CN115028617A - Cbp/ep300的杂环抑制剂及其在治疗癌症中的用途 - Google Patents
Cbp/ep300的杂环抑制剂及其在治疗癌症中的用途 Download PDFInfo
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Abstract
Description
本申请是申请日为2017年5月24日、申请号为201780045651.4(国际申请号为PCT/US2017/034320)、名称为“CBP/EP300的杂环抑制剂及其在治疗癌症中的用途”的发明专利申请的分案申请。
本申请要求2016年5月24日提交的国际专利申请PCT/CN2016/083124的优先权。通过引用将国际专利申请PCT/CN2016/083124的全部内容并入本申请。
技术领域
本申请涉及可用作CBP/EP300抑制剂的化合物及使用此类抑制剂治疗癌症的方法。
背景技术
染色质是构成染色体的DNA和蛋白质的复杂组合。其在真核细胞的核中被发现且分为异染色质(浓缩)和常染色质(延展)形式。染色质的主要组分是DNA和蛋白质。组蛋白是染色质的主要蛋白质组分,其作为DNA缠绕的线轴。染色质的功能是将DNA包装到较小的体积中以适应细胞、强化DNA以允许有丝分裂和减数分裂并作为控制表达和DNA复制的机制。染色质结构受控于对组蛋白、特别是组蛋白H3和H4且最常为延伸超出核心核小体结构的“组蛋白尾部”进行的一系列翻译后修饰。组蛋白尾部易于发生蛋白质-蛋白质相互作用且也是组蛋白中最易于发生翻译后修饰的部分。这些修饰包括乙酰化、甲基化、磷酸化、泛素化和SUMO化。这些后生标志物被以下特异性酶所写入和消除,所述特异性酶将标签置于组蛋白尾部的特定残基上,从而形成后生密码,其然后由细胞解释以对染色质结构进行基因特异性调节并由此转录。
在所有类别的蛋白质中,组蛋白是最易于发生翻译后修饰的。组蛋白修饰是动态的,这是因为其可响应于特定的刺激而被添加或去除且这些修饰既引导染色质发生结构变化,又引导基因转录发生改变。不同类别的酶即组蛋白乙酰基转移酶(HAT)和组蛋白去乙酰基酶(HDAC)使特定的组蛋白赖氨酸残基发生乙酰化或去乙酰化(Struhl K.,Genes Dev.,1989,12,5,599-606)。
长度为约110个氨基酸的布罗莫结构域在大量染色质相关蛋白质中被发现且已在约70种常常与其它蛋白质基序相邻的人类蛋白质中被鉴定(Jeanmougin F.等人,TrendsBiochem.Sci.,1997,22,5,151-153;和Tamkun J.W.等人,Cell,1992,7,3,561-572)。布罗莫结构域与经修饰的组蛋白之间的相互作用可能是引起染色质结构变化和基因调节的重要机制。含有布罗莫结构域的蛋白质已参与疾病过程,包括癌症、炎症和病毒复制。参见例如Prinjha等人,Trends Pharm.Sci.,33(3):146-153(2012)和Muller等人,Expert Rev.,13(29):1-20(2011年9月)。
细胞型特异性和适当的组织功能性需要对密切受其环境影响的不同转录程序进行严格的控制。该转录稳态的改变与多种疾病状态直接相关,最明显为癌症、免疫性炎症、神经病症和代谢疾病。布罗莫结构域位于对独特的疾病相关转录途径进行控制的关键染色质修饰复合物中。观察结果强调了含有布罗莫结构域的蛋白质中的突变与癌症及免疫和神经功能障碍相关。因此,在特异性家族中选择性抑制布罗莫结构域例如选择性抑制CBP/EP300的布罗莫结构域,这提供了作为人类功能障碍的新颖治疗剂的各种机会。
需要对癌症、免疫病症和其它CBP/EP300布罗莫结构域相关疾病的治疗。
发明内容
式(I)或式(II)化合物
一个方面为式(I)或式(II)化合物或其盐:
其中
R1为氢、-NRaRb、C1-6烷基、C2-6烯基、C2-6炔基和3-8元碳环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基和3-8元碳环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个R2独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rt)2、-CN、-C(O)-N(Rt)2、-O-Rt、-O-C(O)-Rt、-C(O)-Rt和-C(O)-O-Rt,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个卤素;
R3为3-12元碳环或3-12元杂环,其中R3的每个3-12元碳环和3-12元杂环任选取代有一个或多个基团Ru;
Y为O或N(Rc);
m为0、1、2、3或4;
n为0、1、2、3或4;
p为0、1、2、3或4;
环A为稠合环,其选自苯并和6元杂环;
每个R4独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rx和-C(O)-O-Rw,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个氧代或卤素;
每个R5独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rx和-C(O)-O-Rw,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个氧代或卤素;
R6为-N(Rz)-C(O)-Rx、3-12元碳环或3-12元杂环,其中R6的每个3-12元碳环和3-12元杂环任选取代有一个或多个基团Rx;
X为N或C(R7);
R7为H或C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ra和Rb独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或Ra和Rb与和它们连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
Rc为氢、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rt独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rt与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ru独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任意C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、3-12元碳环和C1-6烷基,所述C1-6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rv独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、碳环基和杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rw与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rw独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rt与和它们连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rx独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2和-N(Ry)-S(O)2-N(Ry)2,其中任意C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、3-12元碳环和C1-6烷基,所述C1-6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ry独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Ry与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;且
每个Rz独立选自氢、C1-6烷基。
另一个方面包括组合物,其包含式(I)或式(II)化合物或其药用盐和药用辅料、载体或媒介物。
另一个方面包括在动物中治疗由CBP和/或EP300介导的病症的方法,其包括向所述动物施用式(I)或式(II)化合物或其药用盐。
另一个方面包括在动物中治疗由CBP和/或EP300介导的病症的方法,其中所述病症为癌症,所述方法包括向所述动物施用式(I)或式(II)化合物或其药用盐。
另一个方面包括在动物中治疗由CBP和/或EP300介导的病症的方法,其中所述病症为纤维化疾病,所述方法包括向所述动物施用式(I)或式(II)化合物或其药用盐。
另一个方面包括在动物中治疗由CBP和/或EP300介导的病症的方法,其中所述病症为纤维化肺病,所述方法包括向所述动物施用式(I)或式(II)化合物或其药用盐。
另一个方面包括式(I)或式(II)化合物或其药用盐,其用于医学疗法。
另一个方面包括式(I)或式(II)化合物或其药用盐,其用于预防性或治疗性处置由CBP和/或EP300介导的病症。
另一个方面包括式(I)或式(II)化合物或其药用盐在制备用于在动物(例如哺乳动物例如人类)中治疗由CBP和/或EP300介导的病症的药物中的用途。
另一个方面包括用于对CBP和/或EP300进行研究的化合物。
另一个方面包括可用于制备式(I)或式(II)化合物或其盐的本申请所述合成中间体和合成方法。
附图说明
图1所概述的方案用于测定CBP/p300SMI对TGFβ所致促纤维化基因诱导的抑制。
具体实施方式
定义
以下更详细地描述了定义和术语。化学元素根据Elements,CAS版本,Handbook ofChemistry and Physics,第75版鉴定。
除非另有说明,式I或式II化合物包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如,本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。除非另有说明,本申请包括本申请所述结构的所有互变异构形式。另外,除非另有说明,本申请所述结构还意在包括区别仅在于存在一个或多个同位素富集原子的化合物。例如,本申请包括以下式I或式II化合物,其中用氘或氚对一个或多个氢、用13C或14C碳对一个或多个碳、用15N氮对一个或多个氮、用33S、34S或36S硫对一个或多个硫或用17O或18O氧对一个或多个氧进行独立置换或富集。此类化合物可用作例如分析工具、生物测定中的探针或治疗剂。
当描述具体的对映异构体时,其在某些实施方案中可按基本上不含有相应对映异构体的形式提供且还可称为是“光学富集”的。本申请使用的“光学富集”是指对映异构体的混合物由显著较大比例的一种对映异构体构成且可通过对映异构体过量(ee%)描述。在某些实施方案中,对映异构体的混合物由至少约90重量%的给定对映异构体(约90%ee)构成。在其它实施方案中,对映异构体的混合物由至少约95重量%、98重量%或99重量%的给定对映异构体(约95%、98%或99%ee)构成。对映异构体和非对映异构体可通过本领域技术人员已知的任何方法由外消旋混合物分离(包括从一种立体异构体比另一种立体异构体较易溶解在其中的溶剂中重结晶、手性高压液相色谱(HPLC)、超临界流体色谱(SFC)、手性盐形成和结晶且然后通过上述任何方法分离)或通过不对称合成来制备和任选进一步富集。参见例如Jacques等人,Enantiomers,Racemates and Resolutions(WileyInterscience,New York,1981);Wilen等人,Tetrahedron 33:2725(1977);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions,第268页(E.L.Eliel,Ed.,Univ.ofNotre Dame Press,Notre Dame,1972)。
术语“杂原子”是指独立选自除碳或氢外的原子例如氧、硫、氮、磷或硅(包括氮、硫、磷或硅的任何氧化形式和任何氮的季铵化形式)中的一种或多种的任何原子。
本申请使用的术语“卤代”和“卤素”是指选自氟(-F)、氯(-C1)、溴(-Br)和碘(-I)的原子。
术语“氧代”是指=O。
本申请使用的术语“不饱和”是指基团具有一个或多个不饱和单元。
单独或作为较大基团的一部分使用的术语“碳环基”是指具有3-20个碳原子的饱和、部分不饱和或芳族的环系。在一个实施方案中,碳环基包括3-12个碳原子(C3-C12)。在另一个实施方案中,碳环基包括C3-C8、C3-C10或C5-C10。在另一个实施方案中,作为单环的碳环基包括C3-C8、C3-C6或C5-C6。在另一个实施方案中,作为二环的碳环基包括C7-C12。在另一个实施方案中,作为螺环系统的碳环基包括C5-C12。单环碳环基的实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、全氘代环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、苯基和环十二烷基;具有7-12个环原子的二环碳环基包括[4,3]、[4,4]、[4,5]、[5,5]、[5,6]或[6,6]环系例如二环[2.2.1]庚烷、二环[2.2.2]辛烷、萘和二环[3.2.2]壬烷;且螺环碳环基包括螺[2.2]戊烷、螺[2.3]己烷、螺[2.4]庚烷、螺[2.5]辛烷和螺[4.5]癸烷。术语“碳环基”包括如本申请定义的芳基环系。术语“碳环基”还包括环烷基环(例如饱和或部分不饱和的单环、二环或螺环碳环)。
本申请使用的术语“烷基”是指饱和的直链或支链的烃基。在一个实施方案中,烷基具有1-18个碳原子(C1-C18)。在其它实施方案中,烷基为C0-C6、C0-C5、C0-C3、C1-C12、C1-C10、C1-C8、C1-C6、C1-C5、C1-C4或C1-C3。C0烷基是指键。烷基的实例包括甲基(Me、-CH3)、乙基(Et、-CH2CH3)、1-丙基(n-Pr、正丙基、-CH2CH2CH3)、2-丙基(i-Pr、异丙基、-CH(CH3)2)、1-丁基(n-Bu、正丁基、-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu、异丁基、-CH2CH(CH3)2)、2-丁基(s-Bu、仲丁基、-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu、叔丁基、-C(CH3)3)、1-戊基(正戊基、-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3、庚基、辛基、壬基、癸基、十一烷基和十二烷基。
本申请使用的术语“烯基”是指具有至少一个碳-碳双键的直链或支链的烃基。烯基包括具有“顺式”和“反式”取向或“E”和“Z”取向的基团。在一个实例中,烯基具有2-18个碳原子(C2-C18)。在其它实例中,烯基为C2-C12、C2-C10、C2-C8、C2-C6或C2-C3。实例包括但不限于乙烯基(-CH=CH2)、丙-1-烯基(-CH=CHCH3)、丙-2-烯基(-CH2CH=CH2)、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基。
本申请使用的术语“炔基”是指具有至少一个碳-碳叁键的直链或支链的烃基。在一个实例中,炔基具有2-18个碳原子(C2-C18)。在其它实例中,炔基为C2-C12、C2-C10、C2-C8、C2-C6或C2-C3。实例包括但不限于乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH3)、丙-2-炔基(炔丙基、-CH2C≡CH)、丁-1-炔基、丁-2-炔基和丁-3-炔基。
术语“烷氧基”是指由式-OR表示的直链或支链的基团,其中R是烷基、烯基、炔基或碳环基。烷氧基包括甲氧基、乙氧基、丙氧基、异丙氧基和环丙氧基。
本申请使用的术语“卤代烷基”是指被一个或多个(例如1、2、3或4个)卤素取代的如本申请定义的烷基。
单独或作为“芳基烷基”、“芳基烷氧基”或“芳基氧基烷基”等较大基团的一部分使用的术语“芳基”是指单环、二环或三环碳环系统,其包括其中系统中的至少一个环是芳族的稠环。术语“芳基”可与术语“芳基环”互换使用。在一个实施方案中,芳基包括具有6-20个碳原子的基团(C6-C20芳基)。在另一个实施方案中,芳基包括具有6-10个碳原子的基团(C6-C10芳基)。芳基的实例包括苯基、萘基、蒽基、联苯、菲基、苯并蒽基、1,2,3,4-四氢萘基、1H-茚基、2,3-二氢-1H-茚基等,其可为取代的或独立被一个或多个本申请所述取代基取代。具体的芳基是苯基。在另一个实施方案中,芳基包括与一个或多个碳环稠合的芳基环例如茚满基、二氢菲基或四氢萘基等,其中连接基团或连接点在芳环上。
单独或作为“杂芳基烷基”或“杂芳基烷氧基”等较大基团的一部分使用的术语“杂芳基”是指具有5-14个环原子的单环、二环或三环系统,其中至少一个环为芳族的且含有至少一个杂原子。在一个实施方案中,杂芳基包括4-6元单环芳族基团,其中一个或多个环原子是独立任选取代的氮、硫或氧。在另一个实施方案中,杂芳基包括5-6元单环芳族基团,其中一个或多个环原子是独立任选取代的氮、硫或氧。在一些实施方案中,杂芳基为C1-C20杂芳基,其中杂芳基环含有1-20个碳原子且其余环原子包括一个或多个氮、硫或氧原子。杂芳基的实例包括噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、噁二唑基、四唑基、噻三唑基、噁三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、四嗪基、四唑并[1,5-b]哒嗪基、咪唑并[1,2-a]嘧啶基、嘌呤基、苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并三唑基、苯并咪唑基、吲哚基、1,3-噻唑-2-基、1,3,4-三唑-5-基、1,3-噁唑-2-基、1,3,4-噁二唑-5-基、1,2,4-噁二唑-5-基、1,3,4-噻二唑-5-基、1H-四唑-5-基、1,2,3-三唑-5-基、吡啶-2-基N-氧化物和吡唑并[4,3-c]吡啶基。术语“杂芳基”还包括以下基团,其中杂芳基与一个或多个芳基、碳环基或杂环基环稠合,其中连接基团或连接点在杂芳基环上。非限制性实例包括吲哚基、异吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、四氢喹啉基、四氢异喹啉基和吡啶并[2,3-b]1,4-噁嗪-3(4H)-酮。杂芳基可为单环、二环或三环。
本申请使用的术语“杂环基”或“杂环”是指如本申请定义的“碳环基”,其中一个或多个(例如1、2、3或4个)碳原子已被杂原子(例如O、N或S)代替。在一些实施方案中,杂环基或杂环是指饱和环系例如3-12元饱和杂环基环系。在一些实施方案中,杂环基或杂环是指杂芳基环系例如5-14元杂芳基环系。杂环基或杂环可任选取代有一个或多个独立选自本申请定义的那些取代基的取代基。
在一个实例中,杂环基或杂环包含3-12个环原子且包括单环、二环、三环和螺环系统,其中环原子是碳且1-5个环原子是选自氮、硫或氧的杂原子,其独立任选被一个或多个基团取代。在一个实例中,杂环基或杂环包含1-4个杂原子。在另一个实例中,杂环基或杂环包括具有一个或多个选自氮、硫或氧的杂原子的3-7元单环。在另一个实例中,杂环基或杂环包括具有一个或多个选自氮、硫或氧的杂原子的4-6元单环。在另一个实例中,杂环基或杂环包括3元单环。在另一个实例中,杂环基或杂环包括4元单环。在另一个实例中,杂环基或杂环包括5-6元单环。在一个实例中,杂环基或杂环包含0-3个双键。任何氮或硫杂原子可任选被氧化(例如NO、SO、SO2)且任何氮杂原子可任选被季铵化(例如[NR4]+Cl-、[NR4]+OH-)。杂环基或杂环的实例包括环氧乙烷基、氮丙啶基、硫杂丙环烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁烷基、1,3-二硫杂环丁烷基、吡咯烷基、二氢-1H-吡咯基、二氢呋喃基、四氢呋喃基、二氢噻吩基、四氢噻吩基、咪唑烷基、哌啶基、哌嗪基、吗啉基、硫吗啉基、1,1-二氧代-硫吗啉基、二氢吡喃基、四氢吡喃基、六氢噻喃基、六氢嘧啶基、噁嗪烷基、噻嗪烷基、噻噁烷基、高哌嗪基、高哌啶基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧杂氮杂基、氧氮杂环庚烷基、二氮杂环庚烷基、1,4-二氮杂环庚烷基、二氮杂基、硫氮杂基、硫氮杂环庚烷基、四氢噻喃基、噁唑烷基、噻唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷酮基、噁唑烷酮基、咪唑烷酮基、4,5,6,7-四氢[2H]吲唑基、四氢苯并咪唑基、4,5,6,7-四氢苯并[d]咪唑基、1,6-二氢咪唑并[4,5-d]吡咯并[2,3-b]吡啶基、噻嗪基、噁嗪基、噻二嗪基、噁二嗪基、二噻嗪基、二噁嗪基、噁噻嗪基、噻三嗪基、噁三嗪基、二噻二嗪基、咪唑啉基、二氢嘧啶基、四氢嘧啶基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、噻喃基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧杂环戊烷基、吡唑啉基、吡唑烷基、二噻烷基、二硫杂环戊烷基、嘧啶酮基、嘧啶二酮基、嘧啶-2,4-二酮基、哌嗪酮基、哌嗪二酮基、吡唑烷基、咪唑啉基、3-氮杂二环[3.1.0]己基、3,6-二氮杂二环[3.1.1]庚基、6-氮杂二环[3.1.1]庚基、3-氮杂二环[3.1.1]庚基、3-氮杂二环[4.1.0]庚基、氮杂二环[2.2.2]己基、2-氮杂二环[3.2.1]辛基、8-氮杂二环[3.2.1]辛基、2-氮杂二环[2.2.2]辛基、8-氮杂二环[2.2.2]辛基、7-氧杂二环[2.2.1]庚烷、氮杂螺[3.5]壬基、氮杂螺[2.5]辛基、氮杂螺[4.5]癸基、1-氮杂螺[4.5]癸-2-酮基、氮杂螺[5.5]十一烷基、四氢吲哚基、八氢吲哚基、四氢异吲哚基、四氢吲唑基、1,1-二氧代六氢噻喃基。含有硫或氧原子和1-3个氮原子的5元杂环基或杂环的实例是噻唑基,包括噻唑-2-基和噻唑-2-基N-氧化物;噻二唑基,包括1,3,4-噻二唑-5-基和1,2,4-噻二唑-5-基;噁唑基,例如噁唑-2-基;和噁二唑基,例如1,3,4-噁二唑-5-基和1,2,4-噁二唑-5-基。含有2-4个氮原子的5元杂环基或杂环的实例包括咪唑基,例如咪唑-2-基;三唑基,例如1,3,4-三唑-5-基、1,2,3-三唑-5-基、1,2,4-三唑-5-基;和四唑基,例如1H-四唑-5-基。与苯稠合的5元杂环基或杂环的实例是苯并噁唑-2-基、苯并噻唑-2-基和苯并咪唑-2-基。含有1-3个氮原子且任选含有硫或氧原子的6元杂环基或杂环的实例是吡啶基,例如吡啶-2-基、吡啶-3-基和吡啶-4-基;嘧啶基,例如嘧啶-2-基和嘧啶-4-基;三嗪基,例如1,3,4-三嗪-2-基和1,3,5-三嗪-4-基;哒嗪基,具体是哒嗪-3-基;和吡嗪基。吡啶N-氧化物和哒嗪N-氧化物及吡啶基、嘧啶-2-基、嘧啶-4-基、哒嗪基和1,3,4-三嗪-2-基是杂环基的其它实例。
术语“杂环基”或“杂环”还包括以下基团,其中杂环基与一个或多个芳基、碳环基或杂环基环稠合,其中连接基团或连接点在杂环基环上。非限制性实例包括四氢喹啉基和四氢异喹啉基。
本申请使用的术语“部分不饱和”是指以下环基团,其在环原子之间包含至少一个双键或叁键,但是所述环基团不是芳族的。
本申请使用的术语“抑制剂”是指以下化合物,其以可测量的亲和力和活性结合和抑制CBP和/或EP300的布罗莫结构域。在某些实施方案中,抑制剂具有小于约20μM、小于约1μM、小于约500nM、小于约100nM或小于约10nM的IC50或结合常数。
本申请使用的术语“可测量的亲和力”和“可测量地抑制”是指CBP和/或EP300的布罗莫结构域的活性在(i)包含式I或式II化合物或其组合物和上述布罗莫结构域的样品和(ii)在不存在所述化合物或其组合物的情况下包含上述布罗莫结构域的等同样品之间可测量的降低(例如降低识别对染色质的赖氨酸乙酰基识别)。
“药用盐”包括酸和碱加成盐。应理解的是,当本申请化合物或实施例被显示为具体的盐时,本申请包括相应的游离碱及相应的游离碱的其它盐(包括相应的游离碱的药用盐)。
“药用酸加成盐”是指与无机酸或有机酸形成的保留游离碱的生物有效性和性质且不是在生物学上或在其它方面不期望的那些盐,所述无机酸为例如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等,所述有机酸可选自脂族、环脂族、芳族、芳脂族、杂环羧酸和磺酸类有机酸例如甲酸、乙酸、丙酸、乙醇酸、葡糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、扑酸、苯乙酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、水杨酸等。
“药用碱加成盐”包括衍生自无机碱的那些药用碱加成盐例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。具体地,碱加成盐是铵、钾、钠、钙和镁盐。衍生自药用有机无毒碱的盐包括以下物质的盐:伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代的胺)、环状胺和碱性离子交换树脂例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基氨基乙醇、氨丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤类、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。具体的有机无毒碱是异丙胺、二乙胺、乙醇胺、氨丁三醇、二环己胺、胆碱和咖啡因。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒相互转化的结构异构体。例如,质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的相互转化例如酮-烯醇和亚胺-烯胺异构化。价态互变异构体包括通过重组一些成键电子的相互转化。
“溶剂化物”是指一个或多个溶剂分子和本申请化合物的缔合物或复合物。溶剂的实例包括水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指其中溶剂分子是水的复合物。
“治疗有效量”是指本申请化合物的以下量,其(i)治疗具体的疾病、病症或障碍;(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状;或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状的发作。对于癌症,治疗有效量的药物可减少癌细胞数目;减小肿瘤尺寸;抑制(即在一定程度上减缓且优选停止)癌细胞浸润到周围器官中;抑制(即在一定程度上减缓且优选停止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解与癌症相关的一种或多种症状。对于癌症疗法,效力可例如通过评估疾病进展时间(TTP)和/或确定响应率(RR)来测量。对于免疫障碍,治疗有效量是以下量,其足以减轻或缓解变应性障碍、自身免疫性和/或炎性疾病的症状或急性炎症反应的症状(例如哮喘)。
“治疗”是指试图使所治疗的个体或细胞的自然过程发生改变的临床干预且可出于预防目的或在临床病理过程中实施。治疗的理想效果包括以下一种或多种:预防疾病复发,缓解症状,减轻疾病的任何直接或间接病理后果,使疾病状态得以稳定(即不恶化),预防转移,降低疾病进展速率,改善或缓解疾病状态,与不接受治疗的预期生存期相比延长生存期和缓解或改善预后。在某些实施方案中,式I或式II化合物用于延缓疾病或障碍的发展或减缓疾病或障碍的进展。需要治疗的那些个体包括已患有病症或障碍的那些个体及易患病症或障碍的那些个体(例如由于遗传突变或基因或蛋白质的异常表达)。
“CBP/EP300布罗莫结构域抑制剂”或“CBP和/或EP300布罗莫结构域抑制剂”是指以下化合物,其结合CBP布罗莫结构域和/或EP300布罗莫结构域并抑制和/或降低CBP和/或EP300的生物活性。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂主要(例如唯一)通过与CBP布罗莫结构域和/或EP300布罗莫结构域接触和/或相互作用来结合CBP和/或EP300。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂通过与CBP布罗莫结构域和/或EP300布罗莫结构域及额外的CBP和/或EP300残基和/或结构域接触和/或相互作用来结合CBP和/或EP300。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂基本上或完全抑制CBP和/或EP300的生物活性。在一些实施方案中,生物活性为CBP和/或EP300的布罗莫结构域与染色质(例如组蛋白相关DNA)和/或另一种乙酰化蛋白质的结合。在某些实施方案中,CBP/EP300布罗莫结构域抑制剂阻断CBP/EP300活性以使T细胞的功能性响应(例如增殖、细胞因子产生、靶细胞杀灭)由功能障碍状态恢复到抗原刺激。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂结合并抑制CBP布罗莫结构域。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂结合并抑制EP300布罗莫结构域。
除非另有明确说明,本申请使用的“一个/种”是指一个/种或多个/种。本申请使用的“另一个/种”是指至少另一个/种或更多个/种。
化合物
式(I)化合物
另一个方面包括式(I)化合物或其盐:
在关于式(I)化合物的一个方面,R3不为:
在一个方面,所述化合物为式(Ia)化合物或其盐:
在一个方面,所述化合物为式(Ib)化合物或其盐:
在一个方面,R1为-NHRb。
在一个方面,Rb为C1-6烷基。
在一个方面,R1为甲基或-NH(CH3)。
在一个方面,m为0。
在一个方面,m为1。
在一个方面,R2为-O-Rt。
在一个方面,R2为-OMe。
在一个方面,R3为3-12元碳环,其任选取代有一个或多个基团Ru。
在一个方面,R3为苯基,其任选取代有一个或多个基团Ru。
在一个方面,R3为3-12元杂环,其任选取代有一个或多个基团Ru。
在一个方面,R3为9-10元杂环,其任选取代有一个或多个基团Ru。
在一个方面,R3选自:
在一个方面,所述化合物选自:
及其盐。
式(II)化合物
另一个方面包括式(II)化合物或其盐:
在关于式(II)化合物的一个方面,R6不为:
在一个方面,所述化合物为式(IIa)化合物或其盐:
在一个方面,所述化合物为式(IIb)化合物或其盐:
在一个方面,所述化合物为式(IIc)化合物或其盐:
在一个方面,所述化合物为式(IId)化合物或其盐:
在一个方面,所述化合物为式(IIe)化合物或其盐:
在一个方面,所述化合物为式(IIf)化合物或其盐:
在一个方面,所述化合物为式(IIg)化合物或其盐:
在一个方面,X为N。
在一个方面,X为C(R7)。
在一个方面,R7为H。
在一个方面,R7为二氟甲基。
在一个方面,所述化合物为式(IIh)化合物或其盐:
在一个方面,p为0。
在一个方面,p为1、2、3或4。
在一个方面,R6为3-12元杂环,其任选取代有一个或多个基团Rx。
在一个方面,R6选自:
其任选取代有一个或多个基团Rx。
在一个方面,R6选自:
在一个方面,所述化合物选自:
及其盐。
式(I)或式(II)化合物的用途、制剂和施用
药用组合物
另一个方面包括药物组合物,其包含式(I)或式(II)化合物或其药用盐。在一个实施方案中,组合物还包含药用载体、辅料或媒介物。在另一个实施方案中,组合物还包含一定量的足以可测量地抑制CBP和/或EP300的布罗莫结构域的化合物。在某些实施方案中,将组合物配制成用于施用至有此需要的患者。
本申请使用的术语“患者”或“个体”是指动物例如哺乳动物例如人类。在一个实施方案中,患者或个体是指人类。
术语“药用载体、辅料或媒介物”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。可用于本申请组合物的药用载体、辅料或媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白例如人血清白蛋白、缓冲物质例如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯基吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
包含式I或式II化合物或其盐的组合物可口服、胃肠外、通过吸入喷雾、局部、经皮、经直肠、经鼻、经颊、舌下、经阴道、腹膜内、肺内、皮内、硬膜外或通过植入储库施用。本申请使用的术语“胃肠外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。
在一个实施方案中,将包含式I或式II化合物或其盐的组合物配制成用于口服施用的固体剂型。用于口服施用的固体剂型包括胶囊剂、片剂、丸剂、粉末剂和颗粒剂。在某些实施方案中,包含式(I)或式(II)化合物或其盐的固体口服剂型还包含以下一种或多种物质:(i)惰性药用赋形剂或载体,例如柠檬酸钠或磷酸二钙;(ii)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇或硅酸;(iii)粘合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖或阿拉伯胶;(iv)保湿剂,例如甘油;(v)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐或碳酸钠;(vi)溶解阻滞剂,例如石蜡;(vii)吸收促进剂,例如季铵盐;(viii)润湿剂,例如鲸蜡醇或甘油单硬脂酸酯;(ix)吸附剂,例如高岭土或膨润土;和(x)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、聚乙二醇或月桂基硫酸钠。在某些实施方案中,将固体口服剂型配制成胶囊剂、片剂或丸剂。在某些实施方案中,固体口服剂型还包含缓冲剂。在某些实施方案中,可将用于固体口服剂型的此类组合物配制成包含一种或多种赋形剂例如乳糖、聚乙二醇等的软和硬填充明胶胶囊中的填料。
在某些实施方案中,包含式I或式II化合物或其盐的组合物的片剂、锭剂、胶囊剂、丸剂和颗粒剂任选包含包衣或外壳例如肠溶衣。其可任选包含遮光剂且还可具有以下组分,其仅或优先在肠道的某一部分中任选以延迟方式释放活性成分。包埋用组分的实例包括聚合物和蜡,其也可用作使用乳糖及高分子量聚乙二醇等赋形剂的软和硬填充明胶胶囊中的填料。
在另一个实施方案中,组合物包含微囊化的式(I)或式(II)化合物或其盐且任选还包含一种或多种赋形剂。
在另一个实施方案中,组合物包括用于口服施用的包含式I或式II化合物或其盐的液体剂型且任选还包括一种或多种药用乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。在某些实施方案中,液体剂型任选还包含一种或多种惰性稀释剂例如水或其它溶剂、增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体为棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇或脱水山梨醇的脂肪酸酯及其混合物。在某些实施方案中,液体口服组合物任选还包含一种或多种辅料例如润湿剂、助悬剂、甜味剂、矫味剂和芳香剂。
注射用制剂例如无菌注射用水性或油性混悬剂可根据已知的技术使用合适的分散剂或润湿剂和助悬剂配制。无菌注射用制剂还可为在无毒的胃肠外可接受的稀释剂或溶剂中的无菌注射用溶液剂、混悬剂或乳剂例如在1,3-丁二醇中的溶液剂。可使用的可接受的媒介物和溶剂是水、林格溶液U.S.P.和等渗氯化钠溶液。另外,无菌不挥发性油通常用作溶剂或混悬介质。出于该目的,可使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。另外,脂肪酸例如油酸用于制备注射剂。
注射用制剂可例如如下灭菌:用细菌截留过滤器过滤或将灭菌剂引入到可在使用前溶解或分散在无菌水或其它无菌注射用介质中的无菌固体组合物形式中。
为了延长式(I)或式(II)化合物的作用,通常期望减缓化合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材料的液体混悬液来实现。化合物的吸收速率由此取决于其溶解速率,而溶解速率又可取决于晶体尺寸和结晶形式。可选择地,胃肠外施用的化合物的延迟吸收通过将化合物溶解或混悬在油媒介物中来实现。注射用储库形式通过形成化合物在可生物降解的聚合物例如聚乳酸-聚乙交酯中的微囊基质来制备。取决于化合物与聚合物的比例和所使用的具体聚合物的性质,可控制化合物的释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。储库型注射用制剂也通过将化合物包埋在与身体组织相容的脂质体或微乳液中来制备。
在某些实施方案中,将用于直肠或阴道施用的组合物配制成栓剂,其可如下制备:将式(I)或式(II)化合物或其盐与合适的无刺激性的赋形剂或载体混合,所述赋形剂或载体为例如可可脂、聚乙二醇或栓剂蜡例如在环境温度为固体但在体温为液体且由此在直肠或阴道腔中融化和释放式(I)或式(II)化合物的那些赋形剂或载体。
用于局部或透皮施用式(I)或式(II)化合物的示例性剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、粉末剂、溶液、喷雾剂、吸入剂或贴剂。式(I)或式(II)化合物或其盐在无菌条件下与药用载体和任选的防腐剂或缓冲剂混合。其它制剂实例包括眼用制剂、滴耳剂、滴眼剂、透皮贴剂。透皮剂型可通过将式(I)或式(II)化合物或其盐溶解或分散在介质例如乙醇或二甲基亚砜中来制备。吸收增强剂也可用于增加化合物穿过皮肤的通量。速率可通过提供速率控制膜或将化合物分散在聚合物基质或凝胶中来控制。
可使用苄醇或其它合适的防腐剂、提高生物利用度的吸收促进剂、氟碳化合物和/或其它常规增溶剂或分散剂将式(I)或式(II)化合物或其盐的鼻气雾或吸入制剂制备成在盐水中的溶液。
在某些实施方案中,药物组合物可与食物一起或不与食物一起施用。在某些实施方案中,药用组合物不与食物一起施用。在某些实施方案中,本申请药用组合物与食物一起施用。
用于任何特定患者的具体剂量和治疗方案将取决于多种因素,包括年龄、体重、一般健康、性别、饮食、施用时间、排泄速率、药物组合、主治医生的判断和所治疗的特定疾病的严重性。在组合物中提供的式I或式II化合物或其盐的量还将取决于组合物中的特定化合物。
在一个实施方案中,每剂胃肠外施用的本申请化合物的治疗有效量将为约0.01-100mg/kg患者体重/天或约0.1-20mg/kg患者体重/天,其中所使用的化合物的典型初始范围为0.3-15mg/kg/天。在另一个实施方案中,口服单位剂型例如片剂和胶囊剂含有约5mg至约100mg本申请化合物。
示例性片剂口服剂型包含约2mg、5mg、25mg、50mg、100mg、250mg或500mg式(I)或式(II)化合物或其盐且还包含约5-30mg无水乳糖、约5-40mg交联羧甲基纤维素钠、约5-30mg聚乙烯基吡咯烷酮(PVP)K30和约1-10mg硬脂酸镁。配制片剂的方法包括将粉末状成分混合在一起且进一步与PVP溶液混合。可将所得组合物干燥,制粒,与硬脂酸镁混合且使用常规设备压制成片剂形式。气雾制剂的实例可如下制备:将约2-500mg式I或式II化合物或其盐溶解在合适的缓冲溶液例如磷酸盐缓冲液中且按需添加张力剂例如盐例如氯化钠。溶液可例如使用0.2微米过滤器过滤以去除杂质和污染物。
化合物和药用组合物的用途
另一个方面包括式(I)或式(II)化合物或其盐在抑制布罗莫结构域(体外或体内)(例如体外或体内抑制CBP/EP300的布罗莫结构域)中的用途。
另一个实施方案包括用于在动物中治疗由布罗莫结构域介导的病症(例如由CBP/EP300布罗莫结构域介导的病症)的方法,其包括向所述动物施用式(I)或式(II)化合物或其药用盐。由CBP/EP300介导的病症包括但不限于本申请所述那些病症。
另一个实施方案包括在动物中增加包含细胞毒性剂的癌症治疗的效力的方法,其包括向所述动物施用有效量的式(I)或式(II)化合物或其药用盐。
另一个实施方案包括在动物中延长对癌症疗法的响应的持续时间的方法,其包括向经历所述癌症疗法的动物施用式(I)或式(II)化合物或其药用盐,其中当施用式(I)或式(II)化合物或其药用盐时对所述癌症疗法的响应的持续时间延长超过在不存在施用式(I)或式(II)化合物或其药用盐的情况下对所述癌症疗法的响应的持续时间。
另一个实施方案包括在个体中治疗癌症的方法,其包括向所述个体施用(a)式(I)或式(II)化合物或其药用盐和(b)细胞毒性剂。在一个实施方案中,所述细胞毒性剂选自抗微管剂、铂配位复合物、烷化剂、抗生素、拓扑异构酶II抑制剂、抗代谢剂、拓扑异构酶I抑制剂、激素和激素类似物、信号转导途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂、脂肪酸生物合成抑制剂、细胞周期信号传导抑制剂、HDAC抑制剂、蛋白酶体抑制剂和癌症代谢抑制剂。在一个实施方案中,所述细胞毒性剂为紫杉烷。在一个实施方案中,所述紫杉烷为紫杉醇或多西他赛。在一个实施方案中,所述细胞毒性剂为铂剂。在一个实施方案中,所述细胞毒性剂为EGFR拮抗剂。在一个实施方案中,所述EGFR拮抗剂为N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺或其药用盐(例如厄洛替尼)。在一个实施方案中,所述细胞毒性剂为RAF抑制剂。在一个实施方案中,所述RAF抑制剂为BRAF或CRAF抑制剂。在一个实施方案中,所述RAF抑制剂为威罗菲尼。在一个实施方案中,所述细胞毒性剂为PI3K抑制剂。
在某些实施方案中,治疗可在一种或多种症状已发展后施用。在其它实施方案中,治疗可在没有症状的情况下施用。例如,治疗可在症状发作前施用至易感个体(例如根据症状史和/或遗传或其它易感因素)。治疗还可在症状已消退后持续例如以预防或延迟其复发。
在一些实施方案中,CBP/EP300布罗莫结构域抑制剂干扰CBP和/或EP300与组蛋白且特别是组蛋白中的乙酰化赖氨酸的关联。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂抑制CBP和/或EP300与染色质(例如组蛋白相关DNA)的结合。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂抑制和/或减少CBP布罗莫结构域和/或EP300布罗莫结构域与染色质(例如组蛋白相关DNA)的结合。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂不影响CBP和/或EP300的其它结构域与染色质的关联。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂主要(例如唯一)通过与CBP布罗莫结构域和/或EP300布罗莫结构域接触和/或相互作用来结合CBP和/或EP300。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂通过与CBP布罗莫结构域和/或EP300布罗莫结构域及额外的CBP和/或EP300残基和/或结构域接触和/或相互作用来结合CBP和/或EP300。对与染色质的关联进行测定的方法是本领域已知的且包括但不限于染色质分级、BRET测定(Promega)、FRAP测定、染色质免疫沉淀(ChIP)、生物物理结合测定和/或组蛋白关联测定。参见例如Das等人,BioTechniques 37:961-969(2004)。
在一些实施方案中,CBP/EP300布罗莫结构域抑制剂不影响CD8细胞中的效应子功能(即效应子功能在存在和/或不存在CBP/EP300布罗莫结构域抑制剂的情况下基本上相同)。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂不影响穿孔素、颗粒酶和/或EOMES的表达水平(即一种或多种穿孔素、颗粒酶和/或EOMES的表达水平在存在和/或不存在CBP/EP300布罗莫结构域抑制剂的情况下基本上相同)。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂不影响效应子细胞因子IFN-γ和/或TNFα的表达水平(即效应子细胞因子IFN-γ和/或TNFα的表达水平在存在和/或不存在CBP/EP300布罗莫结构域抑制剂的情况下基本上相同)。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂增强未致敏的T细胞在Treg细胞存在下对CD3/CD28刺激的响应性。
