CN113831344A - 炔苯基苯酰胺类化合物及其应用 - Google Patents
炔苯基苯酰胺类化合物及其应用 Download PDFInfo
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- CN113831344A CN113831344A CN202111057771.0A CN202111057771A CN113831344A CN 113831344 A CN113831344 A CN 113831344A CN 202111057771 A CN202111057771 A CN 202111057771A CN 113831344 A CN113831344 A CN 113831344A
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本发明涉及一种炔苯基苯酰胺类化合物及其应用。本发明的炔苯基苯酰胺类化合物具有式(I)所示结构,该类化合物可作为蛋白激酶抑制剂,能够有效抑制TRK蛋白激酶的活性并且能抑制多种肿瘤细胞的增殖、迁移和侵袭,同时具有较好的药代动力学和毒性低的特点。
Description
技术领域
本发明涉及化学医药技术领域,特别是涉及一种炔苯基苯酰胺类化合物及其应用。
背景技术
原肌球蛋白受体激酶TRK(tropomyosin receptor kinase),属于受体酪氨酸激酶家族 (receptor tyrosine kinase,RTK),它有三个亚型:TRKA、TRKB、TRKC,分别由NTRK1、NTRK2、NTRK3基因编码。TRK是一类跨膜蛋白,由胞外的配体结合区、跨膜区(transmembranedomain,TM)和胞内区组成,TRK主要通过结合神经营养因子(Neurotrophic factors,NTs)发挥作用。神经营养因子是一类由神经所支配的组织(如肌肉)和星形胶质细胞产生的且为神经元生长与存活所必需的一类蛋白质分子。目前主要发现了四种神经营养因子,它们分别是NGF(神经生长因子)、脑源性神经营养因子(BDNF)、神经营养因子3(NT-3) 和神经营养因子4(NT-4),其中NGF与TRKA结合,BDNF和NT-4与TRKB结合,NT-3 可以与三种TRK蛋白结合,但其与TRKC的结合能力更强。当受到信号诱导而活化时,TRK 通过自身二聚化和磷酸化,依次激活下游的信号通路实现各种细胞生理功能。TRK的下游信号通路包括MAPK、PI3K/AKT、PLCγ/PKC通路,这些信号通路调节着细胞的增殖、分化、迁移、凋亡等生理过程,以及神经突触的弹性、神经树突的长出修复、神经元降解的预防和修复以及感觉神经元的维护等与神经元相关的多种生理活动。
大量研究表明,TRK的过量表达、基因融合以及单核苷酸改变与多种类型的肿瘤发生发展密切相关,如非小细胞肺癌、乳腺癌、结肠癌、前列腺癌、甲状腺癌、恶性黑色素瘤、神经母细胞瘤和乳腺样分泌癌等。在TRK异常激活的机制中,最普遍的机制是TRK的基因融合。医学研究最早发现的NTRK融合基因是在结肠癌样本中发现的TPM3-NTRK1融合基因,随着研究的深入,研究人员又陆续发现了CD74-NTRK1、ETV6-NTRK2、QKI-NTRK2、 ETV6-NTRK3等多种类型的融合基因。NTRK融合基因所表达的TRK融合蛋白可以在不依赖与配体结合的情况下持续性激活下游信号通路,从而诱导细胞异常增殖,促进肿瘤的发生与发展。因此,TRK被视为是一个有效的抗癌治疗靶点。
目前已有一款由美国LOXO公司开发的TRK选择性抑制剂Larotrectinib于2018年由FDA 批准上市,由罗氏制药公司开发的TRK抑制剂Entrectinib于2019年6月在日本上市,由 TESARO公司开发的的Belizatinib正在进行临床研究,此外Cabozanitinib、Sitravatinib、 Altiratinib等多靶点抑制剂也具有良好的TRK抑制活性。
持续使用TRK抑制剂而引起的NTRK基因点突变是导致肿瘤产生耐药的关键原因。临床研究已经陆续发现了NTRK1的G595R、G667C、F589L、G667S以及NTRK3的G623R、 G696A突变,目前还没有针对这些突变的抑制剂上市,TRK二代抑制剂LOXO-195、TPX-0005 和ONO-5390556正处于临床研究中。
发明内容
基于此,本发明提供了一种炔苯基苯酰胺类化合物或其药学上可接受的盐或其立体异构体,该类化合物可作为蛋白激酶抑制剂,能够有效抑制TRK蛋白激酶的活性并且能抑制多种肿瘤细胞的增殖、迁移和侵袭,尤其还具有很好的药代动力学性质和抗耐药性。
具体技术方案如下:
具有式(I)结构的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子;
其中,R1任选自:C1~C20烷基;
R2任选自:H、卤素、C1~C20烷基、C1~C20烷氧基或卤素取代的C1~C20烷基;
R3任选自:H、氟取代的C1~C4烷基、取代或未取代的含1-3个N环原子的5-6元杂环基;
R4任选自:H、卤素、硝基、取代或未取代的C1~C20烷基、取代或未取代的C1~C20烷氧基、取代或未取代的含1-3个N环原子的5-10元杂环基、取代或未取代的含1-3个N环原子的5-10元杂芳基;
R5为-NR6R7;
其中,R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)nCR10RnR12、-(CH2)pOR12,或者 R6、R7与它们所连接的氮原子一起形成被取代或未被取代的含有杂原子的单环、稠环、螺环或桥环;
R8、R9分别独立地选自:H、C1~C20烷基;或者R8、R9与它们所连接的氮原子一起形成被取代或未被取代的含有1-3个杂原子的单环、稠环、螺环或桥环;
R10、R11与它们所连接的碳原子一起形成被取代或未被取代的含有1-3个杂原子的单环、稠环、螺环或桥环;
R12选自:H、C1~C20烷基;
m、n、p分别独立地选自:0-10的整数。
在其中一些实施例中,R4任选自:H、卤素、硝基、C1~C10烷基、卤素取代的C1~C10烷基、C1~C10烷氧基、卤素取代的C1~C10烷氧基、-(CH2)xNR17R18、被1-5个R19代或未被取代的含有1-3个N环原子的5-10元杂环基、被1-5个R19取代或未被取代的含有1-3个N环原子的5-10元杂芳基;x=1-5的整数;
R17、R18与它们所连接的氮原子一起形成被1-5个R19取代或未被取代的吗啉基、吡咯烷基、哌啶基或哌嗪基;
各R19分别独立地选自C1-C5烷基。
在其中一些实施例中,R4任选自:H、卤素、硝基、C1~C8烷基、卤素取代的C1~C8烷基、C1~C8烷氧基、卤素取代的C1~C8烷氧基、-(CH2)xNR17R18、被1-5个R19取代或未被取代的含有1-3个N环原子的5-6元杂环基、被1-5个R19取代或未被取代的含有1-3个N环原子的5-6元杂芳基;x为1-5的整数。
在其中一些实施例中,R4任选自:H、卤素、硝基、C1~C4烷基、卤素取代的C1~C4烷基、 C1~C4烷氧基、卤素取代的C1~C4烷氧基、-(CH2)xNR17R18、被1-3个R19取代或未被取代的含有1-3个N环原子的5-6元杂环基、被1-3个R19取代或未被取代的含有1-3个N环原子的 5-6元杂芳基;x=1-5的整数。
在其中一些实施例中,R4任选自:H、卤素、硝基、C1~C4烷基、卤素取代的C1~C4烷基、 C1~C4烷氧基、卤素取代的C1~C4烷氧基、-(CH2)xNR17R18、被1-3个R19取代或未被取代的咪唑基;x为1、2或3;
R17、R18与它们所连接的氮原子一起形成被1-3个R19取代或未被取代的哌嗪基;
各R19分别独立地选自:C1-C5烷基。
各R19分别独立地选自:甲基、乙基、丙基。
在其中一些实施例中,R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)nCR10R11R12、 -(CH2)pOR12,或者R6、R7与它们所连接的氮原子一起形成被1-5个R13取代或未被取代的含有1-3个杂原子的3-15元单环、稠环、螺环或桥环,杂原子选自:O、N、S;
R8、R9分别独立地选自:H、C1~C5烷基;或者R8、R9与它们所连接的氮原子一起形成被1-5个R13取代或未被取代的含有1-3个杂原子的3-10元单环、稠环、螺环或桥环,杂原子选自:O、N;
R10、R11与它们所连接的碳原子一起形成被1-5个R13取代或未被取代的含有1-3个杂原子的3-10元单环、稠环、螺环或桥环,杂原子选自:O、N;
R12选自:H、C1-C5烷基;
各R13分别独立地选自:H、C1-C5烷基、C1-C5烷酰基、羟基、羟基取代的C1-C5烷基、氨基取代的C1-C5烷基、氨基取代的C1-C5烷氧基、C3-C7环烷基取代的C1-C3烷基、-NR15R16、被1-5个R14取代或未被取代的含有1-3个杂原子的3-10元单环、稠环、螺环或桥环,杂原子选自:O、N;
R14、R15、R16分别独立地选自:H、C1-C5烷基;
m、n、p分别独立地选自:0-5的整数。
在其中一些实施例中,R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)pOR12,或者R6、R7与它们所连接的氮原子一起形成被1-3个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或者哌嗪基;
R8、R9分别独立地选自:H、C1~C5烷基,或者R8、R9与它们所连接的氮原子一起形成被1-5个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或哌嗪基;
R12选自:H、C1-C5烷基;
各R13分别独立地选自:H、C1-C5烷基、C1-C5烷酰基、羟基、-NR15R16、被1-2个R14取代或未被取代的氧杂环丁基、被1-4个R14取代或未被取代的吗啉基;
R14、R15、R16分别独立地选自:H、C1-C3烷基;
m、p分别独立地选自:1、2、3、4或5。
在其中一些实施例中,R5选自以下任意一种基团:
在其中一些实施例中,R4为卤素;R5为-NR6R7;
R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)pOR12,或者R6、R7与它们所连接的氮原子一起形成被1-3个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或者哌嗪基;
R8、R9分别独立地选自:H、C1-C3烷基,或者R8、R9与它们所连接的氮原子一起形成被1-2个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或哌嗪基;
