CN111825719A - 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用 - Google Patents
一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用 Download PDFInfo
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- CN111825719A CN111825719A CN201911065662.6A CN201911065662A CN111825719A CN 111825719 A CN111825719 A CN 111825719A CN 201911065662 A CN201911065662 A CN 201911065662A CN 111825719 A CN111825719 A CN 111825719A
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Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
本发明提供了一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用,具体涉及式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,其制备方法及其在制备作为激酶抑制剂的药物中的应用。
Description
技术领域
本发明属于医药技术领域,涉及一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用。
背景技术
蛋白激酶是细胞生命活动重要的信号使者,可催化将ATP末端的γ-磷酸基团转移至底物氨基酸残基(丝氨酸、苏氨酸、酪氨酸)中的羟基受体上,从而激活目标蛋白(JohnsonL.N.,and Lewis R.J.,Structural basis for control by phosphorylation,Cheminform,2001,101,2209.)。蛋白激酶参与了众多的生理过程,包括细胞增殖、存活、凋亡、代谢、转录以及分化等(Adams J.A.,Kinetic and catalytic mechanisms of proteinkinases,Chemical reviews,2001,101,2271.)。在人体现有药物靶点中,蛋白激酶家族成员占比高达10%(Santos R.,Ursu O.,Gaulton A.,et al.,A comprehensive map ofmolecular drug targets,Nature Reviews Drug Discovery,2017,16,19.)。
表皮生长因子受体(ErbB)酪氨酸激酶可通过多种途径调节细胞增殖、迁移、分化、凋亡以及细胞移动。在多种形式的恶性肿瘤中,ErbB家族成员以及其部分配体通常过表达、扩增或突变,这使其成为重要的治疗靶标。该家族蛋白激酶包括:ErbB1/EGFR/HER1、ErbB2/HER2、ErbB3/HER3和ErbB4/HER4。其中EGFR是开发非小细胞肺癌的重要靶点(DienstmannR.,et.al.,Personalizing Therapy with Targeted Agents in Non-Small Cell LungCancer,ONCOTARGET,2001,2(3),165.)。
吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、埃克替尼(Icotinib)是第一代靶向EGFR的可逆型激酶抑制剂,用于治疗非小细胞癌。该类抑制剂同时对野生型和激活突变型EGFR具有抑制作用,且在临床上取得了较大的成功,但是受体患者服用一段时间后耐药性的出现,尤其是T790M突变导致的耐药性使疗效降低或失效。第二代EGFR抑制剂阿法替尼(Afatinib)为非可逆型抑制剂,其含有迈克尔受体,可与位于ATP结合口袋入口处的半胱氨酸残基(Cys797)发生共价键结合,该抑制剂针对T790M突变型EGFR激酶和野生型EGFR激酶均表现出极强的活性,且对于T790M突变型EGFR激酶的抑制活性高于野生型EGFR激酶,这使得该药物临床应用中治疗窗口较窄,使用效果并不理想(Camidge,D.R.,et.al.,Acquiredresistance to TKIs in solid tumours:learning from lung cancer.Nature ReviewsClinical Oncology,2014,11,473.)。第三代的EGFR激酶抑制剂奥希替尼(Osimertinib)和奥莫替尼(Olmutinib)实现了对T790M突变型EGFR激酶相比野生型EGFR激酶的高选择性抑制,拉大了临床使用窗口,实现了对T790M突变病人的有效治疗。不幸的是,三代EGFR激酶抑制剂在临床上使用一段时间后也产生了耐药现象。其原因之一,是由于EGFR产生了C797S的二次突变。现有三代小分子EGFR抑制剂与靶标的作用机制是药物分子与EGFR的Cys797形成共价结合。但病人体内发生C797S的二次突变时,药物分子丧失了与Cys797的共价结合,导致药物的失效(Harun Patel.,et.al.,2017,Recent updates on third generation EGFRinhibitors and emergence of fourth generation EGFR inhibitors to combat C797Sresistance,Eur J Med Chem.,2017,142,32)。基于此,开发具有对T790M突变型EGFR激酶良好的抑制活性,同时具有对C797S突变型EGFR激酶良好抑制活性的新型药物分子具有重要意义。
Brigatinib是一种靶向的ALK抑制剂,由Ariad医药公司研发并于2017年获美国FDA批准上市用于治疗ALK阳性的非小细胞肺癌。根据文献报道,Brigatinib对C797S突变型EGFR激酶具有一定的抑制作用。
发明内容
鉴于上述讨论的内容,本发明旨在提供一种含有芳胺基取代的吡咯并嘧啶类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药,及其药物组合物,并涉及它们在制备作为激酶抑制剂的药物中的应用。
本发明的一个方面提供了一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,
式(I)中,R1为卤素、C1-C3烷基;
R2和R3分别独立地为-H、C3-C8环烷基、或由1至3个选自C1-C6烷氧基、C1-C6烷硫基、C1-C3酰基、羟基、卤素、氰基、-CONH2、-S(=O)2CH3、C3-C6环烷基或-NRaRb的取代基所取代或者非取代的C1-C9烷基、含一个氮原子或含一个氧原子的4-6元杂环基,且R2和R3不同时为甲基,
所述含一个氮原子或含一个氧原子的4-6元杂环基为非取代或被C1-C3的烷基所取代,
Ra、Rb分别独立地为H或C1-C3的烷基,
或者,R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述杂环还含1-2个选自N、O或S的杂原子或含基团-C(=O)-或-S(=O)2-作为环成员,
所述R2、R3与其相连的氮原子构成的4-6元杂环为未被取代或被1-2个选自卤素、氰基、羟基、氨基、C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基、氰基取代的C1-C3烷基、羟基取代的C1-C3烷基、C1-C3烷氧基取代的C1-C3烷基所取代,
所述R2、R3与其相连的氮原子构成的6-9元螺环为包含一个氮原子的单螺环。
根据本申请的一些具体实施方案,R1为氟、甲基、乙基。
根据本申请的一些具体实施方案,R2和R3分别独立地为-H、C3-C6环烷基、或由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、氰基、-CONH2、-S(=O)2CH3、环丙基、环丁基、环戊基、环己基、氨基、甲氨基、二甲氨基、乙氨基、二乙氨基、丙氨基、二丙氨基、甲基乙基氨基、甲基丙基氨基的取代基所取代或者非取代的C1-C6烷基,含一个氮原子或含一个氧原子的4-6元杂环基,且R2和R3不同时为甲基,
所述含一个氮原子或含一个氧原子的4-6元杂环基为非取代或被甲基、乙基、丙基、异丙基所取代,
或者,R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述杂环还含1-2个选自N、O或S的杂原子或含基团-C(=O)-或-S(=O)2-作为环成员,
所述R2、R3与其相连的氮原子构成的4-6元杂环为未被取代或被1-2个选自氟、氯、氰基、羟基、氨基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、氟乙基、氰基甲基、氰基乙基、氰基丙基、羟甲基、羟乙基、羟丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基中的取代基所取代,
所述R2、R3与其相连的氮原子构成的6-9元螺环为包含一个氮原子的单螺环。
更有选地,R2和R3分别独立地选自-H、甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、氧杂环丁烷-3-基、四氢呋喃-3-基、四氢吡喃-4-基、四氢吡喃-3-基、N-甲基哌啶-3-基、N-甲基哌啶-4-基、N-甲基吡咯烷-3-基、N-甲基氮(杂)环丁烷-3-基、甲硫基乙基、甲硫基丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、氨基乙酰基、氨基丙酰基、甲磺酰乙基、甲磺酰丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、氰基丙基、甲氨基乙基、二甲氨基乙基、甲氨基丙基、二甲氨基丙基、环丙基甲基、环丙基乙基、三氟甲基、氟乙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、 且R2和R3不同时为甲基,
或R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述4-6元杂环为取代或非取代的杂环,
所述R2、R3与其相连的氮原子构成的取代或非取代的4-6元杂环选自以下环结构:
R4选自–H、甲氨基、乙氨基、二甲氨基,
R5选自-H、甲基、乙基、丙基、异丙基、甲酰基、乙酰基或甲磺酰基,或者氰基甲基、氰基乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、羟甲基、羟乙基、羟丙基,
