CN113646314B - Fgfr4激酶抑制剂及其制备方法和用途 - Google Patents
Fgfr4激酶抑制剂及其制备方法和用途 Download PDFInfo
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- CN113646314B CN113646314B CN202080026854.0A CN202080026854A CN113646314B CN 113646314 B CN113646314 B CN 113646314B CN 202080026854 A CN202080026854 A CN 202080026854A CN 113646314 B CN113646314 B CN 113646314B
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- dimethoxyphenyl
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本发明涉及FGFR4激酶抑制剂及其制备方法和用途。本发明涉及式I的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体,及其在制备用来治疗FGFR4介导的疾病的药物中的用途。
Description
交叉引用
本申请要求2019年3月8日提交的专利名称为“FGFR4激酶抑制剂及其制备方法和用途”的第201910178024.9号中国专利申请以及2019年7月5日提交的专利名称为“FGFR4激酶抑制剂及其制备方法和用途”的201910602669.0号中国专利申请的优先权,其全部公开内容通过引用整体并入本文。
技术领域
本发明涉及式I的化合物和式II的化合物及其药物组合物作为FGFR4激酶抑制剂,以及所述化合物和组合物在FGFR4介导的疾病的治疗中的用途。
背景技术
FGFR(fibroblast growth factor receptor)酪氨酸激酶家族包括FGFR1、FGFR2、FGFR3和FGFR4。其由胞外变异区、结合硫酸乙酰肝素蛋白聚糖的保守区、FGF结合区、单次跨膜区及胞内酪氨酸激酶区组成。大部分FGFs在共同受体Klotho的帮助下与FGFRs和肝素形成复合物,导致构象改变的FGFR胞内激酶区自磷酸化而活化STAT3信号通路。自磷酸化的FGFR也可以磷酸化其适配体蛋白FRS2α,活化Grb2/Sos1复合物而启动下游MAPK和PI3K/AKT信号通路。此外,FGFR以FRS2α非依赖的方式活化磷脂酶C-γ(PLC-γ),磷酸化RAF,加强MAPK信号,发挥其调节细胞增殖、分化和转移的功能。MAPK信号通路主要跟FGFR介导的细胞增殖和转移相关,而PI3K/AKT信号通路主要跟细胞的运动性和存活相关。在生理状态下,FGFR4信号通路被严格控制,而FGFR4信号失调导致癌症的发生发展、增殖、存活及转移。
肝细胞癌患者中有约30%的人的肿瘤有异常激活的FGFR4。FGFR4抑制剂在临床前试验和临床试验中都显示出优越的治疗HCC的潜力,而且安全性良好,具有足够的毒性/有效性窗口。
小分子酪氨酸激酶抑制剂通过阻断胞内激酶与ATP结合的活性,阻断细胞增殖信号。FGFR4的小分子抑制剂可分为泛FGFR和FGFR4特异性小分子抑制剂。由于FGFR1、FGFR2、FGFR3激酶域的结构相似,现阶段研发的针对这三个激酶的抑制剂效果相差不大。然而,FGFR4激酶域与FGFR1-3激酶域存在一定差异,因此许多能有效抑制FGFR1-3的抑制剂对FGFR4效果不佳。如CH5183284、BGJ398和AZD4547等进入临床I期或者II期小分子抑制剂对FGFR1-3的选择性(IC50<10nmol/L)远高于FGFR4。而JNJ-42756493和LY2874455是少数对FGFR1-4具有同等高效抑制效果的泛FGFR小分子抑制剂,其IC50均达到个位数纳摩尔级别。JNJ-42756493和LY2874455在细胞中均通过抑制FGF/FGFR信号通路,表现出FGFR依赖性抗增殖作用,对FGFR异常的移植瘤具有极强的抑制作用,且呈剂量效应抑制肿瘤生长。JNJ-42756493的临床I期试验(NCT01962532)结果确定其指导临床II期的用药剂量(RP2D)为10毫克/日(用药7天,停药7天)。LY2874455的临床I期试验(NCT01212107)确定其RP2D为16毫克/日,1日2次。在AZD4547的临床I期试验中(NCT00979134),AZD4547对FGFR基因扩增的鳞状非小细胞肺癌患者显示强肿瘤杀伤活性,且在80mg的剂量下有很好的耐受性。而Ponatinib治疗FGFR异常的晚期肺鳞癌患者的临床II/III期试验(NCT01761747)因不良反应而终止。
缺乏选择性的FGFR激酶抑制剂因脱靶而导致高磷酸盐血症、指甲脱离、脱发、黏膜炎、味觉障碍和黏膜干燥、结膜炎、角膜炎、眼睛干燥、无症状视网膜色素层剥离、骨关节疼痛、肌痛等不良反应,限制其临床应用。
本发明所属化合物,是拥有自主知识产权的FGFR4蛋白激酶抑制剂。其可以高选择性的抑制FGFR4酪氨酸激酶,而对FGFR1-3抑制效果较弱,以期安全,有效的治疗FGFR4高表达的肝癌患者。
发明内容
在一个方面,本发明提供了式I的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体,
其中
X为N或CH;
R0为-O-C1-6烷基;
R1选自H和卤素;
式(I)中的两个R0可以相同或不同,两个R1可以相同或不同;
R2和R3各自独立地选自H和C1-6烷基;
R4选自H、C1-6烷基和-O-C1-6烷基;
R14选自
R6和R8各自独立地选自H和C1-6烷基;或者R6和R8连接在一起形成一个键;
R7选自H、C1-6烷基、-O-C1-6烷基和-NR9R10,其中R9和R10各自独立地选自H和C1-6烷基;
R5选自H、卤素、羟基、C1-6烷基、-NR11R12和-(CH2)n-R13;
R11和R12各自独立地选自H、C1-6烷基和-C1-6亚烷基-NR14R15,其中R14和R15各自独立地选自H和C1-6烷基;
R13为3-12元杂环烷基,并且R13可任选地被Boc、-SO2-C1-6烷基、-SO2-N-(C1-6烷基)2、C1-6烷基、羟基、氨基、氰基、乙酰基、-O-C1-6烷基、-(CH2)n-芳基、-(CH2)n-杂芳基、-(CH2)n-C3-8环烷基、或者-C3-8杂环烷基取代,其中所述-C3-8杂环烷基可任选地被C1-6烷基取代;
n独立地为0或1;
在一些实施方式中,R0为甲氧基;
在一些实施方式中,R1为卤素;
在一些实施方式中,R2和R3为H;
在一些实施方式中,R4为-O-C1-6烷基;
在一些实施方式中,R6和R8为H,或者R6和R8连接在一起形成一个键;
在一些实施方式中,R7为H;
在一些实施方式中,R5为3-12元杂环烷基,所述3-12元杂环烷基可任选地被Boc、-SO2-C1-6烷基、-SO2-N-(C1-6烷基)2、C1-6烷基、乙酰基、-C3-8环烷基、或者-C3-8杂环烷基取代,其中所述-C3-8杂环烷基可任选地被C1-6烷基取代;
在一些实施方式中,本发明的化合物选自:
或其药学上可接受的盐、溶剂化物、多晶型物或异构体。
在本发明的另一个方面,本发明提供了式II的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体,
其中
X为N或CH;
R0为-O-C1-6烷基;
R1选自H和卤素;
式(II)中的两个R0可以相同或不同,两个R1可以相同或不同;
R2和R3各自独立地选自H和C1-6烷基;
R4选自H、C1-6烷基和-O-C1-6烷基;
R6和R8各自独立地选自H和C1-6烷基;或者R6和R8连接在一起形成一个键;
R7选自H、C1-6烷基、-O-C1-6烷基和-NR9R10,其中R9和R10各自独立地选自H和C1-6烷基;
R5选自H、卤素、羟基、C1-6烷基、-NR11R12和-(CH2)n-R13;
R11和R12各自独立地选自H、C1-6烷基和-C1-6亚烷基-NR14R15,其中R14和R15各自独立地选自H和C1-6烷基;
R13为3-12元杂环烷基,并且R13任选地被C1-6烷基、羟基、氨基、氰基、乙酰基、-O-C1-6烷基、-(CH2)n-芳基、-(CH2)n-杂芳基、-(CH2)n-C3-8环烷基、以及-C3-8杂环烷基取代,其中所述-C3-8杂环烷基可任选地被C1-6烷基取代;
n为0或1;
在一些实施方式中,R0为甲氧基;
在一些实施方式中,R1为卤素;在一些实施方式中,R2和R3为H;
在一些实施方式中,R4为-O-C1-6烷基;
在一些实施方式中,R6和R8为H,或者R6和R8连接在一起形成一个键;
在一些实施方式中,R7为H;
在一些实施方式中,R5选自-NR11R12和-(CH2)n-R13,其中
R11和R12各自独立地选自H、C1-6烷基和-C1-6亚烷基-NR14R15,其中R14和R15各自独立地选自H和C1-6烷基,
R13为3-12元杂环烷基,并且R13任选地被C1-6烷基、羟基、氨基、氰基、乙酰基、-O-C1-6烷基、-(CH2)n-芳基、-(CH2)n-杂芳基、-(CH2)n-C3-8环烷基、以及-C3-8杂环烷基取代,其中所述-C3-8杂环烷基可任选地被C1-6烷基取代,
n独立地为0或1;
在一些实施方式中,本发明的化合物选自:
或其药学上可接受的盐、溶剂化物、多晶型物或异构体。
本发明的式I化合物和式II化合物可以用于治疗FGFR4介导的疾病;在一些实施方式中,所述FGFR4介导的疾病为非小细胞肺癌、胃癌、多发性骨髓瘤、肝癌、胆管癌、前列腺癌、皮肤癌、卵巢癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤,优选为肝癌和胆管癌。
本发明另一方面还涉及药物组合物,其包含本发明的式I化合物或式II化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体,以及药学上可接受的载体。
在另一方面,本发明提供了治疗FGFR4介导的疾病的方法,所述方法包含给对象施用有效量的式I化合物或式II化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体、或者上述组合物;在一些实施方式中,所述FGFR4介导的疾病为非小细胞肺癌、胃癌、多发性骨髓瘤、肝癌、胆管癌、前列腺癌、皮肤癌、卵巢癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤,优选为肝癌和胆管癌。
在本发明的一些实施方式中,本发明涉及的所述对象为包括人类的哺乳动物。
在另一方面,本发明提供了式I化合物或式II化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体在制备用来治疗FGFR4介导的疾病的药物中的用途;在一些实施方式中,所述FGFR4介导的疾病为非小细胞肺癌、胃癌、多发性骨髓瘤、肝癌、胆管癌、前列腺癌、皮肤癌、卵巢癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤,优选为肝癌和胆管癌。
发明详述
在下文的发明详述中陈述了利用本发明原理的示例性实施方式。通过参考以下发明内容可更好地理解本发明的特征和优点。
应理解本发明各个方面的保护范围由权利要求书决定,并且这些权利要求范围内的方法和结构以及其等价的方法和结构均在本权利要求书涵盖的范围之内。
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解,上述简述和下文的详述都是示例性的、解释性的,而不是对任何本发明主题的限制。除非另有具体说明,否则使用单数形式时也包括复数。除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
某些化学术语
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情况可能发生也可能不发生,该描述包括发生所述事件或情况和不发生所述事件或情况。例如,“任选取代的烷基”表示“未取代的烷基”或“取代的烷基”。并且,任选取代的基团可以是未取代的(例如:-CH2CH3)、完全取代的(例如:-CF2CF3)、单取代的(例如:-CH2CH2F)或者介于单取代和完全取代之间的任意层级(例如:-CH2CHF2、-CF2CH3、-CFHCHF2等)。本领域技术人员可理解,对于包含一个或多个取代基的任何基团,不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、核磁、高效液相色谱、红外和紫外/可见光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和医药化学的有关术语以及实验步骤和技术是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送、以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用术语“基团”、“化学基团”是指分子的一个特定的部分或官能团。化学基团经常被认作为嵌入或附加到一个分子中的化学实体。
一些在此命名的化学基团可以用简略记号表示碳原子的总个数。例如,C1-C6烷基描述了一个烷基基团,如下定义的那样,具有总共1到6个碳原子。简略记号所示碳原子总个数不包括可能的取代基上的碳原子。