R12选自:H、C1-C3烷基;
各R13分别独立地选自:H、C1-C3烷基、乙酰基、羟基、-NR15R16、氧杂环丁基、吗啉基;
R15、R16分别独立地选自:H、C1-C3烷基;
m、p分别独立地选自:2、3或4。
在其中一些实施例中,R4为Cl,
在其中一些实施例中,R1任选自:C1~C10烷基。
在其中一些实施例中,R1任选自:C1~C4烷基。
在其中一些实施例中,R1任选自:甲基、乙基、异丙基、叔丁基。
在其中一些实施例中,R2任选自:H、卤素、C1~C10烷基、卤素取代的C1~C10烷基。
在其中一些实施例中,R2任选自:H、卤素、C1~C4烷基、卤素取代的C1~C4烷基、C1~C4烷氧基。
在其中一些实施例中,R2任选自:氢、氟、甲基、乙基、异丙基、叔丁基、二氟甲基、二氟乙基、三氟甲基或三氟乙基。
在其中一些实施例中,R3选自:H、二氟甲基、二氟乙基、三氟甲基或三氟乙基。
在其中一些实施例中,所述炔苯基苯酰胺类化合物具有式(II)所示结构:
本发明的另一目的是提供一种上述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备TRK抑制剂中的应用。
本发明的另一目的是提供一种上述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗由TRK酪氨酸激酶介导的疾病的药物中的应用。
在其中一些实施例中,所述由TRK酪氨酸激酶介导的疾病为肿瘤,优选为非小细胞肺癌、乳腺癌、结肠癌、前列腺癌、甲状腺癌、恶性黑色素瘤、神经母细胞瘤或乳腺样分泌癌。
本发明的再一目的是提供一种预防和/或治疗肿瘤的药用组合物,包括活性成分和药学上可接受的辅料,所述活性成分包括上述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明提供的炔苯基苯酰胺类化合物,对TRKs激酶有很强的抑制活性,并且对Ba/F3-TRKs稳定株的野生型及耐药型细胞增殖有很强的抑制活性。可以用于制备预防或者治疗由TRK酪氨酸激酶介导的疾病的药物,比如非小细胞肺癌、乳腺癌、结肠癌、前列腺癌、甲状腺癌、恶性黑色素瘤、神经母细胞瘤和乳腺样分泌癌等,同时还具有很好的药代动力学和毒性低的特点。
附图说明
图1为化合物XS3-55的体内抗肿瘤活性。
图2为化合物XS3-55对老鼠体重的影响。
具体实施方式
本发明下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂,均为市售产品。
除非另有定义,本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不用于限制本发明。
本发明的术语“包括”和“具有”以及它们任何变形,意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块,而是可选地还包括没有列出的步骤,或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤。
在本发明中提及的“多个”是指两个或两个以上。“和/或”,描述关联对象的关联关系,表示可以存在三种关系,例如,A和/或B,可以表示:单独存在A,同时存在A和B,单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本发明所述化合物中,当任何变量(例如R10、R11等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C20烷基”中“C1-C20”的定义包括以直链或支链排列的具有1、2、3、4、5、……或20 个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“C3~C7环烷基”包括环丙基、环丁基、环戊基、环己基、环庚基等。
本文所用术语“烷氧基”指烷基与氧直接连接的基团,即具有-O-烷基结构的基团,如 -OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。
本文所用术语“杂环基”是指含有1个或多个选自O、N和S的杂原子的非芳香性杂环基团,例如:哌啶基,四氢吡咯基(吡咯烷基)、吗啉基、哌嗪基等。杂环取代基的连接可以通过碳原子或通过杂原子实现。
本文所用术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环,本发明范围内的杂芳基包括但不限于:喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、恶唑基、异恶唑基、哒嗪基、苯并呋喃基、苯并噻吩基、苯并恶唑、吲哚基等;“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。杂芳基的连接可以通过碳原子或通过杂原子实现。
本文所用术语“取代的”是指用指定取代基的基团置换特定结构中的氢基。
正如本领域技术人员所理解的,本文中所用“卤素”意指包括氯、氟、溴和碘。
本发明包括式(I)或式(II)化合物的游离形式,也包括其药学上可接受的盐、其立体异构体及其前药分子。术语“游离形式”指以非盐形式的化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式(I)或式(II)化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等制备的盐,也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、苯磺酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N′-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
以下结合具体实施例对本发明作进一步详细的说明。
实施例1:3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基-N-(3-((4-甲基哌嗪-1-基)甲基)-5-(三氟甲基)苯基)苯甲酰胺(命名为XS116)的制备
步骤1:2-甲基-3-((三甲基甲硅烷基)乙炔基)苯甲酸甲酯(化合物2)的制备
500mL三颈瓶中,加入化合物110g(36mmol),碘化亚铜689mg(3.6mmol),二(三苯基膦)二氯化钯1.27g(1.8mmol),无水乙腈150mL,N,N-二异丙基乙胺9.3g(72mmol),置换氩气,封闭反应体系,然后用注射器注入三甲基硅乙炔10.6g(108mmol),60℃搅拌6 小时。用硅藻土过滤反应液,旋干溶剂得到黑色混合物,直接用于下一步反应。
步骤2:2-乙炔基-2-甲基苯甲酸甲酯(化合物3)的制备
将上一步粗产品用甲醇溶解,加入约20mL的1mol/L四丁基氟化铵的四氢呋喃溶液,常温搅拌2小时。旋干反应体系,柱层析得到黄棕色油状物4g(两步总产率63%)。
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.78(s,1H),7.58(s,1H),4.27(s,1H),3.85(s, 3H),2.37(s,3H).LC-MS(ESI)m/z 175.5[M+H]+.
步骤3:3-乙炔基-2-甲基苯甲酸(化合物4)的制备
将化合物31.5g(9mmol)溶于体积比为10∶1∶5的四氢呋喃、甲醇和水的混合溶剂中,然后加入氢氧化锂的水合物1.8g(40mmol),60℃搅拌1小时。过滤,旋干反应体系,然后加入4M盐酸溶液直至体系呈酸性,此时有白色固体析出,过滤收集白色固体,干燥,得到白色固体900mg(产率65%)。
1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),7.77(dd,J=7.8,0.9Hz,1H),7.62(d,J=7.6 Hz,1H),7.29(t,J=7.7Hz,1H),4.47(s,1H),2.61(s,3H).LC-MS(ESI)m/z 158.9[M-H]-.
步骤4:3-乙炔基-2-甲基-N-(3-((4-甲基哌嗪-1-基)甲基)-5-(三氟甲基)苯基)苯甲酰胺(化合物6)的制备
将化合物42.3g,化合物53.4g溶于40mL的N,N-二甲基甲酰胺(DMF)中,加入 2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)9.12g(24mmol),N,N-二异丙基乙胺2.3g(18mmol)。70℃加热搅拌2小时。旋干反应体系,加水,用乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋干溶剂,柱层析得到黄色油状物3.4g(产率70%)。
1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.17(s,1H),8.10(s,1H),8.00(d,J=8.0Hz, 1H),7.91(m,1H),7.47(d,J=8.0Hz,1H),7.34(s,1H),4.51(s,1H),3.53(s,2H),2.46(s,3H), 2.39(s,4H),2.33(s,4H),2.15(s,3H).LC-MS(ESI)m/z 416.3[M+H]+.
步骤5:3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基-N-(3-((4-甲基哌嗪-1-基)甲基) -5-(三氟甲基)苯基)苯甲酰胺(XS116)的制备
将化合物6210mg(0.51mmol)和化合物7120mg(0.61mmol)溶于10mL无水N,N-二甲基甲酰胺(DMF)中,然后加入碘化亚铜19mg(0.1mmol),二(三苯基膦)二氯化钯35mg(0.05mmol),N,N-二异丙基乙胺131mg(1.02mmol),置换氩气,封闭反应体系。80℃加热搅拌,过夜反应。用硅藻土过滤,旋干滤液,柱层析得到黄白色固体70mg(产率26%)。
1H NMR(400MHz,Chloroform-d)δ8.50(dd,J=4.4,1.6Hz,1H),8.07(s,1H),8.02(dd,J= 9.2,1.7Hz,1H),7.94(s,1H),7.81(d,J=4.5Hz,2H),7.73(dd,J=7.7,1.4Hz,1H),7.50(d,J= 7.8Hz,1H),7.41(s,1H),7.32(t,J=7.7Hz,1H),7.16(dd,J=9.2,4.4Hz,1H),3.62(s,2H),2.76 (s,3H),2.64(s,8H),2.41(s,3H).LC-MS(ESI)m/z 533.3[M+H]+.