在一些实施方案中,CBP/EP300布罗莫结构域抑制剂基本上不结合(例如不结合)CBP和/或EP300的HAT结构域。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂基本上不结合(例如不结合)CBP和/或EP300的HAT结构域,如Delvecchio等人,Nat.Struct.&Mol.Biol.20:1040-1046(2013)所鉴定,通过引用将其整体并入。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂基本上不结合以下氨基酸序列的一个或多个残基:ENKFSAKRLQTTRLGNHLEDRVNKFLRRQNHPEAGEVFVRVVASSDKTVEVKPGMKSRFVDSGEMSESFPYRTKALFAFEEIDGVDVCFFGMHVQEYGSDCPPPNTRRVYISYLDSIHFFRPRCLRTAVYHEILIGYLEYVKKLGYVTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAFAERIIHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKKEESTAASETTEGSQGDSKNAKKKNNKKTNKNKSSISRANKKKPSMPNVSNDLSQKLYATMEKHKEVFFVIHLHAGPVINTLPPIVDPDPLLSCDLMDGRDAFLTLARDKHWEFSSLRRSKWSTLCMLVELHTQGQD(UniProtNo.Q92793的氨基酸残基1321-1701(SEQ ID NO:1))。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂基本上不结合以下氨基酸序列的一个或多个残基ENKFSAKRLPSTRLGTFLENRVNDFLRRQNHPESGEVTVRVVHASDKTVEVKPGMKARFVDSGEMAESFPYRTKALFAFEEIDGVDLCFFGMHVQEYGSDCPPPNQRRVYISYLDSVHFFRPKCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLSRGNKKKPGMPNVSNDLSQKLYATMEKHKEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLTLARDKHLEFSSLRRAQWSTMCMLVELHTQSQD(UniProt No.Q09472的氨基酸残基1285-1664(SEQ ID NO:2))。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂不抑制CBP和/或EP300的组蛋白乙酰基转移酶(HAT)催化活性。
作为CBP/EP300布罗莫结构域抑制剂的化合物被预期与其它化合物例如“HAT”抑制剂化合物相比具有改善和/或不同的性质。HAT抑制被预期导致蛋白质乙酰化的整体降低(组蛋白和非组蛋白),这可能显著影响细胞活力。在一些实施方案中,CBP/EP300布罗莫结构域抑制保持这些蛋白质的HAT活性同时使相对小的靶基因亚组的转录活性降低。
在一些实施方案中,本申请提供在患有癌症的个体中增强免疫功能的方法,其包括施用有效量的本申请所述任何CBP/EP300布罗莫结构域抑制剂。在任何所述方法的一些实施方案中,个体中的CD8 T细胞与施用CBP/EP300布罗莫结构域抑制剂前相比具有增强的致敏、活化、增殖和/或溶胞活性。在一些实施方案中,CD8 T细胞的数目与施用CBP/EP300布罗莫结构域抑制剂前相比是增加的。在一些实施方案中,CD8 T细胞与施用CBP/EP300布罗莫结构域抑制剂前相比具有一种或多种以下生物标志物的降低的表达水平:IFNA17、IGF1、FSCN1、SUMO2、CIorf129、EIF2S2、TDGF1、AIDA、CCR4、CD160、MC4R、KRTAP2-2、MTIJP、OR4N2、KRTAP4-5、MTIL//MTIL、ILI3、LCEID、KIR2DL2、LOC158696、LIF、IL28A、TAS2R13、CTLA4和/或FOXP3。在一些实施方案中,CD8 T细胞与施用CBP/EP300布罗莫结构域抑制剂前相比具有CD160和/或KIR2DL2的降低的表达水平。
在增强免疫功能的方法的一些实施方案中,增强的免疫功能的特征在于个体中的Treg细胞(例如在一个或多个肿瘤部位)与施用CBP/EP300布罗莫结构域抑制剂前相比具有一种或多种以下标志物的降低的表达水平:IL28A、GPR87、ANKRD37、CABLES1、RAPGEF2、TRIM69、MT1L//MT1L、FAM1138、FOXP3、CSF2、OCM2、GLIPR1、FGFBP2、CTLA4、CST7、GOLGA6L1、IFIT3、FAM13A、APOD、AK2、CLDN1、HSD11B1、DNAJC12、PHEX、IL2、FOXD4L3、GNA15、ZBTB32、RDH10、OR52E5、CYP2A6、GZMH、CCL20、ADM、LOC100131541、RNF122、FAM36A、AMY2B、GPR183、MYOF、IL29、AIDA、SPRYI、ENOPH1、IL1RN、SLAMF1、PGM2L1、SSBP3、MMP23B、HIST1H3J、MYO1B、BEND5、S1PR1、CDK6、GPR56、ZC3HIZA、DOK5、DUSPI、CYB5R2、KCNAB2、LAG3、KLF10、GK、SHC4、IL12RB2、CD109、HAVCR2(TIM-3)、LTA、FAM40B、HMGCSI、HSPA1A、ZNF705A、CMAH、KIF3A、CHN1、KBTBD8、TNF、MOP-1、RASGRP4、INSIG1、SLAMF7、OR10H4、LPL、HIST1H2BJ、LIF、IGF1、IL18RAP、OR52N4、OR1D2、CCR4、CXCR5、IL1R1、MICAL2、NRN1、PICALM、B3GNT5、IFI44L、CXCR3、ICOS、IFIT2、NCR3、HSPA1B、CD80、GNG2、C7orf68、GPR171、RPS10P7、IL23A、LOC283174、PLK2、EMP1、FNBP1L、CD226、RBMS3、IL23R、PTGER4、GZMB、F5和/或HIST1H2BK。在一些实施方案中,Treg细胞生物标志物是LAG3、CTLA4和/或FOXP3中的一种或多种。在增强免疫功能的方法的一些实施方案中,增强的免疫功能的特征在于未致敏的T细胞在Treg细胞存在下对CD3/CD28刺激的增强的响应性。在一些实施方案中,CD8 T细胞致敏的特征在于CD8 T细胞中增加的T细胞增殖和/或增强的溶胞活性。在一些实施方案中,CD8 T细胞活化的特征在于T-IFN+CD8 T细胞的升高的频率。在一些实施方案中,CD8 T细胞为抗原特异性T细胞。在一些实施方案中,免疫逃避被抑制。
在一些实施方案中,本申请提供的方法可用于治疗需要增强免疫原性的病症,例如就治疗癌症而言增加肿瘤免疫原性。例如,本申请提供用于增强T细胞功能以上调由细胞介导的免疫响应和用于治疗T细胞功能障碍病症、肿瘤免疫性的CBP/EP300布罗莫结构域抑制剂。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂通过抑制调节性T(Treg)细胞的抑制功能和/或缓解被长期刺激的CD8+T细胞的T细胞耗竭来促进抗肿瘤免疫性。CBP/EP300布罗莫结构域抑制剂还可用于在胸腺外Treg细胞分化期间降低FOXP3表达。持续的FOXP3表达就维持Treg细胞的抑制活性而言是必要的。在一些实施方案中,通过抑制CBP/EP300布罗莫结构域而减少的FOXP3表达削弱Treg细胞抑制活性并促进肿瘤抗免疫性。Treg细胞在源自多种癌症适应症的肿瘤中是高度富集的,包括黑素瘤、NSCLC、肾癌、卵巢癌、结肠癌、胰腺癌,肝细胞癌和乳腺癌。在这些适应症的一个亚组中,增加的瘤内Treg细胞密度与差的患者预后是相关的。这些适应症包括NSCLC、卵巢癌、胰腺癌、肝细胞癌和乳腺癌。CBP/EP300布罗莫结构域抑制剂被预期削弱这些癌症适应症中的瘤内Treg细胞功能以增强效应子T细胞活性。在其它实施方案中,CBP/EP300布罗莫结构域抑制剂可用于治疗以下感染性疾病,其中一些病原体可能已进化成操纵调节性T(Treg)细胞对宿主进行免疫抑制以确保存活,例如逆转录病毒感染(例如HIV)、分枝杆菌感染(例如结核病)和寄生虫感染(例如利什曼原虫和疟疾)。
在一些实施方案中,本申请提供的方法可用于治疗涉及纤维化的由CBP和/或EP300介导的病症。在一些实施方案中,由CBP和/或EP300介导的病症为纤维化疾病。某些纤维化疾病可包括例如肺纤维化、硅肺病、囊性纤维化、肾纤维化、肝纤维化、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、心内膜纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性大量纤维化、肾源性全身性纤维化、克罗恩病、瘢痕疙瘩、心肌梗塞、全身性硬化和关节纤维化。
在其它实施方案中,由CBP和/或EP300介导的病症为纤维化肺病。纤维化肺病可包括例如特发性肺纤维化、纤维化间质性肺病、间质性肺炎、非特异性间质性肺炎的纤维化变体、囊性纤维化、肺纤维化、慢性阻塞性肺病(COPD)或肺动脉高压。在某些实施方案中,纤维化肺病为特发性肺纤维化。
由CBP和/或EP300介导的病症
“由CBP和/或EP300介导的病症”的特征在于CBP和/或EP300的布罗莫结构域参与病症的一种或多种症状或疾病标志物、严重性或进展的出现、表现。在一个实施方案中,由布罗莫结构域介导的病症为由CBP布罗莫结构域介导的病症。在一个实施方案中,由布罗莫结构域介导的病症为由EP300布罗莫结构域介导的病症。
由CBP和/或EP300介导的病症包括癌症,包括但不限于听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病(单核细胞性、成髓细胞性、腺癌、血管肉瘤、星形细胞瘤、骨髓单细胞性和早幼粒细胞性)、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、子宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性(粒细胞性)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、异常增殖性变化(发育异常和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因瘤、纤维肉瘤、滤泡型淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、胶质肉瘤、重链病、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、淋巴管内皮肉瘤、淋巴管肉瘤、成淋巴细胞性白血病、淋巴瘤(霍奇金和非霍奇金淋巴瘤)、膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增殖性病症、T细胞或B细胞源性淋巴恶性肿瘤、髓样癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体瘤(癌瘤和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和威尔姆斯瘤。
在某些实施方案中,癌症是肺癌、乳腺癌、胰腺癌、结肠直肠癌和/或黑素瘤。在某些实施方案中,癌症是肺癌。在某些实施方案中,肺癌是NSCLC。在某些实施方案中,癌症是乳腺癌。
在某些实施方案中,癌症是黑素瘤。
由CBP和/或EP300介导的病症还包括炎性疾病、炎性病症和自身免疫性疾病,包括但不限于艾迪生病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、贝切特病、大疱性皮肤病、慢性阻塞性肺病(COPD)、克罗恩病、皮炎、湿疹、巨细胞性动脉炎、肾小球性肾炎、肝炎、垂体炎、炎性肠病、川崎病、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆汁性肝硬化、银屑病、银屑病性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、系统性红斑狼疮、高安动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、血管炎和韦格纳肉芽肿病。
由CBP和/或EP300介导的病症还包括AIDS;慢性肾病,包括但不限于糖尿病性肾病、高血压性肾病、HIV相关肾病、肾小球性肾炎、狼疮肾炎、IgA肾病、局灶性节段性肾小球硬化、膜性肾小球性肾炎、微小变化疾病、多囊性肾病和肾小管间质性肾炎;急性肾损伤或疾病或病症,包括但不限于由缺血-再灌注引起的、由心脏手术和大手术引起的、由经皮冠状动脉介入术引起的、由放射性造影剂引起的、由败血症引起的、由肺炎引起的和由药物毒性引起的;肥胖;血脂异常;高胆固醇血症;阿尔茨海默病;代谢综合征;肝脂肪变性;II型糖尿病;胰岛素抵抗;和糖尿病性视网膜病变。
CBP和/或EP300抑制剂还可用于实现男性节育。
由CBP和/或EP300介导的病症还包括纤维化疾病。某些纤维化疾病可包括例如肺纤维化、硅肺病、囊性纤维化、肾纤维化、肝纤维化、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、心内膜纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性大量纤维化、肾源性全身性纤维化、克罗恩病、瘢痕疙瘩、心肌梗塞、全身性硬化和关节纤维化。
由CBP和/或EP300介导的病症还包括纤维化肺病。纤维化肺病可包括例如特发性肺纤维化、纤维化间质性肺病、间质性肺炎、非特异性间质性肺炎的纤维化变体、囊性纤维化、肺纤维化、慢性阻塞性肺病(COPD)或肺动脉高压。在某些实施方案中,纤维化肺病为特发性肺纤维化。
化合物和其它药物的共同施用
式(I)或式(II)化合物或其盐可单独使用或与用于治疗的其它药物组合使用。例如,药物组合制剂或给药方案中的第二药物可具有与式(I)或式(II)化合物互补的活性以使它们不相互不利地影响。化合物可在单一药物组合物中一起施用或分开施用。在一个实施方案中,化合物或其药用盐可与细胞毒性剂共同施用以治疗增殖性疾病和癌症。
术语“共同施用”是指式(I)或式(II)化合物或其盐与另一种或多种活性药物成分(包括细胞毒性剂和放射治疗)的同时施用或任何方式的分开依序施用。若施用不是同时的,则化合物以彼此接近的时间施用。另外,化合物是否以相同剂型施用是无关紧要的,例如一种化合物可局部施用且另一种化合物可口服施用。
这些额外的药物可作为多重给药方案的一部分与含有本申请化合物的组合物分开施用。可选择地,这些药物可为单一剂型的一部分,与本申请化合物在单一组合物中一起混合。若作为多重给药方案的一部分施用,则两种活性剂可同时、依序或在彼此相隔的一段时间内且通常在彼此相隔的5小时内递送。
本申请使用的术语“组合”和相关术语是指根据本申请同时或依序施用治疗剂。例如,本申请化合物可按分开的单位剂型与另一种治疗剂同时或依序施用或按单一单位剂型与另一种治疗剂一起施用。因此,本申请提供单一单位剂型,其包含式I或式II化合物、额外的治疗剂和药用载体、辅料或媒介物。
可与载体物质组合以制备单一剂型的本申请化合物和额外的治疗剂这两者的量(在如上所述包含额外的治疗剂的那些组合物中)将随所治疗的宿主和具体的施用模式而变化。在某些实施方案中,将本申请组合物配制成可施用剂量为0.01-100mg/kg体重/天的本申请化合物。
通常,对所治疗的疾病或病症具有活性的任何药物可共同施用。此类药物的实例可参见Cancer Principles and Practice of Oncology,V.T.Devita和S.Hellman(编者),第6版(2001年2月15日),Lippincott Williams&Wilkins Publishers。本领域技术人员基于所涉及的药物和疾病的具体性质而能够辨别哪些药物组合可为有用的。
在一个实施方案中,治疗方法包括共同施用式(I)或式(II)化合物或其药用盐和至少一种细胞毒性剂。本申请使用的术语“细胞毒性剂”是指抑制或阻止细胞功能和/或引起细胞死亡或破坏的物质。细胞毒性剂包括但不限于放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素);化学治疗剂;生长抑制剂;酶及其片段,例如核酸水解酶;和毒素,例如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/或变体。
示例性细胞毒性剂可选自抗微管剂、铂配位复合物、烷化剂、抗生素、拓扑异构酶II抑制剂、抗代谢剂、拓扑异构酶I抑制剂、激素和激素类似物、信号转导途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂、脂肪酸生物合成抑制剂、细胞周期信号传导抑制剂、HDAC抑制剂、蛋白酶体抑制剂和癌症代谢抑制剂。
“化学治疗剂”包括可用于治疗癌症的化学化合物。化学治疗剂的实例包括厄洛替尼(Genentech/OSI Pharm.)、硼替佐米(MillenniumPharm.)、双硫仑、表没食子儿茶素没食子酸酯、salinosporamide A、卡非佐米、17-AAG(格尔德霉素)、根赤壳菌素、乳酸脱氢酶A(LDH-A)、氟维司群(AstraZeneca)、舒尼替尼(Pfizer/Sugen)、来曲唑(Novartis)、甲磺酸伊马替尼(Novartis)、finasunate(Novartis)、奥沙利铂(Sanofi)、5-FU(5-氟尿嘧啶)、甲酰四氢叶酸、雷帕霉素(Sirolimus,Wyeth)、拉帕替尼(GSK572016,Glaxo Smith Kline)、Lonafamib(SCH 66336)、索拉非尼(Bayer Labs)、吉非替尼(AstraZeneca)、AG1478、烷化剂例如噻替哌和环磷酰胺;烷基磺酸酯类,例如白消安、英丙舒凡和哌泊舒凡;氮丙啶类,例如苯佐替哌、卡波醌、美妥替哌和乌瑞替哌;乙撑亚胺类和甲基密胺类,包括六甲密胺、三乙撑密胺、三乙撑磷酰胺、三乙撑硫代磷酰胺和三羟甲密胺;番荔枝内酯类(尤其是布拉它辛和布拉它辛酮);喜树碱(包括托泊替康和伊立替康);苔藓抑素;callystatin;CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);隐藻素类(具体为隐藻素1和隐藻素8);肾上腺皮质类固醇(包括泼尼松和泼尼松龙);醋酸环丙孕酮;5α-还原酶,包括非那雄胺和度他雄胺;伏立诺他、罗米地辛、帕比司他、丙戊酸、mocetinostat、多拉司他丁;阿地白介素;滑石、倍癌霉素(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇;水鬼蕉碱;匍枝珊瑚醇;海绵抑制素;氮芥类,例如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥、苯芥胆留醇、泼尼莫司汀、曲磷胺、尿嘧啶氮芥;硝基脲类,例如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫斯汀和雷莫司汀;抗生素类,例如烯二炔抗生素类(例如刺孢霉素且尤其是刺孢霉素γ1I和刺孢霉素ω1I(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);达内霉素,包括达内霉素A;二膦酸盐类,例如氯膦酸盐;埃斯培拉霉素;及新制癌菌素生色团和相关色蛋白烯二炔抗生素生色团、阿克拉霉素类、放线菌素、氨茴霉素、重氮丝氨酸、博来霉素、放线菌素C、carabicin、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、(多柔比星)、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星和去氧多柔比星、表柔比星、依索比星、依达比星、麻西罗霉素、丝裂霉素例如丝裂霉素C、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢剂,例如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸、甲氨喋呤、喋罗呤、三甲曲沙;嘌呤类似物,例如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,例如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷;雄激素类,例如卡鲁睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷、睾内酯;抗肾上腺类,例如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,例如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;氨苯吖啶;bestrabucil;比生群;依达曲沙;地磷酰胺;地美可辛;地吖醌;依氟鸟氨酸;依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;美登木素生物碱类,例如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;二胺硝吖啶;喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;丙卡巴肼;
多糖复合物(JHS Natural Products,Eugene,Oreg.);雷佐生;根霉素;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2’,2”-三氯三乙胺;单端孢菌烯类(具体为T-2毒素、verracurin A、杆孢菌素A和蛇形菌素);乌拉坦;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;gacytosine;阿糖胞苷(“Ara-C”);环磷酰胺;噻替哌;类紫杉醇,例如TAXOL(紫杉醇;Bristol-Myers Squibb Oncology,Princeton,NJ)、(不含Cremophor)、紫杉醇的白蛋白工程化纳米粒制剂(AmericanPharmaceutical Partners,Schaumberg,Ill.)和(多西他塞;Sanofi-Aventis)、苯丁酸氮芥;(吉西他滨);6-硫鸟嘌呤;巯基嘌呤;甲氨喋呤;铂类似物,例如顺铂和卡铂;长春碱;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;(长春瑞滨);能灭瘤;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;卡培他滨伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇,例如视黄酸;和上述任何物质的药用盐、酸和衍生物。
化学治疗剂还包括(i)用于调节或抑制激素对肿瘤的作用的抗激素剂,例如抗雌激素类和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(包括枸橼酸他莫昔芬)、雷洛昔芬、屈洛昔芬、iodoxyfene、4-羟基他莫昔芬、曲沃昔芬、keoxifene、LY117018、奥那司酮和(枸橼酸托瑞米芬);(ii)对调节肾上腺中雌激素生成的芳香酶进行抑制的芳香酶抑制剂,例如4(5)-咪唑类、氨鲁米特、(醋酸甲地孕酮)、(依西美坦;Pfizer)、福美坦、法倔唑、(伏氯唑)、(来曲唑;Novartis)和(阿那曲唑;AstraZeneca);(iii)抗雄激素类,例如氟他米特、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;布舍瑞林、曲普瑞林、醋酸甲羟孕酮、己烯雌酚、普雷马林、氟甲睾酮、全反式维甲酸、芬维A胺及曲沙他滨(1,3-二氧杂环戊烷核苷胞嘧啶类似物);(iv)蛋白激酶抑制剂;(v)脂质激酶抑制剂;(vi)反义寡核苷酸,具体为对参与异常细胞增殖的信号传导途径中的基因的表达进行抑制的那些反义寡核苷酸,例如PKC-α、Ralf和H-Ras;(vii)核酶,例如VEGF表达抑制剂(例如)和HER2表达抑制剂;(viii)疫苗,例如基因疗法疫苗,例如和 rIL-2;拓扑异构酶1抑制剂,例如 和(ix)上述任何物质的药用盐、酸和衍生物。
化学治疗剂还包括抗体,例如阿仑单抗(Campath)、贝伐单抗(Genentech);西妥昔单抗(Imclone);帕尼单抗(Amgen)、利妥昔单抗(Genentech/Biogen Idec)、培妥珠单抗(2C4,Genentech)、曲妥珠单抗(Genentech)、托西莫单抗(Bexxar,Corixia)和抗体药物缀合物吉妥珠单抗奥佐米星(Wyeth)。具有作为药物与本申请化合物组合的治疗潜力的其它人源化单克隆抗体包括阿泊珠单抗、阿塞珠单抗、atlizumab、巴品珠单抗、bivatuzumab mertansine、cantuzumab mertansine、西利珠单抗、培舍珠单抗、cidfusituzumab、cidtuzumab、达克珠单抗、依库利珠单抗、依法利珠单抗、依帕珠单抗、厄利珠单抗、非维珠单抗、芳妥珠单抗、吉妥珠单抗奥佐米星、英妥珠单抗奥佐米星、易普利单抗、拉贝珠单抗、林妥珠单抗、马妥珠单抗、美泊利单抗、莫维珠单抗、motovizumab、那他珠单抗、尼妥珠单抗、nolovizumab、numavizumab、ocrelizumab、奥玛珠单抗、帕利珠单抗、帕考珠单抗、pecfusituzumab、pectuzumab、培克珠单抗、ralivizumab、兰尼单抗、reslivizumab、瑞利珠单抗、resyvizumab、罗维珠单抗、鲁利珠单抗、西罗珠单抗、西利珠单抗、索土珠单抗、tacatuzumab tetraxetan、tadocizumab、他利珠单抗、特非珠单抗、托珠单抗、托利珠单抗、tucotuzumab celmoleukin、tucusituzumab、umavizumab、乌珠单抗、优特克单抗、维西珠单抗和抗白细胞介素-12(ABT-874/J695,Wyeth Research and AbbottLaboratories)(其为经遗传修饰以识别白细胞介素-12p40蛋白的排他性重组人序列全长IgG1λ抗体)。
化学治疗剂还包括“EGFR抑制剂”,其是指与EGFR结合或以其它方式与EGFR直接相互作用且抑制或降低其信号传导活性的化合物且还可称为“EGFR拮抗剂”。此类药物的实例包括与EGFR结合的抗体和小分子。与EGFR结合的抗体的实例包括MAb579(ATCC CRLHB8506)、MAb455(ATCC CRL HB8507)、MAb225(ATCC CRL 8508)、MAb528(ATCC CRL 8509)(参见美国专利4,943,533,Mendelsohn等人)及其变体例如嵌合225(C225或西妥昔单抗;)和重构人225(H225)(参见W096/40210,Imclone Systerms Inc.);IMC-11F8,其为完整人EGFR靶向抗体(Imclone);与II型突变EGFR结合的抗体(美国专利5,212,290);与EGFR结合的人源化和嵌合抗体,参见美国专利5,891,996;和与EGFR结合的人抗体,例如ABX-EGF或帕尼单抗(参见WO98/50433,Abgenix/Amgen);EMD55900(Stragliotto等人,Eur.J.Cancer 32A:636-640(1996));EMD7200(matuzumab),其为针对EGFR且与EGF和TGF-α竞争EGFR结合的人源化EGFR抗体(EMD/Merck);人EGFR抗体HuMax-EGFR(GenMab);已知为El.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3和E7.6.3且描述在US6,235,883中的完整人抗体;MDX-447(Medarex Inc);和mAb806或人源化mAb806(Johns等人,J.Biol.Chem.279(29):30375-30384(2004))。抗EGFR抗体可与细胞毒性剂缀合,由此产生免疫缀合物(参见例如EP659,439A2,Merck Patent GmbH)。EGFR拮抗剂包括小分子例如描述在以下文献中的化合物:美国专利5,616,582、5,457,105、5,475,001、5,654,307、5,679,683、6,084,095、6,265,410、6,455,534、6,521,620、6,596,726、6,713,484、5,770,599、6,140,332、5,866,572、6,399,602、6,344,459、6,602,863、6,391,874、6,344,455、5,760,041、6,002,008和5,747,498及以下PCT公开文本:WO98/14451、WO98/50038、WO99/09016和WO99/24037。具体的小分子EGFR拮抗剂包括OSI-774(CP-358774,厄洛替尼,(Genentech/OSIPharmaceuticals);PD183805(CI1033,N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(4-吗啉基)丙氧基]-6-喹唑啉基]-2-丙烯酰胺二盐酸盐,Pfizer Inc.);ZD1839即吉非替尼(4-(3’-氯-4’-氟苯氨基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑琳,Zeneca);ZM105180((6-氨基-4-(3-甲基苯基-氨基)-喹唑琳,Zeneca);BIBX-1382(N8-(3-氯-4-氟-苯基)-N2-(1-甲基-哌啶-4-基)-嘧啶并[5,4-d]嘧啶-2,8-二胺,Boehringer Ingelheim);PKI-166((R)-4-[4-[(1-苯基乙基)氨基]-1H-吡咯并[2,3-d]嘧啶-6-基]-苯酚);(R)-6-(4-羟基苯基)-4-[(1-苯基乙基)氨基]-7H-吡咯并[2,3-d]嘧啶);CL-387785(N-[4-[(3-溴苯基)氨基]-6-喹唑啉基]-2-丁炔酰胺);EKB-569(N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲基氨基)-2-丁烯酰胺)(Wyeth);AG1478(Pfizer);AG1571(SU5271;Pfizer);双重EGFR/HER2酪氨酸激酶抑制剂,例如拉帕替尼(GSK572016或N-[3-氯-4-[(3-氟苯基)甲氧基]苯基]-6[5-[[[2-甲基磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺)。
化学治疗剂还包括“酪氨酸激酶抑制剂”,包括前面段落所描述的EGFR靶向药物;小分子HER2酪氨酸激酶抑制剂,例如可得自Takeda的TAK165;CP-724,714,其为ErbB2受体酪氨酸激酶的口服选择性抑制剂(Pfizer和OSI);双重HER抑制剂,例如EKB-569(可得自Wyeth),其优先与EGFR结合,但是抑制HER2和EGFR过表达细胞;拉帕替尼(GSK572016;可得自Glaxo-SmithKline),其为口服HER2和EGFR酪氨酸激酶抑制剂;PKI-166(可得自Novartis);泛HER抑制剂,例如canertinib(CI-1033;Pharmacia);Raf-1抑制剂,例如可得自ISIS Pharmaceuticals的反义药物ISIS-5132,其抑制Raf-1信号传导;非HER靶向TK抑制剂,例如甲磺酸伊马替尼(可得自Glaxo SmithKline);多靶点酪氨酸激酶抑制剂,例如舒尼替尼(可得自Pfizer);VEGF受体酪氨酸激酶抑制剂,例如瓦他拉尼(PTK787/ZK222584,可得自Novartis/Schering AG);MAPK细胞外调节激酶I抑制剂CI-1040(可得自Pharmacia);喹唑啉类,例如PD153035即4-(3-氯苯氨基)喹唑啉;吡啶并嘧啶类;嘧啶并嘧啶类;吡咯并嘧啶类,例如CGP59326、CGP60261和CGP62706;吡唑并嘧啶类,4-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶类;姜黄素(二阿魏酰甲烷,4,5-二(4-氟苯氨基)邻苯二甲酰亚胺);含有硝基噻吩部分的磷酸酪氨酸类;PD-0183805(Warner-Lamber);反义分子(例如与HER编码核酸结合的那些反义分子);喹喔啉类(美国专利5,804,396);磷酸酪氨酸类(美国专利5,804,396);ZD6474(Astra Zeneca);PTK-787(Novartis/Schering AG);泛HER抑制剂,例如CI-1033(Pfizer);Affinitac(ISIS3521;Isis/Lilly);甲磺酸伊马替尼PKI166(Novartis);GW2016(Glaxo SmithKline);CI-1033(Pfizer);EKB-569(Wyeth);Semaxinib(Pfizer);ZD6474(AstraZeneca);PTK-787(Novartis/ScheringAG);INC-1C11(Imclone);雷帕霉素(西罗莫司,);或描述在以下任何专利公开文本中的化学治疗剂:美国专利5,804,396、WO1999/09016(American Cyanamid)、WO1998/43960(American Cyanamid)、WO1997/38983(Warner Lambert)、WO1999/06378(Warner Lambert)、WO1999/06396(Warner Lambert)、WO1996/30347(Pfizer,Inc)、WO1996/33978(Zeneca)、WO1996/3397(Zeneca)和WO1996/33980(Zeneca)。
化学治疗剂还包括地塞米松、干扰素、秋水仙碱、美托品、环孢菌素、两性霉素、甲硝唑、阿仑单抗、阿利维甲酸、别嘌呤醇、氨磷汀、三氧化二砷、天冬酰胺酶、活卡介苗、贝伐单抗、贝沙罗汀、克拉屈滨、氯法巴明、达比泊汀α、地尼白介素、右雷佐生、阿法依泊汀、厄洛替尼、非格司亭、乙酸组氨瑞林、替伊莫单抗、干扰素α-2a、干扰素α-2b、来那度胺、左旋咪唑、美司钠、甲氧沙林、诺龙、奈拉滨、诺菲妥珠单抗、奥普瑞白介素、帕利夫明、帕米膦酸、培加酶、培门冬酶、培非格司亭、培美曲塞二钠、普拉霉素、卟吩姆钠、奎纳克林、拉布立酶、沙莫司亭、替莫唑胺、VM-26、6-TG、托瑞米芬、维甲酸、ATRA、戊柔比星、唑来膦酸盐和唑来膦酸及其药用盐。
化学治疗剂还包括氢化可的松、醋酸氢化可的松、醋酸可的松、特戊酸替可的松、曲安奈德、曲安西龙醇、莫米松、安西奈德、布地奈德、地奈德、氟轻松、氟西奈德、倍他米松、倍他米松磷酸钠、地塞米松、地塞米松磷酸钠、氟可龙、氢化可的松-17-丁酸酯、氢化可的松-17-戊酸酯、二丙酸阿氯米松、戊酸倍他米松、二丙酸倍他米松、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍他松-17-丙酸酯、己酸氟可龙、特戊酸氟可龙和醋酸氟泼尼定;免疫选择性抗炎肽(ImSAID),例如苯丙氨酸-谷氨酰胺-甘氨酸(FEG)及其D-异构体(feG)(IMULANBioTherapeutics,LLC);抗风湿药物,例如硫唑嘌呤、环孢菌素(环孢霉素A)、D-青霉胺、金盐、羟氯喹、来氟米特、米诺环素、柳氮磺吡啶、肿瘤坏死因子α(TNFα)阻断剂例如依那西普(Enbrel)、英夫利昔单抗(Remicade)、阿达木单抗(Humira)、培舍珠单抗(Cimzia)、戈利木单抗(Simponi)、白细胞介素1(IL-1)阻断剂例如阿那白滞素(Kineret)、T细胞共刺激阻断剂例如阿巴西普(Orencia)、白细胞介素6(IL-6)阻断剂例如托珠单抗白细胞介素13(IL-13)阻断剂,例如雷贝珠单抗;干扰素α(IFN)阻断剂,例如罗利珠单抗;β7整合素阻断剂,例如rhuMAb Beta7;IgE途径阻断剂,例如抗M1引物;分泌同源三聚体LTa3和膜结合异源三聚体LTa1/β2阻断剂,例如抗淋巴毒素α(LTa);放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素);各种研究性药剂,例如thioplatin、PS-341、苯丁酸类、ET-18-OCH3或法尼基转移酶抑制剂(L-739749、L-744832);多酚类,例如槲皮素、白藜芦醇、白皮杉醇、表没食子儿茶素没食子酸酯、茶黄素、黄烷醇类、原花青素类、桦木酸及其衍生物;自噬抑制剂,例如氯喹;δ-9-四氢大麻酚(屈大麻酚,);β-拉帕醌;拉帕醇;秋水仙碱;桦木酸;乙酰喜树碱、莨菪亭和9-氨基喜树碱;鬼臼毒素;替加氟贝沙罗汀二膦酸盐,例如氯膦酸盐(例如或)、依替膦酸盐NE-58095、唑来膦酸/唑来膦酸盐阿仑膦酸盐帕米膦酸盐替鲁膦酸盐或利塞膦酸盐和表皮生长因子受体(EGF-R);疫苗,例如疫苗;哌立福辛、COX-2抑制剂(例如塞来考昔或依托考昔)、蛋白酶体抑制剂(例如PS341);CCI-779;替吡法尼(R11577);奥拉非尼、ABT510;Bcl-2抑制剂,例如奥美林钠pixantrone;法尼基转移酶抑制剂,例如拉那非尼(SCH6636,SARASARTM);和上述任何药物的药用盐、酸或衍生物;及上述两种或更多种药物的组合,例如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙的组合疗法的缩写)和FOLFOX(奥沙利铂(ELOXATINTM)与5-FU和亚叶酸的组合治疗方案的缩写)。
化学治疗剂还包括具有镇痛、解热和抗炎作用的非甾体抗炎药。
NSAID包括环加氧酶的非选择性抑制剂。NSAID的具体实例包括阿司匹林;丙酸衍生物,例如布洛芬、非诺洛芬、酮洛芬、氟比洛芬、奥沙普嗪和萘普生;乙酸衍生物,例如吲哚美辛、舒林酸、依托度酸、双氯芬酸;烯醇酸衍生物,例如吡罗昔康、美洛昔康、替诺昔康、屈噁昔康、氯诺昔康和依索昔康;芬那酸衍生物,例如甲芬那酸、甲氯芬那酸、氟芬那酸、托芬那酸;和COX-2抑制剂,例如塞来考昔、依托考昔、鲁米考昔、帕瑞考昔、罗非考昔、罗非考昔和伐地考昔。NSAID可用于病症的症状缓解,所述病症为例如类风湿性关节炎、骨关节炎、炎性关节病、强直性脊柱炎、银屑病性关节炎、赖特综合征、急性痛风、痛经、转移性骨痛、头痛和偏头痛、术后疼痛、由于炎症和组织损伤而引起的轻度至中度疼痛、发热、肠梗阻和肾绞痛。
在某些实施方案中,化学治疗剂包括但不限于多柔比星、地塞米松、长春新碱、环磷酰胺、氟尿嘧啶、托泊替康、干扰素、铂衍生物、紫杉烷类(例如紫杉醇、多西他赛)、长春花生物碱(例如长春碱)、蒽环类(例如阿霉素)、表鬼臼毒素(例如依托泊苷)、顺铂、mTOR抑制剂(例如雷帕霉素)、甲氨蝶呤、放线菌素D、多拉司他丁10、秋水仙碱、三甲曲沙、美托品、环孢霉素、柔红霉素、替尼泊苷、两性霉素、烷化剂(例如苯丁酸氮芥)、5-氟尿嘧啶、喜树碱、顺铂、甲硝唑和甲磺酸伊马替尼等。在其它实施方案中,本申请化合物与生物药物例如贝伐单抗或帕尼单抗组合施用。
在某些实施方案中,本申请化合物或其药用组合物与选自以下任何一种或多种的抗增殖剂或化学治疗剂组合施用:阿巴瑞克、阿地白介素、阿仑单抗、阿利维A酸、别嘌呤醇、六甲蜜胺、氨磷汀、阿那曲唑、三氧化二砷、天冬酰胺酶、阿扎胞苷、活卡介苗、贝伐单抗,氟尿嘧啶,贝沙罗汀、博来霉素、硼替佐米、白消安、卡鲁睾酮、卡培他滨、喜树碱、卡铂、卡莫司汀、西妥昔单抗、苯丁酸氮芥、克拉屈滨、氯法巴明、环磷酰胺、阿糖胞苷、更生霉素、达比泊汀α、阿柔比星、地尼白介素、右雷佐生、多西他赛、阿霉素(中性)、盐酸阿霉素、丙酸屈他雄酮、表柔比星、阿法依泊汀、厄洛替尼、雌莫司汀、磷酸依托泊苷、依托泊苷、依西美坦、非格司亭、氟尿苷、氟达拉滨、氟维司群、吉非替尼、吉西他滨、吉妥珠单抗、乙酸戈舍瑞林、乙酸组氨瑞林、羟基脲、替伊莫单抗、依达比星、异环磷酰胺、甲磺酸伊马替尼、干扰素α-2a、干扰素α-2b、伊立替康、来那度胺、来曲唑、甲酰四氢叶酸、乙酸亮丙瑞林、左旋咪唑、洛莫司汀、乙酸甲地孕酮、美法仑、巯嘌呤、6-MP、美司钠、甲氨蝶呤、甲氧沙林、丝裂霉素C、米托坦、米托蒽醌、诺龙酮、奈拉滨、诺菲妥珠单抗、奥普瑞白介素、奥沙利铂、紫杉醇、帕利夫明、帕米膦酸盐、培加酶、培门冬酶、培非格司亭、培美曲塞二钠、喷司他丁、哌泊溴烷、普拉霉素、卟吩姆钠、丙卡巴肼、奎纳克林、拉布立酶、利妥昔单抗、沙莫司亭、索拉非尼、链佐星、马来酸舒尼替尼、滑石、他莫昔芬、替莫唑胺、替尼泊苷、VM-26、睾内酯、硫鸟嘌呤、6-TG、噻替哌、托泊替康、托瑞米芬、托西莫单抗、曲妥珠单抗、维A酸、ATRA、尿嘧啶氮芥、戊柔比星、长春碱、长春新碱、长春瑞滨、唑来膦酸盐或唑来膦酸。
化学治疗剂还包括针对阿尔茨海默病的治疗,例如盐酸多奈哌齐和利伐斯的明;针对帕金森病的治疗,例如L-DOPA/卡比多巴、恩他卡朋、罗吡尼洛、普拉克索、溴隐亭、培高利特、trihexephendyl和金刚烷胺;用于治疗多发性硬化(MS)的药物,例如β干扰素(例如和)、醋酸格拉默和米托蒽醌;针对哮喘的治疗,例如沙丁胺醇和孟鲁司特钠;用于治疗精神分裂症的药物,例如再普乐、维思通、思瑞康和氟哌啶醇;抗炎剂,例如皮质类固醇、TNF阻断剂、IL-1RA、硫唑嘌呤、环磷酰胺和柳氮磺胺吡啶;免疫调节剂和免疫抑制剂,例如环孢菌素、他克莫司、雷帕霉素、吗替麦考酚酯、干扰素、皮质类固醇、环磷酰胺、硫唑嘌呤和柳氮磺胺吡啶;神经营养因子,例如乙酰胆碱酯酶抑制剂、MAO抑制剂、干扰素、抗惊厥剂、离子通道阻断剂、利鲁唑和抗帕金森病剂;用于治疗心血管疾病的药物,例如β-阻断剂、ACE抑制剂、利尿剂、硝酸酯、钙通道阻断剂和他汀类;用于治疗肝病的药物,例如皮质类固醇、考来烯胺、干扰素和抗病毒剂;用于治疗血液病症的药物,例如皮质类固醇、抗白血病剂和生长因子;和用于治疗免疫缺陷病症的药物,例如γ球蛋白。
另外,化学治疗剂包括本申请所述任何化学治疗剂的药用盐、酸或衍生物及其中两种或更多种的组合。
在另一个实施方案中,本申请提供使用CBP/EP300布罗莫结构域抑制剂与PD-1轴结合拮抗剂组合治疗癌症和/或延缓癌症进展的方法。本申请还提供在患有癌症的个体中增强免疫功能的方法,其包括向所述个体施用有效量的CBP/EP300布罗莫结构域抑制剂和有效量的PD-1轴结合拮抗剂。PD-1轴结合拮抗剂包括PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。
术语“PD-1轴结合拮抗剂”是以下分子,其抑制PD-1轴结合配偶体与一种或多种其结合配偶体相互作用以去除由于PD-1信号传导轴上的信号传导而引起的T细胞功能障碍,结果是恢复或增强T细胞功能(例如增殖、细胞因子产生、靶细胞杀灭)。本申请使用的PD-1轴结合拮抗剂包括PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。
术语“PD-1结合拮抗剂”是以下分子,其减少、阻断、抑制、消除或干扰由于PD-1与一种或多种其结合配偶体例如PDL1、PDL2相互作用而引起的信号转导。在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其结合配偶体结合的分子。在具体方面,PD-1结合拮抗剂抑制PD-1与PDL1和/或PDL2结合。例如,PD-1结合拮抗剂包括抗PD-1抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和使由于PD-1与PDL1和/或PDL2相互作用而引起的信号转导得以减少、阻断、抑制、消除或干扰的其它分子。在一个实施方案中,PD-1结合拮抗剂减少由在以下T淋巴细胞上表达的细胞表面蛋白介导的负性共刺激信号,所述T淋巴细胞由PD-1介导信号传导,从而使功能失调的T细胞是较少功能失调的(例如增强对抗原识别的效应子响应)。在一些实施方案中,PD-1结合拮抗剂是抗PD-1抗体。在具体方面,PD-1结合拮抗剂为本申请所述纳武单抗(也称为MDX-1106-04、MDX-1106、ONO-4538、BMS-936558和)。在另一个具体方面,PD-1结合拮抗剂为本申请所述派姆单抗(也称为MK-3475、Merck 3475、和SCH-900475)。在另一个具体方面,PD-1结合拮抗剂为本申请所述CT-011(也称为hBAT或hBAT-1)。在另一个具体方面,PD-1结合拮抗剂为本申请所述AMP-224(也称为B7-DCIg)。
术语“PDL1结合拮抗剂”是以下分子,其减少、阻断、抑制、消除或干扰由于PDL1与一种或多种其结合配偶体例如PD-1、B7-1相互作用而引起的信号转导。在一些实施方案中,PDL1结合拮抗剂是抑制PDL1与其结合配偶体结合的分子。在具体方面,PDL1结合拮抗剂抑制PDL1与PD-1和/或B7-1结合。在一些实施方案中,PDL1结合拮抗剂包括抗PDL1抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和使由于PDL1与一种或多种其结合配偶体例如PD-1、B7-1相互作用而引起的信号转导得以减少、阻断、抑制、消除或干扰的其它分子。在一个实施方案中,PDL1结合拮抗剂减少由在以下T淋巴细胞上表达的细胞表面蛋白介导的负性共刺激信号,所述T淋巴细胞由PDL1介导信号传导,从而使功能失调的T细胞是较少功能失调的(例如增强对抗原识别的效应子响应)。在一些实施方案中,PDL1结合拮抗剂是抗PDL1抗体。在具体方面,抗PDL1抗体为本申请所述YW243.55.S70。在另一个具体方面,抗PDL1抗体为本申请所述MDX-1105(也称为BMS-936559)。在另一个具体方面,抗PDL1抗体为本申请所述MPDL3280A。在另一个具体方面,抗PDL1抗体为本申请所述MEDI4736。