术语“卤素”、“卤代”或“卤化物”是指溴、氯、氟或碘。
本文使用的术语“芳香”、“芳香环”、“芳香的”、“芳香性的”、“芳香环的”是指平面的一个环或多个环的环部分,其具有含4n+2个电子的离域化电子共扼体系,其中n为整数。芳环可由5、6、7、8、9或9个以上的原子形成。芳族化合物可被任选地取代,并可为单环或稠合环的多环。术语芳族化合物包括所有碳环(如苯环)和含一个或多个杂原子的环(如吡啶)。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子。杂原子独立地选自氧、氮、硫、磷、硅、硒和锡,但不限于这些原子。在出现两个或更多杂原子的实施方案中,所述两个或更多杂原子可彼此相同,或者所述两个或更多杂原子中的一些或全部彼此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
本文单独或作为其它组分的一部分(比如:单烷基氨基)使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃,其具有1-12个碳原子,优选1-8个碳原子,更优选1-6个碳原子,通过单键与分子的其它部分相连,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、正庚基、2-甲基己基、3甲基己基、正辛基,正壬基、正癸基等。
本文单独或组合使用的术语“亚烷基”是指由上述定义的一价烷基衍生的二价基团。实例包括但不限于亚甲基(-CH2)、亚乙基(-CH2CH2)、亚丙基(-CH2CH2CH2)和异亚丙基(-CH(CH3)CH2)等。
本文单独或作为其它成分的一部分使用的术语“环烷基”是指稳定的单价非芳香单环或多环碳氢基团,只包含碳原子和氢原子,可能包括稠环、螺环或桥环系统,包含3-15个成环碳原子,优选包含3-10个成环碳原子,更优选包含3-8个成环碳原子,可饱和也可不饱和,通过单键与分子的其它部分相连。“环烷基”的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基和环庚基等。
本文单独或作为其它成分的一部分使用的术语“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环,包括2-12个碳原子,1-6个选自氮、氧和硫的杂原子。除非另作说明,杂环基基团可以是单环、双环、三环或四环系统,其可能包含稠环、螺环或桥环系统,杂环基上的氮、碳或硫可选择性的被氧化,氮原子可选择性的被季铵化,杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环,只要与分子的其余部分连接的是非芳香环上的原子。为了本申请,杂环基优选的是一个稳定的4-11元单价非芳香单环或二环,其包含1-3个选自氮、氧和硫的杂原子,更优选的是一个稳定的4-8元单价非芳香单环,其包含1-3个选自氮、氧和硫的杂原子。杂环基的的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。
本文单独或作为其它成分的一部分使用的术语“芳环”、“芳环基”、“芳香基”、“芳基”或前缀“芳”(比如在“芳烷基”中)是指碳氢环状系统,其含有氢,6-18个成环碳原子,优选6-10个成环碳原子,和至少一个芳香性的环。为本发明考虑,芳环基可以是单环、双环、三环或四环系统,其可能包含稠环或桥环系统。芳基碳原子可以通过单键跟分子的其它部分连接。芳基的非限定性实例包括苯基、奈基、蒽基、菲基、芴基等。本发明中,芳基优选的为C6-C10的芳基,更优选的为苯基。
本文单独或作为其它成分的一部分使用的术语“杂芳基”是指5-16元环状系统,其包含1-15个碳原子,优选的1-10个碳原子,1-4个选自氮、氧和硫的杂原子,至少一个芳香环。除非另作说明,杂芳基可以是单环、双环、三环或四环系统,其可能包含稠环或桥环系统,只要与分子其它部分的连接点为芳环原子。杂芳环上的氮原子、碳原子和硫原子可以选择性的被氧化,氮原子可选择性的被季铵化。为了本发明,杂芳基优选的为稳定的4-11元单芳香环,其包含1-3个选自选自氮、氧和硫的杂原子,更优选的为稳定的5-8元单芳香环,其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、苯并二氧芑基、苯并二噁茂基、苯并呋喃酮基、苯并呋喃基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并三唑基、呋喃基、咪唑基、吲唑基、吲哚基、恶唑基、嘌呤基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、奎宁基、四唑基、噻二唑基、噻唑基、噻吩基、三嗪基、三唑基等。本申请中,杂芳基优选为5-8元杂芳基,其包含1-3个选自选自氮、氧和硫的杂原子,更优选为吡啶基、嘧啶基、噻唑基。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶格形态。本发明的一些化合物可能有一个以上的晶体形式,本发明涵盖所有的多晶型态或其混合物。
本发明化合物的中间体化合物及其多晶形物也在本发明的范围内。
除非另有指定,本发明化合物所含有的烯烃双键包括E和Z异构体。
应理解,本发明化合物可能含有不对称中心。这些不对称中心可以独立的为R或S构型。一些本发明化合物也可显示出顺-反异构现象,这对于本领域技术人员而言是显而易见的。应理解,本发明化合物包括它们的单独的几何异构体和立体异构体以及它们的混合物,包括外消旋混合物。通过实施或修改已知方法,例如层析技术和重结晶技术可以从它们的混合物中分离这些异构体,或者可以由它们的中间体的合适的异构体分别制备它们。
本文所用术语“药学上可接受的盐”既包括加酸盐,也包括加碱盐。
“药学上可接受的加酸盐”是指那些保留了化合物的游离碱的生物效力和特性、在生物学上或其它方面并非不合需要、跟无机酸,例如但是不限于,氢氯酸、氢溴酸、硫酸、硝酸、磷酸等,或有机酸,例如但不限于,乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、癸酸、己酸、碳酸、肉桂酸、柠檬酸等形成的盐。“药学上可接受的加碱盐”是指那些保留了化合物的游离酸的生物效力和特性、在生物学上或其它方面并非不合需要的盐。这些盐通过游离酸跟无机碱或有机碱反应制备。通过跟无机碱反应生成的盐包括,但不限于,钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐、和锰盐。
形成盐的有机碱包括,但不限于,伯胺、仲胺、叔胺、环胺等,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、哌嗪、哌啶、胆碱和咖啡因等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
结晶经常产生本发明化合物的溶剂化物。本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合而成的合体。
溶剂可以是水,这种情况下,溶剂化物是水合物。另外还可以是有机溶剂。因此,本发明化合物可作为水合物存在,包括一水合物、二水合物、半水合物、三水合物、四水合物等,以及相应的溶剂化形态。本发明化合物可以是真溶剂化物,但在其它一些情况下,本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物。本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本文所用术语“药物组合物”是指混合有本发明化合物和通常在本领域被接受的用来将具有生物活性的化合物传送给哺乳动物(比如人类)的介质的制剂。这种介质包含所有药学上可接受的载体。
本文所用的跟制剂、组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂、或乳化剂。
本文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体,包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员:人,非人的灵长类动物(例如黑猩猩和其它猿类和猴);家畜,例如牛、马、绵羊、山羊、猪;家养动物,例如兔、狗和猫;实验室动物,包括啮齿类动物,例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中,所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病或病症的治疗,包括
(i)预防哺乳动物,特别是之前已经暴漏在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物,产生相应的疾病或病症;
(ii)抑制疾病或病症,即,控制其发展;
(iii)缓解疾病或病症,即,使疾病或病症消退;
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代,也可以是不同意思,因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚),所以还不能被认作疾病而只能被看做不想要的状况或综合症,所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本发明化合物的制备
下述非限制性实施例仅仅是说明性的,不以任何方式限制本发明。
除非另有说明,否则温度是摄氏温度。试剂购自国药集团化学试剂北京有限公司,阿法埃莎(Alfa Aesar),或北京百灵威科技有限公司等商业供应商,并且这些试剂可直接使用无需进一步纯化,除非另有说明。
除非另有说明,下列反应在室温、无水溶剂中、氮气或氩气的正压下或使用干燥管进行;玻璃器皿烘干和/或加热干燥。
除非另有说明,柱色谱纯化使用青岛海洋化工厂的200-300目硅胶;制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254);MS的测定用ThermoLCQ Fleet型(ESI)液相色谱-质谱联用仪。
核磁数据(1H NMR)使用Varian设备于400MHz运行。核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMSO-d6等,以四甲基硅烷(0.00ppm)为基准或以残留溶剂为基准(CDCl3:7.26ppm;CD3OD:3.31ppm;D2O:4.79ppm;d6-DMSO:2.50ppm)。当标明峰形多样性时,以下简写表示不同峰形:s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数,则以Hertz(Hz)为单位。
具体实施方式
在以下的实施例中提供了本发明的示例性的实施方案。以下的实施例仅通过示例的方式给出,并用于帮助普通技术人员使用本发明。所述实施例并不能以任何方式来限制本发明的范围。
实施例1
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)苯基)丙烯酰胺
步骤1:化合物3的合成
向化合物1(2g)的N-甲基吡咯烷酮(15mL)溶液中加入化合物2(2.49g)和碳酸钾(5.29g)。将反应液加热至100℃反应过夜。将反应液冷却至室温,并倒入到水中。过滤,滤饼用蒸馏水洗涤并干燥,获得化合物3(3.58g)。
步骤2:化合物4的合成
于-20℃下,向化合物3(3.58g)的THF(100mL)溶液中滴加磺酰氯(2.3mL)。反应液于该温度下继续搅拌2小时。用饱和碳酸氢钠水溶液淬灭反应。静置分层,分取有机相。所得水相用乙酸乙酯萃取。合并有机相,无水硫酸钠干燥,并减压浓缩。所得残留物通过快速柱层析纯化(二氯甲烷/甲醇=100/1),获得化合物4(3.24g)。
步骤3:化合物5的合成
向化合物4(3.24g)的乙醇(18mL)溶液中加入氯乙醛(18mL)。反应液加热至80℃并反应过夜。将反应液倒入水中并过滤。将所获得的固体干燥,获得化合物5(3.1g)。
步骤4:化合物7的合成
在氮气保护下,向化合物5(1.23g)的二氧六环/水(20mL/5mL)溶液中加入四(三苯基磷)钯(500mg)、化合物6(1.5g)和无水碳酸钠(1.5g)。将反应液加热至80℃并反应过夜。将反应液降至室温,减压浓缩,所得残留物通过快速硅胶柱层析(二氯甲烷/甲醇=500/1)进行分离纯化,获得化合物7(1.12g)。
步骤5:化合物8的合成
向化合物7(200mg)的DMF(1mL)溶液中加入无水碳酸铯(120mg)和吗啉(0.1mL),并加热至60℃反应过夜。将反应液降至室温,减压浓缩。所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷/甲醇=100/1至50/1),获得化合物8(120mg)。
步骤6:化合物9的合成
向化合物8(120mg)的四氢呋喃(5mL)溶液中加入钯碳(50mg),并将体系置换氢气。反应体系于室温下反应过夜,并通过硅藻土过滤。将滤液减压浓缩获得化合物9(71mg)。
步骤7:化合物10的合成