实施例2:3-(咪唑并[1,2-a]嘧啶-3-基乙炔基)-2-甲基-N-(3-((4-甲基哌嗪-1-基)甲基)-5-(三氟甲基)苯基)苯甲酰胺(命名为XS2-161)的制备
合成方法如实施例1。
1H NMR(400MHz,Chloroform-d)δ9.06(s,1H),8.64(dd,J=4.1,2.0Hz,1H),8.60(dd,J= 6.8,2.0Hz,1H),8.12(s,1H),8.03(s,1H),7.90(s,1H),7.58(dd,J=7.8,1.3Hz,1H),7.50(dd,J= 7.8,1.3Hz,1H),7.40(s,1H),7.25(t,J=7.7Hz,1H),7.09(dd,J=6.8,4.1Hz,1H),3.70(s,2H), 3.11(q,J=7.3Hz,4H),2.91(d,J=5.0Hz,4H),2.73(s,3H),2.61(s,3H).LC-MS(ESI)m/z 533.2[M+H]+.
实施例3:3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(命名为XS2-106)的制备
步骤1:3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基苯甲酸甲酯(化合物3)的制备
将化合物12.5g(14mmol)和化合物23.4g(17mmol)溶于40mL无水N,N-二甲基甲酰胺(DMF)中,然后加入碘化亚铜533mg(2.8mmol),二(三苯基膦)二氯化钯982mg(1.4mmol),N,N-二异丙基乙胺3.6g(28mmol),置换氩气,封闭反应体系。80℃加热搅拌,过夜反应。用硅藻土过滤,旋干滤液,柱层析得到黄色粉末状固体1.38g(收率34%)。
1H NMR(400MHz,DMSO-d6)δ8.74(d,J=4.3Hz,1H),8.27(d,J=8.9Hz,2H),7.83(d,J =7.7Hz,1H),7.75(d,J=7.5Hz,1H),7.44-7.41(m,1H),7.39(d,J=7.6Hz,1H),3.85(s,3H), 2.76(s,3H).LC-MS(ESI)m/z 292.3[M+H]+.
步骤2:3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基苯甲酸(化合物4)
将化合物31.38g(4.7mmol)溶于体积比为10∶1∶5的四氢呋喃、甲醇和水的混合溶剂中,然后加入氢氧化锂的水合物995mg(24mmol),60℃搅拌1小时。过滤,旋干反应体系,然后加入4M盐酸溶液直至体系呈酸性,此时有固体析出,过滤收集固体,干燥,得到黄色固体1.05g(收率81%)。
1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.72(d,J=3.9Hz,1H),8.32-8.19(m,2H), 7.83(d,J=7.6Hz,1H),7.75(d,J=7.3Hz,1H),7.44-7.34(m,2H),2.76(s,3H).LC-MS(ESI) m/z 276.8[M-H]-.
步骤3:3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(XS2-106)
将化合物4100mg(0.36mmol),化合物548mg(0.3mmol)溶于10mL的N,N-二甲基甲酰胺(DMF)中,加入2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)137mg(0.36mmol),N,N-二异丙基乙胺77mg(0.6mmol)。80摄氏度加热搅拌,过夜反应。旋干反应体系,柱层析得到黄白色固体51mg(收率40%)。
1H NMR(400MHz,Chloroform-d)δ8.51(d,J=4.1Hz,1H),8.03(dd,J=23.3,14.3Hz,3H), 7.89(d,J=7.4Hz,1H),7.73(d,J=6.6Hz,2H),7.50(ddd,J=24.8,16.6,7.8Hz,3H),7.32(t,J= 7.7Hz,1H),7.17(dd,J=9.1,4.4Hz,1H),2.76(s,3H).LC-MS(ESI)m/z 419.2[M-H]-.
实施例4:N-(3-氟-5-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基苯甲酰胺(命名为XS2-109)的制备
合成方法如实施例3。
1H NMR(400MHz,Chloroform-d)δ8.53(d,J=4.2Hz,1H),8.08(s,2H),7.91(d,J=10.1 Hz,1H),7.81(s,1H),7.74(d,J=7.8Hz,1H),7.59(s,1H),7.50(d,J=7.5Hz,1H),7.33(t,J=7.7 Hz,1H),7.19(s,1H),7.16(d,J=8.2Hz,1H),2.75(s,3H).LC-MS(ESI)m/z437.6[M-H]-.
实施例5:N-(3-氯-5-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-2-甲基苯甲酰胺(命名为XS2-112)的制备
合成方法如实施例3。
1H NMR(400MHz,Chloroform-d)δ8.50(dd,J=4.4,1.5Hz,1H),8.06(d,J=4.2Hz,2H), 8.01(dd,J=9.2,1.6Hz,1H),7.85(s,1H),7.80(s,1H),7.74(d,J=6.7Hz,1H),7.48(d,J=6.9 Hz,1H),7.44(s,1H),7.32(t,J=7.7Hz,1H),7.16(dd,J=9.2,4.4Hz,1H),2.75(s,3H).LC-MS (ESI)m/z 455.5[M+H]+.
实施例6:2-甲基-3-((6-吗啉代咪唑并[1,2-b]哒嗪-3-基)乙炔基)-N-(3-(三氟甲基) 苯基)苯甲酰胺(命名为XS3-23)的制备
步骤1:3-乙炔基-2-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(化合物3)制备的
将化合物1120mg(0.74mmol),化合物2101mg(0.62mmol)溶于15mL的N,N-二甲基甲酰胺(DMF)中,加入2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU) 353mg(0.93mmol),N,N-二异丙基乙胺160mg(1.24mmol)。80℃加热搅拌2小时。旋干反应体系,加水,用乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋干溶剂,柱层析得到黄色油状物150mg(收率80%)。
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.26(d,J=2.0Hz,1H),7.95-7.90(m,1H), 7.63-7.58(m,2H),7.53(dd,J=7.7,1.4Hz,1H),7.49-7.45(m,1H),7.35(t,J=7.7Hz,1H), 4.52(s,1H),2.47(s,3H).LC-MS(ESI)m/z 304.1[M+H]+.
步骤2:4-(3-碘咪唑并[1,2-b]哒嗪-6-基)吗啉(化合物5)的制备
将化合物4300mg(1.07mmol)溶于15mL的二甲基亚砜(DMSO)中,加入吗啉280mg(3.22mmol),氟化钾744mg(12.84mg)。120℃加热搅拌3小时。过滤,旋干反应体系,柱层析得到黄色粉末状固体260mg(收率74%)。
1H NMR(400MHz,Chloroform-d)δ7.70(d,J=9.8Hz,1H),7.64(s,1H),6.82(d,J=9.9Hz, 1H),3.89(t,J=4.8Hz,4H),3.57(t,J=4.9Hz,4H).LC-MS(ESI)m/z 331.0[M+H]+.
步骤3:2-甲基-3-((6-吗啉代咪唑并[1,2-b]哒嗪-3-基)乙炔基)-N-(3-(三氟甲基)苯基)苯甲酰胺(XS3-23)的制备
将化合物3138mg(0.45mmol)和化合物5300mg(0.91mmol)溶于10mL无水N,N-二甲基甲酰胺(DMF)中,然后加入碘化亚铜7mg(0.036mmol),三二亚苄基丙酮二钯21mg(0.023mmol),三叔丁基磷9mg(0.045mmol),碳酸钾124mg(0.9mmol),置换氩气,封闭反应体系。80℃加热搅拌,过夜反应。用硅藻土过滤,旋干滤液,柱层析得到黄白色固体 120mg(收率52%)。
1H NMR(400MHz,Chloroform-d)δ8.06-7.98(m,2H),7.91(d,J=8.1Hz,1H),7.87-7.74(m,2H),7.64(d,J=7.7Hz,1H),7.54(t,J=8.0Hz,1H),7.47(d,J=6.5Hz,2H),7.30(d,J= 7.6Hz,1H),6.90(d,J=9.5Hz,1H),3.87(t,J=4.7Hz,4H),3.57(t,J=4.8Hz,4H),2.73(s,3H). LC-MS(ESI)m/z 504.2[M-H]-.
实施例7:N-(3-氯-5-(三氟甲基)苯基)-2-甲基-3-((6-吗啉代咪唑并[1,2-b]哒嗪-3- 基)乙炔基)苯甲酰胺(命名为XS3-61)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.13(d,J=2.5Hz,2H),7.98(d,J=10.0Hz, 2H),7.70(dd,J=7.7,1.4Hz,1H),7.61(s,1H),7.56(dd,J=7.7,1.4Hz,1H),7.42(t,J=7.7Hz,1H),7.32(d,J=9.8Hz,1H),3.74(t,J=4.8Hz,4H),3.53(t,J=4.8Hz,4H),2.63(s,3H).LC-MS (ESI)m/z 539.8[M+H]+.
实施例8:N-(3-氟-5-(三氟甲基)苯基)-2-甲基-3-((6-甲基咪唑吡嗪-3-基-3-基) 苯甲酰胺(命名为XS4-80)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.02-7.96(m,2H),7.96-7.89(m,2H),7.70 (dd,J=7.8,1.4Hz,1H),7.55(dd,J=7.8,1.4Hz,1H),7.42(dd,J=8.9,6.3Hz,2H),7.31(d,J= 10.0Hz,1H),3.74(t,J=4.8Hz,4H),3.53(t,J=4.8Hz,4H),2.63(s,3H).HRMS(ESI)for C27H21F4N5O2[M+H]+:calcd 524.1704,found 524.1686.
实施例9:2-甲基-N-(3-甲基-5-(三氟甲基)苯基)-3-((6-甲基-1,2-B]哒嗪-3-基) 苯甲酰胺(命名为XS4-81)的制备
合成方法如实施例6。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.05-7.90(m,3H),7.80(s,1H),7.68(dd,J=7.7,1.4Hz,1H),7.52(dd,J=7.7,1.4Hz,1H),7.40(t,J=7.7Hz,1H), 7.34-7.28(m,2H),3.74(dd,J=5.8,3.9Hz,4H),3.53(t,J=4.8Hz,4H),2.62(s,3H),2.40(s, 3H).HRMS(ESI)for C28H24F3N5O2[M+H]+:calcd 520.1955,found 520.1939.