术语“PDL2结合拮抗剂”是以下分子,其减少、阻断、抑制、消除或干扰由于PD-L2与一种或多种其结合配偶体例如PD-1相互作用而引起的信号转导。在一些实施方案中,PD-L2结合拮抗剂是抑制PD-L2与其结合配偶体结合的分子。在具体方面,PD-L2结合拮抗剂抑制PD-L2与PD-1结合。在一些实施方案中,PD-L2拮抗剂包括抗PD-L2抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和使由于PD-L2与一种或多种其结合配偶体例如PD-1相互作用而引起的信号转导得以减少、阻断、抑制、消除或干扰的其它分子。在一个实施方案中,PD-L2结合拮抗剂减少由在以下T淋巴细胞上表达的细胞表面蛋白介导的负性共刺激信号,所述T淋巴细胞由PD-L2介导信号传导,从而使功能失调的T细胞是较少功能失调的(例如增强对抗原识别的效应子响应)。在一些实施方案中,PD-L2结合拮抗剂为免疫粘附素。
“PD-1”的可选名称包括CD279和SLEB2。“PD-L1”的可选名称包括B7-H1、B7-4、CD274和B7-H。“PD-L2”的可选名称包括B7-DC、Btdc和CD273。在一些实施方案中,PD-1、PD-L1和PD-L2是人PD-1、PD-L1和PD-L2。在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其配体结合配偶体结合的分子。在具体方面,PD-1配体结合配偶体是PD-L1和/或PD-L2。在另一个实施方案中,PD-L1结合拮抗剂是抑制PD-L1与其结合配偶体结合的分子。在具体方面,PD-L1结合配偶体是PD-1和/或B7-1。在另一个实施方案中,PD-L2结合拮抗剂是抑制PD-L2与其结合配偶体结合的分子。在具体方面,PD-L2结合配偶体是PD-1。拮抗剂可为抗体、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。在一些实施方案中,PD-1结合拮抗剂是抗PD-1抗体(例如人抗体、人源化抗体或嵌合抗体)。在一些实施方案中,抗PD-1抗体选自MDX-1106、Merck 3475(也称为派姆单抗、lambrolizumab或MK-3475)、纳武单抗(BMS-936558)、CT-011和MPDL3280A。在一些实施方案中,PD-1结合拮抗剂是免疫粘附素(例如包含与恒定区(例如免疫球蛋白序列的Fc区)融合的PD-L1或PD-L2的细胞外或PD-1结合部分的免疫粘附素)。在一些实施方案中,PD-1结合拮抗剂是AMP-224。在一些实施方案中,PD-L1结合拮抗剂是抗PD-L1抗体。在一些实施方案中,抗PD-L1结合拮抗剂选自YW243.55.S70、MPDL3280A和MDX-1105。MDX-1105(也称为BMS-936559)是在WO2007/005874中描述的抗PD-L1抗体。抗体YW243.55.S70(重链和轻链可变区序列分别如SEQ ID NO:20和21所示)是在WO2010/077634A1中描述的抗PD-L1。MDX-1106(也称为MDX-1106-04、ONO-4538或BMS-936558)是在WO2006/121168中描述的抗PD-1抗体。Merck 3745(也称为MK-3475或SCH-900475)是在WO2009/114335中描述的抗PD-1抗体。CT-011(也称为hBAT或hBAT-1)是在WO2009/101611中描述的抗PD-1抗体。AMP-224(也称为B7-DCIg)是在WO2010/027827和WO2011/066342中描述的PD-L2-Fc融合可溶性受体。在一些实施方案中,抗PD-1抗体是MDX-1106。“MDX-1106”的可选名称包括MDX-1106-04、ONO-4538、BMS-936558或纳武单抗。在一些实施方案中,抗PD-1抗体是纳武单抗(CAS登记号为946414-94-4)。在一些实施方案中,癌症是黑素瘤、NSCLC和肾细胞癌。
为了治疗炎性疾病或自身免疫性疾病,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:甲氨蝶呤、托法替尼、6-巯基嘌呤、硫唑嘌呤、柳氮磺胺吡啶、美沙拉嗪、奥沙拉嗪、氯喹/羟氯喹、青霉胺、金硫苹果酸盐(肌内和口服)、硫唑嘌呤、秋水仙碱、皮质类固醇(口服、吸入和局部注射)、β2肾上腺素受体激动剂(沙丁胺醇、特布他林、salmeteral)、黄嘌呤(茶碱、氨茶碱)、色甘酸盐/酯、奈多罗米、酮替芬、异丙托铵和氧托品、环孢菌素、FK506、雷帕霉素、吗替麦考酚酯、来氟米特、NSAID(例如布洛芬)、皮质类固醇(例如泼尼松龙)、磷酸二酯酶抑制剂、腺苷激动剂、抗血栓形成剂、补体抑制剂、肾上腺素能剂、通过促炎细胞因子例如TNF或IL-1干扰信号传导的药物(例如NIK、IKK、p38或MAP激酶抑制剂)、IL-1转化酶抑制剂、T细胞信号传导抑制剂(例如激酶抑制剂)、金属蛋白酶抑制剂、柳氮磺吡啶、6-巯基嘌呤、血管紧张素转化酶抑制剂、可溶性细胞因子受体(例如可溶性p55或p75TNF受体及衍生物p75TNFRigG(依那西普)和p55TNFRigG(来那西普)、siL-1RI、siL-1RII、siL-6R)、抗炎细胞因子(例如IL-4、IL-10、IL-11、IL-13和TGF)、塞来考昔、叶酸、硫酸羟氯喹、罗非考昔、依那西普、英夫利昔单抗、阿达木单抗、赛妥珠单抗、托珠单抗、阿巴西普、萘普生、伐地考昔、柳氮磺吡啶、甲泼尼龙、美洛昔康、醋酸甲泼尼龙、金硫苹果酸钠、阿司匹林、曲安奈德、萘磺酸丙氧酚/对乙酰氨基酚、叶酸、萘丁美酮、双氯芬酸、吡罗昔康、依托度酸、双氯芬酸钠、奥沙普嗪、盐酸羟考酮、重酒石酸氢可酮/对乙酰氨基酚、双氯芬酸钠/米索前列醇、芬太尼、阿那白滞素、盐酸曲马多、双水杨酯、舒林酸、氰钴胺/fa/吡多辛、对乙酰氨基酚、阿仑膦酸钠、泼尼松龙、可的松、倍他米松、硫酸吗啡、盐酸利多卡因、吲哚美辛、硫酸葡萄糖胺/软骨素、盐酸阿米替林、磺胺嘧啶、盐酸羟考酮、对乙酰氨基酚、盐酸奥洛他定、米索前列醇、萘普生钠、奥美拉唑、环磷酰胺、利妥昔单抗、IL-1 TRAP、MRA、CTLA4-IG、IL-18 BP、抗IL-12、抗ILlS、BIRB-796、SCI0-469、VX-702、AMG-548、VX-740、罗氟司特、IC-485、CDC-801、S1Pl激动剂(例如FTY720)、PKC家族抑制剂(例如Ruboxistaurin或AEB-071)或Mesopram。在某些实施方案中,式(I)或式(II)化合物或其药用盐可与甲氨蝶呤或来氟米特共同施用。在中度或重度类风湿性关节炎病例中,式(I)或式(II)化合物或其药用盐可如上所述与环孢菌素和抗TNF抗体共同施用。式(I)或式(II)化合物或其药用盐也可与以下药物共同施用:布地奈德;表皮生长因子;皮质类固醇;环孢菌素、柳氮磺吡啶;对氨基水杨酸盐/酯;6-巯基嘌呤;硫唑嘌呤;甲硝唑;脂氧合酶抑制剂;美沙拉嗪;奥沙拉嗪;巴柳氮;抗氧化剂;血栓烷抑制剂;IL-1受体拮抗剂;抗IL-1单克隆抗体;抗IL-6单克隆抗体;生长因子;弹性蛋白酶抑制剂;吡啶基-咪唑化合物;针对其它人细胞因子或生长因子(例如TNF、LT、IL-1、IL-2、IL-6、IL-7、IL-8、IL-12、IL-15、IL-16、IL-23、EMAP-II、GM-CSF、FGF和PDGF)的抗体或拮抗剂;细胞表面分子(例如CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69或CD90或其配体);甲氨蝶呤;环孢菌素;FK506;雷帕霉素;吗替麦考酚酯;来氟米特;NSAID(例如布洛芬);皮质类固醇(例如泼尼松龙);磷酸二酯酶抑制剂;腺苷激动剂;抗血栓形成剂;补体抑制剂;肾上腺素能剂;通过促炎细胞因子例如TNF5或IL-1干扰信号传导的药物(例如NIK、IKK或MAP激酶抑制剂);IL-1转化酶抑制剂;TNF转化酶抑制剂;T细胞信号传导抑制剂,例如激酶抑制剂;金属蛋白酶抑制剂;柳氮磺吡啶;硫唑嘌呤;6-巯基嘌呤;血管紧张素转化酶抑制剂;可溶性细胞因子受体(例如可溶性p55或p75TNF受体、siL-1RI、siL-1RII、siL-6R)和抗炎细胞因子(例如IL-4、IL-10、IL-11、IL-13或TGF)。
为了治疗克罗恩病,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:TNF拮抗剂(例如抗TNF抗体)、D2E7(阿达木单抗)、CA2(英夫利昔单抗)、CDP571、TNFR-Ig构建体(p75TNFRigG(依那西普))、p55TNFRigG(LENERCEPTTM)抑制剂或PDE4抑制剂。
为了治疗炎性肠病,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:皮质类固醇(例如布地奈德或地塞米松);柳氮磺吡啶、5-氨基水杨酸;奥沙拉嗪;干扰促炎细胞因子例如IL-1的合成或作用的药物(例如IL-1转化酶抑制剂或IL-1ra);T细胞信号传导抑制剂(例如酪氨酸激酶抑制剂);6-巯基嘌呤;IL-11;美沙拉嗪;泼尼松;硫唑嘌呤;巯基嘌呤;英夫利昔单抗;甲泼尼龙琥珀酸钠;地诺芬酯/硫酸阿托品;盐酸洛哌丁胺;甲氨蝶呤;奥美拉唑;叶酸;环丙沙星/葡萄糖-水;重酒石酸氢可酮/对乙酰氨基酚;盐酸四环素;氟轻松;甲硝唑;硫柳汞/硼酸;考来烯胺/蔗糖;盐酸环丙沙星;硫酸莨菪碱;盐酸哌替啶;盐酸咪达唑仑;盐酸羟考酮/对乙酰氨基酚;盐酸异丙嗪;磷酸钠;磺胺甲噁唑/甲氧苄啶;塞来考昔;聚卡波非;萘磺酸丙氧酚;氢化可的松;多维生素剂;巴柳氮二钠;磷酸可待因/对乙酰氨基酚;盐酸考来维仑;氰钴胺;叶酸;左氧氟沙星;甲泼尼龙;那他珠单抗或干扰素-γ。
为了治疗多发性硬化,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:皮质类固醇;泼尼松龙;甲泼尼龙;硫唑嘌呤;环磷酰胺;环孢菌素;甲氨蝶呤;4-氨基吡啶;替扎尼定;干扰素-1a(Biogen);干扰素-lb(Chiron/Berlex);干扰素-n3(Interferon Sciences/Fujimoto)、干扰素-α(Wassermann/J&J)、干扰素lA-IF(Serono/Inhale Therapeutics)、聚乙二醇化干扰素2b(Enzon/Schering-Plough)、共聚物1(Cop-1;Teva Pharmaceutical Industries,Inc.);高压氧气;静脉用免疫球蛋白;克拉屈滨;针对其它人细胞因子或生长因子及其受体(例如TNF、LT、IL-1、IL-2、IL-6、IL-7、IL-8、IL-12、IL-23、IL-15、IL-16、EMAP-II、GM-CSF、FGF或PDGF)的抗体或拮抗剂。
为了治疗AIDS,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:细胞表面分子例如CD2、CD3、CD4、CD8、CD19、CD20、CD25、CD28、CD30、CD40、CD45、CD69、CD80、CD86、CD90或其配体的抗体。式(I)或式(II)化合物或其药用盐也可与以下药物共同施用:甲氨蝶呤、环孢菌素、FK506、雷帕霉素、吗替麦考酚酯、来氟米特、S1Pl激动剂、NSAID(例如布洛芬)、皮质类固醇(例如泼尼松龙)、磷酸二酯酶抑制剂、腺苷激动剂、抗血栓形成剂、补体抑制剂、肾上腺素能剂、通过促炎细胞因子例如TNF或IL-1干扰信号传导的药物(例如NIK、IKK、p38或MAP激酶抑制剂)、IL-1转化酶抑制剂、TACE抑制剂、T细胞信号传导抑制剂(例如激酶抑制剂)、金属蛋白酶抑制剂、柳氮磺吡啶、硫唑嘌呤、6-巯基嘌呤、血管紧张素转化酶抑制剂、可溶性细胞因子受体(例如可溶性p55或p75TNF受体、siL-1RI、siL-1RII或siL-6R)或抗炎细胞因子(例如IL-4、IL-10、IL-13或TGF)。
式(I)或式(II)化合物或其药用盐也可与以下药物共同施用:例如阿仑单抗、屈大麻酚、达克珠单抗、米托蒽醌、盐酸扎利罗登、氨吡啶、醋酸格拉默、那他珠单抗、sinnabidol、免疫因子NNS03、ABR-215062、AnergiX.MS、趋化因子受体拮抗剂、BBR-2778、calagualine、CPI-1189、LEM(用脂质体包囊的米托蒽醌)、THC.CBD(大麻素激动剂)、MBP-8298、mesopram(PDE4抑制剂)、MNA-715、抗IL-6受体抗体、neurovax、吡非尼酮、allotrap1258(RDP-1258)、sTNF-Rl、他仑帕奈、特立氟胺、TGF-β2、替利莫肽、VLA-4拮抗剂(例如TR-14035、VLA4Ultrahaler或Antegran-ELAN/Biogen)、干扰素γ拮抗剂或IL-4激动剂。
为了治疗强直性脊柱炎,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:布洛芬、双氯芬酸、米索前列醇、萘普生、美洛昔康、吲哚美辛、双氯芬酸、塞来考昔、罗非考昔、柳氮磺吡啶、甲氨蝶呤、硫唑嘌呤、米诺环素、泼尼松、抗TNF抗体、D2E7CA2(英夫利昔单抗)、CDP571、TNFR-Ig构建体、p75TNFRigG或p55TNFRigG
为了治疗哮喘,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:沙丁胺醇、沙美特罗/氟替卡松、孟鲁司特钠、丙酸氟替卡松、布地奈德、泼尼松、昔萘酸沙美特罗、盐酸左旋沙丁胺醇、硫酸沙丁胺醇/异丙托铵、泼尼松龙磷酸钠、曲安奈德、二丙酸倍氯米松、异丙托溴铵、阿奇霉素、醋酸吡布特罗、泼尼松龙、无水茶碱、甲泼尼龙琥珀酸钠、克拉霉素、扎鲁司特、富马酸福莫特罗、流感病毒疫苗、阿莫西林三水合物、氟尼缩松、色甘酸钠、盐酸非索非那定、氟尼缩松/薄荷醇、阿莫西林/克拉维酸盐、左氧氟沙星、愈创木酚甘油醚、地塞米松磷酸钠、盐酸莫西沙星、盐酸多西环素、愈创木酚甘油醚/d-甲吗喃、伪麻黄碱/cod/氯苯那敏、加替沙星、盐酸西替利嗪、糠酸莫米松、昔萘酸沙美特罗、苯佐那酯、头孢氨苄、pe/氢可酮/氯苯那敏、盐酸西替利嗪/伪麻黄碱、去氧肾上腺素/cod/异丙嗪、可待因/异丙嗪、头孢丙烯、地塞米松、愈创木酚甘油醚/伪麻黄碱、氯苯那敏/氢可酮、奈多罗米钠、硫酸特布他林、肾上腺素、甲泼尼龙、抗IL-13抗体或硫酸间羟异丙肾上腺素。
为了治疗COPD,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:硫酸沙丁胺醇/异丙托铵、异丙托溴铵、沙美特罗/氟替卡松、沙丁胺醇、昔萘酸沙美特罗、丙酸氟替卡松、泼尼松、无水茶碱、甲泼尼龙琥珀酸钠、孟鲁司特钠、布地奈德、富马酸福莫特罗、曲安奈德、左氧氟沙星、愈创木酚甘油醚、阿奇霉素、二丙酸倍氯米松、盐酸左旋沙丁胺醇、氟尼缩松、头孢曲松钠、阿莫西林三水合物、加替沙星、扎鲁司特、阿莫西林/克拉维酸盐、氟尼缩松/薄荷醇、氯苯那敏/氢可酮、硫酸间羟异丙肾上腺素、甲泼尼龙、糠酸莫米松、伪麻黄碱/cod/氯苯那敏、醋酸吡布特罗、伪麻黄碱/氯雷他定、硫酸特布他林、噻托溴铵、(R,R)-福莫特罗、TgAAT、西洛司特或罗氟司特。
为了治疗银屑病,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:卡泊三烯、丙酸氯倍他索、曲安奈德、丙酸卤倍他索、他扎罗汀、甲氨蝶呤、氟轻松、二丙酸倍他米松增强型、氟西奈德、阿维A、焦油香波、戊酸倍他米松、糠酸莫米松、酮康唑、普莫卡因/氟新诺龙、戊酸氢化可的松、氟氢缩松、脲、倍他米松、丙酸氯倍他索/润肤剂、丙酸氟替卡松、阿奇霉素、氢化可的松、保湿配方、叶酸、地奈德、吡美莫司、煤焦油、二乙酸二氟拉松、叶酸依那西普、乳酸、甲氧沙林、he/bismuth subgal/znox/resor、醋酸甲泼尼龙、泼尼松、防晒剂、氯氟舒松、水杨酸、地蒽酚、特戊酸氯可托龙、煤提取物、煤焦油/水杨酸、煤焦油/水杨酸/硫、去羟米松、地西泮、润肤剂、氟轻松/润肤剂、矿物油/蓖麻油/na lact、矿物油/花生油、石油/肉豆蔻酸异丙酯、补骨脂素、水杨酸、皂/三溴沙仑、硫柳汞/硼酸、塞来考昔、英夫利昔单抗、环孢菌素、阿来法塞、依法利珠单抗、他克莫司、吡美莫司、PUVA、UVB、柳氮磺吡啶、ABT-874或ustekinamab。
为了治疗银屑病性关节炎,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:甲氨蝶呤、依那西普、罗非考昔、塞来考昔、叶酸、柳氮磺吡啶、萘普生、来氟米特、醋酸甲泼尼龙、吲哚美辛、硫酸羟氯喹、泼尼松、舒林酸、二丙酸倍他米松增强型、英夫利昔单抗、甲氨蝶呤、叶酸、曲安奈德、双氯芬酸、二甲基亚砜、吡罗昔康、双氯芬酸钠、酮洛芬、美洛昔康、甲泼尼龙、萘丁美酮、托美汀钠、卡泊三烯、环孢菌素、双氯芬酸钠/米索前列醇、氟轻松、硫酸葡糖胺、金硫苹果酸钠、重酒石酸氢可酮/对乙酰氨基酚、布洛芬、利塞膦酸钠、磺胺嘧啶、硫鸟嘌呤、伐地考昔、阿来法塞、D2E7(阿达木单抗)或依法利珠单抗。
为了治疗狼疮,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:NSAID(例如双氯芬酸、萘普生、布洛芬、吡罗昔康或吲哚美辛);
COX2抑制剂(例如塞来考昔、罗非考昔或伐地考昔);抗疟剂(例如羟氯喹);类固醇(例如泼尼松、泼尼松龙、布地奈德或地塞米松);细胞毒性剂(例如硫唑嘌呤、环磷酰胺、吗替麦考酚酯或甲氨蝶呤);PDE4抑制剂或嘌呤合成抑制剂(例如)。例如,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:柳氮磺吡啶、5-氨基水杨酸、奥沙拉嗪、干扰促炎细胞因子(例如IL-1)的合成、产生或作用的药物或半胱天冬酶抑制剂(例如IL-1转化酶抑制剂或IL-1ra)。
式(I)或式(II)化合物或其药用盐也可与以下药物共同施用:T细胞信号传导抑制剂(例如酪氨酸激酶抑制剂)或靶向于T细胞活化的分子(例如CTLA-4-IgG、抗B7家族抗体或抗PD-1家族抗体)。
式(I)或式(II)化合物或其药用盐也可与以下药物共同施用:IL-11抗体、抗细胞因子抗体(例如fonotolizumab(抗IFNg抗体))或抗受体受体抗体(例如抗IL-6受体抗体或针对B细胞表面分子的抗体)。
式(I)或式(II)化合物或其药用盐也可与以下药物共同施用:LJP394(阿贝莫司)、消耗或灭活B细胞的药物(例如利妥昔单抗(抗CD20抗体)或lymphostat-B(抗BlyS抗体))、TNF拮抗剂(例如抗TNF抗体)、D2E7(阿达木单抗)、CA2(英夫利昔单抗)、CDP571、TNFR-Ig构建体、p75TNFRigG(依那西普)或p55TNFRigG(LENERCEPTTM)。
式(I)或式(II)化合物或其药用盐也可与用于预防或治疗AIDS的一种或多种药物共同施用:HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、免疫调节剂或其它逆转录病毒药物。逆转录酶抑制剂的实例包括但不限于阿巴卡韦、阿德福韦、去羟肌苷、地拉夫啶二匹酯、依法韦仑、恩曲他滨、拉米夫定、奈韦拉平、利匹韦林、司他夫定、替诺福韦、扎西他宾和齐多夫定。蛋白酶抑制剂的实例包括但不限于安普那韦、阿扎那韦、达瑞那韦、茚地那韦、福沙那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和替拉诺韦。其它逆转录病毒药物的实例包括但不限于埃替格韦、恩夫韦肽、马拉维若和雷特格韦。
为了治疗II型糖尿病、肝脂肪变性、胰岛素抵抗、代谢综合征或相关病症,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:胰岛素或经修饰以改善体内作用时长的胰岛素;刺激胰岛素分泌的药物,例如乙酰己胺、氯丙酰胺、格列本脲、格列美脲、格列吡嗪、格列齐特、格列吡脲、格列喹酮、瑞格列奈、那格列奈、妥拉磺脲或甲苯磺丁脲;作为胰高血糖素样肽激动剂的药物,例如艾塞那肽、利拉鲁肽或他司鲁肽;抑制二肽基肽酶IV的药物,例如维格列汀、西格列汀、沙格列汀、利格列汀、allogliptin或septagliptin;与过氧化物酶体增殖物激活受体γ结合的药物,例如罗格列酮或吡格列酮;减小胰岛素抵抗的药物,例如二甲双胍;或减少小肠中葡萄糖吸收的药物,例如阿卡波糖、米格列醇或伏格列波糖。
为了治疗急性肾病或慢性肾病,式(I)或式(II)化合物或其药用盐可与以下药物共同施用:多巴胺、利尿剂(例如呋塞米)、布美他尼、噻嗪类、甘露醇、葡糖酸钙、碳酸氢钠、沙丁胺醇、帕立骨化醇、度骨化醇、西那卡塞或甲基巴多索隆。
可与载体物质组合以制备单一剂型的式(I)或式(II)化合物或其盐和额外的治疗剂这两者的量(在如上所述包含额外的治疗剂的那些组合物中)将随所治疗的宿主和具体的施用模式而变化。在某些实施方案中,将本申请组合物配制成可施用剂量为0.01-100mg/kg体重/天的本申请化合物。
额外的治疗剂和式(I)或式(II)化合物可协同作用。因此,额外的治疗剂在此类组合物中的量可小于仅使用该治疗剂的单一疗法所需要的量或当使用较低的剂量时,在患者中可存在较少的副作用。在某些实施方案中,可在此类组合物中施用剂量为0.01-1,000μg/kg体重/天的额外的治疗剂。
本申请提供在患有癌症的个体中延长对细胞毒性剂的响应的持续时间的方法,其包括向所述个体施用(a)有效量的式(I)或式(II)化合物或其药用盐和(b)有效量的细胞毒性剂。
在任何所述方法的某些实施方案中,细胞毒性剂是靶向疗法。在某些实施方案中,靶向疗法是一种或多种EGFR拮抗剂、RAF抑制剂和/或PI3K抑制剂。
在任何所述方法的某些实施方案中,靶向疗法是EGFR拮抗剂。在任何所述方法的某些实施方案中,EGFR拮抗剂是N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)-4-喹唑啉胺和/或其药用盐。在某些实施方案中,EGFR拮抗剂是N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)-4-喹唑啉胺。在某些实施方案中,EGFR拮抗剂是N-(4-(3-氟苄基氧基)-3-氯苯基)-6-(5-((2-(甲基磺酰基)乙基氨基)甲基)呋喃-2-基)喹唑啉-4-胺二4-甲基苯磺酸盐或其药用盐(例如拉帕替尼)。
在任何所述方法的某些实施方案中,靶向疗法是RAF抑制剂。在某些实施方案中,RAF抑制剂是BRAF抑制剂。在某些实施方案中,RAF抑制剂是CRAF抑制剂。
在某些实施方案中,BRAF抑制剂是威罗菲尼。在某些实施方案中,RAF抑制剂是3-(2-氰基丙-2-基)-N-(4-甲基-3-(3-甲基-4-氧代-3,4-二氢喹唑啉-6-基氨基)苯基)苯甲酰胺或其药用盐(例如AZ628(CAS#878739-06-1))。
在任何所述方法的某些实施方案中,靶向疗法是PI3K抑制剂。
在任何所述方法的某些实施方案中,细胞毒性剂是化学疗法。在任何所述方法的某些实施方案中,化学疗法是紫杉烷。在某些实施方案中,紫杉烷是紫杉醇。在某些实施方案中,紫杉烷是多西他赛。
在任何所述方法的某些实施方案中,细胞毒性剂是铂剂。在某些实施方案中,铂剂是卡铂。在某些实施方案中,铂剂是顺铂。在任何所述方法的某些实施方案中,细胞毒性剂是紫杉烷和铂剂。在某些实施方案中,紫杉烷是紫杉醇。在某些实施方案中,紫杉烷是多西他赛。在某些实施方案中,铂剂是卡铂。在某些实施方案中,铂剂是顺铂。
在任何所述方法的某些实施方案中,细胞毒性剂是长春花生物碱。在某些实施方案中,长春花生物碱是长春瑞滨。在任何所述方法的某些实施方案中,化学疗法是核苷类似物。在某些实施方案中,核苷类似物是吉西他滨。
在任何所述方法的某些实施方案中,细胞毒性剂是放射疗法。
在任何所述方法的某些实施方案中,式(I)或式(II)化合物或其药用盐与细胞毒性剂(例如靶向疗法、化学疗法和/或放射疗法)同时施用。在某些实施方案中,式(I)或式(II)化合物或其药用盐在细胞毒性剂(例如靶向疗法、化学疗法和/或放射疗法)前和/或与细胞毒性剂(例如靶向疗法、化学疗法和/或放射疗法)并行施用。
实施例
如以下实施例所述,在某些示例性实施方案中,化合物根据以下一般程序制备。应理解的是,虽然一般方法描述了本申请某些化合物的合成,但是以下一般方法和本领域技术人员已知的其它方法可应用于本申请所述所有化合物及这些化合物的亚类和每种。
方案1
式(3)、(4)和(5)化合物可通过如方案1所示的一般合成方法制备。
溴化物(2)可在钯催化剂系统(例如但不限于Xphos预催化剂与Xphos配体的组合或Pd-(ipent-PEPPSI))下在无机碱(例如但不限于叔丁醇钠或碳酸铯)存在下在合适的溶剂(例如1,4-二噁烷)中在升高的温度与四氢喹啉(1)交叉偶联,得到式(3)化合物。在化合物(3)所携带的R1官能团等于OtBu的情况下,使其经受上述质子条件,接着用碱(例如但不限于三乙胺(TEA))和脲(6)处理,得到式(4)化合物。可选择地,可使化合物(3)经受质子条件,接着用碱(例如但不限于三乙胺(TEA))和乙酸酐处理,得到式(5)化合物。
方案2
式(10)化合物可通过如方案2所示的一般合成方法制备。
式(10)化合物可如下由溴化物(7)制备:在钯催化剂条件(例如但不限于Xphos预催化剂与Xphos配体的组合)下在水和无机碱(例如但不限于碳酸钠、碳酸钾或磷酸钾)存在下在有机溶剂(例如但不限于1,4-二噁烷)中在升高的温度用芳基、杂芳基或杂环基硼酸(9)或硼酸酯(8)处理。可选择地,在碱(例如但不限于乙酸钾或2-乙基己酸钾)存在下在钯催化剂条件(例如但不限于[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)或Xphos预催化剂与Xphos配体的组合)下在有机溶剂(例如但不限于1,4-二噁烷或二甲基甲酰胺)存在下使溴化物(7)与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)(B2Pin2)反应,可生成相应的硼酸酯,其在类似的钯催化剂条件下用芳基、杂芳基或杂环基卤化物(11或12)处理,也可得到式(10)化合物。
方案3
式(16)化合物可通过如方案3所示的一般合成方法制备。
溴化物(14或15)可在钯催化剂系统(例如但不限于Xphos预催化剂与Xphos配体的组合或Pd-(ipent-PEPPSI))下在无机碱(例如但不限于叔丁醇钠或碳酸铯)存在下在合适的溶剂(例如1,4-二噁烷)中在升高的温度与胺(13)交叉偶联,得到式(16)化合物。
方案4
式(19)化合物可通过如方案4所示的一般合成方法制备。
式(19)化合物可如下由式(17)氯化物制备:在钯催化剂条件(例如但不限于Xphos预催化剂与Xphos配体的组合)下在水和无机碱(例如但不限于碳酸钠、碳酸钾或磷酸钾)存在下在有机溶剂(例如但不限于1,4-二噁烷)中在升高的温度用杂芳基或杂环基硼酸酯(18)处理。
方案5
式(24)化合物可通过如方案5所示的一般合成方法制备。
溴化物(21)可在钯催化剂系统(例如但不限于Xphos预催化剂与Xphos配体的组合或Pd-(ipent-PEPPSI))下在无机碱(例如但不限于叔丁醇钠或碳酸铯)存在下在合适的溶剂(例如1,4-二噁烷)中在升高的温度与四氢喹啉(20)交叉偶联,得到式(22)和/或(23)化合物。在化合物22得以保留的情况下,酯在水和有机溶剂(例如但不限于甲醇和/或四氢呋喃)存在下用氢氧化物源(例如但不限于氢氧化锂)处理,得到式(22)羧酸。使羧酸(22)与偶联剂(例如但不限于1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU))、碱(例如但不限于TEA或二异丙基乙基胺)和甲胺盐酸盐反应,得到式(24)酰胺。
方案6
式(29)化合物可通过如方案6所示的一般合成方法制备。
溴化物(27)可在钯催化剂系统(例如但不限于Xphos预催化剂与Xphos配体的组合或Pd-(ipent-PEPPSI))下在无机碱(例如但不限于叔丁醇钠或碳酸铯)存在下在合适的溶剂(例如1,4-二噁烷)中在升高的温度与四氢喹啉(26)交叉偶联,得到式(28)化合物。酯在水和有机溶剂(例如但不限于甲醇和/或四氢呋喃)存在下用氢氧化物源(例如但不限于氢氧化锂)处理,得到羧酸。使该羧酸与偶联剂(例如但不限于N,N,N’,N’-四甲基-O-(苯并三唑-1-基)脲鎓四氟硼酸盐(TBTU))、碱(例如但不限于TEA或二异丙基乙基胺)和甲胺盐酸盐反应,得到式(29)酰胺。
方案7
式(33)化合物可通过如方案7所示的一般合成方法制备。
卤化物(31或32)可在钯催化剂系统(例如但不限于Xphos预催化剂与Xphos配体的组合或Pd-(ipent-PEPPSI))下在无机碱(例如但不限于叔丁醇钠或碳酸铯)存在下在合适的溶剂(例如1,4-二噁烷)中在升高的温度与四氢喹啉(30)交叉偶联,得到式(33)化合物。
方案8
式(37)化合物可通过如方案8所示的一般合成方法制备。
卤化物(35或36)可在钯催化剂系统(例如但不限于Xphos预催化剂与Xphos配体的组合或Pd-(ipent-PEPPSI))下在无机碱(例如但不限于叔丁醇钠或碳酸铯)存在下在合适的溶剂(例如1,4-二噁烷)中在升高的温度与四氢喹啉(34)交叉偶联,得到式(37)化合物。
用于中间体A的一般程序
向7-溴-2,3,4,5-四氢-1,4-苯并氧杂氮杂(500mg,2.19mmol)于DCM(11mL)中的溶液中添加三乙胺(444mg,4.40mmol)和N-甲基-1H-咪唑-1-甲酰胺(433mg,3.29mmol)。使用微波将混合物在100℃搅拌12分钟。将粗混合物稀释于DCM(10mL),通过硅藻土过滤并真空浓缩。粗残余物通过硅胶色谱(iPrOAc/MeOH=97:3)纯化,得到标题化合物(中间体A,388mg,62%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.37-7.28(m,2H),6.91(d,J=8.4Hz,1H),4.40(s,2H),4.35(s,1H),4.12-4.05(m,2H),3.85-3.78(m,2H),2.79(d,J=4.6Hz,3H)。LCMS m/z(M+H)285。
用于中间体B的一般程序
向2,3,4,5-四氢-1H-1,4-苯并二氮杂(1.00g,6.75mmol)于DCM(34mL)中的溶液中添加三乙胺(683mg,6.75mmol)和N-甲基-1H-咪唑-1-甲酰胺(801mg,6.08mmol)。将混合物在室温搅拌16小时。将粗混合物稀释于DCM(20mL),通过硅藻土过滤并真空浓缩。粗残余物通过硅胶色谱(iPrOAc/MeOH=96:4)纯化,得到标题化合物(990mg,72%),其为白色固体。1H NMR(400MHz,CDCl3,15/17H)δ7.19-7.06(m,2H),6.86(td,J=7.4,1.2Hz,1H),6.76(dd,J=8.0,1.1Hz,1H),4.35(s,2H),3.97(s,1H),3.75-3.67(m,2H),3.23-3.15(m,2H),2.75(d,J=4.7Hz,3H)。LCMS m/z(M+H)206。
在0℃向N-甲基-1,2,3,5-四氢-1,4-苯并二氮杂-4-甲酰胺(300mg,1.46mmol)于DMF(2.9mL)中的溶液中添加N-溴琥珀酰亚胺(273mg,1.53mmol)。将反应混合物在0℃搅拌30分钟。然后反应混合物用饱和NaHCO3水溶液(50mL)淬灭且混合物用DCM(50mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(iPrOAc/MeOH=97:3)纯化,得到标题化合物(中间体B,225mg,54%),其为灰白色固体。1H NMR(400MHz,CDCl3)δ7.34-7.25(m,1H),7.19(dd,J=8.3,2.3Hz,1H),6.62(d,J=8.5Hz,1H),4.33(s,2H),4.30(s,1H),3.97(s,1H),3.71-3.64(m,2H),3.19(dt,J=5.1,3.2Hz,2H),2.78(d,J=4.7Hz,3H)。LCMS m/z(M+H)284。
用于中间体C的一般程序
步骤1:喹啉-7-甲醛
在160℃历经5分钟向7-甲基喹啉(27.0g,189mmol)的溶液中逐份添加SeO2(21.0g,189mmol)。将混合物在160℃搅拌8小时。将反应混合物冷却至室温后,添加DCM(400mL)且混合物通过硅藻土过滤。真空浓缩有机层。粗残余物通过硅胶色谱(石油醚/EtOAc=10:1)纯化,得到标题化合物(14.0g,47%),其为黄色油状物。1H NMR(400MHz,CDCl3)δ10.23(s,1H),9.03(d,J=2.8Hz,1H),8.56(s,1H),8.22(d,J=8.4Hz,1H),8.04(d,J=8.4Hz,1H),7.93(d,J=8.4Hz,1H),7.55-7.52(m,1H)。
步骤2:7-(二氟甲基)喹啉
在0℃历经20分钟向喹啉-7-甲醛(14.0g,89.2mmol)于DCM(150mL)中的溶液中滴加二乙基氨基三氟化硫(65.0g,446mmol)。将混合物在室温搅拌16小时。在0℃将混合物倾入饱和NaHCO3水溶液(1L)中且用DCM(200mL×2)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=5:1)纯化,得到标题化合物(13.0g,81%),其为黄色油状物。1H NMR(400MHz,CDCl3)δ8.92(d,J=2.8Hz,1H),8.15(d,J=8.4Hz,2H),7.86(d,J=8.4Hz,1H),7.63(d,J=8.8Hz,1H),7.44-7.41(m,1H),6.78(t,J=56.0Hz,1H)。
步骤3:7-(二氟甲基)-1,2,3,4-四氢喹啉
在0℃历经20分钟向7-(二氟甲基)喹啉(13.0g,72.6mmol)和NaBH3CN(23.0g,363mmol)于MeOH(150mL)中的溶液中滴加三氟化硼乙醚合物(17.9mL,145mmol)。将混合物加热至90℃且保持24小时。将反应混合物冷却至室温后,在0℃将混合物倾入饱和NaHCO3水溶液(1L)中且用DCM(200mL×2)萃取。合并的有机层经Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=20:1)纯化,得到标题化合物(8.0g,56%),其为棕色油状物。1H NMR(400MHz,CDCl3)δ7.00(d,J=7.2Hz,1H),6.71(d,J=8.0Hz,1H),6.59(s,1H),6.50(t,J=56.8Hz,1H),3.33(t,J=5.6Hz,2H),2.79(t,J=6.4Hz,2H),1.98-1.92(m,2H)。
步骤4:6-溴-7-(二氟甲基)-1,2,3,4-四氢喹啉
在0℃历经20分钟向7-(二氟甲基)-1,2,3,4-四氢喹啉(7.0g,38.3mmol)于DCM(100mL)中的溶液中逐份添加N-溴琥珀酰亚胺(6.9g,38.3mmol)。将混合物在室温搅拌16小时。将混合物倾入水(100mL)中且用DCM(200mL×2)萃取。合并的有机层经Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=300:1)纯化,得到标题化合物(6.0g,60%),其为浅黄色油状物。1H NMR(400MHz,CDCl3)δ7.13(s,1H),6.78(t,J=55.2Hz,1H),6.72(s,1H),3.31(t,J=5.2Hz,2H),2.74(t,J=6.0Hz,2H),1.95-1.87(m,2H)。
步骤5:7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉
向6-溴-7-(二氟甲基)-1,2,3,4-四氢喹啉(600mg,2.3mmol)于二噁烷(8mL)和H2O(2mL)中的溶液中添加K2CO3(635mg,4.6mmol)、[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(169mg,0.23mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(478mg,2.3mmol)。在氮气气氛下将混合物加热至110℃且保持18小时。将反应混合物冷却至室温后,真空浓缩混合物。粗残余物通过硅胶色谱(石油醚/EtOAc=40:1)纯化,得到标题化合物(中间体C,520mg,86%),其为黄色油状物。1H NMR(400MHz,CDCl3)δ7.52(s,1H),7.39(s,1H),6.96(s,1H),6.81(s,1H),6.54(t,J=55.2Hz,1H),4.12-4.01(m,1H),3.95(s,3H),3.35(t,J=5.2Hz,2H),2.79(t,J=6.0Hz,2H),2.01-1.91(m,2H)。LCMS m/z(M+H)264。
用于中间体D、E和F的一般程序
步骤1:8-氯-3-(1-甲基-1H-吡唑-4-基)异喹啉
向3-溴-8-氯异喹啉(500mg,2.1mmol)于1,4-二噁烷(10mL)和水(2mL)中的溶液中添加[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(75mg,0.1mmol)、Na2CO3(437mg,4.1mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(472mg,2.3mmol)。在氮气气氛下将混合物加热至90℃且保持16小时。将反应混合物冷却至室温后,添加EtOAc(30mL)且用水(20mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(DCM/MeOH=20:1)纯化,得到标题化合物(中间体D,430mg,85%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.37(s,1H),8.14(s,1H),8.10(s,1H),7.89-7.86(m,1H),7.72-7.70(m,2H),3.92(s,3H)。
步骤2:3-(1-甲基-1H-吡唑-4-基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异喹啉
向8-氯-3-(1-甲基-1H-吡唑-4-基)异喹啉(10.0g,41.04mmol)于1,4-二噁烷(220mL)中的溶液中添加2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(1.96g,4.1mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(3.23g,4.1mmol)、KOAc(10.1g,102.59mmol)和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)(31.26g,123.11mmol)。在氮气气氛下将混合物加热至90℃且保持1小时。冷却至室温后,添加EtOAc(400mL)且用水(200mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(中间体E,11.0g,22%纯度),其为棕色固体且不需要进一步纯化。LCMS m/z(M+H)336。
步骤3:(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)硼酸
向3-(1-甲基-1H-吡唑-4-基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异喹啉(10g,粗品)于丙酮(50mL)和水(50mL)中的溶液中添加NaIO4(16.0g,74.6mmol)和NH4OAc(5.7g,74.6mmol)。将混合物在室温搅拌48小时。过滤反应混合物并真空浓缩。添加EtOAc(100mL)且用水(70mL)、盐水(70mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(DCM/MeOH=10:1)纯化,得到标题化合物(中间体F,440mg,4%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.57-8.51(m,2H),8.31(s,1H),8.06(s,1H),8.01(s,1H),7.87(d,J=8.4Hz,1H),7.78(d,J=5.6Hz,1H),7.73-7.63(m,1H),3.91(s,3H)。
用于中间体G的一般程序
步骤1:3-溴-2-氧代-1,5,7,8-四氢-1,6-二氮杂萘-6-甲酸叔丁酯
在0℃向2-氧代-1,5,7,8-四氢-1,6-二氮杂萘-6-甲酸叔丁酯(275mg,1.10mmol)于乙酸(2.2mL)中的溶液中逐份添加溴(67.7μL,1.32mmol)。将混合物在室温搅拌3小时,然后减压浓缩。将所得残余物溶于氯仿(4mL)和水(2.0mL)。向溶液中添加Boc2O(312mg,1.43mmol)和K2CO3(304mg,2.20mmol)。将混合物在室温搅拌14小时。过滤所得析出物,用乙醚洗涤并减压干燥,得到第一批标题化合物。将母液倾入分液漏斗中,分离有机层,经Na2SO4干燥并减压浓缩。所得固体用乙醚洗涤,然后减压干燥,得到第二批标题化合物(总计228mg,63%),其不需要进一步纯化。1H NMR(400MHz,CDCl3,16/17H)δ7.59(s,1H),4.32(s,2H),3.67(t,J=5.8Hz,2H),2.74(t,J=5.8Hz,2H),1.48(s,9H)。
步骤2:3-溴-1-甲基-2-氧代-7,8-二氢-5H-1,6-二氮杂萘-6-甲酸叔丁酯
在0℃向3-溴-2-氧代-1,5,7,8-四氢-1,6-二氮杂萘-6-甲酸叔丁酯(124mg,0.378mmol)于DMF(1.5mL)中的溶液中添加HMDS于己烷中的溶液(1.0M,0.567mL,0.567mmol)。搅拌15分钟后,添加碘甲烷(47.1μL,0.756mmol)。再搅拌30分钟后,减压浓缩反应混合物。残余物通过硅胶色谱(100%庚烷至100%EtOAc梯度)纯化,得到标题化合物(87.5mg,68%)。1H NMR(400MHz,DMSO-d6)δ7.50(s,1H),4.31(t,J=1.6Hz,2H),3.69(t,J=5.8Hz,2H),3.57(s,3H),2.69(t,J=1.7Hz,2H),1.49(s,9H)。
步骤3:6-乙酰基-3-溴-1-甲基-7,8-二氢-5H-1,6-二氮杂萘-2-酮
将3-溴-1-甲基-2-氧代-7,8-二氢-5H-1,6-二氮杂萘-6-甲酸叔丁酯(60mg,0.175mmol)和三氟乙酸(0.5mL)于DCM(4mL)中的混合物在室温搅拌2小时。减压浓缩溶剂且将粗产物重新溶于DCM(4mL)。将溶液冷却至0℃,然后滴加TEA(0.122mL,0.874mmol)和乙酸酐(33.1μL,0.350mmol)。将反应混合物在室温再搅拌3小时,然后其用水淬灭。有机层经无水Na2SO4干燥,过滤并减压浓缩。粗残余物通过硅胶色谱(100%庚烷至10%MeOH/EtOAc梯度)纯化,得到标题化合物(中间体G,39.8mg,80%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.52(d,J=4.6Hz,1H),4.53-4.32(m,2H),3.88-3.74(m,2H),3.57(d,J=1.3Hz,3H),2.82-2.64(m,2H),2.17(d,J=9.4Hz,3H)。
实施例1
向7-溴-N-甲基-3,5-二氢-2H-1,4-苯并氧杂氮杂-4-甲酰胺(中间体A,50mg,0.18mmol)和联硼酸二频哪醇酯(89mg,0.35mmol)于二噁烷(0.88mL)中的溶液中添加KOAc(52mg,0.53mmol)、(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]氯化钯(II)(4.2mg,0.0053mmol)和2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(5.1mg,0.010mmol)。将混合物在80℃在氮气气氛下搅拌16小时。将反应混合物冷却至室温并添加1-溴异喹啉(25mg,0.12mmol)、K3PO4·H2O(71mg,0.30mmol)、水(0.3mL)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]氯化钯(II)(4.2mg,0.0053mmol)。将反应混合物在70℃在氮气气氛下搅拌4小时。然后将反应混合物冷却至室温并真空浓缩。将粗残余物稀释于二氯甲烷(5mL),经无水MgSO4干燥,通过硅藻土过滤并真空浓缩。所得混合物通过反相色谱(乙腈20-60%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(8.4mg,14%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ8.57(d,J=5.7Hz,1H),8.07(td,J=8.0,1.1Hz,2H),7.87-7.76(m,2H),7.73(d,J=2.3Hz,1H),7.66(ddd,J=8.4,6.9,1.4Hz,1H),7.52(dd,J=8.2,2.3Hz,1H),7.14(d,J=8.2Hz,1H),6.55(q,J=4.3Hz,1H),4.56(s,2H),4.11(dd,J=5.2,3.6Hz,2H),3.76(dd,J=5.2,3.4Hz,2H),2.55(d,J=4.3Hz,3H)。LCMS m/z(M+H)334。
以与实施例1类似的方式制备以下化合物:
实施例3
