 2.1×50mm 1.7μm;(1.5min梯度)2-98%B;流速=0.8mL/min;溶剂A:H2O-0.1%TFA;溶剂B:ACN-0.1%TFA)。
步骤5:5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯
(S)-3-溴-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(292mg,0.572mmol)、碘化亚铜(I)(16.34mg,0.086mmol)、四(三苯基膦)钯(0)(49.6mg,0.043mmol)、1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(331mg,0.858mmol)及三乙胺(0.120mL,0.858mmol)于DMF(3.0mL)中的溶液在20mL闪烁瓶中通过鼓泡氩气同时超声波处理2min脱气。将瓶密封且加热至100℃。2h后,冷却反应瓶,用乙酸乙酯稀释,经由硅藻土过滤且用水洗涤。用乙酸乙酯萃取水性部分且用盐水洗涤合并的有机相,经MgSO4干燥,过滤且浓缩,得到黄色固体。通过快速色谱纯化粗物质:24g ISCORediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用甲醇/DCM 0%[5CV]、0-5%[20CV]、5-10%[5CV]洗脱。含有产物的级份得到309mg玻璃状白色固体。通过快速色谱进一步纯化白色固体:24g ISCO RediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用甲醇/DCM0%[165mL]、0-3%[165mL]、3%[660mL]、3-10%[330mL]洗脱。含有产物的级份得到呈白色固体状的标题化合物(109mg,201mmol,35%)。1H NMR(400MHz,CDCl3)δ8.85(s,1H),8.60(s,1H),7.58(d,J=7.5Hz,2H),7.53(s,1H),7.37(t,J=7.5Hz,2H),7.33-7.28(m,1H),6.64(d,J=10.3Hz,1H),4.36(s,3H),4.04(s,3H),4.00(d,J=11.0Hz,1H),3.81-3.73(m,1H),3.70(s,3H),3.51(t,J=11.7Hz,1H),3.29-3.17(m,1H),3.03-2.85(m,J=8.5Hz,1H),2.16(s,3H),2.10(d,J=13.6Hz,1H),1.66-1.51(m,1H),1.37(qd,J=12.3,4.4Hz,1H),0.49(d,J=12.8Hz,1H)。LCMS:Rt=1.254min;(ES):m/z(M+H)+527(Waters AcquitySDS柱:BEH C18 2.1×50mm 1.7μm;(1.5min梯度)2-98%B;流速=0.8mL/min;溶剂A:H2O-0.1%TFA;溶剂B:ACN-0.1%TFA)。HPLC Rt=7.94min(柱:XSELECT CSH C18 3.5μm,3.0×150mm;流动相A:0.1%TFA/95%H2O/5%ACN;流动相B:95:5 0.1%TFA/5%H2O/95%ACN;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm及254nm)。HPLC Rt=6.46min(柱:Zorbax Bonus-RP 3.5μm,3.0×150mm;流动相A:0.1%TFA/95%H2O/5%ACN;流动相B:95:5 0.1%TFA/5%H2O/95%ACN;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV220nm及254nm)。
实施例136
[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]甲醇
在冰水浴中冷却(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(16mg,0.030mmol)于THF(0.5mL)中的混悬液且添加2.0M氢化锂铝/THF(0.030mL,0.061mmol)。40min后,用一滴水、一滴3N NaOH水溶液淬灭混合物且在搅拌五分钟后添加过量的固体硫酸钠。用乙酸乙酯稀释该混合物,过滤且浓缩,得到14mg粗黄色膜状物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到标题化合物(4.1mg,21%)。通过LCMS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。1H NMR(500MHz,DMSO-d6)δ8.57(s,1H),8.16(s,1H),7.98(s,1H),7.68(d,J=7.7Hz,2H),7.40-7.30(m,2H),7.28-7.22(m,1H),6.36(d,J=11.0Hz,1H),5.87(t,J=4.8Hz,1H),5.01(d,J=4.8Hz,2H),4.11(s,3H),3.88(d,J=7.7Hz,1H),3.82(s,3H),3.69(d,J=8.4Hz,1H),3.51-3.49(m,1H),3.48-3.37(m,1H),3.22(t,J=11.6Hz,1H),2.14(s,3H),1.91(t,J=6.2Hz,1H),1.57-1.38(m,2H),0.63(d,J=12.5Hz,1H)。LC/MS(499,[M+H]+)。LCMS:Rt=1.29min;(ES):m/z(M+H)+499(柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm)。
实施例137
[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]甲醇
步骤1:(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸
向(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(15.6mg,0.030mmol)于THF(700μL)及水(100μL)中的溶液中添加一水合氢氧化锂(6.2mg,0.148mmol)。在室温搅拌混合物。40h后,用少量(约200μL)由柠檬酸及氢氧化钠制备的pH 5缓冲液处理混合物,然后萃取至乙酸乙酯中。经MgSO4干燥有机萃取液,过滤且浓缩,得到呈白色固体状的标题化合物(15.1mg,99%)。1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.70(d,J=1.8Hz,1H),7.59-7.53(m,3H),7.40-7.32(m,2H),7.30(d,J=7.3Hz,1H),7.05(d,J=10.5Hz,1H),4.41(s,3H),4.12-4.07(m,1H),3.91-3.83(m,1H),3.73(s,3H),3.56(t,J=11.2Hz,1H),3.37-3.25(m,1H),2.95(d,J=10.8Hz,1H),2.19(s,3H),2.10(d,J=13.6Hz,1H),1.69(d,J=10.5Hz,1H),1.55(dd,J=12.4,3.9Hz,1H),0.60(d,J=12.8Hz,1H)。LCMS:Rt=1.24min;(ES):m/z(M+H)+513(Waters Acquity SDS;柱类型:ACQUITYBEH C18 1.7μm 2.1×50mm;运行时间:2.20min;0-100%B;溶剂A:100%水/0.05%TFA;溶剂B:100%ACN w/0.05%TFA;流速:0.8mL/min;检测:UV=220nm)。
步骤2:[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]甲醇
在室温搅拌(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸(15.1mg,0.029mmol)、3-氟氮杂环丁烷盐酸盐(6.57mg,0.059mmol)、HATU(13.4mg,0.035mmol)及许尼希(Hunig’s)碱(0.013mL,0.074mmol)于DMF(0.5mL)中的混合物。21h后,用乙酸乙酯稀释混合物,用盐水(3×)洗涤,经MgSO4干燥,过滤且浓缩,得到20.8mg透明膜状物。经由制备型LC/MS以1.0mL甲醇的单次注射在以下条件下纯化粗物质:柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min0-100%B且然后在100%B保持1min;流速:30mL/min;检测:254nm。合并含有所需产物的级份且经由离心蒸发干燥,然后将物质吸收于乙酸乙酯中,用盐水洗涤,经MgSO4干燥,过滤且浓缩,得到呈白色固体膜状的标题化合物(4.6mg,26%)。通过HPLC分析估算的纯度为95%。1HNMR(400MHz,CDCl3)δ8.65(d,J=1.8Hz,1H),8.26(br.s.,1H),7.65-7.50(m,3H),7.40-7.29(m,3H),6.27(br.s.,1H),4.40(d,J=6.8Hz,3H),4.36(s,4H),4.04(d,J=11.5Hz,(m,1H),2.23(1H),3.83(d,J=11.8Hz,1H),3.78(s,3H),3.51(t,J=11.4Hz,1H),3.28(t,J=11.9Hz,1H),3.03-2.85s,3H),2.09-2.00(m,1H),1.56-1.52(m,1H),1.46-1.32(m,1H),0.81-0.71(m,2H)。LCMS:Rt=1.079min;(ES):m/z(M+H)+570(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:ACN/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。HPLC Rt=11.11min(柱:XSELECT CSH C18 3.5μm,3.0×150mm;流动相A:0.1%TFA/95%H2O/5%ACN;流动相B:95:50.1%TFA/5%H2O/95%ACN;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm及254nm)。HPLC Rt=13.06min(柱:Zorbax Bonus-RP 3.5μm,3.0×150mm;流动相A:0.1%TFA/95%H2O/5%ACN;流动相B:95:5 0.1%TFA/5%H2O/95%ACN;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm及254nm)。
实施例138
2-{13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基}丙-2-醇
步骤1:13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯
向2-5mL微波瓶中装入4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(286mg,0.735mmol)且用DMF(2449μL)稀释。添加(S)-3-溴-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(250mg,0.490mmol),然后添加三乙胺(102μL,0.735mmol)、碘化亚铜(I)(14.0mg,0.073mmol)及四(三苯基膦)钯(0)(42.5mg,0.037mmol)。将瓶密封且通过鼓泡氩气同时超声波处理2min脱气。然后将瓶置于预加热至80℃的反应区块中。1h后,冷却混合物至室温且用乙酸乙酯及水稀释。经由硅藻土垫过滤两相混合物且转移至分液漏斗,其中各层分离。用水(×2)及盐水(×2)洗涤有机相。用乙酸乙酯(×2)反萃取合并的水相且弃去。再次用盐水(×1)洗涤合并的有机相,经硫酸镁干燥,减压浓缩且通过快速色谱纯化:24g ISCO RediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用甲醇/DCM0%[75mL]、0-5%[402mL]、5%[150mL]洗脱。收集含有产物的级份,得到呈白色固体状的不纯产物。通过快速色谱再次纯化白色固体:24g ISCORediSep Rf,以DCM加载于干燥柱上,在氮气气流下干燥且用甲醇/DCM 0%[150mL]、0-3%[250mL]、3%[500mL]洗脱。收集含有产物的级份,得到呈白色固体状的标题化合物(188mg,0.355mmol,72.5%产率)。1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.63(d,J=1.8Hz,1H),7.57(d,J=7.8Hz,2H),7.52(d,J=2.0Hz,1H),7.43-7.36(m,2H),7.32(s,1H),6.72-6.63(m,1H),4.41-4.38(m,3H),4.06(s,3H),4.07-4.02(m,1H),3.82-3.76(m,1H),3.73(s,3H),3.53(td,J=11.9,1.8Hz,1H),3.24(td,J=11.9,2.1Hz,1H),2.99-2.84(m,1H),2.11(d,J=14.6Hz,1H),1.69-1.56(m,1H),1.39(qd,J=12.5,4.1Hz,1H),0.52(d,J=12.3Hz,1H)。LC/MS(530,[M+H]+)。LCMS:Rt=0.90min;(ES):m/z(M+H)+530(柱:Waters Acquity UPLCBEH C18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:ACN/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。
步骤2:2-{13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基}丙-2-醇
如下制备有机镁盐试剂:
在干冰/丙酮浴温度向含有2.0mL THF的20mL闪烁瓶中添加252μL甲基溴化镁(3.0M于乙醚中),然后添加945μL甲基锂(1.6M于乙醚中)。此试剂基于格氏试剂的有效浓度应为0.24M。搅拌该混合物45min,然后同样在干冰/丙酮浴温度经由塑料针筒将190μL(1.2当量)此试剂添加至13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯(20mg,0.038mmol)于0.5mL THF中的溶液中。2h后,用冰/水浴替换干冰/丙酮浴。在此温度保持1h后,添加额外的300μL(1.9当量)有机镁盐试剂。再保持1h后,LC/MS显示原料转化及形成所需产物(530,[M+H]+)与酮中间体(514,[M+H]+)的约1:1混合物。在干冰丙酮浴中短暂冷却混合物且用氯化铵饱和水溶液淬灭。用乙酸乙酯稀释混合物且升温/搅拌直至其为两相液体。用乙酸乙酯进一步萃取水性部分且用盐水洗涤合并的有机相,经MgSO4干燥,过滤且浓缩,得到17.5mg灰白色固体。经由制备型LC/MS以0.5mL甲醇的两次等效注射在以下条件下纯化粗物质:柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;30%B持续30min;流速:30mL/min;检测:254nm。含有产物的级份(Rt=8.30min)得到呈白色固体状的标题化合物(8.0mg,39%)。通过HPLC分析估算的纯度为97%。1H NMR(400MHz,CDCl3)δ8.61(d,J=2.0Hz,1H),8.36(s,1H),7.43-7.29(m,6H),7.24(d,J=2.0Hz,1H),4.35(s,3H),4.04(dd,J=11.8,3.0Hz,1H),3.70(dd,J=11.2,3.6Hz,1H),3.64(s,3H),3.54(td,J=11.9,1.8Hz,1H),3.18(td,J=12.0,1.9Hz,1H),2.97-2.83(m,1H),2.25(d,J=17.1Hz,2H),2.04(s,3H),1.83(s,3H),1.52-1.40(m,J=12.7,12.7,4.5Hz,2H),0.32(d,J=13.1Hz,1H)。LC/MS(530,[M+H]+)。LCMS:Rt=1.259min;(ES):m/z(M+H)+530(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:ACN/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。HPLC Rt=12.43min(柱:Xbridge C18 3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm及254nm)。HPLC Rt=13.42min(柱:Xbridge Phenyl3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV220nm及254nm)。
实施例139
2-{13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基}丙-2-醇
在冰水浴中冷却13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯(22mg,0.042mmol)于THF(0.5mL)中的溶液且添加2.0M氢化锂铝/THF(0.042mL,0.083mmol)。10min后,用一滴水及两滴15%NaOH水溶液淬灭混合物,用乙酸乙酯稀释且搅拌5min,然后添加过量的固体硫酸钠。过滤混合物且浓缩,得到21.7mg灰白色固体。该物质在SiO2(4g)上纯化,其中以DCM加载于干燥柱上且使用DCM(51mL)、20%丙酮/DCM(50mL)、30%丙酮/DCM(100mL)、50%丙酮/DCM(50mL)、丙酮(约50mL)洗脱。含有产物的级份得到18.2mg透明膜状物。该物质的纯度为94%(通过1H NMR)。其经由制备型LC/MS在以下条件下进一步纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到标题化合物(16.4mg,79%)。通过LCMS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。1H NMR(500MHz,DMSO-d6)δ8.59(s,1H),8.17(s,1H),8.01(s,1H),7.70(d,J=7.7Hz,2H),7.38-7.31(m,2H),7.29-7.23(m,1H),6.37(d,J=10.6Hz,1H),5.02(s,2H),4.12(s,3H),3.88(br.s.,1H),3.83(s,3H),3.70(d,J=10.3Hz,1H),3.55-3.41(m,2H),3.22(t,J=11.4Hz,1H),1.96-1.88(m,3H),1.91(s,1H),1.58-1.39(m,2H),0.64(d,J=11.7Hz,1H)。LCMS:Rt=1.33min;(ES):m/z(M+H)+502(柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm)。
实施例140
5-(二甲基-1,2-噁唑-4-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-甲酸甲酯
(S)-3-溴-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(42.9mg,0.084mmol)、(3,5-二甲基异噁唑-4-基)硼酸(17.8mg,0.126mmol)、PdCl2(dppf)·CH2Cl2(6.9mg,8.41μmol)、2M磷酸三钾水溶液(0.126mL,0.252mmol)及THF(1mL)的混合物在2打兰额定压力瓶中通过鼓泡氩气同时超声波处理1-2min脱气。将瓶密封且加热至80℃。1h后,冷却混合物,用水稀释且萃取至乙酸乙酯中。用盐水洗涤合并的有机相,经MgSO4干燥,过滤且浓缩,得到粗固体棕色残余物。该物质在SiO2(4g)上纯化,其中以DCM加载于干燥柱上且使用DCM(51mL)、20-40%丙酮/DCM洗脱。含有产物的级份得到34.5mg淡棕色固体。使一部分该物质(13mg)由甲醇析出,得到呈白色固体状的标题化合物(2.3mg)。通过HPLC估算的纯度为100%。1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.58(d,J=1.5Hz,1H),7.59(d,J=7.5Hz,2H),7.46-7.43(m,1H),7.41-7.35(m,2H),7.33-7.28(m,1H),6.61(d,J=10.5Hz,1H),4.40-4.32(m,3H),4.07-4.03(m,3H),4.04-3.98(m,1H),3.77(dd,J=11.2,2.6Hz,1H),3.58-3.48(m,1H),3.23(td,J=11.8,1.8Hz,1H),2.92(d,J=10.8Hz,1H),2.25(s,3H),2.15-2.09(m,1H),2.09(s,3H),1.67-1.53(m,1H),1.35(qd,J=12.3,4.4Hz,1H),0.47(d,J=13.1Hz,1H)。LCMS:Rt=1.232min;(ES):m/z(M+H)+527(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:ACN/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。HPLC Rt=14.32min(柱:Xbridge C18 3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm及254nm)。HPLC Rt=15.36min(柱:Xbridge Phenyl 3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min10-100%B;流速:1mL/min;检测:UV 220nm及254nm)。
实施例141
2-[5-(二甲基-1,2-噁唑-4-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇
如下制备有机镁盐试剂:
在干冰/丙酮浴温度向含有2.0mL THF的20mL闪烁瓶中添加252μL甲基溴化镁(3.0M于乙醚中),然后添加945μL甲基锂(1.6M于乙醚中)。此试剂基于格氏试剂的有效浓度应为0.24M。搅拌该混合物45min,然后同样在干冰/丙酮浴温度经由塑料针筒将1.0mL(5.0当量)此试剂添加至(S)-3-(3,5-二甲基异噁唑-4-基)-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(26mg,0.049mmol)于1.0mLTHF中的溶液中。30min后,在干冰/丙酮浴中再次短暂冷却混合物且添加300μL有机镁盐试剂。将瓶转移至冰水浴中。2.5h后,用氯化铵饱和水溶液淬灭混合物,然后升温至室温,用盐水稀释且萃取至乙酸乙酯(3×)中。用盐水洗涤合并的有机相,经MgSO4干燥,过滤且浓缩,得到24.2mg黄色膜状物。柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;33%B持续30min;流速:30mL/min;检测:254nm。合并含有产物的级份(Rt=16.5min),得到呈白色固体状的标题化合物(5.3mg,20%)。通过HPLC估算的纯度为98%。1H NMR(400MHz,CDCl3)δ8.57(d,J=1.8Hz,1H),8.33(s,1H),7.44-7.39(m,2H),7.35(t,J=7.4Hz,2H),7.32-7.29(m,1H),7.18(d,J=1.8Hz,1H),4.34(s,3H),4.04(dd,J=10.8,3.0Hz,1H),3.69(dd,J=11.9,3.6Hz,1H),3.58-3.48(m,J=1.8Hz,1H),3.18(td,J=12.0,1.9Hz,1H),2.96-2.83(m,1H),2.25(br.s.,1H),2.19(s,3H),2.03(s,3H),2.05-2.00(m,1H),2.00(s,3H),1.81(s,3H),1.48-1.37(m,1H),0.30(d,J=13.8Hz,2H)。LCMS:Rt=1.03min;(ES):m/z(M+H)+527(柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:ACN/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。HPLC Rt=12.05min(Waters Xbridge C18 5μm,4.6×50mm;流动相A:95%水/5%ACN及10mM NH4OAc;流动相B:5%水/95%ACN及10mM NH4OAc;梯度:历经15min 0-100%B;流速:0.5mL/min;检测:UV=254nm)。
实施例142
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇
将氯化铈(III)(30.9mg,0.125mmol)及(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯(11mg,0.021mmol)的混合物混悬于THF(500μL)中且搅拌1h,然后在冰水浴中冷却且添加甲基溴化镁(3.0M于乙醚中,42μL,0.125mmol)。五分钟后,移开冷却浴。2h后,在冰水浴中短暂冷却混合物且用氯化铵饱和水溶液淬灭,然后萃取至乙酸乙酯中。用盐水洗涤合并的有机相,经MgSO4干燥,过滤且浓缩,得到11.6mg白色残余物。通过制备型HPLC以0.5mL甲醇的两次等效注射纯化粗物质:柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;历经20min 30%B;流速:30mL/min;检测:254nm。含有产物的级份得到呈白色固体状的标题化合物(10mg,89%)。该物质的估算纯度通过1H NMR及HPLC确定为>98%。1H NMR(400MHz,CDCl3)δ8.60(d,J=1.8Hz,1H),8.36(s,1H),7.42-7.29(m,6H),7.22(d,J=1.8Hz,1H),4.33(s,3H),4.03(dd,J=11.4,2.9Hz,1H),3.67(br.s.,1H),3.62(s,3H),3.54(t,J=11.3Hz,1H),3.17(t,J=11.2Hz,1H),2.89(d,J=9.0Hz,1H),2.25(d,J=14.3Hz,1H),2.11(s,3H),2.03(s,3H),2.08-1.93(m,1H),1.81(s,3H),1.45(qd,J=12.6,4.4Hz,1H),0.28(d,J=12.8Hz,1H)。LCMS:Rt=1.020min;(ES):m/z(M+H)+527(Waters Acquity SDS;柱类型:BEH C18 1.7μm 2.1×50mm;运行时间:2.20min;0-100%B;溶剂A:100%水/0.05%TFA;溶剂B:100%ACN w/0.05%TFA;检测:UV=220nm)。HPLC Rt=12.62min(柱:Xbridge C18 3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV 220nm及254nm)。HPLC Rt=13.58min(柱:Xbridge Phenyl3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min 10-100%B;流速:1mL/min;检测:UV220nm及254nm)。
实施例143
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-甲腈
步骤1:5-(5-溴-3-硝基吡啶-2-基)嘧啶-2-甲腈
向250mL圆底烧瓶中添加5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)嘧啶-2-甲腈(0.65g,2.81mmol)、2,5-二溴-3-硝基吡啶(0.793g,2.81mmol)及50mL THF。向该混合物中添加2M磷酸三钾水溶液(2.81ml,5.63mmol)及PdCl2(dppf)·CH2Cl2(0.230g,0.281mmol)。所得溶液通过鼓泡氩气同时超声波处理1min脱气。将烧瓶密封且在油浴中在65℃加热过夜。浓缩反应混合物,得到黑色残余物。该物质在SiO2(40g)上纯化,其中以DCM加载于干燥柱上且使用己烷(51mL)、20%EtOAc/己烷(252mL)、20至50%EtOAc/己烷(357mL,线性梯度)洗脱。产物级份得到呈白色蓬松固体状的标题化合物(251mg,29%)。1HNMR(400MHz,CDCl3)δ9.08(d,J=2.0Hz,1H),9.01(s,2H),8.64(d,J=2.0Hz,1H)。LC/MS(306,[M+H]+)。LCMS:Rt=1.28min;(ES):m/z(M+H)+306(Waters Acquity SDS;柱类型:ACQUITYBEH C18 1.7μm 2.1×50mm;运行时间:2.20min;0-100%B;溶剂A:100%水/0.05%TFA;溶剂B:100%ACN w/0.05%TFA;流速:0.8mL/min;检测:UV=220nm)。
步骤2:7-溴-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶-2-甲腈
在20mL额定压力瓶中将5-(5-溴-3-硝基吡啶-2-基)嘧啶-2-甲腈(251mg,0.82mmol)及1,2-二(二苯基膦基)乙烷(490mg,1.23mmol)于1,2-二氯苯(328μL)中的混合物加热至160℃。35min后,冷却混合物,用乙醚稀释且通过过滤收集棕色固体。在高真空下浓缩滤液且用DCM研磨。通过过滤收集黄色固体,得到标题化合物(42.6mg,18%)。母液在SiO2(12g)上纯化,其中以DCM加载于干燥柱上且使用0至100%EtOAc/己烷(880mL,线性梯度)洗脱。含有产物的级份得到另一批呈黄色固体状的不纯标题化合物(27.7mg,12%)。1HNMR(400MHz,CD3OD)δ9.58(s,1H),8.77(d,J=2.0Hz,1H),8.32(d,J=2.0Hz,1H)。LCMS:Rt=0.77min;(ES):m/z(M+H)+276(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:ACN/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。
步骤3:(S)-7-溴-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶-2-甲腈
在冰水浴中冷却(R)-苯基(四氢-2H-吡喃-4-基)甲醇(59.3mg,0.309mmol)、7-溴-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶-2-甲腈(42.3mg,0.154mmol)及三苯基膦(81mg,0.309mmol)于二氯甲烷(2.0mL)中的混合物且添加偶氮二甲酸二异丙酯(0.060mL,0.309mmol)。10min后,移开冷却浴。17h后,粗反应混合物在SiO2(12g)上纯化,其中以DCM加载于干燥柱上且使用己烷(54mL)、20%EtOAc/己烷(255mL)、20至50%EtOAc/己烷(429mL,线性梯度)洗脱,得到118mg黄色膜状物。在SiO2(12g)上对该物质进行第二次纯化:以DCM加载于干燥柱上且使用己烷(51mL)、25%EtOAc/己烷(252mL)、25至65%EtOAc/己烷(429mL,线性梯度)洗脱,得到呈不纯黄色泡沫状的标题化合物(86mg,124%)。该物质按原样使用。LCMS:Rt=1.06min;(ES):m/z(M+H)+450(柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:ACN/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。
步骤4:5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-甲腈
(S)-7-溴-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶-2-甲腈(86mg,0.192mmol)、Pd(Ph3P)4(11.1mg,9.59μmol)、碘化亚铜(I)(3.7mg,0.019mmol)、1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(89mg,0.23mmol)及三乙胺(40μL,0.288mmol)于DMF(959μL)中的混合物在5mL额定压力瓶中通过鼓泡氩气同时超声波处理2-3min脱气。将瓶密封且加热至100℃。2h后,由热源取出反应混合物且在室温静置过夜。用乙酸乙酯稀释混合物且用水洗涤。用乙酸乙酯萃取水性部分两次且用盐水洗涤合并的有机相两次,经MgSO4干燥,过滤且浓缩,得到140mg淡棕色油状物。约30mg该物质经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到标题化合物(6.0mg,31%)。通过LCMS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),8.86(s,1H),8.78(br.s.,1H),7.79(d,J=7.3Hz,2H),7.39-7.32(m,2H),7.31-7.26(m,1H),5.94(d,J=11.0Hz,1H),4.04(s,3H),3.93-3.85(m,1H),3.75(d,J=10.3Hz,1H),3.60(d,J=9.9Hz,1H),3.46-3.41(m,1H),3.27(t,J=11.4Hz,1H),2.31(s,3H),1.53(d,J=11.7Hz,1H),1.48-1.36(m,1H),1.32-1.21(m,1H),1.16(d,J=12.5Hz,1H)。LC/MS(465,[M+H]+)。LCMS:Rt=1.67min;(ES):m/z(M+H)+465(柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm)。
实施例144
5-(二甲基-1,2-噁唑-4-基)-11-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-6’-(甲磺酰基)-3-硝基-2,3’-联吡啶
将(6-(甲磺酰基)吡啶-3-基)硼酸(1g,4.97mmol)、2,5-二溴-3-硝基吡啶(1.402g,4.97mmol)、碳酸钾(2.063g,14.9mmol)及PdCl2(dppf)-CH2Cl2加合物(0.406g,0.497mmol)吸收于50mL二噁烷中。添加2mL水。使反应混合物鼓泡氩气5min同时超声波处理。将烧瓶盖好且在80℃加热3h。浓缩且将粘稠黑色残余物吸收于二氯甲烷中且在120gISCO(硅胶)柱上用5%EtOAc/二氯甲烷至80%EtOAc/二氯甲烷(1200mL)洗脱纯化。浓缩含有产物的级份,得到0.43g标题化合物(24%)。LC/MS:RT=0.96min(柱:Waters AcquitySDS;流动相A:100%水,0.1%TFA;流动相B:100%ACN,0.1%TFA;温度:50℃;梯度:历经2.2min 2%B至98%B;流速:0.8mL/min;检测:UV 220nm)。1H NMR(400MHz,DMSO-d6)δ9.25(d,J=2.3Hz,1H),9.01(d,J=2.0Hz,1H),8.99(dd,J=2.3,0.8Hz,1H),8.41-8.34(m,1H),8.21(dd,J=8.2,0.9Hz,1H),3.39(s,3H)。
步骤2:3-溴-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶
向100mL圆底烧瓶中装入5-溴-6’-(甲磺酰基)-3-硝基-2,3’-联吡啶(0.43g,1.20mmol)、三苯基膦(0.787g,3.00mmol)及1,2-二氯苯(50mL)。将烧瓶置于油浴中,用冷凝器将烧瓶盖好且加热至170℃且保持1.5h。在氮气气流下除去挥发物过夜,然后在与真空泵连接的旋转蒸发器上除去。将残余物吸收于二氯甲烷中且在80g ISCO柱上先后用二氯甲烷至40%EtOAc/二氯甲烷(300mL)和40%EtOAc/二氯甲烷至80%EtOAc/二氯甲烷(600mL)洗脱纯化。合并含有第一主要洗脱峰的级份,得到0.1g标题化合物(26%)。LC/MS:RT=0.88min(柱:Waters Acquity SDS;流动相A:100%水,0.1%TFA;流动相B:100%ACN,0.1%TFA;温度:50℃;梯度:历经2.2min 2%B至98%B;流速:0.8mL/min;检测:UV 220nm)。1HNMR(400MHz,DMSO-d6)δ12.79(br.s.,1H),9.02-8.83(m,1H),8.74(d,J=11.0Hz,1H),8.30(d,J=10.8Hz,1H),8.00(t,J=10.3Hz,1H),3.41(br.s.,3H)。
步骤3:(S)-3-溴-7-(甲磺酰基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶
将3-溴-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(0.10g,0.307mmol)、(R)-苯基(四氢-2H-吡喃-4-基)甲醇(0.088g,0.460mmol)及三苯基膦(0.121g,0.460mmol)混悬于20mL THF中。在冰浴中冷却且经由21.5号针头以每5秒1滴的速率逐滴添加DIAD(0.089ml,0.460mmol)。加完DIAD后,搅拌15min,移开浴且搅拌1h。在氮气下浓缩过夜。将残余物吸收于二氯甲烷中且在24g ISCO柱上用5%EtOAc/二氯甲烷至80%EtOAc/二氯甲烷(800mL)洗脱纯化。合并含有标题化合物的级份,得到101mg。LC/MS与标题化合物一致,其混杂有3-溴-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶。物质直接在后续反应中使用。
步骤4:5-(二甲基-1,2-噁唑-4-基)-11-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
将(S)-3-溴-7-(甲磺酰基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.060mmol)溶解于1.5mL二噁烷及(3,5-二甲基异噁唑-4-基)硼酸(12.7mg,0.090mmol)及0.2mL水中。添加碳酸钾(24.9mg,0.180mmol)及PdCl2(dppf)-CH2Cl2加合物(3.4mg,4.20μmol且鼓泡氩气同时超声波处理5min。将瓶盖好且在100℃加热50min。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为6.4mg(21%)且其通过LCMS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.79min。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.50min。1HNMR(500MHz,DMSO-d6)δ8.92(d,J=8.1Hz,1H),8.67(s,1H),8.58(br.s.,1H),8.02(d,J=8.1Hz,1H),7.82(d,J=7.3Hz,2H),7.37-7.29(m,2H),7.28-7.15(m,1H),5.93(d,J=8.8Hz,1H),3.95-3.85(m,1H),3.76(d,J=10.3Hz,1H),3.70(d,J=10.6Hz,1H),3.36(br.s.,3H),3.25(t,J=11.4Hz,1H),2.53(s,3H),2.35(s,3H),1.59-1.39(m,2H),1.35-1.22(m,1H),1.15(d,J=11.7Hz,1H)。
实施例145
5-(二甲基-1H-1,2,3-三唑-5-基)-11-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
将(S)-3-溴-7-(甲磺酰基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.060mmol)溶解于1.5mL NMP中且添加1,4-二甲基-1H-1,2,3-三唑(9.3mg,0.096mmol)。添加四甲基乙酸铵(12.0mg,0.090mmol)及二(三苯基膦)氯化钯(II)(3.0mg,4.20μmol)。使氩气鼓泡通过混合物同时超声波处理5min。将瓶盖好且在100℃加热33h,然后冷却且过滤瓶的内含物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经15min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为2.8mg(9%)且其通过LCMS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=2.27,M+H=517。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.27,M+H=517。1H NMR(500MHz,DMSO-d6)δ8.96(d,J=8.1Hz,1H),8.76(s,2H),8.05(d,J=8.1Hz,1H),7.83(d,J=7.7Hz,2H),7.33(t,J=7.5Hz,2H),7.26(t,J=7.3Hz,1H),5.93(br.s.,1H),4.07(s,3H),3.95-3.83(m,1H),3.82-3.60(m,2H),3.47-3.36(m,1H),3.31-3.19(m,1H),2.34(s,3H),1.59-1.49(m,1H),1.49-1.38(m,1H),1.38-1.22(m,1H),1.16(d,J=12.1Hz,1H)。
实施例146
5-(1,4-二甲基-1H-吡唑-5-基)-11-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
将(S)-3-溴-7-(甲磺酰基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.060mmol)溶解于1.5mL二噁烷及1,4-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(20.0mg,0.090mmol)及0.2mL水中。添加碳酸钾(24.9mg,0.180mmol)及PdCl2(dppf)-CH2Cl2加合物(3.4mg,4.20μmol)且鼓泡氩气同时超声波处理5min。将瓶盖好且在100℃加热50min且过滤。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为6.3mg(20%)且其通过LCMS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.75min,M+H=516。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.52min,M+H=516。1H NMR(500MHz,DMSO-d6)δ8.94(d,J=7.7Hz,1H),8.73-8.64(m,2H),8.04(d,J=7.7Hz,1H),7.83(d,J=7.7Hz,2H),7.47(s,1H),7.36-7.28(m,2H),7.28-7.19(m,1H),5.94(d,J=11.4Hz,1H),3.94-3.85(m,1H),3.80-3.65(m,2H),3.52(s,3H),3.48-3.35(m,2H),3.25(t,J=10.8Hz,1H),2.07(s,3H),1.50(br.s.,1H),1.44(d,J=12.1Hz,1H),1.36-1.21(m,1H),1.17(d,J=12.8Hz,1H)。
实施例147
11-(二甲基-1,2-噁唑-4-基)-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(47.3mg,0.1mmol)及(3,5-二甲基异噁唑-4-基)硼酸(28.2mg,0.200mmol)溶解于1.7mL二噁烷中。添加PdCl2(dppf)-CH2Cl2加合物(8.2mg,10.0μmol)及0.3mL碳酸钠(300μl,0.300mmol)。鼓泡氩气2min同时超声波处理。将瓶盖好且在100℃加热4h,停止加热且搅拌3天。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经35min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为3.6mg(6.7%)且其通过LCMS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.84min,M+H=534。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.82min,M+H=534。1H NMR(500MHz,DMSO-d6)δ8.72(d,J=8.1Hz,1H),8.63(s,1H),8.52(br.s.,1H),7.76(d,J=7.3Hz,2H),7.62(d,J=7.7Hz,1H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),6.06(br.s.,1H),4.02(s,3H),3.94-3.86(m,1H),3.75(d,J=9.2Hz,1H),3.64(br.s.,1H),3.25(t,J=11.2Hz,1H),2.79(s,3H),2.62(s,3H),2.31(s,3H),1.62(br.s.,1H),1.51-1.36(m,1H),1.36-1.20(m,1H),1.15(br.s.,1H)
实施例148
5-(二甲基-1H-1,2,3-三唑-5-基)-11-(1,4-二甲基-1H-吡唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(47.3mg,0.1mmol)及(1,4-二甲基-1H-吡唑-5-基)硼酸(28.0mg,0.200mmol)溶解于1.7mL二噁烷中。添加PdCl2(dppf)-CH2Cl2加合物(8.2mg,10.0μmol)及0.3mL 1M碳酸钠水溶液(300μl,0.300mmol)。鼓泡氩气2min同时超声波处理。在油浴中在100℃加热4h。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为13.6mg(25%)且其通过LCMS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.78min,M+H=533。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.80min,M+H=533。1H NMR(500MHz,DMSO-d6)δ8.70(d,J=8.1Hz,1H),8.64(s,1H),8.54(br.s.,1H),7.81(d,J=8.1Hz,1H),7.76(d,J=7.3Hz,2H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.2Hz,1H),6.80(s,1H),6.04(br.s.,1H),4.36(s,3H),4.03(s,3H),3.90(d,J=11.4Hz,1H),3.75(d,J=9.2Hz,1H),3.65(br.s.,1H),3.25(t,J=11.4Hz,1H),2.31(s,3H),2.26(s,3H),1.62(br.s.,1H),1.52-1.37(m,1H),1.37-1.24(m,1H),1.19(br.s.,1H)。
实施例149
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-[1-(丙-2-基)-1H-吡唑-4-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(47.3mg,0.1mmol)及1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(47.2mg,0.200mmol)溶解于1.7mL二噁烷中。添加PdCl2(dppf)-CH2Cl2加合物(8.2mg,10.0μmol)及0.3mL碳酸钠(300μl,0.300mmol)。鼓泡氩气2min同时超声波处理。在微波中在100℃加热2小时。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min20-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为21.1mg(38%)且其通过LCMS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.82min,M+H=547。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.83min,M+H=547。1H NMR(500MHz,DMSO-d6)δ8.61(s,1H),8.58-8.54(m,2H),8.52(br.s.,1H),8.28(s,1H),7.84(d,J=7.7Hz,2H),7.71(d,J=8.1Hz,1H),7.31(t,J=7.5Hz,2H),7.23(t,J=7.5Hz,1H),5.92(br.s.,1H),4.66(dt,J=13.4,6.5Hz,1H),4.03(s,3H),3.91(d,J=11.4Hz,1H),3.77(d,J=10.6Hz,2H),3.33-3.22(m,1H),2.31(s,3H),1.53(d,J=6.6Hz,7H),1.44(d,J=11.7Hz,1H),1.37-1.25(m,1H),1.25-1.16(m,1H)。
实施例150
11-(1-环丙基-1H-吡唑-4-基)-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(47.3mg,0.1mmol)及1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(46.8mg,0.200mmol)溶解于1.7mL二噁烷中。添加PdCl2(dppf)-CH2Cl2加合物(8.2mg,10.0μmol)及0.3mL碳酸钠(300μl,0.300mmol)。鼓泡氩气2min同时超声波处理。在100℃加热2小时。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经20min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为34.0mg(61%)且其通过LCMS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.81min,M+H=545。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.15min,M+H=545。H NMR(500MHz,DMSO-d6)δ8.63(s,1H),8.58-8.53(m,2H),8.51(br.s.,1H),8.26(s,1H),7.84(d,J=7.7Hz,2H),7.70(d,J=8.1Hz,1H),7.31(t,J=7.5Hz,2H),7.22(t,J=7.2Hz,1H),5.93(br.s.,1H),4.03(s,3H),3.90(dd,J=7.5,3.5Hz,2H),3.76(d,J=10.6Hz,2H),3.26(t,J=11.4Hz,1H),2.30(s,3H),1.56(d,J=10.6Hz,1H),1.51-1.38(m,1H),1.36-1.24(m,1H),1.24-1.14(m,3H),1.14-0.95(m,3H)。
实施例151
11-(4-环丙基哌嗪-1-基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(30mg,0.063mmol)溶解于1.5mL DMSO中。添加1-环丙基哌嗪2HCl(125mg,0.630mmol)及TEA(264μl,1.89mmol)。将瓶盖好且在100℃加热过夜。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 60-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为16.7mg(46%)且其通过LCMS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=2.00min,M+H=566。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.47min,M+H=566。1H NMR(500MHz,DMSO-d6)δ8.40(s,1H),8.32(br.s.,1H),8.26(d,J=8.8Hz,1H),7.77(d,J=7.7Hz,2H),7.34-7.28(m,2H),7.25-7.19(m,1H),6.90(d,J=8.8Hz,1H),5.72(br.s.,1H),4.01(s,3H),3.88(d,J=11.4Hz,1H),3.80(br.s.,1H),3.65(br.s.,1H),3.25(br.s.,1H),2.74(d,J=2.9Hz,4H),1.72(br.s.,1H),1.46(br.s.,1H),1.43-1.32(m,1H),1.25(br.s.,2H)。
实施例152
11-(4-叔丁基哌嗪-1-基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(30mg,0.063mmol)溶解于1mL DMSO中。添加1-(叔丁基)哌嗪(90mg,0.630mmol)及1-(叔丁基)哌嗪(90mg,0.630mmol)。将瓶盖好且在100℃加热2h。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为17.9mg(46%)且其通过LCMS分析估算的纯度为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.74min,M+H=582。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.76min,M+H=582。1H NMR(500MHz,DMSO-d6)δ8.46(s,1H),8.44-8.34(m,2H),7.95(s,1H),7.77(d,J=7.7Hz,2H),7.35-7.27(m,3H),7.27-7.21(m,1H),7.18(s,1H),7.08(s,1H),7.02(d,J=8.8Hz,1H),5.76(br.s.,1H),4.80-4.68(m,2H),4.01(s,3H),3.89(d,J=11.0Hz,1H),3.78(d,J=11.4Hz,3H),3.63(br.s.,1H),3.51(br.s.,2H),3.47-3.35(m,3H),3.35-3.19(m,3H),2.56(t,J=5.5Hz,1H),1.49(br.s.,1H),1.42(s,9H),1.32-1.17(m,2H)。
实施例153
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-[4-(丙-2-基)哌嗪-1-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(30mg,0.063mmol)溶解于1mL DMSO中。添加1-异丙基哌嗪(81mg,0.630mmol)。将瓶盖好且在100℃加热41/2h。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经15min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为42.2mg(82%)且其通过LCMS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.71min,M+H=568。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.75min,M+H=568。1H NMR(500MHz,DMSO-d6)δ8.46(s,1H),8.45-8.35(m,2H),7.76(d,J=7.7Hz,2H),7.36-7.27(m,3H),7.27-7.21(m,1H),7.03(d,J=8.8Hz,1H),5.77(br.s.,1H),4.76(br.s.,2H),4.01(s,3H),3.89(d,J=11.4Hz,1H),3.78(d,J=10.3Hz,1H),3.67(br.s.,2H),3.65-3.57(m,2H),3.45-3.33(m,3H),3.33-3.19(m,3H),1.50(br.s.,1H),1.46-1.37(m,1H),1.35(d,J=6.6Hz,6H),1.30-1.16(m,2H)。
实施例154
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-[4-(2,2,2-三氟乙基)哌嗪-1-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(30mg,0.063mmol)溶解于2mL DMSO中。添加1-(2,2,2-三氟乙基)哌嗪2HCl(152mg,0.630mmol)。将瓶盖好且在100℃加热过夜。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为15.2mg且其通过LCMS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=2.10min,M+H=608。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.98min,M+H=608。1H NMR(500MHz,DMSO-d6)δ8.52-8.41(m,2H),8.31(d,J=8.8Hz,1H),7.77(d,J=7.3Hz,2H),7.35-7.28(m,2H),7.27-7.21(m,2H),6.96(d,J=9.2Hz,1H),5.74(br.s.,1H),4.01(s,3H),3.88(br.s.,1H),3.79(d,J=11.7Hz,1H),3.63(br.s.,1H),3.44-3.22(m,4H),2.85(br.s.,4H),2.56(t,J=5.5Hz,1H),1.46(br.s.,1H),1.38(d,J=12.1Hz,1H),1.24(br.s.,2H)。
实施例155
5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:5-(5-溴-3-硝基吡啶-2-基)-2-氯嘧啶
在250mL厚壁烧瓶中添加(2-氯嘧啶-5-基)硼酸(1g,6.32mmol)、2,5-二溴-3-硝基吡啶(1.780g,6.32mmol)/90mL THF。添加磷酸三钾(2.68g,12.6mmol)及PdCl2(dppf)-CH2Cl2加合物(0.103g,0.126mmol)。使氩气鼓泡通过混合物同时超声波处理1min。将烧瓶盖好且在油浴中在65℃加热过夜。浓缩,得到棕色固体。粗物质在120g ISCO柱上用20%EtOAc/己烷至50%EtOAc/己烷(20倍柱体积)洗脱纯化。浓缩含有标题化合物的级份,得到0.72g(36%产率)黄色固体。1H NMR(400MHz,CDCl3)δ9.04(d,J=2.0Hz,1H),8.83(s,2H),8.58(d,J=2.0Hz,1H)。
步骤2:7-溴-2-氯-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶
将5-(5-溴-3-硝基吡啶-2-基)-2-氯嘧啶(0.76g,2.41mmol)及DPPE(1.440g,3.61mmol)混悬于15mL 1,2-二氯苯中。反应物完全溶解后,将瓶置于160℃的油浴中且加热30min。冷却瓶且在与高真空泵连接的旋转蒸发器上除去挥发物。粗物质在80g ISCO柱上用5%EtOAc/己烷至90%EtOAc/己烷(25倍柱体积)洗脱纯化。浓缩含有标题化合物的级份,得到0.41g(58%产率)。1H NMR(400MHz,DMSO-d6)δ13.00(br.s.,1H),9.43(s,1H),8.73(s,1H),8.28(d,J=1.7Hz,1H)。
步骤3:(S)-7-溴-2-氯-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶
将(R)-苯基(四氢-2H-吡喃-4-基)甲醇(0.556g,2.89mmol)及7-溴-2-氯-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶(0.41g,1.45mmol)溶解于5mL二氯甲烷中。添加三苯基膦(0.759g,2.89mmol)且在冰浴中冷却瓶。添加DIAD(0.562ml,2.89mmol),将瓶盖好且使浴融化且搅拌过夜。在40g ISCO柱上用10%EtOAc/己烷至50%EtOAc/己烷(600mL)洗脱纯化。浓缩含有标题化合物的级份,得到1.2g黄色油状物。物质进一步在40g ISCO柱上用0%EtOAc/己烷至20%EtOAc/己烷(20倍柱体积)洗脱纯化。浓缩主要峰,得到0.67g标题化合物,其如1H NMR所确定仍含有杂质。物质直接用于后续反应。1HNMR(400MHz,CDCl3)δ9.39(s,1H),8.69(d,J=2.0Hz,1H),8.07(d,J=1.7Hz,1H),7.63(d,J=7.3Hz,2H),7.43-7.31(m,14H),6.34(br.s.,3H),4.05(dd,J=11.2,4.9Hz,3H),3.92(d,J=11.5Hz,4H),3.50-3.38(m,4H),3.38-3.23(m,3H),1.54-1.44(m,4H),1.23-1.10(m,5H),0.95-0.85(m,2H)。
步骤4:5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-7-溴-2-氯-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶(325mg,0.710mmol)及1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(274mg,0.710mmol)溶解于4mL DMF中。添加碘化亚铜(27.0mg,0.142mmol)、Et3N(148μl,1.07mmol)及四(三苯基膦)钯(82mg,0.071mmol)。鼓泡氩气30秒同时超声波处理。将瓶盖好且置于100℃的油浴中且加热3h。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及0.1%三氟乙酸;流动相B:95:5甲醇:水及0.1%三氟乙酸;梯度:历经20min 50-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为2.3mg(0.5%)且其通过LCMS分析估算的纯度为86%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.73min,M+H=535。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.32min,M+H=535。1H NMR(500MHz,DMSO-d6)δ9.73(s,1H),8.76(s,1H),8.66(br.s.,1H),7.79(d,J=7.3Hz,2H),7.38-7.30(m,3H),7.29-7.19(m,2H),5.98(br.s.,1H),4.54(s,3H),4.04(s,3H),3.95-3.85(m,1H),3.76(d,J=11.7Hz,1H),3.67(br.s.,1H),3.27(t,J=11.0Hz,1H),2.78(s,3H),2.31(s,3H),1.58(br.s.,1H),1.50-1.38(m,1H),1.37-1.22(m,1H),1.22-1.07(m,1H)。
实施例156
5-(二甲基-1H-1,2,3-三唑-5-基)-11-[4-(2H3)甲基哌嗪-1-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:5-溴-11-[4-(2H3)甲基哌嗪-1-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-7-溴-2-氯-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶(30mg,0.066mmol)溶解于1mL DMSO中。添加4-(2H3)甲基哌嗪2HCl(57.7mg,0.328mmol)。将瓶盖好且在100℃加热1h。将反应混合物分配于EtOAc与水之间。用盐水洗涤有机层,经MgSO4干燥,过滤且汽提,得到37mg呈黄红色油状物的标题化合物。LC/MS及1H NMR与不纯的产物一致。物质直接在后续反应中使用。LC/MS:RT=0.93,M+H=524,纯度=69%(柱:Waters Acquity SDS;流动相A:100%水,0.1%TFA;流动相B:100%ACN,0.1%TFA;温度:50℃;梯度:历经2.2min 2%B至98%B;流速:0.8mL/min;检测:UV 220nm)。
步骤2:5-(二甲基-1H-1,2,3-三唑-5-基)-11-[4-(2H3)甲基哌嗪-1-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将5-溴-11-[4-(2H3)甲基哌嗪-1-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(54.5mg,0.141mmol)溶解于2mL DMF中。添加碘化亚铜(I)(2.69mg,0.014mmol)、Et3N(30μl,0.212mmol)及四(三苯基膦)钯(8.15mg,7.05μmol)。鼓泡氩气30秒同时超声波处理。将瓶盖好且置于100℃的油浴中且加热过夜。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及0.1%三氟乙酸;流动相B:95:5甲醇:水及0.1%三氟乙酸;梯度:历经20min 30-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为1.5mg(3.8%)且其通过LCMS分析估算的纯度为96%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.52min,M+H=541。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.60min,M+H=541。1H NMR(500MHz,DMSO-d6)δ9.10(s,1H),8.46(s,1H),8.36(br.s.,1H),7.76(d,J=7.7Hz,2H),7.33(t,J=7.5Hz,2H),7.25(t,J=7.3Hz,1H),5.64(br.s.,1H),4.03-3.92(m,8H),3.87(d,J=10.3Hz,1H),3.80(d,J=11.7Hz,1H),3.59(br.s.,1H),3.29-3.20(m,1H),2.28(s,3H),1.43(br.s.,1H),1.37(d,J=12.5Hz,1H),1.30-1.19(m,5H)
实施例157
11-(4-环丙基哌嗪-1-基)-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:(S)-7-溴-2-(4-环丙基哌嗪-1-基)-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶
将(S)-7-溴-2-氯-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶(34mg,0.074mmol)溶解于1mL DMSO中。添加1-环丙基哌嗪2HCl(73.9mg,0.371mmol)。将瓶盖好且在100℃加热1h。将反应混合物分配于EtOAc与水之间。用盐水洗涤有机层,经MgSO4干燥,过滤且汽提,得到37mg呈黄红色油状物的标题化合物。使用方法A的LC/MS指示存在杂质。RT=1.0min,M+H=547。物质直接用于后续反应。
步骤2:11-(4-环丙基哌嗪-1-基)-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-7-溴-2-(4-环丙基哌嗪-1-基)-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶(37mg,0.068mmol)及1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(52.2mg,0.135mmol)溶解于2mL DMF中。添加碘化亚铜(I)(2.6mg,0.014mmol)、Et3N(28μl,0.203mmol)及四(三苯基膦)钯(7.8mg,6.76μmol)。鼓泡氩气30秒同时超声波处理。将瓶盖好且置于100℃的油浴中且加热过夜。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为1.9mg且其通过LCMS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.96min,M+H=564。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.96min,M+H=564。1H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.47(br.s.,1H),8.36(br.s.,1H),7.76(d,J=7.7Hz,2H),7.33(t,J=7.3Hz,2H),7.25(t,J=7.3Hz,1H),5.63(br.s.,1H),4.00(s,3H),3.95(br.s.,4H),3.88(d,J=12.1Hz,1H),3.81(d,J=11.4Hz,1H),3.59(br.s.,1H),3.30-3.22(m,1H),2.28(s,3H),1.71(br.s.,1H),1.43(br.s.,1H),1.41-1.32(m,1H),1.28(br.s.,2H)。
实施例158
(2R,6R)-4-[5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2,6-二甲基-1λ6,4-硫吗啉-1,1-二酮
步骤1:(2R,6R)-4-(7-溴-9-((S)-苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶-2-基)-2,6-二甲基硫吗啉1,1-二氧化物
将(S)-7-溴-2-氯-9-(苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶(34mg,0.074mmol)溶解于1mL DMSO中。添加(2R,6R)-2,6-二甲基硫吗啉1,1-二氧化物HCl(44.2mg,0.221mmol)。将瓶盖好且在100℃加热1h。将反应混合物分配于EtOAc与水之间。用盐水洗涤有机层,经MgSO4干燥,过滤且汽提,得到40mg呈红棕色油状物的标题化合物。LC/MS指示存在杂质。RT=1.29min,M+H=584,M+3H=586(柱:WatersAcquity SDS;流动相A:100%水,0.1%TFA;流动相B:100%ACN,0.1%TFA;温度:50℃;梯度:历经2.2min 2%B至98%B;流速:0.8mL/min;检测:UV 220nm)。物质直接用于后续反应。
步骤2:(2R,6R)-4-[5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10,12-四氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2,6-二甲基-1λ6,4-硫吗啉-1,1-二酮
在含有(2R,6R)-4-(7-溴-9-((S)-苯基(四氢-2H-吡喃-4-基)甲基)-9H-吡啶并[2’,3’:4,5]吡咯并[2,3-d]嘧啶-2-基)-2,6-二甲基硫吗啉1,1-二氧化物(8mg,0.014mmol)的20mL厚壁瓶中添加4-甲氧基-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑(5.1mg,0.027mmol)。添加1.5mL DMF、四甲基乙酸铵(7.3mg,0.055mmol)及二(三苯基膦)氯化钯(II)(0.961mg,1.37μmol)。使氩气鼓泡通过混合物1min同时超声波处理。将瓶盖好且在100℃加热15h。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经20min 40-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为0.9mg(11%)且其通过LCMS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.97min,M+H=617。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.68min,M+H=617。1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),8.52(s,1H),8.42(br.s.,1H),7.74(d,J=7.3Hz,3H),7.34(t,J=7.5Hz,2H),7.27(t,J=7.5Hz,1H),5.68(br.s.,1H),5.13(d,J=13.2Hz,2H),4.08(s,3H),4.01(s,3H),3.90(s,3H),3.80(d,J=9.9Hz,1H),3.41-3.31(m,5H),3.24(br.s.,1H),1.42(br.s.,3H),1.33(br.s.,8H),1.23(br.s.,3H)。
实施例159
2-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
步骤1:4-(2H3)甲基-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑
在环境温度将抗坏血酸钠(344mg,1.74mmol)于水(2170μL)中的溶液添加至三甲基(2H3-丙-1-炔-1-基)硅烷(根据PCT国际申请2007112352(2007年10月04日)制备)(200mg,1.74mmol)及(叠氮基甲基)三甲基硅烷(294mg,1.91mmol)于t-BuOH(4340μL)中的搅拌的溶液中。然后逐滴添加五水合硫酸铜(II)(87.0mg,0.347mmol)/水(2170μL)。将反应混合物在环境温度搅拌16h,然后其用水(10mL)及乙酸乙酯(20mL)稀释。分离两层且水层再用乙酸乙酯(2×20mL)洗涤。经硫酸钠干燥合并的有机相,滤除固体且减压除去挥发物。粗物质使用硅胶柱色谱用乙酸乙酯/己烷梯度(0-60%)洗脱纯化。分离呈无色油状物的4-(2H3)甲基-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑(125mg,0.725mmol,42%)。1H NMR(500MHz,CDCl3)δ7.16(br.s.,1H),3.89(s,2H),0.15(s,9H);LC/MS(M+H)=173.2;LC/MS RT=1.20min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90ACN:水及0.1%TFA;流动相B:90:10ACN:水及0.1%TFA;温度:40℃:梯度:历经2min 0-100%B;流速:1mL/min)。
步骤2:4-(2H3)甲基-1-甲基-1H-1,2,3-三唑
在0℃将TBAF(60.9ml,60.9mmol)逐滴添加至4-(2H3)甲基-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑(按照3-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-5-[(S)-氧杂环己烷-4-基(苯基)甲基]-5H-吡啶并[3,2-b]吲哚-7-甲酸甲酯制备)(8.75g,50.8mmol)及水(1.83mL,102mmol)于THF(203mL)中的搅拌的溶液中。在该温度搅拌反应混合物1h,然后将其由冷浴取出且升温至环境温度。在环境温度搅拌反应混合物16小时。由水层减压除去挥发物。所得油状物使用硅胶柱色谱用甲醇/乙酸乙酯梯度(0-20%)纯化。分离呈黄色油状物的1-甲基-4-(2H3)甲基-1H-1,2,3-三唑(4.67g,46.6mmol,92%)。1H NMR(500MHz,DMSO-d6)δ7.76(s,1H),3.98(s,3H);LC/MS(M+H)=101.2;LC/MSRT=0.57min(柱:Waters AquityBEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
步骤3:4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑
在-78℃在氮气下将n-BuLi(9.59mL,24.0mmol)/己烷逐滴添加至1-甲基-4-(2H3)甲基-1H-1,2,3-三唑(2.00g,20.0mmol)于THF(49.9mL)中的搅拌的溶液中。白色析出物在添加时形成。在该温度搅拌反应混合物30min,然后逐滴添加三丁基氯化锡(5.96mL,22.0mmol)。再搅拌反应混合物10min,然后移开冷浴且历经30min将反应混合物升温至环境温度。用氯化铵饱和水溶液(20mL)淬灭反应混合物且用10%LiCl水溶液(20mL)稀释。分离各层且用乙醚(3×30mL)洗涤水层。经硫酸钠干燥合并的有机相,滤除固体且减压除去挥发物。粗物质使用硅胶柱色谱用乙酸乙酯/己烷梯度(0-50%)纯化。分离呈无色油状物的1-甲基-5-(三丁基锡烷基)-4-(2H3)甲基-1H-1,2,3-三唑(6.02g,15.5mmol,77%)。1H NMR(500MHz,DMSO-d6)δ3.97(s,3H),1.62-1.39(m,6H),1.35-1.25(m,6H),1.24-1.10(m,6H),0.91-0.83(m,9H)。
步骤4:11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
使用氮气将3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶(110mg,0.389mmol)、1-甲基-5-(三丁基锡烷基)-4-(2H3)甲基-1H-1,2,3-三唑(167mg,0.428mmol)、四(三苯基膦)钯(0)(45.0mg,0.039mmol)、碘化亚铜(I)(14.8mg,0.078mmol)及三乙胺(65μL,0.334mmol)于DMF(3.89mL)中的溶液脱气3min。然后加热反应混合物至80℃且保持16小时。减压除去挥发物且粗物质使用硅胶柱色谱用甲醇/乙酸乙酯梯度(0-20%)纯化。分离呈白色固体状的11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(68.4mg,0.227mmol,58%)。1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),9.23(s,1H),8.66(d,J=1.8Hz,1H),8.16(d,J=1.8Hz,1H),7.69(s,1H),4.01(s,3H);LC/MS(M+H)=302.15;LC/MS RT=1.048min(柱:Phenomenex Luna 30×2.0mm3μ;流动相A:10:90ACN:水及0.1%TFA;流动相B:90:10ACN:水及0.1%TFA;温度:40℃:梯度:历经2min 0-100%B;流速:1mL/min)。
步骤5:甲磺酸(R)-(4-氟苯基)(氧杂环己烷-4-基)甲基酯
在0℃在氮气下将甲磺酰氯(78μL,0.999mmol)逐滴添加至(R)-(4-氟苯基)(四氢-2H-吡喃-4-基)甲醇(140.0mg,0.666mmol)及Et3N(186μL,1.33mmol)于DCM(6.7mL)中的搅拌的溶液中。搅拌反应混合物15min,然后由冷浴取出反应容器且历经1小时将反应混合物升温至环境温度。用NaHCO3饱和水溶液(5mL)淬灭反应混合物。分离各层且用乙醚(2×7mL)洗涤水层。经硫酸钠干燥合并的有机相,滤除固体且减压除去挥发物。产物不另经纯化即使用。
步骤6:11-氯-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
在60℃在氮气下在DMF(1.1mL)中搅拌11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(65.0mg,0.215mmol)、甲磺酸(R)-(4-氟苯基)(氧杂环己烷-4-基)甲基酯(186.0mg,0.646mmol)及碳酸铯(281mg,0.862mmol)16小时。减压除去挥发物且粗物质使用硅胶柱色谱用甲醇/乙酸乙酯梯度(0-20%)纯化。合并含有所需产物的级份且经由离心蒸发干燥,得到11-氯-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(13.5mg,0.027mmol,13%产率)。LC/MS(M+H)=494.25;LC/MS RT=1.492min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90ACN:水及0.1%TFA;流动相B:90:10ACN:水及0.1%TFA;温度:40℃:梯度:历经2min 0-100%B;流速:1mL/min)。
步骤7:1-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮
在二噁烷(273μL)中用氮气将11-氯-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(13.5mg,0.027mmol)、PdCl2(dppf)-CH2Cl2加合物(2.2mg,2.70μmol)及三丁基(1-乙氧基乙烯基)锡烷(11μL,0.033mmol)脱气3min。然后加热反应容器至80℃且保持16小时。向反应混合物中逐滴添加浓HCl水溶液(1mL)且将其在环境温度搅拌1h。用碳酸氢钠饱和水溶液(7mL)淬灭反应混合物且用乙酸乙酯(10mL)稀释。分离各层且用乙酸乙酯(2×10mL)洗涤水层。经硫酸钠干燥合并的有机相,滤除固体且减压除去挥发物。使用反相制备型HPLC(TFA/MeOH/水)纯化产物。推定产物产率为100%。
步骤8:2-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
在氮气下在-20℃向1-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮(13.0mg,0.026mmol)于THF(259μL)中的搅拌的溶液中添加甲基溴化镁(3M于乙醚中,259μL,0.778mmol)。在该温度搅拌反应混合物2小时。然后仍在-20℃用氯化铵饱和水溶液(8mL)淬灭反应混合物且用乙酸乙酯(20mL)稀释。由冷浴取出混合物且升温至环境温度。分离各层且用第二份乙酸乙酯(20mL)洗涤水相。经硫酸钠干燥合并的有机相,滤除固体且减压除去挥发物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到2-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇(3.2mg,6.1μmol,23%产率)。1H NMR(500MHz,DMSO-d6)δ=9.34(s,1H),8.61(s,1H),8.48(br.s.,1H),8.27(br.s,1H),7.77-7.68(m,2H),7.19(t,J=8.8Hz,2H),5.84(d,J=11.4Hz,1H),4.01(s,3H),3.93-3.87(m,1H),3.76-3.72(m,2H),3.29-3.22(m,1H),3.17(s,1H),1.69-1.63(m,1H),1.60-1.51(m,7H),1.31(d,J=8.8Hz,1H),0.99(d,J=13.2Hz,1H);LC/MS(M+H)=518.30;LC/MSRT=1.128min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90ACN:水及0.1%TFA;流动相B:90:10ACN:水及0.1%TFA;温度:40℃:梯度:历经2min 0-100%B;流速:1mL/min)。
实施例160
8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-11-氯-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
在60℃在氮气下在DMF(1.2mL)中搅拌3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶(67.0mg,0.237mmol)、甲磺酸(R)-(4-氟苯基)(氧杂环己烷-4-基)甲基酯(171.0mg,0.593mmol,按照2-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇制备)及碳酸铯(309.0mg,0.949mmol)。减压除去挥发物且粗物质使用硅胶柱色谱用乙酸乙酯/己烷梯度(0-100%)纯化。合并含有所需产物的级份且经由离心蒸发干燥,得到5-溴-11-氯-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(113.0mg,0.237mmol,100%产率)。LC/MS(M+H)=474.05;LC/MS RT=1.861min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90ACN:水及0.1%TFA;流动相B:90:10ACN:水及0.1%TFA;温度:40℃:梯度:历经2min 0-100%B;流速:1mL/min)。
步骤2:8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
使用氮气将5-溴-11-氯-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(110.0mg,0.232mmol)、1-甲基-5-(三丁基锡烷基)-4-(2H3)甲基-1H-1,2,3-三唑(99.0mg,0.255mmol)、四(三苯基膦)钯(0)(26.8mg,0.023mmol)、碘化亚铜(I)(8.8mg,0.046mmol)及三乙胺(39μL,0.278mmol)于DMF(2.3mL)中的溶液脱气3min。然后加热反应混合物至80℃且保持16小时。减压除去挥发物且经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到经分离的8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(3.3mg,5.7μmol,3%)。1H NMR(500MHz,DMSO-d6)δ9.57(s,1H),8.80-8.54(m,2H),8.33(br.s.,1H),7.82-7.76(m,2H),7.23-7.16(m,2H),5.98(d,J=11.0Hz,1H),4.22(s,3H),4.06(br.s.,3H),3.90(d,J=9.5Hz,1H),3.74(d,J=9.2Hz,1H),3.51-3.42(m,1H),3.38(d,J=4.4Hz,1H),3.25(t,J=11.7Hz,1H),1.68(d,J=12.1Hz,1H),1.61-1.47(m,1H),1.38-1.27(m,1H),1.01(d,J=12.5Hz,1H);LC/MS(M+H)=558.30;LC/MSRT=1.260min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90ACN:水及0.1%TFA;流动相B:90:10ACN:水及0.1%TFA;温度:40℃:梯度:历经2min 0-100%B;流速:1mL/min)。
实施例161
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(丙-1-烯-2-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:5-(3,5-二甲基异噁唑-4-基)吡啶-3-胺
向20mL闪烁瓶中添加(S)-3-溴-7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(0.223mmol,102mg)、1,4-二甲基-1H-1,2,3-三唑(0.223mmol,21.7mg)、Me4NOAc(0.223mmol,29.7mg)及PdCl2(PPh3)2(0.016mmol,11.0mg),然后添加4mLNMP。用氩气代替空气。在搅拌下加热密封的反应瓶至100℃且过夜。将其冷却至室温且用EtOAc稀释且用盐水洗涤两次。有机层经MgSO4干燥且浓缩。其在ISCO 24g硅胶柱上先后用50-100%EtOAc/己烷和0-10%MeOH/EtOAc洗脱纯化,得到标题化合物(139mg,60%纯度)。使用24g硅胶柱用0-100%(10%(2MNH3)/EtOAc)/DCM洗脱进行第二次ISCO,得到58mg标题化合物(粘稠油状物)。LC/MS(M+H)=473.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤2:5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(丙-1-烯-2-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(0.059mmol,28mg)称重至50mL圆底烧瓶中,然后添加4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(0.074mmol,12.44mg),然后添加K2CO3(0.148mmol,20.4mg)。向其中添加4mL THF及2mL水,然后添加Pd(PPh3)4(2.37μmol,2.7mg)。用氮气代替空气且在搅拌下加热所得混合物至85℃且过夜。将其冷却至室温,用EtOAc稀释,用盐水洗涤,经MgSO4干燥且浓缩,得到粗混合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为0.5mg且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=2.12min,LC/MS(M+H)=479.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.11min,LC/MS(M+H)=479.5。1H NMR(500MHz,DMSO-d6)δ8.59(d,J=7.3Hz,3H),7.83(d,J=7.7Hz,2H),7.76(d,J=8.4Hz,1H),7.35-7.28(m,2H),7.26-7.19(m,1H),6.22(s,1H),5.85(br.s.,1H),5.56(s,1H),4.05(s,3H),3.92-3.88(m,1H),3.77(d,J=11.7Hz,2H),3.25(t,J=11.7Hz,1H),2.40(s,3H),2.32(s,3H),1.48(br.s.,1H),1.46-1.37(m,1H),1.28(d,J=9.5Hz,1H),1.25-1.17(m,2H)。LC/MS(M+H)=479.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例162
1-{5-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]噻吩-2-基}乙-1-酮
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(丙-1-烯-2-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的Suzuki偶联反应类似的程序以23%产率将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及(5-乙酰基噻吩-2-基)硼酸转化成标题化合物。通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。RT=1.92min,LCMS(M+H)=563.4。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.92min,LCMS(M+H)=563.5。1H NMR(500MHz,DMSO-d6)δ8.70(d,J=8.1Hz,1H),8.64(s,2H),8.13-8.08(m,2H),8.06(d,J=3.7Hz,1H),7.88(d,J=7.7Hz,2H),7.31(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),5.83(d,J=9.2Hz,1H),4.09-4.02(m,3H),3.98-3.91(m,1H),3.78(d,J=11.4Hz,1H),3.40(br.s.,2H),3.32-3.23(m,1H),2.63(s,3H),2.33(s,3H),1.56-1.39(m,2H),1.37-1.19(m,2H);LC/MS(M+H)=563.3[柱:Waters AquityBEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例163
5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-3-溴-7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(300mg,0.657mmol)、1,4-二甲基-1H-1,2,3-三唑(77mg,0.788mmol)、Me4NOAc(87mg,0.657mmol)及PdCl2(PPh3)2(32.3mg,0.046mmol)称重至瓶中且添加12mL NMP且用氩气代替空气。在搅拌下在100℃加热密封的反应瓶过夜。次日上午,LC/MS显示作为主要峰的单烷基化产物及显著量的二烷基化产物。将其冷却至室温且用EtOAc稀释且用盐水洗涤两次。有机层经MgSO4干燥且浓缩,得到粗混合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为99%。分析型LC/MS注射用于确定最终纯度。条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。RT=1.51min,LC/MS(M+H)=534.5。1H NMR(500MHz,DMSO-d6)δ8.82(d,J=8.1Hz,1H),8.67(s,1H),8.57(br.s.,1H),7.77-7.71(m,3H),7.35-7.29(m,2H),7.27-7.21(m,1H),6.06(br.s.,1H),4.38(s,3H),4.03(s,3H),3.90(s,1H),3.74(d,J=10.6Hz,1H),3.62(br.s.,1H),3.40(s,1H),3.24(t,J=11.2Hz,1H),2.54(s,3H),2.31(s,3H),1.62(br.s.,1H),1.51-1.39(m,1H),1.35-1.21(m,1H),1.14(d,J=12.5Hz,1H);LC/MS(M+H)=534.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例164
5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(R)-3-溴-7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30.0mg,0.066mmol)、1,4-二甲基-1H-1,2,3-三唑(25.5mg,0.263mmol)、Me4NOAc(21.8mg,0.164mmol)及PdCl2(dppf)2.DCM(3.8mg,4.60μmol)称重至20mL闪烁瓶中且添加3mL DMF且用氮气代替空气。在搅拌下加热反应混合物至100℃。1h后,将其冷却至室温,过滤且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为4.2mg且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。RT=1.52min,LC/MS(M+H)=534.5,LC/MS(M+H)=534.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.50min,LC/MS(M+H)=534.5。1H NMR(500MHz,DMSO-d6)δ8.82(d,J=8.1Hz,1H),8.67(s,1H),8.58(br.s.,1H),7.74(t,J=7.2Hz,3H),7.36-7.28(m,2H),7.28-7.20(m,1H),6.07(br.s.,1H),4.39(s,3H),4.03(s,3H),3.89(d,J=13.6Hz,1H),3.75(d,J=9.9Hz,1H),3.61(br.s.,1H),3.43(t,J=11.2Hz,1H),3.24(t,J=11.4Hz,1H),2.55(s,3H),2.31(s,3H),1.62(br.s.,1H),1.51-1.39(m,1H),1.29(d,J=8.4Hz,1H),1.15(br.s.,1H);LC/MS(M+H)=534.3[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min2-98%B;流速:0.8mL/min]。
实施例165
5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的反应类似的程序由(R)-3-溴-7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及4-(2H3)甲基-1-甲基-1H-1,2,3-三唑以39%产率制备标题化合物。通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.51min,LC/MS(M+H)=540.5。注射2:条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.51min,LC/MS(M+H)=540.3。1H NMR(500MHz,DMSO-d6)δ8.82(d,J=8.1Hz,1H),8.67(s,1H),8.58(br.s.,1H),7.74(t,J=7.7Hz,3H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),6.06(br.s.,1H),4.39(s,3H),4.03(s,3H),3.89(d,J=12.1Hz,1H),3.75(d,J=8.4Hz,1H),3.61(br.s.,1H),3.49-3.40(m,1H),3.24(t,J=11.2Hz,1H),1.62(br.s.,1H),1.51-1.38(m,1H),1.36-1.21(m,1H),1.15(br.s.,1H);LC/MS(M+H)=540.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例166
5,11-二(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的反应类似的程序以29%产率将5-溴-11-氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及4-甲氧基-1-[(三甲基硅烷基)甲基]-1H-1,2,3-三唑转化成标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 60-100%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.74min,LC/MS(M+H)=566.3。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.78min,LC/MS(M+H)=566.3。1H NMR(500MHz,DMSO-d6)δ8.76(d,J=8.4Hz,1H),8.65(s,1H),8.49(br.s.,1H),7.90(d,J=8.1Hz,1H),7.74(d,J=7.7Hz,2H),7.34(t,J=7.5Hz,2H),7.26(t,J=7.3Hz,1H),6.07(br.s.,1H),4.59(s,3H),4.16(s,3H),4.08(s,3H),4.03(s,3H),3.90(d,J=11.4Hz,1H),3.73(d,J=11.0Hz,1H),3.55(br.s.,1H),3.41(br.s.,4H),3.25(t,J=10.8Hz,1H),1.66(br.s.,1H),1.52-1.41(m,1H),1.29(d,J=12.1Hz,1H),1.12(br.s.,1H);LC/MS(M+H)=566.2[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例167
11-氯-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的反应类似的程序以54%产率将5-溴-11-氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及4-甲氧基-1-[(三甲基硅烷基)甲基]-1H-1,2,3-三唑转化成标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 50-100%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为89%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.52min,LC/MS(M+H)=489.2。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.02min,LC/MS(M+H)=489.2。1H NMR(500MHz,DMSO-d6)δ8.71-8.64(m,1H),8.60-8.55(m,1H),8.52(br.s.,1H),8.41(d,J=8.4Hz,1H),7.76(t,J=6.2Hz,2H),7.41-7.21(m,4H),5.87(br.s.,1H),4.10(d,J=2.9Hz,3H),4.03(d,J=3.3Hz,3H),3.89(d,J=9.9Hz,1H),3.80-3.71(m,1H),3.68(br.s.,1H),3.56(br.s.,1H),3.29-3.22(m,1H),1.56(br.s.,1H),1.51(br.s.,1H),1.42(d,J=10.3Hz,1H),1.29-1.21(m,1H),1.17(d,J=11.7Hz,1H),1.08(d,J=13.2Hz,1H);LC/MS(M+H)=489.2[柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例168
5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的反应类似的程序以3%产率将5-溴-11-氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及4-(2H3)甲基-1-甲基-1H-1,2,3-三唑转化成标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为0.8mg且其通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.44min,LC/MS(M+H)=540.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.75min,LC/MS(M+H)=540.2。1H NMR(500MHz,DMSO-d6)δ9.57(s,1H),8.72(s,1H),8.66(br.s.,1H),8.31(br.s.,1H),7.73(d,J=7.7Hz,2H),7.40-7.34(m,2H),7.32-7.25(m,1H),5.97(d,J=11.0Hz,1H),4.22(s,3H),4.05(s,3H),3.90(d,J=11.0Hz,1H),3.74(d,J=9.2Hz,1H),3.51-3.44(m,2H),3.26(t,J=11.9Hz,1H),1.71(d,J=13.2Hz,1H),1.60-1.50(m,1H),1.39-1.27(m,1H),1.01(d,J=11.4Hz,1H);LC/MS(M+H)=540.3[柱:Waters Aquity BEHC18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例169
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-甲腈
向微波瓶中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20.0mg,0.042mmol)、二氰基锌(14.9mg,0.127mmol)、Pd(PPh3)4(9.8mg,8.46μmol)及NMP(1.5mL)。鼓泡氩气且在氩气下密封。将其在微波中在150℃加热十分钟。将其过滤且经由制备型LC/MS在以下条件下纯化粗物质(滤液):柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为10.3mg(52%)且其通过LC/MS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.73min,LC/MS(M+H)=464.4。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.66min,LC/MS(M+H)=464.4。1H NMR(500MHz,DMSO-d6)δ8.88(d,J=8.1Hz,1H),8.75(s,1H),8.69(br.s.,1H),8.02(d,J=7.7Hz,1H),7.79(d,J=7.7Hz,2H),7.38-7.31(m,2H),7.30-7.24(m,1H),5.95(br.s.,1H),4.04(s,3H),3.92-3.85(m,1H),3.75(d,J=9.2Hz,1H),3.63(d,J=9.9Hz,1H),3.47-3.40(m,1H),3.30-3.22(m,1H),2.32(s,3H),1.55(br.s.,1H),1.48-1.37(m,1H),1.34-1.22(m,1H),1.11(d,J=13.2Hz,1H);LC/MS(M+H)=464.3[柱:WatersAquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例170
5-(二甲基-1H-1,2,3-三唑-5-基)-11-(1-乙氧基乙烯基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向20mL闪烁瓶中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(42mg,0.089mmol)、三丁基(1-乙氧基乙烯基)锡烷(35.3mg,0.098mmol)及2mL二噁烷。然后添加Pd(dppf)2Cl2.DCM(7.3mg,8.88μmol)且用氩气代替空气且在氩气下将瓶密封。在搅拌下将其加热至100℃且过夜。将其冷却至室温,用2.5mL THF稀释且用针筒过滤器过滤且在旋转蒸发器上将滤液浓缩为总共0.5mL。经由制备型LC/MS在以下条件下纯化该物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经5min 50-90%B且然后在100%B保持15min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为69%且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。RT=2.20min,LC/MS(M+H)=509.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.11min,LC/MS(M+H)=509.5。1H NMR(500MHz,DMSO-d6)δ8.65(d,J=8.1Hz,1H),8.62-8.56(m,2H),7.82(d,J=7.3Hz,2H),7.73(d,J=8.1Hz,1H),7.34-7.28(m,2H),7.26-7.20(m,1H),5.85(br.s.,1H),5.73(s,1H),4.66(s,1H),4.10-4.02(m,5H),3.90(d,J=7.3Hz,1H),3.77(d,J=10.6Hz,2H),3.43-3.38(m,4H),3.28-3.20(m,1H),2.34-2.29(m,3H),1.54-1.37(m,5H),1.33-1.24(m,1H),1.24-1.17(m,1H);LC/MS(M+H)=509.3[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例171
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]乙-1-酮
向装有溶解于5mL THF中的20mg 5-(二甲基-1H-1,2,3-三唑-5-基)-11-(1-乙氧基乙烯基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的20mL闪烁瓶中添加0.5mL 6N HCl水溶液且在室温搅拌。1.5h后,其用5mL K2CO3水溶液(5%溶液)淬灭且用EtOAc稀释。分离有机层,用盐水洗涤,经MgSO4干燥,过滤且在旋转蒸发器上浓缩,得到粗混合物。其经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有标题产物的级份且经由离心蒸发干燥。产物的产率为88%且其通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.85min,LC/MS(M+H)=481.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.19min,LC/MS(M+H)=481.1。1H NMR(500MHz,DMSO-d6)δ8.80(d,J=7.7Hz,1H),8.74-8.68(m,2H),8.02(d,J=8.1Hz,1H),7.86(d,J=7.3Hz,2H),7.33(t,J=7.3Hz,2H),7.25(t,J=7.3Hz,1H),5.91(br.s.,1H),4.07(s,3H),3.94-3.88(m,1H),3.87-3.73(m,2H),3.42-3.38(m,1H),3.29(t,J=11.2Hz,1H),2.92(s,3H),2.33(s,3H),1.56-1.49(m,1H),1.49-1.38(m,1H),1.37-1.27(m,1H),1.25-1.18(m,1H);LC/MS(M+H)=481.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例172
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基](1-2H)乙-1-醇
将(S)-1-(3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-基)乙酮(13.0mg,0.027mmol)溶解于5mL MeOH中且在冰浴中搅拌。添加NaBD4(1.4mg,0.032mmol)且搅拌10min。移开冰浴且使反应混合物在搅拌下升温至室温。2h后,添加额外的1当量NaBD4且搅拌。3天后,添加额外的3当量NaBD4且搅拌。3h后,通过用10mL EtOAc稀释淬灭反应混合物且用盐水洗涤。有机层经MgSO4干燥,过滤且浓缩,得到粗混合物。将粗混合物溶解于1.5mL MeOH中且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为9.7mg(72%)且其通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.49min,LC/MS(M+H)=484.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.45min,LC/MS(M+H)=484.5。1H NMR(500MHz,DMSO-d6)δ8.66-8.45(m,3H),7.84(br.s.,2H),7.58(q,J=7.8Hz,1H),7.31(d,J=5.9Hz,2H),7.28-7.17(m,1H),5.88(br.s.,1H),4.04(d,J=7.7Hz,3H),2.89(d,J=8.1Hz,2H),2.74(d,J=7.7Hz,2H),2.32(d,J=7.7Hz,3H),1.91(br.s.,2H),1.57(t,J=6.8Hz,3H),1.51(br.s.,1H),1.39(br.s.,1H),1.25(d,J=5.1Hz,1H),1.13(br.s.,1H);LC/MS(M+H)=484.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例173
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]乙-1-醇
将(S)-1-(3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-基)乙酮(15.0mg,0.031mmol)溶解于5mL MeOH中且在冰浴中搅拌。添加NaBH4(5.9mg,0.156mmol)且搅拌10min。移开冰浴且使反应混合物在搅拌下升温至室温。20min后,通过用10mL EtOAc稀释淬灭反应混合物且用盐水洗涤。有机层经MgSO4干燥,过滤且浓缩,得到粗混合物。将粗混合物溶解于1.5mL MeOH中且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为12.5mg(83%)且其通过LC/MS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.48min,LC/MS(M+H)=483.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.93min,LC/MS(M+H)=483.5。1H NMR(500MHz,DMSO-d6)δ8.63-8.51(m,3H),7.84(d,J=6.2Hz,2H),7.58(t,J=7.9Hz,1H),7.35-7.26(m,2H),7.26-7.19(m,1H),5.87(br.s.,1H),5.03(t,J=6.4Hz,1H),4.04(s,3H),3.76(br.s.,2H),3.38(br.s.,2H),3.25(t,J=11.2Hz,1H),2.90(s,2H),2.74(s,2H),2.32(s,3H),1.91(s,3H),1.50(d,J=17.6Hz,1H),1.44-1.33(m,1H),1.26(d,J=10.3Hz,1H),1.13(br.s.,1H);LC/MS(M+H)=483.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例174
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇
将(S)-1-(3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-基)乙酮(15.0mg,0.031mmol)溶解于5mL THF中且在冰浴中搅拌。添加甲基溴化镁(3M于乙醚中,0.156mL,0.468mmol)且搅拌。移开冰浴且使反应混合物在搅拌下升温至室温。10min后,通过添加1mL丙酮及用15mL EtOAc稀释淬灭反应混合物。其用盐水洗涤且有机层经MgSO4干燥,过滤且浓缩,得到粗混合物。将粗混合物溶解于1.5mL DMF中。其经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经15min 55-95%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为7.3mg(47%)且其通过LC/MS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.64min,LC/MS(M+H)=497.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.96min,LC/MS(M+H)=497.5。1H NMR(500MHz,DMSO-d6)δ8.63-8.54(m,3H),7.85(d,J=7.7Hz,2H),7.74(d,J=8.1Hz,1H),7.33-7.27(m,2H),7.25-7.20(m,1H),5.80(br.s.,1H),4.05(s,3H),3.93-3.88(m,1H),3.78(d,J=10.3Hz,2H),3.37(s,2H),3.23(t,J=11.2Hz,1H),2.33(s,3H),1.67(s,6H),1.46(br.s.,2H),1.40(d,J=8.8Hz,1H),1.32-1.21(m,1H),1.16(d,J=12.1Hz,1H);LC/MS(M+H)=497.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例175
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇
遵循与在2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇的合成中描述的反应类似的程序以26%产率由1-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮及甲基溴化镁合成标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为20.1mg(26%)且其通过LC/MS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.64min,LC/MS(M+H)=500.0。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.97min,LC/MS(M+H)=500.1。1H NMR(500MHz,DMSO-d6)δ8.64-8.53(m,3H),7.86(d,J=7.7Hz,2H),7.74(d,J=8.1Hz,1H),7.33-7.27(m,2H),7.25-7.19(m,1H),5.80(br.s.,1H),4.06(s,3H),3.90(d,J=10.3Hz,1H),3.78(d,J=10.6Hz,2H),3.40-3.33(m,1H),3.23(t,J=11.6Hz,1H),1.67(s,6H),1.46(br.s.,1H),1.43-1.35(m,1H),1.32-1.21(m,1H),1.16(d,J=12.1Hz,1H);LC/MS(M+H)=500.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例176
2-(5-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}噻吩-2-基)丙-2-醇
步骤1:1-(5-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}噻吩-2-基)乙-1-酮
将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(0.168mmol,80mg)称重至微波瓶中,然后添加(5-乙酰基噻吩-2-基)硼酸(0.252mmol,42.9mg)、K2CO3(0.420mmol,43.0mg)、Pd(PPh3)4(0.017mmol,19.4mg)、6mL二噁烷及3mL水。用氮气代替空气且在微波中在140℃加热所得混合物0.25h。其用EtOAc稀释且用盐水洗涤,经MgSO4干燥且浓缩,得到粗混合物。其在ISCO 12g硅胶柱上用0-25%(10%2N氨/EtOAc)/EtOAc洗脱纯化,得到61mg(52%)标题化合物。LC/MS(M+H)=566.2[柱:Waters Aquity BEHC18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤2:2-(5-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}噻吩-2-基)丙-2-醇.
遵循与在2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇的合成中描述的反应类似的程序以13%产率由1-(5-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}噻吩-2-基)乙-1-酮及甲基溴化镁合成标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min35-45%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.91min,LC/MS(M+H)=582.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.34min,LC/MS(M+H)=582.1。1H NMR(500MHz,DMSO-d6)δ8.62-8.49(m,3H),7.85(d,J=7.7Hz,2H),7.88(d,J=8.1Hz,1H),7.80(d,J=4.0Hz,1H),7.30(t,J=7.5Hz,2H),7.23(t,J=7.3Hz,1H),7.03(d,J=3.7Hz,1H),5.78(br.s.,1H),4.03(s,3H),3.96-3.83(m,2H),3.78(d,J=10.6Hz,1H),3.43-3.35(m,1H),3.30(t,J=10.8Hz,1H),3.17(d,J=4.8Hz,1H),1.59(s,6H),1.53-1.37(m,2H),1.35-1.22(m,2H);LC/MS(M+H)=582.3[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min2-98%B;流速:0.8mL/min]。
实施例177
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基](1,1,1-2H3)丙-2-醇
将(S)-1-(3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-基)乙酮(15.0mg,0.031mmol)溶解于5mL THF中且在冰浴中搅拌。添加甲基锂-D3(3M于乙醚中,0.624mL,0.312mmol)且搅拌。移开冰浴且使反应混合物在搅拌下升温至室温。20min后,通过添加1mL丙酮及用15mL EtOAc稀释淬灭反应混合物。其用盐水洗涤且有机层经MgSO4干燥,过滤且浓缩,得到粗混合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 55-95%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为4.3mg(28%)且其通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.66min,LC/MS(M+H)=500.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.65min,LC/MS(M+H)=500.5。1H NMR(500MHz,DMSO-d6)δ8.63-8.54(m,3H),7.85(d,J=7.3Hz,2H),7.74(d,J=8.4Hz,1H),7.34-7.27(m,2H),7.26-7.21(m,1H),5.80(br.s.,1H),4.05(s,3H),3.92-3.87(m,1H),3.78(d,J=10.6Hz,1H),3.41-3.34(m,3H),3.23(t,J=11.0Hz,1H),2.33(s,3H),1.67(s,3H),1.46(br.s.,1H),1.40(d,J=12.1Hz,1H),1.31-1.21(m,1H),1.16(d,J=12.1Hz,1H);LC/MS(M+H)=500.3[柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例178
5-(二甲基-1H-1,2,3-三唑-5-基)-11-(吗啉-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(25.0mg,0.053mmol)溶解于2mL吗啉中且在150℃微波处理15min。在旋转蒸发器上浓缩反应瓶的内含物,得到粗混合物。将粗混合物溶解于1.5mL DMF中,过滤,经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为17.6mg(64%)且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.67min,LC/MS(M+H)=524.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.67min,LC/MS(M+H)=524.5。1H NMR(500MHz,DMSO-d6)δ8.41(s,1H),8.37-8.26(m,2H),7.77(d,J=7.3Hz,2H),7.35-7.27(m,2H),7.26-7.19(m,1H),6.90(d,J=8.8Hz,1H),5.73(br.s.,1H),4.00(s,3H),3.91-3.70(m,10H),3.63(br.s.,1H),3.39(d,J=4.0Hz,1H),3.26(t,J=10.8Hz,1H),2.29(s,3H),1.48(d,J=11.4Hz,1H),1.43-1.33(m,1H),1.28(br.s.,1H),1.24(br.s.,1H);LC/MS(M+H)=524.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例179
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氮杂环丁烷-3-醇
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-11-(吗啉-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的反应类似的程序以25%产率由(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及氮杂环丁烷-3-醇盐酸盐制备标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经20min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.49min,LC/MS(M+H)=510.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.51min,LC/MS(M+H)=510.5。1H NMR(500MHz,DMSO-d6)δ8.45-8.35(m,2H),8.25(d,J=8.4Hz,1H),7.81(d,J=7.7Hz,2H),7.35-7.28(m,2H),7.26-7.20(m,1H),6.41(d,J=8.4Hz,1H),5.66(br.s.,1H),4.72(br.s.,1H),4.45-4.37(m,2H),4.00(s,3H),3.93(dd,J=8.8,4.0Hz,2H),3.87(d,J=11.4Hz,1H),3.79(d,J=11.7Hz,1H),3.69(br.s.,1H),3.36(t,J=11.6Hz,1H),3.27(t,J=10.3Hz,1H),2.29(s,3H),1.43(br.s.,1H),1.39-1.32(m,1H),1.23(br.s.,2H);LC/MS(M+H)=510.2[柱:WatersAquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例180
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-4-甲基哌啶-4-醇
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-11-(吗啉-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的反应类似的程序以75%产率由11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及4-甲基哌啶-4-醇制备标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经20min 10-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.62min,LC/MS(M+H)=552.1。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.07min,LC/MS(M+H)=552.1。1H NMR(500MHz,DMSO-d6)δ8.46-8.38(m,2H),8.25(d,J=8.8Hz,1H),7.78(d,J=7.3Hz,2H),7.31(t,J=7.5Hz,2H),7.23(t,J=7.3Hz,1H),6.94(d,J=8.8Hz,1H),5.70(br.s.,1H),4.14(d,J=9.2Hz,2H),4.01(s,3H),3.88(d,J=10.3Hz,1H),3.80(d,J=10.6Hz,1H),3.69-3.55(m,3H),3.48(br.s.,2H),3.44(br.s.,3H),3.39-3.31(m,1H),3.28-3.20(m,1H),2.56(t,J=5.5Hz,4H),2.29(s,3H),1.69-1.53(m,4H),1.49-1.35(m,2H),1.26(br.s.,2H),1.21(s,3H);LC/MS(M+H)=552.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例181
5-(二甲基-1H-1,2,3-三唑-5-基)-N,N-二甲基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-胺
标题化合物为在1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氮杂环丁烷-3-醇的合成期间获得的副产物(37%产率)。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经20min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.81min,LC/MS(M+H)=482.5。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.83min,LC/MS(M+H)=482.5。1H NMR(500MHz,DMSO-d6)δ8.49-8.44(m,2H),8.29(d,J=9.2Hz,1H),7.79(d,J=7.3Hz,2H),7.33-7.29(m,2H),7.25-7.20(m,1H),6.78(d,J=8.8Hz,1H),5.71(br.s.,1H),4.00(s,3H),3.87(d,J=12.1Hz,1H),3.78(d,J=10.6Hz,1H),3.65(s,7H),3.36(t,J=11.0Hz,1H),2.96-2.86(m,1H),2.53-2.42(m,1H),2.28(s,3H),1.44(br.s.,1H),1.37(d,J=8.4Hz,1H),1.25(br.s.,2H);LC/MS(M+H)=482.3[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min2-98%B;流速:0.8mL/min]。
实施例182
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(40.0mg,0.085mmol)及硫吗啉1,1-二氧化物(45.7mg,0.338mmol)及三乙胺(94μl,0.677mmol)溶解于1.5mL DMSO中且在175℃微波处理2小时。过滤固体且经由制备型LC/MS在以下条件下纯化粗物质(滤液):柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为15.8mg(32%)且其通过LC/MS分析估算的纯度为99%。注射条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.74min,LC/MS(M+H)=572.5。1H NMR(500MHz,DMSO-d6)δ8.43(s,1H),8.37(d,J=8.8Hz,1H),7.94(s,1H),7.73(d,J=7.3Hz,2H),7.34-7.28(m,2H),7.26-7.20(m,1H),7.05(d,J=8.8Hz,1H),5.73(br.s.,1H),4.37-4.25(m,4H),4.01(s,3H),3.87(d,J=11.4Hz,1H),3.77(d,J=12.1Hz,1H),3.56(d,J=13.2Hz,1H),3.48(br.s.,4H),3.41(t,J=11.4Hz,1H),3.25-3.21(m,1H),2.29(s,3H),1.49(br.s.,1H),1.45-1.35(m,1H),1.29-1.16(m,2H);LC/MS(M+H)=572.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例183
8-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-8-氮杂二环[3.2.1]辛-3-醇
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以22%产率由11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02 ,7]十三碳-1(9),2(7),3,5,10,12-六烯及8-氮杂二环[3.2.1]辛-3-醇获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为10.6mg且其通过LCMS分析估算的纯度为100%。分析型LC/MS注射用于确定最终纯度。注射条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.42min,LC/MS(M+H)=567.6。1H NMR(500MHz,DMSO-d6)δ8.36(s,1H),8.32(br.s.,1H),8.22(d,J=8.8Hz,1H),7.95(s,1H),7.80(d,J=7.7Hz,2H),7.33-7.28(m,2H),7.25-7.19(m,1H),6.73(d,J=8.8Hz,1H),5.64(br.s.,1H),4.71(br.s.,1H),4.01(s,3H),3.94-3.84(m,2H),3.79(d,J=11.0Hz,1H),3.66(br.s.,1H),3.46(br.s.,1H),3.35(t,J=11.6Hz,1H),3.27-3.20(m,1H),2.40(d,J=7.0Hz,2H),2.10(br.s.,2H),2.06(br.s.,3H),1.79(d,J=14.3Hz,2H),1.44(br.s.,1H),1.36(d,J=11.7Hz,1H),1.24(br.s.,2H);LC/MS(M+H)=567.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例184
11-{8-氮杂二环[3.2.1]辛-8-基}-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以14%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及8-氮杂二环[3.2.1]辛烷盐酸盐获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:Waters Xbridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.28min,LC/MS(M+H)=551.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.21min,LC/MS(M+H)=551.3。1H NMR(500MHz,DMSO-d6)δ8.37(s,1H),8.32(br.s.,1H),8.23(d,J=8.8Hz,1H),7.81(d,J=7.7Hz,2H),7.30(t,J=7.5Hz,2H),7.22(t,J=7.3Hz,1H),6.74(d,J=8.8Hz,1H),5.64(br.s.,1H),4.72(br.s.,2H),4.01(s,3H),3.87(d,J=11.4Hz,1H),3.79(d,J=11.0Hz,1H),3.67(br.s.,1H),3.38-3.31(m,1H),3.28-3.19(m,1H),2.12(br.s.,2H),1.94(d,J=7.3Hz,3H),1.86(br.s.,2H),1.53(br.s.,3H),1.43(br.s.,1H),1.40-1.32(m,1H),1.25(br.s.,2H);LC/MS(M+H)=551.3[柱:Waters AquityBEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例185
4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-1λ6,4-硫吗啉-1,1-二酮
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以28%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及硫吗啉1,1-二氧化物获得标题化合物。过滤固体且经由制备型LC/MS在以下条件下纯化粗滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.45min,LC/MS(M+H)=575.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.09min,LC/MS(M+H)=575.3。1H NMR(500MHz,DMSO-d6)δ8.44(s,1H),8.42-8.34(m,2H),7.74(d,J=7.3Hz,2H),7.31(t,J=7.5Hz,2H),7.23(t,J=7.3Hz,1H),7.06(d,J=8.8Hz,1H),5.73(br.s.,1H),4.37-4.25(m,4H),4.01(s,3H),3.87(d,J=9.2Hz,1H),3.77(d,J=11.0Hz,1H),3.56(br.s.,1H),3.42-3.38(m,1H),3.31-3.21(m,5H),1.50(d,J=12.1Hz,1H),1.44-1.37(m,1H),1.28-1.20(m,2H);LC/MS(M+H)=575.3[柱:Waters Aquity BEHC18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例186
4-(1-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}氮杂环丁烷-3-基)-1λ6,4-硫吗啉-1,1-二酮
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以19%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及4-(氮杂环丁烷-3-基)-1λ6-硫吗啉-1,1-二酮盐酸盐获得标题化合物。过滤固体且经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.49min,LC/MS(M+H)=630.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.44min,LC/MS(M+H)=630.7。1H NMR(500MHz,DMSO-d6)δ8.38(br.s.,1H),8.31(br.s.,1H),8.26(br.s.,1H),7.79(br.s.,2H),7.31(br.s.,2H),7.24(br.s.,1H),6.39(br.s.,1H),5.68(br.s.,1H),4.27(br.s.,2H),4.00(br.s.,5H),3.89(br.s.,4H),3.78(br.s.,1H),3.67(br.s.,2H),3.27(br.s.,2H),3.18(br.s.,5H),2.93(br.s.,5H),1.46(br.s.,1H),1.35(br.s.,3H),0.82(br.s.,1H);LC/MS(M+H)=630.3[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例187
N-[(2,4-二甲氧基苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-胺
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(120mg,0.254mmol)、(2,4-二甲氧基苯基)甲胺(424mg,2.54mmol)及三乙胺(0.4mL)称重至瓶中且在175℃微波处理1.5h。将反应混合物直接加载至24g硅胶柱上且在ISCO上纯化。前4min仅用DCM洗脱,然后用0-5%(10%2M NH3/MeOH)/EtOAc洗脱,得到产率为96%的标题化合物。通过LC/MS确定最终纯度:注射条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.98min,LC/MS(M+H)=604.3。1H NMR(500MHz,DMSO-d6)δ8.33(s,1H),8.28(br.s.,1H),8.12(d,J=8.4Hz,1H),7.80(t,J=5.5Hz,1H),7.63(d,J=4.4Hz,2H),7.28-7.13(m,4H),6.67-6.59(m,2H),6.52(dd,J=8.4,1.8Hz,1H),5.54(br.s.,1H),4.73-4.52(m,2H),3.99(s,3H),3.88-3.78(m,4H),3.67(d,J=10.3Hz,1H),3.53-3.38(m,5H),3.26-3.13(m,1H),3.04(t,J=11.0Hz,1H),2.28(s,3H),1.40-1.20(m,2H),1.16-1.00(m,2H);LC/MS(M+H)=604.3[柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例188
5-(二甲基-1H-1,2,3-三唑-5-基)-11-(4-甲磺酰基哌嗪-1-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以21%产率由1-(甲磺酰基)哌嗪获得标题化合物。将其过滤且经由制备型LC/MS在以下条件下纯化粗物质(滤液):柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.57min,LC/MS(M+H)=601.6。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。RT=2.47min,LC/MS(M+H)=601.7。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.37-8.29(m,2H),7.76(d,J=7.3Hz,2H),7.31(t,J=7.5Hz,2H),7.23(t,J=7.3Hz,1H),6.96(d,J=8.8Hz,1H),5.73(br.s.,1H),4.01(s,3H),3.96-3.90(m,4H),3.88(d,J=9.9Hz,1H),3.78(d,J=10.6Hz,1H),3.62(br.s.,1H),3.46-3.40(m,1H),3.38-3.30(m,4H),3.28(t,J=12.1Hz,1H),2.96(s,3H),2.29(s,3H),1.48(br.s.,1H),1.39(d,J=10.3Hz,1H),1.28(br.s.,1H),1.24(br.s.,2H);LC/MS(M+H)=601.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例189
N-(2-甲磺酰基乙基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-胺
向微波瓶中装入11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(18.0mg,0.038mmol)、Xantphos(1.3mg,2.27μmol)、Cs2CO3(24.6mg,0.076mmol)、Pd(OAc)2(0.4mg,1.9μmol)及二噁烷(2mL)。用氩气代替空气。将其在140℃微波处理0.25hr。将其过滤且经由制备型LC/MS在以下条件下纯化粗物质(滤液):柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为1.3mg且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.39min,LC/MS(M+H)=563.6。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.26min,LC/MS(M+H)=563.6。1H NMR(500MHz,DMSO-d6)δ8.38(s,1H),8.35(br.s.,1H),8.15(d,J=8.4Hz,1H),7.81(d,J=7.3Hz,2H),7.70-7.64(m,1H),7.31(t,J=7.3Hz,2H),7.23(t,J=7.3Hz,1H),6.57(d,J=8.4Hz,1H),5.72(br.s.,1H),4.01(s,3H),3.96-3.92(m,1H),3.86(d,J=9.9Hz,1H),3.78(d,J=11.0Hz,1H),3.69(br.s.,1H),3.57(t,J=7.0Hz,2H),3.35-3.28(m,3H),3.09(s,3H),1.90(s,3H),1.47(br.s.,1H),1.38(d,J=8.8Hz,1H),1.30-1.20(m,2H);LC/MS(M+H)=563.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例190
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2,6-二甲基-1λ6,4-硫吗啉-1,1-二酮非对映异构体A
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以2.5%产率由11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02 ,7]十三碳-1(9),2(7),3,5,10,12-六烯及2,6-二甲基硫吗啉1,1-二氧化物盐酸盐获得标题化合物(两种非对映异构体中的一种)。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经25min 10-100%B且然后在100%B保持5min;流速:20mL/min。合并含有非对映异构体的混合物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge Phenyl,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有非对映异构体的混合物的级份且经由离心蒸发干燥。通过手性分离进一步纯化物质。柱:ChiralPak AD-H,21×250mm,5μm;流动相:20%EtOH/80%CO2;压力:150巴;温度:35℃;流速:40mL/min;UV:365nm;注射:0.35mL;级份收集:峰1:8.80’-11.25’;峰2:13.50’-16.00’。产物的产率对于一种非对映异构体(标题化合物)为2.5%且对于另一种非对映异构体为9.5%。绝对立体化学未确定。两种非对映异构体的纯度均为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.62min,LC/MS(M+H)=600.8。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。RT=2.56min,LC/MS(M+H)=600.7。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.38-8.30(m,2H),7.74(d,J=7.7Hz,2H),7.35-7.28(m,2H),7.27-7.20(m,1H),7.08(dd,J=8.6,4.6Hz,1H),5.76(br.s.,1H),4.34-4.23(m,2H),4.03-3.96(m,3H),3.92-3.85(m,1H),3.76(br.s.,1H),3.56(br.s.,1H),3.25(br.s.,1H),2.31-2.25(m,3H),1.53(br.s.,1H),1.41(d,J=9.5Hz,1H),1.31(t,J=6.2Hz,6H),1.23(br.s.,1H),1.17(br.s.,1H);LC/MS(M+H)=600.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例191
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2,6-二甲基-1λ6,4-硫吗啉-1,1-二酮非对映异构体B
标题化合物为与4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2,6-二甲基-1λ6,4-硫吗啉-1,1-二酮(非对映异构体A)的合成一起以9.5%产率获得的非对映异构体。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.62min,LC/MS(M+H)=600.8。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=1.57min,LC/MS(M+H)=600.7。1H NMR(500MHz,DMSO-d6)δ8.44(s,1H),8.41-8.33(m,2H),7.75(d,J=7.3Hz,2H),7.31(t,J=7.5Hz,2H),7.24(t,J=7.0Hz,1H),7.13(d,J=8.8Hz,1H),5.73(br.s.,1H),4.90(d,J=8.8Hz,1H),4.82(d,J=11.0Hz,1H),4.01(s,3H),3.89(d,J=7.3Hz,1H),3.79(d,J=10.3Hz,1H),3.58(br.s.,1H),3.49-3.42(m,4H),3.23(br.s.,1H),2.30(s,3H),1.49(br.s.,1H),1.42(d,J=9.5Hz,1H),1.39-1.33(m,6H),1.25(br.s.,2H)。
实施例192
5-(二甲基-1H-1,2,3-三唑-5-基)-11-(4-甲磺酰基哌啶-1-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-11-(吗啉-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成中描述的反应类似的程序以39%产率由11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及4-(甲磺酰基)哌啶制备标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.48min,LC/MS(M+H)=600.5。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测,RT=2.38min,LC/MS(M+H)=600.6。1H NMR(500MHz,DMSO-d6)δ8.40(s,1H),8.34(br.s.,1H),8.29(d,J=8.8Hz,1H),7.77(d,J=7.7Hz,2H),7.33-7.26(m,2H),7.25-7.20(m,1H),6.96(d,J=9.2Hz,1H),5.69(br.s.,1H),4.74(br.s.,2H),4.00(s,3H),3.88(d,J=12.5Hz,1H),3.78(d,J=11.7Hz,1H),3.63(br.s.,1H),3.26(t,J=10.6Hz,1H),3.18(t,J=12.3Hz,2H),2.98(s,3H),2.29(s,3H),2.21(d,J=12.1Hz,2H),1.69(d,J=12.8Hz,2H),1.51-1.33(m,2H),1.24(br.s.,2H);LC/MS(M+H)=600.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例193
2,6-二甲基-4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-1λ6,4-硫吗啉-1,1-二酮