实施例10:N-(3-甲氧基-5-(三氟甲基)苯基)-2-甲基-3-((6-甲基咪唑吡嗪-3-基-3- 基)苯甲酰胺(命名为XS4-72)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),7.97(d,J=9.9Hz,1H),7.93(s,1H),7.81(s, 1H),7.68(dd,J=7.8,1.4Hz,1H),7.62(t,J=2.2Hz,1H),7.53(dd,J=7.8,1.4Hz,1H),7.41(t,J =7.7Hz,1H),7.31(d,J=9.9Hz,1H),7.01(t,J=2.0Hz,1H),3.84(s,3H),3.74(dd,J=5.8,3.8 Hz,4H),3.53(t,J=4.8Hz,4H),2.62(s,3H).HRMS(ESI)forC27H21ClF3N5O2[M+H]+:calcd 536.1904.found 536.1919.
实施例11:N-(3,5-双(三氟甲基)苯基)-2-甲基-3-((6-甲基咪唑吡嗪-3-基-3-基)苯甲酰胺(命名为XS4-76)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.44(s,2H),7.98(d,J=10.0Hz,2H),7.85(s, 1H),7.71(dd,J=7.8,1.4Hz,1H),7.59(dd,J=7.8,1.4Hz,1H),7.43(t,J=7.7Hz,1H),7.32(d, J=9.5Hz,1H),3.74(t,J=4.8Hz,4H),3.53(t,J=4.8Hz,4H),2.64(s,3H).HRMS(ESI)for C28H21F6N5O2[M+H]+:calcd 574.1672,found 574.1676.
实施例12:2-甲基-3-((6-甲基咪唑吡嗪-3-基)乙炔基)-N-(3-硝基-5-(三氟甲基) 苯基)苯甲酰胺(命名为XS4-77)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.95(t,J=2.1Hz,1H),8.53(s,1H),8.23(d, J=2.1Hz,1H),7.97(d,J=9.9Hz,1H),7.93(s,1H),7.72(dd,J=7.8,1.4Hz,1H),7.60(dd,J= 7.7,1.4Hz,1H),7.44(t,J=7.7Hz,1H),7.31(dd,J=10.1,1.6Hz,1H),3.74(t,J=4.8Hz,4H),3.53(t,J=4.9Hz,4H),2.65(s,3H).HRMS(ESI)for C27H21F3N6O4[M+H]+:calcd551.1649, found 551.1667.
实施例13:2-甲基-N-(3-((4-甲基哌嗪-1-基)甲基)-5-(三氟甲基)苯基)-3-((6-吗啉代咪唑并[1,2-b]哒嗪-3-基)乙炔基)苯甲酰胺(命名为XS3-68)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.22(s,1H),7.98(s,1H),7.82(s,1H),7.77(s,1H),7.70 (d,J=9.8Hz,1H),7.62(dd,J=7.7,1.4Hz,1H),7.45-7.40(m,2H),7.26(d,J=7.7Hz,1H), 6.86(d,J=9.9Hz,1H),3.88-3.84(m,4H),3.59(s,2H),3.57-3.53(m,4H),2.71(s,3H),2.52(s, 8H),2.32(s,3H).LC-MS(ESI)m/z 618.3[M+H]+.
实施例14:(S)-3-((6-(3-羟基吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2- 甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(命名为XS3-35)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),8.05(s,1H),7.91(d,J=8.1Hz,1H),7.74(s,1H),7.65 7.57(m,2H),7.54(t,J=7.9Hz,1H),7.46(d,J=7.8Hz,1H),7.41(d,J=7.9Hz,1H),7.24(t,J=7.6Hz,1H), 6.58(d,J=8.8Hz,1H),5.03(d,J=3.7Hz,1H),4.42(s,1H),3.623.50(m,3H),3.40(d,J=11.3 Hz,1H),2.67(s,3H),2.101.98(m,1H),1.92(d,J=12.9Hz,1H).
.LC-MS(ESI)m/z 504.2[M-H]-.
实施例15:(S)-N-(3-氯-5-(三氟甲基)苯基)-3-((6-(3-羟基吡咯烷-1-基)咪唑并 [1,2-b]哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-58)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.27(s,1H),8.08(s,1H),7.86(s,1H),7.72(s,1H),7.64 -7.59(m,2H),7.44(d,J=1.8Hz,1H),7.39(dd,J=7.7,1.4Hz,1H),7.25(t,J=7.7Hz,1H), 6.60(d,J=9.6Hz,1H),4.66(s,1H),3.70-3.54(m,5H),2.71(s,3H),2.16(dd,J=7.9,3.9Hz, 2H).LC-MS(ESI)m/z 540.0[M+H]+.
实施例16:(S)-3-((6-(3-羟基吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2-甲基-N-(3-((4-甲基哌嗪-1-基)甲基)-5-(三氟甲基)苯基)苯甲酰胺(命名为XS3-36)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.18(s,1H),8.02(s,1H),7.79(s,1H),7.72(s,1H),7.63 -7.58(m,2H),7.41(d,J=5.1Hz,2H),7.25(t,J=7.7Hz,1H),6.58(d,J=9.7Hz,1H),4.64(dd, J=4.3,2.2Hz,1H),3.68-3.56(m,7H),2.74(s,3H),2.51(s,8H),2.31(s,3H),2.17-2.09(m, 2H).LC-MS(ESI)m/z 618.3[M+H]+.
实施例17:3-((6-(4-(二甲基氨基)哌啶-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2- 甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(命名为XS3-57)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.27(d,J=2.3Hz,1H),7.95(d,J=2.6Hz, 1H),7.93(d,J=3.2Hz,1H),7.90(s,1H),7.68(dd,J=7.7,1.4Hz,1H),7.61(t,J=8.1Hz,1H),7.55(dd,J=7.7,1.4Hz,1H),7.48(d,J=7.8Hz,1H),7.42(t,J=7.7Hz,1H),7.34(d,J=10.0Hz, 1H),4.30(d,J=13.4Hz,2H),2.97(t,J=12.0Hz,2H),2.65(s,3H),2.34(s,6H),1.90(d,J=12.1 Hz,2H),1.57-1.41(m,3H).LC-MS(ESI)m/z 547.2[M+H]+.
实施例18:N-(3-氟-5-(三氟甲基)苯基)-3-((6-(4-(二甲基氨基)哌啶-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-56)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.30(s,1H),8.09(d,J=2.3Hz,1H),7.86(s,1H),7.74 (s,1H),7.66-7.60(m,2H),7.44(s,1H),7.40(dd,J=7.7,1.4Hz,1H),7.28-7.23(m,1H),6.90 (d,J=9.9Hz,1H),4.26(d,J=12.9Hz,2H),2.98(t,J=12.8Hz,2H),2.72(s,3H),2.41(t,J= 11.2Hz,1H),2.33(s,6H),2.01-1.93(m,2H),1.66-1.54(m,2H).LC-MS(ESI)m/z 579.3[M -H]-.
实施例19:3-((6-(4-(二甲基氨基)哌啶-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2- 甲基-N-(3-((4-甲基哌嗪-1-基)甲基)-5-(三氟甲基)苯基)苯甲酰胺(命名为XS3-67) 的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.15(s,1H),7.92(d,J=9.8Hz,2H),7.89(s, 1H),7.67(d,J=6.4Hz,1H),7.54(d,J=6.9Hz,1H),7.40(t,J=7.7Hz,1H),7.37(s,1H),7.32(d, J=10.0Hz,1H),4.26(d,J=13.0Hz,2H),3.54(s,2H),2.96(t,J=12.1Hz,2H),2.64(s,3H), 2.45-2.29(m,8H),2.18(s,6H),2.16(s,3H),2.00(q,J=7.5Hz,1H),1.83(d,J=11.5Hz,2H), 1.44(q,J=10.5,9.3Hz,2H).LC-MS(ESI)m/z 658.3[M+H]+.
实施例20:N-(3-氯-5-(三氟甲基)苯基)-2-甲基-3-((6-(4-甲基哌嗪-1-基)咪唑并 [1,2-b]哒嗪-3-基)乙炔基)苯甲酰胺(命名为XS3-51)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.08(s,2H),7.86(s,1H),7.83(d,J=3.4Hz,1H),7.78 -7.72(m,1H),7.66(d,J=7.6Hz,1H),7.46(d,J=7.7Hz,1H),7.43(s,1H),7.32(d,J=7.7Hz, 1H),6.89(d,J=9.9Hz,1H),3.80(s,4H),3.13(s,3H),2.74(s,3H),2.53(d,J=21.6Hz,4H). LC-MS(ESI)m/z 553.2[M+H]+.
实施例21:(R)-N-(3-氯-5-(三氟甲基)苯基)-3-((6-(3,4-二甲基哌嗪-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-52)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.13(s,2H),8.06(s,1H),7.97(s,1H),7.71 (d,J=7.2Hz,1H),7.62(s,1H),7.58(d,J=7.3Hz,1H),7.44(t,J=7.6Hz,1H),7.39(d,J=9.5 Hz,1H),3.13-3.06(m,4H),2.91(s,2H),2.75(m,1H),2.65(s,3H),2.46(s,3H),1.24(s,3H). LC-MS(ESI)m/z 567.2[M+H]+.