向7-溴-N-甲基-3,5-二氢-2H-1,4-苯并氧杂氮杂-4-甲酰胺(中间体A,50mg,0.18mmol)和(1,5-二甲基吲唑-4-基)硼酸(67mg,0.35mmol)于二噁烷(1.2mL)和水(0.4mL)中的溶液中添加K3PO4·H2O(103mg,0.438mmol)、(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]甲磺酸钯(II)(9.4mg,0.010mmol)和2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(5.1mg,0.010mmol)。将混合物在90℃在氮气气氛下搅拌16小时。然后将反应混合物冷却至室温并真空浓缩。将粗残余物稀释于二氯甲烷(5mL),经无水MgSO4干燥,通过硅藻土过滤并真空浓缩。所得混合物通过反相色谱(乙腈20-60%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(52mg,82%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.60(d,J=1.0Hz,1H),7.53(dd,J=8.5,1.0Hz,1H),7.49(d,J=2.2Hz,1H),7.34(d,J=8.6Hz,1H),7.25(dd,J=8.2,2.2Hz,1H),7.09(d,J=8.2Hz,1H),6.54(q,J=4.3Hz,1H),4.51(s,2H),4.11-4.05(m,2H),4.04(s,3H),3.78-3.71(m,2H),2.55(d,J=4.2Hz,3H),2.32(s,3H)。LCMS m/z(M+H)351。
以与实施例3类似的方式制备以下化合物:
实施例16
向7-溴-N-甲基-1,2,3,5-四氢-1,4-苯并二氮杂-4-甲酰胺(中间体B,45mg,0.16mmol)于2-甲基-2-丁醇(0.32mL)和二噁烷(0.40mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(13mg,0.016mmol)、t-BuONa(46mg,0.48mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,83mg,0.32mmol)。将反应混合物在90℃在氮气气氛下搅拌16小时。将粗残余物稀释于二氯甲烷(5mL),经无水MgSO4干燥,通过硅藻土过滤并真空浓缩。所得混合物先后通过反相色谱(乙腈20-60%/0.1%甲酸水溶液)和SFC(吡啶基酰胺150×30.0mm I.D.5μm;20-60%(0.1%氢氧化铵/MeOH)/超临界CO2)纯化,得到标题化合物(9.2mg,12%),其为白色固体。1HNMR(400MHz,DMSO-d6,27/28H)δ7.72(s,1H),7.47(d,J=0.8Hz,1H),7.18(d,J=2.5Hz,1H),7.06(s,1H),6.96-6.82(m,2H),6.75-6.55(m,1H),6.27(q,J=4.3Hz,1H),5.59(t,J=3.5Hz,1H),4.29(s,2H),3.86(s,3H),3.55-3.42(m,4H),3.03(s,2H),2.83(d,J=12.8Hz,2H),2.52(d,J=4.2Hz,3H),2.04-1.94(m,2H)。LCMS m/z(M+H)467。
以与实施例16类似的方式制备以下化合物:
实施例21
5-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-3-甲基-1,3-苯并噻唑-2-酮
步骤1:5-溴-3H-1,3-苯并噻唑-2-酮
向2-氨基-4-溴苯硫酚(544mg,2.67mmol)于乙酸(26.7mL)中的溶液中添加三光气(530mg,1.79mmol)。将混合物加热回流18小时。冷却至室温后,减压部分浓缩溶液,添加水且所得析出物经由过滤除去且用NaOH水溶液(1.0M)洗涤。滤液用HCl(2N)酸化至pH 2并在冰箱中放置12小时。过滤所得析出物,用水洗涤并减压干燥,得到标题化合物(94mg,15%),其为白色粉末且不需要进一步纯化。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),7.55(d,J=8.4Hz,1H),7.30(d,J=8.0Hz,1H),7.24(s,1H)。
步骤2:5-溴-3-甲基-1,3-苯并噻唑-2-酮
向5-溴-3H-1,3-苯并噻唑-2-酮(94.4mg,0.410mmol)于水(2.1mL)中的溶液中先后添加NaOH(16.4mg,0.410mmol)和硫酸二甲酯(62.1mg,0.492mmol)。在室温搅拌3小时后,过滤所得析出物,用水洗涤并减压干燥,得到标题化合物(89.3mg,89%),其为白色粉末且不需要进一步纯化。1H NMR(400MHz,CDCl3)δ7.32-7.29(m,2H),7.20(dd,J=1.5,0.6Hz,1H),3.45(s,3H)。
步骤3:5-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-3-甲基-1,3-苯并噻唑-2-酮
向小瓶中添加7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,25.0mg,0.0950mmol)、5-溴-3-甲基-1,3-苯并噻唑-2-酮(27.8mg,0.114mmol)、[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(11.9mg,0.0142mmol)、t-BuONa(18.2mg,0.190mmol)和1,4-二噁烷(0.20mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至120℃且保持16小时。将反应混合物冷却至室温后,添加DCM(3mL)且反应混合物通过硅藻土过滤并减压浓缩。粗残余物通过反相制备型HPLC(乙腈30-70%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(9.6mg,24%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.76(d,J=0.8Hz,1H),7.66(d,J=8.4Hz,1H),7.51(d,J=0.8Hz,1H),7.26(d,J=2.1Hz,1H),7.18-7.14(m,1H),7.11(dd,J=8.4,2.1Hz,1H),6.87-6.77(m,2H),3.87(s,3H),3.70-3.63(m,2H),3.38(s,3H),2.86(t,J=6.4Hz,2H),2.06-1.96(m,2H)。LCMS m/z(M+H)427。
以与实施例21类似的方式制备以下化合物:
实施例27
4-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-N-甲基-喹啉-6-甲酰胺
步骤1:4-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]喹啉-6-甲酸甲酯
向小瓶中添加7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,200mg,0.760mmol)、4-溴喹啉-6-甲酸甲酯(243mg,0.912mmol)、[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(95.2mg,0.114mmol)、t-BuONa(146.0mg,1.519mmol)和1,4-二噁烷(1.52mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至120℃且保持16小时。将反应混合物冷却至室温后,添加DCM(4mL)且反应混合物通过硅藻土过滤并减压浓缩。残余物通过硅胶色谱(1%TEA/庚烷至100%EtOAc梯度)纯化,得到标题化合物(23.6g,7%),其为黄色固体。1H NMR(400MHz,CDCl3)δ8.92(d,J=4.9Hz,1H),8.76(dd,J=2.0,0.6Hz,1H),8.31(dd,J=8.8,1.9Hz,1H),8.18(dd,J=8.8,0.6Hz,1H),7.57(d,J=0.8Hz,1H),7.45(d,J=0.7Hz,1H),7.31-7.27(m,1H),7.18(t,J=1.1Hz,1H),6.88(s,1H),6.58-6.30(m,1H),3.96(s,3H),3.96(s,3H),3.80(dd,J=6.7,4.2Hz,2H),3.03(t,J=6.6Hz,2H),2.18-2.08(m,2H)。
步骤2:4-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-N-甲基-喹啉-6-甲酰胺
向4-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]喹啉-6-甲酸甲酯(23.4mg,0.0522mmol)于THF(0.5mL)和水(0.5mL)中的溶液中添加一水合氢氧化锂(2.6mg,0.063mmol)。将混合物在室温搅拌1小时。反应完成后,减压浓缩反应混合物。将所得残余物溶于DMF并添加TEA(21.1mg,0.209mmol)、甲胺盐酸盐(10.6mg,0.157mmol)和TBTU(34.2mg,0.104mmol)。将混合物在室温搅拌14小时,然后减压浓缩。粗残余物通过反相制备型HPLC(乙腈5-50%/0.1%甲酸水溶液)纯化,得到标题化合物(13.7mg,57%,2步),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ8.96(d,J=4.8Hz,1H),8.69(q,J=4.5Hz,1H),8.46(dd,J=2.0,0.6Hz,1H),8.19(dd,J=8.8,1.9Hz,1H),8.13(dd,J=8.8,0.6Hz,1H),7.78(d,J=0.8Hz,1H),7.53(d,J=0.8Hz,1H),7.45(d,J=4.8Hz,1H),7.26(s,1H),6.87-6.50(m,2H),3.87(s,3H),3.73(t,J=5.4Hz,2H),3.00(t,J=6.5Hz,2H),2.80(d,J=4.5Hz,3H),2.19-1.90(m,2H)。LCMS m/z(M+H)448。
以与实施例27类似的方式制备以下化合物:
实施例31
5-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1-乙基-3-甲基-苯并咪唑-2-酮
步骤1:5-溴-3-甲基-1H-苯并咪唑-2-酮
向2-氨基-4-溴苯硫酚(500mg,2.50mmol)于乙酸(25mL)中的溶液中添加三光气(490mg,1.70mmol)。将混合物加热回流18小时。冷却至室温后,减压部分浓缩溶液,添加水且所得析出物经由过滤除去且用NaOH水溶液(1M)洗涤。滤液用HCl水溶液(2N)酸化至pH 2并在冰箱中放置12小时。过滤所得析出物,用水洗涤并减压干燥,得到标题化合物(133mg,24%),其为白色粉末且不需要进一步纯化。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.33(d,J=1.9Hz,1H),7.13(dd,J=8.2,1.9Hz,1H),6.91(d,J=8.2Hz,1H),3.26(s,3H)。
步骤2:5-溴-1-乙基-3-甲基-苯并咪唑-2-酮
向5-溴-3-甲基-1H-苯并咪唑-2-酮(30mg,0.132mmol)于DMF(1.2mL)中的溶液中添加NaH(60%于矿物油中,11.6mg,0.291mmol)。将所得混合物在室温搅拌10分钟,然后添加碘乙烷(21.1μL,0.26mmol)。将反应混合物再搅拌4小时,然后添加水(20mL)且混合物用EtOAc(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,然后减压浓缩。粗残余物通过反相制备型HPLC(乙腈20-60%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(20.0mg,59%)。1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ7.44-7.39(m,1H),7.22(dd,J=8.3,1.9Hz,1H),7.16(dd,J=8.3,0.4Hz,1H),3.86(q,J=7.2Hz,2H),3.32(s,3H),1.18(t,J=7.2Hz,3H)。LCMS m/z(M+H)255。
步骤3:5-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1-乙基-3-甲基-苯并咪唑-2-酮
向小瓶中添加7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,50.0mg,0.190mmol)、5-溴-1-乙基-3-甲基-苯并咪唑-2-酮(58.1mg,0.228mmol)、[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(23.8mg,0.0285mmol)、t-BuONa(36.5mg,0.380mmol)和1,4-二噁烷(0.4mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至120℃且保持16小时。将反应混合物冷却至室温后,添加DCM(3mL)且反应混合物通过硅藻土过滤并减压浓缩。粗残余物通过反相色谱(乙腈20-60%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(14.1mg,32%),其为白色固体。1H NMR(400MHz,DMSO-d6,22/25H)δ7.72(d,J=0.9Hz,1H),7.47(d,J=0.8Hz,1H),7.25(d,J=8.3Hz,1H),7.14(d,J=2.0Hz,1H),7.08(s,1H),6.97(dd,J=8.2,2.0Hz,1H),6.88-6.54(m,2H),3.95-3.79(m,5H),3.65-3.56(m,2H),2.87(t,J=6.1Hz,2H),2.07-1.96(m,2H),1.23(t,J=7.1Hz,3H)。LCMS m/z(M+H)437。
以与实施例31类似的方式制备以下化合物:
实施例33
4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
步骤1:6-溴-4-氯-1H-苯并[d]咪唑-2(3H)-酮
向5-溴-3-氯苯-1,2-二胺(200mg,0.90mmol)于氯仿(3mL)中的溶液中添加二(1H-咪唑-1-基)甲酮(220mg,1.35mmol)。在氮气气氛下将混合物加热至60℃且保持12小时。将反应混合物冷却至室温后,滤出白色析出物,用氯仿(3mL×2)洗涤并真空干燥,得到标题化合物(170mg,76%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),11.05(s,1H),7.21(d,J=1.6Hz,1H),7.04(d,J=1.6Hz,1H)。
步骤2:6-溴-4-氯-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
在0℃向6-溴-4-氯-1H-苯并[d]咪唑-2(3H)-酮(170mg,0.69mmol)于DMF(2mL)中的搅拌的溶液中添加NaH(69mg,1.72mmol,60%)且将混合物搅拌15分钟。滴加碘甲烷(0.13mL,2.06mmol)且将混合物在室温再搅拌12小时。添加水(30mL)且用EtOAc(30mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=5:1)纯化,得到标题化合物(150mg,79%),其为白色固体。LCMS m/z(M+H)275。
步骤3:4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,143mg,0.54mmol)、6-溴-4-氯-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(150mg,0.54mmol)和K3PO4(347mg,1.63mmol)于2-甲基-2-丁醇(5mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(46mg,0.054mmol)。在氩气气氛下将混合物加热至95℃且保持12小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈35-65%/0.2%甲酸水溶液)纯化,得到标题化合物(28mg,11%),其为黄色固体。1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.42(s,1H),7.07(s,1H),6.94(d,J=1.6Hz,1H),6.88(s,1H),6.80(d,J=1.6Hz,1H),6.49(t,J=55.6Hz,1H),3.96(s,3H),3.76(s,3H),3.64-3.61(m,2H),3.38(s,3H),2.92-2.89(m,2H),2.11-2.09(m,2H)。LCMS m/z(M+H)458。
以与实施例33类似的方式制备以下化合物:
实施例36
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3,4-三甲基-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,100mg,0.22mmol)于甲苯(4mL)和水(0.4mL)中的溶液中添加甲基三氟硼酸钾(40mg,0.33mmol)、[(二(1-金刚烷基)-正丁基膦)-2-(2-氨基联苯)]氯化钯(II)(15mg,0.022mmol)和Cs2CO3(213mg,0.66mmol)。在氮气气氛下将混合物加热至100℃且保持16小时。将反应混合物冷却至室温后,添加EtOAc(20mL)且用水(20mL×3)和盐水(20mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈35-65%/0.2%甲酸水溶液)纯化,得到标题化合物(7mg,7%),其为黄色固体。1H NMR(400MHz,CDCl3)δ7.54(s,1H),7.41(s,1H),7.05(s,1H),6.81(s,1H),6.75-6.74(m,2H),6.47(t,J=55.6Hz,1H),3.95(s,3H),3.70(s,3H),3.63(t,J=5.2Hz,2H),3.37(s,3H),2.91(t,J=5.2Hz,2H),2.61(s,3H),2.14-2.08(m,2H)。LCMS m/z(M+H)438。
以与实施例36类似的方式制备以下化合物:
实施例41
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-(二甲基氨基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,100mg,0.22mmol)于1,4-二噁烷(2mL)中的溶液中添加二甲胺(0.44mL,0.87mmol)、[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(17mg,0.022mmol)和t-BuONa(63mg,0.66mmol)。将混合物在微波中在120℃照射0.5小时。添加DCM(15mL)且用水(15mL×2)、盐水(15mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈48-78%/0.05%NH4OH水溶液)纯化,得到标题化合物(17mg,16%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.54(s,1H),7.41(s,1H),7.05(s,1H),6.90(s,1H),6.80(s,1H),6.63(s,1H),6.48(t,J=56.0Hz,1H),3.95(s,3H),3.74(s,3H),3.66(t,J=5.6Hz,2H),3.37(s,3H),2.92(t,J=5.6Hz,2H),2.72(s,6H),2.15-2.09(m,2H)。LCMS m/z(M+H)467。
以与实施例41类似的方式制备以下化合物:
实施例46
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3,6-三甲基-1H-苯并[d]咪唑-2(3H)-酮
步骤1:4-溴-5-氯苯-1,2-二胺
向4-溴-5-氯-2-硝基-苯胺(8.0g,31.81mmol)于EtOAc(20mL)中的溶液中添加氯化亚锡(II)二水合物(0.05mL,0.65mmol)。在氮气气氛下将混合物加热至80℃且保持3小时。将反应混合物冷却至室温后,添加EtOAc(50mL)且用饱和NaHCO3水溶液(20mL×2)和盐水(20mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=2:1)纯化,得到标题化合物(5.5g,78%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ6.74(s,1H),6.64(s,1H),4.89-4.85(m,4H)。
步骤2:5-溴-6-氯-1H-苯并[d]咪唑-2(3H)-酮
向4-溴-5-氯苯-1,2-二胺(1.0g,4.52mmol)于THF(10mL)中的溶液中添加二(1H-咪唑-1-基)甲酮(1.1g,6.77mmol)。在氮气气氛下将混合物加热至60℃且保持1小时。将反应混合物冷却至室温后,滤出白色析出物,用氯仿(3mL×2)洗涤并真空干燥,得到标题化合物(580mg,52%),其为白色固体且无需进一步纯化即直接用于下一步。
步骤3:5-溴-6-氯-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
在0℃向5-溴-6-氯-1H-苯并[d]咪唑-2(3H)-酮(5.5g,22.22mmol)于DMF(100mL)中的搅拌的溶液中添加NaH(2.22g,55.56mmol,60%)且将混合物搅拌10分钟。滴加碘甲烷(9.46g,66.67mmol)且将混合物在室温再搅拌12小时。添加水(100mL)且用EtOAc(100mL×3)萃取。合并的有机层用盐水(100mL×3)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=4:1)纯化,得到标题化合物(5.3g,87%),其为黄色油状物。1H NMR(400MHz,DMSO-d6)δ7.59(s,1H),7.49(s,1H),3.31(s,6H)。
步骤4:5-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,95mg,0.36mmol)、5-溴-6-氯-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(100mg,0.36mmol)和4,5-二(二苯基膦基)-9,9-二甲基呫吨(21mg,0.04mmol)于甲苯(5mL)中的溶液中添加t-BuONa(104mg,1.09mmol)和三(二亚苄基丙酮)二钯(33mg,0.04mmol)。在氩气气氛下将混合物加热至130℃且保持16小时,将反应混合物冷却至室温后,添加DCM(20mL)且用水(10mL×3)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=2:1)纯化,得到标题化合物(100mg,60%),其为黄色固体。LCMS m/z(M+H)458。
步骤5:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3,6-三甲基-1H-苯并[d]咪唑-2(3H)-酮
向5-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(100mg,0.22mmol)于甲苯(4mL)和水(0.4mL)中的溶液中添加甲基三氟硼酸钾(40mg,0.33mmol)、[(二(1-金刚烷基)-正丁基膦)-2-(2-氨基联苯)]氯化钯(II)(15mg,0.022mmol)和Cs2CO3(213mg,0.66mmol)。在氮气气氛下将混合物加热至100℃且保持16小时。将反应混合物冷却至室温后,添加EtOAc(20mL)且用水(5mL×3)和盐水(5mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈40-70%/0.05%NH4OH水溶液)纯化,得到标题化合物(7mg,7%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ7.70(s,1H),7.45(s,1H),7.16(s,1H),7.08-7.06(m,2H),6.67(t,J=55.2Hz,1H),6.10(s,1H),3.85(s,3H),3.66-3.57(m,1H),3.34(s,4H),3.29(s,3H),2.94-2.81(m,2H),2.14(s,3H),2.09-2.01(m,2H)。LCMS m/z(M+H)438。
以与实施例46类似的方式制备以下化合物:
使用与本申请所述那些程序类似的程序制备以下化合物:
实施例50
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-1H-吲哚-3-甲酰胺
步骤1:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-1H-吲哚-3-甲酸
向5-溴-1-甲基-1H-吲哚-3-甲酸甲酯(200mg,0.75mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,235mg,0.90mmol)于1,4-二噁烷(5mL)中的溶液中添加(2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(54mg,0.07mmol)、2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯(33mg,0.07mmol)和t-BuONa(215mg,2.24mmol)。在氮气气氛下将混合物加热至120℃且保持12小时。将反应混合物冷却至室温后,添加EtOAc(70mL)且用水(60mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(DCM/MeOH=10:1)纯化,得到标题化合物(100mg,31%),其为无色油状物。LCMS m/z(M+H)437。
步骤2:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-1H-吲哚-3-甲酸(150mg,0.34mmol)和N,N-二异丙基乙胺(0.18mL,1.03mmol)于DMF(2mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(144mg,0.38mmol)和甲胺盐酸盐(28mg,0.41mmol)。将反应混合物在室温搅拌1小时。添加EtOAc(50mL)且用水(50mL×3)和盐水(50mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈38-68%/0.2%甲酸水溶液)纯化,得到标题化合物(22mg,14%),其为黄色固体。1H NMR(400MHz,CDCl3)δ7.84(s,1H),7.66(s,1H),7.54(s,1H),7.44-7.36(m,2H),7.22-7.20(m,1H),7.05(s,1H),6.77(s,1H),6.45(t,J=56.0Hz,1H),5.90-5.88(m,1H),3.95(s,3H),3.84(s,3H),3.71(t,J=5.6Hz,2H),3.02(d,J=4.4Hz,3H),2.93(t,J=5.6Hz,2H),2.16-2.11(m,2H)。LCMS m/z(M+H)450。
以与实施例50类似的方式制备以下化合物:
实施例52
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1H-吲哚-3-甲酰胺
步骤1:5-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯
在0℃向5-溴-1H-吲哚-3-甲酸甲酯(800mg,3.15mmol)于DMF(3mL)中的溶液中逐份添加NaH(60%,139mg,3.48mmol)。将混合物在室温搅拌0.5小时。滴加(2-(氯甲氧基)乙基)三甲基甲硅烷(0.61mL,3.47mmol)且将混合物在室温再搅拌3小时。混合物用水(20mL)淬灭且用EtOAc(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=10:1)纯化,得到标题化合物(800mg,66%),其为无色油状物。1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.87(s,1H),7.43-7.38(m,2H),5.48(s,2H),3.94(s,3H),3.47(t,J=8.0Hz,2H),0.89(t,J=8.0Hz,2H),-0.03(s,9H)。
步骤2:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸
向5-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯(200mg,0.52mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,164mg,0.62mmol)于1,4-二噁烷(4mL)中的溶液中添加(2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(39mg,0.05mmol)、2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯(23mg,0.05mmol)和t-BuONa(150mg,1.56mmol)。在氮气气氛下将混合物加热至120℃且保持12小时。将反应混合物冷却至室温后,添加DCM(40mL)且用水(30mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(DCM/MeOH=10:1)纯化,得到标题化合物(100mg,35%),其为白色固体。LCMS m/z(M+H)553。
步骤3:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸(140mg,0.25mmol)和N,N-二异丙基乙胺(0.13mL,0.76mmol)于DMF(3mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(116mg,0.31mmol)和甲胺盐酸盐(21mg,0.31mmol)。将反应混合物在室温搅拌2小时。添加EtOAc(50mL)且用水(50mL×3)和盐水(50mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(135mg,94%),其为白色固体且不需要进一步纯化。LCMS m/z(M+H)566。
步骤4:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酰胺(135mg,0.24mmol)于THF(2mL)中的溶液中添加TBAF(4.0mL,4.0mmol,1M于THF中)。在氮气气氛下将混合物加热至50℃且保持40小时。冷却至室温后,过滤混合物并真空浓缩。添加EtOAc(40mL)且用水(30mL×2)、盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈28-58%/0.05%NH4OH水溶液)纯化,得到标题化合物(28mg,26%),其为白色固体。1HNMR(400MHz,DMSO-d6)δ11.61(s,1H),8.02(d,J=1.2Hz,1H),8.00(d,J=2.8Hz,1H),7.87(d,J=4.4Hz,1H),7.72(s,1H),7.50(d,J=8.4Hz,1H),7.47(s,1H),7.07(s,1H),7.05-7.03(m,1H),6.68(t,J=55.2Hz,1H),6.49(s,1H),3.85(s,3H),3.65-3.55(m,2H),2.91-2.86(m,2H),2.75(d,J=4.4Hz,3H),2.11-1.98(m,2H)。LCMS m/z(M+H)436。
以与实施例52类似的方式制备以下化合物:
实施例54
7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-1H-吲哚-3-甲酰胺
步骤1:1-(5-溴-7-氯-1H-吲哚-3-基)-2,2,2-三氯乙酮
向5-溴-7-氯-1H-吲哚(4.0g,17.35mmol)和2,2,2-三氯乙酰氯(7.73mL,69.42mmol)于DCM(20mL)中的溶液中滴加吡啶(5.59mL,69.42mmol)。在氮气气氛下将混合物加热至48℃且保持12小时。冷却至室温后,将混合物倾入冰水(20mL)中且用DCM(20mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(9g,粗品),其为棕色固体且不需要进一步纯化。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.64-8.47(m,1H),8.29(d,J=2.0Hz,1H),7.68(s,1H)。
步骤2:5-溴-7-氯-1H-吲哚-3-甲酸甲酯
向1-(5-溴-7-氯-1H-吲哚-3-基)-2,2,2-三氯乙酮(7.0g,18.62mmol)于MeOH(20mL)中的溶液中逐份添加KOH(1.1g,0.02mol)。将混合物在室温在氮气气氛下搅拌12小时。添加水(100mL)且混合物用HCl(1N)酸化至pH6,然后用EtOAc(100mL×3)萃取。合并的有机层用盐水(200mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(2.4g,44%),其为棕色固体。1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.24(s,1H),7.96(s,1H),7.42(s,1H),3.94(s,3H)。
步骤3:5-溴-7-氯-1-甲基-1H-吲哚-3-甲酸甲酯
在0℃向5-溴-7-氯-1H-吲哚-3-甲酸甲酯(1.2g,4.16mmol)于DMF(10mL)中的溶液中逐份添加NaH(60%,249mg,6.24mmol)。将混合物在室温搅拌0.5小时。滴加碘甲烷(0.39mL,6.24mmol)且将混合物在室温再搅拌2小时。混合物用水(20mL)淬灭且用EtOAc(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(0.8g,63%),其为浅黄色固体。1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.71(s,1H),7.36(s,1H),4.16(s,3H),3.92(s,3H)。
步骤4:7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-1H-吲哚-3-甲酸甲酯
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,835mg,3.17mmol)、5-溴-7-氯-1-甲基-1H-吲哚-3-甲酸甲酯(800mg,2.64mmol)和K3PO4(1.68g,7.93mmol)于2-甲基-2-丁醇(9mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(223mg,0.26mmol)。在氩气气氛下将混合物加热至95℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=2:1)纯化,得到标题化合物(250mg,19%),其为黄色固体。LCMS m/z(M+H)485。
步骤5:7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-1H-吲哚-3-甲酸
向7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-1H-吲哚-3-甲酸甲酯(70mg,0.14mmol)于MeOH(0.05mL)、THF(2mL)和水(0.5mL)中的溶液中添加一水合氢氧化锂(61mg,1.44mmol)。在氮气气氛下将混合物加热至50℃且保持12小时。将反应混合物冷却至室温后,真空浓缩混合物。添加水(10mL)且混合物用HCl(2N)酸化至pH 4,然后用DCM(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(60mg,88%),其为无色油状物且不需要进一步纯化。LCMS m/z(M+H)471。
步骤6:7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-1H-吲哚-3-甲酰胺
向7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-1H-吲哚-3-甲酸(60mg,0.13mmol)和N,N-二异丙基乙胺(0.033mL,0.19mmol)于DMF(2mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(58mg,0.15mmol)和甲胺盐酸盐(13mg,0.19mmol)。将反应混合物在室温搅拌12小时。添加EtOAc(30mL)且用水(30mL×3)和盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈30-60%/0.05%NH4OH水溶液)纯化,得到标题化合物(10mg,16%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.97-7.96(m,2H),7.74(s,1H),7.49(s,1H),7.15(s,1H),7.11(s,1H),6.72(t,J=55.2Hz,1H),6.56(s,1H),4.13(s,3H),3.86(s,3H),3.62-3.58(m,2H),2.89-2.85(m,2H),2.74(d,J=4.4Hz,3H),2.04-2.01(m,2H)。LCMS m/z(M+H)484。
以与实施例54类似的方式制备以下化合物:
实施例62
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-异丙基-N-甲基-1H-吲哚-3-甲酰胺
步骤1:5-溴-7-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯
在0℃向5-溴-7-氯-1H-吲哚-3-甲酸甲酯(300mg,1.04mmol)于DMF(3mL)中的溶液中逐份添加NaH(60%,54mg,1.35mmol)。将混合物在室温搅拌0.5小时。滴加(2-(氯甲氧基)乙基)三甲基甲硅烷(0.22mL,1.25mmol)且将混合物在室温再搅拌2小时。混合物用水(20mL)淬灭且用EtOAc(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(330mg,76%),其为浅黄色固体。LCMS m/z(M+H)418。
步骤2:7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯
向5-溴-7-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯(500mg,1.19mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,380mg,1.44mmol)和K3PO4(760mg,3.58mmol)于2-甲基-2-丁醇(10mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(103mg,0.12mmol)。在氮气气氛下将混合物加热至95℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。添加EtOAc(50mL)且用水(40mL×2)和盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=4:1)纯化,得到标题化合物(350mg,49%),其为白色固体。LCMS m/z(M+H)601
步骤3:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯
向7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯(100mg,0.17mmol)于THF(3mL)和水(0.6mL)中的溶液中添加(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(13mg,0.017mmol)、Na2CO3(53mg,0.50mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(42mg,0.25mmol)。在氮气气氛下将混合物加热至90℃且保持3小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(65mg,64%),其为浅黄色油状物。LCMS m/z(M+H)607。
步骤4:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸甲酯(50mg,0.08mmol)于THF(3mL)和水(0.5mL)中的溶液中添加一水合氢氧化锂(35mg,0.08mmol)。在氮气气氛下将混合物加热至50℃且保持12小时。将反应混合物冷却至室温后,真空浓缩混合物。添加水(10mL)且混合物用HCl(2N)酸化至pH 4,然后用DCM(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(38mg,78%),其为白色固体且不需要进一步纯化。LCMS m/z(M+H)593。
步骤5:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-7-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酸(250mg,0.42mmol)和N,N-二异丙基乙胺(0.24mL,1.35mmol)于DMF(2mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(177mg,0.46mmol)和甲胺盐酸盐(43mg,0.63mmol)。将反应混合物在室温搅拌12小时。添加EtOAc(20mL)且用水(10mL×2)和盐水(5mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(220mg,79%),其为白色固体且不需要进一步纯化。LCMS m/z(M+H)607。
步骤6:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-异丙基-N-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-7-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酰胺(260mg,0.43mmol)于MeOH(10mL)中的溶液中添加10%Pd/C(30mg)。将混合物在室温在氢气气氛(15Psi)下搅拌12小时。过滤混合物并真空浓缩滤液。粗残余物通过硅胶色谱(DCM/MeOH=10:1)纯化,得到标题化合物(240mg,92%),其为浅黄色固体。LCMS m/z(M+H)608。
步骤7:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-异丙基-N-甲基-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-异丙基-N-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲哚-3-甲酰胺(100mg,0.16mmol)于THF(1mL)中的溶液中添加TBAF(0.82mL,0.82mmol,1M于THF中)。在氮气气氛下将混合物加热至50℃且保持12小时。将反应混合物冷却至室温后,真空浓缩混合物。将粗残余物溶于DCM(25mL),用水(20mL×2)和盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈36-66%/0.2%甲酸水溶液)纯化,得到标题化合物(32mg,41%),其为浅黄色固体。1H NMR(400MHz,CDCl3)δ11.59(s,1H),8.00-7.99(m,1H),7.86-7.85(m,2H),7.72(s,1H),7.47(s,1H),7.06(s,1H),6.94(s,1H),6.68(t,J=55.6Hz,1H),6.58(s,1H),3.85(s,3H),3.84-3.79(m,1H),3.64-3.61(m,2H),2.90-2.85(m,2H),2.75(d,J=4.4Hz,3H),2.06-2.03(m,2H),1.27(d,J=7.2Hz,6H)。LCMS m/z(M+H)478。