在冰浴下,向化合物9(71mg)的二氯甲烷(2mL)溶液中加入DIEA(5μL)和丙烯酰氯(11μL)。反应液于冰浴下搅拌2h,加入甲醇淬灭反应并减压浓缩。所得残留物通过制备薄层色谱(二氯甲烷/甲醇=30/1)分离纯化获得化合物10(35mg)。1H NMR(400MHz,CDCl3),9.21(1H,s),9.00(1H,s),8.35(1H,s),8.22(1H,s),8.12(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.50(1H,s),6.81(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.91-3.95(5H,m),3.68(2H,s),2.85-2.99(4H,m),1.87(2H,t,J=7.2Hz),1.78-1.83(4H,m)。
实施例2
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)苯基)丙烯酰胺
实施例2的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.12(1H,s),8.41(1H,s),8.11(1H,s),8.01(1H,s),7.68(1H,s),7.46(1H,s),7.22(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.31(1H,dd,J=16.8Hz,10.8Hz),6.09(1H,s),5.78(1H,d,J=10.8Hz),3.97(6H,s),3.94(3H,s),3.77(4H,s),3.60-3.67(4H,m),1.77-1.83(4H,m)。
实施例3
N-(2-(8-环丙基-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例3的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.20(1H,s),8.95(1H,s),8.42(1H,s),8.37(1H,s),8.13(1H,s),7.69(1H,s),7.49(1H,s),7.02-7.13(1H,brs),6.70(1H,s),6.45(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.78(1H,d,J=10.0Hz),3.96(6H,s),3.88(3H,s),3.21-3.78(4H,m),2.79(2H,d,J=10.4Hz),2.20-2.38(2H,m),1.97-2.18(3H,m),0.81-0.91(2H,m),0.56-0.70(2H,m)。
实施例4
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)苯基)丙烯酰胺
实施例4的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.20(1H,s),8.87(1H,s),8.37(1H,s),8.15(1H,s),8.12(1H,d,J=1.6Hz),7.68(1H,d,J=1.6Hz),7.49(1H,s),6.79(1H,s),6.70(1H,s),6.43(1H,d,J=17.2Hz),6.30(1H,dd,J=17.2Hz,10.0Hz),5.76(1H,d,J=10.0Hz),3.88-4.01(11H,m),3.76(2H,d,J=10.0Hz),3.17-3.24(2H,m),2.96-3.07(4H,m)。
实施例5
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-氧杂-7-氮杂螺[2.5]辛烷-7-基)苯基)丙烯酰胺
实施例5的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.20(1H,s),9.01(1H,s),8.37(2H,s),8.12(1H,s),7.69(1H,s),7.49(1H,s),6.88(1H,s),6.70(1H,s),6.44(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.8Hz),5.78(1H,d,J=10.8Hz),3.90-4.01(11H,m),3.10(2H.t,J=7.2Hz),2.87(2H,s),0.91-0.99(2H,m),0.58-0.66(2H,m)。
实施例6
N-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例6的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.19(1H,s),8.85(1H,s),8.38(1H,s),8.12(1H,s),7.84(1H,s),7.68(1H,s),7.49(1H,s),6.70(1H,s),6.61(1H,s),6.43(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.4Hz),5.78(1H,d,J=10.4Hz),3.88-3.98(11H,m),3.75(2H,d,J=10.8Hz),3.62-3.65(2H,m),2.01-2.18(4H,m)。
实施例7
N-(2-(8-乙酰基-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例7的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.36(1H,s),8.32(1H,s),8.12(1H,d,J=1.6Hz),7.69(1H,d,J=1.6Hz),7.50(1H,s),6.86(1H,s),6.70(1H,s),6.46(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8Hz,10.0Hz),5.80(1H,d,J=10.0Hz),4.85-4.90(1H,m),4.24-4.28(1H,m),3.97(6H,s),3.90(3H,s),3.21(1H,d,J=9.6Hz),2.93-3.01(2H,m),2.85(1H,d,J=9.6Hz),1.98-2.28(7H,m)。
实施例8
N-(2-(3-环丙基-3,8-二氮杂双环[3.2.1]辛烷-8-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例8的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.01(1H,s),8.41(1H,s),8.27(1H,s),8.09(1H,s),7.49(1H,s),7.40(1H,s),6.63(1H,s),6.51(1H,s),6.19-6.33(2H,m),5.67(1H,d,J=10.0Hz),3.97(3H,s),3.86(6H,s),3.57-3.63(2H,m),3.19-3.24(1H,m),2.76(2H,d,J=10.8Hz),2.54(2H,d,J=10.8Hz),1.68-1.83(4H,m),0.29-0.36(2H,m),0.19-0.25(2H,m)。
实施例9
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4,7-二氮杂螺[2.5]辛烷-7-基)苯基)丙烯酰胺三氟乙酸盐
实施例9的合成方法与实施例1的合成方法相同。1H NMR(400MHz,DMSO),9.44(2H,s),9.32(1H,s),9.28(1H,s),8.79(1H,s),8.73(1H,s),8.34(1H,s),7.80(1H,s),7.68(1H,s),7.08(1H,s),6.88(1H,s),6.62(1H,dd,J=16.8Hz,10.0Hz),6.23(1H,d,J=16.8Hz),5.75(1H,d,J=10.0Hz),3.99(6H,s),3.96(3H,s),3.39-3.48(2H,m),3.23-3.32(2H,m),3.05(2H,s),1.06-1.12(2H,m),0.83-0.90(2H,m)。
实施例10
N-(2-(4-环丙基-4,7-二氮杂螺[2.5]辛烷-7-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例10的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.20(1H,s),8.99(1H,s),8.47(1H,s),8.35(1H,s),8.12(1H,s),7.69(1H,s),7.49(1H,s),6.90(1H,s),6.70(1H,s),6.43(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.0Hz),5.78(1H,d,J=10.0Hz),3.97(6H,s),3.90(3H,s),3.02-3.21(4H,m),2.63-2.85(2H,m),1.95-2.15(1H,m),1.02-1.16(2H,m),0.40-0.61(6H,m)。
实施例11
N-(2-(4-乙酰基-4,7-二氮杂螺[2.5]辛烷-7-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例11的合成方法与实施例1的合成方法相同。1H NMR(400MHz,DMSO),9.28(1H,s),9.22(1H,s),8.72(1H,d,J=1.2Hz),8.70(1H,s),8.32(1H,s),7.72(1H,s),7.60(1H,d,J=1.2Hz),7.07(1H,s),6.95(1H,s),6.57(1H,dd,J=16.8Hz,10.4Hz),6.23(1H,dd,J=16.8Hz,1.6Hz),5.75(1H,d,J=10.4Hz),3.67-4.05(11H,m),2.65-3.12(4H,m),2.13(2.4H,s),2.03(0.6H,s),0.78-1.06(4H,m)。
实施例12
N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)乙烯基磺酰胺
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实施例12的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.20(1H,s),8.39(1H,s),8.11(2H,s),7.70(1H,s),7.49(1H,s),7.40-7.47(1H,brs),6.93(1H,s),6.70(1H,s),6.66(1H,dd,J=16.4Hz,9.6Hz),6.42(1H,d,J=16.4Hz),6.01(1H,d,J=9.6Hz),3.98(6H,s),3.89(3H,s),3.63-3.69(1H,m),2.84-3.14(4H,m),1.66-1.92(4H,m),0.80-0.90(2H,m),0.56-0.66(2H,m)。
实施例13
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-(4-(N,N-二甲基磺酰胺基)哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺
实施例13的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.36(1H,s),8.12(2H,s),7.69(1H,s),7.50(1H,s),6.84(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.4Hz),5.78(1H,d,J=10.4Hz),3.97(6H,s),3.92(3H,s),3.43-3.48(4H,m),3.01-3.06(4H,m),2.90(6H,s)。
实施例14
N-(2-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例14的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.07(1H,s),8.39(1H,s),8.10(1H,s),7.95(1H,s),7.70-7.82(1H,brs),7.65(1H,s),7.43(1H,s),6.68(1H,s),6.36-6.44(2H,m),5.99-6.04(1H,m),5.70-5.75(1H,m),3.95(6H,s),3.90(3H,s),3.69-3.81(4H,m),3.48-3.55(2H,m),3.29-3.38(2H,m),2.06(3H,s),1.69-1.80(4H,m)。
实施例15
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-(7,7-二氧代-7-硫代-2-氮杂螺[3.5]壬烷-2-基)-4-甲氧基苯基)丙烯酰胺
实施例15的合成方法与实施例1的合成方法相同。1H NMR(400MHz,DMSO),9.39(1H,s),9.20(1H,s),8.67(1H,s),8.66(1H,s),7.88(1H,s),7.66(1H,s),7.58(1H,s),7.06(1H,s),6.46(1H,dd,J=16.8Hz,10.4Hz),6.20(1H,dd,J=16.8Hz,1.6Hz),6.15(1H,s),5.69(1H,dd,J=10.4Hz,1.6Hz),3.98(6H,s),3.95(3H,s),3.80(4H,s),3.08-3.13(4H,m),2.17-2.23(4H,m)。