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以27%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及2,6-二甲基硫吗啉1,1-二氧化物获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为98%。甲基的绝对构型未确定。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。RT=1.63min,LC/MS(M+H)=603.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.57min,LC/MS(M+H)=603.3。1H NMR(500MHz,DMSO-d6)δ8.44(s,1H),8.37(d,J=8.8Hz,1H),7.95(s,1H),7.75(d,J=7.7Hz,2H),7.31(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),7.13(d,J=8.8Hz,1H),5.74(br.s.,1H),4.90(d,J=9.5Hz,1H),4.82(d,J=12.5Hz,1H),4.02(s,3H),3.90(d,J=11.4Hz,1H),3.79(d,J=11.7Hz,1H),3.57(br.s.,1H),3.42(s,1H),3.38-3.28(m,6H),3.27-3.19(m,1H),1.49(br.s.,1H),1.47-1.39(m,1H),1.38-1.33(m,6H),1.25(br.s.,2H)。LC/MS(M+H)=603.3[柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例194
5-(二甲基-1H-1,2,3-三唑-5-基)-11-(甲基硫基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向微波瓶中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(11.0mg,0.023mmol),然后添加甲硫醇钠(2.4mg,0.035mmol)。向其中添加DMF(1.5mL)且在微波中在125℃加热所得混合物10min。通过添加一滴水将其淬灭且在室温搅拌几分钟。然后将其过滤且经由制备型LC/MS在以下条件下纯化滤液(粗):柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为42%且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.82min,LC/MS(M+H)=485.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.01min,LC/MS(M+H)=485.4。1H NMR(500MHz,DMSO-d6)δ8.61-8.51(m,2H),8.43(d,J=8.1Hz,1H),7.79(d,J=7.3Hz,2H),7.38-7.29(m,3H),7.25(d,J=7.0Hz,1H),5.84(br.s.,1H),4.04(s,3H),3.89(d,J=11.7Hz,1H),3.78(d,J=10.6Hz,1H),3.72(br.s.,1H),3.42-3.33(m,2H),3.28(t,J=11.9Hz,1H),2.80(s,3H),2.31(s,3H),1.49(br.s.,1H),1.47-1.37(m,1H),1.33-1.18(m,2H)。LC/MS(M+H)=485.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例195
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-磺酰胺
向溶解于1.5mL DSMO中的(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(25.0mg,0.053mmol)中添加Na2S.9H2O(0.264mmol)。在微波中加热所得混合物至170℃且保持20min。用盐水稀释反应混合物且用10%MeOH/EtOAc萃取三次。在旋转蒸发器上浓缩合并的有机层且溶解于10mL MeCN中。缓慢添加含有0.6mL 30%过氧化氢、20mL MeCN及0.14mL亚硫酰氯的另一个瓶的内含物,然后在室温搅拌4min。然后添加1mL 28%氢氧化铵且冷却至0℃。向该混合物中添加2滴吡啶且然后移开冰浴。搅拌所得反应混合物0.5hr。通过添加5mL 1M HCl淬灭反应混合物且然后用稀K2CO3中和。使用EtOAc萃取产物且在旋转蒸发器上浓缩有机层。将残余物溶解于2mL二噁烷中,过滤且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为2.5mg且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.31min,LC/MS(M+H)=518.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.30min,LC/MS(M+H)=518.4。1H NMR(500MHz,DMSO-d6)δ8.87(d,J=8.1Hz,1H),8.74-8.64(m,2H),7.96(d,J=7.7Hz,1H),7.90(d,J=7.3Hz,2H),7.80(s,2H),7.31(t,J=7.2Hz,2H),7.25(t,J=7.2Hz,1H),5.98(br.s.,1H),4.06(s,3H),3.88(d,J=10.6Hz,1H),3.83(br.s.,1H),3.73(d,J=10.6Hz,1H),3.47(t,J=11.4Hz,1H),3.39(d,J=1.1Hz,1H),3.32-3.24(m,1H),2.33(s,3H),1.52(br.s.,1H),1.47-1.37(m,1H),1.30(d,J=8.4Hz,1H),1.12(d,J=11.4Hz,1H)。LC/MS(M+H)=518.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例196
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(吡咯烷-1-磺酰基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-磺酰胺的合成中描述的反应类似的程序以13%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及吡咯烷获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.75min,LC/MS(M+H)=572.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.59min,LC/MS(M+H)=572.5。1H NMR(500MHz,DMSO-d6)δ8.92(d,J=7.7Hz,1H),8.76-8.67(m,2H),7.96(d,J=7.7Hz,1H),7.81(d,J=7.3Hz,2H),7.36-7.30(m,2H),7.29-7.21(m,1H),5.89(d,J=8.8Hz,1H),4.05(s,3H),3.90(d,J=5.5Hz,1H),3.77(d,J=12.1Hz,1H),3.66(d,J=10.3Hz,1H),3.59-3.46(m,4H),3.39(s,1H),3.21(t,J=11.4Hz,1H),2.33(s,3H),1.76(br.s.,4H),1.53(br.s.,1H),1.47-1.35(m,1H),1.33-1.21(m,1H),1.16(d,J=10.6Hz,1H)。LC/MS(M+H)=572.3[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例197
5-(二甲基-1H-1,2,3-三唑-5-基)-11-(吗啉-4-磺酰基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-磺酰胺的合成中描述的反应类似的程序以8%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及吗啉获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为96%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.61min,LC/MS(M+H)=588.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.50min,LC/MS(M+H)=588.5。1H NMR(500MHz,DMSO-d6)δ8.94(d,J=8.1Hz,1H),8.82-8.74(m,2H),7.95(d,J=8.1Hz,1H),7.86(d,J=7.3Hz,2H),7.35-7.30(m,2H),7.29-7.23(m,1H),5.87(d,J=10.3Hz,1H),4.08(s,3H),3.93-3.86(m,1H),3.77(d,J=12.8Hz,1H),3.71(t,J=4.4Hz,5H),3.42-3.19(m,6H),2.35(s,3H),1.51(d,J=12.5Hz,1H),1.46-1.36(m,1H),1.29(d,J=8.1Hz,1H),1.17(d,J=12.5Hz,1H)。LC/MS(M+H)=588.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例198
5-(二甲基-1H-1,2,3-三唑-5-基)-11-[(4-甲基哌嗪-1-基)磺酰基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-磺酰胺的合成中描述的反应类似的程序以7%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及1-甲基哌嗪获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经25min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.56min,LC/MS(M+H)=601.5。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.51min,LC/MS(M+H)=601.5。1H NMR(500MHz,DMSO-d6)δ8.93(d,J=8.1Hz,1H),8.81-8.73(m,2H),7.94(d,J=8.1Hz,1H),7.87(d,J=7.3Hz,2H),7.32(t,J=7.5Hz,2H),7.26(t,J=7.0Hz,1H),5.86(d,J=10.3Hz,1H),4.08(s,3H),3.93-3.85(m,2H),3.76(d,J=9.9Hz,1H),3.71(br.s.,1H),3.44-3.29(m,4H),3.25(t,J=11.2Hz,1H),2.43(br.s.,4H),2.34(s,3H),2.18(s,3H),1.49(br.s.,1H),1.45-1.35(m,1H),1.34-1.22(m,1H),1.15(d,J=11.7Hz,1H)。LC/MS(M+H)=601.4[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例199
5-(二甲基-1H-1,2,3-三唑-5-基)-N-甲基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-磺酰胺
遵循与在5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-磺酰胺的合成中描述的反应类似的程序以21%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及甲胺获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为93%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.47min,LC/MS(M+H)=532.2。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.29min,LC/MS(M+H)=532.2。1H NMR(500MHz,DMSO-d6)δ8.89(d,J=8.1Hz,1H),8.72(s,2H),7.96(s,1H),7.88(d,J=7.3Hz,2H),7.35-7.29(m,2H),7.27-7.22(m,1H),5.91(br.s.,1H),4.06(s,3H),3.81-3.71(m,2H),3.33(br.s.,1H),3.26(t,J=11.2Hz,1H),2.71(s,3H),2.33(s,3H),1.98(br.s.,1H),1.94(br.s.,1H),1.51(br.s.,1H),1.44-1.37(m,1H),1.26(dd,J=19.1,10.6Hz,2H)。LC/MS(M+H)=532.1[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例200
5-(二甲基-1H-1,2,3-三唑-5-基)-11-甲亚磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向微波瓶中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(43.0mg,0.091mmol),然后添加甲硫醇钠(9.6mg,0.136mmol)及DMF(1.5mL)。在微波中在125℃加热所得混合物10min。通过添加一滴水将其淬灭且在室温搅拌五分钟。其用10%MeOH/EtOAc稀释且用盐水洗涤。浓缩有机层且然后添加10mL甲醇/水(比例为1:1)且在室温搅拌。向此搅拌的溶液中添加FeCl3(2.9mg,0.018mmol),然后添加30%H2O2水溶液(15.5mg,0.455mmol)。4h后,其用10%MeOH/EtOAc稀释且用盐水洗涤。浓缩有机层,溶解于2mL MeOH中。经由制备型LC/MS在以下条件下纯化此粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.33min,LC/MS(M+H)=501.4。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.46min,LC/MS(M+H)=501.4。1H NMR(500MHz,DMSO-d6)δ8.92(dd,J=7.9,4.6Hz,1H),8.73-8.63(m,2H),7.92(dd,J=7.9,5.7Hz,1H),7.78(t,J=6.6Hz,2H),7.32(dd,J=7.3,3.7Hz,2H),7.26(d,J=8.1Hz,1H),5.91(br.s.,1H),4.06(s,3H),3.75(br.s.,1H),3.65(d,J=16.9Hz,1H),3.37(d,J=15.0Hz,2H),3.24(t,J=11.6Hz,1H),3.03(s,2H),2.98(s,2H),2.33(s,3H),1.57(d,J=12.5Hz,1H),1.51-1.36(m,2H),1.34-1.21(m,1H),1.16(d,J=13.2Hz,1H),1.13-1.02(m,1H)。LC/MS(M+H)=501.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例201
11-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(60mg,0.126mmol)、甲亚磺酸钠(15.4mg,0.151mmol)、二((三氟甲基)磺酰基)铜(6.2mg,0.019mmol)及N1,N2-二甲基乙烷-1,2-二胺(3.3mg,0.038mmol)称重至瓶中且然后添加3mLDMSO且在氮气下密封。加热反应瓶至100℃且在该温度保持24h。将其冷却至室温,用10%MeOH/EtOAc稀释且用盐水洗涤两次。有机层经MgSO4干燥且浓缩,得到粗混合物。将其吸收于2mL DMF中且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为16%且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.38min,LC/MS(M+H)=520.0。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.50min,LC/MS(M+H)=520.0。1H NMR(500MHz,DMSO-d6)δ9.59(s,1H),8.93(br.s.,1H),8.78(s,1H),8.63(br.s.,1H),7.69(d,J=7.3Hz,2H),7.40-7.33(m,2H),7.32-7.26(m,1H),6.16(d,J=11.0Hz,1H),4.01(s,3H),3.90(d,J=9.2Hz,1H),3.73(d,J=9.9Hz,1H),3.52-3.46(m,1H),3.44(s,3H),3.25(t,J=11.6Hz,1H),1.75-1.59(m,2H),1.36(d,J=8.1Hz,1H),0.92(d,J=12.1Hz,1H)。LC/MS(M+H)=520.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例202
1-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮
遵循与在1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]乙-1-酮的合成中描述的反应类似的程序以89%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及三丁基(1-乙氧基乙烯基)锡烷获得标题化合物。在Biotage上使用用5-100%EtOAc/己烷洗脱的24g硅胶柱对粗混合物进行纯化。通过LC/MS分析估算的纯度为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.78min,LC/MS(M+H)=484.1。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=3.09min,LC/MS(M+H)=484.0。1H NMR(500MHz,DMSO-d6)δ8.79(d,J=7.7Hz,1H),8.75-8.68(m,2H),8.02(d,J=8.1Hz,1H),7.87(d,J=7.7Hz,2H),7.34(t,J=7.5Hz,2H),7.25(t,J=7.2Hz,1H),5.93(br.s.,1H),4.08(s,3H),3.91(d,J=9.9Hz,1H),3.77(d,J=11.7Hz,1H),3.46-3.38(m,1H),3.35(d,J=4.8Hz,1H),3.30(t,J=11.2Hz,1H),2.93(s,3H),1.53(d,J=11.0Hz,1H),1.49-1.39(m,1H),1.38-1.27(m,1H),1.22(d,J=12.1Hz,1H)。LC/MS(M+H)=484.3[柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例203
11-(3,6-二氢-2H-噻喃-4-基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(200mg,0.420mmol)称重至50mL圆底烧瓶中,然后添加2-(3,6-二氢-2H-噻喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(114mg,0.504mmol)、PdCl2(dppf)2.DCM(34.4mg,0.042mmol)、二(二叔丁基(4-二甲基氨基苯基)膦)二氯化钯(II)(8.9mg,0.013mmol)及三乙胺(0.585mL,4.20mmol)。用氮气代替空气且在搅拌下加热所得混合物至85℃且保持4h。将其冷却至室温,用EtOAc稀释,用盐水洗涤,经MgSO4干燥且浓缩,得到粗混合物。在Biotage上对其进行用0-10%(10%(2M NH3/MeOH)/EtOAc)/EtOAc洗脱的40g硅胶柱色谱,得到227mg(71%)标题化合物。1H NMR(500MHz,DMSO-d6)δ8.64-8.48(m,3H),7.78(d,J=7.3Hz,2H),7.31(t,J=7.3Hz,2H),7.26-7.15(m,2H),5.86(br.s.,1H),4.03(s,3H),3.89(d,J=8.8Hz,1H),3.76(d,J=9.9Hz,2H),3.35-3.49(m,4H),3.25(t,J=11.0Hz,1H),2.99(d,J=5.5Hz,3H),1.50(br.s.,2H),1.41(d,J=10.3Hz,1H),1.28-1.18(m,2H)。LC/MS(M+H)=540.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例204
4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-3,6-二氢-2H-1λ6-噻喃-1,1-二酮
将11-(3,6-二氢-2H-噻喃-4-基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(93mg,0.172mmol)溶解于DCM(25mL)中且在氮气下冷却至-78℃。添加固体3-氯过氧苯甲酸(77mg,0.345mmol)且搅拌。0.5hr后,移开冷却浴且将反应混合物升温至室温。2hr后,通过添加Na2S2O3饱和水溶液淬灭反应混合物。在旋转蒸发器上除去DCM且用10%MeOH/EtOAc稀释残余物且搅拌。分离有机层且再次溶解于2mL MeOH中,过滤且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 45-90%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为59%且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.46min,LC/MS(M+H)=572.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.34min,LC/MS(M+H)=572.3。1H NMR(500MHz,DMSO-d6)δ8.65-8.59(m,2H),8.56(br.s.,1H),7.75(d,J=8.1Hz,1H),7.79(d,J=7.7Hz,2H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),6.94(br.s.,1H),5.92(br.s.,1H),4.10(br.s.,2H),4.04(s,3H),3.90(d,J=10.6Hz,1H),3.76(d,J=11.4Hz,2H),3.56-3.50(m,2H),3.49-3.40(m,2H),3.37(s,1H),3.27(t,J=11.7Hz,1H),1.53(br.s.,1H),1.48-1.37(m,1H),1.34-1.23(m,1H),1.18(d,J=11.4Hz,1H);LC/MS(M+H)=572.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例205
4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-1λ6-硫杂环己烷-1,1-二酮
在氢气下在室温搅拌含有4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-3,6-二氢-2H-1λ6-噻喃-1,1-二酮(25mg,0.044mmol)于20mL甲醇中的溶液及Pd/C(0.9mg,4.4μmol)的200mL圆底烧瓶。2h后,经由硅藻土过滤反应混合物且浓缩。将粗物质溶解于2mL MeOH中且经由制备型LC/MS在以下条件下纯化:柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为20%且其通过LC/MS分析估算的纯度为96%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.54min,LC/MS(M+H)=574.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.77min,LC/MS(M+H)=574.3。1H NMR(500MHz,DMSO-d6)δ8.63-8.52(m,3H),7.82(d,J=7.7Hz,2H),7.36(d,J=8.1Hz,1H),7.33-7.27(m,2H),7.26-7.20(m,1H),5.82(br.s.,1H),4.03(s,3H),3.89(s,1H),3.77(d,J=10.3Hz,2H),3.50-3.33(m,4H),3.25(br.s.,1H),2.49-2.42(m,2H),2.41-2.33(m,2H),1.49(d,J=11.7Hz,1H),1.45-1.35(m,1H),1.32-1.22(m,1H),1.15(d,J=12.1Hz,1H);LC/MS(M+H)=574.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例206
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氨基甲酸丙-2-基酯
步骤1:(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺
向含有溶解于DCM(5mL)中的(S)-N-(2,4-二甲氧基苄基)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺(95mg,0.157mmol)的圆底烧瓶中添加TFA(1.58mL,2.36mmol)且在室温搅拌所得混合物。0.5h后,LC/MS指示反应已完成。在旋转蒸发器上浓缩反应混合物且添加10mL水且搅拌。用乙醚萃取有机副产物且然后用1N NaOH溶液将水层的pH调节至约9。用5%MeOH/EtOAc萃取水层,除去溶剂后得到标题化合物(94%)。LC/MS(M+H)=454.2[柱:Waters Aquity BEHC18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤2:N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氨基甲酸丙-2-基酯
向混悬于DCM(4mL)中的(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺(22.0mg,0.049mmol)中添加氯甲酸异丙酯(0.146mL,0.146mmol),然后添加三乙胺(0.169ml,1.21mmol)且在室温搅拌所得混合物。1h后,其用15mL5%MeOH/EtOAc稀释,用盐水洗涤且浓缩有机层至干燥。将其再次溶解于2mL甲醇中,过滤且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;梯度:历经20min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产量为8.8mg且其通过LC/MS分析估算的纯度为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.90min,LC/MS(M+H)=540.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.88min,LC/MS(M+H)=540.6。1H NMR(500MHz,DMSO-d6)δ8.57-8.47(m,3H),7.96-7.86(m,3H),7.30(t,J=7.3Hz,2H),7.22(t,J=7.2Hz,1H),5.68(br.s.,1H),5.02(dt,J=12.6,6.4Hz,1H),4.03(s,3H),3.89(d,J=13.9Hz,2H),3.75(d,J=10.6Hz,1H),3.31(br.s.,1H),2.31(s,3H),1.43(br.s.,1H),1.34(d,J=6.2Hz,6H),1.31-1.13(m,3H);LC/MS(M+H)=540.3[柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例207
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2,2-二甲基丙酰胺
向混悬于1,4-二噁烷(4mL)中的(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺(20.0mg,0.044mmol)中添加特戊酰氯(16.0mg,0.132mmol),然后添加三乙胺(0.153ml,1.102mmol)且在室温搅拌所得混合物。0.5h后,其用15mL5%MeOH/EtOAc稀释,用盐水洗涤且浓缩有机层至干燥。将其再次溶解于2mL甲醇中,过滤且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为26%且其通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.90min,LC/MS(M+H)=538.2。注射2条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.09min,LC/MS(M+H)=538.2。1H NMR(500MHz,DMSO-d6)δ9.91(br.s.,1H),8.59-8.52(m,2H),8.42(br.s.,1H),8.13(d,J=8.4Hz,1H),7.86(d,J=7.3Hz,2H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.2Hz,1H),5.98(br.s.,1H),4.00(s,3H),3.93-3.87(m,1H),3.76(d,J=9.2Hz,2H),3.45(t,J=11.4Hz,1H),3.28(t,J=11.9Hz,1H),2.29(s,3H),1.60(br.s.,1H),1.37(s,10H),1.32-1.22(m,1H),1.11(d,J=12.5Hz,1H);LC/MS(M+H)=538.1[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例208
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]甲磺酰胺
遵循与在N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2,2-二甲基丙酰胺的合成中描述的反应类似的程序以13%产率由(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺及甲磺酰氯获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为13%且其通过LC/MS分析估算的纯度为93%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.56min,LC/MS(M+H)=532.1。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.99min,LC/MS(M+H)=532.1。1H NMR(500MHz,DMSO-d6)δ8.52-8.47(m,2H),8.45(d,J=8.4Hz,1H),7.93-7.85(m,J=7.3Hz,2H),7.31-7.26(m,2H),7.25-7.19(m,1H),6.86(d,J=8.1Hz,1H),5.74(br.s.,1H),4.03(s,3H),3.91-3.85(m,1H),3.75(d,J=11.7Hz,2H),3.51(s,3H),3.36(d,J=19.8Hz,2H),3.32-3.26(m,1H),2.31(s,3H),1.45(br.s.,1H),1.35(d,J=11.4Hz,1H),1.24(br.s.,2H);LC/MS(M+H)=532.1[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例209
4-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮
步骤1:(S)-4-(3-溴-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-基)硫吗啉1,1-二氧化物
将(S)-3-溴-7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(150mg,0.328mmol)、硫吗啉1,1-二氧化物(311mg,2.30mmol)及三乙胺(0.365mL,2.63mmol)溶解于1.2mL DMSO中且在175℃微波处理2小时。其用1%MeOH/EtOAc稀释且用盐水洗涤两次。经MgSO4干燥有机层且浓缩,得到181mg粗物质。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为76%。1H NMR(500MHz,DMSO-d6)δ8.62(br.s.,1H),8.43(s,1H),8.30(d,J=8.4Hz,1H),7.73(d,J=7.3Hz,2H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),7.03(d,J=8.8Hz,1H),5.61(br.s.,1H),4.28(br.s.,4H),3.90-3.82(m,1H),3.76(d,J=10.3Hz,1H),3.53(br.s.,1H),3.30-3.16(m,6H),1.50-1.38(m,2H),1.24(d,J=7.3Hz,1H),1.13(d,J=11.0Hz,1H);LC/MS(M+H)=555.0[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤2:4-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮
将(S)-4-(3-溴-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-基)硫吗啉1,1-二氧化物(30.0mg,0.054mmol)、(3,5-二甲基异噁唑-4-基)硼酸(11.4mg,0.081mmol)、K2CO3(14.9mg,0.108mmol)及PdCl2(dppf)2.DCM(4.4mg,5.40μmol)溶解于3:1二噁烷/水中且在140℃微波处理0.25h。其用1%MeOH/EtOAc稀释且用盐水洗涤两次。经MgSO4干燥有机层且浓缩,得到粗样品。将其溶解于2mL甲醇中且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为32%且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.73min,LC/MS(M+H)=572.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.57min,LC/MS(M+H)=572.6。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.37(s,1H),7.74(d,J=7.3Hz,2H),7.36-7.29(m,2H),7.28-7.20(m,2H),7.08(d,J=8.8Hz,1H),5.76(br.s.,1H),4.31(br.s.,4H),3.92-3.84(m,1H),3.77(d,J=7.0Hz,1H),3.58(br.s.,1H),3.49-3.40(m,4H),3.28-3.21(m,2H),2.48(s,3H),2.31(s,3H),1.49(br.s.,1H),1.42(d,J=9.2Hz,1H),1.29-1.14(m,2H);LC/MS(M+H)=572.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例210
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-3-甲基-1λ6,4-硫吗啉-1,1-二酮
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20.00mg,0.042mmol)、3-甲基硫吗啉1,1-二氧化物(12.6mg,0.085mmol)、RuPhos(1.6mg,3.38μmol)、Pd(OAc)2(0.5mg,2.11μmol)及Cs2CO3(55.1mg,0.169mmol)溶解于1.5mL二噁烷中且在微波中在110℃加热1h。将其过滤且经由制备型LC/MS在以下条件下纯化粗滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:Waters CSH C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为18%且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。RT=1.54min,LC/MS(M+H)=586.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.43min,LC/MS(M+H)=586.7。1H NMR(500MHz,DMSO-d6)δ8.47(s,1H),8.37(d,J=8.8Hz,1H),7.73(d,J=7.7Hz,2H),7.31(t,J=7.3Hz,2H),7.24(t,J=7.2Hz,1H),7.17(s,1H),7.05(d,J=9.2Hz,1H),5.74(br.s.,1H),5.45(br.s.,1H),4.89(d,J=13.2Hz,1H),4.01(d,J=2.9Hz,3H),3.90-3.79(m,2H),3.77(br.s.,1H),3.48(dd,J=13.8,5.3Hz,1H),3.43-3.32(m,3H),3.32-3.20(m,2H),2.29(d,J=2.6Hz,3H),1.56(d,J=6.6Hz,3H),1.51(br.s.,1H),1.41(d,J=5.1Hz,1H),1.32-1.14(m,2H);LC/MS(M+H)=586.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例211
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-6-甲基-1λ6,4-硫杂氮杂环庚烷-1,1-二酮
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-3-甲基-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以21%产率由(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及6-甲基-1,4-硫杂氮杂环庚烷1,1-二氧化物获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.57min,LC/MS(M+H)=600.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.46min,LC/MS(M+H)=600.7。1H NMR(500MHz,DMSO-d6)δ8.40(s,1H),8.30(d,J=8.8Hz,2H),7.77(d,J=7.0Hz,2H),7.30(t,J=7.0Hz,2H),7.23(t,J=7.2Hz,1H),6.81(d,J=8.8Hz,1H),5.70(br.s.,1H),4.45(br.s.,1H),4.24(br.s.,1H),4.00(s,3H),3.93-3.85(m,3H),3.77(br.s.,1H),3.71(d,J=19.4Hz,2H),3.59(br.s.,1H),3.36(br.s.,1H),3.32-3.15(m,3H),2.60(br.s.,1H),2.29(s,3H),1.47(br.s.,1H),1.40(br.s.,1H),1.24(d,J=13.6Hz,2H),1.17(t,J=6.1Hz,3H);LC/MS(M+H)=600.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例212
4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}哌嗪-2,6-二酮
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-3-甲基-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以27%产率由11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及哌嗪-2,6-二酮获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 30-100%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;梯度:历经20min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.40min,LC/MS(M+H)=554.6。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。RT=2.30min,LC/MS(M+H)=554.7。1H NMR(500MHz,DMSO-d6)δ8.48-8.39(m,2H),8.34(d,J=9.2Hz,1H),7.76(d,J=7.0Hz,1H),7.69(br.s.,1H),7.34-7.27(m,3H),7.23(d,J=6.6Hz,1H),5.71(br.s.,1H),4.65(d,J=3.7Hz,1H),4.59-4.54(m,1H),4.26(br.s.,1H),4.00(d,J=11.7Hz,3H),3.90(s,2H),3.77(d,J=11.7Hz,1H),3.72(s,2H),3.65(br.s.,1H),3.35-3.26(m,1H),1.47(br.s.,1H),1.44-1.28(m,2H),1.24(br.s.,2H);LC/MS(M+H)=554.2[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例213
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2-甲基-1λ6,4-硫吗啉-1,1-二酮
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-3-甲基-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以18%产率由(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及2-甲基硫吗啉1,1-二氧化物获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 40-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。RT=1.62min,LC/MS(M+H)=586.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.45min,LC/MS(M+H)=586.7。1H NMR(500MHz,DMSO-d6)δ8.46-8.32(m,3H),7.74(d,J=6.6Hz,2H),7.31(d,J=4.4Hz,2H),7.24(d,J=7.7Hz,1H),7.12-7.05(m,1H),5.73(br.s.,1H),4.91-4.77(m,1H),4.72-4.57(m,1H),4.01(d,J=5.1Hz,3H),3.90(s,2H),3.77(d,J=10.6Hz,2H),3.56(d,J=10.3Hz,2H),3.35-3.19(m,3H),2.29(d,J=4.4Hz,3H),1.50(br.s.,1H),1.41(br.s.,1H),1.31(d,J=4.4Hz,3H),1.24(br.s.,2H);LC/MS(M+H)=586.3[柱:Waters Aquity BEHC18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例214
5-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2λ6-硫杂-5-氮杂二环[2.2.1]庚烷-2,2-二酮
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-3-甲基-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以18%产率由(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及(1R,4R)-2-硫杂-5-氮杂二环[2.2.1]庚烷2,2-二氧化物氢溴酸盐获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.56min,LC/MS(M+H)=584.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.79min,LC/MS(M+H)=584.1。1H NMR(500MHz,DMSO-d6)δ8.44-8.36(m,2H),8.33(d,J=8.8Hz,1H),7.77(d,J=7.7Hz,2H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),6.64(d,J=8.4Hz,1H),5.69(br.s.,1H),5.24(br.s.,1H),4.19(br.s.,1H),4.02(s,3H),3.94-3.85(m,2H),3.76(d,J=9.9Hz,1H),3.65(br.s.,1H),3.46(s,4H),3.41-3.37(m,1H),3.31-3.16(m,2H),2.74-2.67(m,1H),2.66-2.60(m,1H),2.30(s,3H),1.48(br.s.,1H),1.43-1.32(m,1H),1.24(d,J=9.2Hz,1H),1.17(br.s.,1H);LC/MS(M+H)=584.2[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例215
(2-{[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氨基}乙基)膦酸二乙酯
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-3-甲基-1λ6,4-硫吗啉-1,1-二酮的合成中描述的反应类似的程序以31%产率由(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及(2-氨基乙基)膦酸二乙酯草酸盐获得标题化合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。通过LC/MS分析估算的纯度为96%。分析型LC/MS注射用于确定最终纯度。注射条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.44min,LC/MS(M+H)=618.1。1H NMR(500MHz,DMSO-d6)δ8.38-8.31(m,2H),8.12(d,J=8.4Hz,1H),7.84(d,J=7.3Hz,2H),7.59(br.s.,1H),7.31(t,J=7.5Hz,2H),7.23(t,J=7.2Hz,1H),6.51(d,J=8.4Hz,1H),5.68(br.s.,1H),4.09-4.02(m,4H),4.01(s,3H),3.87(d,J=8.1Hz,1H),3.78(d,J=12.1Hz,2H),3.69(br.s.,2H),3.44(d,J=10.3Hz,2H),3.30(t,J=11.2Hz,2H),2.33(br.s.,1H),2.30(s,3H),1.46(br.s.,1H),1.43-1.33(m,1H),1.28-1.19(m,8H);LC/MS(M+H)=618.3[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例216
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-1λ6,4-硫吗啉-1,1-二酮
在微波瓶中向(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(12mg,0.025mmol)中添加硫吗啉1,1-二氧化物(3.4mg,0.025mmol)、RuPhos(1.1mg,2.54μmol)、Pd(OAc)2(0.570mg,2.54μmol)、K3PO4(33.0mg,0.101mmol),然后添加二噁烷(2mL)。在氩气下将瓶密封且在130℃微波处理0.5hr。将其过滤且经由制备型LC/MS在以下条件下纯化粗物质(滤液):柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经30min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为3.5%且其通过LC/MS分析估算的纯度为100%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:1.0mL/min;检测:UV 220nm。RT=1.45min,LC/MS(M+H)=572.2。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。RT=2.68min,LC/MS(M+H)=572.2。1H NMR(500MHz,DMSO-d6)δ9.01(s,1H),8.43(s,1H),7.68(d,J=7.7Hz,3H),7.34(d,J=7.7Hz,3H),7.27(s,1H),5.75(s,1H),4.28(br.s.,4H),3.95(br.s.,3H),3.89(br.s.,2H),3.20(br.s.,4H),2.25(s,3H),1.70(d,J=10.6Hz,2H),1.53(d,J=16.5Hz,2H),1.37(s,1H);LC/MS(M+H)=572.1[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例217
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2-甲基-1λ6,4-硫吗啉-1,1-二酮非对映异构体A
步骤1A:硫吗啉-4-甲酸叔丁酯1,1-二氧化物
在0℃将硫吗啉1,1-二氧化物(2.00g,14.8mmol)溶解于THF(20mL)中。添加一缩二碳酸二叔丁酯(3.55g,16.3mmol),然后添加三乙胺(4.12mL,29.6mmol)。在室温搅拌所得混合物过夜。其用EtOAc稀释且用盐水洗涤。经MgSO4干燥有机层且浓缩。在ISCO上使用用0-70%EtOAc/己烷洗脱的80g柱对所得粗残余物进行纯化(5%KMnO4水溶液用于使TLC板显色)。合并合适的级份且浓缩,得到标题化合物(3.46g,99%)。1H NMR(400MHz,CDCl3)δ4.00-3.89(m,4H),3.06-2.97(m,4H),1.51(s,10H)。
步骤1B:2-甲基硫吗啉-4-甲酸叔丁酯1,1-二氧化物
在搅拌下将硫吗啉-4-甲酸叔丁酯1,1-二氧化物(1.000g,4.25mmol)于THF(25mL)中的溶液冷却至-78℃。缓慢添加二异丙基氨基锂(2.125mL,4.25mmol)且在-78℃搅拌所得混合物0.5h。添加碘甲烷(0.905g,6.37mmol)且搅拌1h。移开冷却浴且将反应混合物升温至室温且搅拌过夜。用盐水淬灭反应混合物且用EtOAc稀释。分离各层且用EtOAc萃取水层一次。合并的有机层经Na2SO4干燥且过滤。将其浓缩,得到粗混合物。在Biotage上用5-100%EtOAc/己烷洗脱对粗混合物进行纯化,得到标题化合物(85%,0.898g,白色固体)。1H NMR(400MHz,CDCl3)δ4.30-4.21(m,1H),4.00-3.90(m,2H),3.12-2.97(m,4H),1.52-1.48(m,9H),1.39-1.36(m,3H)。
步骤1C:手性分离
对外消旋2-甲基硫吗啉-4-甲酸叔丁酯1,1-二氧化物进行手性分离,得到单独的对映异构体。柱:ChiralPak AD-H,30×250mm,5μm;流动相:20%MeOH/80%CO2;压力:100巴;温度:40℃;流速:70mL/min;UV:205nm;注射:0.35mL(约20mg/mL);级份收集:峰1:3.30’-3.75’,峰2:4.30’-5.00’。绝对立体化学未确定。将峰1指定为对映异构体A且将峰2指定为对映异构体B。
步骤1D:2-甲基硫吗啉1,1-二氧化物盐酸盐对映异构体A及2-甲基硫吗啉1,1-二氧化物盐酸盐对映异构体B
向2-甲基硫吗啉-4-甲酸叔丁酯1,1-二氧化物对映异构体A及B中的每种(26mg,0.104mmol)于2mL二噁烷中的溶液中添加4M HCl/二噁烷(1.043mL,4.17mmol)且在室温搅拌10min。通过浓缩每种反应混合物以100%产率获得标题化合物。
步骤2:4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2-甲基-1λ6,4-硫吗啉-1,1-二酮非对映异构体A
将(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(25.0mg,0.053mmol)、2-甲基硫吗啉1,1-二氧化物盐酸盐对映异构体A(24.5mg,0.132mmol)、RuPhos(2.0mg,4.23μmol)、Pd(OAc)2(0.95mg,4.23μmol)及K3PO4(44.8mg,0.211mmol)溶解于2mL二噁烷中且在微波中在120℃加热0.5h。在旋转蒸发器上浓缩反应混合物,溶解于2mL甲醇中,过滤且经由制备型LC/MS在以下条件下纯化粗物质(滤液):柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;梯度:历经20min15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物的级份且经由离心蒸发干燥。产物的产率为13%且其通过LC/MS分析估算的纯度为92%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV220nm。RT=1.81min,LC/MS(M+H)=586.1。注射2条件:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。RT=1.45min,LC/MS(M+H)=586.2。1H NMR(500MHz,DMSO-d6)δ8.47(br.s.,2H),8.36(d,J=8.8Hz,1H),7.75(d,J=7.7Hz,2H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.0Hz,1H),7.11(d,J=8.8Hz,1H),5.75(br.s.,1H),4.84(d,J=16.1Hz,1H),4.69(d,J=14.3Hz,1H),4.02(s,3H),3.89(d,J=12.1Hz,1H),3.85-3.74(m,2H),3.64(br.s.,1H),3.62-3.52(m,2H),3.49-3.29(m,3H),3.23(br.s.,2H),2.31(s,3H),1.50(br.s.,1H),1.47-1.37(m,1H),1.32(d,J=7.0Hz,3H),1.29-1.15(m,2H);LC/MS(M+H)=586.0[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例218
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2-甲基-1λ6,4-硫吗啉-1,1-二酮非对映异构体B
遵循与在4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]-2-甲基-1λ6,4-硫吗啉-1,1-二酮非对映异构体A的合成中描述的反应类似的程序以31%产率由7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶及2-甲基硫吗啉1,1-二氧化物盐酸盐对映异构体B获得标题化合物。分析型LC/MS注射1条件:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。RT=1.96min,LC/MS(M+H)=586.1。分析型LC/MS注射2条件:柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。RT=1.47min,LC/MS(M+H)=586.1。1H NMR(500MHz,DMSO-d6)δ8.47(br.s.,1H),8.43(br.s.,1H),8.37(d,J=8.8Hz,1H),7.75(d,J=7.3Hz,2H),7.35-7.29(m,2H),7.26-7.21(m,1H),7.12(d,J=8.8Hz,1H),5.75(br.s.,1H),4.88(d,J=16.1Hz,1H),4.64(d,J=13.9Hz,1H),4.01(s,3H),3.90-3.85(m,1H),3.84-3.74(m,2H),3.64-3.50(m,4H),3.50-3.37(m,3H),3.36-3.21(m,3H),2.29(s,3H),1.49(br.s.,1H),1.46-1.35(m,1H),1.32(d,J=6.6Hz,3H),1.25(br.s.,2H);LC/MS(M+H)=586.1。
实施例219
(2-{[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氨基}乙基)膦酸
在微波瓶中向(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(40.0mg,0.085mmol)中添加(2-氨基乙基)膦酸二乙酯(30.6mg,0.169mmol)、RuPhos(1.2mg,2.54μmol)、Pd(OAc)2(0.95mg,4.23μmol)、K3PO4(108mg,0.507mmol)及二噁烷(2mL)。在120℃微波处理所得混合物0.5h。LC/MS显示步骤1成功(M+1=618)。用EtOAc稀释反应混合物且用盐水洗涤。有机层经MgSO4干燥且浓缩。将残余物溶解于DCM(5mL)中且冷却至0℃。添加溴三甲基硅烷(51.8mg,0.338mmol),移开冰浴且在室温搅拌所得混合物过夜。将其浓缩且添加10:1甲醇/水的20mL溶液且搅拌6h。LC/MS表明制得所需产物,但是单乙基副产物为主要产物(参见下文)。将其在旋转蒸发器上浓缩且将固体残余物吸收于含有一滴TFA的10:1甲醇/H2O溶液中。将其过滤且经由制备型LC/MS在以下条件下纯化粗物质(滤液):柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 40-85%B且然后在100%B保持5min;流速:20mL/min。合并含有标题化合物(呈NH4OAc盐形式)的级份且经由离心蒸发干燥。产物的产率为7%且其通过LC/MS分析估算的纯度为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters AcquityUPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。RT=1.10min,LC/MS(M+H)=562.0。注射2条件:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。RT=1.13min,LC/MS(M+H)=562.0。1H NMR(500MHz,DMSO-d6)δ8.39-8.31(m,2H),8.05(d,J=8.4Hz,1H),7.85(d,J=7.0Hz,2H),7.30(t,J=7.7Hz,3H),7.18(t,J=7.3Hz,1H),6.46(d,J=8.4Hz,1H),5.64(br.s.,1H),4.01(s,3H),3.82(d,J=10.3Hz,2H),3.73(br.s.,2H),3.51-3.45(m,2H),3.32(br.s.,2H),2.30(s,4H),1.98-1.84(m,4H),1.47(br.s.,1H),1.34(d,J=8.1Hz,1H),1.22(br.s.,2H);LC/MS(M+H)=562.3[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例220
(2-{[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氨基}乙基)膦酸乙酯
在(2-{[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]氨基}乙基)膦酸的合成及纯化期间以26%产率获得标题化合物。分析型LC/MS注射1条件:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。RT=1.20min,LC/MS(M+H)=590.0。分析型LC/MS注射2条件:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95ACN:水及0.1%三氟乙酸;流动相B:95:5ACN:水及0.1%三氟乙酸;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV220nm。RT=1.25min,LC/MS(M+H)=590.0。1H NMR(500MHz,DMSO-d6)δ8.39-8.31(m,2H),8.05(d,J=8.4Hz,1H),7.85(d,J=7.0Hz,2H),7.30(t,J=7.7Hz,3H),7.18(t,J=7.3Hz,1H),6.46(d,J=8.4Hz,1H),5.64(br.s.,1H),4.01(s,3H),3.82(d,J=10.3Hz,2H),3.73(br.s.,2H),3.51-3.45(m,2H),3.32(br.s.,2H),2.30(s,4H),1.98-1.84(m,4H),1.47(br.s.,1H),1.34(d,J=8.1Hz,1H),1.22(br.s.,2H);HPLC:注射1RT=1.20min,注射2RT=1.25min;LC/MS(M+H)=590.3。
实施例221
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-甲磺酰基-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:2-(甲磺酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶
在配备有磁性搅拌棒的压力容器中添加4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-联(1,3,2-二氧杂硼杂环戊烷)(1.291g,5.08mmol)及5-溴-2-(甲磺酰基)吡啶(1g,4.24mmol)。将固体混悬于二噁烷(15mL)及DMSO(0.5mL)中。添加乙酸钾(0.831g,8.47mmol)且反应混合物用氩气在超声波处理下脱气5min。添加PdCl2(dppf)-CH2Cl2加合物(0.173g,0.212mmol)。将容器盖好且在油浴中在90℃加热3h。3h后,在搅拌下冷却反应混合物至室温。过滤反应混合物且浓缩滤液。用水稀释水层且用乙酸乙酯萃取。使用盐水促进分层。有机层经MgSO4干燥,过滤且真空浓缩,得到1.56g棕色固体。
步骤2:5-溴-6’-(甲磺酰基)-3-硝基-2,3’-联吡啶
在配备有磁性搅拌棒的压力容器中添加2-(甲磺酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶(800mg,2.12mmol)及2,5-二溴-3-硝基吡啶(597mg,2.12mmol)。将固体混悬于二噁烷(25mL)及水(8.33mL)中。添加碳酸钾(879mg,6.36mmol)及PdCl2(dppf)-CH2Cl2加合物(138mg,0.170mmol)。使氩气鼓泡通过混合物同时超声波处理5min。将容器盖好且在90℃加热2h。冷却反应容器至室温。过滤反应混合物且浓缩滤液。用水稀释剩余的水层且用乙酸乙酯萃取。有机层经MgSO4干燥,过滤且真空浓缩,得到半固体。将物质吸收于DCM中且通过硅胶色谱(80g ISCO硅胶柱,用5-100%乙酸乙酯/己烷(900mL)洗脱,TLC Rf=0.52(50%乙酸乙酯/己烷))纯化。浓缩类似的级份,得到470mg(56%)黄色固体。LC/MS(M+H)=359.9。LC/MS纯度:>91%;Rt=0.98min。柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min。
步骤3:3-溴-7-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶及3-溴-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶
在配备有磁性搅拌棒的50mL圆底烧瓶中添加5-溴-6’-(甲磺酰基)-3-硝基-2,3’-联吡啶(300mg,0.838mmol)及二(二苯基膦基)乙烷(417mg,1.05mmol)。将固体混悬于1,2-二氯苯(1414μL)中。加热反应混合物至150℃(油浴)同时在烧瓶敞开于空气的情况下搅拌。使反应继续0.75h。在氮气气流下在加热下除去溶剂。将黑色残余物吸收于甲醇中(在搅拌下)以通过制备型HPLC纯化:条件:20-100%B;溶剂B:90%甲醇/0.1%TFA水溶液;Phenomenex AXIA LUNA C18 30×100mm,10微米;流速:30mL/min;UV 254nm。峰1(100mg,29%)Rt:10.6min;峰2(23%)Rt:11.5min。峰1:1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.56(s,1H),8.77(d,J=2.0Hz,1H),8.49(d,J=2.0Hz,1H),8.29(d,J=0.8Hz,1H)。峰2:1HNMR(400MHz,DMSO-d6)δ12.81(s,1H),8.92(d,J=8.0Hz,1H),8.74(d,J=2.0Hz,1H),8.30(d,J=2.0Hz,1H),8.00(d,J=7.8Hz,1H)。
步骤4:(S)-3-溴-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶
在配备有磁性搅拌棒且在冰浴中冷却至0℃的圆底烧瓶中添加3-溴-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(70mg,0.215mmol)、(R)-(2-氟苯基)(四氢-2H-吡喃-4-基)甲醇(67.7mg,0.322mmol)及Ph3P(84mg,0.322mmol)。将固体溶解于THF(15mL)中。历经15min向该混悬液中逐滴添加DIAD(0.063mL,0.322mmol)。移开冰浴且历经3h将反应混合物升温至室温。浓缩反应混合物。将残余物溶解于DMF中,过滤且通过制备型HPLC纯化:条件:20-100%B;溶剂B:90%甲醇/0.1%TFA水溶液;Phenomenex AXIA LUNA C18 30×100mm,10微米;流速:30mL/min;UV 254nm。所需产物峰在Rt=16.1min洗脱。浓缩类似的级份,得到60mg(46%)黄色油状物。以>85%纯度纯化物质。LC/MS(M+H)=520.1;HPLC条件:Rt=3.25min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
步骤5:5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-甲磺酰基-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(50mg,0.096mmol)、1,4-二甲基-1H-1,2,3-三唑(14.1mg,0.145mmol)及NMP(1.5mL)。添加四甲基乙酸铵(19.3mg,0.145mmol)及二(三苯基膦)氯化钯(II)(4.7mg,6.75μmol)。在超声波处理下使氩气鼓泡至混合物中5min。将容器盖好且置于在100℃预加热的油浴中且搅拌反应混合物过夜。过滤反应混合物且用DCM洗涤固体。真空浓缩滤液。用DMF稀释剩余的油状物且过滤以除去固体。通过制备型HPLC纯化混合物:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到1.4mg(3%)标题化合物,其平均纯度通过LC/MS分析为96%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.48min;LC/MS(M+H)=535.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.29min;LC/MS(M+H)=535.3。1H NMR(500MHz,DMSO-d6)δ8.95(d,J=8.1Hz,1H),8.82-8.75(m,1H),8.70(br.s.,1H),8.26(t,J=7.0Hz,1H),8.01(d,J=8.1Hz,1H),7.34(d,J=5.9Hz,1H),7.31-7.25(m,1H),7.16-7.09(m,1H),6.25(br.s.,1H),4.07(s,3H),3.93-3.85(m,2H),3.74(d,J=12.1Hz,1H),3.62(d,J=10.3Hz,1H),3.37(d,J=8.8Hz,1H),3.27-3.19(m,2H),2.35(s,3H),1.72-1.60(m,3H),1.56-1.46(m,1H),0.98(d,J=13.2Hz,1H)。LC/MS(M+H)=535.3;HPLC条件:Rt=2.56min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例222
5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-甲磺酰基-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的小压力容器中添加(S)-3-溴-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-7-(甲磺酰基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(50mg,0.096mmol)及(3,5-二甲基异噁唑-4-基)硼酸(20.4mg,0.145mmol)。将固体混悬于二噁烷(3mL)及水(1mL)中。添加碳酸钾(40.0mg,0.289mmol)及PdCl2(dppf)-CH2Cl2加合物(6.3mg,7.72μmol)。使氩气鼓泡通过混合物同时超声波处理5min。将容器盖好且在90℃加热2h。过滤反应混合物且将滤液吸收于水及乙酸乙酯中。有机层经MgSO4干燥,过滤且浓缩,得到油状物。油状物用DMF稀释,然后过滤以通过制备型HPLC纯化:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 35-75%B且然后在100%B保持5min;流速:20mL/min。经由制备型LC/MS在以下条件下再次纯化物质:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 50-90%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到9.1mg(17%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.75min;LC/MS(M+H)=535.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.52min;LC/MS(M+H)=535.2。1H NMR(500MHz,DMSO-d6)δ8.90(d,J=8.1Hz,1H),8.68(s,1H),8.52(br.s.,1H),8.25(t,J=7.3Hz,1H),7.99(d,J=8.1Hz,1H),7.34(q,J=6.6Hz,1H),7.31-7.23(m,1H),7.18-7.07(m,1H),6.21(br.s.,1H),3.97-3.85(m,1H),3.74(d,J=9.5Hz,1H),3.62(d,J=10.6Hz,1H),3.39(d,J=3.7Hz,3H),3.27-3.13(m,2H),2.51(br.s.,3H),2.35(s,3H),1.66(d,J=12.8Hz,1H),1.58-1.45(m,1H),1.43-1.28(m,1H),0.96(d,J=12.1Hz,1H)。LC/MS(M+H)=535.3;HPLC条件:Rt=2.60min(Phenomenex LUNAC18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例223
1-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基](2H3)乙-1-酮
在配备有磁性搅拌棒且在干冰/丙酮浴中冷却至-78℃的小圆底烧瓶中添加(S)-3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯(50mg,0.087mmol)及THF(10mL)。当在-78℃时逐滴添加CD3Li(1.75mL,0.875mmol,0.5M于乙醚中,呈LiI复合物形式)。2h后,移开冷却浴且将反应混合物升温至室温。用甲醇淬灭反应混合物同时在室温搅拌。真空除去溶剂且将油状物吸收于甲醇中且过滤。通过制备型HPLC纯化溶液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min 10-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到1.6mg(3%)标题化合物,其平均纯度通过LC/MS分析为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。Rt=1.25min;LC/MS(M+H)=502.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.51min;LC/MS(M+H)=502.1。1H NMR(500MHz,DMSO-d6)δ9.42(s,1H),8.77(br.s.,1H),8.63(s,1H),8.40(br.s.,1H),7.79-7.65(m,2H),7.18(t,J=8.6Hz,2H),6.00(d,J=11.0Hz,1H),3.94-3.85(m,2H),3.71(d,J=9.2Hz,1H),3.36(br.s.,1H),3.24(t,J=11.4Hz,1H),2.48(s,3H),2.30(s,3H),1.66(br.s.,1H),1.60(d,J=11.0Hz,1H),1.30(d,J=8.1Hz,1H),0.92(d,J=13.2Hz,1H)。LC/MS(M+H)=502.1;HPLC条件:Rt=3.46min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例224
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基](2H6)丙-2-醇
在配备有磁性搅拌棒且在干冰/丙酮浴中冷却至-78℃的小圆底烧瓶中添加(S)-3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯(50mg,0.087mmol)及THF(10mL)。当在-78℃时逐滴添加CD3Li(1.75mL,0.875mmol,0.5M于乙醚中,呈LiI复合物形式)。2h后,移开冷却浴且将反应混合物升温至室温。用甲醇淬灭反应混合物同时在室温搅拌。真空除去溶剂且将残余的油状物吸收于甲醇中且过滤。通过制备型HPLC纯化溶液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经30min 10-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到22.3mg(48%)标题化合物,其平均纯度通过LC/MS分析为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.69min;LC/MS(M+H)=521.3。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.97min;LC/MS(M+H)=521.3。1H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.52(s,1H),8.30(br.s.,1H),8.24(br.s.,1H),7.72(dd,J=8.1,5.5Hz,2H),7.18(t,J=8.6Hz,2H),5.83(d,J=11.4Hz,1H),3.96-3.83(m,1H),3.74(d,J=9.5Hz,1H),3.47(t,J=11.2Hz,2H),3.37(d,J=10.3Hz,1H),3.26(t,J=11.6Hz,1H),2.47(s,3H),2.29(s,3H),1.73-1.63(m,1H),1.63-1.49(m,1H),1.37-1.23(m,1H),0.97(d,J=11.7Hz,1H)。LC/MS(M+H)=521.2;HPLC条件:Rt=3.13min(Phenomenex LUNA C182×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例225