以与实施例62类似的方式制备以下化合物:
实施例64
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,7-二甲基-1H-吡咯并[2,3-c]吡啶-3-甲酰胺
步骤1:5-氯-7-甲基-1H-吡咯并[2,3-c]吡啶
在-78℃向6-氯-2-甲基-3-硝基吡啶(14.0g,81.13mmol)于THF(200mL)中的溶液中滴加乙烯基溴化镁(284mL,283.94mmol)。将混合物在-20℃在氮气气氛下搅拌2小时。将混合物倾入冰水(300mL)中且用EtOAc(200mL×2)萃取。合并的有机层用盐水(400mL×3)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(6.5g,48%),其为黄色油状物。LCMS m/z(M+H)167。
步骤2:1-(5-氯-7-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-2,2,2-三氯乙酮
向5-氯-7-甲基-1H-吡咯并[2,3-c]吡啶(4.0g,24.01mmol)和AlCl3(24.0g,180mmol)于DCM(120mL)中的溶液中滴加2,2,2-三氯乙酰氯(13.4mL,120.04mmol)。在氮气气氛下将混合物加热至48℃且保持2小时。冷却至室温后,将混合物倾入冰水(200mL)中且用DCM(200mL×3)萃取。合并的有机层用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(5.0g,66%),其为棕色固体。
步骤3:5-氯-7-甲基-1H-吡咯并[2,3-c]吡啶-3-甲酸甲酯
向1-(5-氯-7-甲基-1H-吡咯并[2,3-c]吡啶-3-基)-2,2,2-三氯乙酮(5.0g,13.3mmol)于MeOH(50mL)中的溶液中逐份添加KOH(989mg,17.63mmol)。将混合物在室温在氮气气氛下搅拌2小时。添加水(50mL)且混合物用HCl(1N)酸化至pH 6,然后用EtOAc(80mL×2)萃取。合并的有机层用盐水(150mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(3.0g,83%),其为浅黄色固体。LCMS m/z(M+H)225。
步骤4:5-氯-7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酸甲酯
在0℃向5-氯-7-甲基-1H-吡咯并[2,3-c]吡啶-3-甲酸甲酯(2.5g,11.13mmol)于DMF(30mL)中的溶液中逐份添加NaH(60%,667mg,16.69mmol)。将混合物在室温搅拌0.5小时。滴加(2-(氯甲氧基)乙基)三甲基甲硅烷(1.63mL,22.26mmol)且将混合物在室温再搅拌3小时。混合物用水(100mL)淬灭且用EtOAc(100mL×3)萃取。合并的有机层用盐水(150mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(2.5g,63%),其为浅黄色固体。LCMS m/z(M+H)355。
步骤5:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酸甲酯
向5-氯-7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酸甲酯(500mg,1.41mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,371mg,1.41mmol)和Cs2CO3(1.4g,4.23mmol)于1,4-二噁烷(10mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(112mg,0.14mmol)。在氮气气氛下将混合物加热至110℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。添加EtOAc(50mL)且用水(40mL×2)和盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(550mg,67%),其为黄色油状物。LCMS m/z(M+H)582。
步骤6:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酸
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酸甲酯(550mg,0.95mmol)于MeOH(2mL)、THF(5mL)和水(1mL)中的溶液中添加一水合氢氧化锂(397mg,9.45mmol)。在氮气气氛下将混合物加热至50℃且保持12小时。将反应混合物冷却至室温后,真空浓缩混合物。添加水(10mL)且混合物用HCl(2N)酸化至pH 4,然后用DCM(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(500mg,93%),其为黄色油状物。LCMS m/z(M+H)568。
步骤7:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,7-二甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酸(500mg,0.88mmol)和N,N-二异丙基乙胺(0.44mL,2.64mmol)于DMF(5mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(402mg,1.06mmol)和甲胺盐酸盐(89mg,1.32mmol)。将反应混合物在室温搅拌2小时。添加EtOAc(20mL)且用水(20mL×2)和盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(DCM/MeOH=20:1)纯化,得到标题化合物(350mg,68%),其为黄色油状物。LCMS m/z(M+H)581。
步骤8:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,7-二甲基-1H-吡咯并[2,3-c]吡啶-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,7-二甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-3-甲酰胺(350mg,0.60mmol)于THF(3mL)中的溶液中添加TBAF(6.03mL,6.03mmol,1M于THF中)。在氮气气氛下将混合物加热至50℃且保持48小时。将反应混合物冷却至室温后,真空浓缩混合物。将粗残余物溶于EtOAc(20mL),用水(20mL×2)和盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈18-48%/0.05%NH4OH水溶液)纯化,得到标题化合物(78mg,28%),其为白色固体。1H NMR(400MHz,CDCl3)δ9.90(s,1H),7.79(s,1H),7.56(s,1H),7.54(s,1H),7.43(s,1H),7.36(s,1H),7.07(s,1H),6.53(t,J=55.6Hz,1H),5.93-5.86(m,1H),3.96(s,3H),3.88(t,J=4.8Hz,2H),2.99(d,J=5.2Hz,3H),2.90-2.83(m,2H),2.68(s,3H),2.07-2.04(m,2H)。LCMS m/z(M+H)451。
以与实施例64类似的方式制备以下化合物:
实施例72
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基咪唑并[1,2-b]哒嗪-3-甲酰胺
步骤1:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)咪唑并[1,2-b]哒嗪-3-甲酸乙酯
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,700mg,2.67mmo)、6-氯咪唑并[1,2-b]哒嗪-3-甲酸乙酯(600mg,2.67mmol)和K3PO4(1.69g,7.98mmol)于2-甲基-2-丁醇(10mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(225mg,0.27mmol)。在氩气气氛下将混合物加热至95℃且保持12小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过制备型TLC(石油醚/EtOAc=1:1)纯化,得到标题化合物(110mg,9%),其为黄色油状物。LCMS m/z(M+H)453。
步骤2:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)咪唑并[1,2-b]哒嗪-3-甲酸
向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)咪唑并[1,2-b]哒嗪-3-甲酸乙酯(110mg,0.28mmol)于MeOH(1mL)、THF(3mL)和水(0.5mL)中的溶液中添加一水合氢氧化锂(116mg,2.76mmol)。在氮气气氛下将混合物加热至50℃且保持12小时。将反应混合物冷却至室温后,真空浓缩混合物。添加水(10mL)且混合物用HCl(2N)酸化至pH 4,然后用DCM(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(80mg,78%),其为黄色油状物且不需要进一步纯化。LCMS m/z(M+H)425。
步骤3:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基咪唑并[1,2-b]哒嗪-3-甲酰胺
向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)咪唑并[1,2-b]哒嗪-3-甲酸(80mg,0.19mmol)和N,N-二异丙基乙胺(0.09mL,0.57mmol)于DMF(2mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(86mg,0.23mmol)和甲胺盐酸盐(19mg,0.28mmol)。将反应混合物在室温搅拌2小时。添加EtOAc(20mL)且用水(20mL×2)和盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈37-67%/0.05%NH4OH水溶液)纯化,得到标题化合物(19mg,22%),其为黄色固体。1H NMR(400MHz,CDCl3)δ8.46-8.40(m,1H),8.33(s,1H),7.89(s,1H),7.86(s,1H),7.61(d,J=12Hz,1H),7.52(s,1H),7.24(s,1H),6.60(t,J=55.6Hz,1H),4.00(s,3H),3.95(t,J=6.4Hz,2H),3.03(d,J=4.8Hz,3H),2.86(t,J=6.4Hz,2H),2.19-2.12(m,2H)。LCMS m/z(M+H)438。
以与实施例72类似的方式制备以下化合物:
实施例74
7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1-(7-(1-甲基-1H-吡唑-4-基)-5H-吡咯并[2,3-b]吡嗪-2-基)-1,2,3,4-四氢喹啉
步骤1:2-溴-5-(苯基磺酰基)-5H-吡咯并[2,3-b]吡嗪
在0℃向2-溴-5H-吡咯并[2,3-b]吡嗪(1.0g,5.05mmol)于THF(10mL)中的搅拌的溶液中添加NaH(225mg,5.63mmol,60%)且将混合物搅拌30分钟。滴加苯磺酰氯(0.72mL,5.66mmol)且将混合物在室温再搅拌2小时。混合物用饱和NH4Cl水溶液(30mL)淬灭且用EtOAc(30mL×2)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(1.4g,82%),其为黄色固体且不需要进一步纯化。1H NMR(400MHz,CD3OD)δ8.45(s,1H),8.24(d,J=4.0Hz,1H),8.20-8.15(m,2H),7.74-7.67(m,1H),7.64-7.59(m,2H),6.85(d,J=4.0Hz,1H)。
步骤2:7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1-(5H-吡咯并[2,3-b]吡嗪-2-基)-1,2,3,4-四氢喹啉
向2-溴-5-(苯基磺酰基)-5H-吡咯并[2,3-b]吡嗪(500mg,1.48mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,468mg,1.78mmol)于1,4-二噁烷(10mL)中的溶液中添加(2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(116mg,0.15mmol)、2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯(70mg,0.15mmol)和t-BuONa(710mg,7.39mmol)。在氮气气氛下将混合物加热至120℃且保持12小时。将反应混合物冷却至室温后,添加DCM(60mL)且用水(40mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(DCM/MeOH=99:1)纯化,得到标题化合物(292mg,52%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.72(d,J=3.6Hz,1H),7.70(s,1H),7.57(s,1H),7.22(s,1H),7.17(s,1H),6.60(t,J=56.0Hz,1H),6.56(d,J=4.4Hz,1H),3.96(s,3H),3.90(t,J=6.0Hz,2H),2.95(t,J=6.0Hz,2H),2.15-2.09(m,2H)。
步骤3:1-(7-溴-5H-吡咯并[2,3-b]吡嗪-2-基)-7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉
在0℃向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1-(5H-吡咯并[2,3-b]吡嗪-2-基)-1,2,3,4-四氢喹啉(200mg,0.53mmol)于DMF(2mL)中的溶液中逐份添加N-溴琥珀酰亚胺(89mg,0.47mmol)。将混合物在室温搅拌1小时。将混合物倾入水(50mL)中且用DCM(50mL×2)萃取。合并的有机层经Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(DCM/MeOH=49:1)纯化,得到标题化合物(132mg,55%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.27(s,1H),7.99(d,J=2.4Hz,1H),7.83(s,1H),7.57(s,1H),7.39(s,1H),7.25(s,1H),6.84(t,J=54.8Hz,1H),3.92-3.81(m,2H),3.89(s,3H),2.86(t,J=6.0Hz,2H),2.07-1.93(m,2H)。
步骤4:7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1-(7-(1-甲基-1H-吡唑-4-基)-5H-吡咯并[2,3-b]吡嗪-2-基)-1,2,3,4-四氢喹啉
向1-(7-溴-5H-吡咯并[2,3-b]吡嗪-2-基)-7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(150mg,0.33mmol)于THF(5mL)和水(1mL)中的溶液中添加1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(82mg,0.39mmol)、2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(14mg,
0.03mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(24mg,0.03mmol)和Na2CO3(105mg,0.99mmol)。在氮气气氛下将反应混合物加热至60℃且保持12小时。冷却至室温后,过滤混合物并真空浓缩。添加DCM(30mL)且用水(30mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈42-52%/0.05%NH4OH水溶液)纯化,得到标题化合物(20mg,13%),其为黄色固体。1HNMR(400MHz,DMSO-d6)δ11.90(d,J=2.4Hz,1H),8.23(s,1H),8.10(s,1H),8.02(d,J=3.2Hz,1H),7.92(s,1H),7.83(s,1H),7.58(s,1H),7.55(s,1H),7.25(s,1H),6.87(t,J=52.0,1H),3.93(t,J=6.0Hz,2H),3.89(s,3H),3.85(s,3H),2.87(t,J=6.0Hz,2H),2.08-1.98(m,2H)。LCMS m/z(M+Na)483。
以与实施例74类似的方式制备以下化合物:
实施例76
向7-溴-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(800mg,2.44mmol)于1,4-二噁烷(5mL)中的溶液中添加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)(1.24g,4.88mmol)、KOAc(718mg,7.31mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(178mg,0.24mmol)。在氮气气氛下将混合物加热至90℃且保持3小时。冷却至室温后,添加EtOAc(60mL)且用水(50mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(710mg,78%),其为白色固体。LCMS m/z(M+Na)398。
步骤2:2-溴-4-氯-3-(二氟甲基)-1-甲基苯
在0℃向2-溴-6-氯-3-甲基苯甲醛(300mg,1.28mmol)于DCM(10mL)中的溶液中滴加二乙基氨基三氟化硫(0.34mL,2.57mmol)。将混合物在室温在氮气气氛下搅拌1小时。反应用水(5mL)淬灭且用DCM(10mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=100:1)纯化,得到标题化合物(210mg,64%),其为无色油状物。1H NMR(400MHz,CD3OD)δ7.39-7.38(m,2H),7.35(t,J=52.0Hz,1H),2.42(s,3H)。
向7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(709mg,1.89mmol)和2-溴-4-氯-3-(二氟甲基)-1-甲基苯(460mg,1.8mmol)于1,4-二噁烷(5mL)和水(1mL)中的溶液中添加[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(131mg,0.18mmol)和Na2CO3(572mg,5.4mmol)。将混合物在微波中在90℃照射0.5小时。添加EtOAc(70mL)且用水(60mL×2)、盐水(60mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(400mg,52%),其为白色固体。1H NMR(400MHz,CD3OD)δ7.44-7.38(m,2H),7.16-7.06(m,1H),7.05-6.94(m,2H),6.54(t,J=54.0Hz,1H),4.58-4.41(m,2H),4.22-4.00(m,2H),3.93-3.71(m,2H),2.03-1.97(m,3H),1.39-1.35(m,9H)。
向7-(3-氯-2-(二氟甲基)-6-甲基苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(200mg,0.47mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(196mg,0.94mmol)于THF(5mL)和水(1mL)中的溶液中添加2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(22mg,0.05mmol)、(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(37mg,0.04mmol)和Na2CO3(150mg,1.42mmol)。将混合物在微波中在60℃照射0.5小时。添加EtOAc(70mL)且用水(60mL×2)、盐水(60mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(210mg,95%),其为无色油状物。LCMS m/z(M+H)470。
向7-(2-(二氟甲基)-6-甲基-3-(1-甲基-1H-吡唑-4-基)苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(210mg,0.45mmol)于DCM(2mL)中的溶液中添加三氟乙酸(0.33mL,4.47mmol)。将反应混合物在室温搅拌12小时并真空浓缩。添加DCM(50mL),用饱和NaHCO3水溶液(30mL×2)和水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(140mg,85%),其为棕色油状物且不需要进一步纯化。LCMS m/z(M+H)370。
向7-(2-(二氟甲基)-6-甲基-3-(1-甲基-1H-吡唑-4-基)苯基)-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂(140mg,0.38mmol)和N-甲基-1H-咪唑-1-甲酰胺(71mg,0.57mmol)于DCM(3mL)中的溶液中添加三乙胺(0.16mL,1.14mmol)。将反应混合物在室温搅拌12小时并真空浓缩。添加DCM(50mL)且用水(40mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(DCM/MeOH=10:1)纯化,得到标题化合物(35mg,21%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.52(s,1H),7.37(d,J=8.0Hz,1H),7.30(d,J=8.0Hz,1H),7.12-7.06(m,3H),6.48(t,J=54.0Hz,1H),4.54-4.32(m,3H),4.27-4.18(m,1H),4.16-4.06(m,2H),3.98(s,3H),3.78-3.72(m,1H),2.75(d,J=4.0Hz,3H),2.07(s,3H)。LCMS m/z(M+Na)449。
以与实施例76类似的方式制备以下化合物:
实施例78
向7-溴-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(2.0g,6.09mmol)于DCM(20mL)中的溶液中滴加三氟乙酸(4.51mL,60.94mmol)。将反应混合物在室温搅拌1小时并真空浓缩。残余物用DCM(30mL)稀释,用饱和NaHCO3水溶液(30mL×2)和水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(1.4g,粗品),其为黄色油状物且不需要进一步纯化。LCMS m/z(M+Na)228。
在0℃向7-溴-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂(1.4g,6.14mmol)和三乙胺(2.52mL,18.41mmol)于DCM(30mL)中的溶液中滴加丙酰氯(0.8mL,9.21mmol)于DCM(2mL)中的溶液。将反应混合物在20℃搅拌10分钟并真空浓缩。粗残余物通过硅胶柱色谱(洗脱剂为石油醚/EtOAc=100:1至1:1)纯化,得到标题化合物(1.15g,66%),其为黄色油状物。LCMSm/z(M+H)285。
向1-(7-溴-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-基)丙-1-酮(300mg,1.06mmol)、7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,278mg,1.06mmol)和t-BuONa(254mg,2.64mmol)于1,4-二噁烷(6mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(84mg,0.11mmol)。在氮气气氛下将反应混合物加热至120℃且保持16小时。冷却至室温后,过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈44-74%/0.2%甲酸水溶液)纯化,得到标题化合物(67mg,14%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.49(s,1H),7.34-6.98(m,4H),6.90-6.58(m,2H),4.60-4.55(m,2H),4.20-4.00(m,2H),3.88-3.78(m,5H),3.63-3.51(m,2H),2.86-2.82(m,2H),2.39-2.22(m,2H),2.00-1.96(m,2H),0.97-0.91(m,3H)。LCMS m/z(M+Na)489。
以与实施例78类似的方式制备以下化合物:
实施例80
(S)-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-3-甲基-3,4-二氢喹喔啉-2(1H)-酮
步骤1:7-(二氟甲基)-1-(2-氟-3-硝基苯基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉
向1-溴-2-氟-3-硝基苯(100mg,0.45mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,92mg,0.35mmol)于1,4-二噁烷(2mL)中的溶液中添加Cs2CO3(228mg,0.70mmol)和乙酸钯(II)(8mg,0.04mmol)。将混合物在微波中在140℃照射1小时。过滤混合物并真空浓缩。粗残余物通过制备型TLC(石油醚/EtOAc=1:1)纯化,得到标题化合物(40mg,22%),其为红色油状物。LCMS m/z(M+H)403。
步骤2:(S)-2-((2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-6-硝基苯基)氨基)丙酸
向7-(二氟甲基)-1-(2-氟-3-硝基苯基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(40mg,0.10mmol)于DMF(3mL)中的溶液中添加(S)-2-氨基丙酸(13mg,0.15mmol)和Cs2CO3(65mg,0.20mmol)。将反应混合物加热至100℃且保持4小时。冷却至室温后,添加EtOAc(30mL)且用水(20mL×3)洗涤。合并的水层用HCl(2N)酸化至pH 4,然后用EtOAc(40mL×3)萃取。合并的有机层用盐水(30mL×3)洗涤,经无水Na2SO4干燥并真空浓缩,得到标题化合物(24mg,51%),其为棕色固体且不需要进一步纯化。LCMS m/z(M+H)472。
步骤3:(S)-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-3-甲基-3,4-二氢喹喔啉-2(1H)-酮
向(S)-2-((2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-6-硝基苯基)氨基)丙酸(40mg,0.08mmol)于AcOH(2mL)中的溶液中添加Fe粉(24mg,0.42mmol)。在氮气气氛下将反应混合物加热至100℃且保持12小时。冷却至室温后,过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈36-56%/0.2%甲酸水溶液)纯化,得到标题化合物(2mg,5%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),7.71(s,1H),7.46(s,1H),7.14-7.03(m,1H),6.87-6.55(m,4H),6.34-6.25(m,1H),5.43-5.40(m,1H),4.01-3.72(m,1H),3.86(s,3H),2.89-2.85(m,2H),2.27-1.91(m,4H),1.30-1.06(m,3H)。LCMS m/z(M+H)424。
以与实施例80类似的方式制备以下化合物:
实施例83
3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-甲酰胺
步骤1:3-溴-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-甲酸甲酯
向3-溴-1H-吲唑-5-甲酸甲酯(2.0g,7.8mmol)和Cs2CO3(5.1g,15.7mmol)于DMF(10mL)中的溶液中添加甲磺酸四氢-2H-吡喃-4-基酯(2.1g,11.7mmol)。将反应混合物加热至80℃且保持12小时。冷却至室温后,真空浓缩反应混合物。添加EtOAc(80mL)且用水(100mL×3)、盐水(100mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=10:1)纯化,得到标题化合物(400mg,15%),其为黄色固体。1HNMR(400MHz,DMSO-d6)δ8.39(s,1H),8.12-8.09(m,1H),7.47(d,J=8.8Hz,1H),4.67-4.59(m,1H),4.20-4.16(m,2H),3.97(s,3H),3.67-3.55(m,2H),2.47-2.36(m,2H),2.00-1.96(m,2H)。
步骤2:3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-甲酸
向3-溴-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-甲酸甲酯(500mg,1.47mmol)、7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,388mg,1.47mmol)于1,4-二噁烷(10mL)中的溶液中添加(2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(115mg,0.15mmol)、2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯(69mg,0.15mmol)和t-BuONa(425mg,4.4mmol)。在氮气气氛下将反应混合物加热至120℃且保持16小时。冷却至室温后,真空浓缩反应混合物。添加EtOAc(30mL)且用水(10mL×3)、盐水(10mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(DCM/MeOH=20:1)纯化,得到标题化合物(320mg,43%),其为黄色固体。LCMS m/z(M+H)508。
步骤3:3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-甲酰胺
向3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-甲酸(300mg,0.59mmol)于DCM(5mL)中的溶液中添加N,N-二异丙基乙胺(0.314mL,1.77mmol)、HATU(337mg,0.89mmol)和甲胺(1.2mL,1.2mmol,1M于THF中)。将反应混合物在室温搅拌2小时并真空浓缩。添加EtOAc(30mL)且用水(10mL×3)、盐水(10mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈30-60%/0.05%NH4OH水溶液)纯化,得到标题化合物(11mg,55%),其为白色固体。1HNMR(400MHz,DMSO-d6)δ8.45-8.42(m,1H),8.07(s,1H),7.93-7.88(m,1H),7.86-7.80(m,1H),7.77(s,1H),7.52(s,1H),7.19(s,1H),6.94(s,1H),6.74(t,J=56Hz,1H),4.96-4.90(m,1H),4.02-3.99(m,2H),3.90-3.81(m,2H),3.87(s,3H),3.59-3.54(m,2H),2.96-2.92(m,2H),2.76(d,J=4.4Hz,3H),2.16-2.03(m,4H),1.93-1.90(m,2H)。LCMS m/z(M+H)521。
以与实施例83类似的方式制备以下化合物:
实施例85
向7-溴-N-甲基-1,2,3,5-四氢-1,4-苯并二氮杂-4-甲酰胺(中间体B,50mg,0.18mmol)于乙腈(0.75mL)和DMF(0.75mL)中的溶液中添加碳酸钾(31mg,0.23mmol)和碘甲烷(107mg,0.754mmol)。将反应混合物在60℃在氮气气氛下搅拌16小时。真空浓缩混合物。然后向混合物中添加邻甲苯基硼酸(41mg,0.30mmol)、二噁烷(1.0mL)、水(0.2mL)、K3PO4·H2O(89mg,0.38mmol)、(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]甲磺酸钯(II)(8.1mg,0.0090mmol)和2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(4.4mg,0.0090mmol)。将混合物在70℃在氮气气氛下搅拌3小时。将粗残余物稀释于二氯甲烷(5mL),经无水MgSO4干燥,通过硅藻土过滤并真空浓缩。所得混合物通过反相色谱(乙腈30-70%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(37mg,69%),其为白色固体。1HNMR(400MHz,DMSO-d6)δ7.32(d,J=2.3Hz,1H),7.29-7.12(m,5H),6.95(d,J=8.3Hz,1H),6.38(q,J=4.4Hz,1H),4.36(s,2H),3.59-3.51(m,2H),3.01-2.94(m,2H),2.88(s,3H),2.53(d,J=4.3Hz,3H),2.26(s,3H)。LCMS m/z(M+H)310。
实施例86
步骤1:5-溴-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶
向6-溴吡啶-2-胺(500mg,2.89mmol)于2-丙醇(5.8mL)中的溶液中添加2-溴-1-(4-甲氧基苯基)乙酮(794mg,3.47mmol)。将混合物在80℃搅拌20小时。然后将反应混合物冷却至室温并真空浓缩。将粗残余物在DCM(50mL)与饱和NaHCO3水溶液(50mL)之间分配且将两相分离。水层用DCM(2×50mL)萃取。合并的有机层经无水MgSO4干燥,过滤并真空浓缩。所得混合物通过硅胶色谱(iPrOAc/庚烷=2:8)纯化,得到标题化合物(112mg,50%纯度),其为橙色固体且无需进一步纯化即用于下一步。LCMS m/z(M+H)303。
向7-溴-N-甲基-3,5-二氢-2H-1,4-苯并氧杂氮杂-4-甲酰胺(中间体A,50mg,0.17mmol)和联硼酸二频哪醇酯(89mg,0.35mmol)于二噁烷(0.88mL)中的溶液中添加KOAc(52mg,0.53mmol)、(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]氯化钯(II)(4.2mg,0.0053mmol)和2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(5.1mg,0.010mmol)。将混合物在80℃在氮气气氛下搅拌16小时。将反应混合物冷却至室温并添加5-溴-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶(36mg,0.12mmol)、K3PO4·H2O(71mg,0.30mmol)、水(0.3mL)、二噁烷(0.5mL)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]氯化钯(II)(4.2mg,0.0053mmol)。将反应混合物在70℃在氮气气氛下搅拌5小时。然后将反应混合物冷却至室温并真空浓缩。将粗残余物稀释于二氯甲烷(5mL),经无水MgSO4干燥,通过硅藻土过滤并真空浓缩。所得混合物通过反相色谱(乙腈20-60%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(7.8mg,10%),其为白色固体。1HNMR(400MHz,DMSO-d6)δ8.19(s,1H),7.99-7.89(m,2H),7.84(d,J=2.4Hz,1H),7.58(dd,J=8.1,1.9Hz,2H),7.34(dd,J=9.0,7.0Hz,1H),7.18(d,J=8.3Hz,1H),7.01-6.93(m,2H),6.86(dd,J=7.0,1.2Hz,1H),6.59-6.48(m,1H),4.55(s,2H),4.12(dd,J=5.5,3.3Hz,2H),3.83-3.74(m,5H),2.56(d,J=4.3Hz,3H)。LCMS m/z(M+H)429。
实施例87
1-[6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-3,4-二氢-2H-喹啉-1-基]乙酮
步骤1
1-(3,4-二氢-2H-喹啉-1-基)乙酮
在0℃向1,2,3,4-四氢喹啉(2.00g,15.0mmol)于DCM(30mL)中的溶液中添加TEA(3.14mL,22.5mmol)和乙酸酐(1.70mL,18.0mmol)。将混合物加热至32℃且保持2小时。将反应混合物温热至室温并搅拌2.5小时。添加水(50mL)且混合物用DCM(50mL×2)萃取。合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,然后减压浓缩。残余物通过硅胶色谱(100%庚烷至50%EtOAc/庚烷梯度)纯化,得到标题化合物(2.32g,88%),其为淡黄色油状物。1HNMR(400MHz,DMSO-d6)δ7.26-7.05(m,4H),3.81(t,J=6.6Hz,2H),2.73(t,J=6.7Hz,2H),2.24(s,3H),1.97(p,J=6.6Hz,2H)。
步骤2
1-(6-溴-3,4-二氢-2H-喹啉-1-基)乙酮
在0℃向1-(3,4-二氢-2H-喹啉-1-基)乙酮(400mg,2.0mmol)于DCM(10mL)中的溶液中逐份添加N-溴琥珀酰亚胺(400mg,2.0mmol)。将混合物在室温搅拌2小时,然后在45℃加热14小时。冷却至室温后,减压浓缩反应混合物。残余物通过硅胶色谱(100%庚烷至60%EtOAc/庚烷梯度)纯化,得到标题化合物(0.542g,90%),其为黄色油状物。1H NMR(400MHz,CDCl3)δ7.40-7.03(m,3H),3.76(t,J=6.5Hz,2H),2.71(t,J=6.6Hz,2H),2.22(s,3H),2.04-1.86(m,2H)。
步骤3
1-[6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-3,4-二氢-2H-喹啉-1-基]乙酮
向小瓶中添加7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,70.0mg,0.266mmol)、1-(6-溴-3,4-二氢-2H-喹啉-1-基)乙酮(243mg,0.912mmol)、[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(33.3mg,0.0399mmol)、t-BuONa(51.1mg,0.532mmol)和1,4-二噁烷(0.53mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至120℃且保持16小时。将反应混合物冷却至室温后,添加DCM(3mL)且反应混合物通过硅藻土过滤并减压浓缩。粗残余物通过反相色谱(乙腈30-70%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(40.5mg,32%),其为白色固体。1H NMR(400MHz,DMSO-d6,330K)δ7.72(s,1H),7.53(s,1H),7.48(d,J=0.8Hz,1H),7.13-7.02(m,3H),6.87-6.60(m,2H),3.86(s,3H),3.73-3.67(m,2H),3.62-3.55(m,2H),2.83(t,J=6.5Hz,2H),2.71(t,J=6.6Hz,2H),2.18(s,3H),2.03-1.95(m,2H),1.93-1.84(m,2H)。LCMSm/z(M+H)437。
实施例88
6-乙酰基-1-甲基-3-[3-(1-甲基吡唑-4-基)-8-异喹啉基]-7,8-二氢-5H-1,6-二氮杂萘-2-酮
向小瓶中添加6-乙酰基-3-溴-1-甲基-7,8-二氢-5H-1,6-二氮杂萘-2-酮(中间体G,14.6mg,0.0512mmol)、3-(1-甲基吡唑-4-基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异喹啉(中间体E,25.7mg,0.0768mmol)、2-二环己基膦基-2’,4’,6’-三异丙基联苯(1.2mg,0.0026mmol)、(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2-氨基乙基)苯基)]氯化钯(II)(1.9mg,0.0026mmol)、K3PO4·H2O(35.4mg,0.154mmol)、1,4-二噁烷(0.5mL)和水(0.1mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至120℃且保持16小时。将反应混合物冷却至室温后,添加DCM(3mL)且反应混合物通过硅藻土过滤并减压浓缩。粗残余物通过反相色谱(乙腈5-50%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(16.1mg,75%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ8.92(dt,J=16.1,0.9Hz,1H),8.32-8.26(m,1H),8.06(q,J=1.3,0.8Hz,2H),7.87(d,J=8.3Hz,1H),7.74(ddd,J=8.3,7.0,3.6Hz,1H),7.51-7.47(m,1H),7.40(ddd,J=8.3,7.0,1.1Hz,1H),4.48(d,J=17.7Hz,2H),3.91(s,3H),3.78(t,J=5.9Hz,2H),3.51(s,3H),3.02-2.93(m,1H),2.92-2.83(m,1H),2.51-2.07(m,3H)。LCMS m/z(M+H)414。
实施例89
6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1-甲基-二氢吲哚-2,3-二酮
步骤1:6-溴-1-甲基-二氢吲哚-2,3-二酮
向6-溴二氢吲哚-2,3-二酮(0.504g,2.23mmol)于乙腈(11mL)中的溶液中先后添加K2CO3(1.23g,8.92mmol)和碘甲烷(0.278mL,4.46mmol)。将反应混合物在60℃加热1.5小时。冷却至室温后,添加水(30mL)且混合物用DCM(30mL×3)萃取。合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,然后减压浓缩,得到标题化合物(0.506g,95%),其不需要进一步纯化。1H NMR(400MHz,CDCl3)δ7.46(dd,J=7.9,1.0Hz,1H),7.32-7.28(m,1H),7.08(d,J=1.5Hz,1H),3.25(d,J=0.6Hz,3H)。