实施例16
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(1-氧杂-8-氮杂螺[4.5]癸烷-8-基)苯基)丙烯酰胺
实施例16的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.20(1H,s),8.99(1H,s),8.36(1H,s),8.31(1H,s),8.12(1H,s),7.68(1H,s),7.49(1H,s),6.90(1H,s),6.70(1H,s),6.41(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8Hz,10.4Hz),5.75(1H,d,J=10.4Hz),3.97(6H,s),3.91(2H,t,J=6.8Hz),3.90(3H,s),3.07-3.13(2H,m),2.85-2.92(2H,m),1.99(2H,qui,J=6.8Hz),1.77-1.91(6H,m)。
实施例17
N-(2-(7-环丙基-2,7-二氮杂螺[3.5]壬烷-2-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例17的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.04(1H,s),9.38(1H,s),8.24(1H,s),8.09(1H,s),7.94(1H,s),7.63(1H,s),7.40(1H,s),6.67(1H,s),6.49(1H,dd,J=16.8Hz,10.0Hz),6.38(1H,d,J=16.8Hz),6.01(1H,s),5.70(1H,d,J=10.0Hz),3.93(6H,s),3.89(3H,s),3.74(4H,s),2.62-2.98(4H,m),1.89-2.06(5H,m),0.79-0.88(2H,m),0.55-0.64(2H,m)。
实施例18
N-(2-(6-环丙基-2,6-二氮杂螺[3.4]辛烷-2-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例18的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.10(1H,s),8.41(1H,s),8.11(1H,s),7.99(1H,s),7.60-7.75(2H,m),7.44(1H,S),6.69(1H,s),6.38-6.45(2H,m),6.07(1H,s),5.74-5.77(1H,m),3.88-4.09(11H,m),2.92-3.24(4H,m),2.16-2.25(2H,m),1.88-2.06(3H,m),0.80-0.90(2H,m),0.53-0.62(2H,m)。
实施例19
N-(2-(9-环丙基-3,9-二氮杂螺[5.5]十一烷-3-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例19的合成方法与实施例1的合成方法相同。1H NMR(400MHz,DMSO),9.27(1H,s),9.09(1H,s),8.70(1H,s),8.69(1H,s),8.40(1H,s),7.70(1H,s),7.59(1H,s),7.06(1H,s),6.85(1H,s),6.65(1H,dd,J=16.8Hz,10.4Hz),6.22(1H,d,J=16.8Hz),5.71(1H,d,J=10.4Hz),3.98(6H,s),3.94(3H,s),2.88-2.96(4H,m),1.36-2.02(13H,m),0.96-1.12(2H,m),0.66-0.86(2H,m)。
实施例20
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(2-氧杂-6-氮杂螺[3.4]辛烷-6-基)苯基)丙烯酰胺
实施例20的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.14(1H,s),8.41(1H,s),8.35(1H,s),8.11(1H,s),7.68(1H,s),7.47(1H,s),7.42(1H,s),6.70(1H,s),6.51(1H,s),6.42(1H,d,J=16.4Hz),6.29(1H,dd,J=16.4Hz,10.0Hz),5.77(1H,d,J=10.0Hz),4.64-4.71(4H,m),3.97(6H,s),3.94(3H,s),3.55(2H,s),3.33(2H,t,J=7.2Hz),2.27(2H,t,J=7.2Hz)。
实施例21
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(3-氧杂-9-氮杂螺[5.5]十一烷-9-基)苯基)丙烯酰胺
实施例21的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.20(1H,s),8.99(1H,s),8.36(1H,s),8.21(1H,s),8.12(1H,d,J=1.6Hz),7.69(1H,d,J=1.2Hz),7.50(1H,s),6.86(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.4Hz),5.77(1H,d,J=10.4Hz),3.97(6H,s),3.92(3H,s),3.71-3.75(4H,m),2.90-2.95(4H,m),1.74-1.79(4H,m),1.61-1.66(4H,m)。
实施例22
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-yl)-4-甲氧基-2-(7-甲基-2,7-二氮杂螺[4.4]壬烷-2-基)苯基)丙烯酰胺
实施例22的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.08(1H,s),8.42(1H,s),8.11(1H,s),8.09(1H,s),7.66(1H,s),7.44(1H,s),6.67-6.71(2H,m),6.49-6.61(1H,m),6.41(1H,d,J=16.8Hz),6.36(1H,s),5.73(1H,d,J=10.8Hz),3.93-4.01(13H,m),3.37-3.56(4H,m),2.81(3H,s),1.99-2.26(4H,m)。
实施例23
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-甲基-4,7-二氮杂螺[2.5]辛烷-7-基)苯基)丙烯酰胺
实施例23的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),9.02(1H,s),8.44(1H,s),8.36(1H,s),8.12(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.50(1H,s),6.90(1H,s),6.70(1H,s),6.44(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.78(1H,d,J=10.0Hz),3.98(6H,s),3.93(3H,s),3.09-3.13(2H,m),3.02-3.08(2H,m),2.67-2.78(2H,m),2.46(3H,s),0.84-0.90(2H,m),0.49-0.52(2H,m)。
实施例24
N-(2-(5-环丙基六氢吡咯并[3,4-c]吡咯-2(1H)-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例24的合成方法与实施例1的合成方法相同。1H NMR(400MHz,DMSO),9.25(1H,s),9.05(1H,s),8.70(2H,s),8.17(1H,s),7.69(1H,s),7.59(1H,s),7.06(1H,s),6.61-6.74(2H,m),6.21-6.30(1H,m),5.69-5.78(1H,m),3.94-4.01(9H,m),3.54-3.63(4H,m),3.06-3.14(4H,m),2.90-3.02(3H,m),1.20-1.30(2H,m),0.74-0.84(2H,m)。
实施例25
N-(2-(8-环丙基-2,8-二氮杂螺[4.5]癸烷-2-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例25的合成方法与实施例1的合成方法相同。1H NMR(400MHz,DMSO),9.52(1H,s),9.20(1H,s),8.68(1H,s),8.66(1H,s),7.91(1H,s),7.66(1H,s),7.58(1H,s),7.06(1H,s),6.38-6.51(2H,m),6.19(1H,d,J=16.8Hz),5.70(1H,d,J=10.4Hz),3.99(3H,s),3.98(6H,s),3.38-3.54(4H,m),3.14-3.30(4H,m),2.76-2.94(1H,m),1.69-1.91(4H,m),1.39-1.62(2H,m),0.96-1.12(2H,m),0.69-0.87(2H,m)。
实施例26
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(2-氧杂-7-氮杂螺[4.4]壬烷7-基)苯基)丁-2-炔酰胺
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实施例26的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.15(1H,s),8.40(1H,s),8.15(1H,s),8.11(1H,s),7.68(1H,s),7.62(1H,s),7.46(1H,s),6.70(1H,s),6.42(1H,s),3.89-3.97(11H,m),3.75(1H,d,J=8.4Hz),3.67(1H,d,J=8.4Hz),3.44-3.49(2H,m),3.34(1H,d,J=9.2Hz),3.30(1H,d,J=9.2Hz),1.88-2.03(7H,m)。
实施例27
N-(2-((1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丁-2-炔酰胺
实施例27的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.16(1H,s),8.39(1H,s),8.26(1H,s),8.11(1H,s),7.68(1H,s),7.53(1H,s),7.47(1H,s),6.70(1H,s),6.49(1H,s),4.65(1H,s),4.29(1H,s),4.10(1H,d,J=8.0Hz),3.97(6H,s),3.93(3H,s),3.87(1H,d,J=8.0Hz),3.49(1H,d,J=9.2Hz),3.49(1H,d,J=9.2Hz),1.96-2.06(5H,m)。
实施例28
N-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丁-2-炔酰胺
实施例28的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.19(1H,s),8.67(1H,s),8.34(1H,s),8.11(1H,s),7.88(1H,s),7.68(1H,s),7.49(1H,s),6.70(1H,s),6.60(1H,s),3.93-4.01(8H,m),3.89(3H,s),3.76-3.79(2H,m),3.64-3.68(2H,m),2.01-2.17(7H,m)。
实施例29
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-吗啡啉苯基)丁-2-炔酰胺
实施例29的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.80(1H,s),8.33(1H,s),8.25(1H,s),8.12(1H,s),7.68(1H,s),7.49(1H,s),6.84(1H,s),6.70(1H,s),3.96(6H,s),3.89-3.95(7H,m),2.95-2.98(4H,m),2.03(3H,s)。
实施例30
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-(1,1-二氧代硫代吗啉)-4-甲氧基苯基)丁-2-炔酰胺
实施例30的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.22(1H,s),8.74(1H,s),8.33(1H,s),8.12(1H,s),7.96(1H,s),7.70(1H,s),7.51(1H,s),6.87(1H,s),6.71(1H,s),3.98(6H,s),3.92(3H,s),3.49-3.53(4H,m),3.31-3.35(4H,m),2.05(3H,s)。
实施例31
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-吗啉哌啶-1-基)苯基)丁-2-炔酰胺