R6和R7分别独立地选自-H、-F、-CF3、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、氰基甲基、氰基乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、羟甲基、羟乙基、羟丙基,
所述R2、R3与其相连的氮原子构成的6-9元螺环选自以下螺环结构:
更优选地,R2和R3分别独立地选自-H、甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲硫基乙基、甲硫基丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、氨基乙酰基、氨基丙酰基、甲磺酰乙基、甲磺酰丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、氰基丙基、甲氨基乙基、二甲氨基乙基、甲氨基丙基、二甲氨基丙基、环丙基甲基、环丙基乙基、三氟甲基、氟乙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、 且R2和R3不同时为甲基,
或R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述4-6元杂环为取代或非取代的杂环,
所述R2、R3与其相连的氮原子构成的取代或非取代的4-6元杂环选自以下环结构:
R4选自–H、甲氨基、乙氨基、二甲氨基,
R5选自-H、甲基、乙基、丙基、异丙基、甲酰基、乙酰基或甲磺酰基,
R6和R7分别独立地选自-H、-F、-CF3、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、氰基甲基、氰基乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、羟甲基、羟乙基、羟丙基。
根据本发明的一方面,提供如下化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药:
根据本申请的一些具体实施方案,R1为氟、甲基;R2为甲基或乙基;
R3为乙基、丙基、异丙基、环丙基、环丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、氰基丙基、环丙基甲基、环丙基乙基、三氟甲基、氟乙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基。
根据本申请的一些具体实施方案,R1为氟、甲基;
R2、R3与其相连的氮原子构成以下基团:
根据本申请的一些具体实施方案,提供如下化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,所述化合物选自:
根据本申请的一些具体实施方案,提供如下化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药,所述化合物选自:
根据本发明的又一方面,提供一种制备所述化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法,包括以下步骤,其中,R1、R2、R3如前文所述,
PG选自:三甲硅基乙氧基甲基、叔丁氧羰基、苄氧羰基、对甲苯磺酰基、苯磺酰基、乙酰基、三氟乙酰基、芴甲氧羰基、苄基;优选为三甲硅基乙氧基甲基(SEM基)。
具体实施方式
除非另有说明,在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中,除非另外说明,使用“或”或“和”意味着“和/或”。此外,术语“包括”以及其它形式的使用,例如“包含”、“含有”和“具有”,不是限制性的。本文使用的章节标题仅仅是为了组织的目的,而不应解释为对所述的主题的限制。
发明详述
除非有特殊说明,烷基表示具有指定数目碳原子的饱和直链、支链烃基,术语C1-C10烷基表示含有1至10个碳原子的烷基部分,同理C1-C3烷基表示含有1至3个碳原子的烷基部分,比如,C1-C6烷基包括甲基、乙基、丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、n-戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、n-己基、2-己基和2-甲基戊基等。
当取代基术语例如“烷基”与其它取代基术语组合使用时,例如在术语“C1-C3烷氧基C1-C6烷硫基”或“羟基取代C1-C10烷基”中,该连接取代基术语(例如烷基或烷硫基)旨在包含二价的部分,其中连接点通过所述连接取代基。“C1-C3烷氧基C1-C6烷硫基”的实例包括但不限于甲氧基甲硫基、甲氧基乙硫基和乙氧基丙硫基等。“羟基取代C1-C10烷基”的实例包括但不限于羟基甲基、羟基乙基和羟基异丙基等。
烷氧基由先前描述的直链或支链烷基与-O-形成的烷基-O-基团,例如,甲氧基、乙氧基等等。类似的,烷硫基由先前描述的直链或支链烷基与-S-形成的烷基-S-基团,例如,甲硫基,乙硫基等等。
烯基和炔基包括直链、支链烯基或炔基,术语C2-C6烯基或者C2-C6炔基表示具有至少一个烯基或炔基的直链或支链C2-C6烃基。
术语“卤代C1-C3烷基”表示在包括1到3个碳原子的烷基部分的一个或多个碳原子上具有一个或多个可以相同或不同的卤素原子的基团。“卤代C1-C3烷基”的实例可以包括但不限于-CF3(三氟甲基)、-CCl3(三氯甲基)、1,1-二氟乙基、2,2,2-三氟乙基和六氟异丙基等。类似的,术语“卤代C1-C3烷氧基”表示由所述的卤代C1-C3烷基与-O-形成的卤代烷基-O-基团,可以为例如三氟甲氧基、三氯甲氧基等等。
术语“C1-C3酰基”包括甲酰基(-CHO)、乙酰基(CH3CO-)、乙酰基(C2H5CO-)。
“环烷基”表示含有指定数目碳原子的非芳香的、饱和的、环状的烃基。例如,术语“(C3-C6)环烷基”指的是具有3-6个环碳原子的非芳香的环状烃环。示例性的“(C3-C6)环烷基”包括环丙基、环丁基、环戊基和环己基。
术语“芳基”表示包含芳香的单环或双环烃原子团的基团或部分,其含有6到12个碳环原子且具有至少一个芳香环。“芳基”的实例为苯基、萘基、茚基和二氢茚基(茚满基)。通常,在本发明化合物中,芳基为苯基。
在这里使用的术语“杂环烷基”,除非有特殊说明,代表未被取代的或已被取代的稳定的4至7元非芳香的单环饱和环体系,它们由碳原子以及从N,O,S中选的1至3个杂原子组成,其中N,S杂原子可以被随意氧化,N杂原子还可以被随意季铵化。这类杂环的例子包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑烷基、吡唑啉基、咪唑烷基、咪唑啉基、噁唑啉基、噻唑啉基、四氢呋喃基、二氢呋喃基、四氢噻吩基、1,3-二氧杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、二氢吡喃基、四氢噻喃基、1,3-二噁烷基、1,4-二噁烷基、1,3-氧硫杂环戊烷基、1,3-氧硫杂环己烷基、1,3-二噻烷基、1,4-氧硫杂环戊烷基、1,4-氧硫杂环己烷基、1,4-二噻烷基、吗啉基、硫吗啉基。
在这里使用的术语“杂芳基”表示包含芳香的单环或双环原子团(可以含有5到10个环原子)的基团或部分,其包括1到3个独立地选自氮、氧和硫的杂原子。该术语还包括双环杂环芳基,其中含有与杂环烷基环部分稠合的芳基环部分,或者含有与环烷基环部分稠合的杂芳基环部分。除非有特别说明,代表未被取代或已被取代的稳定的5或6元单环芳香环体系,也可以代表未被取代或已被取代的9或10个环原子的苯稠杂芳环体系或二环杂芳环体系,它们由碳原子和由1至3个从N,O,S中选择的杂原子组成,其中N、S杂原子可以被氧化,N杂原子还可以被季铵化。杂芳基可以和任何杂原子或碳原子连接组成一个稳定的结构。杂芳基的示例性实例包括但不限于呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、异噻唑基、吡啶基、氧代-吡啶基(吡啶基-N-氧化物)、哒嗪基、吡嗪基、嘧啶基、三嗪基、苯并呋喃基、异苯并呋喃基、2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、二氢苯并二氧杂环己烯基、苯并噻吩基、吲嗪基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、二氢苯并咪唑基、苯并噁唑基、二氢苯并噁唑基、苯并噻唑基、苯并异噻唑基、二氢苯并异噻唑基、吲唑基、咪唑并吡啶基、吡唑并吡啶基、苯并三唑基、三唑并吡啶基、嘌呤基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、噌啉基、酞嗪基、喹唑啉基、1,5-二氮杂萘基、1,6-二氮杂萘基、1,7-二氮杂萘基、1,8-二氮杂萘基和蝶啶基。
术语“羰基”指的是-C(O)-基。术语“卤素”和“卤”表示氯、氟、溴或碘取代基。“氧代”表示双键的氧部分;例如,如果直接连接到碳原子上形成一个羰基部分(C=O)。“羟基”旨在表示-OH原子团。本文所用术语“氰基”是指基团-CN。
术语“各自独立地”是指当一个以上的取代基选自许多可能的取代基时,那些取代基可以相同或不同。
很清楚,式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本申请中术语“异构体”为具有相同分子式的不同化合物,可以包括立体异构、互变异构等各种异构形式。“立体异构体”是仅原子在空间的排列方式不同的异构体。本文描述的某些化合物含有一个或多个不对称中心,且因此可以产生对映体、非对映体和其他依据绝对立体化学可以被定义为(R)-或(S)-的立体异构形式。本发明的化学实体、药物组合物和方法旨在包括所有这些可能的异构体,包括外消旋混合物、光学纯形式和中间的混合物。旋光(R)-和(S)-异构体可以使用手性合成子或手性试剂来制备,或使用常规技术来拆分。化合物的光学活性可以通过任何合适的方法进行分析,包括但不限于手性色谱法和旋光测定法,且可确定一种立体异构体超越其他异构体的优势程度。
可使用本领域技术人员已知的方法拆分本发明单独的异构体(或异构体富集的混合物)。例如,可如下进行所述拆分:(1)通过形成非对映异构体盐、复合物或其他衍生物;(2)通过与立体异构体特异性试剂的选择性反应,例如通过酶促氧化或还原;或(3)通过在手性环境中的气-液色谱或液相色谱,所述手性环境例如在手性载体上(例如结合有手性配体的硅胶)或在手性溶剂存在下。本领域技术人员将会理解,当将所需立体异构体通过上述分离方法之一转化成另一化学实体时,需要其他步骤来释放所需形式。或者,特异性立体异构体可通过使用光学活性试剂、底物、催化剂或溶剂的不对称合成法来合成,或通过不对称转化将一种对映异构体转化成另一种异构体。
当本文所述的化合物含有烯烃双键时,除非另有说明,其意指该化合物包括各种顺反异构体。