步骤2:6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1-甲基-二氢吲哚-2,3-二酮
向小瓶中先后添加7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,290mg,1.10mmol)、6-溴-1-甲基-二氢吲哚-2,3-二酮(317mg,1.32mmol)、(2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]甲磺酸钯(II)(147mg,0.165mmol)、K3PO4(0.723g,3.30mmol)和2-甲基-2-丁醇(7.3mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至100℃且保持16小时。将反应混合物冷却至室温后,添加DCM(3mL)且反应混合物通过硅藻土过滤并减压浓缩。粗残余物通过反相色谱(乙腈30-70%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(86.6mg,18%),其为红色固体。1H NMR(400MHz,DMSO-d6)δ7.90-7.85(m,1H),7.62(d,J=0.8Hz,1H),7.51(s,1H),7.45(d,J=8.4Hz,1H),7.36(d,J=1.3Hz,1H),7.09-6.77(m,3H),3.90(s,3H),3.86-3.78(m,2H),3.11(s,3H),2.80(t,J=6.4Hz,2H),1.99(t,J=6.2Hz,2H)。LCMS m/z(M+H)423。
实施例90
6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1-甲基-二氢吲哚-2-酮
将6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1-甲基-二氢吲哚-2,3-二酮(实施例89,15mg,0.174mmol)于一水合肼(1.0mL)中的溶液在100℃加热2小时。冷却至室温后,减压浓缩反应混合物。粗残余物先后通过反相色谱(乙腈30-70%/0.1%氢氧化铵水溶液)和SFC(吡啶基酰胺150×30.0mm I.D.5μm;0.1%氢氧化铵/MeOH 5-60%/超临界CO2)纯化,得到标题化合物(4.3mg,60%)。1H NMR(400MHz,DMSO-d6)δ7.75(d,J=0.8Hz,1H),7.50(d,J=0.8Hz,1H),7.28(dd,J=7.8,1.1Hz,1H),7.12(d,J=1.2Hz,1H),6.93(d,J=1.9Hz,1H),6.91-6.86(m,1H),6.86-6.59(m,2H),3.86(s,3H),3.70-3.59(m,2H),3.55(d,J=1.1Hz,2H),3.09(s,3H),2.85(t,J=6.3Hz,2H),2.08-1.94(m,2H)。LCMSm/z(M+H)409。
实施例91
5-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-3-甲基-1,3-苯并噁唑-2-酮
向小瓶中先后添加7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,50.0mg,0.190mmol)、5-溴-3-甲基-1,3-苯并噁唑-2-酮(43.3mg,0.190mmol)、4,5-二(二苯基膦基)-9,9-二甲基呫吨(11.0mg,0.0190mmol)、[(4,5-二(二苯基膦基)-9,9-二甲基呫吨)-2-(2’-氨基-1,1’-联苯)]氯化钯(II)(16.9mg,0.0190mg)、Cs2CO3(124mg,0.380mmol)和甲苯(1.3mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至120℃且保持14小时。将反应混合物冷却至室温后,添加DCM(3mL)且反应混合物通过硅藻土过滤并减压浓缩。粗残余物通过反相色谱(乙腈30-70%/0.1%氢氧化铵水溶液)纯化,得到标题化合物(20.7mg,27%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.78-7.71(m,1H),7.49(d,J=0.8Hz,1H),7.40-7.36(m,1H),7.27(d,J=2.2Hz,1H),7.12(d,J=1.4Hz,1H),7.02(dd,J=8.5,2.2Hz,1H),6.91-6.58(m,2H),3.86(s,3H),3.64-3.57(m,2H),3.34-3.32(m,3H),2.86(s,2H),2.06-1.96(m,2H)。LCMS m/z(M+H)411。
实施例92和93
(S)-6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1,3-二甲基-二氢吲哚-2-酮和(R)-6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1,3-二甲基-二氢吲哚-2-酮
向小瓶中先后添加7-(二氟甲基)-6-(1-甲基吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,26.8mg,0.0634mmol)、6-溴-1,3-二甲基-二氢吲哚-2-酮(119mg,0.494mmol)、4,5-二(二苯基膦基)-9,9-二甲基呫吨(28.6mg,0.0494mmol)、[(4,5-二(二苯基膦基)-9,9-二甲基呫吨)-2-(2’-氨基-1,1’-联苯)]氯化钯(II)(43.9mg,0.0494mg)、Cs2CO3(322mg,0.988mmol)和甲苯(3.3mL)。混合物用氩气气球冲洗,然后在氩气气氛下加热至120℃且保持14小时。将反应混合物冷却至室温后,添加DCM(3mL)且反应混合物通过硅藻土过滤并减压浓缩。粗残余物通过反相色谱(乙腈30-70%/0.1%氢氧化铵水溶液)纯化,得到外消旋6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1,3-二甲基-二氢吲哚-2-酮(26.8mg,13%),其为黄色固体且通过手性SFC(Chiralpak AD 150×21.2mm I.D.5μm;0.1%氢氧化铵/MeOH 35%/超临界CO2)分离,得到(R)-6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1,3-二甲基-二氢吲哚-2-酮(实施例92,4.3mg,第一峰)和(S)-6-[7-(二氟甲基)-6-(1-甲基吡唑-4-基)-3,4-二氢-2H-喹啉-1-基]-1,3-二甲基-二氢吲哚-2-酮(实施例93,4.2mg,第二峰)。将绝对构型任意归属于每种非对映异构体。实施例92:1H NMR(400MHz,DMSO-d6)δ7.72(d,J=0.8Hz,1H),7.47(d,J=0.8Hz,1H),7.23-7.16(m,2H),7.08(s,1H),6.98(dd,J=8.2,2.0Hz,1H),6.64(s,2H),3.89-3.83(m,J=4.1Hz,4H),3.67-3.56(m,2H),3.37-3.34(m,3H),2.86(d,J=6.6Hz,2H),2.08-1.98(m,2H),1.17(t,J=7.1Hz,3H)。LCMS m/z(M+H)423.2。实施例93:1H NMR(400MHz,DMSO-d6)δ7.72(d,J=0.8Hz,1H),7.47(d,J=0.8Hz,1H),7.23-7.16(m,2H),7.08(s,1H),6.98(dd,J=8.2,2.0Hz,1H),6.64(s,2H),3.89-3.83(m,J=4.1Hz,4H),3.67-3.56(m,2H),3.37-3.34(m,3H),2.86(d,J=6.6Hz,2H),2.08-1.98(m,2H),1.17(t,J=7.1Hz,3H)。LCMS m/z(M+H)423。
实施例94
1,3-二甲基-5-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-1H-苯并[d]咪唑-2(3H)-酮
步骤1:5-溴-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
在0℃向5-溴-1H-苯并[d]咪唑-2(3H)-酮(1.0g,4.69mmol)于THF(10mL)中的搅拌的溶液中添加NaH(469mg,11.74mmol,60%)且将混合物搅拌30分钟。滴加碘甲烷(0.88mL,14.08mmol)且将混合物在室温再搅拌16小时。混合物用饱和NH4Cl(20mL)淬灭且用EtOAc(20mL×2)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=5:1)纯化,得到标题化合物(630mg,56%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.23(d,J=8.4Hz,1H),7.12(d,J=2.0Hz,1H),6.84(d,J=8.4Hz,1H),3.41(s,6H)。
步骤2:1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-苯并[d]咪唑-2(3H)-酮
向5-溴-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(100mg,0.41mmol)于二噁烷(4mL)中的溶液中添加[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(30mg,0.04mmol)、KOAc(122mg,1.24mmol)和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)(211mg,0.83mmol)。在氮气气氛下将混合物加热至90℃且保持1小时。将反应混合物冷却至室温后,反应混合物无需进一步纯化即直接用于下一步。LCMS m/z(M+H)289。
步骤3:1,3-二甲基-5-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-1H-苯并[d]咪唑-2(3H)-酮
向来自上述步骤的冷却的溶液中添加8-氯-3-(1-甲基-1H-吡唑-4-基)异喹啉(中间体D,89mg,0.36mmol)、2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(17mg,0.035mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(27mg,0.035mmol)、Na2CO3(110mg,1.04mmol)、1,4-二噁烷(1mL)和水(1mL)。在氮气气氛下将反应混合物加热至90℃且保持3小时。冷却至室温后,过滤混合物并真空浓缩。添加DCM(30mL)且用水(30mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈37-47%/0.05%NH4OH水溶液)纯化,得到标题化合物(14mg,9%),其为黄色固体。1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.07(s,1H),8.03(s,1H),7.85(s,1H),7.82-7.76(m,1H),7.66-7.44(m,1H),7.47(d,J=6.8Hz,1H),7.29-7.26(m,1H),7.15(s,1H)7.11(d,J=8.0Hz,1H),3.99(s,3H),3.52(s,3H),3.47(s,3H)。LCMS m/z(M+H)370。
实施例95
1,3-二甲基-5-(4-甲基-6-(1-甲基-1H-吡唑-4-基)-7-(三氟甲基)-3,4-二氢喹喔啉-1(2H)-基)-1H-苯并[d]咪唑-2(3H)-酮
步骤1:2-((5-溴-2-硝基-4-(三氟甲基)苯基)(甲基)氨基)乙醇
向1-溴-5-氟-4-硝基-2-(三氟甲基)苯(7.0g,24.3mmol)于DMF(50mL)中的溶液中添加N,N-二异丙基乙胺(12.9mL,72.9mmol)和2-(甲基氨基)乙醇(2.2g,29.2mmol)。将混合物加热至80℃且保持16小时。将反应混合物冷却至室温后,添加水(50mL)且用EtOAc(50mL×3)萃取。合并的有机层用盐水(50mL×3)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(7.5g,90%),其为黄色固体。
步骤2:5-溴-N-(2-氯乙基)-N-甲基-2-硝基-4-(三氟甲基)苯胺
在0℃向2-((5-溴-2-硝基-4-(三氟甲基)苯基)(甲基)氨基)乙醇(4g,11.7mmol)和吡啶(0.94mL,11.7mmol)于DCM(40mL)中的溶液中滴加亚硫酰氯(1.7mL,23.3mmol)。将混合物在室温搅拌16小时。添加DCM(50mL),用饱和NaHCO3水溶液(50mL×3)、盐水(50mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(2.7g,64%),其为黄色油状物。
步骤3:5-溴-N1-(2-氯乙基)-N1-甲基-4-(三氟甲基)苯-1,2-二胺
向5-溴-N-(2-氯乙基)-N-甲基-2-硝基-4-(三氟甲基)苯胺(2.7g,7.5mmol)于AcOH(20mL)中的溶液中添加Fe粉(2.1g,37.3mmol)。将混合物在室温搅拌1小时。滤出不溶性固体,通过添加饱和NaHCO3水溶液将滤液调节至pH=8且用EtOAc(50mL×3)萃取。合并的有机层用盐水(50mL×3)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(2.2g,粗品),其为棕色固体且不需要进一步纯化。LCMS m/z(M+H)333。
步骤4:7-溴-1-甲基-6-(三氟甲基)-1,2,3,4-四氢喹喔啉
向5-溴-N1-(2-氯乙基)-N1-甲基-4-(三氟甲基)苯-1,2-二胺(2.0g,6.0mmol)于DMF(20mL)中的溶液中添加碘化钾(2.0g,12.1mmol)和碳酸钾(2.5g,18.1mmol)。将混合物加热至80℃且保持3小时。将反应混合物冷却至室温后,添加水(50mL)且用EtOAc(50mL×3)萃取。合并的有机层用盐水(100mL×2)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(830mg,47%),其为浅黄色固体。1H NMR(400MHz,DMSO-d6)δ6.72(s,1H),6.63(s 1H),6.07(s,1H),3.29-3.26(m,2H),3.24-3.21(m,2H),2.83(s,3H)。
步骤5:1-甲基-7-(1-甲基-1H-吡唑-4-基)-6-(三氟甲基)-1,2,3,4-四氢喹喔啉
向7-溴-1-甲基-6-(三氟甲基)-1,2,3,4-四氢喹喔啉(830mg,2.8mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(702mg,3.4mmol)和碳酸钠(894mg,8.4mmol)于THF(10mL)和水(2mL)中的溶液中添加(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(221mg,0.28mmol)和2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(134mg,0.28mmol)。在氮气气氛下将混合物加热至60℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(383mg,46%),其为棕色固体。LCMS m/z(M+H)297。
步骤6:1,3-二甲基-5-(4-甲基-6-(1-甲基-1H-吡唑-4-基)-7-(三氟甲基)-3,4-二氢喹喔啉-1(2H)-基)-1H-苯并[d]咪唑-2(3H)-酮
向1-甲基-7-(1-甲基-1H-吡唑-4-基)-6-(三氟甲基)-1,2,3,4-四氢喹喔啉(246mg,0.83mmol)、5-溴-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(200mg,0.83mmol)和K3PO4(528mg,2.49mmol)于2-甲基-2-丁醇(6mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(70mg,0.083mmol)。在氮气气氛下将混合物加热至95℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈30-60%/0.2%甲酸水溶液)纯化,得到标题化合物(63mg,17%),其为黄色固体。1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.43(s,1H),7.00-6.90(m,2H),6.87(s,1H),6.78(s,1H),6.55(s,1H),3.95(s,3H),3.77-3.75(m,2H),3.50-3.47(m,2H)3.45(s,3H),3.41(s,3H),3.00(s,3H)。LCMS m/z(M+H)457。
实施例96
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-异丙基-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
步骤1:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-(丙-1-烯-2-基)-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,100mg,0.22mmol)于THF(8mL)和水(2mL)中的溶液中添加2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(9mg,0.02mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(16mg,0.02mmol)、Cs2CO3(213mg,0.66mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(44mg,0.26mmol)。在氮气气氛下将混合物加热至100℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:2)纯化,得到标题化合物(90mg,89%),其为无色油状物。LCMS m/z(M+H)464。
步骤2:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-异丙基-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-(丙-1-烯-2-基)-1H-苯并[d]咪唑-2(3H)-酮(90mg,0.19mmol)于MeOH(10mL)中的溶液中添加10%Pd/C(100mg)。将混合物在室温在氢气气氛(15Psi)下搅拌16小时。过滤混合物并真空浓缩滤液。粗残余物通过硅胶色谱(EtOAc)纯化,得到标题化合物(34mg,37%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),7.48(s,1H),7.08(s,1H),6.97(d,J=2.0Hz,1H),6.91(d,J=2.0Hz,1H),6.73(s,1H),6.72(t,J=55.2Hz,1H),3.86(s,3H),3.63-3.61(m,3H),3.58(s,3H),3.30(s,3H),2.86(t,J=5.6Hz,2H),2.05-2.00(m,2H),1.24(d,J=6.4Hz,6H)。LCMS m/z(M+H)466。
实施例97
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2(3H)-酮
步骤1:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-(3,6-二氢-2H-吡喃-4-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,200mg,0.44mmol)于THF(5mL)和水(1mL)中的溶液中添加2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(21mg,0.044mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(34mg,0.044mmol)、Na2CO3(139mg,1.31mmol)和2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(110mg,0.53mmol)。在氮气气氛下将混合物加热至100℃且保持12小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(110mg,50%),其为浅黄色油状物。LCMSm/z(M+H)506。
步骤2:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2(3H)-酮
向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-(3,6-二氢-2H-吡喃-4-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(45mg,0.09mmol)于EtOH(10mL)中的溶液中添加Pd(OH)2(62mg)。将混合物在室温在氢气气氛(15psi)下搅拌12小时。过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈40-70%/0.05%NH4OH水溶液)纯化,得到标题化合物(8mg,18%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),7.48(s,1H),7.09(s,1H),6.99(d,J=1.2Hz,1H),6.86(s,1H),6.73(t,J=55.2Hz,1H),6.72,(s,1H),3.93-3.90(m,2H),3.86(s,3H),3.64-3.62(m,1H),3.61(s,3H),3.53-3.48(m,4H),3.30(s,3H),2.88-2.84(m,2H),2.03-2.01(m,2H),1.75-1.65(m,4H)。LCMS m/z(M+H)508。
实施例98
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-(1-氧化-3,6-二氢-2H-噻喃-4-基)-1H-苯并[d]咪唑-2(3H)-酮
步骤1:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-(3,6-二氢-2H-噻喃-4-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,500mg,1.09mmol)于THF(10mL)和水(2mL)中的溶液中添加2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(52mg,0.11mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(43mg,0.05mmol)、Na2CO3(347mg,3.28mmol)和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(59mg,0.26mmol)。在氮气气氛下将混合物加热至80℃且保持16小时。将反应混合物冷却至室温后,添加水(50mL)且用EtOAc(30mL×3)萃取。合并的有机层用盐水(30mL×2)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(DCM/MeOH=20:1)纯化,得到标题化合物(320mg,56%),其为白色固体。LCMS m/z(M+H)522。
步骤2:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-(1-氧化-3,6-二氢-2H-噻喃-4-基)-1H-苯并[d]咪唑-2(3H)-酮
在0℃向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-(3,6-二氢-2H-噻喃-4-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(100mg,0.19mmol)于THF(5mL)和水(1mL)中的溶液中逐份添加过硫酸氢钾制剂(59mg,0.1mmol)。将混合物在25℃搅拌2小时。反应通过饱和Na2SO3水溶液(5mL)淬灭且用EtOAc(30mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(DCM/MeOH=20:1)纯化,得到标题化合物(40mg,36%),其为黄色固体。1H NMR(400MHz,CDCl3)δ9.54(s,1H),7.41(s,1H),7.06(s,1H),6.90(s,1H),6.84(s,1H),6.79(s,1H),6.48(t,J=55.6Hz,1H),5.73-5.69(m,1H),3.96(s,3H),3.67-3.64(m,2H),3.51(s,3H),3.40(s,3H),3.28-3.25(m,1H),3.11-2.91(m,5H),2.65-2.61(m,2H),2.12-2.10(m,2H)。LCMS m/z(M+H)538。
实施例99
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-丙基-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,100mg,0.22mmol)于甲苯(4mL)和水(0.4mL)中的溶液中添加异丙基三氟硼酸钾(49mg,0.33mmol)、[(二(1-金刚烷基)-正丁基膦)-2-(2-氨基联苯)]氯化钯(II)(15mg,0.022mmol)和Cs2CO3(213mg,0.66mmol)。在氮气气氛下将混合物加热至100℃且保持16小时。将反应混合物冷却至室温后,添加EtOAc(20mL)且用水(20mL×3)和盐水(20mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈38-68%/0.2%甲酸水溶液)纯化,得到标题化合物(1mg,1%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.47(s,1H),7.07(s,1H),6.98(d,J=1.6Hz,1H),6.76(d,J=1.6Hz,1H),6.71(t,J=55.6Hz,1H),6.66(s,1H),3.86(s,3H),3.60-3.58(m,2H),3.55(s,3H),3.30(s,3H),2.86-2.85(m,4H),2.02-1.99(m,2H),1.63-1.58(m,2H),0.93(t,J=6.8Hz,3H)。LCMS m/z(M+H)466。
实施例100
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-甲氧基-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,100mg,0.22mmol)于1,4-二噁烷(4mL)中的溶液中添加甲醇(0.044mL,1.09mmol)、(2-(二叔丁基膦基)-3-甲氧基-6-甲基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)甲磺酸钯(II)(37mg,0.044mmol)和t-BuONa(29mg,0.31mmol)。在氮气气氛下将混合物加热至100℃且保持20小时。冷却至室温后,过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈38-68%/0.05%NH4OH水溶液)纯化,得到标题化合物(13mg,13%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),7.48(s,1H),7.09(s,1H),6.80(s,1H),6.73(t,J=55.2Hz,1H),6.68-6.67(m,2H),3.86(s,3H),3.85(s,3H),3.62-3.59(m,2H),3.51(s,3H),3.27(s,3H),2.86(t,J=5.6Hz,2H),2.03-2.01(m,2H)。LCMS m/z(M+H)454。
实施例101
6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-乙炔基-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
步骤1:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-((三异丙基甲硅烷基)乙炔基)-1H-苯并[d]咪唑-2(3H)-酮
向4-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例33,100mg,0.22mmol)于MeCN(5mL)中的溶液中添加二(乙腈)二氯化钯(II)(6mg,0.022mmol)、2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(10mg,0.022mmol)、乙炔基三异丙基甲硅烷(0.13mL,0.66mmol)和Cs2CO3(213mg,0.66mmol)。在氮气气氛下将混合物加热至90℃且保持15小时。将反应混合物冷却至室温后,添加EtOAc(50mL)且用水(30mL)和盐水(30mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=2:1)纯化,得到标题化合物(70mg,53%),其为白色固体。LCMS m/z(M+H)604。
步骤2:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-乙炔基-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-4-((三异丙基甲硅烷基)乙炔基)-1H-苯并[d]咪唑-2(3H)-酮(70mg,0.11mmol)于THF(2mL)中的溶液中添加TBAF(0.2mL,0.2mmol,1M于THF中)。将反应混合物在室温搅拌12小时。真空浓缩反应混合物。将粗残余物溶于DCM(25mL),用水(20mL×2)和盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(石油醚/EtOAc=1:1)纯化,得到标题化合物(10mg,19%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.49(s,1H),7.23-7.22(m,1H),7.11(s,1H),7.01-7.00(m,1H),6.74(t,J=54.8Hz,1H),6.61(s,1H),4.49(s,1H),3.86(s,3H),3.63(s,3H),3.60-3.56(m,2H),3.31(s,3H),2.87-2.84(m,2H),2.02-2.00(m,2H)。LCMS m/z(M+H)448。
实施例102
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-6-乙炔基-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
步骤1:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-6-((三异丙基甲硅烷基)乙炔基)-1H-苯并[d]咪唑-2(3H)-酮
向5-氯-6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例46,150mg,0.33mmol)于DMF(5mL)中的溶液中添加二[二环己基(2,4,6-三异丙基-[1,1’:3’,1”-三联苯]-2-基)膦]二氯化钯(II)(42mg,0.03mmol)、乙炔基三异丙基甲硅烷(0.19mL,0.98mmol)和NaHCO3(83mg,0.98mmol)。在氮气气氛下将混合物加热至120℃且保持15小时。将反应混合物冷却至室温后,添加DCM(20mL)且用水(10mL)和盐水(10mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=10:1)纯化,得到标题化合物(100mg,51%),其为黄色油状物。LCMS m/z(M+H)604。
步骤2:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-6-乙炔基-1,3-二甲基-1H-苯并[d]咪唑-2(3H)-酮
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1,3-二甲基-6-((三异丙基甲硅烷基)乙炔基)-1H-苯并[d]咪唑-2(3H)-酮(100mg,0.17mmol)于THF(4mL)中的溶液中添加TBAF(0.33mL,0.33mmol,1M于THF中)。将反应混合物在室温搅拌12小时。真空浓缩反应混合物。将粗残余物溶于DCM(20mL),用水(20mL×3)和盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(石油醚/EtOAc=1:1)纯化,得到标题化合物(12mg,17%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.47(s,1H),7.42(s,1H),7.22(s,1H),7.06(s,1H),6.69(t,J=55.2Hz,1H),6.25(s,1H),4.08(s,1H),3.85(s,3H),3.59-3.55(m,2H),3.36(s,3H),3.31(s,3H),2.88-2.84(m,2H),2.06-2.02(m,2H)。LCMS m/z(M+H)448。
实施例103
N,1-二甲基-3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-甲酰胺
步骤1:1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-甲酸甲酯
向1-甲基-2-氧代-3H-苯并咪唑-5-甲酸甲酯(200mg,0.96mmol)于DCM(10mL)中的溶液中添加(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)硼酸(中间体F,368mg,1.46mmol)、吡啶-N-氧化物(276mg,2.9mmol)、吡啶(1.0mL,9.6mmol)和乙酸铜(II)(528mg,2.9mmol)。将混合物在室温在氧气气氛下搅拌48小时。添加水(50mL)且用DCM(30mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(石油醚/EtOAc=2:3)纯化,得到标题化合物(70mg,17%),其为黄色油状物。LCMS m/z(M+H)414。
步骤2:1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-甲酸
向1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-甲酸甲酯(70mg,0.17mmol)于MeOH(5mL)和水(1mL)中的溶液中添加一水合氢氧化锂(43mg,1.02mmol)。在氮气气氛下将混合物加热至50℃且保持12小时。将反应混合物冷却至室温后,添加DCM(50mL)且用水(20mL×2)和盐水(10mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(55mg,81%),其为黄色固体且不需要进一步纯化。LCMS m/z(M+H)400。
步骤3:N,1-二甲基-3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-甲酰胺
向1-甲基-3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-甲酸(55mg,0.14mmol)和N,N-二异丙基乙胺(0.1mL,0.4mmol)于DMF(2.5mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(78mg,0.21mmol)和甲胺(0.3mL,0.3mmol,1M于THF中)。将反应混合物在室温搅拌1小时。添加EtOAc(30mL)且用水(30mL×3)和盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈46-76%/0.05%NH4OH水溶液)纯化,得到标题化合物(6mg,10%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.32(s,1H),8.27-8.26(m,1H),8.23(s,1H),8.13-8.06(m,2H),7.95-7.91(m,1H),7.78-7.74(m,1H),7.70-7.68(m,1H),7.42-7.40(m,1H),7.20(s,1H),3.91(s,3H),3.51(s,3H),2.67(d,J=4.4Hz,3H)。LCMS m/z(M+H)413。
实施例104
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1,7-三甲基-1H-吲哚-3-甲酰胺
向7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-1H-吲哚-3-甲酰胺(实施例54,100mg,0.21mmol)于甲苯(5mL)和水(0.5mL)中的溶液中添加甲基三氟硼酸钾(38mg,0.31mmol)、[(二(1-金刚烷基)-正丁基膦)-2-(2-氨基联苯)]氯化钯(II)(14mg,0.021mmol)和Cs2CO3(202mg,0.62mmol)。在氮气气氛下将混合物加热至100℃且保持16小时。将反应混合物冷却至室温后,添加EtOAc(20mL)且用水(20mL×3)和盐水(20mL)洗涤。有机相经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈43-73%/0.05%NH4OH水溶液)纯化,得到标题化合物(17mg,18%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.89(d,J=1.8Hz,1H),7.85-7.80(m,2H),7.72(s,1H),7.47(s,1H),7.07(s,1H),6.82(s,1H),6.69(t,J=55.2Hz,1H),6.51(s,1H),4.08(s,3H),3.85(s,3H),3.57(t,J=5.6Hz,2H),2.89-2.85(m,2H),2.80-2.69(m,6H),2.07-2.01(m,2H)。LCMS m/z(M+H)464。
实施例105
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-7-(四氢-2H-吡喃-4-基)-1H-吲哚-3-甲酰胺
步骤1:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-(3,6-二氢-2H-吡喃-4-基)-N,1-二甲基-1H-吲哚-3-甲酰胺
向7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-1H-吲哚-3-甲酰胺(实施例54,77mg,0.16mmol)于1,4-二噁烷(5mL)和水(1mL)中的溶液中添加2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(8mg,0.016mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(13mg,0.016mmol)、Na2CO3(51mg,0.48mmol)和2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(50mg,0.24mmol)。在氮气气氛下将混合物加热至100℃且保持3小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(65mg,77%),其为浅黄色油状物。LCMS m/z(M+H)532。
步骤2:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-7-(四氢-2H-吡喃-4-基)-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-(3,6-二氢-2H-吡喃-4-基)-N,1-二甲基-1H-吲哚-3-甲酰胺(30mg,0.06mmol)于EtOAc(6mL)中的溶液中添加氧化铂(IV)(64mg)。将混合物在室温在氢气气氛(50psi)下搅拌24小时。过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈40-70%/0.05%NH4OH水溶液)纯化,得到标题化合物(2mg,8%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.91-7.89(m,1H),7.82-7.79(m,2H),7.70(s,1H),7.45(s,1H),7.05(s,1H),6.97(s,1H),6.67(t,J=55.2Hz,1H),6.60(s,1H),4.05(s,3H),3.92-3.91(m,2H),3.83(s,3H),3.61-3.59(m,2H),3.54-3.48(m,2H),2.87-2.83(m,2H),2.71(d,J=4.4Hz,3H),2.03-2.00(m,2H),1.76-1.71(m,4H)。LCMS m/z(M+H)534。
实施例106
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-甲氧基-N,1-二甲基-1H-吲哚-3-甲酰胺
向7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-1H-吲哚-3-甲酰胺(实施例54,100mg,0.21mmol)于1,4-二噁烷(4mL)中的溶液中添加甲醇(0.042mL,1.09mmol)、(2-(二叔丁基膦基)-3-甲氧基-6-甲基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)甲磺酸钯(II)(35mg,0.041mmol)和t-BuONa(28mg,0.29mmol)。在氮气气氛下将混合物加热至100℃且保持20小时。冷却至室温后,过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈43-73%/0.05%NH4OH水溶液)纯化,得到标题化合物(10mg,11%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.83-7.78(m,2H),7.72(s,1H),7.62(d,J=1.6Hz,1H),7.47(s,1H),7.08(s,1H),6.70(t,J=55.2Hz,1H),6.64-6.59(m,2H),4.02(s,3H),3.86(s,3H),3.85(s,3H),3.61(t,J=5.2Hz,2H),2.89-2.86(m,2H),2.73(d,J=4.4Hz,3H),2.08-2.00(m,2H)。LCMS m/z(M+H)480。
实施例107
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-7-(丙-1-烯-2-基)-1H-吲哚-3-甲酰胺
步骤1:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-7-(丙-1-烯-2-基)-1H-吲哚-3-甲酸甲酯
向7-氯-5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-1H-吲哚-3-甲酸甲酯(实施例54,71mg,0.15mmol)于1,4-二噁烷(5mL)和水(1mL)中的溶液中添加2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(7mg,0.015mmol)和(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(12mg,0.015mmol)、Na2CO3(47mg,044mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(37mg,0.22mmol)。在氮气气氛下将混合物加热至90℃且保持12小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(70mg,98%),其为浅黄色油状物。LCMS m/z(M+H)491。