2-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
在配备有磁性搅拌棒的20mL压力瓶中添加(S)-2-(3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-基)丙-2-醇(35mg,0.068mmol)及CD3OD(3mL)。向在室温溶解的溶液中添加叔丁醇钾(38.2mg,0.340mmol)。将瓶置于在80℃预加热的油浴中且搅拌过夜。浓缩反应混合物。将残余物吸收于2mL甲醇中且过滤以通过制备型HPLC纯化:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到16.8mg(45%)标题化合物,其平均纯度通过LC/MS分析为94%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。Rt=1.63min;LC/MS(M+H)=576.6。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。1H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.53(s,1H),8.31(br.s.,1H),8.25(br.s.,1H),7.71(dd,J=8.1,5.5Hz,2H),7.18(t,J=8.8Hz,2H),5.83(d,J=11.4Hz,1H),3.94-3.85(m,1H),3.74(d,J=9.5Hz,1H),3.47(t,J=11.0Hz,1H),3.40(d,J=5.1Hz,2H),3.26(t,J=11.7Hz,1H),2.30(s,3H),1.68(d,J=12.5Hz,1H),1.58(d,J=9.2Hz,6H),1.51(d,J=13.2Hz,1H),1.37-1.23(m,1H),0.97(d,J=13.2Hz,1H)。LC/MS(M+H)=576.6;HPLC条件:Rt=2.76min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例226
11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-6’-氯-3-硝基-2,3’-联吡啶
在配备有磁性搅拌棒的75mL压力烧瓶中添加(6-氯吡啶-3-基)硼酸(1g,6.35mmol)、2,5-二溴-3-硝基吡啶(1.791g,6.35mmol)。将固体混悬于THF(30mL)中。用PdCl2(dppf)-CH2Cl2加合物(0.259g,0.318mmol)及K3PO4(9.53mL,19.1mmol)(25g K3PO4/60mL水=2M溶液)处理混合物。使氩气鼓泡通过混合物5min同时超声波处理。将烧瓶盖好且在预加热的油浴中加热至80℃且保持2小时。冷却反应容器至室温。过滤反应混合物且浓缩滤液以除去有机溶剂。用水稀释剩余的水层且用乙酸乙酯萃取(形成乳液且添加盐水)。有机层经MgSO4干燥,过滤且浓缩,得到固体。将物质吸收于DCM及乙酸乙酯中。通过快速柱色谱(80g硅胶ISCO,0-50%乙酸乙酯/己烷(600mL总溶剂),然后50-100%(300mL溶剂);TLCRf=0.88(50%乙酸乙酯/己烷))纯化溶液。浓缩类似的级份,得到660mg(33%)浅黄色固体,其纯度为99%(通过LC/MS)。LC/MS(M+H)=315.9;HPLC条件:Rt=3.43min(PhenomenexLUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
步骤2:3-溴-7-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶及3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶
在配备有磁性搅拌棒的圆底烧瓶中添加5-溴-6’-氯-3-硝基-2,3’-联吡啶(4.5g,14.3mmol)及二(二苯基膦基)乙烷(7.13g,17.9mmol)。将固体混悬于1,2-二氯苯(16.1ml,143mmol)中。用氮气冲洗烧瓶且在搅拌下加热反应混合物至150℃(油浴)。使反应在敞开于空气的情况下继续1h。通过在氮气气流下蒸发除去大部分溶剂同时加热至100℃。用100mL二氯甲烷稀释反应混合物且在室温搅拌过夜。形成白色析出物且通过过滤除去,用额外的二氯甲烷洗涤固体。所过滤的该物质(2.08g,52%)为3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶:1H NMR(400MHz,DMSO-d6)δ12.47(br.s.,1H),8.68-8.57(m,2H),8.19(d,J=1.8Hz,1H),7.42(d,J=8.3Hz,1H)。浓缩含有另一种异构体+多种杂质的剩余滤液以除去剩余的1,2-二氯苯。除去溶剂(氮气气流伴随在100℃加热)后,将油状残余物吸收于50mL乙酸异丙酯中且在室温搅拌混合物数小时。过滤棕色固体。真空浓缩滤液,得到油状物。将该油状物吸收于DCM中且转移至40g ISCO硅胶柱的顶部以纯化。物质用5-100%THF/己烷(800mL总体积)洗脱。合并类似的级份(通过LC/MS鉴定;双点,通过TLC(Rf=0.64/0.73,30%THF/己烷))且真空浓缩,得到600mg(15%)呈灰白色固体状的3-溴-7-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶。1H NMR(400MHz,CDCl3)δ1封端0.45(br,s.,1H),9.33(s,1H),8.69(d,J=1.8Hz,1H),8.04(d,J=1.8Hz,1H),7.29(s,1H)。
步骤3:(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶
在配备有磁性搅拌棒且在冰浴中冷却至0℃的圆底烧瓶中添加3-溴-7-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶(1000mg,1.77mmol)、(R)-(2-氟苯基)(四氢-2H-吡喃-4-基)甲醇(558mg,2.65mmol)及Ph3P(696mg,2.65mmol)。将固体混悬于二氯甲烷(40mL)中。向该混悬液中逐滴添加DIAD(0.516mL,2.65mmol)。移开冰浴且历经2h将反应混合物升温至室温。在室温保持2h后,过滤出保留在反应混合物中的白色析出物。真空浓缩滤液,得到残余物。将残余物吸收于DCM中且转移至80g ISCO硅胶柱的顶部。物质用0-100%乙酸乙酯/己烷(溶剂总体积为900mL)洗脱。合并类似的级份(Rf=0.86,50%乙酸乙酯/己烷),然后真空浓缩,得到660mg(71%)纯度>90%的白色泡沫状物。LC/MS(M+H)=476.0;HPLC条件:Rt=1.22min。柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min。
步骤4:11-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的75mL压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(650mg,1.37mmol)、1,4-二甲基-1H-1,2,3-三唑(199mg,2.05mmol)及NMP(10mL)。添加四甲基乙酸铵(274mg,2.05mmol)及二(三苯基膦)氯化钯(II)(67.3mg,0.096mmol)。在超声波处理下使氩气鼓泡至混合物中5min且然后将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物过夜。在氮气气流下除去溶剂同时在油浴中在100℃加热容器。将剩余的残余物吸收于DCM中且转移至80gISCO硅胶柱。物质用0-75%[10%(2M氨/甲醇)/乙酸乙酯](其余部分为己烷)(1L总体积)洗脱。合并类似的级份(TLC Rf=0.58,50%[10%(2M氨/甲醇)/乙酸乙酯]/己烷),真空浓缩。用己烷研磨剩余的油状物且过滤所得固体,得到197mg(22%)纯度>75%的呈黄色泡沫状物的标题化合物。1H NMR(500MHz,DMSO-d6)δ8.71-8.62(m,2H),8.21(t,J=7.3Hz,1H),7.46(d,J=8.1Hz,1H),7.41-7.24(m,2H),7.12(t,J=9.4Hz,1H),6.18(br.s.,1H),4.01(br.s.,3H),3.93-3.82(m,2H),3.74(d,J=9.9Hz,1H),3.53(d,J=8.8Hz,1H),3.49-3.36(m,1H),3.30-3.12(m,1H),2.29(s,3H),1.66(d,J=11.7Hz,1H),1.53-1.39(m,1H),1.39-1.26(m,1H),0.96(d,J=12.5Hz,1H)。LC/MS(M+H)=491.4;HPLC条件:Rt=3.30min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例227
5,11-二(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的75mL压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(650mg,1.37mmol)、1,4-二甲基-1H-1,2,3-三唑(199mg,2.05mmol)及NMP(10mL)。添加四甲基乙酸铵(274mg,2.05mmol)及二(三苯基膦)氯化钯(II)(67.3mg,0.096mmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物过夜。在氮气气流下除去大部分溶剂同时在油浴中在100℃加热数小时。将剩余的混合物吸收于2mL DMF中,然后过滤以通过制备型HPLC纯化:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min 10-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到4.7mg(0.6%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.50min;LC/MS(M+H)=552.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=2.51min;LC/MS(M+H)=552.5。1H NMR(500MHz,DMSO-d6)δ8.81(d,J=8.1Hz,1H),8.68(s,1H),8.46(br.s.,1H),8.20(br.s.,1H),7.71(d,J=8.1Hz,1H),7.34(d,J=5.5Hz,1H),7.29(d,J=7.7Hz,1H),7.17-7.04(m,1H),6.36(br.s.,1H),4.34(br.s.,3H),4.00(br.s.,3H),3.93-3.83(m,1H),3.72(d,J=9.5Hz,1H),3.47-3.38(m,4H),3.27-3.15(m,1H),2.29(br.s.,3H),1.72(d,J=11.7Hz,1H),1.58-1.42(m,1H),1.33(d,J=12.1Hz,1H),0.98(d,J=13.2Hz,1H)。LC/MS(M+H)=552.5;HPLC条件:Rt=2.57min(PhenomenexLUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例228
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-N-甲基-N-[2-(甲基氨基)乙基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-胺
在配备有磁性搅拌棒的压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(60mg,0.122mmol)、甲亚磺酸钠(37.4mg,0.367mmol)及三氟甲磺酸铜(II)(6.6mg,0.018mmol)及DMSO(1.5mL)。添加N,N’-二甲基乙二胺(4μl,0.037mmol)且用氮气净化瓶。将容器盖好且置于在100℃预加热的油浴中。将反应混合物搅拌5h。通过过滤除去反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经35min10-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到25.7mg(38%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.20min;LC/MS(M+H)=543.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=2.15min;LC/MS(M+H)=543.5。1H NMR(500MHz,DMSO-d6)δ8.39(s,1H),8.27-8.11(m,3H),7.32(d,J=6.6Hz,1H),7.28-7.20(m,1H),7.12(t,J=9.5Hz,1H),6.66(d,J=8.8Hz,1H),6.00(br.s.,1H),4.01(s,3H),3.94-3.80(m,2H),3.77(d,J=8.1Hz,2H),3.58(br.s.,1H),3.49-3.33(m,4H),3.29-3.22(m,1H),3.18(s,2H),2.85(br.s.,2H),2.40(s,3H),2.30(s,3H),1.96(br.s.,3H),1.60(d,J=12.1Hz,1H),1.42(d,J=11.7Hz,1H),1.38-1.26(m,1H),1.03(d,J=11.4Hz,1H)。LC/MS(M+H)=543.6;HPLC条件:Rt=2.36min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例229
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-(1-甲基-1H-吡唑-5-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.061mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(19.1mg,0.092mmol)、二噁烷(2mL)及水(1mL)。添加碳酸钾(21.1mg,0.153mmol)及Pd(Ph3P)4(5.30mg,4.58μmol)。使氮气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物4h。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经35min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到18.0mg(55%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.65min;LC/MS(M+H)=537.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.67min;LC/MS(M+H)=537.5。1H NMR(500MHz,DMSO-d6)δ8.71(d,J=8.1Hz,1H),8.65(s,1H),8.41(br.s.,1H),8.23(br.s.,1H),7.85(d,J=8.1Hz,1H),7.59(s,1H),7.40-7.25(m,2H),7.12(t,J=9.4Hz,1H),7.00(br.s.,1H),6.39(br.s.,1H),4.40(br.s.,3H),3.99(br.s.,3H),3.94-3.85(m,1H),3.73(d,J=8.1Hz,1H),3.54(br.s.,1H),3.28-3.12(m,1H),2.28(br.s.,3H),1.73(br.s.,1H),1.47(d,J=12.5Hz,1H),1.35(d,J=7.7Hz,1H),1.00(d,J=11.0Hz,1H)。LC/MS(M+H)=537.5;HPLC条件:Rt=2.78min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例230
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的微波压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.061mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶(20.45mg,0.092mmol)、二噁烷(2mL)及水(1mL)。添加碳酸钾(21.1mg,0.153mmol)及Pd(Ph3P)4(5.3mg,4.58μmol)。使氩气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物4h。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到27.3mg(79%)标题化合物,其平均纯度通过LC/MS分析为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.34min;LC/MS(M+H)=552.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.77min;LC/MS(M+H)=552.5。1H NMR(500MHz,DMSO-d6)δ8.60(s,1H),8.54(d,J=8.1Hz,1H),8.47(br.s.,1H),8.22(t,J=7.5Hz,1H),7.64(d,J=8.4Hz,1H),7.32(d,J=6.6Hz,1H),7.28-7.21(m,1H),7.12(t,J=9.4Hz,1H),6.96(br.s.,1H),6.17(br.s.,1H),4.04(s,3H),3.94-3.85(m,1H),3.74(d,J=9.9Hz,1H),3.65(br.s.,1H),3.47-3.41(m,1H),3.26-3.19(m,1H),3.17(br.s.,2H),2.80(d,J=18.3Hz,2H),2.69(d,J=5.5Hz,2H),2.32(s,3H),2.35(s,3H),1.87(s,1H),1.63(d,J=11.7Hz,1H),1.53-1.41(m,1H),1.35(d,J=7.7Hz,1H),1.00(d,J=13.2Hz,1H)。LC/MS(M+H)=552.6;HPLC条件:Rt=2.45min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例231
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-(4-甲基哌嗪-1-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)及1-甲基哌嗪(1mL,0.041mmol)。将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物1h。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到13.6mg(58%)标题化合物,其平均纯度通过LC/MS分析为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.41min;LC/MS(M+H)=555.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.81min;LC/MS(M+H)=555.5。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.25(d,J=8.8Hz,2H),8.14(t,J=7.9Hz,1H),7.37-7.28(m,1H),7.28-7.19(m,1H),7.12(t,J=9.2Hz,1H),6.87(d,J=8.8Hz,1H),6.02(br.s.,1H),4.01(s,3H),3.95-3.85(m,1H),3.55(br.s.,1H),3.42(d,J=10.6Hz,2H),3.22(t,J=11.6Hz,1H),2.30(s,3H),2.26(s,3H),1.91(s,2H),1.60(d,J=13.2Hz,1H),1.49-1.39(m,1H),1.33(d,J=8.1Hz,1H),1.05(d,J=13.6Hz,1H)。LC/MS(M+H)=555.3;HPLC条件:Rt=0.70min。柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min。
实施例232
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(35mg,0.074mmol)、4-(2H3)甲基-1-甲基-1H-1,2,3-三唑(16.2mg,0.162mmol)及NMP(1mL)。添加四甲基乙酸铵(14.7mg,0.111mmol)及二(三苯基膦)氯化钯(II)(3.62mg,5.16μmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物过夜。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经30min 15-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到14.0mg(34%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.52min;LC/MS(M+H)=558.5。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.51min;LC/MS(M+H)=558.5。1H NMR(500MHz,DMSO-d6)δ8.81(d,J=8.1Hz,1H),8.68(s,1H),8.45(br.s.,1H),8.21(br.s.,1H),7.71(d,J=8.1Hz,1H),7.34(d,J=5.1Hz,1H),7.29(d,J=8.1Hz,1H),7.16-7.05(m,1H),6.37(br.s.,1H),4.35(br.s.,3H),4.00(br.s.,3H),3.93-3.84(m,1H),3.73(d,J=9.9Hz,1H),3.54(br.s.,1H),3.48-3.35(m,4H),3.21(t,J=11.9Hz,1H),1.71(br.s.,1H),1.48(d,J=8.4Hz,1H),1.40-1.27(m,1H),0.98(d,J=12.5Hz,1H)。LC/MS(M+H)=558.4;HPLC条件:Rt=3.60min。Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液历经4min洗脱,0.8mL/min,在254nm监测,温度:40℃。
实施例233
11-氯-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(35mg,0.074mmol)、4-(2H3)甲基-1-甲基-1H-1,2,3-三唑(16.2mg,0.162mmol)及NMP(1mL)。添加四甲基乙酸铵(14.7mg,0.111mmol)及二(三苯基膦)氯化钯(II)(3.6mg,5.16μmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物过夜。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min 15-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到7.2mg(20%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.89min;LC/MS(M+H)=494.4。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.90min;LC/MS(M+H)=494.4。1H NMR(500MHz,DMSO-d6)δ8.71-8.64(m,2H),8.51(br.s.,1H),8.22(t,J=7.5Hz,1H),7.47(d,J=8.1Hz,1H),7.41-7.25(m,2H),7.12(t,J=9.5Hz,1H),6.17(d,J=8.4Hz,1H),4.01(s,3H),3.89(d,J=13.6Hz,1H),3.75(d,J=9.2Hz,1H),3.53(d,J=9.9Hz,1H),3.49-3.41(m,1H),3.23(t,J=11.9Hz,1H),1.67(d,J=13.6Hz,1H),1.46(d,J=12.1Hz,1H),1.35(d,J=7.7Hz,1H),0.97(d,J=13.2Hz,1H)。LC/MS(M+H)=494.2;HPLC条件:Rt=4.08min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例234
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-11-(4-甲基哌嗪-1-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加11-氯-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(15mg,0.030mmol)及1-甲基哌嗪(0.5mL,0.030mmol),然后将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物1h。在氮气气流下除去剩余的1-甲基哌嗪同时加热。将呈油状物形式的残余物吸收于甲醇中,过滤且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到15.1mg(87%)标题化合物,其平均纯度通过LC/MS分析为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.38min;LC/MS(M+H)=558.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=2.58min;LC/MS(M+H)=558.6。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.25(d,J=8.4Hz,2H),8.14(t,J=7.7Hz,1H),7.36-7.29(m,1H),7.28-7.19(m,1H),7.16-7.06(m,1H),6.87(d,J=9.2Hz,1H),6.02(br.s.,1H),4.01(s,4H),3.88(d,J=12.1Hz,1H),3.53(br.s.,1H),3.40(br.s.,2H),3.36(br.s.,2H),3.28-3.16(m,1H),2.26(s,4H),1.59(d,J=12.5Hz,1H),1.50-1.39(m,1H),1.33(d,J=12.8Hz,1H),1.05(d,J=10.3Hz,1H)。LC/MS(M+H)=558.4;HPLC条件:Rt=0.68min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例235
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(50mg,0.101mmol)、甲亚磺酸钠(31.0mg,0.304mmol)及三氟甲磺酸铜(II)(5.5mg,0.015mmol)。将固体溶解于DMSO(1.5mL)中。添加N,N’-二甲基乙二胺(3μl,0.030mmol)且用氩气净化瓶,然后盖好且置于在100℃预加热的油浴中。将反应混合物搅拌4h。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到24.8mg(43%)标题化合物,其平均纯度通过LC/MS分析为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=2.11min;LC/MS(M+H)=538.4。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.34min。1H NMR(500MHz,DMSO-d6)δ8.95(d,J=7.7Hz,1H),8.77(s,1H),8.69(br.s.,1H),8.25(t,J=7.7Hz,1H),8.02(d,J=8.1Hz,1H),7.34(q,J=6.8Hz,1H),7.31-7.23(m,1H),7.13(t,J=9.4Hz,1H),6.24(br.s.,1H),4.06(s,3H),3.90(d,J=11.0Hz,1H),3.74(d,J=8.8Hz,1H),3.62(d,J=9.2Hz,1H),3.49-3.45(m,1H),3.42(br.s.,3H),3.22(t,J=11.7Hz,1H),1.67(d,J=12.1Hz,1H),1.56-1.44(m,1H),1.44-1.30(m,1H),0.98(d,J=12.5Hz,1H)。LC/MS(M+H)=538.2;HPLC条件:Rt=0.87min;LC/MS(M+H)=538.4(柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例236
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-N-[2-(甲基氨基)乙基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-胺
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(50mg,0.101mmol)、甲亚磺酸钠(31.0mg,0.304mmol)及三氟甲磺酸铜(II)(5.5mg,0.015mmol)。将固体溶解于DMSO(1.5mL)中。添加N,N’-二甲基乙二胺(3μl,0.030mmol)且用氩气净化瓶,然后盖好且置于在100℃预加热的油浴中。将反应混合物搅拌4h。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到24.8mg(43%)标题化合物,其平均纯度通过LC/MS分析为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.99min;LC/MS(M+H)=546.5。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.19min;LC/MS(M+H)=546.5。1HNMR(500MHz,DMSO-d6)δ8.39(s,1H),8.25-8.13(m,3H),7.37-7.29(m,1H),7.25(t,J=7.3Hz,1H),7.17-7.06(m,1H),6.66(d,J=8.8Hz,1H),6.01(br.s.,1H),4.00(s,3H),3.92-3.81(m,2H),3.76(d,J=8.1Hz,2H),3.28-3.14(m,4H),2.89(s,2H),2.85(br.s.,1H),2.74(s,1H),2.39(br.s.,2H),1.88(br.s.,1H),1.60(d,J=13.6Hz,1H),1.42(d,J=8.8Hz,1H),1.33(d,J=8.8Hz,1H),1.03(d,J=8.8Hz,2H)。LC/MS(M+H)=546.3;HPLC条件:Rt=0.71min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例237
11-[(2R,6S)-2,6-二甲基吗啉-4-基]-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.061mmol)及(2S,6R)-2,6-二甲基吗啉(0.5mL,0.061mmol)。将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物1h。在氮气气流下除去剩余的(2S,6R)-2,6-二甲基吗啉(0.5mL,0.061mmol)同时加热。将残余物吸收于甲醇中且过滤。通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经20min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到14.9mg(42%)标题化合物,其平均纯度通过LC/MS分析为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.93min;LC/MS(M+H)=573.2。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.31min;LC/MS(M+H)=573.2。1H NMR(500MHz,DMSO-d6)δ8.43(s,1H),8.27(d,J=8.8Hz,2H),8.09(t,J=7.2Hz,1H),7.38-7.28(m,1H),7.28-7.20(m,1H),7.13(t,J=9.2Hz,1H),6.89(d,J=8.8Hz,1H),6.02(br.s.,1H),4.40(t,J=11.7Hz,2H),4.01(s,3H),3.90(d,J=9.9Hz,1H),3.77(d,J=9.9Hz,1H),3.67(br.s.,2H),3.52(br.s.,1H),3.46-3.37(m,1H),3.28-3.10(m,1H),2.71-2.57(m,2H),1.60(d,J=11.7Hz,1H),1.45(d,J=9.9Hz,1H),1.33(d,J=9.5Hz,1H),1.25(d,J=5.9Hz,6H),1.06(d,J=11.7Hz,1H)。LC/MS(M+H)=573.4;HPLC条件:Rt=0.94min(柱:Waters Aquity BEHC18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例238
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-N,N-二甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-胺
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(26mg,0.053mmol)及二甲胺(5mL,10.0mmol,2M于THF中)。将容器盖好且置于在100℃预加热的油浴中。搅拌反应混合物16h。在氮气气流下除去剩余的二甲胺(5mL,10.0mmol)。将残余物吸收于甲醇及DMF中,然后过滤。通过制备型HPLC纯化滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到11.1mg(42%)标题化合物,其平均纯度通过LC/MS分析为99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.87min;LC/MS(M+H)=503.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.24min;LC/MS(M+H)=503.2。1H NMR(500MHz,DMSO-d6)δ8.39(s,1H),8.27-8.14(m,4H),7.36-7.28(m,1H),7.28-7.19(m,1H),7.12(t,J=9.4Hz,1H),6.67(d,J=8.8Hz,1H),5.99(br.s.,1H),4.01(s,3H),3.88(d,J=10.3Hz,1H),3.76(d,J=9.5Hz,1H),3.62(br.s.,1H),3.43-3.34(m,1H),1.58(d,J=13.6Hz,1H),1.49-1.37(m,1H),1.37-1.26(m,1H),1.07(d,J=11.7Hz,1H)。LC/MS(M+H)=503.2;HPLC条件:Rt=1.02min(柱:Waters Aquity BEHC18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例239
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-胺
在配备有磁性搅拌棒的压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(26mg,0.053mmol)及甲胺(1mL,0.053mmol,2M于甲醇中)。将容器盖好且置于在80℃预加热的油浴中。搅拌反应混合物数日。在氮气气流下除去过量的甲胺同时加热。将残余物吸收于甲醇中且过滤。通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到17.2mg(66%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.66min;LC/MS(M+H)=489.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.00min;LC/MS(M+H)=489.1。1H NMR(500MHz,DMSO-d6)δ8.37(s,1H),8.29-8.16(m,2H),8.09(d,J=8.4Hz,1H),7.38-7.28(m,2H),7.28-7.20(m,1H),7.12(t,J=9.4Hz,1H),6.48(d,J=8.8Hz,1H),5.98(br.s.,1H),4.00(s,3H),3.94-3.82(m,1H),3.77(d,J=8.1Hz,1H),3.65(br.s.,1H),3.24(t,J=11.4Hz,1H),3.00(d,J=4.8Hz,3H),1.56(d,J=12.5Hz,1H),1.49-1.27(m,2H),1.07(d,J=12.8Hz,1H)。LC/MS(M+H)=489.2;HPLC条件:Rt=0.82min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例240
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]甲磺酰胺
在配备有磁性搅拌棒的压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.061mmol)、甲磺酰胺(8.72mg,0.092mmol)、碳酸铯(39.8mg,0.122mmol)、Pd(OAc)2(0.4mg,1.83μmol)及Xantphos(2.1mg,3.67μmol)。将固体混悬于二噁烷(2mL)中。使氩气鼓泡通过混合物5min且然后将容器置于在100℃预加热的油浴中。在搅拌下加热反应混合物16h。过滤反应混合物且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到26.8mg(79%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。Rt=1.41min;LC/MS(M+H)=550.0。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.66min;LC/MS(M+H)=550.0。1H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.45(d,J=8.4Hz,1H),8.40(br.s.,1H),8.34(br.s.,1H),7.32(d,J=7.0Hz,1H),7.22(t,J=7.0Hz,1H),7.12(t,J=9.4Hz,1H),6.85(d,J=8.1Hz,1H),6.04(br.s.,1H),4.01(s,3H),3.89(d,J=9.5Hz,1H),3.74(d,J=8.4Hz,1H),3.67(br.s.,1H),3.51(s,1H),3.46(br.s.,2H),3.28-3.15(m,1H),2.34-2.23(m,3H),1.56(br.s.,1H),1.48-1.31(m,2H),1.24(br.s.,1H),1.16(br.s.,1H),1.03(br.s.,3H)。LC/MS(M+H)=550.1;HPLC条件:Rt=0.82min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例241
2-{8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
步骤1:1-{8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}乙-1-酮
在配备有磁性搅拌棒的压力瓶中添加11-氯-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯(125mg,0.253mmol)、三丁基(1-乙氧基乙烯基)锡烷(101mg,0.278mmol)及PdCl2(dppf)-CH2Cl2加合物(6.2mg,7.59μmol)。将固体混悬于二噁烷(2mL)中。使氩气鼓泡通过混合物5min。将容器置于在100℃预加热的油浴中。在搅拌下加热反应混合物16h。冷却容器至室温。中间体LC/MS(M+H)=530.3;HPLC条件:Rt=1.12min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。过滤粗混合物且真空浓缩。将残余物吸收于10mL THF中且用2mL 2M HCl溶液处理同时在室温搅拌2小时。用K2CO3水溶液中和溶液且用乙酸乙酯萃取。有机层经MgSO4干燥,过滤且真空浓缩,得到125mg(84%)黄色残余物。LC/MS(M+H)=502.5;HPLC条件:Rt=2.92min(Phenomenex LUNA C18 2×50mm,4min梯度,用含有10mM NH4OAc的5-95%ACN水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
步骤2:2-{8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
在配备有磁性搅拌棒且在冰/甲醇浴中冷却至-10℃的圆底烧瓶中添加1-{8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}乙-1-酮(35mg,0.070mmol)及二氯甲烷(5mL)。向该混悬液中逐滴添加MeMgBr(3M于乙醚中,0.233mL,0.698mmol)。移开冷却浴后,将反应混合物缓慢升温至室温且保持1h。用NH4Cl饱和溶液淬灭反应混合物。将反应混合物转移至分液漏斗且用DCM萃取。合并所有有机相且经MgSO4干燥,过滤且浓缩,得到黄色残余物。将残余物溶解于甲醇中且过滤。通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到24.8mg(68%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.62min;LC/MS(M+H)=518.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.98min;LC/MS(M+H)=518.1。1H NMR(500MHz,DMSO-d6)δ8.63-8.54(m,2H),8.49(br.s.,1H),8.24(t,J=7.0Hz,1H),7.71(d,J=8.1Hz,1H),7.31(d,J=5.1Hz,1H),7.26-7.18(m,1H),7.12(t,J=9.5Hz,1H),6.14(br.s.,1H),4.05(s,3H),3.90(d,J=6.6Hz,1H),3.81-3.66(m,2H),3.44(br.s.,1H),3.24-3.11(m,2H),1.65(s,3H),1.58(s,4H),1.46(d,J=8.8Hz,1H),1.34(d,J=8.4Hz,1H),0.96(d,J=12.5Hz,1H)。LC/MS(M+H)=518.3;HPLC条件:Rt=0.89min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例242及243
1-环丙基-1-{8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}乙-1-醇
在配备有磁性搅拌棒且在干冰/丙酮浴中冷却至-78℃的圆底烧瓶中添加1-{8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}乙-1-酮(35mg,0.070mmol)及THF(2mL)。向该混悬液中逐滴添加环丙基溴化镁(1.794mL,1.79mmol,1M于2-甲基四氢呋喃中)。移开冷却浴且历经1h将反应混合物缓慢升温至室温。用NH4Cl饱和溶液淬灭反应混合物。将反应混合物转移至分液漏斗且用DCM萃取。合并所有有机相且经MgSO4干燥,过滤且浓缩,得到黄色残余物。将残余物溶解于甲醇中且过滤。通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到29mg非对映异构体的混合物。对该物质进行手性纯化:手性SFC条件:Phenomenex LUX Cellulose-2制备型柱,20×250mm,5μm;流动相:35%甲醇/CO2;130巴;温度:35℃;流速:45.0mL/min持续30min;在UV 318nm监测;注射:0.25ml约10mg/mL于MeOH中的溶液(29mg通过堆迭注射纯化);Rt:异构体A:21.6min;异构体B:23.4min。合并含有所需产物的级份且经由蒸发干燥,得到7.7mg(8%)异构体A,其平均纯度通过LC/MS分析为>97%。合并含有所需产物的级份且经由蒸发干燥,得到10.7mg(11%)异构体B,其平均纯度通过LC/MS分析为>99%。异构体A:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。Rt=1.77min;LC/MS(M+H)=544.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.81min;LC/MS(M+H)=544.2。异构体B:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.79min;LC/MS(M+H)=544.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.84min;LC/MS(M+H)=544.2。绝对立体化学未确定。非对映异构体A:1H NMR(500MHz,DMSO-d6)δ8.64-8.53(m,2H),8.49(br.s.,1H),8.26(t,J=7.3Hz,1H),7.66(d,J=8.1Hz,1H),7.37-7.28(m,1H),7.28-7.19(m,1H),7.12(t,J=9.4Hz,1H),6.15(br.s.,1H),4.05(s,3H),3.89(d,J=9.9Hz,1H),3.74(d,J=9.5Hz,2H),3.42-3.30(m,1H),3.17(t,J=11.4Hz,1H),1.70-1.55(m,4H),1.52-1.41(m,2H),1.34(d,J=8.4Hz,1H),0.94(d,J=12.5Hz,1H),0.58-0.48(m,1H),0.48-0.34(m,2H),0.22(d,J=8.4Hz,1H)。非对映异构体B:1HNMR(500MHz,DMSO-d6)δ8.64-8.54(m,2H),8.49(br.s.,1H),8.25(t,J=7.2Hz,1H),7.65(d,J=8.1Hz,1H),7.30(d,J=6.2Hz,1H),7.21(t,J=7.3Hz,1H),7.12(t,J=9.2Hz,1H),6.14(br.s.,1H),4.05(s,3H),3.90(d,J=10.3Hz,1H),3.75(d,J=12.1Hz,2H),3.26-3.12(m,1H),1.69(s,3H),1.59(br.s.,1H),1.52-1.30(m,3H),0.97(d,J=12.1Hz,1H),0.61-0.49(m,1H),0.48-0.41(m,1H),0.38(d,J=4.8Hz,1H),0.20-0.09(m,1H)。LC/MS(M+H)=544.2;HPLC条件:Rt=0.95min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例244
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-11-(4-甲基哌嗪-1-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加11-氯-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(40mg,0.040mmol)、三乙胺(3滴)及1-甲基哌嗪(1mL,0.040mmol)。将容器盖好,置于在100℃预加热的油浴中且搅拌48h。冷却反应容器且在氮气气流下除去剩余的1-甲基哌嗪同时加热。将残余物吸收于甲醇中且过滤。通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到5.2mg(23%)标题化合物,其平均纯度通过LC/MS分析为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.20min;LC/MS(M+H)=558.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.43min;LC/MS(M+H)=558.3。1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.42(s,1H),8.23(t,J=7.3Hz,2H),7.43-7.26(m,3H),7.20-7.05(m,2H),5.94(d,J=11.4Hz,1H),3.95(br.s.,3H),3.89(d,J=9.5Hz,2H),3.74(d,J=9.9Hz,2H),3.66(br.s.,4H),3.54-3.45(m,1H),3.37(d,J=11.7Hz,1H),3.29-3.15(m,1H),2.47(br.s.,3H),2.26(s,3H),1.74-1.67(m,1H),1.67-1.51(m,1H),1.40(d,J=8.1Hz,1H),0.88(d,J=12.8Hz,1H)。LC/MS(M+H)=558.4;HPLC条件:Rt=2.85min。柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液历经4min洗脱,0.8mL/min,在254nm监测,温度:40℃。
实施例245
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加11-氯-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(80mg,0.081mmol)、甲亚磺酸钠(24.8mg,0.243mmol)及三氟甲磺酸铜(II)(4.4mg,0.012mmol)。将固体溶解于DMSO(1.5mL)中。添加N,N’-二甲基乙二胺(1滴)且用氩气净化瓶。将容器盖好,置于在100℃预加热的油浴中且搅拌16h。添加额外的1当量甲亚磺酸钠、三氟甲磺酸铜(II)及2当量N,N’-二甲基乙二胺。用氩气净化反应混合物,盖好且再次加热至100℃且保持4h。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 40-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到4.9mg(11%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.32min;LC/MS(M+H)=538.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.18min;LC/MS(M+H)=538.3。1H NMR(500MHz,DMSO-d6)δ9.59(s,1H),8.79(s,2H),8.54(br.s.,1H),8.34-8.21(m,1H),7.46-7.29(m,3H),7.14(t,J=9.4Hz,1H),6.33(d,J=11.0Hz,1H),3.98(br.s.,3H),3.90(d,J=11.0Hz,1H),3.72(d,J=8.1Hz,1H),3.49(br.s.,2H),3.41(s,2H),3.21(t,J=11.6Hz,1H),1.73(br.s.,2H),1.42(d,J=9.9Hz,1H),0.78(d,J=12.1Hz,1H)。LC/MS(M+H)=538.3;HPLC条件:Rt=3.32min。柱:PhenomenexLUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液历经4min洗脱,0.8mL/min,在254nm监测,温度:40℃。
实施例246
11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加3-溴-7-氯-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(70mg,0.147mmol)、4-(2H3)甲基-1-甲基-1H-1,2,3-三唑(36.8mg,0.368mmol)及NMP(1.5mL)。添加四甲基乙酸铵(29.4mg,0.221mmol)及二(三苯基膦)氯化钯(II)(7.2mg,10.3μmol)。在超声波处理下使氩气鼓泡至混合物中5min。将容器盖好,置于在100℃预加热的油浴中且搅拌过夜。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min 5-45%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到15.8mg(20%)标题化合物,其平均纯度通过LC/MS分析为>91%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.81min;LC/MS(M+H)=495.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=3.16min;LC/MS(M+H)=495.0。1H NMR(500MHz,DMSO-d6)δ8.69(d,J=5.9Hz,2H),8.57(br.s.,2H),7.73(t,J=9.4Hz,1H),7.50(d,J=8.1Hz,2H),6.49(d,J=11.0Hz,1H),4.09-3.97(m,3H),3.89-3.77(m,1H),3.69(d,J=9.5Hz,1H),3.45(d,J=10.6Hz,1H),3.42-3.30(m,1H),3.27-3.10(m,1H),1.59(d,J=13.2Hz,1H),1.51-1.34(m,1H),1.31-1.14(m,1H),0.85(d,J=13.2Hz,1H)。LC/MS(M+H)=495.1;HPLC条件:Rt=0.96min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例247及248
8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加3-溴-7-氯-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(70mg,0.147mmol)、4-(2H3)甲基-1-甲基-1H-1,2,3-三唑(36.8mg,0.368mmol)及NMP(1.5mL)。添加四甲基乙酸铵(29.4mg,0.221mmol)及二(三苯基膦)氯化钯(II)(7.2mg,10.3μmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好,置于在100℃预加热的油浴中且搅拌过夜。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min5-45%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到15mg对映异构体的混合物。对该物质进行手性纯化:手性SFC条件:Chiralcel OJ-H制备型柱,20×250mm,5μm;流动相:20%甲醇/CO2;150巴;温度:35℃;流速:70.0mL/min持续14min;在UV 334nm监测;注射:0.35ml约4mg/mL于MeOH中的溶液(15mg通过堆迭注射纯化);Rt:异构体A:7.0min;异构体B:10.5min。合并含有所需产物的级份且经由蒸发干燥,得到6.0mg(7%)异构体A,其平均纯度通过LC/MS分析为>99%。合并含有所需产物的级份且经由蒸发干燥,得到6.6mg(8%)异构体B,其平均纯度通过LC/MS分析为99%。异构体A:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.40min;LC/MS(M+H)=559.3。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=2.39min;LC/MS(M+H)=559.3。异构体B:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.37min;LC/MS(M+H)=559.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=2.39min;LC/MS(M+H)=559.3。1H NMR(500MHz,DMSO-d6)δ8.82(d,J=8.1Hz,1H),8.70(s,1H),8.65(s,1H),8.58(d,J=4.0Hz,1H),7.78-7.68(m,2H),7.55-7.43(m,1H),6.67(br.s.,1H),4.39(s,3H),4.05(s,3H),3.83(d,J=9.5Hz,1H),3.66(d,J=10.3Hz,1H),3.38-3.31(m,2H),3.20(t,J=11.7Hz,1H),1.58(br.s.,1H),1.45(d,J=12.5Hz,1H),1.22(br.s.,1H),0.84(d,J=13.2Hz,1H)。LC/MS(M+H)=559.3;HPLC条件:Rt=0.82min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例249
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-11-[4-(2H3)甲基哌嗪-1-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(30mg,0.063mmol)、三乙胺(0.088mL,0.630mmol)及1-(2H3)甲基哌嗪盐酸盐(44.0mg,0.315mmol)。将固体溶解于DMSO(1.5mL)中。将容器盖好,置于在100℃预加热的油浴中且搅拌16h。冷却容器至室温。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到15.3mg(43%)标题化合物,其平均纯度通过LC/MS分析为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.51min;LC/MS(M+H)=543.4。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.57min;LC/MS(M+H)=543.4。1H NMR(500MHz,DMSO-d6)δ8.40(s,1H),8.31(br.s.,1H),8.27(d,J=8.8Hz,1H),7.77(d,J=7.7Hz,2H),7.30(t,J=7.5Hz,2H),7.22(t,J=7.3Hz,1H),6.90(d,J=8.8Hz,1H),5.70(br.s.,1H),4.00(s,3H),3.88(d,J=11.4Hz,1H),3.79(br.s.,5H),3.63(br.s.,1H),3.31-3.21(m,1H),3.18(d,J=3.7Hz,5H),1.46(br.s.,1H),1.44-1.31(m,1H),1.25(br.s.,2H)。LC/MS(M+H)=543.4;HPLC条件:Rt=0.66min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例250
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基哌嗪-1-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:1-(2H3)甲基哌嗪盐酸盐
在配备有磁性搅拌棒且在冰水浴中冷却至0℃的圆底烧瓶中将哌嗪-1-甲酸叔丁酯(1g,5.37mmol)溶解于THF(30mL)中。向在氮气气氛下及经排气的溶液中分批添加60%氢化钠(0.258g,6.44mmol;于矿物油中)。5min后,向混合物中逐滴添加CD3I(0.856g,5.91mmol)。将反应混合物升温至室温且搅拌过夜。用水淬灭反应混合物,转移至分液漏斗且用乙酸乙酯萃取两次。合并有机层,经MgSO4干燥,过滤且真空浓缩,得到1.45g部分固化的混浊油状物。将500mg该中间体在室温在含有磁性搅拌棒的小圆底烧瓶中混悬于10mL4MHCl/二噁烷中。搅拌混合物30min。几乎在将HCl添加至基质后立即形成粘稠固体。在真空下缓慢除去二噁烷且然后将剩余的物质吸收于乙醚中。搅拌乙醚混悬液15min以破碎及洗涤固体。然后真空除去乙醚,得到400mg浅黄色固体,其为HCl盐。
步骤2:5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基哌嗪-1-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(14mg,0.029mmol)、三乙胺(0.032mL,0.228mmol)及1-(2H3)甲基哌嗪盐酸盐(15.9mg,0.114mmol)。将固体溶解于DMSO(1.5mL)中。将容器盖好,置于在100℃预加热的油浴中且搅拌16h过夜。冷却容器至室温。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到14.6mg(84%)标题化合物,其平均纯度通过LC/MS分析为>91%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.50min;LC/MS(M+H)=558.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.56min;LC/MS(M+H)=558.3。1HNMR(500MHz,DMSO-d6)δ8.40(s,1H),8.29-8.19(m,2H),8.12(t,J=7.3Hz,1H),7.36-7.27(m,1H),7.27-7.18(m,1H),7.11(t,J=9.2Hz,1H),6.86(d,J=8.8Hz,1H),6.00(br.s.,1H),3.99(s,3H),3.87(d,J=10.6Hz,1H),3.74(br.s.,4H),3.45-3.34(m,1H),3.22(t,J=11.2Hz,1H),3.17(s,3H),2.48(br.s.,3H),2.28(s,3H),1.59(d,J=11.7Hz,1H),1.42(d,J=11.7Hz,1H),1.32(d,J=12.1Hz,1H),1.03(d,J=12.1Hz,1H)。LC/MS(M+H)=558.3;HPLC条件:Rt=0.65min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min2-98%B;流速:0.8mL/min)。
实施例251
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(哌嗪-1-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加11-氯-8-[(S)-苯基(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(45mg,0.095mmol)、三乙胺(0.264mL,1.89mmol)及1-哌嗪盐酸盐(99mg,0.473mmol)。将混合物溶解于DMSO(1.5mL)中。将容器盖好,置于在100℃预加热的油浴中且搅拌16h。冷却容器至室温。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 10-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到24.7mg(48%)标题化合物,其平均纯度通过LC/MS分析为>96%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.18min;LC/MS(M+H)=526.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.14min;LC/MS(M+H)=526.3。1H NMR(500MHz,DMSO-d6)δ8.44-8.36(m,1H),8.31(br.s.,1H),8.27-8.20(m,1H),7.77(d,J=7.3Hz,2H),7.30(t,J=7.5Hz,2H),7.26-7.13(m,1H),6.87(d,J=9.2Hz,1H),5.72(br.s.,1H),4.08-3.94(m,4H),3.88(d,J=10.6Hz,1H),3.79(d,J=11.0Hz,1H),3.60(br.s.,1H),3.37(t,J=11.0Hz,1H),3.33-3.21(m,1H),2.89(s,2H),2.92(s,3H),1.90(br.s.,2H),1.47(br.s.,1H),1.46-1.33(m,2H),1.25(br.s.,3H)。LC/MS(M+H)=526.3;HPLC条件:Rt=2.77min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液历经4min洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例252
11-[(3R,5S)-3,5-二甲基哌嗪-1-基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加11-氯-8-[(S)-苯基(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(45mg,0.095mmol)、三乙胺(0.132mL,0.945mmol)及(2S,6R)-2,6-二甲基哌嗪(54.0mg,0.473mmol)。将固体溶解于DMSO(1.5mL)中。将容器盖好,置于在100℃预加热的油浴中且搅拌反应混合物1h。冷却容器至室温。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到28.4mg(52%)标题化合物,其平均纯度通过LC/MS分析为95%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.37min;LC/MS(M+H)=554.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.36min;LC/MS(M+H)=554.7。1H NMR(500MHz,DMSO-d6)δ8.38(s,1H),8.31(s,1H),8.24(d,J=8.8Hz,1H),7.76(d,J=7.7Hz,2H),7.29(t,J=7.5Hz,2H),7.22(t,J=7.3Hz,1H),6.90(d,J=8.8Hz,1H),5.66(d,J=8.8Hz,1H),4.55-4.32(m,2H),4.00(s,3H),3.94-3.85(m,1H),3.81(d,J=11.0Hz,1H),3.67(br.s.,1H),3.59(d,J=13.9Hz,1H),3.33(t,J=11.0Hz,1H),3.29-3.21(m,1H),2.92-2.81(m,3H),2.59(t,J=11.6Hz,2H),2.51(br.s.,1H),1.90(s,3H),1.50-1.33(m,2H),1.28(br.s.,2H),1.13(dd,J=5.9,2.2Hz,6H)。LC/MS(M+H)=554.3;HPLC条件:Rt=0.68min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例253
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5,11-二(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在已配备有磁性搅拌棒的小压力容器中添加(S)-3-溴-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(155mg,0.326mmol)、4-甲氧基-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑(72.6mg,0.392mmol)及NMP(2mL)。添加四甲基乙酸铵(54.4mg,0.408mmol)及二(三苯基膦)氯化钯(II)(16.0mg,0.023mmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好,置于在100℃预加热的油浴中且搅拌反应混合物过夜。冷却容器至室温且过滤反应混合物。通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到18.0mg(9%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.74min;LC/MS(M+H)=584.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=2.75min;LC/MS(M+H)=584.7。1H NMR(500MHz,DMSO-d6)δ8.75(d,J=8.1Hz,1H),8.67(s,1H),8.39(br.s.,1H),8.21(br.s.,1H),7.88(d,J=8.1Hz,1H),7.45-7.26(m,2H),7.19-7.07(m,1H),6.39(br.s.,1H),4.56(s,3H),4.15(s,3H),4.10-3.98(m,6H),3.90(d,J=8.4Hz,1H),3.71(d,J=10.6Hz,1H),3.53-3.43(m,2H),3.27-3.13(m,1H),1.73(br.s.,1H),1.58-1.42(m,1H),1.32(d,J=8.1Hz,1H),0.94(br.s.,1H)。LC/MS(M+H)=584.3;HPLC条件:Rt=0.97min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例254
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-11-(4-甲基哌嗪-1-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的20mL闪烁瓶中添加(S)-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-3-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.059mmol)、三乙胺(0.082mL,0.592mmol)及1-甲基哌嗪(29.6mg,0.296mmol)。将固体溶解于DMSO(1mL)中。将容器盖好,置于在100℃预加热的铝块中且搅拌反应混合物16h。冷却至室温后,过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到15.2mg(44%)标题化合物,其平均纯度通过LC/MS分析为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.53min;LC/MS(M+H)=571.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.65min;LC/MS(M+H)=571.7。1HNMR(500MHz,DMSO-d6)δ8.45(s,1H),8.24(d,J=8.4Hz,2H),8.11(t,J=7.5Hz,1H),7.32(d,J=6.6Hz,1H),7.28-7.21(m,1H),7.13(t,J=9.2Hz,1H),6.86(d,J=8.8Hz,1H),6.00(br.s.,1H),4.07(s,3H),4.01(s,3H),3.89(d,J=15.8Hz,2H),3.44(d,J=14.3Hz,3H),3.38(br.s.,1H),3.27-3.14(m,1H),2.26(s,4H),1.91(s,3H),1.59(d,J=12.1Hz,1H),1.48-1.37(m,1H),1.31(d,J=12.1Hz,1H),1.03(d,J=13.2Hz,1H)。LC/MS(M+H)=571.3;HPLC条件:Rt=0.66min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例255
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-N-甲基-N-[2-(甲基氨基)乙基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-胺
在配备有磁性搅拌棒的20mL闪烁瓶中添加(S)-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-3-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.059mmol)、三乙胺(0.082mL,0.592mmol)及N1,N2-二甲基乙烷-1,2-二胺(26.1mg,0.296mmol)。将固体溶解于DMSO(1mL)中。将容器盖好,置于在100℃预加热的铝块中且搅拌反应混合物16h。冷却容器至室温。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到17.1mg(51%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.22min;LC/MS(M+H)=559.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.20min;LC/MS(M+H)=559.7。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.22(d,J=8.8Hz,2H),8.16(t,J=7.3Hz,1H),7.38-7.30(m,1H),7.30-7.20(m,1H),7.13(t,J=9.2Hz,1H),6.66(d,J=8.8Hz,1H),6.02(br.s.,1H),4.06(s,3H),4.00(s,3H),3.94-3.80(m,2H),3.76(d,J=11.7Hz,2H),3.49(d,J=7.3Hz,3H),3.40(t,J=10.8Hz,1H),3.31-3.20(m,1H),2.89(s,2H),2.41(s,3H),1.89(s,3H),1.60(d,J=11.4Hz,1H),1.42(d,J=10.6Hz,1H),1.31(d,J=8.1Hz,1H),1.00(d,J=12.8Hz,1H)。LC/MS(M+H)=559.3;HPLC条件:Rt=0.65min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例256
4-{8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}-1λ6,4-硫吗啉-1,1-二酮