“互变异构体”是可通过互变异构化互相转换的结构上不同的异构体。“互变异构化”是异构化的一种形式,且包括质子移变或质子转移互变异构化,可认为它是酸碱化学的子集。“质子移变互变异构化”或“质子转移互变异构化”涉及伴有键级变换的质子迁移,往往是单键与相邻的双键的互换。当可能发生互变异构化时(例如,在溶液中),可达到互变异构体的化学平衡。互变异构化的一个实例为酮-烯醇互变异构化。
作为活性成分的本发明的化合物,以及制备该化合物的方法,都是本发明的内容。而且,一些化合物的晶型形式可以作为多晶体存在,这种形式也可以被包括在目前的发明里。另外,一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物,这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗,或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用,术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐,此盐适用于人类和低等动物,无过度毒性、刺激性、过敏反应等,具有合理的利益/风险比。胺,羧酸,膦酸盐,和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于,与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐,或通过使用本领域熟知的方法,例如离子交换法,来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵,和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根,低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外,本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化受前体药物在血液中水解或在血液或组织中经酶转化为母体化合物的影响。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子,多肽,抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂;以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用,也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时,治疗剂可以配制成同时给药或顺序地在不同的时间给药,或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”,指的是使用本发明的化合物与另一种药剂一起使用,给药方式为每种药剂同时共同给药或每种药剂顺序给药,无论哪种情况,目的都是要达到药物的最佳效果。共同给药包括同时递送剂型,以及每种化合物分别的单独剂型。因此,本发明的化合物的给药可以与已知的本领域的其他疗法同时使用,例如,在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序;本发明的化合物可以先前施用,同时施用,或在其他抗癌剂或细胞毒性剂之后施用。或者,可以组合使用一个或多个其他疗法,包括手术、放疗(如γ-射线、中子束放射疗法、电子束放射治疗、质子治疗、近距离放射治疗和全身放射性同位素等)、内分泌疗法、生物应答调节剂(例如,干扰素、白介素和肿瘤坏死因子(TNF))、热疗、冷冻疗法、减弱任何不良影响(例如,止吐剂)以及其他的治疗药物。
为了制备这一发明的药学成分,作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起,这是根据传统的制药配料技术而进行的,其中的载体可根据按不同的给药方式(例如,口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到,该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式,比如说,适合口服给药,例如药片,胶囊,药丸,药粉,持续释放的形式,溶液或悬浮液;用于胃肠外注射如透明液,悬浮液,乳状液;或者用于局部用药如膏,霜;亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物,另外,也可以包括其他的医学或药学制剂,载体,辅助剂,等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊,大丸药,药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式,药学合成药可以同动物饲料混合在一起喂给动物,因此,浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗自身免疫疾病和癌症的方法,其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。可被这样治疗的自身免疫疾病、癌症在本文别处会注明,包括具有对Tofacitinib、Peficitinib、Roxolitinib、Decernotinib或其他激酶抑制剂治疗有抗药性的自身免疫疾病、癌症等。
本发明的给药方法包括对需要本发明化合物的受试者确定治疗有效量。“治疗有效剂量”依疾病的阶段、进展或严重程度而不同。本发明的化合物和组合物的每日剂量将取决于患者的多种因素,包括所治疗的病症、该病症的严重程度、所采用的具体化合物的药效、特定组合物、年龄、体重、一般健康状况、性别和饮食、给药的途径和时间表、代谢和/或所述化合物的排泄速率、治疗的持续时间等。此外,本发明的化合物所需剂量与药学上可接受的载体制成药剂后,可施用于人和其他动物。给药模式包括口服、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如通过透皮贴剂、粉剂、软膏、或滴剂)、舌下、经颊、或鼻喷雾等。本发明的化合物的有效剂量通常以每公斤患者体重所施药量来计量,优选于0.1~125毫克/千克体重,一般为0.01~500毫克/千克体重。给药可以是一次或多次、每天、每周、每隔一日或每隔多日、或一个间歇时间表。例如,所述化合物可以每天给药、每周给药(例如,每周一)、无限期给药或延续数周给药(例如4-10周)。本发明的化合物的有效剂量将根据所使用的化合物,给药模式、疾病的严重性、所治疗条件以及相关的患者的各种物理因素而变化。在多数情况下,当本发明的优选化合物的每日剂量约为0.01~500毫克/公斤时,可以达到令人满意的治疗效果。优选剂量为0.1~125毫克/千克,更优选的剂量为1~25毫克/千克。肠胃外给药剂量通常是在大约10%-20%的口服剂量水平。当本发明的化合物被用作组合治疗方案的一部分时,每一个组合物的组分将在一个所需的治疗期间被施用。无论是作为单独的剂量单元或者作为单一剂型包含两种组分,组合物中的组分可以在治疗期中同时施用,也可以在治疗期中的不同时间施用,或者某个可以作为另一个的预处理施用。
本发明还包括本申请所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与酪氨酸激酶EGFR、HER2或ALK突变或过表达相关的癌症及自身免疫疾病的药物中的应用,其中所述癌症及自身免疫疾病包括:眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌中的任一种。
本发明还提供了制备相应化合物的方法,可以使用多种合成方法制备本文所述的化合物,包括下述实施例中所涉及的方法,本发明的化合物或者其药学上可接受的盐,异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法,或通过本领域技术人员理解对这些方法的变化方法合成,优选方法包括但不限于下述方法。
一种典型的制备本发明化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法,包括以下步骤:
其中,R1、R2、R3如前文所定义。所用的保护基除上述结构式中的SEM基,也可以使用其他可以利用的保护基团,例如,叔丁氧羰基、苄氧羰基、对甲苯磺酰基、苯磺酰基、乙酰基、三氟乙酰基、芴甲氧羰基、苄基。
反应条件:
步骤1)中的式(IV)与式(III)所示化合物充分接触得到式(II)所示化合物;
优选地,该反应可在有机溶剂中进行,所述的有机溶剂包含但不限于:N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)、乙二醇二甲醚、异丙醇、正丁醇、2-丁醇(仲丁醇)、叔丁醇的一种或两种以上的组合;
优选地,该反应可在碱的存在下进行,所述的碱包含但不限于:碳酸钾、碳酸钠、醋酸钠、三乙胺、二异丙基乙基胺、三乙烯二胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯或N-甲基吗啉的一种或两种以上的组合;
优选地,该反应可在酸存在下进行,所述的酸包含但不限于:三氟乙酸、对甲苯磺酸;
优选地,该反应可在钯金属催化偶联反应条件下进行,所述的钯金属催化偶联反应条件为常见的Buchward-Hartwig反应所用的钯配体、溶剂及碱;
步骤2)中式(II)所示化合物在四丁基氟化铵存在的条件下得到式(I)所示化合物。
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合具体实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明,除非特别说明,所有的温度为摄氏度。
实施例1.(2-((2-((3-氟-4-(4-((2-羟基-2-甲基丙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺的制备
将1-(2-氟-4-硝基苯基)哌啶-4-酮2.38克(10mmol),2M甲胺的四氢呋喃溶液5毫升(10mmol)置于反应瓶中,加入醋酸硼氢化钠2.11克(10mmol),室温搅拌至反应完毕,加入二氯甲烷与水萃取,有机相浓缩后柱层析得到产品2.02克,产率80%。MS:254[M+H]+.
步骤2)1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇的制备
将1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺2.02克(8mmol),2,2-二甲基环氧乙烷0.72克(10mmol)置于反应瓶中,加入乙醇,加热搅拌至反应完毕,蒸去溶剂后柱层析得产品1.56克,产率60%。MS:326[M+H]+.