实施例22:N-(3-氯-5-(三氟甲基)苯基)-3-((6-(4-羟基哌啶-1-基)咪唑并[1,2-b] 哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-55)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.14(d,J=1.8Hz,2H),7.94-7.88(m,2H),7.69(dd,J=7.7,1.4Hz,1H),7.61(s,1H),7.56(dd,J=7.7,1.4Hz,1H),7.42(t,J=7.7Hz,1H),7.32(d,J=10.0Hz,1H),4.71(d,J= 4.2Hz,1H),4.00-3.93(m,2H),3.74(m,1H),3.25(t,J=13.1Hz,2H),2.64(s,3H),1.82(d,J=12.8Hz,2H),1.49- 1.40(m,2H).LC-MS(ESI)m/z 552.1[M-H]-.
实施例23:3-((6-(4-乙酰基哌嗪-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-N-(3-氯 -5-(三氟甲基)苯基)-2-甲基苯甲酰胺(命名为XS3-54)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.14(d,J=1.7Hz,2H),7.98(d,J=9.9Hz, 1H),7.93(s,1H),7.71(dd,J=7.7,1.3Hz,1H),7.61(d,J=2.0Hz,1H),7.57(dd,J=7.7,1.4Hz, 1H),7.43(t,J=7.7Hz,1H),7.34(d,J=10.0Hz,1H),3.66-3.53(m,8H),2.65(s,3H),2.04(s, 3H).LC-MS(ESI)m/z581.5[M+H]+.
实施例24:N-(3-氟-5-(三氟甲基)苯基)-2-甲基-3-((6-((2-吗啉代乙基)氨基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)苯甲酰胺(命名为XS3-53)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.28(s,1H),8.08(s,1H),7.87(s,1H),7.66(d,J=7.7 Hz,2H),7.47(d,J=7.5Hz,1H),7.44(s,1H),7.34(d,J=7.9Hz,1H),7.31(s,1H),6.73(s,2H), 4.01(s,4H),3.78(s,2H),3.19(s,2H),3.05(s,4H),2.71(s,3H).LC-MS(ESI)m/z583.2[M+H]+
实施例25:3-((6-(4-羟基哌啶-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2-甲基-N- (3-(((4-甲基哌嗪-1-基)甲基)-5-(三氟甲基)苯基)苯甲酰胺(命名为XS3-81)的制备
合成方法如实施例6。
1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),8.01(s,1H),7.80(s,1H),7.73(s,1H),7.62 (d,J=9.9Hz,1H),7.59(dd,J=7.8,1.4Hz,1H),7.43-7.38(m,2H),7.24(t,J=7.7Hz,1H), 6.88(d,J=9.9Hz,1H),4.0-3.91(m,3H),3.59(s,2H),3.28(t,J=13.1Hz,2H),2.70(s,3H), 2.51(s,8H),2.31(s,3H),1.99-1.95(m,2H),1.69-1.61(m,2H).LC-MS(ESI)m/z632.3[M +H]+.
实施例26:N-(3-氟-5-(三氟甲基)苯基)-2-甲基-3-((6-(4-吗啉哌啶-1-基)咪唑并 [1,2-b]哒嗪-3-基)乙炔基)苯甲酰胺(命名为XS3-130)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.13(s,2H),7.92(d,J=9.8Hz,2H),7.69(d,J=7.3Hz,1H),7.61(s,1H),7.56(d,J=7.4Hz,1H),7.42(t,J=7.7Hz,1H),7.33(d,J=9.8Hz, 1H),4.26(d,J=13.0Hz,2H),3.54(s,4H),2.97(t,J=12.3Hz,2H),2.64(s,3H),2.45(s,5H), 1.86(d,J=12.8Hz,2H),1.45(d,J=12.2Hz,2H).HRMS(ESI)forC32H30ClF3N6O2[M+H]+: calcd 623.2144.found 623.2126.
实施例27:N-(3-氯-5-(三氟甲基)苯基)-2-甲基-3-((6-(4-(氧杂环丁基-3-基)哌嗪-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)苯甲酰胺(命名为XS3-138)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.13(s,2H),7.98-7.87(m,2H),7.69(d,J= 8.2Hz,1H),7.61(s,1H),7.56(d,J=6.9Hz,1H),7.42(t,J=7.7Hz,1H),7.34(d,J=9.9Hz,1H), 4.55(t,J=6.5Hz,2H),4.47(t,J=6.1Hz,2H),3.60(t,J=5.1Hz,4H),3.45(m,1H),2.63(s, 3H),2.40(t,J=5.0Hz,4H).HRMS(ESI)for C30H26ClF3N6O2[M+H]+:calcd595.1831,found 595.1811.
实施例28:N-(3-氯-5-(三氟甲基)苯基)-3-((6-((2-(二甲氨基)乙基)(甲基) 氨基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-134)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.13(d,J=1.8Hz,2H),7.90-7.82(m,2H), 7.68(dd,J=7.7,1.4Hz,1H),7.60(d,J=1.8Hz,1H),7.55(dd,J=7.8,1.3Hz,1H),7.41(t,J= 7.7Hz,1H),7.14(d,J=10.0Hz,1H),3.64(t,J=6.7Hz,2H),3.09(s,3H),2.63(s,3H),2.45(t,J =6.7Hz,2H),2.16(s,6H).HRMS(ESI)for C28H26ClF3N6O[M+H]+:calcd555.1881,found 555.1862.
实施例29:N-(3-氯-5-(三氟甲基)苯基)-3-((6-((2-甲氧基乙基)氨基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-135)的制备
合成方法如实施例6。
1H NMR(600MHz,DMSO-d6)δ10.93(s,1H),8.14-8.09(m,2H),7.81-7.73(m,2H),7.67 (dd,J=7.7,1.3Hz,1H),7.59(d,J=1.9Hz,1H),7.54(dd,J=7.7,1.3Hz,1H),7.41(t,J=7.7Hz, 1H),7.27(t,J=5.5Hz,1H),6.82(d,J=9.6Hz,1H),3.54(t,J=5.5Hz,2H),3.47-3.45(m,2H), 3.26(s,3H),2.63(s,3H).HRMS(ESI)for C26H21ClF3N5O2[M+H]+:calcd528.1409,found 528.1394.
实施例30:N-(3-氯-5-(三氟甲基)苯基)-3-((6-((4-羟基丁基)氨基)咪唑[1,2-b] 哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-139)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.12(s,2H),7.76(d,J=9.6Hz,2H),7.68(dd,J=7.7,1.4Hz,1H),7.61(s,1H),7.55(dd,J=7.7,1.4Hz,1H),7.41(t,J=7.7Hz,1H),7.16 (t,J=5.3Hz,1H),6.77(d,J=8.9Hz,1H),4.38(t,J=5.1Hz,1H),3.43-3.37(m,2H),3.30- 3.25(m,2H),2.65(s,3H),1.70-1.59(m,2H),1.53-1.46(m,2H).HRMS(ESI)forC27H23ClF3N5O2[M+H]+:calcd 542.1565,found 542.1552.
实施例31:3-((6-(4-氨基哌啶-1-基)咪唑[1,2-b]哒嗪-3-基)乙炔基)-N-(3-氯-5-(三氟甲基)苯基)-2-甲基苯甲酰胺(命名为XS3-131)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.15(s,2H),7.96(d,J=9.9Hz,1H),7.92(s, 1H),7.70(dd,J=7.8,1.3Hz,1H),7.61(d,J=2.3Hz,1H),7.57(dd,J=7.7,1.3Hz,1H),7.43(t, J=7.7Hz,1H),7.34(d,J=10.0Hz,1H),4.23(d,J=13.4Hz,2H),3.17(s,2H),3.12-3.02(m,2H),2.65(s,3H),2.63(m,1H),1.89(d,J=11.2Hz,2H),1.48(q,J=11.7,10.8Hz,2H).HRMS (ESI)for C28H24ClF3N6O[M+H]+:calcd 553.1725,found553.1708.
实施例32:(R)-3-((6-(3-氨基哌啶-1-基)咪唑[1,2-b]哒嗪-3-基)乙炔基)-N-(3- 氯-5-(三氟甲基)苯基)-2-甲基苯甲酰胺(命名为XS3-137)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.13(s,2H),7.92-7.85(m,2H),7.69(d,J= 7.6Hz,1H),7.60(s,1H),7.55(d,J=7.6Hz,1H),7.42(t,J=7.7Hz,1H),7.28(d,J=10.0Hz, 1H),4.04(dd,J=10.6,6.5Hz,2H),2.98(m,1H),2.78-2.69(m,2H),2.65(s,3H),1.86(m,1H), 1.74(m,1H),1.61-1.43(m,2H).HRMS(ESI)for C28H24ClF3N6O[M+H]+:calcd553.1725, found 553.1706.
实施例33:(S)-3-((6-(3-氨基哌啶-1-基)咪唑[1,2-b]哒嗪-3-基)乙炔基)-N-(3- 氯-5-(三氟甲基)苯基)-2-甲基苯甲酰胺(命名为XS3-136)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.13(s,2H),7.95-7.84(m,2H),7.69(d,J= 7.6Hz,1H),7.60(s,1H),7.55(d,J=7.6Hz,1H),7.42(t,J=7.7Hz,1H),7.28(d,J=10.0Hz, 1H),4.04(dd,J=11.5,5.9Hz,2H),3.04-2.93(m,2H),2.80-2.70(m,2H),2.65(s,3H),1.86(d, J=12.0Hz,1H),1.74(m,1H),1.53(q,J=11.8Hz,1H).HRMS(ESI)forC28H24ClF3N6O[M+ H]+:calcd 553.1725,found 553.1703.