步骤2:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-7-(丙-1-烯-2-基)-1H-吲哚-3-甲酸
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-7-(丙-1-烯-2-基)-1H-吲哚-3-甲酸甲酯(70mg,0.14mmol)于MeOH(2mL)和水(0.4mL)中的溶液中添加一水合氢氧化锂(60mg,1.43mmol)。在氮气气氛下将混合物加热至50℃且保持12小时。将反应混合物冷却至室温后,真空浓缩混合物。添加水(10mL)且混合物用HCl(2N)酸化至pH 4,然后用DCM(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(70mg,粗品),其为无色油状物且不需要进一步纯化。LCMS m/z(M+H)477。
步骤3:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-7-(丙-1-烯-2-基)-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-甲基-7-(丙-1-烯-2-基)-1H-吲哚-3-甲酸(70mg,0.15mmol)和N,N-二异丙基乙胺(0.08mL,0.44mmol)于DMF(3mL)中的溶液中添加O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(67mg,0.18mmol)和甲胺盐酸盐(15mg,0.22mmol)。将反应混合物在室温搅拌12小时。添加EtOAc(30mL)且用水(30mL×3)和盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈30-60%/0.05%NH4OH水溶液)纯化,得到标题化合物(6mg,8%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ8.01-7.95(m,1H),7.90(s,1H),7.88-7.84(m,1H),7.73(s,1H),7.47(s,1H),7.08(s,1H),6.82(s,1H),6.70(t,J=54.8Hz,1H),6.64(s,1H),5.38(s,1H),4.98(s,1H),3.86(s,3H),3.65-3.60(m,2H),3.31(s,3H),2.89-2.85(m,2H),2.74(d,J=4.4Hz,3H),2.15(s,3H),2.05-2.01(m,2H)。LCMS m/z(M+H)490。
实施例108
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-7-异丙基-N,1-二甲基-1H-吲哚-3-甲酰胺
向5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N,1-二甲基-7-(丙-1-烯-2-基)-1H-吲哚-3-甲酰胺(实施例107,40mg,0.08mmol)于MeOH(5mL)中的溶液中添加10%Pd/C(30mg)。将混合物在室温在氢气气氛(15Psi)下搅拌3小时。过滤混合物并真空浓缩滤液。粗残余物通过反相色谱(乙腈25-55%/0.05%NH4OH水溶液)纯化,得到标题化合物(6mg,16%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.91-7.90(m,1H),7.84-7.81(m,2H),7.72(s,1H),7.47(s,1H),7.07(s,1H),7.02-7.01(m,1H),6.69(t,J=55.6Hz,1H),6.64(s,1H),4.06(s,3H),3.86(s,3H),3.85-3.79(m,1H),3.63(t,J=5.2Hz,2H),2.90-2.85(m,2H),2.74(d,J=4.4Hz,3H),2.05-2.03(m,2H),1.28(d,J=6.8Hz,6H)。LCMS m/z(M+H)492。
实施例109
向7-溴-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(1.0g,3.05mmol)、2-甲基苯基硼酸(414mg,3.05mmol)和碳酸钠(969mg,9.14mmol)于THF(20mL)和水(4mL)中的溶液中添加(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(240mg,0.30mmol)和2-(二环己基膦基)-2’,4’,6’-三异丙基联苯(145mg,0.30mmol)。在氮气气氛下将混合物加热至60℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(1.0g,97%),其为浅黄色固体。LCMS m/z(M-Boc+H)240。
在0℃向7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(1g,2.95mmol)于乙腈(10mL)中的搅拌的溶液中逐份添加N-氯琥珀酰亚胺(393mg,2.95mmol),然后加热至50℃且保持12小时。冷却至室温后,真空浓缩反应混合物。添加EtOAc(100mL)且用水(100mL×3)、盐水(100mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=20:1)纯化,得到标题化合物(900mg,82%),其为黄色油状物。1H NMR(400MHz,DMSO-d6)7.33-7.23(m,4H),7.17-7.13(m,2H),4.55-4.47(m,2H),4.20-4.10(m,2H),3.76(s,2H),2.23(s,3H),1.36-1.30(m,9H)。
向9-氯-7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(900mg,2.41mmol)于DCM(4mL)中的溶液中滴加三氟乙酸(2.0mL,26.31mmol)。将反应混合物在室温搅拌1小时并真空浓缩,得到标题化合物(780mg),其为浅黄色油状物且不需要进一步纯化。
向N-甲基-1H-咪唑-1-甲酰胺(1.07g,8.55mmol)于DCM(5mL)中的溶液中添加9-氯-7-(邻甲苯基)-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂(780mg,2.85mmol)和三乙胺(0.40mL,2.85mmol)。将反应混合物在室温搅拌12小时并真空浓缩。添加EtOAc(100mL)且用水(50mL×3)和盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(650mg,69%),其为黄色固体。LCMS m/z(M+H)331。
向9-氯-N-甲基-7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酰胺(100mg,0.22mmol)于甲苯(5mL)和水(0.50mL)中的溶液中添加乙基三氟硼酸钾(45mg,0.33mmol)、[(二(1-金刚烷基)-正丁基膦)-2-(2-氨基联苯)]氯化钯(II)(15mg,0.02mmol)和Cs2CO3(213mg,0.66mmol)。在氮气气氛下将混合物加热至100℃且保持16小时。冷却至室温后,真空浓缩反应混合物。添加EtOAc(10mL)且用水(5mL×3)和盐水(5mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈30-60%/0.05%NH4OH水溶液)纯化,得到标题化合物(41mg,58%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ7.31-7.15(m,5H),7.04(d,J=2.0Hz,1H),6.52-6.48(m,1H),4.43(s,2H),4.02-3.94(m,2H),3.75-3.68(m,2H),2.60(q,J=7.6Hz,2H),2.52(s,3H),2.24(s,3H),1.13(t,J=7.6Hz,3H)。LCMS m/z(M+H)325。
实施例110
向9-氯-N-甲基-7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酰胺(实施例109,200mg,0.60mmol)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(203mg,1.21mmol)和K3PO4(385mg,1.81mmol)于1,4-二噁烷(3mL)和水(0.60mL)中的溶液中添加二环己基(2’,6’-二甲氧基-[1,1’-联苯]-2-基)膦(297mg,0.73mmol)和Pd(OAc)2(14mg,0.06mmol)。将混合物在微波中在80℃照射0.5小时。添加DCM(10mL)且用水(10mL×2)、盐水(10mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=4:1)纯化,得到标题化合物(130mg,64%),其为浅黄色油状物。LCMS m/z(M+H)337。
向N-甲基-9-(丙-1-烯-2-基)-7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酰胺(130mg,0.39mmol)于MeOH(10mL)中的溶液中添加10%Pd/C(100mg)。所得混合物在室温用氢气气氛(15psi)吹扫16小时。过滤反应混合物并真空浓缩。粗残余物通过反相色谱(乙腈55-85%/0.05%NH4OH水溶液)纯化,得到标题化合物(48mg,36%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.29-7.16(m,5H),7.05(s,1H),6.48-6.44(m,1H),4.41(s,2H),3.95-3.94(m,2H),3.74-3.70(m,2H),3.28-3.24(m,1H),2.51(s,3H),2.22(s,3H),1.15(d,J=6.8Hz,6H)。LCMS m/z(M+H)339。
实施例111
在0℃向7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(实施例109,100mg,0.29mmol)于乙腈(2mL)中的搅拌的溶液中逐份添加N-溴琥珀酰亚胺(175mg,0.88mmol),然后加热至50℃且保持12小时。冷却至室温后,真空浓缩反应混合物。添加EtOAc(30mL)且用水(20mL×3)、盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=20:1)纯化,得到标题化合物(70mg,57%),其为黄色油状物。
向9-溴-7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(70mg,0.17mmol)于DCM(2mL)中的溶液中滴加三氟乙酸(1.0mL,13.16mmol)。将反应混合物在室温搅拌1小时并真空浓缩,得到标题化合物(55mg,粗品),其为浅黄色油状物且不需要进一步纯化。
向N-甲基-1H-咪唑-1-甲酰胺(194mg,1.55mmol)于DCM(3mL)中的溶液中添加9-溴-7-(邻甲苯基)-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂(55mg,0.17mmol)和三乙胺(0.024mL,0.17mmol)。将反应混合物在室温搅拌5小时并真空浓缩。添加DCM(30mL)且用水(10mL×3)和盐水(10mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈50-80%/0.05%NH4OH水溶液)纯化,得到标题化合物(14mg,22%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ7.44(s,1H),7.38(s,1H),7.31-7.23(m,3H),7.21-7.17(m,1H),6.53-6.52(m,1H),4.51(s,2H),4.11-4.06(m,2H),3.79-3.74(m,2H),2.52(d,J=4.0Hz,3H),2.25(s,3H)。LCMS m/z(M+H)375。
向9-溴-N-甲基-7-(邻甲苯基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酰胺(150mg,0.40mmol)、MeOH(0.081mL,2mmol)和t-BuONa(54mg,0.56mmol)于1,4-二噁烷(4mL)中的溶液中添加(2-(二叔丁基膦基)-3-甲氧基-6-甲基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)甲磺酸钯(II)(67mg,0.08mmol)。在氮气气氛下将混合物加热至100℃且保持20小时。冷却至室温后,真空浓缩反应混合物。粗残余物通过反相色谱(乙腈17-47%/0.05%NH4OH水溶液)纯化,得到标题化合物(62mg,47%),其为白色固体。1HNMR(400MHz,DMSO-d6)δ7.25-7.20(m,4H),6.92(d,J=1.8Hz,1H),6.82(d,J=1.8Hz,1H),6.48-6.45(m,1H),4.42(s,2H),3.97-3.90(m,2H),3.73(s,3H),3.71-3.67(m,2H),2.49(d,J=6.4Hz,3H),2.23(s,3H)。LCMS m/z(M+H)327。
实施例112
向7-溴-3,5-二氢-2H-1,4-苯并氧杂氮杂-4-甲酸叔丁酯(800mg,2.44mmol)、7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,642mg,2.44mmol)和t-BuONa(586mg,6.09mmol)于1,4-二噁烷(6mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(193mg,0.24mmol)。在氮气气氛下将反应混合物加热至120℃且保持16小时。冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=3:2)纯化,得到标题化合物(670mg,54%),其为黄色固体。LCMS m/z(M+H)511。
在0℃向7-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(870mg,1.7mmol)于DCM(5mL)中的溶液中滴加三氟乙酸(1.26mL,17.04mmol)。将反应混合物在室温搅拌1小时并真空浓缩,得到标题化合物(600mg,86%),其为黄色固体且不需要进一步纯化。LCMS m/z(M+H)411
向7-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂(150mg,0.37mmol)和TEA(0.25mL,1.83mmol)于DCM(3mL)中的溶液中滴加乙酸酐(0.1mL,1.1mmol)。将混合物在室温搅拌10小时。添加水(30mL)且用DCM(20mL×2)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈37-67%/0.2%甲酸水溶液)纯化,得到标题化合物(90mg,53%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.49(s,1H),7.31(d,J=2.2Hz,1H),7.15-7.00(m,3H),6.89-6.58(m,2H),4.62-4.48(m,2H),4.19-4.01(m,2H),3.93-3.77(m,5H),3.62-3.50(m,2H),2.86-2.82(m,2H),2.07-1.88(m,5H)。LCMS m/z(M+Na)475。
实施例113
向7-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂(实施例112,150mg,0.37mmol)和三乙胺(0.25mL,1.83mmol)于DCM(5mL)中的搅拌的溶液中添加N-甲基-1H-咪唑-1-甲酰胺(92mg,0.74mmol)。将反应混合物在室温搅拌16小时并真空浓缩。粗残余物通过反相色谱(乙腈35-65%/0.2%甲酸水溶液)纯化,得到标题化合物(83mg,48%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.49(s,1H),7.31(d,J=2.2Hz,1H),7.13-7.04(m,2H),7.03-6.96(m,1H),6.90-6.59(m,2H),6.48-6.43(m,1H),4.42(s,2H),4.01-3.98(m,2H),3.86(s,3H),3.72-3.69(m,2H),3.59-3.51(m,2H),2.88-2.79(m,2H),2.52(s,3H),2.03-1.92(m,2H)。LCMS m/z(M+Na)490。
实施例114
步骤1:4-溴-2-(((2-羟基丙基)氨基)甲基)苯酚
向1-氨基丙-2-醇(1.87g,24.87mmol)于MeOH(6mL)中的搅拌的溶液中添加5-溴-2-羟基苯甲醛(5.0g,24.87mmol)。在室温搅拌2小时后,伴随剧烈搅拌逐份添加硼氢化钠(0.38g,9.95mmol)。将混合物在室温再搅拌30分钟。反应混合物无需进一步纯化即直接用于下一步。LCMS m/z(M+H)260。
步骤2:5-溴-2-羟基苄基(2-羟基丙基)氨基甲酸叔丁酯
向来自上述步骤的溶液中添加MeOH(24mL)、于水(15mL)中的NaOH(3.32g,83.03mmol)和一缩二碳酸二叔丁酯(9.0g,30.58mmol)。在室温搅拌2小时后,添加额外的一缩二碳酸二叔丁酯(1.07g,4.90mmol)。将反应混合物在室温再搅拌12小时并真空浓缩。添加水(5mL)且混合物用HCl(1N)酸化至pH 5,然后用DCM(30mL)萃取。有机层用水(10mL×2)、盐水(10mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(6g,72%),其为无色油状物且不需要进一步纯化。LCMS m/z(M-Boc)260。
在0℃向5-溴-2-羟基苄基(2-羟基丙基)氨基甲酸叔丁酯(2.2g,6.11mmol)和三苯基膦(3.20g,12.21mmol)于THF(15mL)中的溶液中缓慢添加DIAD(2.47g,12.21mmol)。将反应混合物加热至70℃且保持16小时。冷却至室温后,反应混合物用水(20mL)稀释且用EtOAc(20mL)萃取。有机层用HCl(1N,20mL)、NaOH(1N,20mL)、盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=9:1)纯化,得到标题化合物(1.3g,62%),其为白色固体。LCMS m/z(M+H)342。
向7-溴-2-甲基-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(200mg,0.58mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,185mg,0.70mmol)于1,4-二噁烷(6mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(46mg,0.06mmol)和t-BuONa(168mg,1.75mmol)。在氩气气氛下将混合物加热至120℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=4:1)纯化,得到标题化合物(150mg,49%),其为黄色油状物。LCMS m/z(M+H)525。
向7-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-2-甲基-2,3-二氢苯并[f][1,4]氧杂氮杂-4(5H)-甲酸叔丁酯(150mg,0.29mmol)于DCM(5mL)中的溶液中添加三氟乙酸(0.81mL,10.83mmol)。将混合物在室温搅拌1小时并真空浓缩,得到标题化合物(120mg,99%),其为黄色固体且不需要进一步纯化。LCMS m/z(M+H)425。
向7-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-2-甲基-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂(120mg,0.28mmol)于DCM(5mL)中的溶液中添加三乙胺(0.12mL,0.85mmol)和N-甲基-1H-咪唑-1-甲酰胺(42mg,0.34mmol)。将反应混合物在室温搅拌12小时并真空浓缩。添加DCM(10mL)且用水(10mL×3)和盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈42-72%/0.05%NH4OH水溶液)纯化,得到标题化合物(83mg,61%),其为黄色固体。1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.42(s,1H),7.12-7.06(m,4H),6.97(s,1H),6.49(t,J=55.2Hz,1H),4.45-4.28(m,3H),4.21-4.17(m,1H),4.05-4.03(m,1H),3.96(s,3H),3.62(t,J=5.6Hz,2H),3.30-3.24(m,1H),2.94-2.85(m,2H),2.78(d,J=4.4Hz,3H),2.09-2.05(m,2H),1.38(d,J=6.0Hz,3H)。LCMS m/z(M+Na)504。
实施例115
(R)-8-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-2-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
步骤1:(R)-2-(2-溴-6-硝基苯氧基)丙酸甲酯
向2-溴-6-硝基苯酚(2.0g,9.17mmol)、(S)-2-羟基丙酸甲酯(1.15g,11.01mmol)和三苯基膦(3.61g,13.76mmol)于DCM(20mL)中的溶液中滴加DIAD(2.78mL,13.76mmol)。将反应混合物在室温在氮气气氛下搅拌15小时。真空浓缩混合物。添加EtOAc(80mL),用盐水(30mL×3)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=7:3)纯化,得到标题化合物(2.5g,81%),其为白色固体。
步骤2:(R)-8-溴-2-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
向(R)-2-(2-溴-6-硝基苯氧基)丙酸甲酯(3.3g,10.85mmol)于AcOH(45mL)中的溶液中添加Fe粉(3.03g,54.26mmol)。将反应混合物加热至80℃且保持2小时。冷却至室温后,过滤混合物并真空浓缩。添加EtOAc(80mL),混合物用水(60mL)、饱和NaHCO3水溶液(40mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(900mg,34%),其为白色固体。LCMS m/z(M+H)242。
步骤3:(R)-8-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-2-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮
向(R)-8-溴-2-甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(300mg,1.24mmol)和7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,326mg,1.24mmol)于1,4-二噁烷(3mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(98mg,0.12mmol)和t-BuONa(357mg,3.72mmol)。在氮气气氛下将反应混合物加热至120℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈20-50%/0.2%甲酸水溶液)纯化,得到标题化合物(2mg,0.4%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.54(s,1H),7.41(s,1H),7.05-6.96(m,3H),6.72-6.68(m,2H),6.49(t,J=55.6Hz,1H),4.61(d,J=6.4Hz,1H),3.96(s,3H),3.63-3.58(m,2H),2.94-2.90(m,2H),2.10(t,J=6.4Hz,2H),1.44(d,J=6.4Hz,3H)。LCMS m/z(M+H)425。
实施例116
5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-3-甲基-3,4-二氢喹唑啉-2(1H)-酮
步骤1:1-溴-2-(溴甲基)-3-硝基苯
向1-溴-2-甲基-3-硝基苯(3.0g,13.89mmol)于CCl4(20mL)中的溶液中添加NBS(2.47g,13.89mmol)和BPO(336mg,1.39mmol)。将反应混合物加热至80℃且保持12小时。将反应混合物冷却至室温后,真空浓缩混合物。添加EtOAc(20mL),用水(20mL×2)和盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=4:1)纯化,得到标题化合物(3.2g,78%),其为黄色固体。
步骤2:1-(2-溴-6-硝基苯基)-N-甲基甲胺
向甲胺于THF中的溶液(2.0M,50mL,100mmol)中添加1-溴-2-(溴甲基)-3-硝基苯(3.0g,10.17mmol)。将反应混合物在室温搅拌12小时。添加DCM(50mL)且混合物用水(50mL×3)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(石油醚/EtOAc=4:1)纯化,得到标题化合物(1.6g,64%),其为黄色固体。
步骤3:3-溴-2-((甲基氨基)甲基)苯胺
向1-(2-溴-6-硝基苯基)-N-甲基甲胺(1.5g,6.12mmol)于乙酸(40mL)中的溶液中添加Fe粉(342mg,6.12mmol)。将反应混合物在室温搅拌2小时。滤出不溶性固体,通过添加饱和NaHCO3水溶液将滤液调节至pH 8且用EtOAc(20mL)萃取。有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(800mg,61%),其为黄色固体且不需要进一步纯化。
步骤4
5-溴-3-甲基-3,4-二氢喹唑啉-2(1H)-酮
向3-溴-2-((甲基氨基)甲基)苯胺(700mg,3.25mmol)于DCM(10mL)中的溶液中添加二(1H-咪唑-1-基)甲酮(792mg,4.88mmol)。将反应混合物在室温搅拌12小时。添加DCM(20mL)且用水(20mL×2)、盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=4:1)纯化,得到标题化合物(400mg,51%),其为黄色固体。1H NMR(400MHz,CDCl3)δ7.12(d,J=8.0Hz,1H),7.04-6.99(m,1H),6.65(d,J=7.2Hz,1H),4.47(s,2H),3.06(s,3H)。
步骤5:5-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-3-甲基-3,4-二氢喹唑啉-2(1H)-酮
向5-溴-3-甲基-3,4-二氢喹唑啉-2(1H)-酮(100mg,0.32mmol)于1,4-二噁烷(2mL)中的溶液中添加7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,84mg,0.32mmol)、t-BuONa(92mg,0.95mmol)和[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(25mg,0.03mmol)。将混合物在微波中在150℃照射4小时。过滤混合物并真空浓缩。粗残余物通过反相色谱(乙腈38-68%/0.2%甲酸水溶液)纯化,得到标题化合物(5mg,4%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.34(s,1H),7.16(s,1H),7.00(s,1H),6.77(d,J=8.0Hz,1H),6.61(s,1H),6.54-6.25(m,3H),4.22(s,2H),3.88(s,3H),2.91-2.86(m,2H),2.88(s,3H),2.06-2.03(m,2H),1.52-1.49(m,2H)。LCMS m/z(M+H)424。
实施例117和118
(S)-2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-6,7-二氢-5H-环戊并[b]吡啶-7-甲酰胺和(R)-2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-6,7-二氢-5H-环戊并[b]吡啶-7-甲酰胺
步骤1:2-氯-6,7-二氢-5H-环戊并[b]吡啶-7-甲酸甲酯
在-30℃在氮气气氛下向2-氯-6,7-二氢-5H-环戊并[b]吡啶(500mg,3.26mmol)于乙醚(30mL)中的溶液中滴加LiHMDS(2M于THF中,3.26mL,6.51mmol)。将混合物在-30℃搅拌1小时并添加碳酸二甲酯(0.30mL,3.58mmol)。在-30℃搅拌1小时后,将混合物温热至室温并再搅拌12小时。反应混合物用饱和NH4Cl水溶液(20mL)淬灭且用DCM(20mL)萃取。有机层用水(20mL×2)、盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(EtOAc)纯化,得到标题化合物(260mg,38%),其为无色油状物。LCMS m/z(M+H)212。
步骤2:2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-6,7-二氢-5H-环戊并[b]吡啶-7-甲酸
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,187mg,0.71mmol)于1,4-二噁烷(3mL)中的溶液中添加2-氯-6,7-二氢-5H-环戊并[b]吡啶-7-甲酸甲酯(150mg,0.71mmol)、t-BuONa(170mg,1.77mmol)、2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯(33mg,0.07mmol)和(2-二环己基膦基-2’,6’-二异丙氧基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)氯化钯(II)(55mg,0.07mmol)。在氮气气氛下将反应混合物加热至110℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶柱色谱(DCM/MeOH=10:1)纯化,得到标题化合物(260mg,48%),其为深色油状物。LCMS m/z(M+H)425。
步骤3:(S)-2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-6,7-二氢-5H-环戊并[b]吡啶-7-甲酰胺和(R)-2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-6,7-二氢-5H-环戊并[b]吡啶-7-甲酰胺
向2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-6,7-二氢-5H-环戊并[b]吡啶-7-甲酸(260mg,0.61mmol)于DMF(5mL)、HATU(303mg,0.80mmol)和N,N-二异丙基乙胺(0.41mL,2.45mmol)中的溶液中添加甲胺盐酸盐(50mg,0.74mmol)。将反应混合物在室温搅拌1小时并真空浓缩。粗残余物通过反相色谱(乙腈40-70%/0.05%NH4OH水溶液)纯化,得到外消旋化合物(40mg,15%),其为白色固体且通过使用手性SFC(Chiralpak AD 250×30mm I.D.5μm;超临界CO2/EtOH+NH3·H2O=70/30;60mL/min)分离,得到呈白色固体的(S)-2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-6,7-二氢-5H-环戊并[b]吡啶-7-甲酰胺(实施例117,15mg,第一峰)和呈白色固体的(R)-2-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-6,7-二氢-5H-环戊并[b]吡啶-7-甲酰胺(实施例118,8mg,第二峰)。将绝对构型任意归属于每种对映异构体。实施例117:1H NMR(400MHz,DMSO-d6)δ7.97-7.93(m,1H),7.80(s,1H),7.56-7.50(m,2H),7.43(s,1H),7.20(s,1H),6.97-6.93(m,1H),6.82(d,J=55.2Hz,1H),3.86(s,3H),3.81-3.69(m,3H),2.94-2.75(m,4H),2.59(d,J=4.8Hz,3H),2.26-2.17(m,2H),1.94-1.86(m,2H)。LCMS m/z(M+H)438。实施例118:1H NMR(400MHz,DMSO-d6)δ7.99-7.96(m,1H),7.82(s,1H),7.56-7.50(m,2H),7.46(s,1H),7.22(s,1H),6.99-6.96(m,1H),6.84(d,J=55.2Hz,1H),3.88(s,3H),3.79-3.42(m,3H),2.94-2.75(m,4H),2.58-2.59(m,3H),2.30-2.17(m,2H),1.98-1.84(m,2H)。LCMS m/z(M+H)438。
实施例119
4-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基异喹啉-6-甲酰胺
步骤1:4-溴异喹啉-6-甲酸甲酯
向异喹啉-6-甲酸甲酯(700mg,3.74mmol)于乙酸(9mL)中的溶液中添加NBS(798.67mg,4.49mmol)。将反应混合物加热至90℃且保持2小时。将反应混合物冷却至室温后,真空浓缩混合物.粗残余物通过硅胶柱色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(600mg,60%),其为棕色固体。LCMS m/z(M+H)266。
步骤2:4-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)异喹啉-6-甲酸
向4-溴异喹啉-6-甲酸甲酯(300mg,1.13mmol)、7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,297mg,1.13mmol)和K3PO4(718mg,3.38mmol)于2-甲基-2-丁醇(10mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(95mg,0.11mmol)。在氮气气氛下将反应混合物加热至100℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶柱色谱(DCM/MeOH=10:1)纯化,得到标题化合物(270mg,55%),其为棕色固体。LCMSm/z(M+H)435。
步骤3
4-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基异喹啉-6-甲酰胺
向4-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)异喹啉-6-甲酸(100mg,0.23mmol)、N,N-二异丙基乙胺(0.082mL,0.46mmol)和HATU(105mg,0.28mmol)于DMF(3mL)中的溶液中添加甲胺盐酸盐(19mg,0.28mmol)。将反应混合物在室温搅拌3小时并真空浓缩。粗残余物通过反相色谱(乙腈40-70%/0.2%甲酸水溶液)纯化,得到标题化合物(28mg,25%),其为白色固体。1H NMR(400MHz,CDCl3)δ9.41(s,1H),8.83(d,J=4.4Hz,1H),8.58(s,1H),8.38-8.33(m,2H),8.14(d,J=9.2Hz,1H),7.74(s,1H),7.49(s,1H),7.19(s,1H),6.65(t,J=55.2Hz,1H),6.12(s,1H),3.85(s,3H),3.70(t,J=5.6Hz,2H),3.02-2.99(m,2H),2.81(d,J=4.4Hz,3H),2.17-2.16(m,2H)。LCMS m/z(M+H)448。
实施例120
7-(二氟甲基)-N-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-[1,8’-联喹啉]-2’-甲酰胺
步骤1:8-溴-N-甲基喹啉-2-甲酰胺
向8-溴喹啉-2-甲酸(300mg,1.2mmol)、HATU(543mg,1.4mmol)和N,N-二异丙基乙胺(0.62mL,3.57mmol)于DMF(5mL)中的溶液中添加甲胺盐酸盐(161mg,2.4mmol)。将反应混合物在室温搅拌16小时并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(180mg,57%),其为黄色固体。LCMS m/z(M+H)265。
步骤2:7-(二氟甲基)-N-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢-2H-[1,8’-联喹啉]-2’-甲酰胺
向8-溴-N-甲基喹啉-2-甲酰胺(100mg,0.22mmol)、7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,115mg,0.44mmol)和t-BuONa(63mg,0.66mmol)于1,4-二噁烷(5mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(17mg,0.02mmol)。在氮气气氛下将反应混合物加热至120℃且保持16小时。冷却至室温后,真空浓缩反应混合物。添加DCM(50mL)且用水(30mL×3)、盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈46-76%/0.05%NH4OH水溶液)纯化,得到标题化合物(16mg,16%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ8.62(d,J=8.4Hz,1H),8.13(d,J=8.4Hz,1H),7.97-7.95(m,1H),7.84-7.80(m,1H),7.79-7.72(m,3H),7.51(s,1H),7.22(s,1H),6.67(t,J=56.0Hz,1H),6.45(s,1H),3.86(s,3H),2.99-2.96(m,2H),2.76(d,J=5.2Hz,3H),2.57-2.53(m,2H),2.11-2.06(m,2H)。LCMS m/z(M+H)448。
实施例121
N-甲基-2-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)苯并[d]噁唑-4-甲酰胺
步骤1:2-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)苯并[d]噁唑-4-甲酸甲酯
向8-氯-3-(1-甲基-1H-吡唑-4-基)异喹啉(中间体D,310mg,1.27mmol)、苯并[d]噁唑-4-甲酸甲酯(150mg,0.85mmol)和K3PO4(539mg,2.54mmol)于NMP(8mL)中的溶液中添加二(1-金刚烷基)-丁基-膦(61mg,0.17mmol)和乙酸钯(II)(19mg,0.08mmol)。将反应混合物在室温搅拌15分钟并在氮气气氛下加热至125℃且保持24小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=3:1)纯化,得到标题化合物(150mg,46%),其为棕色固体。LCMS m/z(M+H)385。
步骤2:2-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)苯并[d]噁唑-4-甲酸
向2-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)苯并[d]噁唑-4-甲酸甲酯(150mg,0.39mmol)于MeOH(10mL)和水(2mL)中的溶液中添加一水合氢氧化锂(82mg,1.95mmol)。将反应混合物在室温搅拌2小时。混合物用水(15mL)淬灭且用EtOAc(15mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(90mg,62%),其为棕色固体。LCMS m/z(M+H)371。
步骤3:N-甲基-2-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)苯并[d]噁唑-4-甲酰胺
向2-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)苯并[d]噁唑-4-甲酸(80mg,0.22mmol)、N,N-二异丙基乙胺(0.077mL,0.43mmol)和HATU(99mg,0.26mmol)于DMF(4mL)中的溶液中添加甲胺盐酸盐(22mg,0.32mmol)。将反应混合物在室温搅拌2小时并真空浓缩。粗残余物通过反相色谱(乙腈20-50%/0.2%甲酸水溶液)纯化,得到标题化合物(2mg,2%),其为白色固体。1H NMR(400MHz,CDCl3)δ10.58(s,1H),8.97(s,1H),8.48(d,J=6.8Hz,1H),8.33(d,J=7.6Hz,1H),8.12(s,1H),8.05(d,J=8.0Hz,1H),7.91(s,1H),7.85-7.81(m,2H),7.59-7.57(m,1H),4.03(s,3H),3.23(d,J=4.8Hz,3H)。LCMS m/z(M+H)384。
实施例122
1-(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)吡啶-2-基)-3-甲基脲
步骤1:(6-溴吡啶-2-基)氨基甲酸叔丁酯
向6-溴吡啶-2-胺(1.0g,5.78mmol)、一缩二碳酸二叔丁酯(1.4g,6.2mmol)于DCM(10mL)中的溶液中添加三乙胺(1.58mL,11.91mmol)和4-二甲基氨基吡啶(140mg,1.17mmol)。将反应混合物在室温搅拌10小时并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=10:1)纯化,得到标题化合物(1.1g,67%),其为白色固体。1H NMR(400MHz,CDCl3)δ7.55-7.48(m,1H),7.31(d,J=8.0Hz,1H),7.19(t,J=4.0Hz,2H),1.44(s,9H)。
步骤2:(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)吡啶-2-基)氨基甲酸叔丁酯
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,290mg,1.1mmol)、(6-溴吡啶-2-基)氨基甲酸叔丁酯(301mg,1.1mmol)和t-BuONa(265mg,2.75mmol)于1,4-二噁烷(2mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(86mg,0.11mmol)。在氮气气氛下将反应混合物加热至120℃且保持12小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(402mg,80%),其为黄色油状物。LCMSm/z(M+H)456。