步骤3)1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇的制备
将1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇1.56克(4.8mmol),雷尼镍2克置于反应瓶中,加入乙醇,在氢气环境下搅拌至反应完毕,过滤后浓缩得产品1.41克,产率100%。MS:296[M+H]+.
步骤4)(2-((2-((3-氟-4-(4-((2-羟基-2-甲基丙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
将1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇296毫克(1mmol)、(2-((2-氯-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧磷450毫克(1mmol)、对甲苯磺酸17毫克(0.1mmol)置于反应瓶中,加入10毫升仲丁醇,加热搅拌至反应完毕,旋蒸浓缩后柱层析得到产品355毫克,产率50%。MS:710[M+H]+.
步骤5)(2-((2-((3-氟-4-(4-((2-羟基-2-甲基丙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
将(2-((2-((3-氟-4-(4-((2-羟基-2-甲基丙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦355毫克置于反应瓶中,加入三氟乙酸和二氯甲烷的混合溶液,室温搅拌至原料消失后蒸去溶剂,加入甲醇和饱和氢氧化钠水溶液,搅拌至反应完全,乙酸乙酯和水萃取,有机相浓缩柱层析得产品145毫克,产率50%。1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),11.35–11.33(m,1H),9.09(dd,J=8.6,4.2Hz,1H),9.01(s,1H),7.92(dd,J=15.6,2.4Hz,1H),7.61–7.55(m,1H),7.53–7.48(m,1H),7.34(dd,J=8.6,2.4Hz,1H),7.10–7.06(m,1H),6.98–6.93(m,2H),6.38–6.36(m,1H),3.99(s,1H),3.32–3.28(m,2H),2.63–2.56(m,2H),2.48–2.40(m,1H),2.34(s,3H),2.30(s,2H),1.85(s,3H),1.82(s,3H),1.79–1.73(m,2H),1.64–1.54(m,2H),1.08(s,6H).MS:580[M+H]+.
实施例2.(2-((2-((4-(4-(二乙氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)N,N-二乙基-1-(2-氟-4-硝基苯基)哌啶-4-胺的制备
N,N-二乙基-1-(2-氟-4-硝基苯基)哌啶-4-胺的制备参考实施例1的制备步骤1),其中以等摩尔当量的二乙胺替代甲胺的四氢呋喃溶液。MS:296[M+H]+.
步骤2)至步骤4)(2-((2-((4-(4-(二乙氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的N,N-二乙基-1-(2-氟-4-硝基苯基)哌啶-4-胺替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.34(t,J=2.2Hz,1H),9.13–9.05(m,1H),9.01(s,1H),7.98–7.83(m,1H),7.65–7.45(m,2H),7.39–7.29(m,1H),7.12–7.04(m,1H),7.02–6.90(m,2H),6.45–6.31(m,1H),3.32(d,J=11.3Hz,2H),2.82–2.58(m,7H),1.84(d,J=13.5Hz,8H),1.71–1.55(m,2H),1.04(t,J=7.1Hz,6H).MS:550[M+H]+.
实施例3.(2-((2-((3-氟-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
实施例3的制备方法参考实施例1的制备步骤4)和步骤5),其中起始步骤中以等摩尔当量的3-氟-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺替代1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.65–11.63(m,1H),11.34(s,1H),9.12–9.06(m,1H),9.02–8.98(m,1H),7.95–7.88(m,1H),7.61–7.54(m,1H),7.53–7.48(m,1H),7.36–7.31(m,1H),7.08(t,J=7.4,7.4Hz,1H),6.98–6.92(m,2H),6.39–6.35(m,1H),3.29(d,J=11.2Hz,2H),2.61(t,J=12.0,12.0Hz,3H),2.56–2.52(m,2H),2.38–2.23(m,6H),2.15(s,3H),1.85(s,3H),1.84–1.83(m,1H),1.82(s,3H),1.81–1.79(m,1H),1.61–1.52(m,2H).MS:577[M+H]+.
实施例4.(2-((2-((4-(4-((2-羟基-2-甲基丙基)(甲基)氨基)哌啶-1-基)-3-甲基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
实施例4的制备方法参考实施例1的制备步骤1)至步骤5),其中步骤1)中以等摩尔当量的1-(2-甲基-4-硝基苯基)哌啶-4-酮替代1-(2-氟-4-硝基苯基)哌啶-4-酮。
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),11.23(t,J=2.1Hz,1H),9.11(dd,J=8.5,4.3Hz,1H),8.73(s,1H),7.60–7.52(m,3H),7.51–7.45(m,1H),7.09–7.04(m,1H),6.96–6.91(m,2H),6.36(dd,J=3.5,2.0Hz,1H),3.09–3.02(m,2H),2.62–2.51(m,4H),2.41(s,3H),2.39(s,2H),2.25(s,3H),1.85(s,3H),1.82(s,3H),1.78(s,2H),1.67–1.56(m,2H),1.11(s,6H).MS:576[M+H]+.
实施例5.(2-((2-((4-(4-(二甲基氨基)哌啶-1-基)-3-甲基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
实施例5的制备方法参考实施例1的制备步骤4)和步骤5),其中起始步骤中以等摩尔当量的1-(4-氨基-2-甲基苯基)-N,N-二甲基哌啶-4-胺替代1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),11.23(t,J=2.2Hz,1H),9.11(dd,J=8.4,4.2Hz,1H),8.73(s,1H),7.61–7.53(m,3H),7.47(dd,J=8.6,7.0Hz,1H),7.09–7.04(m,1H),6.96–6.91(m,2H),6.36(dd,J=3.5,1.9Hz,1H),3.05(d,J=11.3Hz,2H),2.63–2.56(m,2H),2.35–2.31(m,1H),2.29(s,6H),2.24(s,3H),1.85(s,5H),1.82(s,3H),1.62–1.52(m,2H).MS:518[M+H]+.
实施例6.二甲基(2-((2-((3-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)氧膦的制备
实施例6的制备方法参考实施例1的制备步骤4)和步骤5),其中起始步骤中以等摩尔当量的3-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺替代1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),11.23(d,J=2.2Hz,1H),9.11(dd,J=8.5,4.3Hz,1H),8.73(s,1H),7.60–7.52(m,3H),7.49–7.44(m,1H),7.08–7.04(m,1H),6.96–6.90(m,2H),6.36(dd,J=3.5,1.9Hz,1H),3.04(d,J=11.4Hz,2H),2.63–2.52(m,6H),2.43–2.27(m,5H),2.24(s,3H),2.17(s,3H),1.83(d,J=13.5Hz,8H),1.62–1.52(m,2H).MS:573[M+H]+.
实施例7.(2-((2-((3-氟-4-(4-(4-(2-甲氧乙基)哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)叔-丁基-4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪-1-甲酸酯)的制备
叔-丁基4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪-1-甲酸酯)的制备方法参考实施例1的制备步骤1),其中以等摩尔当量的叔-丁基哌嗪-1-甲酸酯替代甲胺的四氢呋喃溶液。MS:409[M+H]+.
步骤2)1-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪的制备
将叔-丁基-4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪-1-甲酸酯)4.09克(10mmol)置于反应瓶中,加入二氯甲烷40毫升,三氟醋酸10毫升,室温搅拌至反应完毕。旋干反应液,加入饱和碳酸钾溶液重新溶解,二氯甲烷萃取。有机相浓缩后柱层析得产品2.78克,产率90%。
MS:309[M+H]+.
步骤3)1-(1-(2-氟-4-硝基苯基)哌啶-4-基)-4-(2-甲氧基乙基)哌嗪的制备
将1-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪2.78克(9mmol),1-溴-2-甲氧基乙烷1.88克(13.5mmol),碳酸钾2.5克(18mmol),DMF 30毫升置于反应瓶中,加热搅拌至反应完毕。加入饱和食盐水和乙酸乙酯萃取,有机相用饱和食盐水洗涤三次,干燥浓缩得产品2.63克,产率80%。MS:367[M+1]+.