实施例34:N-(3-氯-5-(三氟甲基)苯基)-3-(6-(4-羟基-4-甲基哌啶-1-基)咪唑并[1,2-b] 哒嗪-3-基)乙炔基)-2-甲基苯甲酰胺(命名为XS3-153)的制备
合成方法如实施例6。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.13(t,J=2.1Hz,2H),7.90(d,J=10.2Hz,2H),7.69(dd,J=7.7,1.4Hz,1H),7.61(d,J=1.8Hz,1H),7.56(dd,J=7.7,1.4Hz,1H),7.42(t, J=7.7Hz,1H),7.32(d,J=10.0Hz,1H),4.39(s,1H),3.92-3.83(m,2H),3.44-3.37(m,2H), 2.64(s,3H),1.55(t,J=5.6Hz,4H),1.15(s,3H).HRMS(ESI)forC29H25ClF3N5O2[M+H]+: calcd 568.1722,found 568.1699.
实施例35:2-甲基-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)-3-((6-吗啉代咪唑并[1,2-b]吡啶并-3-基乙炔基)苯甲酰胺(命名为XS3-91)的制备
步骤1:4-甲基-1-(3-硝基-5-(三氟甲基)苯基)-1H-咪唑(化合物3)的制备
将化合物1 1g(4.5mmol),化合物2800mg(9.5mmol)溶于20mL二甲基亚砜(DMSO)中,然后加入850mg(7mmo1)碳酸钾。120℃加热搅拌,过夜反应。旋干反应体系,柱层析得到黄白色固体430mg(收率36%)。
1H NMR(400MHz,Chloroform-d)δ8.46(q,J=1.9Hz,2H),8.02-7.97(m,2H),7.17(s, 1H),2.36(d,J=1.0Hz,3H).LC-MS(ESI)m/z 272.1[M+H]+.
步骤2:3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯胺(化合物4)的制备
将化合物3430mg(1.59mmol)溶于乙醇∶水为7∶3的混合溶剂中,加入盐酸溶液使得反应体系称弱酸性,然后加入444mg(7.93mmol)铁粉。70℃加热搅拌2小时。硅藻土过滤,旋干反应体系,粗产品直接用于下一步反应。
步骤3:3-乙炔基-2-甲基-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)苯甲酰胺(化合物6)的制备
将化合物4270mg(1.12mmol),化合物5215mg(1.3mmol)溶于15mL的N,N-二甲基甲酰胺(DMF)中,然后加入638mg(1.68mmo1)2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU),216mg(1.68mmol)N,N-二异丙基乙胺(DIPEA)。80℃加热搅拌,过夜反应。旋干反应体系,加水,用乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋干溶剂,柱层析得到黄色油状物220mg(收率51%)。
1H NMR(400MHz,Chloroform-d)δ9.41(s,1H),8.22(s,1H),7.91(s,1H),7.73(s,1H),7.55 (d,J=7.6Hz,1H),7.43(d,J=7.2Hz,1H),7.34(s,1H),7.19(t,J=7.7Hz,1H),7.09(s,1H),3.34 (s,1H),2.58(s,3H),2.25(s,3H).LC-MS(ESI)m/z 384.1[M+H]+.
步骤4:2-甲基-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)-3-((6-吗啉代咪唑并[1,2-b]吡啶并-3-基乙炔基)苯甲酰胺(命名为XS3-91)的制备
将化合物6150mg(0.39mmol)和化合物7130mg(0.47mmol)溶于10mL无水N,N-二甲基甲酰胺(DMF)中,然后加入碘化亚铜6mg(0.03mmol),三二亚苄基丙酮二钯17mg(0.019mmol),三叔丁基磷8mg(0.039mmol),碳酸钾107mg(0.78mmol),置换氩气,封闭反应体系。80℃加热搅拌,过夜反应。用硅藻土过滤,旋干滤液,柱层析得到黄白色固体 40mg(收率18%)。
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.20(d,J=1.6Hz,2H),8.10(s,1H),7.98(d, J=9.9Hz,1H),7.93(s,1H),7.76(s,1H),7.72-7.69(m,1H),7.57(d,J=7.4Hz,1H),7.48(s, 1H),7.44(d,J=7.7Hz,1H),7.32(d,J=10.0Hz,1H),3.77-3.72(m,4H),3.54(t,J=4.9Hz, 4H),2.65(s,3H),2.19(d,J=1.0Hz,3H).LC-MS(ESI)m/z 586.6[M+H]+.
实施例36:3-((6-(4-羟基哌啶-1-基)咪唑并[1,2-b]哒嗪-3-基)乙炔基)-2-甲基-N- (3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)苯甲酰胺(命名为XS3-87)的制备
合成方法如实施例35。
1H NMR(400MHz,Chloroform-d)δ8.25(s,1H),7.97(s,1H),7.88(s,1H),7.83(s,1H),7.75 -7.70(m,2H),7.68(d,J=7.7Hz,1H),7.47(d,J=7.5Hz,1H),7.42(s,1H),7.33(t,J=7.7Hz, 1H),7.13(s,1H),6.93(d,J=9.9Hz,1H),4.05-3.97(m,3H),3.37-3.29(m,2H),2.78(s,3H), 2.33(d,J=1.0Hz,3H),2.03(d,J=9.6Hz,2H),1.69(d,J=9.5Hz,3H).LC-MS(ESI)m/z 600.0[M+H]+.
实施例37化合物对TRKs激酶的IC50测试
激酶活性检测:应用Z′-LYTETM技术(采用荧光进行检测、酶偶联形式,以磷酸化和非磷酸化多肽对蛋白水解切割的敏感性差异为基础),采用荧光共振能量转移(FRET)原理,使用Z′-LYTETM FRET肽类底物,二级反应检测化合物对TRKs(TRK1,TRK2,TRK3)激酶(美国生命技术公司,PV3144,PV3616,PV3617)的抑制活性。
酶促反应:384孔板中,加入5μL酶-底物体系[50mM 4-羟乙基哌嗪乙磺酸(HEPES)pH 7.5, 0.01%BRIJ-35,10mM氯化镁(MgCl2),1mM乙二醇双(2-氨基乙基醚)四乙酸(EGTA),2 μM Tyr 01肽底物,利用echo520超微量液体移液系统转入5nL化合物(浓度梯度),室温震荡10-20min后,利用echo520超微量液体移液系统分别转入200nL,12.5nL,25nLATP(终浓度分别为400uM,25uM,50uM),震荡混匀后离心,30℃避光反应1.5h。
检测反应:每孔加入2.5μL反应液(Development Solution)(1∶128稀释)37℃避光孵育1h,然后加入5μL终止液(Stop Reagent)。
读板:多标记微孔板检测仪(Perkin Elmer EnVision Multimode Plate Reader)检测荧光信号(激发光波长为400nm,发射光波长为460nm、535nm)。
计算:通过全活性孔和对照信号孔计算出每个孔的抑制率,数据分析方法如下:
磷酸化比率=1-{(发射比×F100%-C100%)/[C 0%-C 100%+发射比×(F100%- F0%)]}×100;
抑制率=100×(1-化合物磷酸化比率/阴性对照磷酸化比率)。
IC50值采用医学绘图软件(GraphPad Prism5.0)软件计算求得。
激酶活性测试结果如表1所示。
表1化合物激酶活性测试结果(IC50:nM)
IC50:<10nM=*;10-100nM=**;100-1000nM=***;>1uM=****。
从表1数据可以看出,本发明的炔苯基苯酰胺类化合物对TRKs激酶有很强的抑制活性。
实施例38:基于Ba/F3-TRKs稳定株的细胞增殖抑制活性研究
本实验使用的BaF3细胞(小鼠前B细胞)购自日本细胞库,BaF3-CD74-NTRK1、BaF3-ETV6-NTRK2、BaF3-ETV6-NTRK3单克隆稳定株均由本实验室构建,并通过阳性药活性、蛋白表达及基因测序等实验鉴定完全正确。
稳定株构建的简要步骤如下:构建携带CD74-NTRK1、ETV6-NTRK2、ETV6-NTRK3等基因的pCDNA3.1(+)质粒载体;使用Cell Line KitV试剂盒将质粒电转入Ba/F3细胞;电转48小时后,加入终浓度为1000μg/ml的遗传霉素(G418)筛选两周并撤去白介素3(IL3)继续筛选,获得多克隆稳定株;然后通过极限稀释法挑选单克隆;进而使用阳性药、蛋白免疫印迹(Western Blot,WB)、基因测序对稳定株进行鉴定;鉴定完全正确的单克隆即可用于抑制剂的细胞增殖抑制活性研究。