在配备有磁性搅拌棒的20mL闪烁瓶中添加(S)-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-3-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.059mmol)、三乙胺(0.082mL,0.592mmol)及硫吗啉1,1-二氧化物(40.0mg,0.296mmol)。将混合物溶解于DMSO(1mL)中。将容器盖好,置于在100℃预加热的铝块中且搅拌反应混合物16h。将反应混合物转移至微波压力瓶中且在170℃加热160min。冷却瓶至室温。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到2.2mg(6%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。Rt=1.51min;LC/MS(M+H)=606.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.42min;LC/MS(M+H)=606.2。1H NMR(500MHz,DMSO-d6)δ8.49(s,1H),8.34(d,J=8.4Hz,2H),8.10(t,J=7.5Hz,1H),7.42-7.22(m,2H),7.14(t,J=9.5Hz,1H),7.03(d,J=8.8Hz,1H),6.02(br.s.,1H),4.27(br.s.,4H),4.09(s,3H),4.02(s,3H),3.86(d,J=9.5Hz,2H),3.74(d,J=10.6Hz,2H),3.47-3.40(m,2H),3.29-3.13(m,7H),2.21-1.98(m,12H),1.62(d,J=13.2Hz,2H),1.45(d,J=8.4Hz,2H),1.30(d,J=12.8Hz,1H),0.98(d,J=12.1Hz,2H)。LC/MS(M+H)=606.3;HPLC条件:Rt=0.78min(柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min2-98%B;流速:0.8mL/min)。
实施例257
N-[2-(二甲基氨基)乙基]-N-乙基-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-胺
在配备有磁性搅拌棒的20mL闪烁瓶中添加(S)-7-氯-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-3-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(30mg,0.059mmol)、三乙胺(0.082mL,0.592mmol)及N1-乙基-N2,N2-二甲基乙烷-1,2-二胺(34.4mg,0.296mmol)。将混合物溶解于DMSO(1mL)中。将容器盖好,置于在100℃预加热的铝块中且搅拌反应混合物48h。冷却反应容器至室温。过滤反应混合物中的固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到4.0mg(11%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.49min;LC/MS(M+H)=587.9。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.63min;LC/MS(M+H)=587.9。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.23-8.18(m,2H),8.15(t,J=8.1Hz,1H),7.38-7.31(m,1H),7.26(t,J=7.2Hz,1H),7.14(t,J=9.4Hz,1H),6.63(d,J=8.8Hz,1H),6.05(br.s.,1H),4.10-4.03(m,3H),4.00(s,3H),3.89(d,J=12.1Hz,1H),3.77(br.s.,1H),3.69-3.59(m,2H),3.43-3.33(m,2H),3.28-3.15(m,1H),2.60(d,J=7.0Hz,2H),2.28(s,6H),1.87(s,3H),1.60(br.s.,1H),1.45-1.28(m,2H),1.25(t,J=7.0Hz,2H),1.01(d,J=10.3Hz,1H)。LC/MS(M+H)=587.3;HPLC条件:Rt=0.70min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例258
11-(4-环丙烷羰基哌嗪-1-基)-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的小压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(25mg,0.051mmol)、环丙基(哌嗪-1-基)甲酮(9.8mg,0.064mmol)及二噁烷(2mL)。将固体溶解于二噁烷(2mL)中。添加Pd(OAc)2(0.343mg,1.53μmol)、RuPhos(1.4mg,3.06μmol)及Cs2CO3(24.9mg,0.076mmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好,置于在100℃预加热的油浴中且搅拌1.5h。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 40-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到5.3mg(17%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.67min;LC/MS(M+H)=609.8。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.71min;LC/MS(M+H)=609.8。1H NMR(500MHz,DMSO-d6)δ8.40(s,1H),8.37-8.26(m,2H),7.88-7.75(m,2H),7.15(t,J=8.8Hz,2H),6.91(d,J=8.8Hz,1H),5.72(br.s.,1H),4.01(s,3H),3.94(br.s.,2H),3.92-3.83(m,3H),3.78(br.s.,3H),3.71(br.s.,2H),3.60(br.s.,1H),3.40(t,J=11.6Hz,1H),3.25(t,J=11.4Hz,1H),2.29(s,3H),2.07(d,J=5.1Hz,1H),1.44(br.s.,1H),1.39(d,J=8.1Hz,1H),1.33-1.15(m,2H),0.85-0.69(m,4H)。LC/MS(M+H)=609.4;HPLC条件:Rt=3.59min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例259
11-氯-8-[(4,4-二氟环己基)(苯基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的小压力容器中添加3-溴-7-氯-5-((4,4-二氟环己基)(苯基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(50mg,0.102mmol)、4-(2H3)甲基-1-甲基-1H-1,2,3-三唑(20.4mg,0.204mmol)及NMP(2mL)。添加四甲基乙酸铵(17.0mg,0.127mmol)及二(Ph3P)氯化钯(II)(5.0mg,7.13μmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的油浴中。加热反应混合物且搅拌16小时。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 30-90%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到13.5mg(26%)标题化合物,其平均纯度通过LC/MS分析为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=2.28min;LC/MS(M+H)=510.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.14min;LC/MS(M+H)=510.2。1H NMR(500MHz,DMSO-d6)δ8.73-8.65(m,2H),8.61(br.s.,1H),7.78(d,J=7.3Hz,2H),7.51(d,J=8.1Hz,1H),7.35(t,J=7.3Hz,2H),7.26(t,J=7.2Hz,1H),5.92(d,J=10.6Hz,1H),4.03(s,3H),3.55(d,J=12.1Hz,1H),3.36(br.s.,1H),2.08(br.s.,1H),1.95(br.s.,2H),1.84-1.64(m,2H),1.51-1.34(m,2H),1.34-1.25(m,1H)。LC/MS(M+H)=510.2;HPLC条件:Rt=1.14min(柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例260及261
8-[(4,4-二氟环己基)(苯基)甲基]-5,11-二[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的小压力容器中添加3-溴-7-氯-5-((4,4-二氟环己基)(苯基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(50mg,0.102mmol)、4-(2H3)甲基-1-甲基-1H-1,2,3-三唑(20.4mg,0.204mmol)及NMP(2mL)。添加四甲基乙酸铵(17.0mg,0.127mmol)及二(Ph3P)氯化钯(II)(5.0mg,7.13μmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的油浴中。加热反应混合物且搅拌16小时。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 30-90%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到19mg对映异构体的混合物。对该物质进行手性纯化:手性SFC条件:Chiralcel OJ-H制备型柱,30×250mm,5μm;流动相:15%甲醇/CO2;150巴;温度:35℃;流速:70.0mL/min持续25min;在UV 254nm监测;注射:0.25ml约9mg/mL于MeOH中的溶液(19mg通过堆迭注射纯化);Rt:异构体A:13.6min;异构体B:17.9min。合并含有所需产物的级份且经由蒸发干燥,得到9.1mg(15%)异构体A,其平均纯度通过LC/MS分析为>99%。合并含有所需产物的级份且经由蒸发干燥,得到8.6mg(15%)异构体B,其平均纯度通过LC/MS分析为>99%。异构体A:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。Rt=1.79min;LC/MS(M+H)=574.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.73min;LC/MS(M+H)=574.7。异构体B:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.79min;LC/MS(M+H)=574.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.74min;LC/MS(M+H)=574.7。1H NMR(500MHz,DMSO-d6)δ8.82(d,J=8.1Hz,1H),8.67(s,1H),8.54(br.s.,1H),7.73(d,J=7.7Hz,3H),7.38-7.29(m,2H),7.29-7.20(m,1H),6.10(br.s.,1H),4.36(s,3H),4.03(s,3H),3.53(br.s.,1H),2.07(br.s.,1H),1.94(br.s.,2H),1.82(br.s.,1H),1.68(d,J=13.2Hz,1H),1.52-1.41(m,1H),1.37(br.s.,1H),1.30(d,J=13.6Hz,1H)。LC/MS(M+H)=574.3;HPLC条件:Rt=0.93min(柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例262及263
8-[(4,4-二氟环己基)(苯基)甲基]-5,11-二(二甲基-1H-1,2,3-三唑-5-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的压力容器中添加3-溴-7-氯-5-((4,4-二氟环己基)(苯基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(240mg,0.489mmol)、1,4-二甲基-1H-1,2,3-三唑(52.2mg,0.538mmol)及DMF(5mL)。添加四甲基乙酸铵(98mg,0.734mmol)及PdCl2(dppf)-CH2Cl2加合物(28.0mg,0.034mmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好,置于在100℃预加热的铝块中且搅拌16小时。过滤固体且通过制备型HPLC纯化滤液:20-100%B;溶剂B:90%MeCN/0.1%TFA水;Phenomenex LUNA C18 30×100mm,10微米;流速:30mL/min;UV 254nm;Rt=11.6min。浓缩类似的级份且通过制备型HPLC再次纯化:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到18mg对映异构体的混合物。对该物质进行手性纯化:手性SFC条件:Chiralcel OJ-H制备型柱,30×250mm,5μm;流动相:15%甲醇/CO2;150巴;温度:35℃;流速:70.0mL/min持续25min;在UV 254nm监测;注射:0.25ml约9mg/mL于MeOH中的溶液(18mg通过堆迭注射纯化);Rt:异构体A:13.8min;异构体B:18.3min。合并含有所需产物的级份且经由蒸发干燥,得到6.9mg(2%)异构体A,其平均纯度通过LC/MS分析为>99%。合并含有所需产物的级份且经由蒸发干燥,得到7.5mg(3%)异构体B,其平均纯度通过LC/MS分析为>99%。异构体A:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.76min;LC/MS(M+H)=568.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.77min;LC/MS(M+H)=568.7。异构体B:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.86min;LC/MS(M+H)=568.7。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.73min;LC/MS(M+H)=568.7。1H NMR(500MHz,DMSO-d6)δ8.82(d,J=8.1Hz,1H),8.67(s,1H),8.54(br.s.,1H),7.73(d,J=8.1Hz,3H),7.32(t,J=7.5Hz,2H),7.25(t,J=7.3Hz,1H),6.09(br.s.,1H),4.36(s,3H),4.02(s,3H),3.52(br.s.,1H),2.30(s,3H),2.07(br.s.,1H),1.92(d,J=7.3Hz,1H),1.82(br.s.,1H),1.73(br.s.,1H),1.66(br.s.,1H),1.45(d,J=12.1Hz,1H),1.37(br.s.,1H),1.30(d,J=11.7Hz,1H)。LC/MS(M+H)=568.2;HPLC条件:Rt=0.93min(柱:Waters AquityBEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例264及265
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-11-(4-甲基哌嗪-1-基)-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的20mL闪烁瓶中添加7-氯-5-((4,4-二氟环己基)(苯基)甲基)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(40mg,0.079mmol)、三乙胺(0.110mL,0.789mmol)及1-甲基哌嗪(39.5,0.394mmol)。将混合物溶解于DMSO(1mL)中。将容器盖好,置于在100℃预加热的铝反应块中且搅拌反应混合物16h。冷却容器至室温。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到对映异构体的混合物。对该物质进行手性纯化:手性HPLC条件:Chiralpak AS制备型柱,21×250mm,10μm;流动相:A:0.1%二乙胺/庚烷;B:乙醇;等度8%B持续60min运行时间;流速:15.0mL/min持续60min;在UV 254nm监测;注射:0.25mL;Rt:异构体A:32.4min;异构体B:41.8min。合并含有所需产物的级份且经由蒸发干燥,得到6.0mg(13%)异构体A,其平均纯度通过LC/MS分析为>99%。合并含有所需产物的级份且经由蒸发干燥,得到5.0mg(11%)异构体B,其平均纯度通过LC/MS分析为>99%。异构体A:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.71min;LC/MS(M+H)=571.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.37min;LC/MS(M+H)=571.1。异构体B:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.70min;LC/MS(M+H)=571.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.37min;LC/MS(M+H)=571.1。1H NMR(500MHz,DMSO-d6)δ8.40(s,1H),8.33(br.s.,1H),8.27(d,J=8.8Hz,1H),7.76(d,J=7.3Hz,2H),7.35-7.27(m,2H),7.26-7.17(m,1H),6.90(d,J=9.2Hz,1H),5.77(br.s.,1H),4.00(s,3H),3.57(br.s.,1H),3.43(d,J=7.7Hz,6H),2.28(d,J=8.4Hz,6H),2.06(br.s.,1H),1.97(br.s.,2H),1.90(br.s.,1H),1.74(br.s.,1H),1.67(s,1H),1.53-1.44(m,1H),1.40(d,J=11.7Hz,1H),1.32-1.18(m,2H)。LC/MS(M+H)=571.3;HPLC条件:Rt=0.72min(柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例266及267
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-N-甲基-N-[2-(甲基氨基)乙基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-胺
在配备有磁性搅拌棒的20mL闪烁瓶中添加7-氯-5-((4,4-二氟环己基)(苯基)甲基)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(40mg,0.079mmol)、三乙胺(0.110mL,0.789mmol)及N1,N2-二甲基乙烷-1,2-二胺(34.8mg,0.394mmol)。将混合物溶解于DMSO(1mL)中。将容器盖好,置于在100℃预加热的铝反应块中且搅拌反应混合物16h。冷却容器至室温。过滤固体且通过制备型HPLC纯化滤液:柱:WatersXBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到21mg对映异构体的混合物。对该物质进行手性纯化:手性SFC条件:Lux Cellulose-1制备型柱,20×250mm,5μm;流动相:15%甲醇(0.1%二乙胺)/CO2;150巴;温度:35℃;流速:45.0mL/min持续25min;在UV 254nm监测;注射:0.25ml约7mg/mL于MeOH中的溶液(21mg通过堆迭注射纯化);Rt:异构体A:19.6min;异构体B:21.3min。合并含有所需产物的级份且经由蒸发干燥,得到11.5mg(26%)异构体A,其平均纯度通过LC/MS分析为>99%。合并含有所需产物的级份且经由蒸发干燥,得到4.9mg(11%)异构体B,其平均纯度通过LC/MS分析为>99%。异构体A:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.50min;LC/MS(M+H)=559.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=2.85min;LC/MS(M+H)=559.1。异构体B:两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mMNH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.50min;LC/MS(M+H)=559.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.85min;LC/MS(M+H)=559.1。1H NMR(500MHz,DMSO-d6)δ8.37(s,1H),8.25(d,J=8.8Hz,2H),7.78(d,J=7.0Hz,2H),7.31(t,J=7.3Hz,2H),7.23(t,J=7.3Hz,1H),6.71(d,J=8.8Hz,1H),5.79(br.s.,1H),3.99(s,3H),3.88(d,J=14.3Hz,2H),3.57(br.s.,1H),3.23(s,3H),2.94(t,J=6.4Hz,2H),2.92-2.84(m,1H),2.73(s,1H),2.44(s,3H),2.28(s,3H),2.06(br.s.,1H),1.95(br.s.,1H),1.76(br.s.,1H),1.70(br.s.,1H),1.47-1.33(m,2H),1.32-1.19(m,2H),1.15(t,J=7.2Hz,1H)。LC/MS(M+H)=559.3;HPLC条件:Rt=0.72min(柱:Waters AquityBEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:ACN及0.05%TFA;温度:40℃:梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
实施例268
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]-N,N-二甲基哌嗪-1-甲酰胺
在配备有磁性搅拌棒的小压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、N,N-二甲基哌嗪-1-甲酰胺(7.7mg,0.049mmol)及二噁烷(2mL)。添加Pd(OAc)2(0.3mg,1.22μmol)、RuPhos(1.1mg,2.44μmol)及Cs2CO3(19.9mg,0.061mmol)。在超声波处理下使氩气鼓泡至混合物中5min,将容器盖好,置于在100℃预加热的铝块中且搅拌反应混合物48h。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到3.3mg(13%)标题化合物,其平均纯度通过LC/MS分析为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.75min;LC/MS(M+H)=612.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.25min;LC/MS(M+H)=612.2。1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.27(d,J=8.8Hz,2H),8.15(t,J=7.3Hz,1H),7.37-7.28(m,1H),7.28-7.22(m,1H),7.11(t,J=9.4Hz,1H),6.87(d,J=8.8Hz,1H),6.02(br.s.,1H),4.00(s,3H),3.94-3.84(m,2H),3.55(br.s.,1H),3.43(d,J=8.4Hz,6H),3.32(br.s.,4H),3.27-3.15(m,1H),2.83(s,6H),2.29(s,3H),1.61(d,J=13.2Hz,1H),1.50-1.39(m,1H),1.38-1.24(m,1H),1.03(d,J=12.5Hz,1H)。LC/MS(M+H)=612.3;HPLC条件:Rt=3.35min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例269
4-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]-N,N-二甲基哌嗪-1-磺酰胺
在配备有磁性搅拌棒的小压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、N,N-二甲基哌嗪-1-磺酰胺(9.5mg,0.049mmol)及二噁烷(2mL)。添加Pd(OAc)2(0.3mg,1.22μmol)、RuPhos(1.1mg,2.44μmol)及Cs2CO3(19.9mg,0.061mmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好且置于在100℃预加热的铝块中且搅拌反应混合物48h。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:WatersXBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到2.7mg(10%)标题化合物,其平均纯度通过LC/MS分析为96%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.85min;LC/MS(M+H)=648.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.12min;LC/MS(M+H)=648.1。1H NMR(500MHz,DMSO-d6)δ8.44(s,1H),8.30(d,J=8.4Hz,2H),8.15(t,J=7.5Hz,1H),7.32(d,J=6.6Hz,1H),7.28-7.20(m,1H),7.11(t,J=9.2Hz,1H),6.90(d,J=8.8Hz,1H),6.02(br.s.,1H),4.01(s,3H),3.90(s,2H),3.87-3.79(m,4H),3.75(d,J=10.3Hz,1H),3.53(br.s.,1H),3.49-3.43(m,3H),3.34(br.s.,2H),3.28-3.15(m,1H),2.87-2.77(m,6H),2.30(s,3H),1.62(d,J=12.5Hz,1H),1.45(d,J=12.1Hz,1H),1.33(d,J=8.4Hz,1H),1.10-0.96(m,1H)。LC/MS(M+H)=648.3;HPLC条件:Rt=3.52min(柱:Phenomenex LUNA C182×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例270
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-11-[4-(1-甲基哌啶-4-基)哌嗪-1-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在配备有磁性搅拌棒的小微波压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、1-(1-甲基哌啶-4-基)哌嗪(9.0mg,0.049mmol)及二噁烷(2mL)。添加Pd(OAc)2(0.3mg,1.22μmol)、RuPhos(1.1mg,2.44μmol)及Cs2CO3(19.9mg,0.061mmol)。在超声波处理下使氩气鼓泡至混合物中5min,然后将容器盖好,置于微波反应器中且在搅拌下加热至120℃且保持0.25h。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridgeC18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经30min 30-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到11.5mg(44%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:WatersBEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.37min;LC/MS(M+H)=638.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.01min;LC/MS(M+H)=638.2。1H NMR(500MHz,DMSO-d6)δ8.41(s,1H),8.24(d,J=8.1Hz,2H),8.14(t,J=7.3Hz,1H),7.35-7.28(m,1H),7.28-7.19(m,1H),7.12(t,J=9.4Hz,1H),6.85(d,J=8.8Hz,1H),6.00(br.s.,1H),4.00(s,3H),3.92-3.83(m,1H),3.77(br.s.,1H),3.55(br.s.,1H),3.39(br.s.,4H),3.22(t,J=11.6Hz,1H),2.81(d,J=11.0Hz,2H),2.65(br.s.,4H),2.29(s,3H),2.24-2.17(m,1H),2.15(s,3H),1.90-1.81(m,2H),1.78(d,J=11.0Hz,2H),1.59(d,J=12.1Hz,1H),1.53-1.38(m,3H),1.33(d,J=8.8Hz,1H),1.04(d,J=12.1Hz,1H)。LC/MS(M+H)=638.5;HPLC条件:Rt=2.70min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例271
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]-N,N-二甲基哌啶-4-甲酰胺
在配备有磁性搅拌棒的小压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、N,N-二甲基哌啶-4-甲酰胺(6.4mg,0.041mmol)及THF(2mL)。添加RuPhos预催化剂(1.8mg,2.44μmol)、RuPhos(1.1mg,2.44μmol)及叔丁醇钠(11.7mg,0.122mmol)。在超声波处理下使氩气鼓泡至混合物中5min。将容器盖好,置于在100℃预加热的油浴中且搅拌反应混合物16h。过滤固体且通过制备型HPLC纯化滤液:柱:WatersXBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到13.7mg(54%)标题化合物,其平均纯度通过LC/MS分析为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.71min;LC/MS(M+H)=611.1。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.50min;LC/MS(M+H)=611.1。1H NMR(500MHz,DMSO-d6)δ8.41(s,1H),8.24(d,J=8.4Hz,2H),8.14(t,J=7.3Hz,1H),7.32(d,J=5.5Hz,1H),7.28-7.18(m,1H),7.12(t,J=9.4Hz,1H),6.87(d,J=8.8Hz,1H),6.00(br.s.,1H),4.57(d,J=11.7Hz,2H),4.00(s,3H),3.91-3.83(m,1H),3.76(d,J=10.6Hz,1H),3.55(br.s.,1H),3.22(t,J=11.4Hz,1H),3.19-3.12(m,3H),3.10(s,3H),3.08-2.98(m,1H),2.83(s,3H),2.29(s,3H),1.80(d,J=12.1Hz,2H),1.59(d,J=11.4Hz,3H),1.42(d,J=11.4Hz,1H),1.33(d,J=9.9Hz,1H),1.05(d,J=11.7Hz,1H)。LC/MS(M+H)=611.4;HPLC条件:Rt=3.28min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例272
2-{1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]哌啶-4-基}丙-2-醇
在配备有磁性搅拌棒的小微波压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、2-(哌啶-4-基)丙-2-醇(8.8mg,0.061mmol)及THF(2mL)。然后添加RuPhos预催化剂(1.8mg,2.44μmol)、RuPhos(1.1mg,2.44μmol)及叔丁醇钠(11.7mg,0.122mmol)。在超声波处理下使氩气鼓泡至混合物中5min。将容器盖好,置于设定在100℃的微波反应器中且搅拌反应混合物0.25h。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到7.3mg(29%)标题化合物,其平均纯度通过LC/MS分析为98%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.75min;LC/MS(M+H)=598.3。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mMNH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.90min;LC/MS(M+H)=598.3。LC/MS(M+H)=598.4;HPLC条件:Rt=3.55min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例273
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]-2,2,6,6-四甲基哌啶-4-醇
在配备有磁性搅拌棒的小微波压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、2,2,6,6-四甲基哌啶-4-醇(9.6mg,0.061mmol)及THF(2mL)。添加RuPhos预催化剂(1.8mg,2.44μmol)、RuPhos(1.1mg,2.44μmol)及叔丁醇钠(11.7mg,0.122mmol)。在超声波处理下使氩气鼓泡至混合物中5min。将容器盖好,置于设定在100℃的微波反应器中且搅拌反应混合物0.25h。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到0.5mg(2%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.39min;LC/MS(M+H)=612.4。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV220nm。Rt=3.17min;LC/MS(M+H)=612.4。1HNMR(500MHz,DMSO-d6)δ8.53(s,1H),8.46(d,J=8.8Hz,1H),8.26(br.s.,1H),7.35(br.s.,1H),7.25(br.s.,1H),7.16(t,J=8.8Hz,1H),6.76(d,J=8.1Hz,1H),5.70(br.s.,1H),4.00(br.s.,3H),3.90(br.s.,1H),3.79(br.s.,1H),3.55-3.45(m,4H),3.22(t,J=12.1Hz,1H),2.29(br.s.,3H),2.18(d,J=14.3Hz,2H),1.36(br.s.,9H),1.24(br.s.,1H),1.16(s,6H),1.05(br.s.,1H)。LC/MS(M+H)=612.4;HPLC条件:Rt=3.47min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例274
1-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]哌啶-4-甲腈
在配备有磁性搅拌棒的小压力瓶中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、哌啶-4-甲腈(6.7mg,0.061mmol)及THF(2mL)。添加RuPhos预催化剂(1.8mg,2.44μmol)、RuPhos(1.1mg,2.44μmol)及叔丁醇钠(11.7mg,0.122mmol)。在超声波处理下使氩气鼓泡至混合物中5min。将瓶盖好,置于在100℃预加热的油浴中且搅拌反应混合物16h。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Water XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经15min 35-75%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到5.0mg(22%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.74min;LC/MS(M+H)=565.2。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.62min;LC/MS(M+H)=565.2。1H NMR(500MHz,DMSO-d6)δ8.43(s,1H),8.26(d,J=8.8Hz,2H),8.14(t,J=7.5Hz,1H),7.39-7.28(m,1H),7.28-7.20(m,1H),7.13(t,J=9.2Hz,1H),6.90(d,J=8.8Hz,1H),6.03(br.s.,1H),4.06(br.s.,2H),4.01(s,3H),3.92-3.84(m,1H),3.76(d,J=11.0Hz,1H),3.63(br.s.,2H),3.55(br.s.,1H),3.47-3.39(m,1H),3.22(t,J=11.0Hz,2H),2.30(s,3H),2.03(br.s.,2H),1.81(dd,J=18.5,9.0Hz,2H),1.61(d,J=12.1Hz,1H),1.45(d,J=8.1Hz,1H),1.33(d,J=9.2Hz,1H),1.03(d,J=14.3Hz,1H)。LC/MS(M+H)=565.3;HPLC条件:Rt=3.38min(柱:Phenomenex LUNAC18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例275
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]-2-甲基丙酰胺
步骤1:(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺
在配备有磁性搅拌棒的小压力容器中添加(S)-7-氯-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(20mg,0.041mmol)、3-氨基-3-甲基四氢噻吩1,1-二氧化物(9.1mg,0.061mmol)及THF(2mL)。添加RuPhos预催化剂(1.8mg,2.44μmol)、RuPhos(1.1mg,2.44μmol)及叔丁醇钠(11.7mg,0.122mmol)。在超声波处理下使氩气鼓泡至混合物中5min。将容器盖好,置于在100℃预加热的油浴中且搅拌16h。冷却反应容器至室温。过滤固体且真空浓缩滤液,得到20mg(78%)残余物。LC/MS(M+H)=472.3;HPLC条件:Rt=2.91min(柱:Phenomenex LUNAC18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
步骤2:N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]-2-甲基丙酰胺
在配备有磁性搅拌棒的20mL闪烁瓶中添加于二氯甲烷(1.5mL)中的(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺(10mg,0.021mmol)。添加三乙胺(9μl,0.064mmol)及异丁酰氯(3.4mg,0.032mmol)。将瓶盖好,然后在20℃搅拌1h。真空除去二氯甲烷且将剩余的残余物吸收于甲醇中。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mMNH4OAc;梯度:历经15min 55-95%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到4.7mg(41%)标题化合物,其平均纯度通过LC/MS分析为>99%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mMNH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV 220nm。Rt=1.74min;LC/MS(M+H)=540.2。注射2条件:柱:Waters BEHC18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=3.17min;LC/MS(M+H)=540.2。1H NMR(500MHz,DMSO-d6)δ10.66(br.s.,1H),8.55(d,J=4.0Hz,2H),8.43(br.s.,1H),8.34(br.s.,1H),8.19(d,J=8.1Hz,1H),7.40-7.21(m,2H),7.11(t,J=9.4Hz,1H),6.15(br.s.,1H),3.99(br.s.,3H),3.91(d,J=10.6Hz,1H),3.75(d,J=11.4Hz,1H),3.25(t,J=11.4Hz,1H),3.00-2.91(m,1H),2.28(br.s.,3H),1.64(br.s.,1H),1.52-1.32(m,2H),1.27-1.09(m,6H),0.99(d,J=12.1Hz,1H)。LC/MS(M+H)=540.3;HPLC条件:Rt=3.84min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例276
N-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基]环丙烷甲酰胺
在配备有磁性搅拌棒的20mL闪烁瓶中添加于二氯甲烷(2mL)中的(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-((2-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-7-胺(10mg,0.021mmol)。添加三乙胺(9μl,0.064mmol)及环丙烷甲酰氯(3.3mg,0.032mmol)。将瓶盖好且在20℃搅拌1h。真空除去二氯甲烷且将残余物吸收于甲醇中。过滤固体且通过制备型HPLC纯化滤液:柱:Waters XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;梯度:历经15min 55-95%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到2.5mg(21%)标题化合物,其平均纯度通过LC/MS分析为97%。两种分析型LC/MS注射用于确定最终纯度。注射1条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95ACN:水及10mM NH4OAc;流动相B:95:5ACN:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:1mL/min;检测:UV220nm。Rt=1.70min;LC/MS(M+H)=540.2。注射2条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95甲醇:水及10mM NH4OAc;流动相B:95:5甲醇:水及10mM NH4OAc;温度:50℃;梯度:0%B,历经3min 0-100%B且然后在100%B保持0.5min;流速:0.5mL/min;检测:UV 220nm。Rt=2.63min;LC/MS(M+H)=540.2。1H NMR(500MHz,DMSO-d6)δ11.00(br.s.,1H),8.60-8.52(m,2H),8.44(br.s.,1H),8.34(br.s.,1H),8.17(d,J=8.4Hz,1H),7.44-7.22(m,2H),7.12(t,J=9.4Hz,1H),6.14(br.s.,1H),4.00(br.s.,3H),3.91(d,J=10.3Hz,1H),3.76(d,J=9.5Hz,2H),3.57-3.45(m,1H),3.26(t,J=11.0Hz,1H),2.29(br.s.,3H),2.22-2.12(m,1H),1.63(br.s.,1H),1.51-1.32(m,2H),1.00(d,J=11.7Hz,1H),0.92(d,J=5.9Hz,4H)。LC/MS(M+H)=540.2;HPLC条件:Rt=3.79min(柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
实施例277
10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-N-(2,2,2-三氟乙基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
步骤1:13-氯-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向100mL圆底烧瓶中装入10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(336mg,0.611mmol)及DMF(6113μL)。向该溶液中添加POCl3(570μL,6.11mmol)。将瓶置于预加热至80℃的油浴中且排气于部分填充有氮气的气囊中。1.5h后,将混合物倾至冰上且用乙酸乙酯稀释。用固体碳酸氢钠缓慢淬灭反应混合物。将经淬灭的溶液转移至分液漏斗且分离各层。用水(×2)洗涤有机相。用乙酸乙酯萃取水相且弃去。合并的有机相用盐水(×2)洗涤,经硫酸镁干燥,减压浓缩且通过快速色谱纯化:24g ISCO RediSep Rf,丙酮/DCM 0%[75mL]、0-25%[250mL]、25%[200mL]、25-100%[400mL]。收集级份,得到标题化合物(282mg,83%)。1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.77(d,J=1.8Hz,1H),7.54(d,J=1.8Hz,1H),7.52-7.48(m,2H),7.45-7.36(m,3H),6.97(d,J=10.0Hz,1H),4.12-4.04(m,1H),3.84-3.79(m,1H),3.72(s,3H),3.55(td,J=11.8,1.8Hz,1H),3.48(s,3H),3.23(td,J=11.8,1.8Hz,1H),3.04-2.91(m,1H),2.24-2.19(m,1H),2.05-1.92(m,1H),1.70-1.59(m,1H),0.37(d,J=14.3Hz,1H)。LCMS:(M+H)+554.0。
步骤2:10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-N-(2,2,2-三氟乙基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
向1打兰瓶中装入13-氯-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(66mg,0.119mmol)及NMP(250μL)。向该溶液中添加2,2,2-三氟乙胺(200μL,2.51mmol)。将瓶密封且在搅拌下加热至65℃过夜。16h后,添加额外的200μL胺且再继续搅拌24h。冷却粗混合物,经由0.45μ针筒头过滤器过滤且通过制备型HPLC直接纯化:柱:Waters XBridge C18 100×30mm 5μm,溶剂:A:95:5水/乙腈;B:95:5乙腈/水;缓冲剂:10mM乙酸铵,%B梯度(时间):49%(11min),流速:30mL/min,4次注射,在254nm监测。减压浓缩含有产物的级份。经由硅胶塞过滤所得固体,用50%丙酮/DCM洗脱。将经分离的产物溶解于1mL乙醇中且逐滴添加1mL去离子水,使瓶略微涡旋,得到白色析出物。将固体超声波处理2min且通过过滤收集,得到标题化合物(36.5mg,50%)。LCMS:m/z(M+H)+617。1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.50(d,J=1.8Hz,1H),8.31(t,J=6.5Hz,1H),7.50(d,J=7.8Hz,2H),7.43(d,J=1.8Hz,1H),7.42-7.30(m,3H),6.92(d,J=10.3Hz,1H),4.67-4.52(m,2H),4.11-4.03(m,J=11.3Hz,1H),3.83(dd,J=11.7,3.4Hz,1H),3.73-3.70(m,3H),3.59-3.48(m,1H),3.35(s,3H),3.30-3.19(m,1H),2.94(d,J=10.0Hz,1H),2.23-2.11(m,1H),1.93(d,J=12.8Hz,1H),1.73-1.60(m,1H),0.48(d,J=11.5Hz,1H)。
实施例278
2-{10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
步骤1:3-氟-5-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-甲酸甲酯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯步骤1(实施例135)所描述的程序使用5-溴-3-氟吡啶-2-甲酸甲酯制备标题化合物。通过快速色谱纯化物质:40g ISCO RediSep Rf,乙酸乙酯/己烷0%[100mL]、0-15%[150mL]、15%[200mL]、15-50%[400mL]。收集含有产物+杂质的级份且减压浓缩。用10mL冷乙醚稀释此黄色油状物且缓慢添加己烷直至形成白色固体。冷收集固体且用己烷洗涤,得到标题化合物(1.38g,58%)。1H NMR(400MHz,CDCl3)δ8.82(t,J=1.4Hz,1H),7.91(dd,J=10.5,1.3Hz,1H),4.03(s,3H),1.38(s,12H)。
步骤2:5-(5-溴-3-硝基吡啶-2-基)-3-氟吡啶-2-甲酸甲酯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤1(实施例3)所描述的程序使用3-氟-5-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-甲酸甲酯制备标题化合物。通过快速色谱纯化物质:40g ISCO RediSep Rf,乙酸乙酯/DCM 0%[100mL]、0-15%[750mL]。减压浓缩含有产物的级份,得到标题化合物(764mg,43%)。1HNMR(500MHz,CDCl3)δ9.03(d,J=2.0Hz,1H),8.67(dd,J=1.7,1.1Hz,1H),8.52(d,J=2.0Hz,1H),7.79(dd,J=10.1,1.8Hz,1H),4.08(s,3H)。LCMS:(M+H)+355.9。
步骤3:5-溴-12-氟-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-11-甲酸甲酯及5-溴-10-氟-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-1-甲酸甲酯
向40mL压力瓶中装入5-(5-溴-3-硝基吡啶-2-基)-3-氟吡啶-2-甲酸甲酯(764mg,2.15mmol)及1,2-二(二苯基膦基)乙烷(1282mg,3.22mmol)。将混合物混悬于1,2-二氯苯(5mL)中且置于预加热至160℃的反应块中。20min后,在高真空压力下浓缩混合物。用二氯甲烷稀释所得黑色浆液且超声波处理几分钟。通过过滤收集呈区域异构产物的1:1混合物(30%合并产率)形式的茶色固体(212mg)。该物质以混合物形式继续使用。LCMS:TR=0.68min;(ES):m/z(M+H)+325.9。Waters Acquity SDS;柱类型:ACQUITYBEH C181.7μm 2.1×50mm;运行时间:2.20min;0-100%B;溶剂A:水/0.05%TFA;溶剂B:乙腈/0.05%TFA;流速:0.8mL/min;检测:UV=254nm。
步骤4:(S)-3-溴-6-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯
根据针对13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例128)所描述的程序由5-溴-12-氟-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-11-甲酸甲酯及5-溴-10-氟-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-1-甲酸甲酯制备标题化合物。通过制备型HPLC纯化物质:柱:Waters XBridge C18100×30mm 5μm,溶剂:A:95:5水/乙腈;B:95:5乙腈/水;缓冲剂:10mM乙酸铵,%B梯度(时间):0%(1min)、0-100%(15min),流速:30mL/min,7次注射,在254nm监测。减压浓缩含有产物的级份。经由硅胶塞过滤所得固体,用丙酮洗脱产物,得到标题化合物(91mg,28%)。1H NMR(400MHz,CDCl3)δ9.42(d,J=1.3Hz,1H),8.70(d,J=1.3Hz,1H),8.06(br.s.,1H),7.50(d,J=7.3Hz,2H),7.43-7.37(m,2H),7.36-7.33(m,1H),6.07-5.91(m,1H),4.10(s,3H),4.05(dd,J=11.9,2.6Hz,1H),3.89(dd,J=11.8,2.8Hz,1H),3.56(td,J=11.9,2.0Hz,1H),3.45-3.33(m,1H),3.13-3.00(m,1H),1.99(d,J=13.6Hz,1H),1.62-1.50(m,2H),0.95(d,J=12.5Hz,1H)。LCMS:(M+H)+499.9。
步骤5:10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-甲酸甲酯
向经烘箱干燥的5mL瓶中装入4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(86mg,0.221mmol)且用DMF(1mL)稀释。向该溶液中添加(S)-3-溴-6-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-甲酸甲酯(91.8mg,0.184mmol)、碘化亚铜(I)(5.3mg,0.028mmol)、三乙胺(0.039mL,0.276mmol)及Pd(Ph3P)4(16.0mg,0.014mmol)。将瓶密封且通过用氩气鼓泡同时超声波处理2min脱气。将瓶置于预加热至80℃的油浴中。40min后,冷却混合物至室温且经由硅藻土垫过滤且通过制备型HPLC直接纯化:柱:Waters XBridge C18 100×30mm 5μm,溶剂:A:95:5水/乙腈;B:95:5乙腈/水;缓冲剂:10mM乙酸铵,%B梯度(时间):0%(1min)、0-100%(15min)、100%(4min),流速:30mL/min,2次注射,在254nm监测。减压浓缩含有产物的级份。将所得固体溶解于DCM中且经由硅胶塞过滤,用丙酮洗脱产物,得到70.6mg(74%)。1H NMR(400MHz,CDCl3)δ9.51(s,1H),8.62(d,J=1.8Hz,1H),7.69(s,1H),7.54-7.46(m,2H),7.44-7.32(m,3H),6.21-6.06(m,1H),4.14(s,3H),4.10-4.03(m,1H),3.94-3.87(m,1H),3.85(s,3H),3.61-3.50(m,1H),3.41-3.29(m,1H),3.14-2.96(m,1H),2.10-2.04(m,1H),1.66-1.50(m,2H),0.99-0.93(m,1H)。LCMS:(M+H)+518.1。
步骤6:2-{10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
根据针对2-[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇(实施例142)所描述的程序由10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-11-甲酸甲酯制备标题化合物。通过制备型HPLC纯化该物质:柱:Waters XBridge C18 100×30mm 5μm,溶剂:A:95:5水/乙腈;B:95:5乙腈/水;缓冲剂:10mM乙酸铵,%B梯度(时间):35%(15min),流速:30mL/min,2次注射,在254nm监测。减压浓缩含有产物的级份。将所得固体溶解于DCM中且经由硅胶塞过滤,用1:1DCM/丙酮溶液洗脱产物,得到标题化合物(9mg,36%)。1H NMR(400MHz,CDCl3)δ9.31(d,J=1.8Hz,1H),8.54(d,J=1.5Hz,1H),7.60(d,J=1.5Hz,1H),7.54-7.47(m,2H),7.45-7.38(m,2H),7.38-7.32(m,1H),6.10-6.04(m,1H),4.07(dd,J=11.7,2.6Hz,1H),3.91(dd,J=11.8,2.8Hz,1H),3.83(s,3H),3.56(td,J=11.9,1.8Hz,1H),3.36(td,J=11.9,1.9Hz,1H),3.12-2.96(m,1H),2.07(d,J=13.6Hz,1H),1.77(dd,J=5.8,1.3Hz,6H),1.69-1.57(m,2H),1.51(qd,J=12.3,4.1Hz,1H),1.00(d,J=12.8Hz,1H)。LCMS:(M+H)+518.1。
实施例279
13-[(2,2-二氟环丙基)甲氧基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
根据针对13-乙氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(实施例129)所描述的程序使用(2,2-二氟环丙基)甲醇制备标题化合物。通过制备型HPLC纯化该物质:柱:Waters XBridge C18100×30mm 5μm,溶剂:A:95:5水/乙腈;B:95:5乙腈/水;缓冲剂:10mM乙酸铵,%B梯度(时间):45%(10min),流速:30mL/min,3次注射,在254nm监测。减压浓缩含有产物的级份。经由硅胶塞过滤所得固体,用50%丙酮洗脱产物,得到标题化合物(13.6mg,46%)。1H NMR(400MHz,CDCl3)δ8.63(d,J=1.8Hz,1H),8.26(d,J=6.0Hz,1H),7.60(s,1H),7.46-7.40(m,2H),7.40-7.33(m,3H),7.32-7.28(m,1H),5.47(d,J=10.5Hz,1H),4.96-4.87(m,1H),4.82-4.71(m,1H),4.06(dd,J=11.9,2.6Hz,1H),3.87(s,3H),3.92-3.83(m,1H),3.55(td,J=11.8,1.8Hz,1H),3.41-3.31(m,1H),3.15-3.01(m,1H),2.46(ddd,J=13.4,11.3,7.2Hz,1H),2.03(d,J=13.1Hz,1H),1.66-1.46(m,3H),1.45-1.33(m,1H),1.08(d,J=13.6Hz,1H)。LCMS:(M+H)+548.2。
实施例280
13-氯-10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:2-氯-5-氟-3-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯步骤1(实施例135)所描述的程序使用3-溴-2-氯-5-氟吡啶制备标题化合物。通过快速色谱纯化该物质:80g ISCO RediSep Rf,二氯甲烷/己烷0%(250mL)、0-100%(1000mL)、100%(250mL)且然后0-5%乙酸乙酯/DCM(625mL)。收集级份,得到标题化合物(1.75g,74%)。1H NMR(400MHz,CDCl3)δ8.28(d,J=3.3Hz,1H),7.75(dd,J=7.9,3.1Hz,1H),1.39(s,12H)。
步骤2:3-(5-溴-3-硝基吡啶-2-基)-2-氯-5-氟吡啶
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤1(实施例3)所描述的程序使用2-氯-5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶制备标题化合物。通过快速色谱纯化该物质:40g ISCO RediSep Rf,二氯甲烷/己烷0%(102mL)、10-100%(501mL)、100%(501mL)。收集级份,得到标题化合物(717mg,35%)。1H NMR(400MHz,CDCl3)δ9.02(d,J=2.0Hz,1H),8.67(d,J=2.0Hz,1H),8.44-8.34(m,1H),7.59(dd,J=7.5,3.0Hz,1H)。LCMS:(M+H)+331/333。
步骤3:5-溴-13-氯-10-氟-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤2(实施例3)所描述的程序使用3-(5-溴-3-硝基吡啶-2-基)-2-氯-5-氟吡啶制备标题化合物。通过快速色谱纯化该物质:40g ISCO RediSep Rf,丙酮/DCM0%(102mL)、10%(102mL)、20%(501mL)、20-50%(150mL)、50%(150mL)、50-70%(150mL)。收集所有含有产物的级份且减压浓缩。用DCM研磨所得固体,得到黄色固体。通过过滤收集固体,得到标题化合物(98mg,15%)。1H NMR(400MHz,DMSO-d6)δ13.10(br.s.,1H),8.78(d,J=2.0Hz,1H),8.43(d,J=2.3Hz,1H),8.27(d,J=2.0Hz,1H)。
步骤4:13-氯-10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤3(实施例3)所描述的程序使用4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑及5-溴-13-氯-10-氟-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯制备标题化合物。通过快速色谱纯化该物质:24g ISCO RediSep Rf,丙酮/DCM 0%(102mL)、0-25%(450mL)、25%(351mL)。收集级份,减压浓缩且用DCM研磨产物,得到标题化合物(45.7mg,43%)。1H NMR(400MHz,DMSO-d6)δ13.17(br.s.,1H),8.79(d,J=1.8Hz,1H),8.45(d,J=2.5Hz,1H),8.17(d,J=1.8Hz,1H),4.01(s,3H)。LCMS:(M+H)+320。
步骤5:13-氯-10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例3)所描述的程序使用13-氯-10-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯制备标题化合物。通过快速色谱纯化该物质:24g ISCO RediSep Rf,丙酮/DCM0%(75mL)、0-15%(150mL)、15%(150mL)、15-25%(150mL)、25%(250mL)。收集级份,得到标题化合物(60mg,85%)。1H NMR(400MHz,CDCl3)δ8.71(d,J=1.8Hz,1H),8.42(d,J=4.3Hz,1H),7.69(s,1H),7.50-7.45(m,2H),7.43-7.32(m,3H),6.09-5.99(m,1H),4.05(dd,J=11.4,2.1Hz,1H),3.90(dd,J=12.4,3.1Hz,1H),3.83(s,3H),3.55(td,J=11.9,2.0Hz,1H),3.36(td,J=11.9,1.9Hz,1H),3.13-3.00(m,1H),2.08(br.s.,1H),1.66-1.55(m,1H),1.54-1.42(m,1H),0.98(d,J=13.1Hz,1H)。LCMS:(M+H)+494。
实施例281及282
2-{8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇
步骤1:5-溴-8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯步骤4(实施例135)所描述的程序使用(4,4-二氟环己基)(苯基)甲醇及3-溴-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶-6-甲酸甲酯制备标题化合物。该物质在SiO2(24g)上用己烷(51mL)、20%EtOAc/己烷(252mL)、20至50%EtOAc/己烷(357mL,线性梯度)洗脱纯化。收集含有产物的级份,得到标题化合物(215mg,66%)。1H NMR(400MHz,CDCl3)δ8.79(s,1H),8.68(d,J=0.8Hz,1H),7.77(d,J=1.8Hz,1H),7.51(d,J=7.5Hz,2H),7.36(t,J=7.3Hz,2H),7.32-7.25(m,2H),6.52(d,J=10.8Hz,1H),4.32(s,3H),4.06-3.94(m,3H),2.79(q,J=10.7Hz,1H),2.19(d,J=12.3Hz,1H),1.91-1.77(m,1H),1.70-1.50(m,2H),1.48-1.32(m,2H),0.80(d,J=12.3Hz,1H)。LCMS:(M+H)+544.10/546.10。
步骤2:8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯步骤5(实施例135)所描述的程序由5-溴-8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯及4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑制备标题化合物。该物质在SiO2(24g)上用己烷(51mL)、25%EtOAc/己烷(252mL)、DCM(100mL)、25%丙酮/DCM(300mL)、50%丙酮/DCM(150mL)洗脱纯化。含有产物的级份得到标题化合物(74.8mg,34%),其含有杂质,但是按原样使用。1H NMR(400MHz,CDCl3)δ8.85(s,1H),8.61(d,J=1.3Hz,1H),7.53(d,J=7.0Hz,3H),7.40-7.34(m,2H),7.31(d,J=7.3Hz,1H),6.67(d,J=10.0Hz,1H),4.39-4.34(m,3H),4.04(s,3H),3.70(d,J=2.0Hz,3H),2.84(br.s.,1H),2.25(d,J=13.6Hz,1H),2.03-1.76(m,3H),1.70-1.49(m,2H),1.48-1.34(m,1H),0.81(d,J=12.3Hz,1H)。LCMS:(M+H)+564.25。
步骤3:2-{8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇
根据针对2-[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇(实施例142)所描述的程序由8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯制备标题化合物。通过制备型HPLC纯化粗物质:Waters X-Bridge C18,30×100mm S5,A=95%水、5%乙腈、10mM乙酸铵,B=5%水、95%乙腈、10mM乙酸铵,20min 40%B,30mL/min,254nm检测。收集含有产物的级份,得到39.6mg白色固体。通过手性HPLC分离对映异构产物:Chiralcel OJ-H制备型柱,30×250mm,5μm;流动相:10%MeOH/CO2;150巴;温度:35℃;流速:70mL/min持续19min;在UV 252nm监测。注射:0.25mL约10mg/mL于MeOH中(40mg通过堆迭注射纯化)。峰1提供对映异构体1(17.1mg,22%)。峰2提供对映异构体2(18.8mg,25%)。对映异构体1(手性HPLC TR=10.92min):1HNMR(400MHz,CDCl3)δ8.61(d,J=1.8Hz,1H),8.37(s,1H),7.40-7.30(m,5H),7.25(s,1H),7.17(d,J=1.8Hz,1H),4.35(s,3H),3.60(s,3H),2.80-2.65(m,1H),2.46-2.35(m,1H),2.25(br.s.,2H),2.04(s,3H),1.96(s,1H),1.84(s,4H),1.45(br.s.,2H),0.91-0.78(m,1H),0.61-0.50(m,1H)。LCMS:(M+H)+564.40。
对映异构体2(手性HPLC TR=14.05min):1H NMR(400MHz,CDCl3)δ8.61(d,J=1.8Hz,1H),8.37(s,1H),7.40-7.30(m,5H),7.25(s,1H),7.17(d,J=1.8Hz,1H),4.35(s,3H),3.60(s,3H),2.80-2.65(m,1H),2.46-2.35(m,1H),2.25(br.s.,2H),2.04(s,3H),1.96(s,1H),1.84(s,4H),1.45(br.s.,2H),0.91-0.78(m,1H),0.61-0.50(m,1H)。LCMS:m/z(M+H)+564.35。
实施例283
5-(二甲基-1H-1,2,3-三唑-5-基)-11-甲氧基-13-甲基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:5-溴-2-(6-甲氧基-2-甲基吡啶-3-基)-3-硝基吡啶
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤1(实施例3)所描述的程序使用(6-甲氧基-2-甲基吡啶-3-基)硼酸制备标题化合物。该物质在SiO2(40g)上用己烷(95mL)、0至100%DCM/己烷(300mL,线性梯度)、20%DCM(200mL)、0至20%EtOAc/DCM(300mL,线性梯度)洗脱纯化。收集含有产物的级份,得到标题化合物(990mg,55.7%)。1H NMR(400MHz,CDCl3)δ8.95(d,J=0.5Hz,1H),8.48-8.40(m,1H),7.43(d,J=8.3Hz,1H),6.66(d,J=8.5Hz,1H),3.97(d,J=2.8Hz,3H),2.28(s,3H)。LCMS:(M+H)+324/326。
步骤2:5-溴-11-甲氧基-13-甲基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤2(实施例3)所描述的程序使用5-溴-2-(6-甲氧基-2-甲基吡啶-3-基)-3-硝基吡啶制备标题化合物。冷却混合物且浓缩至接近干燥,然后添加DCM。通过过滤收集呈灰白色固体状的标题化合物(228mg,26%)。再次浓缩母液且重复该过程。残余的母液在SiO2(24g)上用DCM(200mL)、5%丙酮/DCM(200mL)、10%丙酮/DCM(200mL)洗脱纯化。浓缩含有产物的级份,得到363mg(25.6%)灰白色固体,其含有所需产物、1,2-二(二苯基膦基)乙烷一氧化物及二氧化物。1H NMR(400MHz,CDCl3)δ8.60(d,J=2.0Hz,1H),8.12-8.01(m,1H),7.77(d,J=1.8Hz,1H),6.53(s,1H),4.04(s,3H),3.10(s,3H)。LCMS:(M+H)+292.0。
步骤3:5-溴-11-甲氧基-13-甲基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例3)所描述的程序使用5-溴-11-甲氧基-13-甲基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。该物质在SiO2(24g)上用己烷(51mL)、20%EtOAc/己烷(396mL)、20至100%EtOAc/己烷(645mL,线性梯度)洗脱纯化。收集含有产物的级份,得到标题化合物(180mg,定量)。1H NMR(400MHz,CDCl3)δ8.54(d,J=1.8Hz,1H),7.82(d,J=1.8Hz,1H),7.46-7.41(m,2H),7.37-7.28(m,3H),6.67(s,1H),5.20(d,J=10.8Hz,1H),4.04(s,3H),4.04-4.00(m,1H),3.85(d,J=8.5Hz,1H),3.51(td,J=11.8,1.8Hz,1H),3.37(td,J=11.9,1.8Hz,1H),3.08-3.05(m,1H),3.07(s,3H),1.91(d,J=13.1Hz,1H),1.56-1.50(m,1H),1.39-1.29(m,J=13.2,4.4Hz,1H),1.11(d,J=14.3Hz,1H)。LCMS:(M+H)+466/468。
步骤4:5-(二甲基-1H-1,2,3-三唑-5-基)-11-甲氧基-13-甲基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
根据针对12-氯-5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例4)所描述的程序在以下调整(80℃,16h)下使用5-溴-11-甲氧基-13-甲基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯及1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑制备标题化合物。经由制备型LC/MS在以下条件下纯化该物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经20min 50-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为25.5mg(37%)。1H NMR(500MHz,DMSO-d6)δ8.56(s,1H),7.66(d,J=8.1Hz,2H),7.38-7.31(m,3H),7.29-7.23(m,2H),5.73(d,J=11.4Hz,1H),4.02-3.95(m,6H),3.88(d,J=10.6Hz,1H),3.73(d,J=8.4Hz,1H),3.46(t,J=11.4Hz,1H),3.34(d,J=10.6Hz,1H),3.28-3.23(m,1H),3.02(s,3H),2.29(br.s.,3H),1.67(d,J=11.7Hz,1H),1.53(d,J=8.8Hz,1H),1.29(d,J=11.0Hz,1H),1.01(d,J=13.6Hz,1H)。LCMS:(M+H)+483。
实施例284
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇
步骤1:2,4-二氯-5-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶
向圆底烧瓶中装入5-溴-2,4-二氯吡啶(10.0g,44.1mmol)、二噁烷(300mL)、4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-联(1,3,2-二氧杂硼杂环戊烷)(16.79g,66.1mmol)、乙酸钾(12.98g,132mmol)及PdCl2(dppf)2二氯甲烷加合物(1.800g,2.20mmol)。通过使氩气鼓泡通过溶液2min将混合物脱气。将其在95℃加热2h。蒸发溶剂且粗物质直接用于后续反应。
步骤2:5-(5-溴-3-硝基吡啶-2-基)-2,4-二氯吡啶
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤1(实施例3)所描述的程序在以下调整(65℃,1.5h)下使用2,4-二氯-5-(四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶制备标题化合物。该物质在330g硅胶柱上用2-50%[5%DCM/丙酮]/己烷洗脱纯化,得到标题化合物(7.44g,48.4%)。1H NMR(400MHz,CDCl3)δ9.05(d,J=2.0Hz,1H),8.68(d,J=2.3Hz,1H),8.47(s,1H),7.52(s,1H)。LCMS:(M+H)+349.9。