步骤4)至步骤6)(2-((2-((3-氟-4-(4-(4-(2-甲氧乙基)哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤4)至步骤6)参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等摩尔当量的1-(1-(2-氟-4-硝基苯基)哌啶-4-基)-4-(2-甲氧基乙基)哌嗪替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.34(t,J=2.0,2.0Hz,1H),9.09(dd,J=8.4,4.4Hz,1H),9.00(s,1H),7.92(dd,J=15.6,2.4Hz,1H),7.61–7.55(m,1H),7.53–7.48(m,1H),7.34(dd,J=8.8,2.4Hz,1H),7.11–7.06(m,1H),6.98–6.93(m,2H),6.39–6.37(m,1H),3.42(t,J=5.8,5.8Hz,2H),3.31–3.28(m,2H),3.23(s,3H),2.64–2.58(m,2H),2.56–2.51(m,4H),2.50–2.46(m,2H),2.44(t,J=5.8,5.8Hz,4H),2.42–2.38(m,2H),2.29–2.23(m,1H),1.85(s,3H),1.82(s,3H),1.60–1.52(m,2H).MS:621[M+H]+.
实施例8.(2-((2-((3-氟-4-(4-(4-(2-羟乙基)哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)2-(4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪-1-基)乙基-1-醇的制备
2-(4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪-1-基)乙基-1-醇的制备方法参考实施例7的制备步骤3),其中以等摩尔量的2-溴乙醇替代1-溴-2-甲氧基乙烷。MS:353[M+H]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-(4-(2-羟乙基)哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的步骤3)至步骤5),其中起始步骤中以等摩尔当量的2-(4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪-1-基)乙基-1-醇替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.34(t,J=2.2,2.2Hz,1H),9.09(dd,J=8.6,4.2Hz,1H),9.00(s,1H),7.92(dd,J=15.4,2.4Hz,1H),7.61–7.55(m,1H),7.53–7.48(m,1H),7.36–7.32(m,1H),7.10–7.06(m,1H),6.98–6.93(m,2H),6.38–6.37(m,1H),4.36(t,J=5.4,5.4Hz,1H),3.5–3.46(m,2H),3.31–3.27(m,3H),2.64–2.58(m,2H),2.42(s,4H),2.35(t,J=6.4,6.4Hz,3H),2.30–2.23(m,1H),1.88–1.79(m,10H),1.61–1.51(m,2H).MS:607[M+H]+.
实施例9.(2-((2-((4-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-乙基-4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪的制备
1-乙基-4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪的制备参考实施例1的制备步骤1),其中以等摩尔当量的1-乙基哌嗪替代甲胺的四氢呋喃溶液。MS:337[M+H]+.
步骤2)至步骤4)(2-((2-((4-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的1-乙基-4-(1-(2-氟-4-硝基苯基)哌啶-4-基)哌嗪替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.34(t,J=2.2,2.2Hz,1H),9.10(dd,J=8.4,4.2Hz,1H),9.00(s,1H),7.92(dd,J=15.6,2.4Hz,1H),7.61–7.55(m,1H),7.51(t,J=8.0,8.0Hz,1H),7.34(dd,J=8.6,2.4Hz,1H),7.11–7.06(m,1H),6.98–6.93(m,2H),6.39–6.37(m,1H),3.31–3.28(m,2H),2.64–2.58(m,2H),2.56–2.51(m,4H),2.36–2.33(m,4H),2.32–2.26(m,4H),2.26–2.22(m,1H),1.85(s,3H),1.82(s,3H),1.60–1.52(m,2H),0.98(t,J=7.2,7.2Hz,3H).MS:591[M+H]+.
实施例10.(2-((2-((3-氟-4-(4-(4-异丙基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-(1-(2-氟-4-硝基苯基)哌啶-4-基)-4-异丙基哌嗪的制备
1-(1-(2-氟-4-硝基苯基)哌啶-4-基)-4-异丙基哌嗪的制备参考实施例1的制备步骤1),其中以等摩尔当量的1-异丙基哌嗪替代甲胺的四氢呋喃溶液。MS:351[M+H]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-(4-异丙基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的1-(1-(2-氟-4-硝基苯基)哌啶-4-基)-4-异丙基哌嗪替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.34(t,J=2.2,2.2Hz,1H),9.09(dd,J=8.4,4.2Hz,1H),9.00(s,1H),7.92(dd,J=15.6,2.4Hz,1H),7.61–7.55(m,1H),7.53–7.49(m,1H),7.36–7.33(m,1H),7.10–7.06(m,1H),6.98–6.93(m,2H),6.39–6.37(m,1H),3.33–3.25(m,4H),2.64–2.60(m,2H),2.59–2.54(m,2H),2.54–2.51(m,2H),2.49–2.48(m,1H),2.44–2.42(m,4H),2.28–2.21(m,1H),1.85(s,3H),1.82(s,3H),1.60–1.53(m,2H),0.97(s,3H),0.95(s,3H).MS:605[M+H]+.
实施例11.(2-((2-((3-氟-4-(4-(吡咯烷-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
实施例11的制备参考实施例1的制备步骤4)和步骤5),其中起始步骤中以等摩尔量的3-氟-4-(4-(吡咯烷-1-基)哌啶-1-基)苯胺替代1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.35–11.30(m,1H),9.11–9.06(m,1H),9.03(s,1H),7.98–7.91(m,1H),7.61–7.54(m,1H),7.53–7.48(m,1H),7.37–7.33(m,1H),7.10–7.06(m,1H),7.00–6.94(m,2H),6.39–6.36(m,1H),3.35–3.29(m,3H),3.12–3.02(m,4H),2.90–2.80(m,1H),2.69–2.62(m,2H),2.10–2.04(m,2H),1.91–1.86(m,3H),1.85(s,3H),1.81(s,3H),1.73–1.64(m,2H).MS:548[M+H]+.
实施例12.(2-((2-((4-([1,4’-联哌啶]-1’-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
实施例12的制备参考实施例1的制备步骤4)和步骤5),其中起始步骤中以等摩尔量的4-([1,4’-联哌啶]-1’-基)-3氟苯基替代1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.35–11.31(m,1H),9.10–9.06(m,1H),9.02(s,1H),7.96–7.90(m,1H),7.61–7.55(m,1H),7.53–7.48(m,1H),7.37–7.33(m,1H),7.10–7.06(m,1H),7.00–6.95(m,2H),6.38–6.36(m,1H),3.40–3.32(m,3H),2.96–2.90(m,4H),2.68–2.62(m,2H),2.00–1.95(m,2H),1.85(s,3H),1.81(s,3H),1.78–1.71(m,2H),1.70–1.64(m,4H),1.53–1.47(m,2H).MS:562[M+H]+.
实施例13.(2-((2-((3-氟-4-(4-吗啉哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
实施例13的制备参考实施例1的制备步骤4)和步骤5),其中起始步骤中以等摩尔量的3-氟-4-(4-吗啉哌啶-1-基)苯胺替代1-((1-(4-氨基-2-氟苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.35–11.30(m,1H),9.10–9.06(m,1H),9.02(s,1H),7.98–7.88(m,1H),7.61–7.54(m,1H),7.53–7.48(m,1H),7.37–7.32(m,1H),7.10–7.05(m,1H),7.00–6.94(m,2H),6.38–6.36(m,1H),4.05–4.02(m,1H),3.65–3.60(m,3H),3.43–3.32(m,3H),3.31–3.19(m,2H),3.19–2.75(m,1H),2.73–2.56(m,3H),2.28–1.88(m,2H),1.85(s,3H),1.81(s,3H),1.78–1.52(m,2H).MS:564[M+H]+.
实施例14.(2-((2-((3-氟-4-(4-羟基-[1,4’-联哌啶]-1’-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1’-(2-氟-4-硝基苯基)-[1,4’-联哌啶]-4-醇的制备
1’-(2-氟-4-硝基苯基)-[1,4’-联哌啶]-4-醇的制备参考实施例1的制备步骤1),其中以等摩尔当量的4-羟基哌啶替代甲胺的四氢呋喃溶液。MS:324[M+H]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-羟基-[1,4’-联哌啶]-1’-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的1’-(2-氟-4-硝基苯基)-[1,4’-联哌啶]-4-醇替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),11.35–11.30(m,1H),9.11–9.06(m,1H),9.00(s,1H),7.94–7.87(m,1H),7.60–7.48(m,2H),7.36–7.32(m,1H),7.10–7.05(m,1H),6.98–6.93(m,2H),6.38–6.36(m,1H),4.98–4.11(m,1H),3.49–3.42(m,2H),3.33–3.27(m,3H),2.87–2.81(m,2H),2.65–2.57(m,2H),2.46–2.40(m,1H),2.36–2.29(m,2H),1.85(s,3H),1.81(s,3H),1.77–1.72(m,2H),1.66–1.57(m,2H),1.44–1.35(m,2H).MS:578[M+H]+.