细胞增殖抑制活性研究:将对数生长期的细胞按8000-12000个/孔接种到96孔板,次日加入不同浓度的抑制剂(0-10μM),继续培养72小时;然后每孔加入10μL CellCounting Kit-8 细胞计数试剂(CCK-8试剂),继续孵育1-3小时;接着用超级酶标仪测定其在450nm及650nm 的吸光值。使用医学绘图软件(GraphPad Prism8.0.0)计算半数抑制浓度(IC50)。
测试结果如表2所示。
表2化合物细胞活性测试结果(IC50:nM)
IC50:<10nM=*;10-100nM=**;100-1000nM=***;>1uM=****。
从表2数据可以看出,本发明的炔苯基苯酰胺类化合物对Ba/F3-TRKs稳定株的细胞增殖有很强的抑制活性。
实施例39:基于Ba/F3-TRKs稳定株的耐药细胞增殖抑制活性研究
本实验使用的BaF3细胞(小鼠前B细胞)购自日本细胞库,BaF3-CD74-NTRK1-G667C、 BaF3-CD74-NTRK1-F589L、BaF3-CD74-NTRK1-G595R、BaF3-CD74-NTRK1-G667A、BaF3-CD74-NTRK1-V573M、BaF3-ETV6-NTRK2-G639R、BaF3-ETV6-NTRK2-G709C、 BaF3-ETV6-NTRK2-V617M、BaF3-ETV6-NTRK2-F633L、BaF3-ETV6-NTRK3-G696C、 BaF3-ETV6-NTRK3-G696A、BaF3-ETV6-NTRK3-G623R、BaF3-ETV6-NTRK3-G623E、 BaF3-ETV6-NTRK3-F617L、BaF3-ETV6-NTRK3-V601M单克隆稳定株均由本实验室构建,并通过阳性药活性、蛋白表达及基因测序等实验鉴定完全正确。
稳定株构建的简要步骤如下:构建携带BaF3-CD74-NTRK1-G667C、 BaF3-CD74-NTRK1-F589L、BaF3-CD74-NTRK1-G595R、BaF3-CD74-NTRK1-G667A、 BaF3-CD74-NTRK1-V573M、BaF3-ETV6-NTRK2-G639R、BaF3-ETV6-NTRK2-G709C、 BaF3-ETV6-NTRK2-V617M、BaF3-ETV6-NTRK2-F633L、BaF3-ETV6-NTRK3-G696C、 BaF3-ETV6-NTRK3-G696A、BaF3-ETV6-NTRK3-G623R、BaF3-ETV6-NTRK3-G623E、 BaF3-ETV6-NTRK3-F617L、BaF3-ETV6-NTRK3-V601M等基因的pCDNA3.1(+)质粒载体;使用Cell Line Kit V试剂盒将质粒电转入Ba/F3细胞;电转48小时后,加入终浓度为1000μg/ml的遗传霉素(G418)筛选两周并撤去白介素3(IL3)继续筛选,获得多克隆稳定株;然后通过极限稀释法挑选单克隆;进而使用阳性药、蛋白免疫印迹 (Westem Blot,WB)、基因测序对稳定株进行鉴定;鉴定完全正确的单克隆即可用于抑制剂的细胞增殖抑制活性研究。
细胞增殖抑制活性研究:将对数生长期的细胞按8000-12000个/孔接种到96孔板,次日加入不同浓度的抑制剂(0-10μM),继续培养72小时;然后每孔加入10μL CellCounting Kit-8 细胞计数试剂(CCK-8)试剂,继续孵育1-3小时;接着用超级酶标仪测定其在450nm及650nm 的吸光值。使用医学绘图软件(GraphPad Prism 8.0.0)计算半数抑制浓度(IC50)。
测试结果如表3所示。
表3化合物耐药细胞活性测试结果(IC50:nM)
IC50:<10nM=*;10-100nM=**;100-1000nM=***;>1uM=****。
从表3数据可以看出,本发明的炔苯基苯酰胺类化合物对Ba/F3-TRKs稳定株的耐药细胞增殖有很强的抑制活性。
实施例40化合物XS3-55激酶选择性的IC50测试
激酶活性检测:应用Z′-LYTETM技术(采用荧光进行检测、酶偶联形式,以磷酸化和非磷酸化多肽对蛋白水解切割的敏感性差异为基础),采用荧光共振能量转移(FRET)原理,使用Z′-LYTETM FRET肽类底物,二级反应检测化合物XS3-55及对照分子XS4-128和Ponatinib(帕纳替尼)对Bcr-Abl,SRC,RET,,PDGFRA,PDGFRB,VEGFR2和Kit激酶的抑制活性。
其中,化合XS4-128的结构式如下:
其制备方法如下:
步骤1:甲基4-甲基-3-((三甲基甲硅烷基)乙炔基)苯甲酸酯(化合物2)的制备
100mL三颈瓶中,加入化合物11g(3.6mmol),碘化亚铜69mg(0.36mmol),二(三苯基膦)二氯化钯127mg(0.18mmol),无水乙腈50mL,N,N-二异丙基乙胺934mg(7.2mmol),置换氩气,封闭反应体系,然后用注射器注入三甲基硅乙炔1.06g(10.8mmol),60℃搅拌6 小时。用硅藻土过滤反应液,旋干溶剂得到黑色混合物,直接用于下一步反应。
步骤2:甲基3-乙炔基-4-甲基苯甲酸甲酯(化合物3)的制备
将上一步粗产品用甲醇溶解,加入约2mL的1mol/L四丁基氟化铵的四氢呋喃溶液,常温搅拌2小时。旋干反应体系,柱层析得到黄棕色油状物470mg(两步总产率75%)。
1H NMR(400MHz,DMSO-d6)δ8.06(d,J=1.5Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.25 (dd,J=7.5,1.0Hz,1H),4.25(s,1H),3.86(s,3H),2.39(s,3H).LC-MS(ESI)m/z175.5[M+H]+.
步骤3:3-乙炔基-4-甲基苯甲酸(化合物4)的制备
将化合物3400mg(2.29mmol)溶于体积比为10∶1:5的四氢呋喃、甲醇和水的混合溶剂中,然后加入氢氧化锂的水合物482mg(11.4mmol),60℃搅拌1小时。过滤,旋干反应体系,然后加入4M盐酸溶液直至体系呈酸性,此时有白色固体析出,过滤收集白色固体,干燥,得到白色固体350mg(产率96%)。
1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.93(d,J=1.8Hz,1H),7.85(dd,J=7.9,1.9 Hz,1H),7.43(d,J=8.0Hz,1H),4.48(s,1H),2.45(s,3H).LC-MS(ESI)m/z 160.9[M+H]+.
步骤4:N-(3-氯-5-(三氟甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺(化合物6)的制备
将化合物4300mg(1.9mmol),化合物5305mg(1.6mmol)溶于20mL的N,N-二甲基甲酰胺(DMF)中,加入2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)912mg(2.4mmol),N,N-二异丙基乙胺413mg(3.2mmol)。70℃加热搅拌2小时。旋干反应体系,加水,用乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋干溶剂,柱层析得到黄色油状物340mg (产率63%)。
1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.11(d,J=1.8Hz,2H),7.64-7.57(m,2H), 7.54(dd,J=7.7,1.4Hz,1H),7.36(t,J=7.7Hz,1H),4.51(s,1H),2.47(s,3H).MS(ESI)m/z 335.8[M-H]-.
步骤5:N-(3-氯-5-(三氟甲基)苯基)-3-((6-(4-羟基哌啶-1-基)咪唑[1,2-B]哒嗪-3-基)乙炔基)-4-甲基苯甲酰胺(XS4-128)的制备
将化合物670mg(0.2mmol)和化合物783mg(1.2mmol)溶于10mL无水N,N-二甲基甲酰胺(DMF)中,然后加入碘化亚铜8mg(0.016mmol),二(三苯基膦)二氯化钯19mg(0.01mmol),N,N-二异丙基乙胺145mg(0.4mmol),置换氩气,封闭反应体系。80℃加热搅拌,过夜反应。用硅藻土过滤,旋干滤液,柱层析得到黄白色固体80mg(产率73%)。
1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.25(s,2H),8.16(d,J=9.2Hz,2H),7.96(s, 1H),7.90(dd,J=8.0,1.9Hz,1H),7.55(s,1H),7.52(d,J=8.1Hz,1H),7.34(s,1H),4.75(d,J=4.2Hz,1H),3.98(d,J=14.5Hz,2H),3.80-3.71(m,1H),3.26(t,J=11.5Hz,2H),2.61(s,3H), 1.89-1.78(m,2H),1.54-1.40(m,2H).HRMS(ESI)for C28H23ClF3N5O2[M+H]+:calcd 554.1565.found 554.1562.