步骤3:5-溴-2-(4,6-二氯吡啶-3-基)吡啶-3-胺
向20mL闪烁瓶中装入5-(5-溴-3-硝基吡啶-2-基)-2,4-二氯吡啶(113mg,0.324mmol)、Fe(54.3mg,0.971mmol)、CaCl2(35.9mg,0.324mmol)、EtOH(10mL)及水(0.5mL)。使氮气鼓泡通过溶液。将瓶密封且加热至65℃。2h后,浓缩混合物至干燥且粗残余物在24g SiO2柱上用0-50%(10%(2NNH3/MeOH)/EtOAc)/DCM洗脱纯化,得到标题化合物(83mg,80%)。1H NMR(400MHz,CDCl3)δ8.44(s,1H),8.21(d,J=1.8Hz,1H),7.56(s,1H),7.31(d,J=1.8Hz,1H),3.72(br.s.,2H)。LCMS:(M+H)+319.8。
步骤4:5-溴-11-氯-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向250mL圆底烧瓶中装入5-溴-2-(4,6-二氯吡啶-3-基)吡啶-3-胺(2.00g,6.27mmol)及THF(80mL)。对其进行搅拌且冷却至0℃。逐滴添加二(三甲基硅烷基)氨基钠(1M于THF中,21.3mL,21.3mmol)且在0℃搅拌溶液0.5h。0.5h后,移开冰浴。3h后,用NHCl4饱和水溶液淬灭反应混合物。用EtOAc稀释混合物且萃取有机层,经MgSO4干燥,过滤且浓缩,得到深棕色固体。其在80g硅胶柱上用0-10%丙酮/DCM洗脱纯化,得到标题化合物(761mg,43%)。1H NMR(400MHz,DMSO-d6)δ12.15(br.s.,1H),9.18(d,J=0.8Hz,1H),8.65(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),7.68(d,J=0.8Hz,1H)。LCMS:(M+H)+283.8。
步骤5:5-溴-11-氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例3)所描述的程序使用5-溴-11-氯-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯制备标题化合物。该物质在80g硅胶柱上用10-100%EtOAc/己烷洗脱纯化,得到标题化合物(1.04g,69.9%)。1HNMR(400MHz,DMSO-d6)δ9.17(d,J=0.5Hz,1H),8.82-8.76(m,1H),8.67(d,J=1.8Hz,1H),8.29-8.20(m,1H),7.68(d,J=7.3Hz,2H),7.41-7.34(m,2H),7.32-7.25(m,1H),5.83(d,J=11.3Hz,1H),3.89(dd,J=11.3,2.0Hz,1H),3.73(dd,J=11.3,2.5Hz,1H),3.55-3.48(m,1H),3.46-3.36(m,1H),3.30-3.26(m,1H),1.71-1.63(m,1H),1.61-1.47(m,J=3.8Hz,1H),1.36-1.24(m,J=4.8Hz,1H),0.91(d,J=12.0Hz,1H)。LCMS:(M+H)+457.9。
步骤6:11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向含有5-溴-11-氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(230mg,0.403mmol)、Pd(Ph3P)4(34.9mg,0.030mmol)及碘化亚铜(I)(11.51mg,0.060mmol)的2打兰额定压力瓶中添加4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(157mg,0.403mmol),其经由配衡吸管用DMF(2.5mL)冲洗至瓶中。向该溶液中添加TEA(0.084mL,0.604mmol)且通过用氩气鼓泡同时超声波处理1-2min将混合物脱气。将瓶密封且加热至80℃。16h后,冷却混合物,经由硅藻土使用二氯甲烷过滤且在高真空下浓缩成棕色油状物。该物质在SiO2(12g)上用丙酮/二氯甲烷(0-60%)洗脱纯化。收集级份,得到标题化合物(110mg,57%)。1H NMR(400MHz,氯仿-δ)δ9.38(s,1H),8.54(s,1H),7.71-7.62(m,2H),7.48-7.31(m,5H),5.42(d,J=10.5Hz,1H),4.10-4.01(m,1H),3.89(s,3H),3.94-3.84(m,1H),3.63-3.48(m,1H),3.38(td,J=11.9,1.9Hz,1H),3.09(d,J=8.8Hz,1H),2.01(d,J=13.6Hz,1H),1.67-1.50(m,1H),1.49-1.35(m,1H),1.11(d,J=12.5Hz,1H)。LCMS:(M+H)+476。
步骤7:5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(丙-1-烯-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向40mL额定压力瓶中装入11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(212mg,0.445mmol)、Pd2(dba)3(30.6mg,0.033mmol)、碳酸铯(290mg,0.891mmol)及2.5mL二噁烷。经由用1.0mL二噁烷冲洗的配衡针筒向该混合物中添加异丙烯基硼酸频哪醇酯(150mg,0.891mmol),然后经由针筒(使用1.0mL二噁烷冲洗针筒至反应混合物中)添加三环己基膦(1M于甲苯中,67μL,0.067mmol)。将瓶密封且反应混合物使用超声波处理同时用氩气鼓泡2min脱气。将瓶置于预加热至115℃的反应块中。18h后,冷却混合物且浓缩。该物质在SiO2(24g)上用DCM(51mL)、20%丙酮/DCM(300mL)、20至100%丙酮/DCM(456mL,线性梯度)洗脱纯化。含有产物的级份得到标题化合物(185.2mg,86%)。1H NMR(400MHz,CDCl3)δ9.59(d,J=0.8Hz,1H),8.52(d,J=1.8Hz,1H),7.70(s,1H),7.60(d,J=1.5Hz,1H),7.46-7.41(m,2H),7.40-7.31(m,3H),6.11(s,1H),5.51(d,J=10.5Hz,1H),5.46(t,J=1.5Hz,1H),4.05(d,J=3.0Hz,1H),3.89(s,3H),3.92-3.85(m,1H),3.55(td,J=11.9,2.0Hz,1H),3.36(td,J=11.9,2.0Hz,1H),3.14-3.02(m,1H),2.38(s,3H),2.04(d,J=12.8Hz,1H),1.67-1.55(m,1H),1.52-1.35(m,J=12.4,12.4,4.3Hz,1H),1.14(d,J=12.5Hz,1H)。LCMS:(M+H)+482.3。
步骤8:2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇
向含有5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(丙-1-烯-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(185.2mg,0.385mmol)的20mL闪烁瓶中添加2-丙醇(3.2mL)及DCM(0.6mL)。用氧气净化烧瓶且在冰水浴中冷却。一次性添加呈固体状的三(2,2,6,6-四甲基-3,5-庚二酮酸)锰(III)(23.3mg,0.038mmol),然后添加呈纯净液体状的苯基硅烷(95μL,0.77mmol)。在氧气气囊气氛下剧烈搅拌45min后,用20%硫代硫酸钠水溶液淬灭混合物且萃取至乙酸乙酯中。用盐水洗涤有机相,经MgSO4干燥,过滤且浓缩,得到292mg淡棕色透明残余物。该物质在SiO2(12g)上用DCM(51mL)、30%丙酮/DCM(200mL)、50%丙酮/DCM(200mL)、70%丙酮/DCM(300mL)洗脱纯化。含有产物的级份得到156mg白色膜状物。该物质与先前以相同方式制备的23.5mg产物合并且通过制备型HPLC以每次1.7mL甲醇的八次等效注射进一步纯化:柱:XBridge phenyl,30×100mm,5μm粒子;流动相A:5:95甲醇:水及10mM碳酸氢铵;流动相B:95:5甲醇:水及10mM碳酸氢铵;20%B持续30秒,历经20min45-70%B;流速:50mL/min;检测:254nm。浓缩合并的级份且将白色固体残余物分配于乙酸乙酯与盐水之间。有机部分经MgSO4干燥,过滤且浓缩,得到标题化合物(132mg,56%)。1H NMR(400MHz,CDCl3)δ9.53(s,1H),8.52(s,1H),7.72(br.s.,1H),7.62(br.s.,1H),7.45-7.40(m,2H),7.40-7.29(m,3H),5.52(d,J=10.5Hz,1H),4.07(d,J=8.5Hz,1H),3.92-3.85(m,1H),3.89(s,3H),3.60-3.49(m,1H),3.41-3.31(m,1H),3.16-3.01(m,1H),2.03(d,J=13.6Hz,1H),1.73(s,3H),1.71(s,3H),1.68-1.56(m,1H),1.47-1.32(m,1H),1.12(d,J=13.3Hz,1H)。LCMS:TR=0.794min;(ES):m/z(M+H)+500.30(Waters Acquity SDS;柱类型:BEHC18 1.7μm 2.1×50mm;运行时间:2.20min;2-98%B;溶剂A:水/0.05%TFA;溶剂B:乙腈/0.05%TFA;温度:40℃;流速:0.8mL/min;检测:UV=220nm)。HPLC TR=10.01min(柱:Xbridge C18 3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min 40-80%B;流速:1mL/min;检测:UV 220nm及254nm)。HPLC TR=12.07min(柱:Xbridge Phenyl 3.5μm,3.0×150mm;流动相A:10mM碳酸氢铵(pH=9.5)/95%H2O/5%甲醇;流动相B:10mM碳酸氢铵(pH=9.5)/5%H2O/95%甲醇;梯度:历经15min 40-80%B;流速:1mL/min;检测:UV 220nm及254nm)。
实施例285
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇
根据用于2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇的程序使用4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑进行制备。1H NMR(400MHz,CDCl3)δ9.54(d,J=0.8Hz,1H),8.54(d,J=1.8Hz,1H),7.71(s,1H),7.60(s,1H),7.46-7.29(m,5H),5.53(d,J=10.5Hz,1H),4.08(dd,J=11.4,2.6Hz,1H),3.89(s,3H),3.94-3.85(m,1H),3.56(td,J=11.9,1.8Hz,1H),3.36(td,J=11.9,2.0Hz,1H),3.08(s,1H),2.29(s,3H),2.08-2.03(m,1H),1.74(s,3H),1.72(s,3H),1.69-1.56(m,J=12.6,12.6,4.4Hz,1H),1.47-1.34(m,J=13.3,4.5Hz,1H),1.10(d,J=13.3Hz,1H)。LCMS:TR=0.63min;(ES):m/z(M+H)+497.2(Waters Acquity柱:Waters Acquity UPLCBEH C18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA:流动相B:乙腈/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。
实施例286
10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤3(实施例128)所描述的程序由3-溴-9-甲氧基-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶制备标题化合物。浓缩粗反应混合物且将所得固体混悬于DCM中且通过过滤收集。先后用少量DCM和几倍体积的己烷洗涤滤饼,得到155mg所需产物。将上清液直接加载至柱上且通过快速色谱纯化:24g ISCO RediSep Rf,甲醇/DCM 0%[75mL]、0-4%[201mL]、4%[201mL]、4-10%[200mL]。收集级份,得到呈茶色固体状的产物。将固体与先前批料合并,得到标题化合物(771mg,62%产率)。1HNMR(400MHz,CDCl3)δ9.93(s,1H),8.75(d,J=1.8Hz,1H),8.72(s,1H),7.85(d,J=2.0Hz,1H),4.41(s,3H),4.05(s,3H),3.27(s,3H)。LCMS:TR=0.60min;(ES):m/z(M+H)+376.0。
步骤2:10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例128)所描述的程序由10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(250mg,0.666mmol)制备标题化合物。通过快速色谱纯化粗物质:40g ISCORediSep Rf,丙酮/DCM 0%[102mL]、0-35%[400mL]、35%[400mL]、35-60%[600mL]。收集级份,得到标题化合物(336mg,0.611mmol,92%产率)。1H NMR(500MHz,CDCl3)δ9.02(s,1H),8.69(d,J=1.8Hz,1H),7.49(d,J=7.9Hz,2H),7.46(d,J=1.8Hz,1H),7.43-7.37(m,2H),7.37-7.32(m,1H),6.93(d,J=9.9Hz,1H),4.43(s,3H),4.07(dd,J=11.7,2.7Hz,1H),3.79(dd,J=11.8,3.1Hz,1H),3.71(s,3H),3.54(t,J=11.9Hz,1H),3.39(s,3H),3.22(td,J=11.9,1.9Hz,1H),3.00-2.90(m,1H),2.19(d,J=13.4Hz,1H),2.02-1.91(m,1H),1.67-1.58(m,1H),0.37(d,J=12.8Hz,1H);LCMS(M+H)=550。
步骤3:13-氯-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤3(实施例118)所描述的程序使用10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。通过快速色谱纯化该物质:24g ISCO RediSep Rf,丙酮/DCM 0%[75mL]、0-25%[250mL]、25%[200mL]、25-100%[400mL]。收集级份,得到标题化合物(282mg,83%)。1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.77(d,J=1.8Hz,1H),7.54(d,J=1.8Hz,1H),7.52-7.47(m,2H),7.45-7.33(m,3H),6.97(d,J=10.0Hz,1H),4.08(dd,J=11.2,3.6Hz,1H),3.84-3.77(m,1H),3.72(s,3H),3.55(td,J=11.8,1.8Hz,1H),3.48(s,3H),3.28-3.18(m,J=1.8Hz,1H),3.05-2.89(m,1H),2.23-2.19(m,1H),2.04-1.91(m,J=4.3Hz,1H),1.70-1.59(m,J=5.3Hz,1H),0.37(d,J=13.3Hz,1H)。LCMS:(M+H)+554.0。
步骤4:10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向13-氯-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(27mg,0.049mmol)于甲醇(0.5mL)中的混悬液中添加一滴三乙胺及10%Pd/C(小刮勺尖,未量测)。在两打兰瓶中进行反应。用氢气净化瓶且在室温在剧烈搅拌下保持在氢气气囊气氛下。6.5h后,经由硅藻土使用甲醇过滤混合物且浓缩,得到31.2mg黄色膜状物。通过制备型HPLC以500μL及1mL甲醇的两次大致等效注射纯化粗物质:Waters X-BridgeC18,30×100mm S5,A=95%水、5%乙腈、10mM乙酸铵,B=5%水、95%乙腈、10mM乙酸铵,30min 28%B,30mL/min,254nm检测。收集级份,得到标题化合物(17.9mg,69%)。1H NMR(400MHz,CDCl3)δ9.86(s,1H),9.35(s,1H),8.62(d,J=1.8Hz,1H),7.57-7.47(m,3H),7.40(d,J=7.8Hz,3H),6.98-6.91(m,1H),4.14-4.02(m,1H),3.85-3.76(m,1H),3.73(s,3H),3.60-3.51(m,1H),3.48(s,3H),3.29-3.18(m,1H),3.07-2.88(m,1H),2.25-2.12(m,1H),2.01-1.88(m,1H),1.73-1.60(m,1H),0.46-0.31(m,1H)。LCMS:(M+H)+520。
实施例287
11-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
如下制备甲醇钠溶液:在冰水浴中冷却含有1.0mL无水甲醇的瓶且添加钠(56.0mg,2.44mmol)。对瓶进行搅拌且短暂及间歇超声波处理直至金属耗尽。在另一个2打兰瓶中,将11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(27.3mg,0.057mmol)溶解于0.5mL无水甲醇中且在冰水浴中冷却。向该溶液中添加0.5mL甲醇钠溶液。加热反应瓶至60℃。19h后,添加额外的300μL甲醇钠/甲醇溶液且升高温度至80℃。再加热22h后,冷却混合物且经由SiO2塞用DCM-10%MeOH/DCM过滤,得到24mg白色固体。通过制备型HPLC以700μL甲醇的单次注射纯化粗物质:Waters X-Bridge C18,30×100mmS5,A=95%水、5%乙腈、10mM乙酸铵,B=5%水、95%乙腈、10mM乙酸铵,30min 30%B,30mL/min,254nm检测。合并含有产物的级份,在高真空下浓缩且通过SiO2吸管塞(DCM且然后5%MeOH/DCM),得到标题化合物(16.2mg,56.9%)。1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.43(d,J=1.8Hz,1H),7.52(d,J=1.8Hz,1H),7.46-7.41(m,2H),7.40-7.29(m,3H),6.93(s,1H),5.33(d,J=11.0Hz,1H),4.11(s,3H),4.04(dd,J=11.5,2.8Hz,1H),3.89(s,3H),3.93-3.86(m,1H),3.53(td,J=11.9,1.9Hz,1H),3.38(td,J=11.8,2.0Hz,1H),3.12-2.99(m,1H),1.96(d,J=13.6Hz,1H),1.63-1.49(m,J=13.3,4.0Hz,1H),1.48-1.35(m,J=13.1,4.5Hz,1H),1.20(d,J=12.5Hz,1H)。LCMS:(M+H)+472。
实施例288
11-(环丙基甲氧基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
根据针对13-乙氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤2(实施例129)所描述的程序使用11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯制备标题化合物。该物质经由制备型HPLC以800μL甲醇的单次注射在以下条件下纯化:柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;历经30min 30%B;流速:30mL/min;检测:254nm。合并含有产物的级份且浓缩。将残余物吸收于二氯甲烷中且通过硅胶塞,用0-100%DCM/丙酮洗脱,得到纯度为96%的标题化合物(3.9mg,22%)及不纯的级份(2.0mg,79%纯度)。1H NMR(400MHz,CDCl3)δ9.17(d,J=0.5Hz,1H),8.42(d,J=1.8Hz,1H),7.50(d,J=1.8Hz,1H),7.44(d,J=7.0Hz,2H),7.40-7.30(m,3H),6.99(s,1H),5.32(d,J=10.8Hz,1H),4.32(d,J=6.5Hz,2H),4.05(d,J=9.0Hz,1H),3.89(s,3H),3.93-3.87(m,1H),3.53(td,J=11.9,1.9Hz,1H),3.38(td,J=11.9,1.9Hz,1H),3.14-2.98(m,J=11.1,11.1,11.1Hz,1H),1.96(d,J=13.1Hz,1H),1.56(td,J=12.5,4.1Hz,1H),1.47-1.36(m,2H),1.20(d,J=12.5Hz,1H),0.75-0.66(m,2H),0.49-0.41(m,2H)。LCMS:(M+H)+512。
实施例289及290
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤3(实施例128)所描述的程序由3-溴-9-甲氧基-6-(甲磺酰基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶及1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑化合物制备标题化合物。浓缩粗混合物且将所得固体混悬于DCM中且通过过滤收集。先后用少量DCM和几倍体积的己烷洗涤滤饼,得到111mg所需产物。将上清液直接加载至柱上且通过快速色谱纯化:24g ISCO RediSep Rf,甲醇/DCM 0%[75mL]、0-4%[201mL]、4%[201mL]、4-10%[200mL]。收集级份,得到呈茶色固体状的产物。将固体与先前批料合并,得到标题化合物(300mg,57%)。1H NMR(400MHz,CDCl3)δ9.92(s,1H),8.75(d,J=2.0Hz,1H),8.72(s,1H),7.84(d,J=1.8Hz,1H),4.41(s,3H),4.04(s,3H),3.27(s,3H)。LCMS:(M+H)+376.0。
步骤2:8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例128)所描述的程序使用5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。通过快速色谱纯化该物质:40g ISCO RediSep Rf,丙酮/DCM 0%[102mL]、0-30%[400mL]、30%[400mL]、30-100%[400mL]。收集级份,得到额外的297mg所需产物。合并多批,得到标题化合物(343mg,73%)。1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.69(d,J=2.0Hz,1H),7.51-7.46(m,2H),7.44-7.34(m,J=1.8Hz,4H),6.92(d,J=10.0Hz,1H),4.43(s,3H),3.68(s,3H),3.42(s,3H),2.85-2.73(m,1H),2.41-2.30(m,1H),2.28-2.18(m,1H),2.14(s,3H),1.99-1.85(m,3H),1.72-1.60(m,1H),1.52-1.42(m,1H),0.59(d,J=9.8Hz,1H)。LCMS:(M+H)+581.0。
步骤3:13-氯-8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤3(实施例118)所描述的程序使用8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。用DCM研磨粗物质,得到白色固体,其通过过滤收集为所需产物。浓缩上清液且重复研磨过程三次,得到合并产量的197mg纯产物。通过快速色谱纯化上清液:24g ISCO RediSep Rf,乙酸乙酯/DCM 0%[102mL]、0-30%[252mL]、30%[300mL]、30-100%[252mL]。合并的批料提供标题化合物(267mg,77%)。1HNMR(400MHz,CDCl3)δ9.10(s,1H),8.77(d,J=1.8Hz,1H),7.52-7.35(m,7H),6.96(d,J=10.3Hz,1H),3.70(s,3H),3.50(s,3H),2.86-2.70(m,1H),2.42-2.32(m,1H),2.29-2.20(m,1H),2.15(s,3H),2.03-1.89(m,4H),1.72-1.61(m,1H)。LCMS:(M+H)+585.0。
步骤4:8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有13-氯-8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(21.5mg,0.037mmol)于甲醇(0.7mL)中的混悬液的2打兰瓶中添加一滴三乙胺及10%Pd/C(7.8mg,7.35μmol)。用氢气冲洗瓶且在室温在氢气气囊气氛下搅拌。4h后,经由硅藻土塞过滤混合物,用1:1DCM/甲醇冲洗,得到24.6mg黄色固体。用DCM研磨该固体,得到呈灰白色固体状的标题化合物的外消旋混合物(12.2mg,60%)。通过手性制备型HPLC分离对映异构体:Chiralcel OJ-H制备型柱,30×250mm,5μm;流动相:30%MeOH/CO2;150巴;35℃;流速:70mL/min持续14min;在UV 220nm监测;注射:0.35mL约6mg/mL于1:1MeOH:CHCl3中(12mg通过堆迭注射纯化)。手性SFC峰1(TR=4.74min):1H NMR(400MHz,CDCl3)δ9.86(s,1H),9.32(s,1H),8.62(d,J=1.8Hz,1H),7.53-7.48(m,2H),7.47(d,J=1.5Hz,1H),7.44-7.34(m,3H),6.94(d,J=10.0Hz,1H),3.70(s,3H),3.51(s,3H),2.88-2.75(m,1H),2.34(br.s.,1H),2.28-2.20(m,1H),2.16(s,3H),1.95(d,J=2.8Hz,3H),1.67(d,J=12.0Hz,2H),0.67-0.56(m,1H)。LCMS:TR=1.079min;(ES):m/z(M+H)+551。
手性SFC峰2(TR=11.24min):1H NMR(400MHz,CDCl3)δ9.86(s,1H),9.32(s,1H),8.62(d,J=1.8Hz,1H),7.53-7.49(m,2H),7.47(d,J=1.8Hz,1H),7.44-7.33(m,3H),6.94(d,J=10.0Hz,1H),3.70(s,3H),3.51(s,3H),2.88-2.75(m,1H),2.39-2.31(m,1H),2.29-2.20(m,1H),2.16(s,3H),2.02-1.91(m,1H),1.70-1.70(m,1H),1.77-1.66(m,J=15.1,3.3Hz,2H),0.68-0.57(m,1H)。LCMS:(M+H)+551。
实施例291
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇
步骤1:13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-10-(丙-1-烯-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯
根据针对8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-(丙-2-基氧基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤3(实施例118)所描述的程序使用2-{13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇制备标题化合物。以相同方式对混合物进行后处理,得到标题化合物(13.4mg,61%)。LCMS:TR=1.182min;(ES):m/z(M+H)+516.25(Waters Acquity SDS;柱类型:BEH C18 1.7μm 2.1×50mm;运行时间:2.20min;2-98%B;溶剂A:水/0.05%TFA;溶剂B:乙腈/0.05%TFA;温度:40℃;流速:0.8mL/min;检测:UV=220nm)。
步骤2:2-{13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇
根据针对5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-11-(丙-1-烯-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯所描述的程序使用13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-10-(丙-1-烯-2-基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯制备标题化合物。LCMS:TR=1.027min;(ES):m/z(M+H)+534.25。Waters Acquity SDS;柱类型:AcquityBEH C18 1.7μm 2.1×50mm;运行时间:2.20min;2-98%B;溶剂A:水/0.05%TFA;溶剂B:乙腈/0.05%TFA;温度:40℃;流速:0.8mL/min;检测:UV=220nm。
步骤3:2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇
向含有2-{13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇(13.4mg,0.025mmol)/甲醇(1.0mL)的2打兰瓶中添加10%Pd/C(5.3mg,5.00μmol)及三乙胺(2.5mg,0.025mmol)。用氢气净化瓶且在氢气气囊气氛下剧烈搅拌。4h后,经由硅藻土过滤混合物且浓缩。经由制备型HPLC纯化粗物质:柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;历经15min 20至70%B;流速:30mL/min;254nm检测。浓缩含有产物的级份,溶解于DCM中,通过硅胶塞(用5-10%甲醇/DCM)且浓缩,得到标题化合物(4.1mg,32%)。1H NMR(400MHz,CDCl3)δ9.64(s,1H),8.78(s,1H),8.51(d,J=1.8Hz,1H),7.44-7.28(m,6H),7.25(d,J=1.8Hz,1H),4.05(dd,J=11.4,2.9Hz,1H),3.71(dd,J=11.7,3.4Hz,1H),3.65(s,3H),3.60-3.52(m,J=1.8Hz,1H),3.20(td,J=11.9,1.8Hz,1H),2.99-2.85(m,1H),2.26(d,J=13.3Hz,1H),2.08(s,3H),2.03(s,1H),1.88(s,3H),1.49(qd,J=12.7,4.8Hz,1H),0.34(d,J=13.1Hz,1H)。LCMS:(M+H)+500。
实施例292
2-{13-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇
步骤1:5-溴-2-(2-氯-3-氟吡啶-4-基)-3-硝基吡啶
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤1(实施例3)所描述的程序由(2-氯-3-氟吡啶-4-基)硼酸制备标题化合物。该物质在SiO2(120g)上用己烷(100mL)、30%DCM/己烷(750mL)、30至100%DCM/己烷(1500mL,线性梯度)、DCM(700mL)洗脱纯化。收集含有产物的级份,得到标题化合物(1.22g,31%)。1H NMR(400MHz,CDCl3)δ9.07-9.01(m,1H),8.65-8.60(m,1H),8.41(dd,J=5.0,1.3Hz,1H),7.52(t,J=4.8Hz,1H)。LCMS:(M+H)+333。
步骤2:5-溴-12-氯-13-氟-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向含有5-溴-2-(2-氯-3-氟吡啶-4-基)-3-硝基吡啶(1.22g,3.67mmol)及1,2-二氯苯(15mL)的40mL额定压力瓶中添加1,2-二(二苯基膦基)乙烷(3.65g,9.17mmol)。将瓶密封且加热至165℃。15min后,冷却混合物且在高真空下浓缩,得到深色残余物。粗物质在SiO2(12g)上用己烷(51mL)、20%EtOAc/己烷(252mL)、20至50%EtOAc/己烷(357mL,线性梯度)洗脱纯化。收集含有产物的级份,得到标题化合物(131mg,12%)。1H NMR(400MHz,DMSO-d6)δ12.41(br.s.,1H),8.72(d,J=2.0Hz,1H),8.72(d,J=1.3Hz,1H),8.43(d,J=2.3Hz,1H)。
步骤3:5-溴-12-氯-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例128)所描述的程序使用5-溴-12-氯-13-氟-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。该物质在SiO2(24g)上用己烷(51mL)、0至100%EtOAc/己烷(825mL,线性梯度)洗脱纯化。收集含有产物的级份,得到243mg标题化合物(黄色膜状物)。1H NMR与所需产物+杂质一致。该物质按原样继续使用。LCMS:TR=1.10min;(ES):m/z(M+H)+475.6(Waters Acquity柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA:流动相B:乙腈/0.05%TFA;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm)。
步骤4:12-氯-13-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯所描述的程序使用5-溴-12-氯-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯及4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑制备标题化合物。该物质在SiO2(12g)上用DCM(37mL)、15%EtOAc/DCM(200mL)、15至100%EtOAc/DCM(400mL,线性梯度)、EtOAc(100mL)洗脱纯化。收集含有产物的级份,得到标题化合物(55mg,42%)。1H NMR(400MHz,CDCl3)δ8.82(s,1H),8.67(s,1H),7.81(br.s.,1H),7.48-7.33(m,5H),5.54(d,J=10.5Hz,1H),4.09-4.02(m,1H),3.94(s,3H),3.90(dd,J=12.0,3.0Hz,1H),3.55(td,J=11.9,1.8Hz,1H),3.38(td,J=11.9,2.0Hz,1H),3.12(d,J=10.8Hz,1H),1.99(d,J=13.3Hz,1H),1.66-1.52(m,1H),1.43(qd,J=12.3,4.6Hz,1H),1.15(d,J=12.5Hz,1H)。LCMS:(M+H)+494。
步骤5:1-{13-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}乙-1-酮
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-11-(1-乙氧基乙烯基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(实施例170)所描述的程序使用12-氯-13-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。该物质在SiO2(4g)上用DCM(60mL)、10%丙酮/DCM(100mL)、20%丙酮/DCM(50mL)、30%丙酮/DCM(50mL)、50%丙酮/DCM(50mL)洗脱纯化。浓缩含有产物的级份,得到24.9mg(44.6%)。1H NMR(400MHz,CDCl3)δ9.10(d,J=1.8Hz,1H),8.71(d,J=1.8Hz,1H),7.85(d,J=1.8Hz,1H),7.53-7.44(m,2H),7.43-7.31(m,3H),5.62(d,J=10.5Hz,1H),4.07(dd,J=11.7,2.9Hz,1H),3.96-3.93(m,3H),3.93-3.86(m,1H),3.55(td,J=11.9,1.9Hz,1H),3.39(td,J=11.9,2.0Hz,1H),3.22-3.08(m,1H),2.83(s,3H),2.01(d,J=13.1Hz,1H),1.68-1.54(m,1H),1.44(qd,J=12.3,4.3Hz,1H),1.14(d,J=12.3Hz,1H)。LCMS:(M+H)+502。
步骤6:2-{13-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇
根据针对2-[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇(实施例142)所描述的程序使用1-{13-氟-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}乙-1-酮制备标题化合物。经由制备型HPLC以每次0.5mL甲醇的三次注射在以下条件下纯化该物质:柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;历经30min 29%B,然后100%B持续5min;流速:30mL/min;检测:254nm。合并含有产物的级份且在高真空下浓缩至干燥。使所得白色残余物通过硅胶塞(先后使用DCM和10-50%丙酮/DCM),得到标题化合物(9.4mg,36%)。1H NMR(400MHz,CDCl3)δ8.95(d,J=1.8Hz,1H),8.65(d,J=1.8Hz,1H),7.77(d,J=1.8Hz,1H),7.49-7.43(m,3H),7.42-7.32(m,3H),7.21(dd,J=6.0,3.5Hz,1H),5.58(s,1H),5.53(d,J=10.5Hz,1H),4.07(dd,J=11.5,2.8Hz,1H),3.95(s,3H),3.91(dd,J=12.2,3.1Hz,1H),3.55(td,J=11.9,1.9Hz,1H),3.40(td,J=11.9,2.0Hz,1H),3.20-3.06(m,J=11.0Hz,1H),1.99(d,J=13.1Hz,1H),1.74(s,6H),1.66-1.54(m,1H),1.51-1.38(m,J=13.1,4.3Hz,1H),1.21(d,J=12.5Hz,1H)。LCMS:TR=0.915min;(ES):m/z(M+H)+518:(Waters Acquity SDS;柱类型:BEH C18 1.7μm 2.1×50mm;运行时间:2.20min;0-100%B;溶剂A:100%水/0.05%TFA;溶剂B:100%ACN w/0.05%TFA;检测:UV=220nm)。
实施例293及294
2-{11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}丙-2-醇及2-{13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
步骤1:5-溴-2-(2,6-二氯吡啶-3-基)-3-硝基吡啶
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤1(实施例3)所描述的程序使用(2,6-二氯吡啶-3-基)硼酸制备标题化合物。该物质在SiO2(40g)上用己烷(51mL)、10%EtOAc/己烷(1000mL)、10至100%EtOAc/己烷(850mL,线性梯度)洗脱纯化。收集含有产物的级份,得到标题化合物(891mg,56%)。1H NMR(400MHz,CDCl3)δ9.01(d,J=2.0Hz,1H),8.66(d,J=2.0Hz,1H),7.87-7.72(m,1H),7.47(d,J=8.0Hz,1H)。LCMS:(M+H)+349。
步骤2:5-溴-11,13-二氯-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-氟-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤2(实施例3)所描述的程序使用5-溴-2-(2,6-二氯吡啶-3-基)-3-硝基吡啶制备标题化合物。1HNMR(400MHz,DMSO-d6)δ12.55-12.50(m,1H),8.74(d,J=2.0Hz,1H),8.34(d,J=2.0Hz,1H),7.73(s,1H)。LCMS:(M+H)+317.8。
步骤3:5-溴-11,13-二氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯步骤4(实施例128)所描述的程序使用5-溴-11,13-二氯-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。该物质在SiO2(24g)上用己烷(100mL)、20%EtOAc/己烷(600mL)、20至100%EtOAc/己烷(650mL,线性梯度)洗脱纯化。LCMS:TR=1.565min;(ES):m/z(M+H)+492.05(Waters Acquity SDS;柱类型:BEH C18 1.7μm 2.1×50mm;运行时间:2.20min;2-98%B;溶剂A:水/0.05%TFA;溶剂B:乙腈/0.05%TFA;温度:40℃;流速:0.8mL/min;检测:UV=220nm)。
步骤4:11,13-二氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-甲酸甲酯步骤5(实施例135)所描述的程序由5-溴-11,13-二氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯及4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑制备标题化合物。该物质在SiO2(12g)上用DCM(37mL)、15%EtOAc/DCM(252mL)、15至100%EtOAc/DCM(400mL,线性梯度)、EtOAc(100mL)洗脱纯化。收集含有产物的级份,得到标题化合物(51.6mg,40%)。1H NMR(500MHz,CDCl3)δ8.70(d,J=1.7Hz,1H),7.75-7.66(m,1H),7.63-7.61(m,1H),7.50-7.32(m,7H),5.46(d,J=10.5Hz,1H),4.10-4.04(m,1H),3.94-3.86(m,4H),3.61-3.49(m,1H),3.38(td,J=11.9,1.8Hz,1H),3.09(d,J=10.8Hz,1H),1.66-1.55(m,1H),1.41(qd,J=12.3,4.6Hz,1H),1.07(d,J=13.0Hz,1H)。LCMS:(M+H)+510。
步骤5:1-{11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}乙-1-酮及1-{13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}乙-1-酮
根据针对5-(二甲基-1H-1,2,3-三唑-5-基)-11-(1-乙氧基乙烯基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(实施例170)所描述的程序使用11,13-二氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯制备标题化合物。该物质在SiO2(4g)上用10-30%丙酮/DCM洗脱纯化。收集含有产物的级份,得到标题化合物(45mg,86%)。1H NMR与区域异构偶联产物的混合物一致,所述混合物按原样继续使用。
步骤6:2-{11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}丙-2-醇及2-{13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
根据针对2-[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇(实施例142)所描述的程序使用来自本实施例步骤5的产物制备标题化合物。该物质在SiO2(4g)上用DCM(30mL)、5%丙酮/DCM(50mL)、10%丙酮/DCM(50mL)、20%丙酮/DCM(50mL)、50%丙酮/DCM(50mL)洗脱纯化。收集的级份得到两批(级份A及B)富含单独区域异构产物的物质。级份A及B分别通过制备型HPLC进一步纯化:柱:XBridge C18,30×100mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;历经5min 35%B,然后历经20min 35-100%B,然后100%B持续2min;流速:30mL/min;254nm检测。
分离呈白色固体状的2-{11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基}丙-2-醇(异构体1,4.8mg):1H NMR(400MHz,CDCl3)δ8.50(d,J=1.8Hz,1H),7.67(d,J=1.5Hz,1H),7.56(s,1H),7.48-7.31(m,5H),5.47(d,J=10.5Hz,1H),4.07(dd,J=11.7,2.9Hz,1H),3.90(dd,J=11.7,2.6Hz,1H),3.87(s,3H),3.55(td,J=11.9,1.9Hz,1H),3.37(td,J=11.9,2.0Hz,1H),3.15-2.99(m,1H),2.07-2.00(m,1H),1.83(s,3H),1.81(s,3H),1.67-1.53(m,1H),1.48-1.35(m,1H),1.10(d,J=12.3Hz,1H)。LCMS:TR=0.97min;(ES):m/z(M+H)+534.0。Waters Acquity柱:Waters Acquity UPLC BEHC18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:乙腈/0.05%TFA;温度:50℃;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm。
分离呈白色固体状的2-{13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇(异构体2,25.4mg):1H NMR(400MHz,CDCl3)δ8.68(d,J=1.8Hz,1H),7.72(s,1H),7.62(d,J=1.8Hz,1H),7.44-7.32(m,5H),5.55(d,J=10.5Hz,1H),4.11-4.04(m,1H),3.88(s,3H),3.92-3.86(m,1H),3.58-3.52(m,1H),3.36(td,J=11.9,2.0Hz,1H),3.15-3.00(m,1H),2.07(d,J=13.6Hz,1H),1.74(s,3H),1.72(s,3H),1.69-1.59(m,J=4.3Hz,1H),1.39(qd,J=12.3,4.1Hz,1H),1.06(d,J=13.3Hz,1H)。LCMS:TR=0.83min;(ES):m/z(M+H)+534.1。Waters Acquity柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:水/0.05%TFA;流动相B:乙腈/0.05%TFA;温度:50℃;梯度:历经1min 2-98%B且然后在98%B保持0.5min;流速:0.8mL/min;检测:UV=220nm。
实施例295
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-N-[2-(1H-1,2,3,4-四唑-5-基)乙基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-胺
在微波瓶中向11-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(13mg,0.027mmol)中添加2-(1H-四唑-5-基)乙胺盐酸盐(12.3mg,0.082mmol)、K3PO4(89mg,0.273mmol)及DMSO(1.5mL)。在氩气下将瓶密封且在微波中在180℃加热0.5h。将其过滤且经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到产物(56%产率)。1H NMR(500MHz,DMSO-d6)δ8.36(s,1H),8.32(br.s.,1H),8.10(d,J=8.4Hz,1H),7.96(s,1H),7.84(d,J=7.3Hz,2H),7.57(br.s.,1H),7.30(t,J=7.3Hz,2H),7.22(t,J=7.5Hz,1H),6.52(d,J=8.4Hz,1H),5.68(br.s.,1H),4.01(s,3H),3.98-3.91(m,1H),3.83(d,J=8.1Hz,2H),3.76(d,J=11.0Hz,2H),3.36(t,J=11.4Hz,1H),3.28(d,J=7.0Hz,2H),1.92(s,3H),1.44(br.s.,1H),1.36(d,J=9.5Hz,1H),1.25(br.s.,2H);LCMS(M+1)=553;TR=0.66min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例296
10,13-二氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:5-溴-2’,5’-二氯-3-硝基-2,4’-联吡啶
在100mL圆底烧瓶中向(2,5-二氯吡啶-4-基)硼酸(1.000g,5.21mmol)及2,5-二溴-3-硝基吡啶(1.470g,5.21mmol)中添加THF(30mL)。向其中添加K3PO4(2.211g,10.4mmol)于水(15mL)中的溶液,然后添加PdCl2(dppf)2.DCM(0.213g,0.261mmol)。用氮气代替空气且将烧瓶密封。在搅拌下在回流条件下加热所得混合物至80℃。2.5h后,将其冷却至室温,用EtOAc稀释且用盐水洗涤。分离有机层,经MgSO4干燥,经由薄硅胶垫(约1英寸)过滤且在旋转蒸发器上浓缩。所得残余物通过ISCO 80g柱用0-50%EtOAc/己烷洗脱纯化,得到563mg(31%)。1H NMR(500MHz,CDCl3)δ9.05(d,J=2.1Hz,1H),8.70(d,J=2.0Hz,1H),8.50-8.48(m,1H),7.45(d,J=0.5Hz,1H)。
步骤2:3-溴-6,9-二氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶
在160℃加热5-溴-2’,5’-二氯-3-硝基-2,4’-联吡啶(535mg,1.53mmol)及1,2-二(二苯基膦基)乙烷(764mg,1.92mmol)于1,2-二氯苯(10mL)中的混合物。3h后,冷却反应混合物至室温且浓缩。残余物在40g硅胶柱上用0-100%EtOAc/DCM洗脱纯化,得到26%所需产物。1H NMR(400MHz,丙酮)δ8.80(d,J=2.0Hz,1H),8.35(d,J=2.0Hz,1H),8.29-8.26(m,1H)。
步骤3:5-溴-10,13-二氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向50mL圆底烧瓶中装入3-溴-6,9-二氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶(120mg,0.379mmol)及THF(5mL)。向其中添加(R)-苯基(四氢-2H-吡喃-4-基)甲醇(146mg,0.757mmol)、PPh3(199mg,0.757mmol)及三乙胺(0.106mL,0.757mmol)。添加呈固体状的偶氮二甲酸二叔丁酯(174mg,0.757mmol)。在室温搅拌反应混合物过夜。浓缩反应混合物,加载至24g硅胶柱上且用2-70%EtOAc/己烷洗脱,得到365mg物质。物质再次在24g硅胶柱上用2-25%丙酮/己烷洗脱纯化,得到131mg(70%)。1H NMR(400MHz,CDCl3)δ8.76(d,J=1.8Hz,1H),8.38-8.34(m,1H),8.02-7.98(m,1H),7.54(d,J=7.5Hz,2H),7.42(t,J=7.4Hz,2H),7.08(d,J=11.0Hz,1H),4.09(dd,J=11.5,2.5Hz,1H),3.88(dd,J=11.2,3.1Hz,1H),3.60(td,J=11.9,1.9Hz,1H),3.36(td,J=11.9,2.0Hz,1H),3.13-2.99(m,1H),2.13(d,J=14.1Hz,1H),1.74-1.62(m,1H),1.35-1.25(m,1H),0.93-0.81(m,1H),0.67(d,J=13.6Hz,1H)。
步骤4:10,13-二氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-3-溴-6,9-二氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶(50.0mg,0.102mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(36.9mg,0.102mmol)、CuI(2.9mg,0.015mmol)、Pd(PPh3)4(8.2mg,7.13μmol)、三乙胺(0.028mL,0.204mmol)及DMF(2mL)称重至20mL闪烁瓶中且在氩气下密封。将瓶置于预加热至100℃的反应块中。7h后,冷却反应混合物至室温且过滤。经由制备型LC/MS在以下条件下纯化滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min45-85%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到产率为23%的所需产物。1H NMR(500MHz,DMSO-d6)δ8.79(s,1H),8.43(s,1H),8.30(s,1H),7.67(d,J=7.3Hz,2H),7.37(t,J=7.3Hz,2H),7.28(t,J=7.3Hz,1H),6.98(d,J=11.4Hz,1H),3.73(d,J=10.3Hz,1H),3.61-3.47(m,3H),3.24(t,J=11.7Hz,1H),2.51(br.s.,1H),1.94(d,J=13.2Hz,1H),1.53-1.36(m,2H),0.86(d,J=11.4Hz,1H)。LCMS(M+1)=510。
实施例297
1-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-基}乙-1-酮
步骤1:5-溴-3’-氯-3-硝基-2,4’-联吡啶
遵循与5-溴-2’,5’-二氯-3-硝基-2,4’-联吡啶的合成类似的程序以44%产率由(3-氯吡啶-4-基)硼酸合成标题化合物。1H NMR(400MHz,CDCl3)δ9.05(d,J=2.0Hz,1H),8.72(s,1H),8.71-8.67(m,2H),7.41(dd,J=5.0,0.5Hz,1H)。
步骤2:3-溴-9-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶
遵循与3-溴-6,9-二氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶的合成类似的程序以38%产率由5-溴-3’-氯-3-硝基-2,4’-联吡啶合成标题化合物。LCMS(M+1)=282;TR=0.65min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤3:(S)-3-溴-9-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶
遵循与5-溴-10,13-二氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成类似的程序以60%产率由3-溴-9-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶合成标题化合物。LCMS(M+1)=456;TR=0.97min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤4:13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(S)-3-溴-9-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶(350mg,0.766mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(36.9mg,0.102mmol)、CuI(21.9mg,0.115mmol)、Pd(PPh3)4(62.0mg,0.054mmol)、三乙胺(0.214mL,1.53mmol)及DMF(15mL)称重至20mL闪烁瓶中且在氩气下密封。将瓶置于预加热至100℃的加热区块中。3h后,冷却反应混合物至室温,用5%MeOH/EtOAc稀释,用盐水淬灭且分离有机层且浓缩。通过快速色谱纯化粗混合物(24g ISCO RediSep,0-50%[10%(2MNH3/EtOAc)]/EtOAc),得到(271mg,74%产率)。1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.73(d,J=1.8Hz,1H),8.60(s,1H),7.78(d,J=1.8Hz,1H),7.49-7.44(m,2H),7.43-7.33(m,3H),5.60(d,J=10.5Hz,1H),3.95(s,3H),3.90(dd,J=11.5,3.0Hz,1H),3.62-3.51(m,1H),3.44-3.34(m,1H),3.14(q,J=11.1Hz,1H),2.09-2.00(m,2H),1.51-1.39(m,1H),1.28(t,J=7.2Hz,1H),1.13(d,J=13.1Hz,1H),0.98-0.77(m,1H)。
步骤5:1-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-基}乙-1-酮
向20mL闪烁瓶中装入13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯、三丁基(1-乙氧基乙烯基)锡烷(41.7mg,0.116mmol)及二噁烷(2mL)。然后添加Pd(dppf)2Cl2.DCM(8.6mg,10.50μmol)且用氩气代替空气且在氩气下将瓶密封。在搅拌下将其加热至100℃过夜。冷却反应混合物至室温,用2.5mL THF稀释且用针筒过滤器过滤。添加约0.5mL 6N HCl水溶液并搅拌。1.5h后,用几滴K2CO3水溶液(10%溶液)中和反应混合物且用EtOAc稀释。分离有机层,用盐水洗涤,经MgSO4干燥,过滤且在旋转蒸发器上浓缩,得到粗混合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min 15-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为21%。1H NMR(500MHz,DMSO-d6)δ9.73(br.s.,1H),8.76(s,1H),8.50(s,1H),7.74(d,J=7.7Hz,2H),7.39-7.33(m,2H),7.31-7.24(m,1H),6.05(d,J=11.4Hz,1H),4.06(s,3H),3.94-3.86(m,1H),3.73(d,J=8.8Hz,1H),3.50(q,J=10.9Hz,2H),3.38(s,1H),3.29(t,J=11.6Hz,1H),3.01-2.96(m,3H),1.73(d,J=12.5Hz,1H),1.63-1.51(m,1H),1.34(d,J=8.8Hz,1H),0.97(d,J=12.5Hz,1H)。
实施例298
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-基}丙-2-醇
在室温向溶解于3mL THF中的1-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-基}乙-1-酮(20mg,0.041mmol)中添加甲基锂(0.129mL,0.207mmol)。搅拌30min后,用0.5mL丙酮淬灭反应混合物且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经20min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为4.0mg。1H NMR(500MHz,DMSO-d6)δ8.79(s,1H),8.54(s,1H),7.96(s,2H),7.73(d,J=7.0Hz,2H),7.35(t,J=7.3Hz,2H),7.27(t,J=7.0Hz,1H),6.03(d,J=11.4Hz,1H),4.08(br.s.,3H),3.94-3.88(m,2H),3.72(d,J=11.4Hz,2H),3.32-3.24(m,1H),3.17(s,1H),1.77-1.73(m,6H),1.71(br.s.,1H),1.57(d,J=11.4Hz,1H),1.33(d,J=7.0Hz,1H),0.95(d,J=12.5Hz,1H)。LCMS(M+1)=500,TR=0.66min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min2-98%B;流速:0.8mL/min]。
实施例299
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(25mg,0.053mmol)、2,2,2-三氟乙胺(13.0mg,0.131mmol)、2-甲基丙-2-醇钠(25.2mg,0.263mmol)、Pd(OAc)2(0.6mg,2.6μmol)、RuPhos(0.5mg,1.05μmol)及二噁烷(2mL)装入微波瓶中。用氩气代替空气且在120℃加热混合物50min。过滤反应混合物且经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经25min 10-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为64%。1H NMR(500MHz,DMSO-d6)δ9.58(br.s.,1H),8.69(s,2H),8.52(d,J=5.1Hz,1H),8.20(d,J=5.1Hz,1H),7.73(d,J=7.7Hz,2H),7.38-7.31(m,2H),7.30-7.24(m,1H),5.95(d,J=11.0Hz,1H),4.06(s,3H),3.90(d,J=11.7Hz,1H),3.73(d,J=8.8Hz,1H),3.56-3.44(m,2H),3.29(t,J=11.6Hz,1H),1.69(d,J=12.5Hz,1H),1.60-1.48(m,1H),1.40-1.27(m,1H),1.00(d,J=12.5Hz,1H)。LCMS(M+1)=442。
实施例300
13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将13-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(10mg,0.021mmol)、甲醇钠(22.7mg,0.105mmol)及二噁烷(1.5mL)装入微波瓶中。用氮气代替空气且在120℃加热反应混合物10min。通过添加丙酮淬灭样品且浓缩。其然后经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经30min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为36%。1H NMR(500MHz,DMSO-d6)δ9.21(br.s.,1H),8.67(s,2H),8.25(s,1H),7.70(d,J=7.3Hz,2H),7.37-7.31(m,2H),7.30-7.24(m,1H),5.92(d,J=11.4Hz,1H),4.12(s,3H),4.04(s,2H),3.91-3.87(m,1H),3.73(d,J=9.9Hz,1H),3.52-3.41(m,2H),3.36-3.32(m,3H),3.28(t,J=11.2Hz,1H),3.18(d,J=5.1Hz,1H),1.92(s,2H),1.70(d,J=13.2Hz,1H),1.62-1.49(m,1H),1.31(d,J=9.2Hz,1H),0.96(d,J=11.7Hz,1H)。LCMS(M+1)=472;TR=0.61min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例301
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-13-(2,2,2-三氟乙氧基)-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(11mg,0.023mmol)、2,2,2-三氟乙醇(1.66mL,23.1mmol)及二噁烷(1.5mL)装入微波瓶中。用氮气代替空气且在微波中在120℃加热反应混合物0.5h。LC/MS显示没有产物。向其中添加5当量K2CO3且在微波中在185℃加热反应混合物1.5h。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min 30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为41%。1HNMR(500MHz,DMSO-d6)δ9.32(br.s.,1H),8.76(s,1H),8.34(s,1H),7.96(s,1H),7.71(d,J=7.7Hz,2H),7.38-7.32(m,2H),7.30-7.24(m,1H),5.97(d,J=11.4Hz,1H),5.21(q,J=8.9Hz,2H),4.05(s,3H),3.91-3.86(m,1H),3.73(d,J=9.9Hz,1H),3.52-3.44(m,3H),3.32-3.24(m,2H),1.91(s,9H),1.71(d,J=12.1Hz,1H),1.61-1.49(m,1H),1.39-1.26(m,1H)。LCMS(M+1)=540;TR=0.74min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例302
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-N-(2,2,2-三氟乙基)-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-胺
向含有13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(11mg,0.023mmol)及2,2,2-三氟乙胺(229mg,2.311mmol)/二噁烷(1.5mL)的微波瓶中添加RuPhos(0.216mg,0.462μmol),然后添加Pd(OAc)2(0.2mg,0.69μmol)。用氩气代替空气且在微波中在125℃加热反应混合物25min。过滤反应混合物。经由制备型LC/MS在以下条件下纯化滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为61%。1HNMR(500MHz,DMSO-d6)δ8.88(br.s.,1H),8.68-8.57(m,2H),8.13(s,1H),7.69(d,J=7.7Hz,2H),7.37-7.31(m,2H),7.29-7.23(m,1H),6.92(t,J=7.0Hz,1H),5.83(d,J=11.4Hz,1H),4.51-4.39(m,2H),4.04(s,3H),3.88(d,J=9.2Hz,1H),3.73(d,J=9.2Hz,1H),3.53-3.46(m,2H),3.29(t,J=11.7Hz,1H),2.55(s,6H),1.66(d,J=12.5Hz,1H),1.58-1.46(m,1H),1.32(d,J=12.1Hz,1H),1.03(d,J=14.3Hz,1H)。LCMS(M+1)=539;TR=0.72min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例303及304
8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-N-(2,2,2-三氟乙基)-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-胺
步骤1:5-溴-3’-氯-3-硝基-2,4’-联吡啶
遵循与5-溴-2’,5’-二氯-3-硝基-2,4’-联吡啶的合成类似的程序以44%产率由(3-氯吡啶-4-基)硼酸合成标题化合物。1H NMR(400MHz,CDCl3)δ9.05(d,J=2.0Hz,1H),8.72(s,1H),8.71-8.67(m,2H),7.41(dd,J=5.0,0.5Hz,1H)。
步骤2:3-溴-9-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶
遵循与3-溴-6,9-二氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶的合成类似的程序以24%产率由5-溴-3’-氯-3-硝基-2,4’-联吡啶合成标题化合物。LCMS(M+1)=282;TR=0.69min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤3:5-溴-13-氯-8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
遵循与5-溴-10,13-二氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成类似的程序以35%产率由3-溴-9-氯-5H-吡咯并[3,2-b:5,4-c’]二吡啶及(S)-(3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲醇合成标题化合物。LCMS(M+1)=475;TR=0.92min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤4:13-氯-8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将(R)-3-溴-9-氯-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:5,4-c’]二吡啶(100mg,0.210mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(36.9mg,0.102mmol)、CuI(6.0mg,0.032mmol)、Pd(PPh3)4(17.0mg,0.015mmol)、三乙胺(0.059mL,0.420mmol)及DMF(15mL)称重至20mL闪烁瓶中且在氩气下密封。将瓶置于预加热至100℃的反应块中。3h后,冷却反应混合物至室温,用5%MeOH/EtOAc稀释,用盐水淬灭且分离有机层且浓缩。粗混合物通过快速色谱使用24g硅胶柱且用0-50%B/EtOAc[B=10%(2M NH3/EtOAc)]洗脱纯化,得到65mg(62.5%)。LCMS(M+1)=495;TR=0.79min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤5:8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-N-(2,2,2-三氟乙基)-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-胺
向含有13-氯-8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(25mg,0.051mmol)及2,2,2-三氟乙胺(500mg,5.05mmol)/二噁烷(1.5mL)的微波瓶中添加RuPhos(0.471mg,1.01μmol),然后添加Pd(OAc)2(0.3mg,1.52μmol)。用氩气代替空气且在微波中在125℃加热反应混合物25min。手性中心如下差向异构化。浓缩反应混合物且用MeOH(4mL)及KotBu(60mg)处理。在搅拌下在100℃加热所得混合物过夜。过滤反应混合物且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。经由手性分离使用以下条件进一步纯化物质:柱:Chiralpak AD 21×250mm 5μ;流速:15mL/min;收集时间:10至40min;溶剂A:100%庚烷;溶剂B:100%乙醇;瓶:20;通过UV等度收集;起始%B:15;波长:254nm。对映异构体1的保留时间=12.72min。对映异构体2的保留时间=17.59min。对映异构体1的产率为3.5mg(12%)。对映异构体2的产率为4.1mg(15%)。1H NMR(500MHz,DMSO-d6)δ8.73(s,2H),8.62(d,J=4.4Hz,1H),8.17(br.s.,1H),7.72(t,J=9.0Hz,1H),7.51(dt,J=8.6,4.5Hz,1H),7.12-7.03(m,1H),6.26(d,J=11.4Hz,1H),4.54-4.43(m,2H),4.07(s,2H),3.86(d,J=10.6Hz,1H),3.69(d,J=9.5Hz,1H),3.27-3.20(m,1H),2.90(s,1H),2.74(s,1H),1.64(br.s.,1H),1.58(dd,J=11.7,4.0Hz,1H),1.41-1.31(m,1H),0.77(d,J=12.5Hz,1H);LCMS(M+1)=558;TR=0.69min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例305
11-氯-8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向圆底烧瓶中装入11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(450mg,1.36mmol)、(R)-(3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲醇(372mg,1.76mmol)、PPh3(711mg,2.71mmol)、偶氮二甲酸二叔丁酯(625mg,2.71mmol)及THF(5mL)。用氩气代替空气且在室温搅拌反应混合物。16h后,浓缩反应混合物,加载至80g硅胶柱上且在Biotage上用0-30%(10%(2M NH3/MeOH)/EtOAc)/EtOAc洗脱纯化,得到372mg(52%)。1H NMR(400MHz,CD3OD)δ8.65-8.57(m,3H),7.76(s,1H),7.61(ddd,J=9.9,8.5,1.3Hz,1H),7.48(dt,J=8.5,4.4Hz,1H),6.09(d,J=11.3Hz,1H),4.21(s,3H),4.09(s,3H),4.00-3.92(m,1H),3.82(dd,J=11.7,3.1Hz,1H),3.61-3.49(m,2H),3.40-3.35(m,1H),1.78(d,J=12.8Hz,1H),1.59(qd,J=12.1,4.6Hz,1H),1.43(qd,J=12.5,4.3Hz,1H),0.92-0.84(m,1H);LC/MS[M+H]+=525.0。
实施例306及307