实施例15.1’-(4-((4-((2-(二甲基氧磷)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟苯基)-[1,4’-联哌啶]-4-腈的制备
步骤1)1’-(2-氟-4-硝基苯基)-[1,4’-联哌啶]-4-腈的制备
1’-(2-氟-4-硝基苯基)-[1,4’-联哌啶]-4-腈的制备参考实施例1的制备步骤1),其中等摩尔当量的4-氰基哌啶替代甲胺的四氢呋喃溶液。MS:333[M+H]+.
步骤2)至步骤4)1’-(4-((4-((2-(二甲基氧磷)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟苯基)-[1,4’-联哌啶]-4-腈的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的1’-(2-氟-4-硝基苯基)-[1,4’-联哌啶]-4-腈替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),11.34–11.31(m,1H),9.10–9.06(m,1H),8.99(s,1H),7.93–7.88(m,1H),7.60–7.48(m,2H),7.35–7.32(m,1H),7.10–7.05(m,1H),6.97–6.93(m,2H),6.38–6.36(m,1H),3.33–3.27(m,3H),2.88–2.83(m,1H),2.71–2.66(m,2H),2.64–2.58(m,2H),2.47–2.41(m,2H),2.39–2.33(m,1H),1.89–1.86(m,1H),1.85(s,3H),1.81(s,3H),1.80–1.75(m,2H),1.71–1.57(m,4H).MS:587[M+H]+.
实施例16.(2-((2-((3-氟-4-(4-氟-[1,4’-联哌啶]-1’-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)4-氟-1’-(2-氟-4-硝基苯基)-1,4’-联哌啶的制备
4-氟-1’-(2-氟-4-硝基苯基)-1,4’-联哌啶的制备参考实施例1的制备步骤1),其中起始步骤中以等摩尔当量的4-氟哌啶替代甲胺的四氢呋喃溶液。MS:326[M+H]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-氟-[1,4’-联哌啶]-1’-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的4-氟-1’-(2-氟-4-硝基苯基)-1,4’-联哌啶替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),11.42–11.24(m,1H),9.11–9.02(m,1H),8.99(s,1H),7.95–7.85(m,1H),7.60–7.47(m,2H),7.37–7.29(m,1H),7.11–7.03(m,1H),7.00–6.90(m,2H),6.41–6.32(m,1H),3.30–3.27(m,3H),2.72–2.66(m,2H),2.64–2.57(m,2H),2.47–2.43(m,2H),2.42–2.39(m,1H),2.39–2.31(m,1H),1.92–1.87(m,1H),1.84(s,3H),1.81(s,3H),1.79–1.77(m,1H),1.76–1.63(m,3H),1.63–1.52(m,2H).MS:580[M+H]+.
实施例17.(2-((2-((4-(4-(环丙基(甲基)氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)N-环丙基-1-(2-氟-4硝基苯基)-N-甲基哌啶-4-胺的制备
N-环丙基-1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺的制备参考实施例1的制备步骤1),其中以等摩尔当量的N-甲基环丙胺替代甲胺的四氢呋喃溶液。MS:294[M+H]+.
步骤2)至步骤4)(2-((2-((4-(4-(环丙基(甲基)氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的N-环丙基-1-(2-氟-4硝基苯基)-N-甲基哌啶-4-胺替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.33(s,1H),9.09(dd,J=8.5,4.2Hz,1H),9.00(s,1H),7.92(dd,J=15.6,2.4Hz,1H),7.62–7.49(m,2H),7.34(dd,J=8.6,2.4Hz,1H),7.12–7.05(m,1H),6.99–6.94(m,2H),6.38(dd,J=3.5,1.9Hz,1H),3.32–3.28(m,3H),2.67–2.59(m,2H),2.33(d,J=1.8Hz,1H),2.30(s,3H),1.89(s,2H),1.85(s,3H),1.82(s,3H),1.71–1.62(m,2H),0.47(d,J=5.9Hz,2H),0.35–0.29(m,2H).MS:548[M+H]+.
实施例18.(2-((2-((4-(4-(环丁基(甲基)氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)N-环丁基-1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺的制备
N-环丁基-1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺的制备参考实施例1的制备步骤1),其中以等摩尔当量的N-甲基环丁胺替代甲胺的四氢呋喃溶液。MS:308[M+H]+.
步骤2)至步骤4)(2-((2-((4-(4-(环丁基(甲基)氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的N-环丁基-1-(2-氟-4硝基苯基)-N-甲基哌啶-4-胺替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.33(s,1H),9.09(dd,J=8.5,4.2Hz,1H),9.00(s,1H),7.95–7.88(m,1H),7.61–7.48(m,2H),7.34(dd,J=8.8,2.4Hz,1H),7.12–7.05(m,1H),6.99–6.93(m,2H),6.37(dd,J=3.5,1.9Hz,1H),3.31–3.26(m,3H),3.23–3.14(m,1H),2.65–2.57(m,2H),2.09(s,3H),2.02–1.95(m,2H),1.85(s,3H),1.82(s,3H),1.82–1.77(m,2H),1.68–1.57(m,6H).MS:562[M+H]+.
实施例19.(2-((2-((4-(4-(乙基(甲基)氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)N-乙基-1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺的制备
N-乙基-1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺的制备参考实施例1的制备步骤1),其中以等摩尔当量的N-甲基乙胺替代甲胺的四氢呋喃溶液。282[M+H]+.
步骤2)至步骤4)(2-((2-((4-(4-(乙基(甲基)氨基)哌啶-1-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的N-乙基-1-(2-氟-4硝基苯基)-N-甲基哌啶-4-胺替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.33(t,J=2.1Hz,1H),9.09(dd,J=8.6,4.3Hz,1H),9.01(s,1H),7.92(dd,J=15.6,2.4Hz,1H),7.61–7.48(m,2H),7.35(dd,J=8.6,2.4Hz,1H),7.11–7.06(m,1H),7.00–6.94(m,2H),6.38(dd,J=3.5,1.9Hz,1H),2.68–2.57(m,5H),2.52–2.51(m,2H),2.28(s,3H),1.85(s,3H),1.82(s,3H),1.82–1.78(m,2H),1.69–1.58(m,2H),1.04(t,J=7.1Hz,3H).MS:536[M+H]+.
实施例20.(2-((2-((3-氟-4-(4-(甲基(丙基)氨基)哌啶-1-基)-苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-(2-氟-4-硝基苯基)-N-甲基-N-丙基哌啶-4-胺的制备
1-(2-氟-4-硝基苯基)-N-甲基-N-丙基哌啶-4-胺的制备参考实施例1的制备步骤1),其中以等摩尔当量的N-甲基丙-1-胺替代甲胺的四氢呋喃溶液。MS:296[M+H]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-(甲基(丙基)氨基)哌啶-1-基)-苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的1-(2-氟-4-硝基苯基)-N-甲基-N-丙基哌啶-4-胺替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.33(t,J=2.2Hz,1H),9.09(dd,J=8.5,4.2Hz,1H),9.01(s,1H),7.92(dd,J=15.7,2.4Hz,1H),7.62–7.48(m,2H),7.34(dd,J=8.8,2.4Hz,1H),7.11–7.06(m,1H),6.99–6.93(m,2H),6.38(dd,J=3.5,1.9Hz,1H),2.67–2.55(m,3H),2.53–2.51(m,2H),2.48(s,2H),2.29(s,3H),1.85(s,3H),1.82(s,3H),1.80(s,2H),1.70–1.60(m,2H),1.51–1.41(m,2H),0.87(t,J=7.3Hz,3H).MS:550[M+H]+.
实施例21.(2-((2-((3-氟-4-(4-((2-氟乙基)(甲基)氨基)哌啶-1-基)-苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-(2-氟-4-硝基苯基)-N-(2-氟乙基)-N-甲基哌啶-4-胺的制备
将1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺2.53克(10mmol),1-溴-2-氟乙烷1.89克(15mmol),碳酸钾2.78克(20mmol),DMF 30毫升置于反应瓶中,加热搅拌至反应完毕。加入饱和食盐水和乙酸乙酯萃取,有机相用饱和食盐水洗涤三次,干燥浓缩得产品2.40克,产率80%。MS:300[M+1]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-((2-氟乙基)(甲基)氨基)哌啶-1-基)-苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的1-(2-氟-4-硝基苯基)-N-(2-氟乙基)-N-甲基哌啶-4-胺替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.33(t,J=2.2Hz,1H),9.15–9.05(m,1H),9.00(s,1H),7.97–7.86(m,1H),7.62–7.54(m,1H),7.53–7.46(m,1H),7.40–7.28(m,1H),7.17–7.05(m,1H),7.02–6.89(m,2H),6.45–6.29(m,1H),4.55(t,J=5.2Hz,1H),4.43(t,J=5.2Hz,1H),3.33–3.28(m,3H),2.79(t,J=5.2Hz,1H),2.72(t,J=5.2Hz,1H),2.69–2.55(m,2H),2.28(s,3H),1.84(d,J=13.5Hz,6H),1.81–1.72(m,2H),1.67–1.47(m,2H).MS:554[M+H]+.