实施例31的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.79(1H,s),8.32(1H,s),8.17(1H,s),8.11(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.49(1H,s),6.82(1H,s),6.70(1H,s),3.97(6H,s),3.79-3.92(7H,m),3.18-3.24(2H,m),2.61-2.84(6H,m),2.13-2.23(1H,m),2.04(3H,s),1.59-1.91(4H,m)。
实施例32
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-甲基-4,7-二氮杂螺[2.5]辛烷-7-基)苯基)丁-2-炔酰胺
实施例32的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.79(1H,s),8.32(2H,s),8.11(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.49(1H,s),6.86(1H,s),6.70(1H,s),3.98(6H,s),3.92(3H,s),3.02-3.28(4H,m),2.38-2.87(5H,m),2.04(3H,s),0.79-0.96(2H,m),0.61-0.77(2H,m)。
实施例33
N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1′,2′:1,6]吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(4-(氧杂环丁烷-3-基)哌嗪-1-基)苯基)丙烯酰胺
实施例33的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.34(1H,s),9.07(1H,s),8.58(1H,s),8.26(1H,s),7.68(1H,s),7.43(1H,s),6.94(1H,s),6.71(1H,s),6.41(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8Hz,10.4Hz),5.77(1H,d,J=10.4Hz),4.66-4.75(4H,m),3.98(6H,s),3.93(3H,s),3.60-3.66(1H,m),3.02-3.09(4H,m),2.48-2.64(4H,m)。
实施例34
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)苯基)丙烯酰胺
实施例34的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.07(1H,s),8.84(1H,s),8.40(1H,s),8.35(1H,s),8.10(1H,s),7.63(1H,s),7.42(1H,s),6.61-6.75(3H,m),6.39(1H,dd,J=16.8Hz,1.2Hz),5.69(1H,d,J=10.4Hz),4.44-4.50(1H,m),4.10-4.20(2H,m),3.91-3.98(9H,m),3.64-3.81(1H,m),3.43-3.52(1H,m),3.19-3.27(1H,m),2.87(3H,s),2.26-2.38(2H,m)。
实施例35
N-(2-(4-环丙基哌嗪-1-基)-5-(6-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1′,2′:1,6]吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基苯基)丙烯酰胺
实施例35的合成方法与实施例1的合成方法相同。1H NMR(400MHz,DMSO),9.55(1H,s),9.17(1H,s),8.51(1H,d,J=1.6Hz),8.33(1H,s),7.75(1H,s),7.64(1H,d,J=1.6Hz),7.09(1H,s),6.87(1H,s),6.63(1H,dd,J=16.8Hz,10.4Hz),6.23(1H,dd,J=16.8Hz,1.6Hz),5.73(1H,dd,J=10.4Hz,1.6Hz),3.99(6H,s),3.89(3H,s),2.92-2.97(4H,m),2.74-2.79(4H,m),1.68-1.74(1H,m),0.42-0.47(2H,m),0.30-0.36(2H,m)。
实施例36
N-(2-((1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基)-5-(6-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1′,2′:1,6]吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基苯基)丙烯酰胺
实施例36的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.31(1H,s),8.58(1H,s),8.55(1H,s),7.69(1H,s),7.43(1H,s),7.39(1H,s),6.72(1H,s),6.62(1H,s),6.46(1H,d,J=16.8Hz),6.33(1H,dd,J=16.8Hz,10.0Hz),5.81(1H,d,J=10.0Hz),4.65-4.69(1H,m),4.27-4.31(1H,m),4.12(1H,d,J=8.0Hz),3.99(6H,s),3.97(3H,s),3.88(1H,d,J=8.0Hz),3.42-3.46(2H,m),1.99-2.09(2H,m)。
实施例37
N-(2-(4-乙酰基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例37的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.39(1H,s),8.24(1H,s),8.14(1H,s),7.70(1H,s),7.51(1H,s),6.81(1H,s),6.71(1H,s),6.43(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.94(3H,s),3.79-3.87(2H,m),3.64-3.70(2H,m),2.94-2.99(4H,m),2.17(3H,s)。
实施例38
(S)-N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(2-甲基吗啉)苯基)丙烯酰胺
实施例38的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),9.01(1H,s),8.39(1H,s),8.28(1H,s),8.14(1H,d,J=1.2Hz),7.68(1H,d,J=1.2Hz),7.50(1H,s),6.83(1H,s),6.70(1H,s),6.41(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.0Hz),5.76(1H,dd,J=10.0Hz,1.2Hz),4.04(1H,d,J=11.6Hz),3.96(6H,s),3.92(3H,s),3.77-3.86(2H,m),2.88-2.95(3H,m),2.63(1H,t,J=10.8Hz),1.24(3H,t,J=6.4Hz)。
实施例39
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-(甲基磺酰基)哌嗪-1-基)苯基)丙烯酰胺
实施例39的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.19(1H,s),8.96(1H,s),8.37(1H,s),8.11(1H,d,J=1.6Hz),8.10(1H,s),7.68(1H,d,J=1.2Hz),7.49(1H,s),6.83(1H,s),6.69(1H,s),6.42(1H,d,J=16.8Hz),6.27(1H,dd,J=16.8Hz,10.0Hz),5.76(1H,d,J=10.0Hz),3.96(6H,s),3.91(3H,s),3.42-3.46(4H,m),3.05-3.08(4H,m),2.88(3H,s)。
实施例40
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-(2,2-二甲基吗啉)-4-甲氧基苯基)丙烯酰胺
实施例40的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.22(1H,s),8.99(1H,s),8.39(1H,s),8.22(1H,s),8.13(1H,d,J=1.2Hz),7.70(1H,d,J=1.2Hz),7.51(1H,s),6.84(1H,s),6.71(1H,s),6.46(1H,d,J=16.8Hz),6.26(1H,dd,J=16.8Hz,10.4Hz),5.78(1H,d,J=10.4Hz),3.92-4.02(11H,m),2.97(2H,t,J=4.4Hz),2.71(2H,s),1.41(6H,s)。
实施例41
(R)-N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(2-甲基吗啉)苯基)丙烯酰胺
实施例41的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.39(1H,s),8.27(1H,s),8.14(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.51(1H,s),6.84(1H,s),6.70(1H,s),6.41(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),4.04(1H,d,J=11.2Hz),3.96(6H,s),3.92(3H,s),3.78-3.87(2H,m),2.88-2.98(3H,m),2.63(1H,dd,J=11.2Hz,10.0Hz),1.25(3H,d,J=6.4Hz)。
实施例42
N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)-2-甲基咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例42的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.17(1H,s),8.97(1H,s),8.36(1H,s),8.28(1H,s),7.86(1H,s),7.43(1H,s),6.85(1H,s),6.68(1H,s),6.42(1H,d,J=16.8Hz),6.32(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),3.96(6H,s),3.82(3H,s),2.75-3.05(8H,m),2.47(3H,s),1.70-1.81(1H,m),0.46-0.61(4H,m)。
实施例43
叔丁基2-(2-丙烯酰胺-4-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-yl)-5-甲氧基苯基)-2,7-二氮杂螺[3.5]壬烷-7-甲酸酯
实施例43的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.11(1H,s),8.42(1H,s),8.11(1H,s),8.04(1H,s),7.68(1H,s),7.45(1H,s),7.03(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.29(1H,dd J=16.8Hz,10.0Hz),6.12(1H,s),5.78(1H,d,J=10.0Hz),3.97(6H,s),3.95(3H,s),3.76(4H,s),3.35-3.41(4H,m),1.72-1.81(4H,m),1.46(9H,s)。
实施例44
N-(2-(8-氧杂-3-氮杂双环[3.2.1]辛烷-3-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例44的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.22(1H,s),9.01(1H,s),8.38(1H,s),8.36(1H,s),8.13(1H,d,J=1.2Hz),7.71(1H,d,J=1.2Hz),7.51(1H,s),6.93(1H,s),6.72(1H,s),6.47(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.81(1H,d,J=10.0Hz),4.52(2H,s),3.99(6H,s),3.92(3H,s),3.19(2H,d,J=11.2Hz),2.78(2H,d,J=11.2Hz),2.09-2.05(4H,m)。
实施例45
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(2,7-二氮杂螺[3.5]壬烷-2-yl)苯基)丙烯酰胺盐酸盐