2-({11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-8-基}(氧杂环己烷-4-基)甲基)吡啶-3-醇及11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10-五烯-13-酮
在闪烁瓶中向溶解于3mL MeOH中的20mg 11-氯-8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(0.038mmol)中添加KOtBu(8.6mg,0.076mmol)。在搅拌下加热所得混合物至80℃过夜。过滤反应混合物且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及0.1%三氟乙酸;流动相B:95:5乙腈:水及0.1%三氟乙酸;梯度:历经30min10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。2-({11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-8-基}(氧杂环己烷-4-基)甲基)吡啶-3-醇(20%产率):1H NMR(500MHz,DMSO-d6)δ8.54(br.s.,1H),8.33(br.s.,1H),7.48-7.44(m,1H),7.40(br.s.,1H),7.17(br.s.,3H),6.00(br.s.,1H),3.97(br.s.,2H),3.91(m,2H),3.82(d,J=11.7Hz,1H),3.70(d,J=9.5Hz,2H),3.27-3.14(m,1H),2.55(s,5H),1.64(br.s.,1H),1.49(d,J=11.7Hz,1H),1.33(br.s.,1H),0.64(d,J=11.7Hz,1H);LCMS(M+1)=523;TR=0.65min。
11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10-五烯-13-酮(49%产率):1H NMR(500MHz,DMSO-d6)δ8.63(d,J=4.4Hz,1H),8.58(br.s.,1H),7.75(t,J=9.2Hz,1H),7.54(d,J=3.7Hz,1H),7.13(br.s.,1H),6.12(br.s.,1H),4.00(br.s.,2H),3.90(3,2H),3.84(d,J=9.5Hz,1H),3.72(d,J=7.3Hz,1H),3.18(d,J=4.8Hz,1H),2.55(s,3H),1.60(d,J=15.0Hz,2H),1.33(br.s.,1H),0.72(d,J=11.4Hz,1H)。方法A保留时间=1.26min。方法B保留时间=1.17min。LC/MS[M+H]+=511.0。
实施例308
1-{8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮
向20mL闪烁瓶中装入11-氯-8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(75mg,0.143mmol)、三丁基(1-乙氧基乙烯基)锡烷(56.8mg,0.157mmol)及2mL二噁烷。然后添加Pd(dppf)2Cl2.DCM(11.7mg,0.014mmol)且用氩气代替空气且在氩气下将瓶密封。在搅拌下将其加热至100℃过夜。冷却反应混合物至室温,用2.5mL THF稀释且用针筒过滤器过滤。在20mL闪烁瓶中向滤液中添加2mL 1N HCl水溶液且搅拌。1.5h后,用5mL K2CO3水溶液(5%溶液)淬灭反应混合物且用5%MeOH/EtOAc溶液稀释。分离有机层,用盐水洗涤,经MgSO4干燥,过滤且在旋转蒸发器上浓缩,得到粗混合物。其使用12g硅胶柱且用0-40%B/EtOAc[B=10%(2N氨/MeOH)/EtOAc]洗脱纯化,得到产率为72%的标题化合物。1H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.63(d,J=4.4Hz,1H),8.36(br.s.,1H),7.96(s,1H),7.71(t,J=9.2Hz,1H),7.51(dt,J=8.5,4.4Hz,1H),6.34(d,J=10.6Hz,1H),4.21(s,3H),4.06(br.s.,3H),3.86(d,J=11.0Hz,1H),3.67(d,J=8.4Hz,1H),3.47(br.s.,1H),3.25-3.14(m,1H),2.76-2.72(m,3H),1.67(d,J=12.1Hz,2H),1.37-1.28(m,1H),0.66(d,J=11.7Hz,1H);LC/MS[M+H]+=533.1。
实施例309
2-{8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇
将1-{8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮(25.0mg,0.047mmol)溶解于THF(5mL)中且添加CeCl3(23.1mg,0.094mmol)。在室温搅拌所得混合物一分钟,然后添加甲基溴化镁(0.078mL,0.235mmol)且然后搅拌10min。通过用10mL EtOAc稀释淬灭反应混合物且用盐水洗涤。有机层经MgSO4干燥,过滤且浓缩,得到粗混合物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为19.7mg。1H NMR(500MHz,DMSO-d6)δ8.61(br.s.,3H),7.96(s,1H),7.82(br.s.,1H),7.72(t,J=9.4Hz,1H),7.51(dt,J=8.5,4.4Hz,1H),6.13(br.s.,1H),4.09(s,4H),4.04(br.s.,3H),3.86(d,J=8.8Hz,1H),3.70(d,J=8.1Hz,1H),3.26-3.15(m,1H),2.57-2.53(m,3H),1.91(s,3H),1.37-1.24(m,1H),0.70(d,J=12.5Hz,1H);LC/MS[M+H]+=549.1。
实施例310
1-{8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮
通过遵循与1-{8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮的合成类似的程序制备标题化合物。1H NMR(500MHz,DMSO-d6)δ8.74(s,1H),8.63(d,J=4.8Hz,2H),7.96(s,1H),7.71(t,J=9.4Hz,1H),7.51(dt,J=8.5,4.4Hz,1H),6.34(d,J=11.0Hz,1H),4.20(s,4H),4.06(br.s.,2H),3.86(d,J=12.1Hz,1H),3.67(d,J=8.1Hz,1H),3.25-3.15(m,1H),2.90(s,4H),2.77-2.69(m,6H),1.65(br.s.,3H),1.33(td,J=12.3,7.7Hz,1H),0.66(d,J=13.2Hz,1H);LC/MS[M+H]+=533.1。
实施例311及312
2-{8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇及8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-(2-羟基丙-2-基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-醇
向1-{8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮(20.0mg,0.038mmol)于THF(5mL)中的溶液中添加CeCl3(46.3mg,0.188mmol)且在室温搅拌所得混合物。添加甲基溴化镁(0.063mL,0.188mmol)且在室温搅拌10min。通过用10mL EtOAc稀释淬灭反应混合物且用盐水洗涤。分离有机层,经MgSO4干燥,过滤且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经20min 15-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。2-{8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇(16%产率):1H NMR[乙酸盐](500MHz,DMSO-d6)δ8.61(br.s.,2H),7.96(s,1H),7.82(br.s.,1H),7.72(t,J=9.2Hz,1H),7.51(dt,J=8.5,4.4Hz,1H),6.13(br.s.,1H),4.09(s,3H),4.04(br.s.,3H),3.86(d,J=9.9Hz,1H),3.70(d,J=8.8Hz,1H),3.25-3.17(m,1H),2.55(s,3H),1.90(s,3H),1.69(br.s.,1H),1.58(br.s.,1H),1.30(dd,J=12.3,4.2Hz,1H),0.71(d,J=11.7Hz,1H);LC/MS[M+H]+=549.1。
8-[(R)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-(2-羟基丙-2-基)-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-13-醇(69%产率):1H NMR[乙酸盐](500MHz,DMSO-d6)δ8.61(d,J=4.8Hz,1H),8.53(s,1H),7.96(s,1H),7.74(t,J=9.0Hz,1H),7.52(dt,J=8.3,4.3Hz,1H),7.08(br.s.,1H),6.08(br.s.,1H),4.00(br.s.,3H),3.86(d,J=10.3Hz,1H),3.73(d,J=8.4Hz,1H),3.29-3.16(m,1H),2.74(s,2H),2.55(s,4H),1.90(s,3H),1.66(br.s.,1H),1.33(d,J=13.6Hz,1H);LC/MS[M+H]+=535.1。
实施例313
8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-N-甲基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-N-[2-(甲基氨基)乙基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-胺
在微波瓶中向11-氯-8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(15.0mg,0.029mmol)中添加N1,N2-二甲基乙烷-1,2-二胺(252mg,2.86mmol),然后添加三乙胺(0.020mL,0.143mmol)。在微波中加热所得混合物0.5h。过滤反应混合物且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经25min 0-35%B且然后在100%B保持6min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及0.1%三氟乙酸;流动相B:95:5乙腈:水及0.1%三氟乙酸;梯度:历经20min 2-42%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为29%。1H NMR(500MHz,DMSO-d6)δ8.62(br.s.,1H),8.40(br.s.,1H),7.71(t,J=9.2Hz,1H),7.51(dt,J=8.5,4.4Hz,1H),7.16(br.s.,2H),6.05(d,J=11.4Hz,1H),4.05(s,5H),3.99-3.82(m,4H),3.72(d,J=9.5Hz,1H),3.43-3.36(m,1H),3.22(d,J=10.6Hz,1H),2.75(s,3H),2.66(s,3H),2.55(s,3H),1.70(br.s.,1H),1.58(d,J=7.3Hz,1H),1.34(br.s.,1H),1.25(d,J=3.3Hz,1H),0.78(d,J=11.7Hz,1H)。LCMS(M+1)=577。
实施例314
11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:5-溴-11-氯-8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向20mL闪烁瓶中装入PPh3(111mg,0.425mmol)及THF(8mL)。在冰水浴中冷却瓶且添加偶氮二甲酸二叔丁酯(98mg,0.425mmol)且搅拌15min。添加(R)-(3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲醇(90mg,0.425mmol)且将所得混合物再搅拌15min。然后添加3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶(60.0mg,0.212mmol)。约10min后,移开冰水浴。3h后,在旋转蒸发器上浓缩反应混合物且在Biotage上用24g硅胶柱且用10-100%EtOAc/己烷洗脱纯化,得到70%标题化合物。LCMS(M+1)=476;TR=0.98min[柱:Waters Aquity BEH C182.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤2:11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向20mL闪烁瓶中装入(S)-3-溴-7-氯-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(60mg,0.126mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(49.1mg,0.126mmol)、CuI(3.6mg,0.019mmol)、三乙胺(25.5mg,0.252mmol)及DMF(8mL)。鼓泡氩气,然后添加Pd(PPh3)4(10.2mg,8.83μmol)且然后在100℃加热。1.5h后,浓缩反应混合物且在12g硅胶柱上用0-50%(10%(2M NH3/MeOH)/EtOAc)/EtOAc洗脱纯化,得到53mg(84%产率)。1H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.72(s,1H),8.64(d,J=4.8Hz,1H),7.74(t,J=9.2Hz,1H),7.53(dt,J=8.5,4.4Hz,1H),6.26(d,J=11.0Hz,1H),4.04(br.s.,2H),3.86(d,J=11.4Hz,1H),3.70(d,J=9.2Hz,1H),2.55(br.s.,3H),1.61(br.s.,2H),1.39(d,J=9.9Hz,1H),0.75(d,J=11.4Hz,1H)。LCMS(M+1)=495;TR=0.83min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例315-323
根据针对实施例314所描述的程序制备表1中的化合物:
表1
a用于表1的HPLC方法:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。b手性分离条件:柱:Chiralpak AD 21×250mm 5μ;流速:15mL/min;收集时间:22至49min;仪器:49;样品盘:4mL瓶;溶剂A:100%庚烷;溶剂B:100%乙醇;瓶:20;通过UV等度收集;起始%B:15;波长:254nm。
实施例324
11-氯-5-(二甲基-1,2-噁唑-4-基)-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
步骤1:3-溴-7-氯-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶
遵循与5-溴-10,13-二氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成类似的程序以95%产率由3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶合成标题化合物。LCMS(M+1)=475;TR=0.98min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
步骤2:11-氯-5-(二甲基-1,2-噁唑-4-基)-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向20mL闪烁瓶中添加3-溴-7-氯-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(35mg,0.074mmol)、3,5-二甲基-4-(三丁基锡烷基)异噁唑(28.4mg,0.074mmol)、CuI(2.1mg,0.011mmol)、三乙胺(14.9mg,0.147mmol)及DMF(2mL)。鼓泡氩气,然后添加Pd(PPh3)4(6.0mg,5.15μmol)且然后在100℃加热2天。浓缩反应混合物,再次溶解于1mL甲醇中且过滤。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为12%。1H NMR(500MHz,DMSO-d6)δ9.15(s,1H),8.60-8.50(m,2H),8.29(br.s.,2H),7.79-7.64(m,2H),7.50(dt,J=8.5,4.4Hz,1H),6.16(d,J=11.0Hz,1H),4.43-4.26(m,2H),3.93-3.84(m,1H),3.71(d,J=8.1Hz,1H),3.21(t,J=11.4Hz,1H),2.55(s,3H),2.21(s,3H),1.71-1.54(m,2H),1.44-1.30(m,1H),0.67(d,J=12.8Hz,1H)。LCMS(M+1)=492;TR=0.84min[柱:Waters AquityBEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例325-328
根据针对实施例324所描述的程序制备表2中的化合物:
表2
a用于表2的HPLC方法:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。b手性分离条件:柱:Chiralpak AD 21×250mm 5μ;通过UV等度收集;起始%B:15;波长:254nm;流速:15mL/min;溶剂A:100%庚烷;溶剂B:100%乙醇;注射体积:250μL;收集时间:12至28min。
实施例329
5-(二甲基-1,2-噁唑-4-基)-11-(1-乙氧基乙烯基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向20mL闪烁瓶中装入(S)-4-(7-氯-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-3-基)-3,5-二甲基异噁唑(75mg,0.153mmol)、三丁基(1-乙氧基乙烯基)锡烷(55.2mg,0.153mmol)及二噁烷(6mL)。然后添加PdCl2(dppf)2-CH2Cl2加合物(6.2mg,7.64μmol)且在氩气下将瓶密封。在搅拌下将其加热至100℃过夜。冷却反应混合物至室温且在旋转蒸发器上浓缩。粗物质在Biotage上使用12g柱且用0-15%(10%(2M NH3/MeOH)/EtOAc)/EtOAc洗脱纯化,得到47mg所需产物。1H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.57(d,J=1.5Hz,1H),8.37(br.s.,1H),8.11(br.s.,1H),7.67(dd,J=8.6,5.3Hz,2H),7.19(t,J=8.8Hz,2H),5.90(d,J=11.0Hz,1H),5.55(s,1H),4.53(s,1H),4.09-3.99(m,2H),3.94-3.85(m,1H),3.73(d,J=9.2Hz,1H),3.44(d,J=8.4Hz,1H),3.30-3.20(m,1H),2.48(s,3H),2.30(s,3H),1.72(d,J=9.9Hz,1H),1.59(d,J=7.3Hz,1H),1.49(t,J=7.0Hz,3H),1.32-1.22(m,1H),0.93(d,J=12.1Hz,1H)。LCMS(M+1)=527;TR=0.78min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min]。
实施例330
1-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]乙-1-酮
向溶解于5mL THF中的20mg 5-(二甲基-1,2-噁唑-4-基)-11-(1-乙氧基乙烯基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯中添加1mL 3N HCl水溶液且搅拌。1.5h后,用5mL K2CO3水溶液(5%溶液)淬灭反应混合物且用EtOAc稀释。分离有机层,用盐水洗涤,经MgSO4干燥,过滤且在旋转蒸发器上浓缩,得到粗混合物。将粗混合物加载至12g硅胶柱上且在Biotage上用0-15%(10%(2M NH3/MeOH)/EtOAc)/EtOAc洗脱纯化,得到58%所需产物。1H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.71(br.s.,1H),8.66(d,J=1.1Hz,1H),8.42(br.s.,1H),7.72(dd,J=8.8,5.5Hz,2H),7.18(t,J=8.8Hz,2H),6.05(d,J=11.7Hz,1H),3.94-3.85(m,1H),3.71(d,J=8.8Hz,1H),3.55-3.39(m,1H),3.23(t,J=11.0Hz,1H),2.78(s,3H),2.48(s,3H),2.30(s,3H),1.71-1.65(m,1H),1.61(d,J=8.8Hz,1H),1.37-1.25(m,1H),0.90(d,J=12.5Hz,1H)。LCMS(M+1)=499;TR=0.80min[柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min2-98%B;流速:0.8mL/min]。
实施例331
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇
在室温向(S)-1-(3-(3,5-二甲基异噁唑-4-基)-5-((4-氟苯基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶-7-基)乙酮(36mg,0.072mmol)于THF(6mL)中的溶液中添加甲基溴化镁(86mg,0.722mmol)。在室温搅拌所得混合物过夜且通过添加丙酮(5mL)淬灭。浓缩样品且经由制备型LC/MS在以下条件下纯化:柱:Waters Xbridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及0.1%三氟乙酸;流动相B:95:5乙腈:水及0.1%三氟乙酸;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产量为2.7mg。1H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.65(s,1H),8.40(br.s.,1H),7.76(dd,J=8.4,5.5Hz,2H),7.25-7.18(m,3H),7.13(s,1H),7.03(s,1H),5.98(d,J=10.3Hz,1H),3.98-3.86(m,1H),3.74(d,J=8.8Hz,1H),3.60-3.42(m,1H),3.39-3.21(m,1H),2.48(s,3H),2.30(s,3H),1.72(br.s.,1H),1.67(br.s.,6H),1.60-1.52(m,1H),1.32(d,J=12.1Hz,1H),0.96(d,J=11.7Hz,1H);LCMS(M+1)=515;TR=0.71min[柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min2-98%B;流速:0.8mL/min]。
实施例332-339
根据针对实施例331所描述的程序制备表3中的化合物。当引入时,通过遵循与10,13-二氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,11-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯的合成类似的程序安装1,4-二甲基-1H-1,2,3-三唑。
表3
a用于表3的HPLC方法:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;温度:50℃;梯度:历经3min 0-100%B且然后在100%B保持0.75min;流速:1.0mL/min;检测:UV 220nm。
实施例340
2-[5-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇
步骤1:甲磺酸(1-甲基-1H-1,2,3-三唑-4-基)甲基酯
在0℃向(1-甲基-1H-1,2,3-三唑-4-基)甲醇(145mg,1.28mmol)及三乙胺(0.45mL,3.2mmol)于DCM(5mL)中的溶液中添加甲磺酰氯(0.150mL,1.92mmol)。移开冰浴且继续搅拌30min。通过添加饱和碳酸氢钠淬灭反应混合物。用乙酸乙酯稀释反应混合物且分离各层。有机相经MgSO4干燥,过滤且浓缩,得到240mg(98%)。其不经纯化即用于下一步。1HNMR(500MHz,CDCl3)δ7.75(s,1H),5.39(s,2H),4.15(d,J=1.6Hz,3H),3.06(s,3H)。
步骤2:4-乙基-1-甲基-1H-1,2,3-三唑
向干燥烧瓶中装入碘化亚铜(I)(717mg,3.77mmol)且用氮气冲洗。向其中添加THF(5mL)。剧烈搅拌所得混悬液15min,冷却至0℃且用甲基溴化镁(2.51mL,7.53mmol)处理。在0℃搅拌15min后,非均质混合物用甲磺酸(1-甲基-1H-1,2,3-三唑-4-基)甲基酯(240mg,1.26mmol)于THF(1mL+1mL冲洗)中的溶液处理。搅拌30min后,通过添加饱和氯化铵淬灭反应混合物且用乙酸乙酯稀释。分离各层。用加有浓氢氧化铵水溶液的盐水洗涤有机相且分离各层。有机相经MgSO4干燥,过滤且浓缩,得到44mg(32%)。1H NMR(500MHz,CDCl3)δ7.27(s,1H),4.06(s,3H),2.75(qd,J=7.6,0.6Hz,2H),1.28(t,J=7.6Hz,3H)。
步骤3:(S)-7-氯-3-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶
向瓶中装入5-溴-11-氯-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(139mg,0.305mmol)、4-乙基-1-甲基-1H-1,2,3-三唑(44mg,0.396mmol)、四甲基乙酸铵(122mg,0.914mmol)及二乙酰氧基钯(27.3mg,0.122mmol)。用氮气冲洗瓶。向其中添加N-甲基吡咯烷酮(2.0mL)且在氮气气流下剧烈搅拌反应混合物10min。将瓶密封,加热至100℃且在该温度保持过夜。用乙酸乙酯稀释反应混合物且用盐水洗涤两次。有机层经MgSO4干燥,浓缩且通过制备型HPLC纯化:柱:Phenomenex Luna Axia,30×100mm;流动相A:10:90甲醇:水及0.1%TFA;流动相B:90:10甲醇:水及0.1%TFA;梯度:历经15min 10-100%B且然后在100%B保持2min;流速:40mL/min。合并含有所需产物的级份且浓缩。将所得残余物混悬于乙酸乙酯/饱和碳酸氢钠中且分离各层。有机相经MgSO4干燥,过滤且浓缩,得到30mg(20%)。LC/MS(M+H)=487.25;LC/MS TR=1.497min。柱:Acquity BEH C18 21×50mm 1.7μm;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min。
步骤4:(S)-3-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-7-(丙-1-烯-2-基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶
向1打兰瓶中装入(S)-7-氯-3-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(30mg,0.062mmol)、Cs2CO3(40.1mg,0.123mmol)及二噁烷(616μL)。所得溶液用氮气净化15min。向该混合物中添加异丙烯基硼酸频哪醇酯(23μL,0.12mmol)、三环己基膦(1M于甲苯中,12μL,0.012mmol)及Pd2(dba)3(5.6mg,6.2μmol)。将瓶再净化5min,密封且浸在预加热至115℃的油浴中。在该温度搅拌反应混合物过夜。将反应混合物倾入EtOAc中,先后用水和盐水洗涤,经MgSO4干燥,过滤且浓缩。柱色谱(0→100%丙酮/DCM)得到21mg(69%)。LC/MS(M+H)=493.20;LC/MS TR=0.925min。柱:Acquity BEH C18 21×50mm1.7μm;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min。
步骤5:2-[5-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇
向瓶中装入(S)-3-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-7-(丙-1-烯-2-基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(21mg,0.043mmol)、2-丙醇(0.5mL)及DCM(0.1mL)。将所得溶液置于0℃浴中,用苯基硅烷(10.5μL,0.085mmol)处理,用氧气净化且用三(2,2,6,6-四甲基-3,5-庚二酮酸)锰(III)(2.6mg,4.3μmol)处理。再次用氧气净化瓶且在氧气气囊下在0℃搅拌30min。通过添加20%硫代硫酸钠水溶液淬灭反应混合物。在0℃搅拌5min后,用乙酸乙酯稀释反应混合物且分离各层。浓缩有机相且经由制备型LC/MS在以下条件下纯化所得残余物:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经15min20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到12.6mg(57%)。1H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.56(s,1H),8.44(s,1H),8.25(s,1H),7.66(d,J=8.1Hz,2H),7.38-7.32(m,2H),7.31-7.25(m,1H),5.80(d,J=11.0Hz,1H),3.97(s,3H),3.91(d,J=10.3Hz,1H),3.76(d,J=9.5Hz,1H),3.53-3.25(m,2H),2.65(dquin,J=15.2,7.6Hz,2H),2.55(s,3H),1.71(d,J=12.1Hz,1H),1.61(s,3H),1.59(s,3H),1.41-1.28(m,1H),1.17(t,J=7.5Hz,3H),1.06(d,J=12.5Hz,1H);LC/MS(M+H)=511.1。
实施例341
8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-N-(2,2,2-三氟乙基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺
根据10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-N-(2,2,2-三氟乙基)-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-胺的程序以8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯为原料制备标题化合物。1H NMR(500MHz,DMSO)δ8.84(s,1H),8.73(d,J=1.5Hz,1H),8.56(d,J=4.4Hz,1H),8.42(t,J=6.6x2Hz,1H),8.1(d,J=1.5Hz,1H),7.7(m,1H),7.52(m,1H),7.1(d,J=9.5Hz,1H),4.7(m,2H),3.9(s,3H),3.88(d,J=11.7Hz,1H),3.68(d,J=6.6Hz,1H),3.46(brs,1H),3.36(m,2H),2.55(s,3H),1.79(d,J=12.1Hz,1H),1.66(d,J=12.1Hz,2H),0.53(d,J=11.4Hz,1H);LCMS(M+H)=636.5。
实施例342
11-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-6’-氯-2’-甲氧基-3-硝基-2,3’-联吡啶
向150mL压力烧瓶中装入(6-氯-2-甲氧基吡啶-3-基)硼酸(2.5g,13.3mmol)及2,5-二溴-3-硝基吡啶(3.38g,12.01mmol)。将固体混悬于THF(60mL)中。用PdCl2(dppf)-CH2Cl2加合物(0.545g,0.667mmol)及K3PO4(2M,20mL,40mmol)处理混合物。使氩气鼓泡通过混合物5min同时超声波处理。将烧瓶盖好且在预加热的油浴中加热至80℃。冷却反应混合物至室温。过滤反应混合物且浓缩滤液以除去THF。用水进一步稀释剩余的水层且用乙酸乙酯萃取。有机层经MgSO4干燥,过滤且真空浓缩,得到固体。将物质吸收于DCM及最少的乙酸乙酯中且通过快速柱色谱纯化:80g ISCO柱,0-30%乙酸乙酯/己烷(600mL),然后50-100%(300mL)。浓缩类似的级份,得到4.5g(78%)。1H NMR(400MHz,CDCl3)δ8.94(d,J=2.0Hz,1H),8.44(d,J=2.0Hz,1H),7.97(d,J=8.0Hz,1H),7.14(d,J=7.8Hz,1H),3.89(s,3H)。LC/MS(M+H)=345.95。
步骤2:3-溴-7-氯-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶
向圆底烧瓶中装入5-溴-6’-氯-2’-甲氧基-3-硝基-2,3’-联吡啶(3g,8.71mmol)及二(二苯基膦基)乙烷(4.34g,10.9mmol)。将固体混悬于1,2-二氯苯(9.80mL)中。用氮气冲洗烧瓶。在预加热的油浴中加热反应混合物至150℃同时搅拌。通过LCMS确定反应完成后,使反应在敞开于空气的情况下继续1h。在氮气气流下除去溶剂同时加热至100℃。向反应混合物中直接添加100mL DCM且在室温搅拌过夜。形成白色析出物且通过过滤收集,用DCM洗涤,得到683mg(23%)。1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.61(d,J=2.3Hz,1H),8.22(d,J=2.0Hz,1H),7.30(s,1H),4.09(s,3H)。LC/MS(M+H)=313.95。
步骤3:(S)-3-溴-7-氯-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶
向圆底烧瓶中装入3-溴-7-氯-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶(380mg,1.22mmol)及THF(15mL)。添加(R)-苯基(四氢-2H-吡喃-4-基)甲醇(467mg,2.43mmol)、三苯基膦(638mg,2.43mmol)及三乙胺(0.339mL,2.43mmol)且在冰水浴中冷却瓶。逐滴添加偶氮二甲酸二叔丁酯(560mg,2.43mmol)且在0℃搅拌反应混合物15min,然后移开冰浴。将反应混合物升温至室温且搅拌过夜。真空浓缩反应混合物。将残余物吸收于DCM中且转移至24g及40g ISCO FCC组合柱的顶部且然后用0-100%乙酸乙酯/己烷(900mL总溶剂)洗脱。合并类似的级份且浓缩,得到650mg(93%)。1H NMR(400MHz,CDCl3)δ8.79(d,J=1.8Hz,1H),8.08(d,J=1.8Hz,1H),7.48-7.33(m,4H),7.29(s,1H),7.23(s,1H),5.30(d,J=11.0Hz,1H),4.23(s,3H),4.10(dd,J=11.9,2.9Hz,1H),3.93(dd,J=12.0,3.3Hz,1H),3.65-3.53(m,1H),3.52-3.32(m,1H),3.05(dt,J=11.4,3.6Hz,1H),2.00(d,J=13.1Hz,1H),1.65-1.51(m,1H),1.45-1.33(m,1H),1.02(d,J=13.3Hz,1H)。LC/MS(M+H)=488.04。
步骤4:11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向压力容器中装入(S)-3-溴-7-氯-9-甲氧基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[3,2-b:4,5-c’]二吡啶(100mg,0.205mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(84mg,0.216mmol)及(Ph3P)4Pd(23.7mg,0.021mmol)。将固体混悬于DMF(2.5mL)中。搅拌反应混合物且鼓泡氩气5min,然后添加碘化亚铜(I)(7.8mg,0.041mmol)及三乙胺(0.043mL,0.308mmol)。再次使氩气鼓泡通过混合物5min且将容器置于在100℃预加热的油浴中。在搅拌下将反应混合物继续加热16h。冷却反应混合物至室温,经由针筒过滤器过滤且用过量的水及乙酸乙酯稀释。取出有机层且经MgSO4干燥,过滤且真空浓缩。通过制备型HPLC纯化残余物:20-100%B;溶剂B:90%CH3CN/0.1%TFA水;Phenomenex AXIA LUNA C18 30×100mm,10微米;UV 254nm;30mL/min;所需产物的TR:10.7min。合并类似的级份且真空浓缩,得到70mg(61%)。1H NMR(500MHz,DMSO-d6)δ8.63(d,J=1.5Hz,1H),8.45(br.s.,1H),7.68(d,J=7.3Hz,3H),7.36(t,J=7.6Hz,2H),7.31-7.23(m,1H),5.85(d,J=11.1Hz,1H),4.10(s,3H),3.98(s,3H),3.88(d,J=11.0Hz,1H),3.74(d,J=12.1Hz,1H),3.51-3.37(m,2H),3.26(t,J=11.5Hz,1H),2.12-2.03(m,3H),1.72-1.63(m,1H),1.62-1.46(m,1H),1.36-1.20(m,2H),0.94(d,J=12.2Hz,1H)。LC/MS(M+H)=506.1。
步骤5:11-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向压力容器中装入11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.040mmol)、甲亚磺酸钠(12.1mg,0.119mmol)及三氟甲磺酸铜(II)(14.3mg,0.040mmol)。将固体溶解于DMSO(1mL)中。添加N,N’-二甲基乙二胺(0.013mL,0.119mmol)。用氩气净化瓶,盖好且置于在100℃预加热的油浴中。搅拌反应混合物4小时。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Water XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经15min 10-50%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到4.9mg(21%)。1H NMR(500MHz,DMSO-d6)δ8.74(s,1H),8.56(br.s.,1H),7.67(d,J=7.7Hz,2H),7.36(t,J=7.2Hz,2H),7.29(t,J=7.9Hz,1H),6.11(d,J=11.7Hz,1H),4.20(s,3H),4.16-4.07(m,1H),3.99(s,3H),3.93-3.84(m,3H),3.73(d,J=9.2Hz,1H),3.56-3.44(m,1H),3.42(s,3H),3.24(t,J=11.7Hz,1H),3.18(d,J=5.1Hz,3H),1.69(br.s.,2H),1.33(d,J=9.5Hz,1H),0.88(d,J=13.6Hz,1H)。LC/MS(M+H)=550.25。
实施例343
11-(4,4-二氟哌啶-1-基)-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向压力瓶中装入11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.040mmol)、4,4-二氟哌啶HCl(9.3mg,0.059mmol)及二噁烷(2mL)。向其中添加(2-二环已基膦基-2’,6’-二异丙基-1,1’-联苯)[2-(2-氨基乙基)苯基]钯(II)(1.7mg,2.4μmol)、Pd(OAc)2(0.5mg,2.4μmol)、RuPhos(1.1mg,2.4μmol)及叔丁醇钠(15.2mg,0.16mmol)。在超声波处理下使氩气鼓泡至混合物中5min。将瓶盖好且置于在100℃预加热的油浴中。搅拌反应混合物16h。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Water XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经16min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到5.0mg(21%)。1H NMR(500MHz,DMSO-d6)δ8.37(s,1H),8.11(br.s.,1H),7.67(d,J=7.3Hz,2H),7.34(t,J=7.3Hz,2H),7.30-7.20(m,1H),5.73(d,J=11.0Hz,1H),4.03(s,3H),3.98-3.83(m,9H),3.75(d,J=8.8Hz,1H),3.47(t,J=11.2Hz,1H),3.26(t,J=11.7Hz,1H),3.17(br.s.,1H),2.10(br.s.,4H),1.70(d,J=13.6Hz,1H),1.55(d,J=10.6Hz,1H),1.33(d,J=11.0Hz,1H),1.00(d,J=12.1Hz,1H)。LC/MS(M+H)=591.34。
实施例344
2-{13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
向20mL瓶中装入11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(20mg,0.039mmol)、氯化铈(III)(19.2mg,0.078mmol)及THF(2mL)。冷却瓶至0℃且添加甲基溴化镁(3M于乙醚中,0.13mL,0.39mmol)。搅拌反应混合物1h同时将其升温至室温。在室温保持1h后,用氯化铵饱和溶液淬灭混合物且用乙酸乙酯稀释。将混合物转移至分液漏斗且分离各层。添加盐水以使乳液分解。有机层经MgSO4干燥,过滤且浓缩,得到灰白色残余物。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:WaterXBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经15min25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到14.9mg(72%)。1H NMR(500MHz,DMSO-d6)δ8.56(d,J=1.8Hz,1H),8.38(br.s.,1H),7.88(br.s.,1H),7.65(d,J=7.7Hz,2H),7.41-7.31(m,2H),7.31-7.13(m,1H),5.77(d,J=11.4Hz,1H),5.33(s,1H),4.10(s,3H),3.98(s,3H),3.94-3.84(m,1H),3.74(d,J=10.3Hz,1H),3.37(d,J=4.4Hz,1H),3.32-3.21(m,1H),1.71(d,J=13.2Hz,1H),1.56(s,3H),1.58(s,4H),1.39-1.20(m,1H),0.97(d,J=12.1Hz,1H)。LC/MS(M+H)=530.37。
实施例345及346
2-{8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
步骤1:11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将3-溴-7-氯-9-甲氧基-5H-吡咯并[3,2-b:4,5-c’]二吡啶(1.0g,3.2mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(36.9mg,0.102mmol)、CuI(0.091g,0.480mmol)、Pd(PPh3)4(0.259g,0.224mmol)、三乙胺(0.892mL,6.40mmol)及DMF(20mL)称重至20mL闪烁瓶中且在氩气下密封。将瓶置于预加热至100℃的反应块中且搅拌16小时。在加热下真空浓缩反应混合物至干燥。通过快速色谱纯化粗混合物(40g ISCO RediSep,0-40%[10%(2MNH3)/EtOAc]/EtOAc),得到734mg(69%)。1H NMR(400MHz,DMSO-d6)δ8.61(d,J=1.8Hz,1H),8.08(d,J=2.0Hz,1H),7.31(s,1H),4.12(s,3H),4.00(s,3H)。
步骤2:11-氯-8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向20mL瓶中装入11-氯-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(150mg,0.452mmol)及DCM(10mL)。添加(4,4-二氟环己基)(苯基)甲醇(205mg,0.904mmol)、Ph3P(237mg,0.904mmol)及三乙胺(0.126mL,0.904mmol)且冷却瓶至0℃。添加DIAD(0.088mL,0.452mmol)。在0℃搅拌反应混合物15min且将其升温至室温过夜。真空浓缩反应混合物。将该残余物吸收于DCM中,转移至40g ISCO硅胶柱的顶部且用0-100%B(B=10%(2M NH3/甲醇)/乙酸乙酯)/己烷(750mL总溶剂)洗脱。合并类似的级份且浓缩,得到100mg(41%)。LC/MS(M+H)=540.25;HPLC条件:TR=4.27min;纯度:98%。柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤3:1-{8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}乙-1-酮
向压力容器中装入11-氯-8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯(50mg,0.093mmol)、三丁基(1-乙氧基乙烯基)锡烷(36.8mg,0.102mmol)及PdCl2(dppf)-CH2Cl2加合物(7.6mg,9.3μmol)。将固体混悬于二噁烷(3mL)中。使氩气鼓泡通过混合物5min。将容器置于在100℃预加热的油浴中。在搅拌下将反应混合物继续加热16h。冷却反应混合物至室温。经由针筒过滤器过滤混合物且真空浓缩。将残余物吸收于10mL THF中且用2mL 2M HCl溶液处理同时在室温搅拌2h。用K2CO3水溶液中和溶液,用乙酸乙酯萃取,经MgSO4干燥,过滤且真空浓缩。将物质吸收于DCM中且通过快速柱色谱(24+40g ISCO柱,0-50%且然后50-100%B[10%(2M氨/甲醇)/乙酸乙酯]/己烷,900mL)纯化。浓缩类似的级份,得到40mg(39%)。LC/MS(M+H)=548.30;HPLC条件:TR=4.15min;纯度:99%。柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤4:2-{8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
向20mL瓶中装入1-{8-[(4,4-二氟环己基)(苯基)甲基]-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}乙-1-酮(40mg,0.073mmol)及THF(3mL)。冷却瓶至0℃且添加甲基溴化镁(3M于乙醚中,0.146mL,0.438mmol)。搅拌反应混合物1h同时将其升温至室温。在室温保持1h后,用氯化铵饱和溶液淬灭混合物且用乙酸乙酯稀释。将混合物转移至分液漏斗且分离各层。添加盐水以使乳液分解。有机层经MgSO4干燥,过滤且真空浓缩,得到灰白色残余物。过滤反应混合物中的固体且对该物质进行手性分离:Chiralcel OD制备型柱,21×250mm,10μm;流动相:历经32min 15%乙醇/庚烷;流速:15.0mL/min;在UV 254nm监测;TR:对映异构体A:14.7min;对映异构体B:21.1分钟。合并含有所需产物的级份且经由蒸发干燥,得到9.1mg(22%)对映异构体A及12.1mg(29%)对映异构体B。1H NMR(500MHz,DMSO-d6)δ8.57(d,J=1.8Hz,1H),8.39(br.s.,1H),7.90(br.s.,1H),7.65(d,J=7.7Hz,2H),7.43-7.31(m,2H),7.31-7.21(m,1H),5.82(d,J=11.7Hz,1H),5.30(s,1H),4.10(s,3H),4.00(s,3H),2.16-2.03(m,2H),2.03-1.84(m,3H),1.83-1.67(m,1H),1.58(d,J=9.2Hz,8H),1.39-1.17(m,2H)。LC/MS(M+H)=564.33。
实施例347
12-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
步骤1:5-溴-5’-氯-3-硝基-2,3’-联吡啶
向压力烧瓶中装入(5-氯吡啶-3-基)硼酸(5g,31.8mmol)及2,5-二溴-3-硝基吡啶(8.06g,28.6mmol)。将固体混悬于THF(100mL)中。用PdCl2(dppf)-CH2Cl2加合物(1.297g,1.589mmol)及K3PO4(2M,47.7mL,95mmol)处理混合物。使氩气鼓泡通过混合物5min同时超声波处理。将烧瓶盖好且在预加热的油浴中加热至80℃且保持2小时。冷却反应混合物至室温,过滤且浓缩滤液以除去THF。用水进一步稀释剩余的水层且用乙酸乙酯萃取。有机层经MgSO4干燥,过滤且真空浓缩,得到固体。用乙醇研磨物质且真空干燥剩余的棕色固体(6.8g,68%)。LC/MS(M+H)=315.97;HPLC条件:TR=3.73min。柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤2:3-溴-8-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶
向圆底烧瓶中装入5-溴-5’-氯-3-硝基-2,3’-联吡啶(3g,9.54mmol)及二(二苯基膦基)乙烷(4.75g,11.9mmol)。将固体混悬于1,2-二氯苯(10.7mL)中。用氮气冲洗烧瓶。在预加热的油浴中加热反应混合物至150℃同时搅拌。通过LCMS确定反应完成后,使反应在敞开于空气的情况下继续1h。在氮气气流下除去溶剂同时加热至100℃。用100mL DCM稀释反应混合物,在0℃搅拌且升温至室温过夜。形成白色析出物(175mg,6%)且通过过滤收集,用DCM洗涤。TLC:30%B/己烷(B:10%(2M NH3/甲醇)/EtOAc);Rf=0.40;其它异构体Rf=0.67。LC/MS(M+H)=283.98;HPLC条件:TR=3.84min。柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤3:(S)-3-溴-8-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶
向100mL圆底烧瓶中装入3-溴-8-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶(425mg,1.50mmol)及DCM(20mL)。添加(R)-苯基(四氢-2H-吡喃-4-基)甲醇(578mg,3.01mmol)、Ph3P(789mg,3.01mmol)及三乙胺(0.419mL,3.01mmol)且冷却瓶至0℃。添加DIAD(0.585mL,3.01mmol)且在0℃搅拌反应混合物15min。将反应混合物升温至室温过夜。真空浓缩反应混合物。将残余物吸收于DCM中且转移至80g ISCO硅胶柱的顶部且用0-100%乙酸乙酯/己烷(900mL总溶剂)洗脱。合并类似的级份(在50%EA/己烷中的Rf为0.67)且浓缩,得到560mg(82%)。LC/MS(M+H)=457.9;HPLC条件:TR=1.21min。柱:Phenomenex LUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤4:12-氯-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向压力容器中装入(S)-3-溴-8-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(50mg,0.11mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(44.7mg,0.115mmol)及(Ph3P)4Pd(12.7mg,11.0μmol)。将固体混悬于DMF(2mL)中且搅拌同时鼓泡氩气5min。向其中添加碘化亚铜(I)(4.2mg,0.022mmol)及三乙胺(0.031mL,0.22mmol)。使氩气鼓泡通过混合物5min且然后将容器置于在100℃预加热的油浴中且保持16小时。冷却反应混合物至室温。经由针筒过滤器过滤混合物,然后用DMF稀释以通过制备型HPLC纯化:20-100%B;溶剂B:90%CH3CN/0.1%TFA水;Phenomenex AXIALUNA C18 30×100mm,10微米;UV 254nm;30mL/min;TR=13.7min。合并类似的级份,然后真空浓缩,得到50mg(91%)。1H NMR(400MHz,DMSO-d6)δ8.79(d,J=2.5Hz,1H),8.74(d,J=2.5Hz,1H),8.67(d,J=1.8Hz,1H),8.62(s,1H),7.80(d,J=7.3Hz,2H),7.37-7.29(m,2H),7.29-7.17(m,1H),5.92(d,J=9.5Hz,1H),4.04(s,3H),3.88(d,J=8.5Hz,1H),3.80-3.57(m,2H),3.45-3.35(m,1H),1.60-1.49(m,1H),1.46-1.35(m,1H),1.32-1.22(m,1H),1.21-1.04(m,2H)。LC/MS(M+H)=476.31。
实施例348
5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-甲酸甲酯
步骤1:5-溴-3-硝基-[2,3’-联吡啶]-5’-甲酸甲酯
向压力烧瓶中装入5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-甲酸甲酯(1.4g,5.32mmol)及2,5-二溴-3-硝基吡啶(1.35g,4.79mmol)。将固体混悬于THF(40mL)中。用PdCl2(dppf)-CH2Cl2加合物(0.217g,0.266mmol)及K3PO4(2M,8mL,16mmol)处理混合物。在超声波处理下使氩气鼓泡通过混合物5min。将烧瓶盖好且置于在80℃预加热的油浴中。2h后,冷却容器至室温且过滤反应混合物。真空浓缩滤液至接近干燥。用水稀释剩余的水层且用乙酸乙酯萃取。添加盐水且取出有机层,经MgSO4干燥,过滤且真空浓缩,得到2.14g(95%)。1H NMR(400MHz,CDCl3)δ9.35(d,J=2.0Hz,1H),9.02(d,J=2.0Hz,1H),8.94(d,J=2.3Hz,1H),8.57-8.43(m,2H),4.01(s,3H)。LC/MS(M+H)=348.10。
步骤2:3-溴-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯
向圆底烧瓶中装入5-溴-3-硝基-[2,3’-联吡啶]-5’-甲酸甲酯(450mg,1.33mmol)及二(二苯基膦基)乙烷(663mg,1.66mmol)。将固体混悬于1,2-二氯苯(1.5mL)中。用氮气冲洗烧瓶。在预加热的油浴中加热反应混合物至150℃同时搅拌。通过LCMS确定反应完成后,使反应在敞开于空气的情况下继续1h。在氮气气流下除去溶剂同时加热至100℃。用75mLDCM稀释反应混合物且在0℃搅拌,然后将其升温至室温过夜。形成白色析出物且通过过滤收集,用DCM洗涤(150mg,31%)。1H NMR(500MHz,DMSO-d6)δ12.69(s,1H),9.14(d,J=1.9Hz,1H),8.98(d,J=2.2Hz,1H),8.69(d,J=1.9Hz,1H),8.22(d,J=1.9Hz,1H),3.94(s,3H)。LC/MS(M+H)=308.05。
步骤3:(S)-3-溴-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯
在0℃向圆底烧瓶中装入3-溴-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(100mg,0.327mmol)、(R)-苯基(四氢-2H-吡喃-4-基)甲醇(126mg,0.653mmol)、Ph3P(171mg,0.653mmol)及DCM(10mL)。向混悬液中逐滴添加DIAD(0.127mL,0.653mmol)。将反应混合物升温至室温且搅拌16小时。真空浓缩反应混合物。将残余物吸收于最少量的DCM中且转移至组合的24g及40g ISCO硅胶柱的顶部。用0-100%乙酸乙酯/己烷(1000mL)洗脱物质。合并类似的级份且真空浓缩,得到150mg(95%)。LC/MS(M+H)=480.20;HPLC条件:TR=4.27min。柱:Phenomenex C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤4:5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-甲酸甲酯
向压力容器中装入(S)-3-溴-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(112mg,0.233mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(95mg,0.245mmol)、(Ph3P)4Pd(26.9mg,0.023mmol)。将固体混悬于DMF(3mL)中。搅拌混悬液且用氩气鼓泡5min,然后添加碘化亚铜(I)(8.9mg,0.047mmol)及三乙胺(0.049mL,0.350mmol)。使氩气鼓泡通过混合物5min且然后将容器置于在100℃预加热的油浴中且保持16小时。冷却反应混合物至室温且经由针筒过滤器过滤。通过制备型HPLC纯化物质:20-100%B;溶剂B:90%CH3CN/0.1%TFA水;Phenomenex AXIA LUNA C18 30×100mm,10微米;UV 254nm;30mL/min;TR=11.4min。合并类似的级份,然后真空浓缩,得到89mg(65%)。1H NMR(500MHz,DMSO-d6)δ9.29(d,J=2.2Hz,1H),9.05(d,J=1.8Hz,1H),8.72(d,J=1.8Hz,1H),8.66(br.s.,1H),7.82(d,J=7.3Hz,2H),7.39-7.29(m,2H),7.29-7.18(m,1H),6.00(br.s.,1H),4.04(s,3H),3.96(s,3H),3.93-3.80(m,1H),3.74(d,J=11.7Hz,2H),1.77(s,1H),1.54(br.s.,1H),1.41(d,J=8.1Hz,1H),1.34-1.17(m,1H),1.12(d,J=12.1Hz,1H)。LC/MS(M+H)=500.40。
实施例349
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇
向20mL瓶中装入5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-甲酸甲酯(45mg,0.090mmol)及THF(3mL)。添加甲基溴化镁(3M于乙醚中,0.45mL,1.35mmol)。在室温保持1h后,用NH4Cl饱和溶液淬灭反应混合物同时在室温搅拌。添加乙酸乙酯且继续搅拌。将混合物转移至分液漏斗且分离各层。添加盐水以使乳液分解。有机层经MgSO4干燥,过滤且真空浓缩,得到黄色残余物。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Water XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到21.0mg(46%)。1HNMR(500MHz,DMSO-d6)δ8.88(d,J=1.8Hz,1H),8.68(d,J=2.2Hz,1H),8.60(s,1H),8.54(br.s.,1H),7.81(d,J=8.1Hz,2H),7.37-7.27(m,2H),7.27-7.12(m,1H),5.91(br.s.,1H),4.03(s,3H),3.88(d,J=11.4Hz,1H),3.75(d,J=10.6Hz,1H),3.42(br.s.,1H),3.35-3.17(m,1H),2.55(s,1H),1.86(s,1H),1.61(s,6H),1.53(br.s.,1H),1.48-1.32(m,1H),1.32-1.18(m,1H),1.12(d,J=12.5Hz,1H)。LC/MS(M+H)=500.40。
实施例350
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基]丙-2-醇
步骤1:(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯
向压力容器中装入(S)-3-溴-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(126mg,0.262mmol)、1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(106mg,0.275mmol)及(Ph3P)4Pd(30.3mg,0.026mmol)。将固体混悬于DMF(3mL)中。搅拌混悬液且用氩气鼓泡5min,然后添加碘化亚铜(I)(9.99mg,0.052mmol)及三乙胺(0.055mL,0.393mmol)。使氩气鼓泡通过混合物5min且然后将容器置于在100℃预加热的油浴中。在搅拌下将反应混合物继续加热16h。冷却反应混合物至室温且经由针筒过滤器过滤。通过制备型HPLC纯化物质:20-100%B;溶剂B:90%CH3CN/0.1%TFA水;PhenomenexAXIA LUNA C18 30×100mm,10微米;UV 254nm;30mL/min;TR=11.5min。合并类似的级份,然后真空浓缩,得到135mg(83%)。LC/MS(M+H)=497.20;HPLC条件:TR=3.80min。柱:Phenomenex C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤2:2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基]丙-2-醇
向20mL瓶中装入(S)-3-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(60mg,0.121mmol)及THF(3mL)。添加甲基溴化镁(3M于乙醚中,0.60mL,1.8mmol)。在室温保持1h后,用NH4Cl饱和溶液淬灭反应混合物同时在室温搅拌。在搅拌下向其中添加乙酸乙酯。将混合物转移至分液漏斗且分离各层。添加盐水以使乳液分解。有机层经MgSO4干燥,过滤且真空浓缩,得到黄色残余物。将残余物溶解于2mL DMF中。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Water XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经15min 25-65%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到14.3mg(24%)。1H NMR(500MHz,DMSO-d6)δ8.89(d,J=2.2Hz,1H),8.68(d,J=2.2Hz,1H),8.60(d,J=1.5Hz,1H),8.55(br.s.,1H),7.81(d,J=7.7Hz,2H),7.36-7.28(m,2H),7.28-7.17(m,1H),5.92(br.s.,1H),4.03(s,3H),3.88(d,J=10.6Hz,1H),3.75(d,J=9.2Hz,2H),3.37(s,1H),3.26(t,J=12.3Hz,1H),2.31(s,3H),1.61(s,6H),1.53(br.s.,1H),1.45-1.34(m,1H),1.34-1.18(m,1H),1.13(d,J=14.3Hz,1H)。LC/MS(M+H)=497.25。
实施例351
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基]丙-2-醇
步骤1:3,5-二甲基-4-(三丁基锡烷基)异噁唑
将3,5-二甲基异噁唑(1.20g,12.4mmol)于THF(25mL)中的溶液冷却至-78℃。在氮气下向其中逐滴添加丁基锂(5.93mL,14.8mmol)。将该混合物搅拌0.5h。然后逐滴添加三丁基氯锡烷(4.15g,12.4mmol)。在-78℃搅拌反应混合物10min,移开冷却浴且历经1h将反应混合物升温至室温。用15mL NH4Cl饱和溶液淬灭反应混合物且然后用15mL 10%LiCl水溶液稀释。分离各层且用乙醚(3×20mL)萃取水层。合并的有机层经Na2SO4干燥且过滤。浓缩滤液且通过快速柱色谱在80g硅胶柱上使用2-30%EtOAc/己烷纯化,得到3.21g(67%)。
步骤2:(S)-3-(3,5-二甲基异噁唑-4-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯
向20mL压力容器中装入(S)-3-溴-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(97mg,0.202mmol)、3,5-二甲基-4-(三丁基锡烷基)异噁唑(82mg,0.212mmol)及(Ph3P)4Pd(23.3mg,0.020mmol)。将固体混悬于DMF(3mL)中。搅拌混悬液且用氩气鼓泡5min,然后添加碘化亚铜(I)(7.7mg,0.040mmol)及三乙胺(0.042mL,0.303mmol)。使氩气鼓泡通过混合物5min且然后将容器置于在100℃预加热的油浴中。在搅拌下将反应混合物继续加热16h。冷却反应混合物至室温且经由针筒过滤器过滤。通过制备型HPLC纯化物质:20-100%B;溶剂B:90%CH3CN/0.1%TFA水;PhenomenexAXIA LUNA C18 30×100mm,10微米;UV 254nm;30mL/min;TR=12.0min。合并类似的级份,然后真空浓缩,得到47mg(47%)。1H NMR(400MHz,DMSO-d6)δ9.22(d,J=2.3Hz,1H),8.98(d,J=2.3Hz,1H),8.58(d,J=1.5Hz,1H),8.52(s,1H),7.77(d,J=7.3Hz,2H),7.35-7.23(m,3H),5.91(d,J=10.0Hz,1H),3.95(s,3H),3.89(d,J=11.0Hz,1H),3.74(d,J=11.8Hz,1H),3.42(s,1H),3.26(d,J=1.5Hz,1H),2.11-2.07(m,6H),1.59(s,1H),1.51(br.s.,1H),1.45(d,J=4.3Hz,1H),1.36-1.27(m,1H),1.07(d,J=10.0Hz,1H),0.89(t,J=7.3Hz,1H)。LC/MS(M+H)=497.25。
步骤3:2-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基]丙-2-醇
向20mL瓶中装入(S)-3-(3,5-二甲基异噁唑-4-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(41mg,0.083mmol)及THF(3mL)。添加甲基溴化镁(3M于乙醚中,0.41mL,1.23mmol)。在室温保持1h后,用NH4Cl饱和溶液淬灭反应混合物同时在室温搅拌。在搅拌下向其中添加乙酸乙酯。将混合物转移至分液漏斗且分离各层。添加盐水以使乳液分解。有机层经MgSO4干燥,过滤且真空浓缩,得到黄色残余物。将残余物溶解于2mL DMF中。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:WaterXBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经20min30-70%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到18.7mg(45%)。1H NMR(500MHz,DMSO-d6)δ8.80(d,J=2.2Hz,1H),8.60(d,J=2.2Hz,1H),8.44(s,1H),8.37(s,1H),7.75(d,J=7.3Hz,2H),7.35-7.27(m,2H),7.27-7.14(m,1H),5.80(br.s.,1H),4.34(s,2H),3.88(d,J=12.5Hz,1H),3.74(d,J=11.0Hz,1H),3.37(d,J=6.6Hz,1H),3.31-3.17(m,1H),2.55(s,6H),1.59(s,6H),1.51(d,J=13.2Hz,1H),1.47-1.35(m,1H),1.31-1.15(m,1H),1.08(d,J=11.0Hz,1H)。LC/MS(M+H)=497.1。
实施例352
2-{8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇
步骤1:(S)-3-溴-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯
在0℃向圆底烧瓶中装入3-溴-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(159mg,0.519mmol)、(R)-(3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲醇(219mg,1.04mmol)、Ph3P(272mg,1.04mmol)及DCM(10mL)。向该混悬液中逐滴添加DIAD(0.202mL,1.04mmol)。移开冰浴且将反应混合物升温至室温且搅拌16小时。真空浓缩反应混合物。将残余物吸收于最少量的DCM中且转移至40g ISCO硅胶柱的顶部。物质用0-100%乙酸乙酯/己烷(1000mL)洗脱。合并类似的级份且真空浓缩,得到420mg(81%)。LC/MS(M+H)=499.10;HPLC条件:TR=4.31min。柱:Phenomenex C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤2:8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-甲酸甲酯
向压力容器中装入(S)-3-溴-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(260mg,0.521mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(213mg,0.547mmol)及(Ph3P)4Pd(60.2mg,0.052mmol)。将固体混悬于DMF(4mL)中。搅拌混悬液且用氩气鼓泡5min,然后添加碘化亚铜(I)(19.8mg,0.104mmol)及三乙胺(0.109mL,0.781mmol)。使氩气鼓泡通过混合物5min且将容器置于在100℃预加热的油浴中。16h后,冷却反应混合物至室温且经由针筒过滤器过滤。通过制备型HPLC纯化物质:20-100%B;溶剂B:90%CH3CN/0.1%TFA水;Phenomenex AXIA LUNA C18 30×100mm,10微米;UV 254nm;30mL/min;TR=9.6min。合并类似的级份,然后真空浓缩,得到180mg(57%)。LC/MS(M+H)=519.1;TR=0.85min。柱:Waters Aquity BEH C18 2.1×50mm1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min2-98%B;流速:0.8mL/min。
步骤3:2-{8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇
向50mL圆底烧瓶中装入8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-甲酸甲酯(75mg,0.145mmol)及THF(10mL)。添加甲基溴化镁(3M于乙醚中,0.72mL,2.16mmol)。在室温保持1h后,用NH4Cl饱和溶液淬灭反应混合物同时在室温搅拌。在搅拌下添加乙酸乙酯。将混合物转移至分液漏斗且分离各层。添加盐水以使乳液分解。有机层经MgSO4干燥,过滤且真空浓缩,得到黄色残余物。将该残余物吸收于2mLDMF中。通过过滤除去固体且通过制备型HPLC纯化滤液:柱:Water XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经20min 15-55%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到33.0mg(44%)。1H NMR(500MHz,DMSO-d6)δ8.85(d,J=1.8Hz,1H),8.68(d,J=2.2Hz,1H),8.63(d,J=1.5Hz,1H),8.60-8.52(m,2H),7.71(t,J=9.2Hz,1H),7.48(dt,J=8.5,4.4Hz,1H),6.66(d,J=11.4Hz,1H),5.37(s,1H),4.04(s,3H),3.84(d,J=12.1Hz,1H),3.68(d,J=9.9Hz,1H),3.21(t,J=11.6Hz,1H),1.66-1.54(m,8H),1.43(d,J=8.4Hz,1H),1.23(dd,J=12.3,4.2Hz,1H),0.83(d,J=12.8Hz,1H)。LC/MS(M+H)=519.30。
实施例353及354
2-{8-[(5-氯吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇
步骤1:3-溴-5-((5-氯吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯
在0℃向圆底烧瓶中装入3-溴-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(75mg,0.245mmol)、(5-氯吡啶-2-基)(四氢-2H-吡喃-4-基)甲醇(112mg,0.490mmol)、Ph3P(129mg,0.490mmol)及DCM(5mL)。向该混悬液中逐滴添加DIAD(0.095mL,0.490mmol)。移开冰浴且将反应混合物升温至室温且搅拌16小时。真空浓缩反应混合物。将残余物吸收于最少的新鲜DCM中且转移至40g ISCO硅胶柱的顶部。物质用0-100%乙酸乙酯/己烷(1100mL)洗脱。合并类似的级份且真空浓缩,得到145mg(57%)。LC/MS(M+H)=516.8;TR=1.16min。柱:Waters Aquity BEH C18 2.1×50mm 1.7μ;流动相A:水及0.05%TFA;流动相B:乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min。
步骤2:8-[(5-氯吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-甲酸甲酯