实施例22.(2-((2-((3-氟-4-(4-((2-羟基乙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)2-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)乙-1-醇的制备
2-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)乙-1-醇的制备参考实施例21的制备步骤1),其中以等摩尔当量的2-溴乙醇替代1-溴-2-氟乙烷。MS:298[M+H]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-((2-羟基乙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5),其中起始步骤中以等当量的2-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)乙-1-醇替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.33(t,J=2.2Hz,1H),9.14–9.04(m,1H),9.00(s,1H),8.01–7.82(m,1H),7.66–7.53(m,1H),7.54–7.46(m,1H),7.38–7.28(m,1H),7.15–7.03(m,1H),7.03–6.86(m,2H),6.48–6.29(m,1H),3.48(t,J=6.4Hz,2H),3.34–3.30(m,5H),2.69–2.61(m,1H),2.57(t,J=6.5Hz,2H),2.28(s,3H),1.84(d,J=13.5Hz,6H),1.81–1.75(m,2H),1.65–1.56(m,2H).MS:552[M+H]+.
实施例23.(2-((2-((3-氟-4-(4-((2-甲氧基乙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤1)1-(2-氟-4-硝基苯基)-N-(2-甲氧基乙基)-N-甲基哌啶-4-胺的制备
1-(2-氟-4-硝基苯基)-N-(2-甲氧基乙基)-N-甲基哌啶-4-胺的制备参考实施例7的制备步骤2),其中以等摩尔当量的1-(2-氟-4-硝基苯基)-N-甲基哌啶-4-胺替代1-(1-(2-氟-4-硝基-苯基)哌啶-4-基)哌嗪。MS:312[M+H]+.
步骤2)至步骤4)(2-((2-((3-氟-4-(4-((2-甲氧基乙基)(甲基)氨基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)苯基)二甲基氧膦的制备
步骤2)至步骤4)的操作参考实施例1的制备步骤3)至步骤5)其中起始步骤中以等当量的1-(2-氟-4-硝基苯基)-N-(2-甲氧基乙基)-N-甲基哌啶-4-胺替代1-((1-(2-氟-4-硝基苯基)哌啶-4-基)(甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.33(s,1H),9.12–9.05(m,1H),9.00(s,1H),7.99–7.86(m,1H),7.65–7.47(m,2H),7.38–7.28(m,1H),7.15–7.02(m,1H),6.99–6.90(m,2H),6.42–6.27(m,1H),3.41(t,J=6.2Hz,4H),3.25(s,3H),2.65–2.58(m,4H),2.45–2.40(m,1H),2.25(s,3H),1.84(d,J=13.5Hz,6H),1.80–1.73(m,2H),1.65–1.54(m,2H).MS:566[M+H]+.
生物活性测试
主要的仪器、试剂和细胞
表1.所用主要的仪器、试剂和细胞
二.试剂配制:
EDTA(0.5M pH8.0)溶液配制:准确称量14.612g EDTA粉末,加入超纯水后定容到100mL(若有不溶加热到37℃,用NaOH溶液调pH至8.0)
1×Kinase Assay Buffer:于试剂瓶中分别加入25mL HEPES溶液(1M)、190.175mgEGTA、5mL MgCl2溶液(1M)、1mL DTT、50μL Tween-20,加超纯水定容到500mL(调pH到7.5)。1×Detection Buffer:取1mL 10×Detection Buffer加入9mL水混匀。
4×终止液:将0.8mL上述EDTA(0.5M、pH 8.0)溶液、1mL 10×Detection Buffer及8.2mL超纯水混匀。
4×EGFR T790M激酶溶液:用1×Kinase Assay Buffer稀释激酶原液到浓度为0.2nM,混匀,冰上保存。
4×底物溶液:用1×Kinase Assay Buffer稀释底物ULightTM-PolyGT原液到400nM,混匀。
4×ATP溶液:用1×Kinase Assay Buffer稀释ATP原液到浓度为20μM,混匀。
4×检测液:用1×Detection Buffer稀释检测抗体Eu-W1024-labeled Anti-Phosphotyrosine Antibody(PT66)到浓度为8nM,混匀。
2×底物/ATP混合液:将4×底物溶液和4×ATP溶液1:1等量混匀(使用前配制)。
实验例1.小分子化合物抑制EGFRT790M激酶活性的测试,测试方法如下:
1)化合物的稀释
在96孔板a中,将浓度为10mM的化合物用DMSO溶液按3倍比例稀释,形成11个梯度,第12个梯度为纯DMSO溶液(作为阳性对照);取一块新的96孔板b,将上述溶液用超纯水稀释25倍(DMSO浓度为4%)。
2)将化合物转盘到384孔板
将上述96孔板b中用超纯水稀释过的化合物溶液按照2复孔的标准转盘到384孔板相应的孔中。
3)加4×激酶溶液:用排枪取2.5μl上述4×激酶溶液加入到384孔板相应的反应孔中,混匀室温预反应5分钟。
4)加2×底物/ATP混合液:用排枪取5μl上述2×底物/ATP混合液到384孔板相应的反应孔中。
5)阴性对照:在384孔板中设置阴性对照孔,每孔加入2.5μl 4×底物、2.5μl 4×酶溶液、2.5μl 1×Kinase Assay Buffer和2.5μl含4%DMSO的超纯水。
6)离心混匀,避光室温反应2小时。
7)终止酶促反应:
吸取5μl上述4×终止液到384孔板相应孔,离心混匀,室温反应5分钟。
8)显色反应:
吸取5μl上述4×检测液加入到384孔板相应孔,离心混匀,室温反应1小时。
9)将384孔板放入读板仪,调取相应的程序检测信号。
10)IC50分析:
孔读值=10000*EU665值/EU615值
抑制率=(阳性对照孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)*100%
将药物浓度和相应抑制率输入GraphPad Prism 5处理可计算出相应的IC50。
实验例2.小分子化合物抑制EGFRL858R-T790M-C797S激酶活性的测试,测试方法如下:
在体外组装的酶促反应中,加入不同浓度的待测化合物,以检测化合物对EGFRT790M-L858R-C797S酶促反应的抑制作用,通过计算EGFRT790M-L858R-C797S酶促反应抑制的IC50来筛选有生化抑制活性的化合物。其测试的具体方法与上述实验例1的方法一致,仅需调整以下条件:1).反应中ATP溶液终浓度为1μM;2).底物ULightTM-PolyGT的终浓度为50nM;3).EGFRL858R-T790M-C797S激酶的终浓度为0.5nM。
表2列出了本申请中部分化合物对EGFRT790M激酶和EGFRL858R-T790M-C797S酪氨酸激酶抑制活性的测定结果。
表2:本发明化合物对EGFRT790M和EGFRL858R-T790M-C797S激酶抑制活性测定结果
实验例3.