实施例45的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CD3OD),9.49(1H,s),9.04(1H,s),9.01(1H,s),8.22(1H,s),8.02(1H,s),7.91(1H,s),7.08(1H,s),6.51(1H,dd,J=16.8Hz,10.0Hz),6.41(1H,dd,J=16.8Hz,2.0Hz),6.27(1H,s),5.86(1H,dd,J=10.0Hz,2.0Hz),4.07(3H,s),4.04(6H,s),3.95(4H,s),3.21-3.24(4H,m),2.07-2.11(4H,m)。
实施例46
N-(2-(((4-(氯甲基)哌啶-4-基)甲基)氨基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-yl)-4-甲氧基苯基)丙烯酰胺盐酸盐
实施例46的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CD3OD),9.59(1H,s),9.20(1H,d,J=2.0Hz),9.09(1H,s),8.36(1H,s),8.14(1H,d,J=2.0Hz),7.97(1H,s),7.11(1H,s),6.75(1H,s),6.62(1H,dd,J=16.8Hz,10.4Hz),6.41(1H,dd,J=16.8Hz,1.2Hz),5.85(1H,dd,J=10.4Hz,1.2Hz),4.13(3H,s),4.05(6H,s),3.83(2H,s),3.53(2H,s),3.30-3.36(2H,m),3.19-3.25(2H,m),1.90-2.03(4H,m)。
实施例47
N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丁-2-炔酰胺
实施例47的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.22(1H,s),8.82(1H,s),8.34(1H,s),8.30(1H,s),8.13(1H,s),7.71(1H,s),7.51(1H,s),6.88(1H,s),6.72(1H,s),3.99(6H,S),3.89(3H,s),2.78-3.11(8H,m),2.06(3H,s),1.77-1.84(1H,m),0.44-0.64(4H,m)。
实施例48
(Z)-N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)-4-甲氧基丁-2-烯酰胺
实施例48的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.89(1H,s),8.44(1H,s),8.33(1H,s),8.11(1H,s),7.68(1H,s),7.49(1H,s),6.85(1H,s),6.70(1H,s),6.25(1H,d,J=6.0Hz),4.66-4.72(1H,m),3.98(6H,s),3.87(3H,s),3.72(3H,s),3.24(2H,d J=7.6Hz),2.77-3.24(8H,m),1.78-1.87(1H,m),0.47-0.59(4H,m)。
实施例49
2-氯-N-(2-(4-环丙基哌嗪-1-yl)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)乙酰胺
实施例49的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.48(1H,s),9.22(1H,s),8.96(1H,s),8.37(1H,s),8.12(1H,d,J=1.2Hz),7.70(1H,d,J=1.2Hz),7.50(1H,s),6.92(1H,s),6.71(1H,s),4.27(2H,s),3.98(6H,s),3.84(3H,s),2.85-3.08(8H,m),1.76-1.82(1H,m),0.49-0.63(4H,m)。
实施例50
2-氰基-N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)乙酰胺
实施例50的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.28(1H,s),9.23(1H,s),8.92(1H,s),8.37(1H,s),8.12(1H,s),7.70(1H,s),7.51(1H,s),6.95(1H,s),6.71(1H,s),3.98(6H,s),3.90(3H,s),3.62(2H,s),2.86-3.17(8H,m),1.76-1.95(1H,m),0.50-0.79(4H,m)。
实施例51
N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丁-3-炔酰胺
实施例51的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.21(1H,s),8.92(1H,s),8.41(1H,s),8.34(1H,s),8.11(1H,d,J=1.6Hz),7.69(1H,d J=1.2Hz),7.49(1H,s),6.87(1H,s),6.70(1H,s),6.03-6.14(1H,m),5.38-5.43(2H,m),3.98(6H,s),3.87(3H,s),3.25(2H,d,J=7.6Hz),2.77-3.02(8H,m),1.69-1.89(1H,m),0.48-0.61(4H,m)。
实施例52
(E)-N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丁-2-烯酰胺
实施例52的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.33(1H,s),9.11(1H,s),8.48(1H,s),8.23-8.26(2H,m),7.81(1H,d,J=1.2Hz),7.62(1H,s),7.08-7.17(1H,m),7.00(1H,s),6.83(1H,s),6.12(1H,d,J=16.8Hz),4.10(6H,s),4.01(3H,s),2.90-3.20(8H,m),2.07(3H,d,J=6.8Hz),1.83-1.96(1H,m),0.57-0.80(4H,m)。
实施例53
N-(2-(4-环丙基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙炔酰胺
实施例53的合成方法与实施例1的合成方法相同。1H NMR(400MHz,CDCl3),9.23(1H,s),8.85(1H,s),8.49-8.55(1H,brs),8.35(1H,s),8.13(1H,s),7.71(1H,s),7.51(1H,s),6.90(1H,s),6.72(1H,s),3.99(6H,s),3.91(3H,s),2.85-3.07(9H,m),1.74-1.83(1H,m),0.46-0.61(4H,m)。
生物活性实验:
1.化合物的体外蛋白活性测定:
采取匀相时间分辨荧光(HTRF)方法建立了FGFR-4激酶活性检测平台,进行化合物活性的测定。将化合物从1000μM用100%DMSO进行3倍的梯度稀释11次(共12个浓度),每个浓度取4μL加入到96μL的反应缓冲液中(50mM HEPES,pH 7.4,5mM MnCl2,0.1mM NaVO3,0.001%Tween-20,0.01%BAS,1mM DTT)混匀,作为4*化合物(终浓度0.017nM~1000nM)待用。使用反应缓冲液配制2*FGFR-4激酶(终浓度为1nM),用反应缓冲液配制4*底物(ATP+TKpeptide)(TK peptide,KinEASETM-TK,购买于Cisbio,TK肽,终浓度为1μM,ATP终浓度为25μM)。取2.5μL的4*化合物加入到384孔板(OptiPlate-384,购买于PerkinElmer),然后加入5μL的2*FGFR-4激酶,离心混匀,再加入2.5μL的4*底物混合物启动反应(总反应体积为10μL)。将384孔板放于孵育箱中23℃下搅拌60分钟,然后加入5μL的Eu3+ cryptate-labled anti-phosphotyrosine antibody(/>KinEASETM-TK,购买于Cisbio),5μL的Streptavidin-XL-665(/>KinEASETM-TK,购买于Cisbio)停止反应。在孵育箱中孵育1小时后,在Envision(购买于PerkinElmer)上读取荧光值(320nm激发,检测665nm与620nm的发射光,二者比值为酶活性)。每个化合物分别在12个浓度下测定酶的活性,数据使用GraphPad prism 5.0软件计算得到该化合物的IC50值。
2.化合物的细胞增殖活性测定:
采用Promega公司的Cell检测试剂建立了悬浮细胞增殖抑制筛选方法。人肝癌细胞Hep3b(协和细胞研究中心)用补充有10%胎牛血清/>的MEM培养基进行培养,培养条件是37℃,95%空气和5%的CO2,培养于25cm2或75cm2塑料组织培养瓶/>中,一周传代培养2~3次。
将Hep3b细胞以3×103细胞/孔的密度接种在96-孔细胞培养板中,195mL/孔,并在37℃,95%空气和5%的CO2中进行培养。24小时后加入待测化合物:将化合物从10mM(溶于DMSO中)开始用DMSO进行3倍梯度稀释,每个浓度取4mL加入到96mL的无血清培养基中,最后取5mL培养基稀释后的化合物加入到接种有细胞的培养版中。细胞培养液中DMSO的终浓度为0.1%,所试化合物的终浓度是0.3nM~10mM。将上述细胞37℃温育3天。
3天后,通过Cell Titer-Glo(Promega)试剂盒进行细胞活力测定,最后通过GraphPad Prism 5.0程序计算化合物对细胞增殖的半抑制浓度,即IC50值。
表1.实施例化合物对FGFR4抑制作用
3.药代动力学数据
雄性SD大鼠来源于北京维通利华实验动物技术有限公司,将大鼠分组,每组3只,分别口服单次灌胃给予待测样品混悬液(5mg/kg)。动物在实验前禁食过夜,禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8、和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血,放于肝素抗凝管中,样品于4℃、4000rpm离心5min,血浆转移至离心管中,并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取,萃取液通过LC/MS/MS分析。
实施例54
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-吗啉苯基)丙烯酰胺
步骤1:化合物3的合成
向化合物1(2g)的N-甲基吡咯烷酮(15mL)溶液中加入化合物2(2.49g)和碳酸钾(5.29g)。反应液于100℃下加热过夜。将反应液冷却至室温,并倒入到水中。过滤,滤饼用蒸馏水洗涤并干燥,获得化合物3(3.58g)。
步骤2:化合物4的合成
于-20℃下,向化合物3(3.58g)的THF(100mL)溶液中滴加磺酰氯(2.3mL)。反应液于-20℃下继续搅拌2小时至反应结束。用饱和碳酸氢钠水溶液淬灭反应。将有机相分离,水相用乙酸乙酯萃取。合并有机相,无水硫酸钠干燥,并减压浓缩。所得残留物通过快速柱层析纯化(二氯甲烷/甲醇=100/1),获得化合物4(3.24g)。
步骤3:化合物5的合成
向化合物4(3.24g)的乙醇(18mL)溶液中加入氯乙醛(18mL)。反应液加热至80℃并反应过夜。将反应液倒入水中并过滤。将所获得的固体干燥,获得化合物5(3.1g)。
步骤4:化合物7的合成
在氮气保护下,向化合物5(1.23g)在二氧六环/水(20mL/5mL)中的溶液中加入四(三苯基磷)钯(500mg)、化合物6(1.5g)和无水碳酸钠(1.5g)。将反应液加热至80℃并反应过夜。将反应液冷却至室温,减压浓缩,所得残留物通过快速硅胶柱层析(二氯甲烷/甲醇=500/1)进行分离纯化,获得化合物7(1.12g)。
步骤5:化合物8的合成
向化合物7(200mg)的DMF(1mL)溶液中加入无水碳酸铯(120mg)和吗啉(0.1mL),并加热至60℃反应过夜。将反应液冷却至室温,减压浓缩。所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷/甲醇=100/1至50/1),获得化合物8(120mg)。
步骤6:化合物9的合成
向化合物8(120mg)的四氢呋喃(5mL)溶液中加入钯碳(50mg),并将体系置换氢气。反应体系于室温下反应过夜,并通过硅藻土过滤。将滤液减压浓缩获得化合物9(71mg)。
步骤7:实施例54的合成
0℃下,向化合物9(71mg)的二氯甲烷(2mL)溶液中加入DIEA(5μL)和丙烯酰氯(11μL)。反应液于0℃下搅拌2小时,加入甲醇淬灭并减压浓缩。所得残留物通过制备薄层色谱分离纯化(二氯甲烷/甲醇=25/1),获得实施例54(35mg)。1H NMR(400MHz,CDCl3)δ9.22(1H,s),9.02(1H,s),8.38(1H,s),8.27(1H,s),8.14(1H,s),7.70(1H,s),7.51(1H,s),6.86(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.87-3.95(7H,m),2.95-3.02(4H,m)。