步骤3:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)吡啶-2-胺
向(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)吡啶-2-基)氨基甲酸叔丁酯(402mg,0.88mmol)于DCM(4mL)中的溶液中滴加三氟乙酸(0.65mL,8.84mmol)。将反应混合物在室温搅拌1小时并真空浓缩,得到标题化合物(285mg,91%),其为黄色油状物且不需要进一步纯化。LCMS m/z(M+H)356。
步骤4:1-(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)吡啶-2-基)-3-甲基脲
在0℃向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)吡啶-2-胺(258mg,0.73mmol)于DMF(3mL)中的溶液中添加NaH(60%,43mg,1.09mmol)。将混合物在0℃搅拌10分钟,添加N-甲基-1H-咪唑-1-甲酰胺(109mg,0.87mmol)。将反应混合物在室温再搅拌5小时。将反应混合物倾入水(50mL)中且用EtOAc(30mL×3)萃取。合并的有机层用盐水(30mL×2)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈38-68%/0.05%NH4OH水溶液)纯化,得到标题化合物(57mg,19%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.01(s,1H),7.85(s,1H),7.62-7.51(m,2H),7.47(s,1H),7.28(s,1H),6.90(t,J=55.2Hz,1H),6.70(d,J=8.0Hz,1H),6.62(d,J=8.0Hz,1H),3.89(s,3H),3.74(t,J=6.4Hz,2H),2.78(t,J=5.6Hz,2H),2.48(s,3H),1.96-1.90(m,2H)。LCMS m/z(M+H)413。
实施例123
1-(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-甲氧基吡啶-2-基)-3-甲基脲
步骤1:(6-溴-4-甲氧基吡啶-2-基)氨基甲酸叔丁酯
向2,6-二溴-4-甲氧基吡啶(2g,7.49mmol)、氨基甲酸叔丁酯(877mg,7.49mmol)和Cs2CO3(4.8g,14.98mmol)于1,4-二噁烷(50mL)中的溶液中添加乙酸钯(II)(168mg,0.75mmol)和4,5-二(二苯基膦基)-9,9-二甲基呫吨(433mg,0.75mmol)。在氮气气氛下将反应混合物加热至100℃且保持16小时。将反应混合物冷却至室温后,添加水(100mL)且用EtOAc(50mL×3)萃取。合并的有机层用盐水(50mL×2)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(石油醚/EtOAc=9:1)纯化,得到标题化合物(900mg,39%),其为白色固体。LCMS m/z(M+H)303。
步骤2:(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-甲氧基吡啶-2-基)氨基甲酸叔丁酯
向(6-溴-4-甲氧基吡啶-2-基)氨基甲酸叔丁酯(460mg,1.52mmol)、7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,400mg,1.52mmol)和t-BuONa(436mg,4.54mmol)于1,4-二噁烷(15mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(120mg,0.15mmol)。在氮气气氛下将反应混合物加热至120℃且保持16小时。将反应混合物冷却至室温后,添加水(50mL)且用EtOAc(30mL×3)萃取。合并的有机层用盐水(30mL×2)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过制备型TLC(石油醚/EtOAc=2:1)纯化,得到标题化合物(100mg,14%),其为白色固体。
步骤3:6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-甲氧基吡啶-2-胺
在0℃向(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-甲氧基吡啶-2-基)氨基甲酸叔丁酯(100mg,0.21mmol)于DCM(10mL)中的溶液中添加三氟乙酸(0.076mL,1.03mmol)。将反应混合物在室温搅拌5小时并真空浓缩,得到标题化合物(80mg,粗品),其为黄色油状物且不需要进一步纯化。LCMS m/z(M+H)386。
步骤4:1-(6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-甲氧基吡啶-2-基)-3-甲基脲
在0℃向6-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-4-甲氧基吡啶-2-胺(40mg,0.1mmol)于无水DMF(2mL)中的溶液中添加NaH(60%,20mg,0.5mmol)。在0℃搅拌10分钟后,添加N-甲基-1H-咪唑-1-甲酰胺(36mg,0.29mmol)。将反应溶液在室温再搅拌2小时。将反应混合物倾入水(50mL)中且用EtOAc(30mL×3)萃取。合并的有机层用盐水(30mL×2)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈40-70%/0.2%甲酸水溶液)纯化,得到标题化合物(8mg,18%),其为白色固体。1HNMR(400MHz,CDCl3)δ8.88(s,1H),7.69(s,1H),7.60(s,1H),7.49(s,1H),7.18(s,1H),7.06(s,1H),6.58(t,J=55.2Hz,1H),6.17(s,1H),5.75(s,1H),3.99(s,3H),3.81-3.76(m,2H),3.79(s,3H),2.82-2.80(m,2H),2.70(d,J=4.0Hz,3H),2.06(t,J=6.0Hz,2H)。LCMS m/z(M+H)443。
实施例124
N4,1-二甲基-N3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-1H-吡唑-3,4-二甲酰胺
步骤1:N-(二苯基亚甲基)-3-(1-甲基-1H-吡唑-4-基)异喹啉-8-胺
向8-氯-3-(1-甲基-1H-吡唑-4-基)异喹啉(中间体D,400mg,1.64mmol)、二苯基甲亚胺(446mg,2.46mmol)和t-BuONa(473mg,4.92mmol)于1,4-二噁烷(8mL)中的溶液中添加[1,3-二(2,6-二(3-戊基)苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)(130mg,0.16mmol)。在氮气气氛下将反应混合物加热至120℃且保持16小时。冷却至室温后,过滤反应混合物并真空浓缩。残余物通过硅胶柱色谱(石油醚/EtOAc=1:1)纯化,得到标题化合物(500mg,78%),其为黄色固体。1H NMR(400MHz,CDCl3)δ9.40(s,1H),8.02(d,J=6.4Hz,2H),7.89(d,J=7.6Hz,2H),7.69(s,1H),7.58-7.40(m,3H),7.35-7.34(m,2H),7.24-7.02(m,5H),6.54-6.50(m,1H),3.98(s,3H)。
步骤2:3-(1-甲基-1H-吡唑-4-基)异喹啉-8-胺
向N-(二苯基亚甲基)-3-(1-甲基-1H-吡唑-4-基)异喹啉-8-胺(500mg,1.29mmol)于THF(6mL)中的溶液中滴加HCl(2N,6.44mL,12.87mmol)。将所得混合物在室温搅拌2小时并真空浓缩。粗残余物用TBME(10mL)洗涤,得到标题化合物(280mg,97%),其为橙色固体。1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.69(s,1H),8.36-8.34(m,2H),7.80-7.75(m,1H),7.12(d,J=7.6Hz,1H),6.88(d,J=8.0Hz,1H),3.97(s,3H)。
步骤3:4-溴-1-甲基-N-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-1H-吡唑-3-甲酰胺
向4-溴-1-甲基-1H-吡唑-3-甲酸(450mg,2.2mmol)于DCM(10mL)中的溶液中添加草酰氯(0.37mL,4.39mmol)和DMF(0.016mL,0.22mmol)。将混合物在室温搅拌2小时并真空浓缩,得到4-溴-1-甲基-1H-吡唑-3-甲酰氯(500mg,粗品),其为白色固体且将其溶于DCM(15mL)。添加3-(1-甲基-1H-吡唑-4-基)异喹啉-8-胺(350mg,1.56mmol)和N,N-二异丙基乙胺(1.09mL,6.24mmol)。将反应混合物在室温搅拌16小时。反应混合物用水(5mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(DCM/MeOH=20:1)纯化,得到标题化合物(400mg,62%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.28(s,1H),8.33(s,1H),8.17(s,1H),8.08-8.06(m,2H),7.77-7.71(m,2H),7.69-7.64(m,1H),4.01(s,3H),3.92(s,3H)。
步骤4:1-甲基-3-((3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)氨甲酰基)-1H-吡唑-4-甲酸甲酯
向4-溴-1-甲基-N-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-1H-吡唑-3-甲酰胺(300mg,0.73mmol)于MeOH(10mL)中的溶液中添加三乙胺(0.51mL,3.65mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(53mg,0.07mmol)。在一氧化碳气氛(50psi)下将反应混合物加热至70℃且保持72小时。将反应混合物冷却至室温后,过滤反应混合物并真空浓缩。粗残余物通过硅胶柱色谱(DCM/MeOH=10:1)纯化,得到标题化合物(200mg,70%),其为黄色固体。LCMS m/z(M+H)391。
步骤5:1-甲基-3-((3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)氨甲酰基)-1H-吡唑-4-甲酸
向1-甲基-3-((3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)氨甲酰基)-1H-吡唑-4-甲酸甲酯(100mg,0.26mmol)于MeOH(1mL)、THF(3mL)和水(0.5mL)中的溶液中添加一水合氢氧化锂(54mg,1.28mmol)。将反应混合物在室温搅拌16小时并真空浓缩。添加水(1mL)且混合物用HCl(1N)酸化至pH 6,然后用DCM/MeOH(10/1,10mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(50mg,52%),其为黄色固体且不需要进一步纯化。LCMS m/z(M+H)377。
步骤6:N4,1-二甲基-N3-(3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)-1H-吡唑-3,4-二甲酰胺
向1-甲基-3-((3-(1-甲基-1H-吡唑-4-基)异喹啉-8-基)氨甲酰基)-1H-吡唑-4-甲酸(50mg,0.13mmol)、HATU(76mg,0.20mmol)和N,N-二异丙基乙胺(0.09mL,0.53mmol)于DMF(2mL)中的溶液中添加甲胺盐酸盐(18mg,0.27mmol)。将反应混合物在室温搅拌16小时。粗残余物通过反相色谱(乙腈24-54%/0.05%NH4OH水溶液)纯化,得到标题化合物(19mg,37%),其为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ9.57-9.53(m,1H),9.39(s,1H),8.42(s,1H),8.34(s,1H),8.09-8.07(m,2H),7.84-7.69(m,3H),4.03(s,3H),3.91(s,3H),2.78(d,J=4.4Hz,3H)。LCMS m/z(M+H)390。
实施例125
3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[4,3-b]吡啶-5-甲酰胺
步骤1:3-溴-1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯
向1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯(800mg,4.52mmol)于THF(10mL)中的溶液中添加NBS(1.21g,6.77mmol)。将反应混合物在室温搅拌12小时并真空浓缩。添加DCM(30mL)且用水(30mL×2)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(483mg,42%),其为黄色固体且不需要进一步纯化。LCMS m/z(M+H)256。
步骤2:3-溴-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯
向3-溴-1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯(480mg,1.87mmol)于DMF(20mL)中的搅拌的溶液中添加甲磺酸四氢-2H-吡喃-4-基酯(507mg,2.81mmol)和Cs2CO3(1.83g,5.62mmol)。在氮气气氛下将反应混合物加热至80℃且保持16小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。将残余物溶于DCM(30mL)且用水(30mL×2)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱(DCM/MeOH=100:1)纯化,得到标题化合物(360mg,57%),其为黄色油状物。1H NMR(400MHz,DMSO-d6)δ8.51(d,J=8.8Hz,1H),8.17(d,J=8.8Hz,1H),5.13-4.19(m,1H),4.03-4.00(m,2H),3.94(s,3H),3.54(t,J=11.6Hz,2H),2.12-2.06(m,2H),1.96-1.93(m,2H)。
步骤3:3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[4,3-b]吡啶-5-甲酸
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,77mg,0.29mmol)、3-溴-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯(100mg,0.29mmol)和K3PO4(187mg,0.88mmol)于2-甲基-2-丁醇(5mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(25mg,0.03mmol)。在氩气气氛下将混合物加热至95℃且保持12小时。将反应混合物冷却至室温后,过滤混合物并真空浓缩。粗残余物通过硅胶柱色谱(DCM/MeOH=10:1)纯化,得到标题化合物(100mg,67%),其为黄色油状物。LCMS m/z(M+H)509。
步骤4:3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[4,3-b]吡啶-5-甲酰胺
向3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[4,3-b]吡啶-5-甲酸(100mg,0.20mmol)、N,N-二异丙基乙胺(0.104mL,0.59mmol)和HATU(150mg,0.39mmol)于DMF(2.5mL)中的溶液中添加甲胺盐酸盐(27mg,0.39mmol)。将反应混合物在室温搅拌1小时并真空浓缩。粗残余物通过反相色谱(乙腈41-71%/0.05%NH4OH水溶液)纯化,得到标题化合物(0.6mg,0.6%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ8.40-8.29(m,2H),8.08(d,J=8.8Hz,1H),7.80(s,1H),7.67(s,1H),7.57-7.51(m,1H),7.20(s,1H),6.82(t,J=55.6Hz,1H),5.00-4.88(m,1H),4.24-4.18(m,2H),4.02-3.98(m,2H),3.88(s,3H),3.55(t,J=11.2Hz,2H),2.96-2.89(m,2H),2.85(d,J=4.8Hz,3H),2.14-2.03(m,4H),1.94-1.91(m,2H)。LCMS m/z(M+H)522。
实施例126
3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酰胺
步骤1:1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸乙酯
向4,5,6,7-四氢-1H-吲唑-5-甲酸乙酯(5.0g,25.74mmol)和Cs2CO3(16.77g,51.49mmol)于DMF(10mL)中的溶液中添加甲磺酸四氢-2H-吡喃-4-基酯(9.28g,51.49mmol)。将反应混合物加热至80℃且保持12小时。冷却至室温后,真空浓缩反应混合物。添加EtOAc(80mL)且用水(100mL×3)、盐水(100mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/(5%MTBE/THF)=1:1)纯化,得到标题化合物(5.3g,74%),其为无色油状物(约7:5的位置异构体混合物)。LCMS m/z(M+H)279。
步骤2:3-溴-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸乙酯
向1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸乙酯(1.5g,5.39mmol)于乙腈(10mL)中的溶液中添加NBS(96mg,5.39mmol)。将反应混合物在室温搅拌2小时。混合物用水(50mL)淬灭且用EtOAc(30mL×3)萃取。合并的有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(石油醚/MTBE/THF/=20:1:1)纯化,得到标题化合物(1.0g,52%),其为黄色固体。1H NMR(400MHz,CDCl3)δ4.18(q,J=7.2Hz,2H),4.12-4.08(m,2H),3.51-3.45(m,2H),2.82-2.55(m,5H),2.33-2.23(m,3H),1.96-1.76(m,3H),1.29(t,J=7.2Hz,3H)。LCMS m/z(M+H)357。
步骤3:3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸乙酯
向7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉(中间体C,177mg,0.67mmol)和3-溴-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸乙酯(200mg,0.56mmol)于2-甲基-2-丁醇(2mL)中的溶液中添加甲磺酸(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)(474mg,0.56mmol)和K3PO4(119mg,0.56mmol)。在氮气气氛下将反应混合物加热至110℃且保持16小时。冷却至室温后,真空浓缩反应混合物。添加DCM(50mL)且用水(30mL×3)、盐水(20mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过硅胶色谱(洗脱剂为石油醚/EtOAc=2:1至1:2)纯化,得到标题化合物(130mg,43%),其为黄色油状物。LCMS m/z(M+H)540。
步骤4:3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸
向3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸乙酯(130mg,0.24mmol)于THF(5mL)中的溶液中添加一水合氢氧化锂(50mg,1.2mmol)。将混合物在室温搅拌3小时并真空浓缩。添加水(10mL)且混合物用柠檬酸(25%)酸化至pH 3,然后用DCM(50mL)萃取。有机层用水(20mL×2)、盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物(90mg,73%),其为黄色固体且不需要进一步纯化。LCMS m/z(M+H)512。
步骤5:3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-N-甲基-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酰胺
向3-(7-(二氟甲基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)-1-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢-1H-吲唑-5-甲酸(90mg,0.18mmol)和HATU(100mg,0.26mmol)于DMF(2.5mL)中的溶液中添加N,N-二异丙基乙胺(0.1mL,0.53mmol)和甲胺(0.4mL,0.4mmol,1M于THF中)。将反应混合物在室温搅拌1小时。添加EtOAc(30mL)且用水(30mL×3)、盐水(30mL)洗涤。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗残余物通过反相色谱(乙腈30-60%/0.05%NH4OH水溶液)纯化,得到标题化合物(53mg,57%),其为黄色固体。1H NMR(400MHz,DMSO-d6)δ7.77-7.71(m,2H),7.48(s,1H),7.06(s,1H),6.77(s,1H),6.76(t,J=55.2Hz,1H),4.30-4.21(m,1H),3.97-3.92(m,2H),3.86(s,3H),3.66-3.58(m,1H),3.53-3.42(m,3H),2.90-2.80(m,3H),2.66-2.58(m,1H),2.55(d,J=4.4Hz,3H),2.40-2.30(m,1H),2.27-2.23(m,2H),2.04-1.90(m,5H),1.85-1.67(m,3H)。LCMS m/z(M+H)525。
实施例127
使用CBP TR-FRET结合测定对抑制剂的IC50进行测量
对经His/Flag表位标记的CBP进行克隆、表达并纯化至均质。CBP结合和抑制如下评估:使用TR-FRET测定技术(Perkin-Elmer)对生物素化小分子化合物与靶标的接合进行监测。具体地,在384孔ProxiPlate中在50mM HEPES(pH 7.5)、50mM NaCl、1mM TCEP、0.01%(w/v)BSA和0.008%(w/v)Brij-35中在DMSO(最终0.2%DMSO)或化合物于DMSO中的系列稀释液存在下将CBP(最终4nM)与生物素-配体(最终60nM)组合。在室温孵育10分钟后,添加Eu-W1024抗6×His抗体(Perkin Elmer AD0110)和SureLightTM别藻蓝蛋白-链霉亲和素(APC-SA,Perkin Elmer CR130-100)至最终浓度分别为0.2nM抗体和50nM APC-SA。平衡20分钟后,板在Envision仪器上读取且使用四参数非线性曲线拟合来计算IC50。
在MV-4-11细胞中进行MYC_RPL19QuantiGene测定
QuantiGene 2.0试剂系统,Affymetrix:人MYCN;源于成神经细胞瘤的V-myc骨髓细胞瘤病毒相关癌基因(禽类);NM_005378SA-15008。在96孔透明平底板(Costar,目录编号3595)中将10,000个MV-4-11细胞(GNE自备)铺板于75μl完全培养基[RPMI-1640(GNE自备)、10%FBS(Life Technologies,目录编号10082)、1%Pen-strep(GNE自备)]中。以1:3系列稀释10点剂量响应添加25μl化合物且在37℃保持4小时,其中DMSO的最终浓度=0.2%。然后根据测定试剂盒方案将细胞裂解并冷冻在-80℃。翌日通过按下列顺序组合以下试剂来制备适当体积的工作探针组:无核酸酶水、裂解混合物、阻断试剂和2.0探针组(MYC或RPL19)。向捕获板的每个测定孔中添加20μl工作探针组,然后将80μl裂解物转移到测定板中。将捕获板置于55℃培养箱中过夜杂交(16-20小时)。翌日根据制造商建议制备洗涤缓冲液。捕获板用300μl/孔1×洗涤缓冲液洗涤3次。然后将100μl预扩增剂添加到板中用于在55℃孵育60分钟。孵育后,捕获板用300μl/孔1×洗涤缓冲液洗涤3次且将100μl扩增剂添加到板中用于在55℃孵育60分钟。捕获板再次用300μl/孔1×洗涤缓冲液洗涤3次且将100μl标签探针添加到板中用于在50℃孵育60分钟。然后捕获板用300μl/孔1×洗涤缓冲液洗涤3次并向板的每个孔中添加100μl 2.0底物。将板在室温在暗处孵育5分钟且在Envision上使用发光方案进行读取,其中将积分时间设定为0.2秒。
来自上述测定的代表性化合物的数据提供在下表中。
虽然已描述了多个实施方案,但是可改变这些实施例以提供利用本申请所述化合物和方法的其它实施方案。因此,本申请的范围通过所附权利要求书而非以示例性方式表示的具体实施方案来限定。
本申请还涉及以下各项:
1.式(I)或式(II)化合物或其盐:
其中
R1为氢、-NRaRb、C1-6烷基、C2-6烯基、C2-6炔基和3-8元碳环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基和3-8元碳环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个R2独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rt)2、-CN、-C(O)-N(Rt)2、-O-Rt、-O-C(O)-Rt、-C(O)-Rt和-C(O)-O-Rt,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个卤素;
R3为3-12元碳环或3-12元杂环,其中R3的每个3-12元碳环和3-12元杂环任选取代有一个或多个基团Ru;
Y为O或N(Rc);
m为0、1、2、3或4;
n为0、1、2、3或4;
p为0、1、2、3或4;
环A为稠合环,其选自苯并和6元杂环;
每个R4独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rx和-C(O)-O-Rw,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个氧代或卤素;
每个R5独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rx和-C(O)-O-Rw,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个氧代或卤素;
R6为-N(Rz)-C(O)-Rx、3-12元碳环或3-12元杂环,其中R6的每个3-12元碳环和3-12元杂环任选取代有一个或多个基团Rx;
X为N或C(R7);
R7为H或C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ra和Rb独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或Ra和Rb与和它们连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
Rc为氢、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rt独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rt与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ru独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任意C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、3-12元碳环和C1-6烷基,所述C1-6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rv独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、碳环基和杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rw与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rw独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rt与和它们连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rx独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2和-N(Ry)-S(O)2-N(Ry)2,其中任意C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、3-12元碳环和C1-6烷基,所述C1-6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ry独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Ry与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;且
每个Rz独立选自氢、C1-6烷基。
2.项1的化合物或盐,其中所述化合物为式(I)化合物:
条件是R3不为:
3.项1的化合物或盐,其为式(Ia)化合物或其盐:
4.项1的化合物或盐,其为式(Ib)化合物或其盐:
5.项1-4中任一项的化合物或盐,其中R1为-NHRb。
6.项5的化合物或盐,其中Rb为C1-6烷基。
7.项1-4中任一项的化合物或盐,其中R1为甲基或-NH(CH3)。
8.项1-3中任一项的化合物或盐,其中m为0。
9.项1-3中任一项的化合物或盐,其中m为1。
10.项1-7和9中任一项的化合物或盐,其中R2为-O-Rt。
11.项1-7和9中任一项的化合物或盐,其中R2为-OMe。
12.项1-11中任一项的化合物或盐,其中R3为3-12元碳环,其任选取代有一个或多个基团Ru。
13.项1-11中任一项的化合物或盐,其中R3为苯基,其任选取代有一个或多个基团Ru。
14.项1-11中任一项的化合物或盐,其中R3为3-12元杂环,其任选取代有一个或多个基团Ru。
15.项1-11中任一项的化合物或盐,其中R3为9-10元杂环,其任选取代有一个或多个基团Ru。
16.项1-11中任一项的化合物或盐,其中R3选自:
17.项1的化合物或盐,其选自:
及其盐。
18.项1的化合物或盐,其中所述化合物为式(II)化合物:
条件是R6不为:
19.项18的化合物或盐,其中所述化合物为式(IIa)化合物:
20.项18的化合物或盐,其中所述化合物为式(IIb)化合物:
21.项18的化合物或盐,其中所述化合物为式(IIc)化合物:
22.项1的化合物或盐,其中所述化合物为式(IId)化合物:
23.项18的化合物或盐,其中所述化合物为式(IIe)化合物:
24.项18的化合物或盐,其中所述化合物为式(IIf)化合物:
25.项18的化合物或盐,其中所述化合物为式(IIg)化合物:
26.项1和18-25中任一项的化合物或盐,其中X为N。
27.项1和18-25中任一项的化合物或盐,其中X为C(R7)。
28.项27的化合物或盐,其中R7为H。
29.项27的化合物或盐,其中R7为二氟甲基。
30.项18的化合物或盐,其中所述化合物为式(IIh)化合物:
31.项1和18-29中任一项的化合物或盐,其中p为0。
32.项1和18-29中任一项的化合物或盐,其中p为1、2、3或4。
33.项1和18-32中任一项的化合物或盐,其中R6为3-12元杂环,其任选取代有一个或多个基团Rx。
34.项1和18-32中任一项的化合物或盐,其中R6选自:
其任选取代有一个或多个基团Rx。
35.项1和18-25中任一项的化合物或盐,其中R6选自:
36.项1的化合物或盐,其选自:
及其盐。
37.一种组合物,其包含项1-36中任一项的式(I)或式(II)化合物或其药用盐和药用辅料、载体或媒介物。
38.项37的组合物,其与额外的治疗剂组合。
39.项38的组合物,其中所述额外的治疗剂为化学治疗剂。
40.在动物中治疗由CBP和/或EP300介导的病症的方法,其包括向所述动物施用项1-36中任一项的式(I)或式(II)化合物或其药用盐。
41.项40的方法,其中所述病症为癌症、炎性病症或自身免疫性疾病。
42.项41的方法,其中所述癌症选自听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、子宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、异常增殖性变化、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因瘤、纤维肉瘤、滤泡型淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、胶质肉瘤、重链病、头颈癌、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、淋巴管内皮肉瘤、淋巴管肉瘤、成淋巴细胞性白血病、淋巴瘤、T细胞或B细胞源性淋巴恶性肿瘤、髓样癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体瘤(癌瘤和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和威尔姆斯瘤。
43.项41的方法,其中所述癌症选自肺癌、乳腺癌、胰腺癌、结直肠癌和黑素瘤。
44.项41的方法,其中所述炎性病症或自身免疫性疾病选自艾迪生病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、贝切特病、大疱性皮肤病、慢性阻塞性肺病、克罗恩病、皮炎、湿疹、巨细胞性动脉炎、纤维化、肾小球性肾炎、肝血管闭塞、肝炎、垂体炎、免疫缺陷综合征、炎性肠病、川崎病、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆汁性肝硬化、银屑病、银屑病性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、系统性红斑狼疮、高安动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、血管炎和韦格纳肉芽肿病。
45.项1-36中任一项的式(I)或式(II)化合物或其药用盐,其用于医学疗法。
46.项1-36中任一项的式(I)或式(II)化合物或其药用盐,其用于预防性或治疗性处置由CBP和/或EP300介导的病症。
47.项1-36中任一项的式(I)或式(II)化合物或其药用盐在制备用于在动物中治疗由CBP和/或EP300介导的病症的药物中的用途。
48.在动物中增加包含细胞毒性剂的癌症治疗的效力的方法,其包括向所述动物施用有效量的项1-36中任一项的式(I)或式(II)化合物或其药用盐。
49.项48的方法,其还包括向所述动物施用所述细胞毒性剂。
50.在动物中延长对癌症疗法的响应的持续时间的方法,其包括向经历所述癌症疗法的动物施用项1-36中任一项的式(I)或式(II)化合物或其药用盐,其中当施用式(I)或式(II)化合物或其药用盐时对所述癌症疗法的响应的持续时间延长超过在不存在施用式(I)或式(II)化合物或其药用盐的情况下对所述癌症疗法的响应的持续时间。
51.在个体中治疗癌症的方法,其包括向所述个体施用(a)项1-36中任一项的式(I)或式(II)化合物或其药用盐和(b)细胞毒性剂。
52.项51的方法,其中所述细胞毒性剂选自抗微管剂、铂配位复合物、烷化剂、抗生素、拓扑异构酶II抑制剂、抗代谢剂、拓扑异构酶I抑制剂、激素和激素类似物、信号转导途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂、脂肪酸生物合成抑制剂、细胞周期信号传导抑制剂、HDAC抑制剂、蛋白酶体抑制剂和癌症代谢抑制剂。
53.项51的方法,其中所述细胞毒性剂为紫杉烷。
54.项53的方法,其中所述紫杉烷为紫杉醇或多西他赛。
55.项51的方法,其中所述细胞毒性剂为铂剂。
56.项51的方法,其中所述细胞毒性剂为EGFR拮抗剂。
57.项56的方法,其中所述EGFR拮抗剂为N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺或其药用盐。
58.项51的方法,其中所述细胞毒性剂为RAF抑制剂。
59.项58的方法,其中所述RAF抑制剂为BRAF或CRAF抑制剂。
60.项58的方法,其中所述RAF抑制剂为威罗菲尼。
61.项51的方法,其中所述细胞毒性剂为PI3K抑制剂。
Claims (10)
1.式(II)化合物或其盐:
其中
R1为氢、-NRaRb、C1-6烷基、C2-6烯基、C2-6炔基和3-8元碳环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基和3-8元碳环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个R2独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rt)2、-CN、-C(O)-N(Rt)2、-O-Rt、-O-C(O)-Rt、-C(O)-Rt和-C(O)-O-Rt,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个卤素;
R3为3-12元碳环或3-12元杂环,其中R3的每个3-12元碳环和3-12元杂环任选取代有一个或多个基团Ru;
Y为O或N(Rc);
m为0、1、2、3或4;
n为0、1、2、3或4;
p为0、1、2、3或4;
环A为稠合环,其选自苯并和6元杂环;
每个R4独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rx和-C(O)-O-Rw,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个氧代或卤素;
每个R5独立选自C1-6烷基、C2-6烯基、C2-6炔基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rx和-C(O)-O-Rw,其中任意C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个氧代或卤素;
R6为-N(Rz)-C(O)-Rx、3-12元碳环或3-12元杂环,其中R6的每个3-12元碳环和3-12元杂环任选取代有一个或多个基团Rx;
X为N或C(R7);
R7为H或C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ra和Rb独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或Ra和Rb与和它们连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
Rc为氢、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基和C2-6炔基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rt独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rt与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ru独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任意C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、3-12元碳环和C1-6烷基,所述C1-6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rv独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、碳环基和杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rw与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rw独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Rt与和它们连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Rx独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基、3-12元杂环基、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2和-N(Ry)-S(O)2-N(Ry)2,其中任意C1-6烷基、C2-6烯基、C2-6炔基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、3-12元碳环和C1-6烷基,所述C1-6烷基任选取代有一个或多个独立选自氧代和卤素的基团;
每个Ry独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、3-12元碳环基和3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基、C1-6烷氧基、3-12元碳环基、3-12元杂环基和C1-C6烷基,所述C1-C6烷基任选取代有一个或多个独立选自氧代和卤素的基团;或两个Ry与和它们连接的氮一起形成3-12元杂环基,所述3-12元杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和C1-3烷基,所述C1-3烷基任选取代有一个或多个独立选自氧代和卤素的基团;且
每个Rz独立选自氢、C1-6烷基。
10.权利要求1-9中任一项的化合物或盐,其中X为N。
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US11168070B2 (en) | 2021-11-09 |
US20200399244A1 (en) | 2020-12-24 |
MA45122A (fr) | 2019-04-10 |
EP4067347B1 (en) | 2024-06-19 |
EP3464270A2 (en) | 2019-04-10 |
WO2017205536A3 (en) | 2018-01-04 |
EP4067347A1 (en) | 2022-10-05 |
US20190152949A1 (en) | 2019-05-23 |
JP7160688B2 (ja) | 2022-10-25 |
JP2019516757A (ja) | 2019-06-20 |
US10696655B2 (en) | 2020-06-30 |
JP2023002643A (ja) | 2023-01-10 |
EP3464270B1 (en) | 2022-02-23 |
CN109476641B (zh) | 2022-07-05 |
CN109476641A (zh) | 2019-03-15 |
WO2017205536A2 (en) | 2017-11-30 |
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