小分子化合物抑制Ba/F3EGFR-L858R/T790M及Ba/F3EGFR-L858R/T790M/C797S细胞增殖的测试,具体方法如下:
1)Ba/F3EGFR-L858R/T790M及Ba/F3EGFR-L858R/T790M/C797S细胞用RPMI 1640完全培养基(RPMI 1640基础培养基+10%FBS)培养。
2)将生长状态良好的细胞收集转移至15mL离心管中,以1000rpm离心4分钟。
3)弃去上清液,加入上述完全培养基,吹打均匀,取10μL细胞悬浮液和10μL 0.4%胎盼蓝混匀,用细胞计数仪进行计数,记录细胞数及存活率。
4)每孔接种80μL的细胞悬液到96孔板中(不同细胞接种细胞密度见表3)。
细胞名称 | 培养基 | 接种密度 |
Ba/F3EGFR-L858R/T790M | RPMI 1640+10%FBS | 5000/孔 |
Ba/F3EGFR-L858R/T790M/C797S | RPMI 1640+10%FBS | 5000/孔 |
表3:细胞密度
5)在96孔板a中,将浓度为10mM的化合物用DMSO溶液按3倍比例稀释,形成9个梯度,第10个梯度为纯DMSO溶液(作为阳性对照);取一块新的96孔板b,将上述溶液用RPMI1640完全培养基稀释80倍得到5×化合物溶液(DMSO浓度为1.25%)。
6)在实验孔中加入20μL上述用培养液稀释过的5×化合物溶液,混合摇匀。
7)在含5%CO2的37℃培养箱中培养72小时后每孔加入10μL CCK-8试剂,培养2小时(可以根据颜色深浅来调节反应时间);
8)在多功能读板机于450nm处读其OD值。
9)数据处理:细胞存活率(%)=[(As-Ab)/(Ac-Ab)]*100%
As:实验孔(含有细胞的培养基、CCK-8、化合物)的OD值;
Ac:对照孔(含有细胞的培养基、CCK-8)的OD值;
Ab:空白孔(不含细胞和化合物的培养基、CCK-8)的OD值。
然后将数值导入Graphpad Prism5软件进行曲线拟合,计算IC50。
表4列出了本发明中部分化合物对Ba/F3EGFR-L858R/T790M和Ba/F3EGFR-L858R/T790M/C797S细胞的活性测定结果,其中A表示IC50小于或等于10nM,B表示IC50大于10nM但小于或等于50nM,C表示IC50大于50nM。
表4.本发明部分化合物对细胞活性的测定结果
如前文所述,由于三代EGFR激酶抑制剂在临床上使用一段时间后也产生了耐药现象,而目前市面上还没有针对C797S突变型的EGFR激酶抑制剂,Brigatinib对于C797S突变的EGFR激酶有一定的抑制活性,但并不是很好。
从蛋白质数据库(RCSB Protein Data Bank)中的晶体结构(5J7H)得知,Brigatinib化合物结构中的哌啶环在与ALK蛋白的相互作用中与其相连接的苯环形成了近于90度的二面角。在先前的该类EGFR抑制剂的化合物的分子设计中,出于选择性的目的,基本上都会在哌啶环相连的苯环上相对于哌啶环的间位设计例如烷氧基等取代基。
然而,哌啶环中的氮原子与其相连接的苯环所形成的共轭体系使得哌啶环倾向于与其相连接的苯环形成近于0度的二面角。
如上述化合物结构(A)所示,在苯环的邻位上引入取代集团(诸如甲基等)将有助于哌啶环与苯环之间的转置,使其化合物三维结构更有利于与ALK蛋白形成相互作用。因此,这种结构修饰很有可能会大大增加化合物(A)以及类似化合物对ALK蛋白的生物活性,基于此,化合物(A)以及类似化合物对C797S突变的EGFR的生物活性也将大大提高。基于以上构思,发明人抛弃了常规的间位取代的结构设计,设计并合成了本申请的系列化合物。
实验数据表明,本发明的化合物在苯环(相对于与其相连的哌啶环)的邻位上引入取代基有效地增强了抑制突变型EGFR的细胞的活性,上表中所有化合物(绝大部分IC50值小于50nm,部分化合物的IC50值小于10nm)对EGFR T790M以及C797S突变细胞的抑制活性远远高于Brigatinib(Brigatinib的IC50值分别为189.3和166.6),从而有希望成为第四代EGFR突变介导的非小细胞肺癌候选药物化合物。
以上所述仅为本发明的较佳实施方式而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (13)
1.一种式(I)所示化合物、其异构体、水合物、溶剂化物、药学上可接受的盐及前药,
式(I)中,
R1为卤素、C1-C3烷基;
R2和R3分别独立地为-H、C3-C8环烷基、或由1至3个选自C1-C6烷氧基、C1-C6烷硫基、C1-C3酰基、羟基、卤素、氰基、-CONH2、-S(=O)2CH3、C3-C6环烷基或-NRaRb的取代基所取代或者非取代的C1-C9烷基、含一个氮原子或含一个氧原子的4-6元杂环基,且R2和R3不同时为甲基,
所述含一个氮原子或含一个氧原子的4-6元杂环基为非取代或被C1-C3的烷基所取代,
Ra、Rb分别独立地为H或C1-C3的烷基,
或者,R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述杂环还含1-2个选自N、O或S的杂原子或含基团-C(=O)-或-S(=O)2-作为环成员,
所述R2、R3与其相连的氮原子构成的4-6元杂环为未被取代或被1-2个选自卤素、氰基、羟基、氨基、C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基、氰基取代的C1-C3烷基、羟基取代的C1-C3烷基、C1-C3烷氧基取代的C1-C3烷基所取代,
所述R2、R3与其相连的氮原子构成的6-9元螺环为包含一个氮原子的单螺环。
2.根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐及前药,其中,R1为氟、甲基、乙基。
3.根据权利要求1或2中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐及前药,其中,R2和R3分别独立地为-H、C3-C6环烷基、或由1至3个选自甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲酰基、乙酰基、羟基、氟、氯、氰基、-CONH2、-S(=O)2CH3、环丙基、环丁基、环戊基、环己基、氨基、甲氨基、二甲氨基、乙氨基、二乙氨基、丙氨基、二丙氨基、甲基乙基氨基、甲基丙基氨基的取代基所取代或者非取代的C1-C6烷基,含一个氮原子或含一个氧原子的4-6元杂环基,且R2和R3不同时为甲基,
所述含一个氮原子或含一个氧原子的4-6元杂环基为非取代或被甲基、乙基、丙基、异丙基所取代,
或者,R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述杂环还含1-2个选自N、O或S的杂原子或含基团-C(=O)-或-S(=O)2-作为环成员,
所述R2、R3与其相连的氮原子构成的4-6元杂环为未被取代或被1-2个选自氟、氯、氰基、羟基、氨基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲基、氟乙基、氰基甲基、氰基乙基、氰基丙基、羟甲基、羟乙基、羟丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、丙氧基甲基、丙氧基乙基、丙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基中的取代基所取代,
所述R2、R3与其相连的氮原子构成的6-9元螺环为包含一个氮原子的单螺环。
4.根据权利要求3所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐及前药,其中,R2和R3分别独立地选自-H、甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、氧杂环丁烷-3-基、四氢呋喃-3-基、四氢吡喃-4-基、四氢吡喃-3-基、N-甲基哌啶-3-基、N-甲基哌啶-4-基、N-甲基吡咯烷-3-基、N-甲基氮(杂)环丁烷-3-基、甲硫基乙基、甲硫基丙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、氨基乙酰基、氨基丙酰基、甲磺酰乙基、甲磺酰丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、氰基丙基、甲氨基乙基、二甲氨基乙基、甲氨基丙基、二甲氨基丙基、环丙基甲基、环丙基乙基、三氟甲基、氟乙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、 且R2和R3不同时为甲基,
或R2、R3与其相连的氮原子构成4-6元杂环或6-9元螺环,所述4-6元杂环为取代或非取代的杂环,
所述R2、R3与其相连的氮原子构成的取代或非取代的4-6元杂环选自以下环结构:
R4选自–H、甲氨基、乙氨基、二甲氨基,
R5选自-H、甲基、乙基、丙基、异丙基、甲酰基、乙酰基或甲磺酰基,或者氰基甲基、氰基乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、羟甲基、羟乙基、羟丙基,
R6和R7分别独立地选自-H、-F、-CF3、羟基、氨基、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、氰基甲基、氰基乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、羟甲基、羟乙基、羟丙基,
所述R2、R3与其相连的氮原子构成的6-9元螺环选自以下螺环结构:
6.根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐及前药,其中,R1为氟、甲基;R2为甲基或乙基;
R3为乙基、丙基、异丙基、环丙基、环丁基、甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、乙氧基丙基、异丙氧基甲基、异丙氧基乙基、异丙氧基丙基、羟甲基、羟乙基、羟丙基、氰基甲基、氰基乙基、氰基丙基、环丙基甲基、环丙基乙基、三氟甲基、氟乙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基。
11.一种药物组合物,包括权利要求1至9中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药,以及一种或多种药学上可接受的载体或赋形剂。
12.如权利要求11所述的药物组合物,其中,所述药物组合物还包括一种或多种其他治疗剂。
13.权利要求1至9中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与酪氨酸激酶EGFR、HER2或ALK突变或过表达相关的癌症及自身免疫疾病的药物中的应用,其中所述癌症及自身免疫疾病包括:眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌中的任一种。
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