实施例55
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-((4-甲基哌嗪-1-基)甲基)苯基)丙烯酰胺
实施例55的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.62-10.21(1H,brs),9.20(1H,s),8.82(1H,s),8.39(1H,s),8.15(1H,s),7.70(1H,s),7.51(1H,s),6.88(1H,s),6.71(1H,s),6.39(1H,d,J=16.8Hz),6.18-6.29(1H,m),5.75(1H,d,J=11.6Hz),3.98(6H,s),3.92(3H,s),3.78(2H,s),2.75-3.02(8H,m),2.69(3H,s)。
实施例56
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-(3-羟基-8-氮杂[3.2.1]辛-8-基)-4-甲氧基苯基)丙烯酰胺
实施例56的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.19(1H,s),8.87(1H,s),8.38(1H,s),8.12(1H,s),7.75(1H,s),7.69(1H,s),7.49(1H,s),6.71(1H,s),6.66(1H,s),6.45(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8,10.4Hz),5.77(1H,d,J=10.4Hz),4.24-4.29(1H,m),3.98(6H,s),3.91(3H,s),3.75-3.83(2H,m),2.32-2.39(2H,m),2.21-2.31(2H,m),2.04-2.12(2H,m),1.94-2.03(2H,m)。
实施例57
N-(2-(4-(环丙基甲基)哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例57的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.21(1H,s),9.04(1H,s),8.37(1H,s),8.33(1H,s),8.12(1H,s),7.70(1H,s),7.50(1H,s),6.93(1H,s),6.71(1H,s),6.42(1H,d,J=17.2Hz),6.29(1H,dd,J=17.2,10.0Hz),5.77(1H,d,J=10.0Hz),3.98(6H,s),3.91(3H,s),3.01-3.08(4H,m),2.67-2.85(4H,m),2.39(2H,d,J=6.4Hz),0.81-0.94(1H,m),0.55-0.63(2H,m),0.15-0.23(2H,m)。
实施例58
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-吗啡啉基哌啶-1-基)苯基)丙烯酰胺
实施例58的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.21(1H,s),9.01(1H,s),8.36(1H,s),8.19(1H,s),8.12(1H,s),7.69(1H,s),7.50(1H,s),6.85(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8,10.0Hz),5.76(1H,d,J=10.0Hz),3.98(6H,s),3.91(3H,s),3.76-3.83(4H,m),3.20(2H,d,J=10.8Hz),2.79(2H,t,J=11.6Hz),2.61-2.71(4H,m),2.30-2.42(1H,m),2.12(2H,d,J=11.6Hz),1.64-1.78(2H,m)。
实施例59
N-(2-(4-环丙基哌啶-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例59的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.21(1H,s),9.03(1H,s),8.30-8.38(2H,m),8.12(1H,s),7.69(1H,s),7.50(1H,s),6.89(1H,s),6.71(1H,s),6.43(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz),5.78(1H,d,J=10.0Hz),3.98(6H,s),3.89(3H,s),2.94-3.04(4H,m),2.79-2.93(4H,m),1.72-1.82(1H,m),0.42-0.59(4H,m)。
实施例60
N-(2-(4-氰基哌嗪-1-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
实施例60的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.21(1H,s),8.99(1H,s),8.37(1H,s),8.13(1H,s),8.05(1H,s),7.70(1H,s),7.51(1H,s),6.84(1H,s),6.71(1H,s),6.43(1H,d,J=17.2Hz),6.28(1H,dd,J=17.2,10.4Hz),5.74(1H,d,J=10.4Hz),3.98(6H,s),3.93(3H,s),3.43-3.53(4H,m),3.03-3.12(4H,m)。
实施例61
N-(2-((1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚-5-基)-5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基苯基)丙烯酰胺
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实施例61的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.15(1H,s),8.41(1H,s),8.40(1H,s),8.13(1H,s),7.69(1H,s),7.60(1H,s),7.48(1H,s),6.70(1H,s),6.52(1H,s),6.41(1H,d,J=16.8Hz),6.31(1H,dd,J=16.8,10.0Hz),5.75(1H,d,J=10.0Hz),4.62(1H,s),4.24(1H,s),4.08(1H,d,J=7.6Hz),3.97(6H,s),3.92(3H,s),3.83(1H,d,J=7.6Hz),3.42(1H,d,J=9.6Hz),3.37(1H,d,J=9.6Hz),1.94-2.01(2H,m)。
实施例62
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(2-氧杂-7-氮杂螺[4,4]壬-7-基)苯基)丙烯酰胺
实施例62的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.14(1H,s),8.42(1H,s),8.28(1H,s),8.12(1H,s),7.68(1H,s),7.63(1H,s),7.47(1H,s),6.70(1H,s),6.46(1H,s),6.37(1H,d,J=16.8Hz),6.31(1H,dd,J=16.8,10.8Hz),5.76(1H,d,J=10.8Hz),3.97(6H,s),3.94(3H,s),3.87-3.93(2H,m),3.72(1H,d,J=8.4Hz),3.65(1H,d,J=8.4Hz),3.37-3.43(2H,m),3.30(1H,d,J=9.2Hz),3.25(1H,d,J=9.2Hz),1.86-2.03(4H,m)。
实施例63
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-氟-4-甲氧基苯基丙烯酰胺
实施例63的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.21(1H,s),8.86(1H,d,J=9.2Hz),8.37(1H,s),8.14(1H,s),7.71(1H,s),7.51(1H,s),7.46(1H,s),6.87(1H,d,J=12.4Hz),6.71(1H,s),6.46(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8,10.0Hz),5.80(1H,d,J=10.0Hz),3.98(6H,s),3.93(3H,s)。
实施例64
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)丙烯酰胺
实施例64的合成方法与实施例54的合成方法相同。1H NMR(400MHz,DMSO-d6)δ9.51(1H,s),9.32(1H,s),9.12(1H,s),8.93(1H,s),8.38(1H,s),8.21(1H,s),8.08(1H,s),7.15(1H,s),6.90(1H,s),6.89(1H,dd,J=17.2,10.0Hz),6.25(1H,d,J=17.2Hz),5.75(1H,d,J=10.0Hz),4.01(6H,s),3.97(3H,s),3.68-3.86(4H,m),3.49-3.65(4H,m),3.32-3.48(3H,m),2.75-2.88(5H,m),2.14-2.26(2H,m),1.96-2.12(2H,m)。
实施例65
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(4-(氧杂环丁-3-基)哌嗪-1-基)苯基)丙烯酰胺
实施例65的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.21(1H,s),9.02(1H,s),8.37(1H,s),8.24(1H,s),8.12(1H,s),7.70(1H,s),7.50(1H,s),6.91(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8,10.0Hz),5.77(1H,d,J=10.0Hz),4.67-4.75(4H,m),3.98(6H,s),3.92(3H,s),3.60-3.68(1H,m),3.01-3.12(4H,m),2.46-2.67(4H,m)。
实施例66
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺
实施例66的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CD3OD)δ9.20(1H,s),8.54(1H,s),8.35(1H,s),8.24(1H,s),7.65(1H,s),7.56(1H,s),6.93(1H,s),6.85(1H,s),6.69(1H,dd,J=17.2,10.4Hz),6.43(1H,d,J=17.2Hz),5.83(1H,d,J=10.4Hz),4.02(6H,s),4.01(3H,s),3.43-3.51(2H,m),3.12-3.21(2H,m),2.83(3H,s),2.75(6H,s)。
实施例67
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-(4-二甲氨基)哌啶-1-基)-4-甲氧基苯基)丙烯酰胺
实施例67的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.18(1H,s),8.92(1H,s),8.37(1H,s),8.12-8.18(2H,m),7.69(1H,s),7.49(1H,s),6.79(1H,s),6.71(1H,s),6.42-6.45(2H,m),5.77-5.80(1H,m),3.98(6H,s),3.90(3H,s),3.31(2H,d,J=12.0Hz),3.12-3.24(1H,m),2.79-2.89(8H,m),2.35(2H,d,J=11.2Hz),2.07-2.22(2H,m)。
实施例68
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-4-甲氧基-2-(8-氧杂-2-氮杂螺[4.5]癸-2-基)苯基)丙烯酰胺
实施例68的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.13(1H,s),8.40(1H,s),8.29(1H,s),8.12(1H,s),7.78(1H,s),7.68(1H,s),7.47(1H,s),6.70(1H,s),6.44(1H,s),6.42(1H,d,J=16.8Hz),6.34(1H,dd,J=16.8,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.94(3H,s),3.61-3.71(4H,m),3.36(2H,t,J=6.8Hz),3.14(2H,s),1.81(2H,t,J=6.8Hz),1.52-1.68(4H,m)。