向压力容器中装入3-溴-5-((5-氯吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-8-甲酸甲酯(126mg,0.244mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(100mg,0.257mmol)、(Ph3P)4Pd(28.2mg,0.024mmol)。将固体混悬于DMF(2mL)中。搅拌混悬液且用氩气鼓泡5min,然后添加碘化亚铜(I)(9.3mg,0.049mmol)及三乙胺(0.051mL,0.366mmol)。使氩气鼓泡通过混合物5min且然后将容器置于在100℃预加热的油浴中。在搅拌下加热反应混合物16h。冷却反应混合物至室温且经由针筒过滤器过滤。通过制备型HPLC纯化物质:20-100%B;溶剂B:90%CH3CN/0.1%TFA水;Phenomenex AXIA LUNA C18 30×100mm,10微米;UV 254nm;30mL/min;TR=11.5min。合并类似的级份,然后真空浓缩,得到70mg(43%)。LC/MS(M+H)=535.25;HPLC条件:TR=2.25min。柱:Phenomenex C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%甲醇水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃。
步骤3:2-{8-[(5-氯吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇
向50mL圆底烧瓶中装入8-[(5-氯吡啶-2-基)(氧杂环己烷-4-基)甲基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-甲酸甲酯(70mg,0.131mmol)及THF(10mL)。添加甲基溴化镁(3M于乙醚中,0.65mL,1.95mmol)。在室温搅拌反应混合物16h。用NH4Cl饱和溶液淬灭反应混合物同时在室温搅拌。在搅拌下向其中添加乙酸乙酯。将混合物转移至分液漏斗且分离各层。添加盐水以使乳液分解。有机层经MgSO4干燥,过滤且真空浓缩,得到黄色残余物。将该残余物吸收于DMF中。过滤反应混合物中的固体且对该物质(8mg)进行手性分离:Chiralcel OD制备型柱,21×250mm,10μm;流动相:历经42min15%乙醇/庚烷;流速:15.0mL/min;在UV254nm监测;TR:对映异构体A:22.5min;对映异构体B:30.1min。合并含有所需产物的级份且经由蒸发干燥,得到2.5mg(4%)对映异构体A及2.6mg(4%)对映异构体B。1H NMR(500MHz,DMSO-d6)δ8.85(d,J=1.8Hz,1H),8.69(d,J=2.2Hz,1H),8.67-8.60(m,2H),8.55(s,1H),7.91(dd,J=8.4,2.6Hz,1H),7.69(d,J=8.1Hz,1H),6.25(d,J=9.5Hz,1H),4.06(s,3H),3.85(d,J=9.9Hz,1H),3.70(d,J=12.5Hz,1H),3.23(s,1H),1.66-1.58(m,7H),1.58-1.52(m,1H),1.52-1.41(m,1H),1.30-1.13(m,2H),0.96(d,J=12.8Hz,1H)。LC/MS(M+H)=535.1。
实施例357及358
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[1-(吡啶-2-基)丁基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
步骤1:1-(5-氟吡啶-2-基)丁-1-醇
在环境温度向镁(72.9mg,3.0mmol)及一个碘晶体于THF(2.6mL)中的搅拌的混悬液中逐滴添加1-溴丙烷(369mg,3.0mmol)。搅拌反应混合物1h,然后在冰水浴中对其进行冷却。逐滴添加5-氟吡啶-2-甲醛(250mg,2.0mmol)。然后搅拌反应混合物1h。用氯化铵饱和水溶液(5mL)淬灭反应混合物且用乙酸乙酯(40mL)及水(30mL)稀释。将产物萃取至有机相中,然后分离各层。用第二份乙酸乙酯(50mL)萃取水层且经硫酸钠干燥合并的有机相。减压除去挥发物。使用硅胶柱色谱用乙酸乙酯/己烷(0-100%)纯化粗反应物质。分离呈浅黄色油状物的1-(5-氟吡啶-2-基)丁-1-醇(243mg,72%产率)。1H NMR(500MHz,DMSO-d6)δ8.46(d,J=3.0Hz,1H),7.74-7.62(m,1H),7.53(dd,J=8.7,4.7Hz,1H),5.35(d,J=5.0Hz,1H),4.67-4.48(m,1H),1.76-1.62(m,1H),1.62-1.52(m,1H),1.43-1.25(m,2H),0.91-0.79(m,3H);LC/MS(M+H)=170.05。
步骤2:5-溴-11-氯-8-[1-(5-氟吡啶-2-基)丁基]-3,8,12-三氮杂三环[7.4.0.02 ,7]十三碳-1(9),2(7),3,5,10,12-六烯
在0℃向5-溴-11-氯-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(100mg,0.354mmol)、1-(5-氟吡啶-2-基)丁-1-醇(120mg,0.71mmol)、三苯基膦(186mg,0.71mmol)及Et3N(99μL,0.71mmol)于THF(3.5mL)中的搅拌的溶液中逐滴添加偶氮二甲酸二叔丁酯(163mg,0.71mmol)/THF(3.5mL)。历经10min将反应混合物升温至环境温度且在该温度再搅拌72h。将粗反应混合物加载至硅胶柱上且使用乙酸乙酯/己烷(0-100%)纯化。分离呈白色固体状的5-溴-11-氯-8-[1-(5-氟吡啶-2-基)丁基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(154mg,定量)及少量的氧化三苯基膦污染物。LC/MS(M+H)=433.0;LC/MSTR=2.115min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min0-100%B;流速:1mL/min)。物质不经额外纯化即使用。
步骤3:11-氯-8-[1-(5-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
将5-溴-11-氯-8-[1-(5-氟吡啶-2-基)丁基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(154mg,0.36mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(207mg,0.53mmol)、Pd(PPh3)4(41.0mg,0.04mmol)、碘化亚铜(I)(13.5mg,0.07mmol)及三乙胺(59μL,0.43mmol)/DMF(1.7mL)用氮气脱气3min。然后在100℃搅拌反应混合物16小时。先后用乙酸乙酯/己烷(0-100%)和甲醇/乙酸乙酯(0-20%)对粗反应混合物进行硅胶柱色谱。分离11-氯-8-[1-(5-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(133mg,83%产率)。LC/MS(M+H)=453.10;LC/MS TR=1.170min(柱:WatersAquity C18 50×2.1mm 1.7μ;流动相A:100%水及0.05%TFA;流动相B:100%乙腈及0.05%TFA;温度:40℃;梯度:历经1.5min 2-98%B;流速:0.8mL/min)。
步骤4:1-{8-[1-(5-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮
将11-氯-8-[1-(5-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(130mg,0.29mmol)、三丁基(1-乙氧基乙烯基)锡(207mg,0.57mmol)、Pd2(dba)3(52.6mg,0.06mmol)、三环己基膦(179μL,0.12mmol,20%wt于甲苯中)及碳酸铯(187mg,0.57mmol)/二噁烷(2.9mL)用氮气脱气3min。然后在115℃搅拌反应混合物16小时。添加1N HCl水溶液(2mL)且搅拌反应混合物20min。用1.5M磷酸二氢钾水溶液(5mL)淬灭反应混合物且分离各层。用乙酸乙酯(3×10mL)萃取水层。经硫酸钠干燥合并的有机相。通过过滤除去固体且减压除去挥发物。粗1-{8-[1-(5-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮不经纯化即使用。LC/MS(M+H)=461.30;LC/MS TR=1.437min(柱:Phenomenex Luna 30×2.0mm3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min)。
步骤5:2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[1-(吡啶-2-基)丁基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
在氮气下在-20℃向1-{8-[1-(5-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}乙-1-酮(132mg,0.29mmol)于THF(2.9mL)中的搅拌的溶液中添加甲基溴化镁(3M于乙醚中,2870μL,8.60mmol)。在该温度搅拌反应混合物1h。然后仍在-20℃用氯化铵饱和水溶液(8mL)淬灭反应混合物且用乙酸乙酯(20mL)稀释。由冷浴取出混合物且升温至环境温度。分离各层且用第二份乙酸乙酯(20mL)萃取水相。经硫酸钠干燥合并的有机相,通过过滤除去固体且减压除去挥发物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridgeC18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经20min 40-80%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到外消旋2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[1-(吡啶-2-基)丁基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇。对映异构体A及B使用手性制备型HPLC(柱:ChiralpakAD 21×250mm 5μ;流动相:15%乙醇/庚烷;流速:15mL/min)分离。将第一洗脱对映异构体(12.61min)定义为对映异构体A(14.2mg,10%产率)且将第二洗脱对映异构体(17.56min)定义为对映异构体B(12.4mg,9%产率)。1H NMR(500MHz,DMSO-d6)δ9.37(s,1H),8.65(s,1H),8.58(d,J=2.9Hz,1H),8.29(s,1H),7.98(br.s.,1H),7.72(td,J=8.8,2.9Hz,1H),7.54(dd,J=8.8,4.4Hz,1H),6.33-6.26(m,1H),4.00(s,3H),2.65-2.58(m,2H),1.55(s,3H),1.51(s,3H),1.34-1.20(m,1H),1.11-0.97(m,1H),0.88(t,J=7.2Hz,3H)。LC/MS(M+H)=477.20。
实施例359及360
2-{8-[1-(3-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇
根据就2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[1-(吡啶-2-基)丁基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇所描述的程序制备2-{8-[1-(3-氟吡啶-2-基)丁基]-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇的对映异构体A及B。对映异构体A及B使用手性制备型SFC(柱:Lux Cellulose-2 21×250mm 5μ;流动相:25%乙醇/CO2;流速:60mL/min;压力:100巴;温度:35℃)分离。将第一洗脱对映异构体(15.5min)定义为对映异构体A(5.1mg,3%产率)且将第二洗脱对映异构体(23.0min)定义为对映异构体B(5.2mg,3%产率)。1H NMR(500MHz,DMSO-d6)δ9.35(s,1H),8.66(s,1H),8.58(d,J=4.4Hz,1H),8.35(s,1H),8.05(s,1H),7.69(t,J=8.8Hz,1H),7.54-7.49(m,1H),6.54-6.47(m,1H),4.02(s,3H),2.74-2.63(m,1H),1.55(s,3H),1.50(s,3H),1.36(d,J=7.0Hz,2H),1.07(d,J=7.3Hz,2H),0.89(t,J=7.3Hz,3H)。LC/MS(M+H)=477.25。
实施例361
2-{12-氟-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基}丙-2-醇
步骤1:5-溴-6’-氯-5’-氟-3-硝基-2,3’-联吡啶
向烧瓶中装入2,5-二溴-3-硝基吡啶(1.608g,5.70mmol)及(6-氯-5-氟吡啶-3-基)硼酸(1.0g,5.7mmol)。用氮气冲洗烧瓶30min。向其中添加四氢呋喃(17.5mL),然后添加2M磷酸三钾水溶液(5.7mL,11.4mmol)。搅拌所得混合物同时使氮气鼓泡通过混合物30min。向其中添加PdCl2(dppf)2.DCM(0.163g,0.200mmol)。将烧瓶密封且浸在温度为75℃的砂浴中。将反应混合物保持在该温度2h,然后缓慢冷却至环境温度。将反应混合物倾入水与EtOAc的搅拌混合物中。分离各层。有机相再先后用水和盐水洗涤两次且浓缩。快速色谱(0→20%EA/己烷)得到1.0g(53%)。LCMS(M+H)=332.5,TR=1.698min(柱:Phenomenex LUNAC18,30×2,3μ;流动相A:90:10水:乙腈及0.1%TFA;流动相B:10:90水:乙腈及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B且保持1min;流速:1mL/min)。
步骤2:3-溴-7-氯-8-氟-5H-吡咯并[2,3-b:4,5-b’]二吡啶
向100mL烧瓶中装入5-溴-6’-氯-5’-氟-3-硝基-2,3’-联吡啶(1.0g,3.0mmol)及1,2-二(二苯基膦基)乙烷(1.5g,3.8mmol)且用氮气冲洗。将固体混悬于1,2-二氯苯(12mL)中且在氮气气流下搅拌15min。将烧瓶密封且浸于在165℃预加热的油浴中3h。将反应混合物冷却至室温且通过过滤收集析出物。弃去母液。在DCM下搅拌固体且通过过滤收集,得到400mg(44%)。LCMS(M+H)=300.15,TR=1.413min(柱:Phenomenex LUNA C18,2×30,3μ;流动相A:95:5水:乙腈及10mM乙酸铵;流动相B:5:95水:乙腈及10mM乙酸铵;温度:40℃;梯度:历经2min 0-100%B且保持1min;流速:1mL/min)。
步骤3:(S)-3-溴-7-氯-8-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶
向干燥瓶中装入3-溴-7-氯-8-氟-5H-吡咯并[2,3-b:4,5-b’]二吡啶(385mg,1.28mmol)、三苯基膦(672mg,2.56mmol)及(R)-苯基(四氢-2H-吡喃-4-基)甲醇(493mg,2.56mmol)。将混合物溶解于THF(12mL)中且冷却至0℃。逐滴添加偶氮二甲酸二叔丁酯(590mg,2.56mmol)/0.5mL THF。将反应混合物逐渐升温至室温过夜。浓缩反应混合物且通过快速色谱纯化,得到840mg(定量)含有偶联副产物的白色泡沫状固体。LCMS(M+H)=474.75,TR=2.177min(柱:Phenomenex LUNA C18,2×30,3μ;流动相A:95:5水:乙腈及10mM乙酸铵;流动相B:5:95水:乙腈及10mM乙酸铵;温度:40℃;梯度:历经2min0-100%B且保持1min;流速:1mL/min)。
步骤4:(S)-1-(7-氯-8-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)乙-1-酮
向烧瓶中装入(S)-3-溴-7-氯-8-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(406mg,0.855mmol)及DMF(8mL)。溶液用氮气气流脱气且用三丁基(1-乙氧基乙烯基)锡烷(618mg,1.71mmol)、三乙胺(0.178mL,1.28mmol)、CuI(16.3mg,0.086mmol)及Pd(PPh3)4(49.4mg,0.043mmol)处理。在搅拌下将反应混合物升温至100℃。4.5h后,冷却反应混合物至室温,用EtOAc稀释且用水及盐水洗涤。浓缩有机层。将残余物溶解于10mL THF中,用5mL 3M HCl处理且在室温搅拌1h。用15mL K2CO3水溶液(5%溶液)淬灭反应混合物且用EtOAc稀释。分离有机层,用盐水洗涤,经MgSO4干燥,过滤且浓缩。所得残余物通过快速色谱(0→40%EA/己烷)纯化,得到120mg(32%)。LCMS(M+H)=438.33,TR=1.897min(柱:Phenomenex LUNA C18,2×30,3μ;流动相A:95:5水:乙腈及10mM乙酸铵;流动相B:5:95水:乙腈及10mM乙酸铵;温度:40℃;梯度:历经2min 0-100%B且保持1min;流速:1mL/min)。
步骤5:(S)-2-(7-氯-8-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)丙-2-醇
在氮气下在-20℃向(S)-1-(7-氯-8-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)乙-1-酮(100mg,0.228mmol)于THF(2.3mL)中的搅拌的溶液中添加甲基溴化镁(3M于乙醚中,2.3mL,6.9mmol)。在该温度搅拌反应混合物1h。仍在-20℃用氯化铵饱和水溶液(6mL)淬灭反应混合物且用乙酸乙酯(14mL)稀释。将混合物升温至环境温度。分离各层且用第二份乙酸乙酯(7mL)洗涤水相。浓缩合并的有机相。所得残余物通过快速色谱(约50%EA/己烷)纯化,得到97mg(94%)。LCMS(M+H)=454.2,TR=1.602min(柱:Phenomenex LUNA C18,30×2,3μ;流动相A:90:10水:乙腈及0.1%TFA;流动相B:10:90水:乙腈及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B且保持1min;流速:1mL/min)。
步骤6:2-{12-氟-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基}丙-2-醇
向2mL微波瓶中装入(S)-2-(7-氯-8-氟-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)丙-2-醇(35.0mg,0.077mmol)、4-(2H3)甲基-1-((三甲基硅烷基)甲基)-1H-1,2,3-三唑(39.9mg,0.231mmol)、四甲基乙酸铵(12.3mg,0.093mmol)及DMF(1.5mL)。所得混合物用氮气气流脱气。向其中添加PdCl2(PPh3)2(5.4mg,7.7μmol)。用氮气冲洗瓶且在搅拌下在110℃加热5h。反应混合物通过制备型HPLC(柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及0.1%三氟乙酸;流动相B:95:5乙腈:水及0.1%三氟乙酸;梯度:历经25min 20-80%B且然后在100%B保持5min;流速:20mL/min)纯化,得到20mg(50%产率)。1H NMR(500MHz,DMSO)δ8.77(s,1H),8.69(d,J=9.54Hz,1H),8.45(s,1H),7.70(m,2H),7.30(m,2H),7.24(m,1H),5.87(m,1H),4.17(s,3H),3.87(m,1H),3.74(m,1H),3.21(m,1H),2.55(m,2H),1.61(s,6H),1.50(m,2H),1.27(m,1H),1.10(m,1H);LCMS(M+H)=517.6。
实施例362及363
2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇
步骤1:5-溴-6’-氯-3-硝基-2,3’-联吡啶
在配备有磁性搅拌棒的75mL压力烧瓶中添加(6-氯吡啶-3-基)硼酸(1g,6.35mmol)、2,5-二溴-3-硝基吡啶(1.791g,6.35mmol)。将固体混悬于THF(30mL)中。混合物用PdCl2(dppf)-CH2Cl2加合物(0.259g,0.318mmol)及K3PO4(9.53mL,19.06mmol)(25gK3PO4/60mL水=2M溶液)处理。使氩气鼓泡通过混合物5min同时超声波处理。将烧瓶盖好且在预加热的油浴中加热至80℃且保持2小时。冷却反应容器至室温。过滤反应混合物且浓缩滤液以除去有机溶剂。用水稀释剩余的水层且用乙酸乙酯萃取(形成乳液且添加盐水)。有机层经MgSO4干燥,过滤且浓缩,得到固体。将物质吸收于DCM及乙酸乙酯中。通过快速柱色谱(80g硅胶ISCO,0-50%乙酸乙酯/己烷(600mL总溶剂),然后50-100%(300mL溶剂);TLCRf=0.88(50%乙酸乙酯/己烷))纯化溶液。浓缩类似的级份,得到660mg(33%)浅黄色固体,其纯度为99%(通过LC/MS)。LC/MS(M+H)=315.9;HPLC条件:TR=3.43min(PhenomenexLUNA C18 2×50mm,4min梯度,用含有0.1%TFA的10-90%MeOH水溶液洗脱,0.8mL/min,在254nm监测,温度:40℃)。
步骤2:3-溴-7-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶及3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶
在配备有磁性搅拌棒的圆底烧瓶中添加5-溴-6’-氯-3-硝基-2,3’-联吡啶(4.5g,14.3mmol)及二(二苯基膦基)乙烷(7.13g,17.9mmol)。将固体混悬于1,2-二氯苯(16.1mL,143mmol)中。用氮气冲洗烧瓶且在搅拌下加热反应混合物至150℃(油浴)。使反应在敞开于空气的情况下继续1h。通过在氮气气流下蒸发除去大部分溶剂同时加热至100℃。用100mL二氯甲烷稀释反应混合物且在室温搅拌过夜。形成白色析出物且通过过滤用额外的二氯甲烷洗涤固体除去。所过滤的该物质(2.08g,52%)为3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶:1H NMR(400MHz,DMSO-d6)δ12.47(br.s.,1H),8.68-8.57(m,2H),8.19(d,J=1.8Hz,1H),7.42(d,J=8.3Hz,1H)。浓缩含有另一种异构体及多种杂质的剩余滤液以除去剩余的1,2-二氯苯。除去溶剂(氮气气流及在100℃加热)后,将油状残余物吸收于50mL乙酸异丙酯中且在室温搅拌混合物几小时。过滤棕色固体。真空浓缩滤液,得到油状物。将该油状物吸收于DCM中且转移至40g ISCO硅胶柱的顶部以纯化。物质用5-100%THF/己烷(800mL总体积)洗脱。合并类似的级份(通过LC/MS鉴定;双点,通过TLC(Rf=0.64/0.73,30%THF/己烷))且真空浓缩,得到600mg(15%)呈灰白色固体状的3-溴-7-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶。1H NMR(400MHz,CDCl3)δ1封端0.45(br,s.,1H),9.33(s,1H),8.69(d,J=1.8Hz,1H),8.04(d,J=1.8Hz,1H),7.29(s,1H)。
步骤3:(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲醇
在环境温度向镁(466mg,19.2mmol)及一个碘晶体于THF(26mL)中的搅拌的混悬液中逐滴添加4-溴氧杂环己烷(3.17g,19.2mmol)。搅拌反应混合物30min,然后将其冷却至0℃。逐滴添加3-氟吡啶-2-甲醛(1.20g,9.59mmol)。然后搅拌反应混合物30min。用氯化铵饱和水溶液(40mL)淬灭反应混合物且用乙酸乙酯(100mL)及水(30mL)稀释。将产物萃取至有机相中,然后分离各层。用第二份乙酸乙酯(50mL)洗涤水层且经硫酸钠干燥合并的有机相。减压除去挥发物。使用硅胶柱色谱纯化粗反应物质。分离呈无色油状物的(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲醇(1.47g,6.96mmol,73%产率)。1H NMR(400MHz,CDCl3)δ8.40-8.45(m,1H),7.40-7.46(m,1H),7.27-7.33(m,1H),4.83-4.88(m,1H),4.00(td,J=2.14,11.37Hz,2H),3.36(ddt,J=2.20,9.23,11.77Hz,2H),1.90-2.03(m,1H),1.65-1.78(m,1H),1.57(dq,J=4.65,12.47Hz,1H),1.39-1.49(m,2H)。
步骤4:5-溴-11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯
在0℃向3-溴-7-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶(200mg,0.71mmol)、(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲醇(224mg,1.06mmol)、三苯基膦(279mg,1.06mmol)及Et3N(148μL,1.06mmol)于THF(7.1mL)中的搅拌的溶液中逐滴添加偶氮二甲酸二叔丁酯(245mg,1.06mmol)/THF(7.0mL)。历经10min将反应混合物升温至环境温度且在该温度再搅拌16h。将粗反应混合物加载至硅胶柱上且使用乙酸乙酯/己烷(0-100%)纯化。分离呈白色固体状的外消旋5-溴-11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯(337mg,0.71mmol,>100%产率)及少量的氧化三苯基膦污染物。LC/MS(M+H)=475.05;LC/MS TR=2.052min(柱:PhenomenexLuna 30×2.0mm 3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min)。物质不经额外纯化即使用。
步骤5:2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇
将5-溴-11-氯-8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯(337mg,0.71mmol)、三丁基(1-乙氧基乙烯基)锡(512mg,1.42mmol)、四(三苯基膦)钯(82.0mg,0.07mmol)、碘化亚铜(I)(27.0mg,0.14mmol)及三乙胺(128μL,0.92mmol)/DMF(3.5mL)用氮气脱气3min。然后在100℃搅拌反应混合物3h。LC/MS显示转化成烯醇醚。添加1N HCl水溶液(2mL)且搅拌反应混合物20min。用1.5M磷酸二氢钾水溶液(5mL)淬灭反应混合物且分离各层。用乙酸乙酯(3×10mL)洗涤水层。经硫酸钠干燥合并的有机相。滤除固体且减压除去挥发物。粗产物使用硅胶柱色谱用乙酸乙酯/己烷(0-100%)纯化。分离2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇(161mg,0.37mmol,52%产率)。LC/MS(M+H)=439.15;LC/MS TR=1.701min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min)。
步骤6:2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇
将2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇(160mg,0.37mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(184mg,0.47mmol)、Pd2(dba)3(66.8mg,0.07mmol)、三环己基膦(227μL,0.15mmol,20%wt于甲苯中)及碳酸铯(238mg,0.73mmol)/二噁烷(3.6mL)用氮气脱气3min。然后在115℃搅拌反应混合物3h。减压除去挥发物且粗反应混合物不经纯化即用于下一步。推定100%产率。LC/MS(M+H)=503.30;LC/MS TR=1.465min(柱:Phenomenex Luna 30×2.0mm3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min)。
步骤7:2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇
在氮气下在-20℃向2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇(180mg,0.36mmol)于THF(3.6mL)中的搅拌的溶液中添加甲基溴化镁(3.58mL,10.8mmol,3M)。在该温度搅拌反应混合物1h。然后仍在-20℃用氯化铵饱和水溶液(8mL)淬灭反应混合物且用乙酸乙酯(20mL)稀释。由冷浴取出混合物且升温至环境温度。分离各层且用第二份乙酸乙酯(20mL)洗涤水相。经硫酸钠干燥合并的有机相,滤除固体且减压除去挥发物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经22min 5-45%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到外消旋2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇。对映异构体A及B使用手性制备型HPLC(柱:Chiralpak AD 21×250mm 5μ;流动相:10%乙醇/庚烷;流速:15mL/min)分离。将第一洗脱对映异构体(30min)定义为对映异构体A(15.0mg,8%产率)且将第二洗脱对映异构体(35min)定义为对映异构体B(16.0mg,8%产率)。1H NMR(500MHz,DMSO-d6)δ8.74-8.68(m,2H),8.60(d,J=4.4Hz,1H),8.50(d,J=1.5Hz,1H),7.70-7.63(m,2H),7.51-7.46(m,1H),6.59(d,J=9.5Hz,1H),5.37(s,1H),4.37(s,3H),3.87(d,J=10.6Hz,1H),3.69(d,J=9.5Hz,1H),3.54-3.29(m,2H),3.23-3.11(m,1H),1.72(d,J=11.4Hz,1H),1.57-1.51(m,6H),1.47(d,J=8.1Hz,1H),1.29-1.18(m,1H),0.77(d,J=14.3Hz,1H);LC/MSTR=1.220min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min0-100%B;流速:1mL/min)。
实施例364
2-{11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇
步骤1:5-溴-11-氯-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯
在0℃向3-溴-7-氯-5H-吡咯并[3,2-b:4,5-c’]二吡啶(按照2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇制备,79.0mg,0.28mmol)、(S)-(氧杂环己烷-4-基)(苯基)甲醇(81.0mg,419μmol)、三苯基膦(110mg,419μmol)及Et3N(58.5μL,419μmol)于THF(2.8mL)中的搅拌的溶液中逐滴添加偶氮二甲酸二叔丁酯(97.0mg,419μmol)/THF(2.8mL)。历经10min将反应混合物升温至环境温度且在该温度再搅拌5h。将粗反应混合物加载至硅胶柱上且使用乙酸乙酯/己烷(0-100%)纯化。分离呈白色固体状的5-溴-11-氯-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯(24.4mg,19%产率)。LC/MS(M+H)=456.10;LC/MS TR=1.818min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min)。
步骤2:1-{11-氯-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}乙-1-酮
将5-溴-11-氯-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯(35.0mg,0.08mmol)、三丁基(1-乙氧基乙烯基)锡(55mg,0.15mmol)、四(三苯基膦)钯(8.9mg,8μmol)、碘化亚铜(I)(2.9mg,15μmol)及三乙胺(14μL,0.10mmol)/DMF(380μL)用氮气脱气3min。然后在100℃搅拌反应混合物5h。LC/MS显示转化成烯醇醚。添加1N HCl水溶液(2mL)且搅拌反应混合物20min。用1.5M磷酸二氢钾水溶液(5mL)淬灭反应混合物且分离各层。用乙酸乙酯(3×10mL)洗涤水层。经硫酸钠干燥合并的有机相。滤除固体且减压除去挥发物。粗产物使用硅胶柱色谱用乙酸乙酯/己烷(0-100%)纯化。分离呈浅黄色油状物的1-{11-氯-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}乙-1-酮(32.2mg,0.08mmol,>100%产率)及一些氧化三苯基膦杂质。LC/MS(M+H)=420.05;LC/MSTR=1.602min(柱:Phenomenex Luna 30×2.0mm3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min)。
步骤3:1-{11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}乙-1-酮
将1-{11-氯-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}乙-1-酮(32.0mg,0.08mmol)、4-(2H3)甲基-1-甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(38.6mg,0.10mmol)、Pd2(dba)3(14.0mg,15μmol)、三环己基膦(47.5μL,0.03mmol,20%wt于甲苯中)及碳酸铯(49.7mg,0.15mmol)/二噁烷(760μL)用氮气脱气3min。然后在115℃搅拌反应混合物5h。减压除去挥发物且粗反应混合物不经纯化即用于下一步。推定100%产率。
步骤4:2-{11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇
在氮气下在-20℃向1-{11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}乙-1-酮(37.0mg,0.08mmol)于THF(765μL)中的搅拌的溶液中添加甲基溴化镁(765μL,2.30mmol,3M)。在该温度搅拌反应混合物1h。然后仍在-20℃用氯化铵饱和水溶液(8mL)淬灭反应混合物且用乙酸乙酯(20mL)稀释。由冷浴取出混合物且升温至环境温度。分离各层且用第二份乙酸乙酯(20mL)洗涤水相。经硫酸钠干燥合并的有机相,滤除固体且减压除去挥发物。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及0.1%TFA;流动相B:95:5乙腈:水及0.1%TFA;梯度:历经20min 8-48%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥,得到2-{11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇(4.5mg,12%产率)。1H NMR(500MHz,DMSO-d6)δ9.49(s,1H),8.80(s,1H),8.51(br.s.,1H),8.17(br.s.,1H),7.67(d,J=7.70Hz,2H),7.33-7.40(m,2H),7.25-7.31(m,1H),7.22(s,1H),7.12(s,1H),7.02(s,1H),5.92(d,J=11.00Hz,1H),4.18(s,3H),3.91(d,J=5.14Hz,1H),3.73(d,J=9.54Hz,1H),3.26(t,J=11.00Hz,1H),1.73(d,J=12.84Hz,1H),1.65-1.53(m,7H),1.38-1.27(m,1H),0.95(d,J=12.10Hz,1H)。LC/MS(M+H)=500.35;LC/MS TR=1.188min(柱:Phenomenex Luna 30×2.0mm 3μ;流动相A:10:90乙腈:水及0.1%TFA;流动相B:90:10乙腈:水及0.1%TFA;温度:40℃;梯度:历经2min 0-100%B;流速:1mL/min)。
实施例365-376
由市售原料或根据针对2-{8-[(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇或2-{11-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-(氧杂环己烷-4-基)(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-5-基}丙-2-醇所描述的类似程序制备的中间体制备表4中的化合物:
表4
a用于表4的HPLC条件:方法A:柱:Chiralcel OD 4.6×100mm 5μ;流动相A:100%庚烷及0.1%二甲胺;流动相B:100%乙醇;梯度:20%B;流速:2mL/min。方法B:柱:Chiralcel OD 21×250mm 10μ;流动相A:100%庚烷;流动相B:100%乙醇;梯度:15%B;流速:15mL/min。方法C:柱:Phenomenex 2×30mm 3μ;流动相A:90%水及10%乙腈及0.1%TFA;流动相B:10%水及90%乙腈及0.1%TFA;梯度:历经2min 0-100%B;流速:1mL/min。方法D:柱:Chiralpak AD 21×250mm 5μ;流动相A:100%庚烷;流动相B:100%乙醇;梯度:13%B;流速:15mL/min。方法E:柱:Chiralcel OJ 21×250mm 10μ;流动相A:庚烷;流动相B:100%乙醇;梯度:20%B;流速:15mL/min。方法F:柱:Chiralpak AD 21×250mm 5μ;流动相A:100%庚烷;流动相B:100%乙醇;梯度:5%B;流速:15mL/min。
实施例377
1-[11-(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基]乙-1-酮
步骤1:5-溴-11-氯-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向3-溴-7-氯-5H-吡咯并[2,3-b:4,5-b’]二吡啶(104mg,0.368mmol)及(S)-苯基(四氢-2H-吡喃-4-基)甲醇(92mg,0.479mmol)于4mL DCM中的混悬液中添加三苯基膦(193mg,0.736mmol)。冷却所得混合物至0℃。向其中添加DIAD(149mg,0.736mmol)。5min后,移开冰浴且在室温继续搅拌过夜。浓缩反应混合物且在Biotage上使用40g柱用2-30%EtOAc/己烷洗脱纯化,得到产率为91%的所需产物。LC/MS[M+H]+=456(三重峰)。
步骤2:1-{11-氯-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基}乙-1-酮
将(R)-3-溴-7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(93mg,0.204mmol)、三丁基(1-乙氧基乙烯基)锡烷(147mg,0.407mmol)、CuI(3.88mg,0.020mmol)、三乙胺(30.8mg,0.305mmol)及Pd(PPh3)4(11.8mg,10.2μmol)称重至20mL闪烁瓶中,然后添加DMF(2mL)。用氩气代替空气且在搅拌下加热混合物至100℃。1h后,添加另一份三丁基(1-乙氧基乙烯基)锡烷(147mg,0.407mmol)且继续加热直至原料耗尽。冷却反应混合物至室温,用EtOAc稀释且用盐水洗涤。浓缩有机层,溶解于10mL THF中且用2mL 3M HCl溶液处理。在室温搅拌1h后,用15mL K2CO3水溶液(5%溶液)淬灭反应混合物且用EtOAc稀释。分离有机层,用盐水洗涤,经MgSO4干燥,过滤且浓缩。对粗混合物进行用5-100%EtOAc/己烷洗脱的快速色谱(24g柱),得到产率为61%的所需产物。LC/MS[M+H]+=420。
步骤3:1-[11-(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基]乙-1-酮
将(R)-1-(7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)乙酮(30.0mg,0.071mmol)、1,4-二甲基-1H-1,2,3-三唑(10.4mg,0.107mmol)、四甲基乙酸铵(11.4mg,0.086mmol)及PdCl2(PPh3)2(5.0mg,7.1μmol)称重至20mL闪烁瓶中。添加DMF(2mL)且用氮气代替空气。在100℃搅拌反应混合物过夜。冷却反应混合物至室温,用EtOAc稀释且用盐水洗涤两次。经MgSO4干燥有机层且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95甲醇:水及10mM乙酸铵;流动相B:95:5甲醇:水及10mM乙酸铵;梯度:历经20min50-90%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为84%。LC/MS[M+H]+=481。1H NMR(500MHz,DMSO-d6)δ9.13(s,1H),8.84(d,J=8.1Hz,2H),7.72(d,J=8.1Hz,3H),7.33-7.28(m,2H),7.25-7.21(m,1H),6.04(br.s.,1H),4.34(s,3H),3.89(d,J=10.3Hz,1H),3.72(d,J=9.2Hz,1H),3.58(br.s.,1H),3.51(s,3H),3.46-3.39(m,1H),3.25-3.15(m,1H),2.78(s,3H),1.59(br.s.,1H),1.51(d,J=8.8Hz,1H),1.31(d,J=10.3Hz,1H),1.07(d,J=14.3Hz,1H)。
实施例378
2-[11-(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基]丙-2-醇
将(R)-1-(7-(1,4-二甲基-1H-1,2,3-三唑-5-基)-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)乙酮(18.0mg,0.037mmol)溶解于5mL THF中且冷却至0℃。向其中添加甲基溴化镁(3M于乙醚中,0.187mL,0.562mmol)。5min后,移开冰浴且搅拌反应混合物过夜。通过添加1mL丙酮淬灭反应混合物且用15mL EtOAc稀释。其用盐水洗涤且有机层经MgSO4干燥,过滤且浓缩。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及0.1%三氟乙酸;流动相B:95:5乙腈:水及0.1%三氟乙酸;梯度:历经20min 20-60%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为69%。LC/MS[M+H]+=497。1H NMR(500MHz,DMSO-d6)δ8.72(d,J=7.7Hz,1H),8.36(br.s.,2H),7.71-7.61(m,3H),7.32-7.27(m,2H),7.26-7.20(m,1H),5.93(br.s.,1H),4.32(s,3H),3.88(d,J=9.9Hz,1H),3.73(d,J=8.4Hz,1H),3.62(s,3H),3.42(t,J=11.4Hz,1H),3.22(t,J=11.6Hz,1H),2.91-2.90(m,4H),1.58(br.s.,7H),1.47(d,J=12.1Hz,1H),1.30-1.20(m,2H),1.09(br.s.,1H)。
实施例379及380
根据针对2-[11-(二甲基-1H-1,2,3-三唑-5-基)-8-[(R)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基]丙-2-醇所描述的程序制备表5中的化合物:
表5
a用于表5的HPLC方法A条件:柱:Waters BEH C18,2.0×50mm,1.7μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;温度:50℃;梯度:历经3分钟0-100%B且然后在100%B保持0.5分钟;流速:1.0mL/min;检测:UV 220nm。
实施例381
4-[11-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基]-1λ6,4-硫吗啉-1,1-二酮
步骤1:(S)-4-(7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)硫吗啉1,1-二氧化物
将(S)-3-溴-7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶(60.0mg,0.131mmol)、硫吗啉1,1-二氧化物(26.6mg,0.197mmol)、RuPhos(4.9mg,10.5μmol)、Pd(OAc)2(1.5mg,6.57μmol)及Cs2CO3(171mg,0.525mmol)溶解于2mL二噁烷中且在微波中在115℃加热1.5h。用EtOAc稀释样品,用盐水洗涤,浓缩且通过快速色谱(24g硅胶柱,用0-10%MeOH/EtOAc洗脱)纯化,得到38%产率。LC/MS[M+H]+=511。1H NMR(500MHz,DMSO-d6)δ8.46-8.39(m,2H),7.88(br.s.,1H),7.78(d,J=7.3Hz,2H),7.38-7.29(m,3H),7.27-7.23(m,1H),5.70(d,J=11.0Hz,1H),4.01(br.s.,4H),3.89(d,J=13.2Hz,1H),3.76(d,J=11.0Hz,1H),3.60(br.s.,1H),3.54-3.47(m,1H),3.41(s,2H),3.24(br.s.,4H),1.53-1.36(m,2H),1.33-1.23(m,1H),1.08(d,J=11.0Hz,1H)。
步骤2:4-[11-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-5-基]-1λ6,4-硫吗啉-1,1-二酮
向20mL闪烁瓶中添加(S)-4-(7-氯-5-(苯基(四氢-2H-吡喃-4-基)甲基)-5H-吡咯并[2,3-b:4,5-b’]二吡啶-3-基)硫吗啉1,1-二氧化物(17mg,0.033mmol)、1,4-二甲基-5-(三丁基锡烷基)-1H-1,2,3-三唑(14.1mg,0.037mmol)及2mL二噁烷。然后添加Pd(dppf)2Cl2.DCM(2.7mg,3.3μmol)。用氩气代替空气且将瓶密封。将其在微波中加热至140℃,在该温度保持0.5h且过滤。经由制备型LC/MS在以下条件下纯化滤液:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水及10mM乙酸铵;流动相B:95:5乙腈:水及10mM乙酸铵;梯度:历经20min 40-100%B且然后在100%B保持5min;流速:20mL/min。合并含有所需产物的级份且经由离心蒸发干燥。产物的产率为35%。LC/MS[M+H]+=572。1H NMR(500MHz,DMSO-d6)δ8.55(d,J=8.1Hz,1H),8.45(s,1H),7.85(br.s.,1H),7.73(d,J=7.3Hz,2H),7.57(d,J=8.1Hz,1H),7.34-7.27(m,2H),7.25-7.19(m,1H),5.85(br.s.,1H),4.31(s,3H),4.02(br.s.,4H),3.93-3.86(m,1H),3.75(d,J=9.2Hz,1H),3.63(br.s.,1H),3.43(d,J=11.4Hz,1H),3.40-3.33(m,1H),3.31-3.16(m,5H),1.56(br.s.,1H),1.50-1.41(m,1H),1.30(d,J=11.4Hz,1H),1.13(d,J=11.4Hz,1H)。
生物活性评估
测试示例性化合物对BRD2、BRD3、BRD4及BRDT活性的抑制。以下提供实验程序及结果。
用于热转移测定(TSA)的人布罗莫结构域的克隆、表达及纯化
编码人类蛋白的布罗莫结构域的重组DNA克隆针对大肠杆菌(E.coli)表达进行优化,经化学合成(GenScript,Piscataway NJ)且插入到经修饰的pET28表达载体中以构建烟草脉斑驳病毒(TVMV)蛋白酶可裂解的N-末端六聚组氨酸融合体。紧随非天然氨基酸(MGSSHHHHHHSSGETVRFQSM)(SEQ ID NO:1)的是具有以下氨基酸残基序列(其后为参考Uniprot Knowledgebase且根据其进行编号的登记号;Uniprot Consortium;www.uniprot.org)的布罗莫结构域蛋白:CECR2(420-543),Q9BXF3-1;FALZ(2917-3037),Q12830-1;GCN5(731-837),Q92830-1;PCAF(715-831),Q92831-1;BRD2(24-472),P25440-1;BRD3(1-434),Q15059-1;BRD4(44-168),BRD4(333-460),BRD4(44-460),O60885-1;BRDT(1-383),Q58F21-1;BAZ1B(1340-1457),Q9UIG0-1;CREBBP(1081-1197),Q92793-1;EP300(1040-1161),Q09472-1;WDR9(1310-1430),Q9NSI6-1;ATAD2(981-1108),Q6PL18-1;BRD1(556-688),O95696-1;BRD7(129-236),Q9NPI1-1;BRD9(134-239),Q9H8M2-1;BRPF1(626-740),P55201-2;ATAD2B(952-1086),Q9ULI0-1;BAZ2B(2054-2168),Q9UIF8-1;SP140L(400-580),Q9H930-4;SP140(687-862),Q13342-1;TIF1(896-1014),O15164-1;TRIM28(619-805),Q13263-1;BRWD3(1295-1443),Q6RI45-1;TAF1(1377-1503),TAF1(1501-1635),P21675-1;TAF1L(1402-1522),TAF1L(1523-1654),Q8IZX4-1;ASH1L(2433-2564),Q9NR48-1;PB1(43-156),PB1(178-291),PB1(388-494),PB1(645-766),PB1(773-917),Q86U86-1;SMARCA2(1367-1511),P51531-1;SMARCA2-2(1367-1493),P51531-2。
将重组载体转化到大肠杆菌BL21(DE3)中。经转化的细胞在2.5L Thomson UltraYield震荡烧瓶中在1L Terrific Broth中在37℃以230rpm在细胞密度为OD600nm=1.0的情况下培养,用0.5mM IPTG诱导且在震荡器中在20℃孵育16-18小时。通过沉降收获细胞团块且在含有0.1mg/ml溶菌酶的缓冲液中通过超声波处理进行溶胞。通过沉降使每个样品澄清且将上清液加载到HisTrap亲和柱(GE Healthcare Life Sciences)上。洗涤柱且然后用咪唑梯度洗脱。汇集含有布罗莫结构域蛋白的峰蛋白级份,浓缩且蛋白质通过在用最终储存缓冲液(20mM Tris-HCl(pH 8.0)、200mM NaCl、5%甘油、2mM DTT)平衡的Superdex 200柱(GE Healthcare Life Sciences)上进行的尺寸排阻色谱进一步纯化。以2-5mg/ml汇集含有经纯化的蛋白质的SEC峰级份且将汇集物分成等分试样,在液氮中快速冷冻且储存于-80℃。
用于TR-FRET测定的生物素化人布罗莫结构域的克隆、表达及纯化
编码人BRD2、BRD3、BRD4及BRDT的布罗莫结构域的重组DNA克隆针对大肠杆菌表达进行优化,经化学合成(GenScript,Piscataway NJ)且插入到经修饰的pET28表达载体中以构建烟草脉斑驳病毒(TVMV)蛋白酶可裂解的N-末端六聚组氨酸融合体,其后为大肠杆菌生物素接合酶(BirA)所识别的位点特异性生物素化基序。紧随非天然氨基酸(MGSSHHHHHHSSGETVRFQGLNDIFEAQKIEWHEDTGHM)(SEQ ID NO:2)的是具有以下氨基酸残基序列(其后为参考Uniprot Knowledgebase且根据其进行编号的BRD4登记号;Uniprot Consortium;www.uniprot.org)的BRD4的布罗莫结构域构建体:BRD4(44-168),BRD4(333-460),BRD4(44-460),BRD4(1-477),O60885-1。
在氯霉素选择下将每种重组载体与编码BirA的质粒一起共转化到大肠杆菌BL21STAR(DE3)中。经转化的细胞在37℃在含有1L M9-CAS培养基(Teknova)(补充有40μg/ml卡那霉素、35μg/ml氯霉素及100μM生物素)的2.5L Thomson Ultra Yield震荡烧瓶中培养。培养物以与OD600nm=0.6相应的细胞密度用0.5mM IPTG诱导且在震荡器中在20℃再孵育20小时。通过沉降收获细胞团块且在含有0.1mg/ml溶菌酶的缓冲液中通过超声波处理进行溶胞。通过沉降使每个样品澄清且将上清液加载到HisTrap亲和柱上。洗涤柱且然后用咪唑梯度洗脱。汇集含有布罗莫结构域蛋白的峰蛋白级份且在4℃与经纯化的His-TVMV蛋白酶(TVMV:BRD4蛋白的质量比为1:15)一起孵育18小时。将样品交换至低咪唑缓冲液中且流经HisTrap柱以捕获所裂解的His-标签及His-TVMV酶。流经HisTrap柱的蛋白质通过在Superdex 200柱上进行的尺寸排阻色谱进一步纯化且交换至最终储存缓冲液(PBS(pH7.0)、5%甘油、1mM DTT)中。为了改善纯度而使BRD4(1-477)及BRD4(44-460)蛋白在尺寸排阻色谱前接受额外的阳离子交换色谱纯化步骤。每种蛋白质基本上定量的单生物素化(+226Da)通过对最终样品进行电喷雾离子化质谱分析来确认。将经纯化的样品分成等分试样,在液氮中快速冷冻且储存于-80℃。
时间分辨荧光共振能量转移(TR-FRET)测定
使用时间分辨荧光共振能量转移结合测定(1)评定化合物与布罗莫结构域BRD4(44-168)、BRD4(333-460)及BRD4(1-477或44-460)的结合,该测定测量经荧光标记的探针分子与布罗莫结构域蛋白的结合。将布罗莫结构域蛋白、荧光探针分子(生物素化组蛋白肽或经荧光标记的小分子)及具有剂量响应的测试化合物一起孵育以达到热力学平衡。在不存在测试化合物的情况下使布罗莫结构域与小分子结合,这产生高荧光性信号。在存在足够浓度的抑制剂的情况下破坏此相互作用,这使荧光共振能量转移失去。
就BRD4(1-477及44-460)而言,将所有测定组分溶解于缓冲液组合物20mM Hepes(pH 7.5)、150mM NaCl、5mM DTT、0.005%Tween 20及100μg/ml BSA中。布罗莫结构域蛋白的最终浓度为1.6nM BRD4(44-168)、1nM BRD4(333-460)及1nM BRD4(1-477或44-460)且荧光探针分子分别为100nM、50nM及7.5nM。所有蛋白质均是生物素化的。用铽穴状化合物(Cisbio SA-Tb)标记的抗生蛋白链菌素用作检测物且与最终浓度为0.2nM的布罗莫结构域蛋白预混合。在就BRD4(44-460)而言的一些情况下,抗His铽穴状化合物用作检测物。将7.5nl具有剂量响应的测试化合物或DMSO媒介物(0.0375%)预点样于黑色Corning 384孔板中且将10μl每种布罗莫结构域/检测试剂及荧光小分子溶液添加至板中且在室温孵育反应混合物60分钟。然后板在EnVision读板器上读取(λ激发=340nm、受体λ发射=520nm且供体λ发射=615nm)(LANCE D400镜)。在两种发射波长测量时间分辨荧光强度且计算受体/供体的比例且用于数据分析。相对于16个高媒介物孔及8个低参比对照孔对所有数据进行归一化且然后应用四参数曲线拟合:
Y=a+((b-a)/(1+(10×/10c)d)
其中‘a’为最小值,‘b’为Hill斜率,‘c’为IC50且‘d’为最大值。
组蛋白肽:购自GenScript。
H4K5K8K12K16
生物素-AHA-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRKV(SEQ ID NO:3)
所使用的经荧光标记的小分子为本领域已知的BRD4抑制剂。
1.F.Degorce,A.Card,S.Soh,E.Trinquet,G.P.Knapik和B.Xie,HTRF:Atechnology tailored for drug discovery-a review of theoretical aspects andrecent applications.Current Chemical Genomics(2009)3,22-32。
热转移测定
使用BioRad CFX实时PCR仪通过监测外部探针(SYPRO橙色)的荧光增强来测量化合物结合对布罗莫结构域热稳定性的作用,这是因为其优先与解折叠的蛋白质结合。解折叠反应在384孔板中在4μL体积中进行,所述体积在含有10mM Hepes(pH 7.4)、500mM NaCl的缓冲液中具有2-8μM布罗莫结构域蛋白、1-2%(v/v)DMSO。以1:500的稀释度添加SYPRO橙色染料。化合物浓度为1.6-100μM。如下监测解折叠反应:首先将仪器在25℃平衡2.4秒,然后以0.5℃的增幅将温度由25℃升至95℃,其中每个温度在平衡60秒后读取。将用于SYPRO橙色染料的激发及发射滤波器设定为在450-490nm的激发范围及560-580nm的发射范围内进行FRET。中点温度通过使用二阶微分计算拐点来确定。将观测到的温度转移记录为含有蛋白质及DMSO但无配体的参比孔的中点与含有蛋白质及化合物的孔的中点的差异。
热转移测定为对在存在及不存在配体的情况下获得的蛋白质的解折叠转变温度的改变进行比较的生物物理技术(1)。荧光染料通常用于在加热蛋白质时监测蛋白质解折叠。在解折叠过程中,蛋白质的疏水性区域被暴露,这使染料结合增加且使荧光强度增加。将蛋白质解折叠转变的中点定义为Tm。与蛋白质结合的配体使蛋白质的热稳定性与配体浓度及其结合亲和力成比例地提高,这由此使Tm提高。
1.M.W.Pantoliano,E.C.Petrella,J.D.Kwasnoski,V.S.Lobanov,J.Myslik,E.Graf,T.Carver,E.Asel,B.A.Springer,P.Lane,F.R.Salemme,High-densityminiaturized thermal shift assays as a general strategy for drugdiscovery.J.Biomol.Screen 6(2001)429-440;
2.M.D.Cummings,M.A.Farnum,M.I.Nelen,Universal screening methods andapplication of ThermoFluor.J.Biomol.Screen 11(2006)854-863。
MYC HCS测定
收集补充有10%FBS的完全RPMI生长培养基(Gibco,11875-085)中的肿瘤细胞且在30μl培养基中以10,000个细胞/孔铺板于384孔黑色透明底PDL细胞培养板中。在37℃用化合物处理4小时后,将细胞在室温在4%甲醛中固定30分钟且然后进行渗透。洗涤且阻断后,接着将板在室温与抗MYC一级抗体1:1000(Cell Signaling Technology,5605)一起孵育过夜。第二天,洗涤细胞且阻断,然后在室温在黑暗中添加二级抗体Alexa 488山羊抗兔1:2000(Invitrogen,A11034)且保持1小时。然后洗涤细胞且在具有10倍物镜的CellomicsArrayScan上扫描。
MTS细胞增殖测定
将肿瘤细胞以某些接种密度以40μl/孔铺板于384孔黑色透明底部Matrix板中且在37℃在5%CO2中孵育过夜,然后进行测定。第二天,一组细胞板(T0板)用于确定零时细胞密度且将来自CellTiter 96AQueous非放射性细胞增殖试剂盒(Promega,G5440)的3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑鎓以4μl/孔添加至T0板中,然后在37℃在5%CO2中孵育三小时。在Envision读取器(Perkin Elmer,Boston,MA)上测量在490nm的吸光度。同一天,其余细胞板(T72板)在37℃在5%CO2中用化合物处理。72小时后,接着将4μl MTS试剂添加于这些细胞板中。将板在37℃在5%CO2中再孵育三小时且在Envision读取器上测量在490nm的吸光度。
小鼠中的人类肿瘤异种移植物模型
所有啮齿动物均获自Jackson Laboratory(Bar Harbor,Maine)且以所限定的无病原体群落保持在无氨环境中。将所有小鼠隔离约1周,然后将其用于肿瘤增殖及药物功效测试。小鼠随意进食及饮水。Bristol-Myers Squibb Pharmaceutical ResearchInstitute的动物管护程序得到American Association for Accreditation ofLaboratory Animal Care(AAALAC)的完全认可。所有实验均根据Bristol-Myers Squibb(BMS)动物测试方法及指南来进行。
肿瘤异种移植物在NSG(NOD scid IL2受体γ链敲除)小鼠(Jackson Lab)中皮下(SC)生长和维持。使用获自供体小鼠的肿瘤片段使肿瘤以皮下移植物形式增殖。
临床前化学疗法试验
实验开始时汇集检测到有意义的应答所需要的所需数目的动物且各自用13号套管针双侧皮下植入两个肿瘤片段(约20mg)。使肿瘤生长至预定尺寸窗(在该范围外的肿瘤被排除)且将动物均等地分到各个处置组及对照组中。每个处置组及对照组通常有8只小鼠。每只动物基于个体体重来处置。每天检查所处置的动物与处置相关的毒性/死亡。开始处置前对每组动物进行称重(Wt1)且然后在最后一次处置后再次称重(Wt2)。体重差(Wt2-Wt1)提供对与处置相关的毒性的度量。
肿瘤应答通过每周两次用测径规测量肿瘤来确定直至肿瘤达到0.5gm或1gm的预定“目标”尺寸(视肿瘤类型而定)。由以下公式评估肿瘤重量(mg):
肿瘤重量=(长度×宽度2)÷2
肿瘤应答标准通过肿瘤生长抑制(%TGI)来表示。将肿瘤生长延迟定义为经处置的肿瘤(T)达到预定目标尺寸所需要的时间(天数)与对照组的肿瘤(C)达到预定目标尺寸所需要的时间(天数)相比的差值。出于此目的,将一组的肿瘤重量表示为中值肿瘤重量(MTW)。
肿瘤生长抑制如下计算:
其中
Ct=处置结束时的中值对照肿瘤尺寸
C0=处置开始时的中值对照肿瘤尺寸
Tt=处置结束时处置组的中值肿瘤尺寸
T0=处置开始时处置组的中值肿瘤尺寸
将活性定义为在等于至少1个肿瘤体积倍增时间的时段对肿瘤生长实现持久的50%或更大(即TGI≥50%)的抑制且药物处置必须持续等于至少2个肿瘤体积倍增时间的时段。
肿瘤应答还通过肿瘤生长迟延来表示且表示为对数细胞杀死值(LCK值),其被定义为经处置的肿瘤(T)达到预定目标尺寸所需要的时间(天数)与对照组的肿瘤(C)达到预定目标尺寸所需要的时间(天数)相比的差值。
只要可能,就在上至最大耐受剂量(MTD)的剂量水平范围内确定抗肿瘤活性,而最大耐受剂量被定义为剂量水平恰低于出现过度毒性(即死亡多于一例)的剂量水平。当出现死亡时,记录死亡日。经处置的在肿瘤达到目标尺寸前死亡的小鼠视为由于药物毒性而死亡。肿瘤小于目标尺寸的对照小鼠均没有死亡。由于药物毒性而导致的死亡多于一例的处置组视为经历了具有过度毒性的处置且其数据不纳入到对化合物的抗肿瘤功效进行的评估中。
影响处置耐受性的潜在药物毒性相互作用为在组合化学疗法试验中需要考虑的重要因素。对组合治疗结果的解释必须基于在可比的耐受剂量下对单一药物与组合的最佳可能应答的抗肿瘤活性进行的比较。因此,将治疗协同性定义为用所组合的药物的耐受方案实现的治疗作用超过任何耐受剂量的单一疗法所实现的最佳作用。使用Gehan’sGeneralized Wilcoxon检验对数据进行统计学评估。p<0.05表示在统计学上具有显著性。
药物给药
为了将BET抑制剂给药于啮齿动物,将化合物溶解于90%PEG300/10%TPGS/10%乙醇中。BET抑制剂通常以QD×7或QD×10的时程(给药5天-停药2天)经口给药,尽管其它时程也已评估且证实是有效的。
如下显示的活性数据是基于使用所描述的FRET测定中的一种。IC50小于1500nM的化合物以(+)显示,IC50小于10nM的化合物以(++)显示且IC50小于1nM的化合物以(+++)显示。
NA=不可得。
序列表
<110> 百时美施贵宝公司
<120> 作为抗癌剂的三环化合物
<130> 12455
<160> 3
<170> PatentIn version 3.5
<210> 1
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<212> PRT
<213> 烟草脉斑驳病毒
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Met Gly Ser Ser His His His His His His Ser Ser Gly Glu Thr Val
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Arg Phe Gln Ser Met
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<210> 2
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<212> PRT
<213> 烟草脉斑驳病毒
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Met Gly Ser Ser His His His His His His Ser Ser Gly Glu Thr Val
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Arg Phe Gln Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp
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His Glu Asp Thr Gly His Met
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<212> PRT
<213> 人工序列
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<223> 生物素化组蛋白肽
<220>
<221> MOD_RES
<222> (5)..(5)
<223> 乙酰化
<220>
<221> MOD_RES
<222> (8)..(8)
<223> 乙酰化
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<221> MOD_RES
<222> (12)..(12)
<223> 乙酰化
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<221> MOD_RES
<222> (16)..(16)
<223> 乙酰化
<400> 3
Ser Gly Arg Gly Lys Gly Gly Lys Gly Leu Gly Lys Gly Gly Ala Lys
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Arg His Arg Lys Val
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Claims (11)
1.一种化合物或其药用盐、互变异构体或立体异构体,所述化合物选自以下:
5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
5-(二甲基-1H-1,2,3-三唑-5-基)-13-乙氧基-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-(2H3)甲氧基-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
13-乙氧基-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
13-(环丙基甲氧基)-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
8-[(S)-(3-氟吡啶-2-基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
8-[(S)-(4,4-二氟环己基)(3-氟吡啶-2-基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
13-(环丙基甲氧基)-8-[(S)-(2-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
13-乙氧基-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
13-(环丙基甲氧基)-8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
8-[(S)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
10-甲磺酰基-13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[氧杂环己烷-4-基(2,4,6-三氟苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
8-[(4,4-二氟环己基)(苯基)甲基]-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-13-甲氧基-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
13-(环丙基甲氧基)-8-[(S)-(4,4-二氟环己基)(苯基)甲基]-10-甲磺酰基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
N-[5-(二甲基-1,2-噁唑-4-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-13-基]环丙磺酰胺,
13-(环丙基甲氧基)-5-(二甲基-1H-1,2,3-三唑-5-基)-10-甲磺酰基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯,
10-甲磺酰基-13-甲氧基-5-(4-甲氧基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯,
[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]甲醇,
2-{13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-10-基}丙-2-醇,
13-甲氧基-5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}甲醇,
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇,
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(4-氟苯基)(氧杂环己烷-4-基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇,
2-[5-(二甲基-1,2-噁唑-4-基)-13-甲氧基-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基]丙-2-醇,
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}丙-2-醇,
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2,4,6,10,12-六烯-10-基}丙-2-醇,
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇,
2-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基}丙-2-醇,
2-[5-(二甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-12-基]丙-2-醇,
2-[5-(二甲基-1,2-噁唑-4-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇,
2-[5-(4-乙基-1-甲基-1H-1,2,3-三唑-5-基)-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基]丙-2-醇,
4-{5-[4-(2H3)甲基-1-甲基-1H-1,2,3-三唑-5-基]-8-[(S)-氧杂环己烷-4-基(苯基)甲基]-3,8,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-11-基}-1λ6,4-硫吗啉-1,1-二酮,或
2-{8-[(S)-(4-氟苯基)(氧杂环己烷-4-基)甲基]-5-[5-(2H3)甲基-3-甲基-1,2-噁唑-4-基]-3,8,12-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯-11-基}丙-2-醇。
2.一种药物组合物,其包含权利要求1的化合物或其药用盐、互变异构体或立体异构体及一种或多种药用载体、稀释剂或赋形剂。
3.一种组合药物产品,其包含权利要求1的化合物或其药用盐、互变异构体或立体异构体及一种或多种其它治疗活性剂。
4.权利要求1的化合物或其药用盐、互变异构体或立体异构体、权利要求2的组合物或权利要求3的产品,其用作药物。
5.权利要求1的化合物或其药用盐、互变异构体或立体异构体、权利要求2的组合物或权利要求3的产品,其用于治疗癌症。
6.权利要求5的化合物或其药用盐、互变异构体或立体异构体、组合物或产品,其中所述癌症为小细胞肺癌、非小细胞肺癌、结肠直肠癌、多发性骨髓瘤、急性髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、胰腺癌、肝癌、成神经细胞瘤、其它实体肿瘤或其它血液癌症。
7.权利要求5的化合物或其药用盐、互变异构体或立体异构体、组合物或产品,其中所述癌症为小细胞肺癌、非小细胞肺癌、结肠直肠癌、多发性骨髓瘤、AML或肝细胞癌。
8.权利要求1的化合物或其药用盐、互变异构体或立体异构体在制备用于抑制布罗莫结构域的药物中的用途。
9.权利要求1的化合物或其药用盐、互变异构体或立体异构体在制备用于治疗癌症的药物中的用途。
10.权利要求9的用途,其中所述癌症为小细胞肺癌、非小细胞肺癌、结肠直肠癌、多发性骨髓瘤、急性髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、胰腺癌、肝癌、成神经细胞瘤、其它实体肿瘤或其它血液癌症。
11.权利要求10的用途,其中所述癌症为小细胞肺癌、非小细胞肺癌、结肠直肠癌、多发性骨髓瘤、AML或肝细胞癌。
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