实施例69
N-(5-(4-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1,2-a][1,6]萘啶-8-基)-2-(4-乙基哌嗪-1-基)-4-甲氧基苯基)丙烯酰胺
实施例69的合成方法与实施例54的合成方法相同。1H NMR(400MHz,CDCl3)δ9.21(1H,s),9.04(1H,s),8.37(1H,s),8.32(1H,s),8.12(1H,s),7.69(1H,s),7.50(1H,s),6.91(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8,10.4Hz),5.77(1H,d,J=10.4Hz),3.98(6H,s),3.90(3H,s),3.01-3.05(4H,m),2.58-2.75(4H,m),2.54(2H,q,J=7.2Hz),1.17(3H,t,J=7.2Hz)。
实施例70
N-(5-(6-(2,6-二氯-3,5-二甲氧基苯基)咪唑并[1′,2′:1,6]吡啶并[2,3-d]嘧啶-2-基)-4-甲氧基-2-(4-(氧杂环丁-3-基)哌嗪-1-基)苯基)丙烯酰胺
步骤1:化合物11的合成
在室温下,向化合物2(3.0g)的四氢呋喃(20mL)溶液中加入氢化钠(774mg),将混合物于室温下搅拌1.5小时,随后向混合物中加入化合物10(2.86g),将混合物于室温下搅拌过夜。用饱和氯化铵水溶液淬灭反应,并用二氯甲烷稀释,将有机相分离,用饱和氯化铵水溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残留物通过快速硅胶柱层析纯化(DCM/MeOH=100/1),获得化合物11(5.2g)。
步骤2:化合物12的合成
在-20℃下,向化合物11(5.2g)的四氢呋喃(100mL)溶液中缓慢滴加磺酰氯(2.81g)。滴加完毕后,将混合物于-20℃下搅拌2小时。随后,用饱和碳酸氢钠水溶液淬灭反应。混合物用乙酸乙酯萃取,萃取液用无水硫酸钠干燥,过滤并浓缩,残留物通过快速硅胶柱层析(DCM/MeOH=100/2)纯化,获得化合物12(4.7g)。
步骤3:化合物13的合成
向化合物12(2.0g)的乙醇(20mL)溶液中加入40%氯乙醛水溶液(8mL),将混合物于80℃下加热过夜。将混合物倒入饱和碳酸氢钠水溶液中,搅拌并过滤,将滤饼干燥,获得淡黄色固体13(2.1g)。该化合物不经进一步纯化直接用于下一步反应。
步骤4:化合物14的合成
向化合物13(2.1g)在二氯甲烷/甲醇/水(20mL/20mL/20mL)中的溶液中加入过硫酸氢钾复合盐(18.4g),将混合物加热至40℃并搅拌过夜。加入水稀释混合物,并用二氯甲烷萃取,萃取液用无水硫酸钠干燥,过滤并浓缩。所得淡黄色固体14不经进一步纯化直接用于下一步反应。
步骤5:化合物15的合成
向化合物14(2.5g)的THF(10mL)溶液中加入氢氧化钾(924mg)的水(10mL)溶液。反应液于室温下搅拌过夜。减压浓缩除去THF,并滴加浓盐酸至pH=2。过滤,将所得白色固体用无水乙腈(5mL)洗涤并干燥,得到化合物15(2.1g)。
步骤6:化合物16的合成
向化合物15(2.1g)的乙腈(20mL)溶液中加入三氯氧磷(20mL)。将反应液加热至80℃反应3小时,然后冷至室温。将反应液减压浓缩后加入冰水。过滤,所得固体用无水乙腈洗涤,并干燥,获得化合物16(1.9g)。
步骤7:化合物17的合成
在氮气保护下,向化合物16(1.14g)在二氧六环/水(20mL/5mL)中的溶液中加入四(三苯基膦)钯(500mg)、化合物6(1.3g)和无水碳酸钠(1.2g)。将反应液加热至80℃并反应过夜。将反应液冷却至室温,减压浓缩,所得残留物通过快速硅胶柱层析(二氯甲烷/甲醇=500/1)进行分离纯化,获得化合物17(920mg)。
步骤8:化合物19的合成
向化合物17(200mg)的DMF(1mL)溶液中加入无水碳酸铯(120mg)和化合物18(120mg),并加热至60℃反应过夜。将反应液冷却至室温,减压浓缩。所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷/甲醇=100/1至50/1),获得化合物19(110mg)。
步骤9:化合物20的合成
向化合物19(110mg)的四氢呋喃(5mL)溶液中加入钯碳(50mg),并将体系置换氢气。反应体系于室温下反应过夜,并通过硅藻土过滤。将滤液减压浓缩获得化合物20(63mg)。
步骤10:实施例70的合成
在冰浴下,向化合物20(63mg)的二氯甲烷(2mL)溶液中加入DIEA(5μL)和丙烯酰氯(11μL)。反应液于冰浴下搅拌2小时,加入甲醇淬灭并减压浓缩。所得残留物通过制备薄层色谱分离纯化(二氯甲烷/甲醇=20/1),获得实施例70(33mg)。1H NMR(400MHz,CDCl3)δ9.34(1H,s),9.07(1H,s),8.58(1H,s),8.26(1H,s),7.68(1H,s),7.43(1H,s),6.93(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8,10.4Hz),5.78(1H,d,J=10.4Hz),4.74(2H,t,J=6.4Hz),4.68(2H,t,J=6.4Hz),3.98(6H,s),3.93(3H,s),3.61-3.67(1H,m),3.03-3.09(4H,m),2.51-2.65(4H,m)。
生物活性实验:
1.化合物的体外蛋白活性测定:
采取匀相时间分辨荧光(HTRF)方法建立了FGFR-4激酶活性检测平台,进行化合物活性的测定。将化合物从1000μM用100%DMSO进行3倍的梯度稀释11次(共12个浓度),每个浓度取4μL加入到96μL的反应缓冲液中(50mM HEPES,pH 7.4,5mM MnCl2,0.1mM NaVO3,0.001%Tween-20,0.01%BAS,1mM DTT)混匀,作为4*化合物(终浓度0.017nM~1000nM)待用。使用反应缓冲液配制2*FGFR-4激酶(终浓度为1nM),用反应缓冲液配制4*底物(ATP+TKpeptide)(TK peptide,KinEASETM-TK,购买于Cisbio,TK肽,终浓度为1μM,ATP终浓度为25μM)。取2.5μL的4*化合物加入到384孔板(OptiPlate-384,购买于PerkinElmer),然后加入5μL的2*FGFR-4激酶,离心混匀,再加入2.5μL的4*底物混合物启动反应(总反应体积为10μL)。将384孔板放于孵育箱中23℃下搅拌60分钟,然后加入5μL的Eu3+cryptate-labledanti-phosphotyrosine antibody(/>KinEASETM-TK,购买于Cisbio),5μL的Streptavidin-XL-665(/>KinEASETM-TK,购买于Cisbio)停止反应。在孵育箱中孵育1小时后,在Envision(购买于PerkinElmer)上读取荧光值(320nm激发,检测665nm与620nm的发射光,二者比值为酶活性)。每个化合物分别在12个浓度下测定酶的活性,数据使用GraphPad prism 5.0软件计算得到该化合物的IC50值。
2.化合物的细胞增殖活性测定:
采用Promega公司的Cell检测试剂建立了悬浮细胞增殖抑制筛选方法。人肝癌细胞Hep3b(协和细胞研究中心)用补充有10%胎牛血清/>的MEM培养基进行培养,培养条件是37℃,95%空气和5%的CO2,培养于25cm2或75cm2塑料组织培养瓶/>中,一周传代培养2~3次。
将Hep3b细胞以3×103细胞/孔的密度接种在96-孔细胞培养板中,195mL/孔,并在37℃,95%空气和5%的CO2中进行培养。24小时后加入待测化合物:将化合物从10mM(溶于DMSO中)开始用DMSO进行3倍梯度稀释,每个浓度取4mL加入到96mL的无血清培养基中,最后取5mL培养基稀释后的化合物加入到接种有细胞的培养版中。细胞培养液中DMSO的终浓度为0.1%,所试化合物的终浓度是0.3nM~10mM。将上述细胞37℃温育3天。
3天后,通过Cell Titer-Glo(Promega)试剂盒进行细胞活力测定,最后通过GraphPadPrism 5.0程序计算化合物对细胞增殖的半抑制浓度,即IC50值。
表2.实施例化合物对FGFR4及Hep3B细胞系抑制作用
3.药代动力学数据
雄性SD大鼠来源于北京维通利华实验动物技术有限公司,将大鼠分组,每组3只,分别口服单次灌胃给予待测样品混悬液(5mg/kg)。动物在实验前禁食过夜,禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8、和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血,放于肝素抗凝管中,样品于4℃、4000rpm离心5分钟,血浆转移至离心管中,并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取,萃取液通过LC/MS/MS分析。
工业实用性
本发明提供一种FGFR4激酶抑制剂及其制备方法和用途。本发明涉及式I的化合物、或其药学上可接受的盐、溶剂化物、多晶型物或异构体,及其在制备用来治疗FGFR4介导的疾病的药物中的用途。本发明所述FGFR4蛋白激酶抑制剂可以高选择性的抑制FGFR4酪氨酸激酶,而对FGFR1-3抑制效果较弱,可安全、有效的治疗FGFR4高表达的肝癌患者,具有较好的经济价值和应用前景。
Claims (4)
1.选自以下的化合物,或其药学上可接受的盐:
2.一种药物组合物,其包含根据权利要求1所述的化合物或其药学上可接受的盐,以及药学上可接受的载体。
3.根据权利要求1所述的化合物或其药学上可接受的盐、以及根据权利要求2所述的组合物在制备用来治疗FGFR4介导的疾病的药物中的用途。
4.根据权利要求3所述的用途,其中所述FGFR4介导的疾病为非小细胞肺癌、胃癌、多发性骨髓瘤、肝癌、胆管癌、前列腺癌、皮肤癌、卵巢癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤。
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CN201910178024.9A CN111662292A (zh) | 2019-03-08 | 2019-03-08 | Fgfr4激酶抑制剂及其制备方法和用途 |
CN2019101780249 | 2019-03-08 | ||
CN2019106026690 | 2019-07-05 | ||
CN201910602669.0A CN112174986A (zh) | 2019-07-05 | 2019-07-05 | Fgfr4激酶抑制剂及其制备方法和用途 |
PCT/CN2020/078098 WO2020182062A1 (zh) | 2019-03-08 | 2020-03-06 | Fgfr4激酶抑制剂及其制备方法和用途 |
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US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
JP2023505258A (ja) | 2019-12-04 | 2023-02-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
KR20220159457A (ko) * | 2020-03-27 | 2022-12-02 | 베타 파머수티컬 컴퍼니 리미티드 | Fgfr4 억제제의 염 형태, 결정 형태 및 그 용도 |
EP4352059A1 (en) | 2021-06-09 | 2024-04-17 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
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EP3705480B1 (en) | 2017-10-30 | 2024-02-28 | Shanghai Ringene BioPharma Co., Ltd. | Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof |
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WO2017050864A1 (en) * | 2015-09-23 | 2017-03-30 | Janssen Pharmaceutica Nv | New compounds |
WO2018004258A1 (ko) * | 2016-06-28 | 2018-01-04 | 한미약품 주식회사 | 신규한 헤테로시클릭 유도체 화합물 및 이의 용도 |
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EP3936509A4 (en) | 2022-03-30 |
EP3936509A1 (en) | 2022-01-12 |
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