酶促反应:384孔板中,加入5μL酶-底物体系(50mM 4-羟乙基哌嗪乙磺酸(HEPES)pH 7.5,0.01%BRIJ-35,10mM氯化镁(MgCl2),1mM乙二醇双(2-氨基乙基醚)四乙酸(EGTA),2μM Tyr 01肽底物),利用echo520超微量液体移液系统转入5nL化合物(浓度梯度),室温震荡10-20min后,利用echo520超微量液体移液系统分别转入200nL,12.5nL,25nLATP (终浓度分别为400uM,25uM,50uM),震荡混匀后离心,30℃避光反应1.5h。
检测反应:每孔加入2.5μL反应液(Development Solution)(1∶128稀释)37℃避光孵育1h,然后加入5μL终止液(Stop Reagent)。
读板:多标记微孔板检测仪(Perkin Elmer EnVision Multimode Plate Reader)检测荧光信号(激发光波长为400nm,发射光波长为460nm、535nm)。
计算:通过全活性孔和对照信号孔计算出每个孔的抑制率,数据分析方法如下:
磷酸化比率=1-{(发射比×F100%-C100%)/[C 0%-C 100%+发射比×(F100%- F0%)]}×100;
抑制率=100×(1-化合物磷酸化比率/阴性对照磷酸化比率)。
IC50值采用医学绘图软件(GraphPad Prism5.0)软件计算求得。
激酶活性测试结果如表4所示。
表4化合物激酶选择性活性测试结果(IC50:nM)
激酶 | XS3-55 | XS4-128 | Ponatinib |
Bcr-Abl | >10000 | 128.8 | 3.9 |
SRC | 526.3 | 20.3 | 2.0 |
RET | >10000 | 10.7 | 3.3 |
VEGFR2 | 832.7 | 18.9 | 3.3 |
Kit | 1669 | 93.5 | 25.1 |
PDGFRA | 5887 | 19.9 | 3.9 |
PDGFRB | >10000 | 118.9 | 18.0 |
从表4数据可以看出,本发明的炔苯基苯酰胺类代表性化合物XS3-55对TRKA,TRKB, TRKC以外的多种代表性酪氨酸激酶的抑制活性较弱,其具有较好的激酶选择性,其激酶选择性远远好于化合物XS4-128和Ponatinib,因此,本发明的炔苯基苯酰胺类化合物的选择性好,毒副作用低。
实施例41:药代动力学评价
以SD大鼠进行药代动力学和口服生物利用度测试,根据药物溶解性,分别口服,静脉注射单次给药,在不同的时间点(0,0.5,1,2,4,6,8,24小时)分别采集动物血样,加肝素抗凝,离心取上清。HPLC-MS方法分析血样,使用DAS2.1进行数据分析,检测半衰期 (T1/2)、最高血药浓度(Cmax)、达峰时间(Tmax)、药时曲线下面积(AUC)、生物利用度(BA)等药代动力学数据。化合物XS3-55和化合物9o(European Journal of Medicinal Chemistry 179(2019)470-482.)的药代动力学数据结果如表5所示:
表5
化合物XS3-55对TRKs激酶有很强的抑制活性,并且对Ba/F3-TRKs稳定株的野生型及耐药型细胞增殖有很强的抑制活性。且化合物XS3-55具有很好的口服吸收性质,在大鼠口服 10mg/kg的剂量下,化合物XS3-55的半衰期为15.19小时,最高血药浓度高达44066.54ng/mL,药时曲线下面积高达878346.33h*ng/mL,药代动力学性质显著高于对照化合物9o。
实施例42:化合物XS3-55体内肿瘤活性
通过口服给药,在Ba/F3-CD74-TRKAG667C同种异体移植小鼠模型中评估了化合物XS3-55 的体内抗肿瘤药效。将培养的BaF3-CD74-TRKAG667C细胞收集、离心,用生理盐水洗涤两次后调整密度至1×107个/mL后置于冰上,尽快皮下注射于CB17-SCID雌鼠右腋(购自北京维通利华,6-8周龄),每只注射200μL。造模9天后,瘤体积生长至约200mm3时随机分组并开始给药,其中对照组8只小鼠,化合物XS3-55四个剂量组(50、25、12.5、6.25mg/kg) 每组6只小鼠。给药方式如下:按给药剂量称取适量化合物XS3-55粉末溶于2%二甲基亚砜(DMSO)+20%氢化蓖麻油+8%无水乙醇+70%生理盐水的混合溶剂中,得到浅黄色至黄色透明液体,口服给药,每天给药一次;对照组口服给予同等体积的混合溶剂。每两天记录一次体重及瘤体积。
结果如图1和图2所示:化合物XS3-55每天给药一次,持续两周,以剂量依赖性方式抑制携带CD74 TRKAG667C突变同种异体移植小鼠模型的生长。以最低剂量6.25mg/kg治疗2天后观察到肿瘤大小显着减小。治疗12天后,化合物XS3-55在6.25mg/kg/天、12.5mg/kg/天、25mg/kg/天和50mg/kg/天的剂量下表现出优异的体内抗肿瘤药效,TGI分别为50.9%、76.3%、89.2和91.6%,而对照组小鼠在第14天时死亡。同时,体内研究显示四种不同剂量的化合物XS3-55都对小鼠体重没有明显的不利影响(图1),这表明化合物XS3-55具有良好的安全性。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (19)
1.具有式(I)结构的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子;
其中,R1任选自:C1~C20烷基;
R2任选自:H、卤素、C1~C20烷基、C1~C20烷氧基或卤素取代的C1~C20烷基;
R3任选自:H、氟取代的C1~C4烷基、取代或未取代的含1-3个N环原子的5-6元杂环基;
R4任选自:H、卤素、硝基、取代或未取代的C1~C20烷基、取代或未取代的C1~C20烷氧基、取代或未取代的含1-3个N环原子的5-10元杂环基、取代或未取代的含1-3个N环原子的5-10元杂芳基;
R5为-NR6R7;
其中,R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)nCR10R11R12、-(CH2)pOR12,或者R6、R7与它们所连接的氮原子一起形成被取代或未被取代的含有杂原子的单环、稠环、螺环或桥环;
R8、R9分别独立地选自:H、C1~C20烷基;或者R8、R9与它们所连接的氮原子一起形成被取代或未被取代的含有1-3个杂原子的单环、稠环、螺环或桥环;
R10、R11与它们所连接的碳原子一起形成被取代或未被取代的含有1-3个杂原子的单环、稠环、螺环或桥环;
R12选自:H、C1~C20烷基;
m、n、p分别独立地选自:0-10的整数。
2.根据权利要求1所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,
R4任选自:H、卤素、硝基、C1~C8烷基、卤素取代的C1~C8烷基、C1~C8烷氧基、卤素取代的C1~C8烷氧基、-(CH2)xNR17R18、被1-5个R19取代或未被取代的含有1-3个N环原子的5-6元杂环基、被1-5个R19取代或未被取代的含有1-3个N环原子的5-6元杂芳基;x为1-5的整数;
R17、R18与它们所连接的氮原子一起形成被1-5个R19取代或未被取代的吗啉基、吡咯烷基、哌啶基或哌嗪基;
各R19分别独立地选自:C1-C5烷基。
3.根据权利要求2所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,
R4任选自:H、卤素、硝基、C1~C4烷基、卤素取代的C1~C4烷基、C1~C4烷氧基、卤素取代的C1~C4烷氧基、-(CH2)xNR17R18、被1-3个R19取代或未被取代的咪唑基;x为1、2或3;
R17、R18与它们所连接的氮原子一起形成被1-3个R19取代或未被取代的哌嗪基;
各R19分别独立地选自:C1-C5烷基。
5.根据权利要求1所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,
R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)nCR10R11R12、-(CH2)pOR12,或者R6、R7与它们所连接的氮原子一起形成被1-5个R13取代或未被取代的含有1-3个杂原子的3-15元单环、稠环、螺环或桥环,杂原子选自:O、N、S;
R8、R9分别独立地选自:H、C1~C5烷基;或者R8、R9与它们所连接的氮原子一起形成被1-5个R13取代或未被取代的含有1-3个杂原子的3-10元单环、稠环、螺环或桥环,杂原子选自:O、N;
R10、R11与它们所连接的碳原子一起形成被1-5个R13取代或未被取代的含有1-3个杂原子的3-10元单环、稠环、螺环或桥环,杂原子选自:O、N;
R12选自:H、C1-C5烷基;
各R13分别独立地选自:H、C1-C5烷基、C1-C5烷酰基、羟基、羟基取代的C1-C5烷基、氨基取代的C1-C5烷基、氨基取代的C1-C5烷氧基、C3-C7环烷基取代的C1-C3烷基、-NR15R16、被1-5个R14取代或未被取代的含有1-3个杂原子的3-10元单环、稠环、螺环或桥环,杂原子选自:O、N;
R14、R15、R16分别独立地选自:H、C1-C5烷基;
m、n、p分别独立地选自:0-5的整数。
6.根据权利要求5所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,
R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)pOR12,或者R6、R7与它们所连接的氮原子一起形成被1-3个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或者哌嗪基;
R8、R9分别独立地选自:H、C1~C5烷基,或者R8、R9与它们所连接的氮原子一起形成被1-5个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或哌嗪基;
R12选自:H、C1-C5烷基;
各R13分别独立地选自:H、C1-C5烷基、C1-C5烷酰基、羟基、-NR15R16、被1-2个R14取代或未被取代的氧杂环丁基、被1-4个R14取代或未被取代的吗啉基;
R14、R15、R16分别独立地选自:H、C1-C3烷基;
m、p分别独立地选自:1、2、3、4或5。
8.根据权利要求1所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,R4为卤素;R5为-NR6R7;
R6、R7分别独立地选自:-(CH2)mNR8R9、-(CH2)pOR12,或者R6、R7与它们所连接的氮原子一起形成被1-3个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或者哌嗪基;
R8、R9分别独立地选自:H、C1-C3烷基,或者R8、R9与它们所连接的氮原子一起形成被1-2个R13取代或未被取代的吗啉基、吡咯烷基、哌啶基或哌嗪基;
R12选自:H、C1-C3烷基;
各R13分别独立地选自:H、C1-C3烷基、乙酰基、羟基、-NR15R16、氧杂环丁基、吗啉基;
R15、R16分别独立地选自:H、C1-C3烷基;
m、p分别独立地选自:2、3或4。
11.根据权利要求1~10任一项所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,
R1任选自:C1~C4烷基;和/或,
R2任选自:H、卤素、C1~C4烷基、卤素取代的C1~C4烷基、C1~C4烷氧基。
12.根据权利要求11所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,
R1任选自:甲基、乙基、异丙基、叔丁基;和/或,
R2任选自:氢、氟、甲基、乙基、异丙基、叔丁基、二氟甲基、二氟乙基、三氟甲基或三氟乙基。
13.根据权利要求1~10任一项所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子,其特征在于,
R3选自:H、二氟甲基、二氟乙基、三氟甲基或三氟乙基。
16.权利要求1~15一项所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备TRK抑制剂中的应用。
17.权利要求1~18一项所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗由TRK酪氨酸激酶介导的疾病的药物中的应用。
18.权利要求17述的应用,其特征在于,所述由TRK酪氨酸激酶介导的疾病为肿瘤,优选为非小细胞肺癌、乳腺癌、结肠癌、前列腺癌、甲状腺癌、恶性黑色素瘤、神经母细胞瘤和乳腺样分泌癌。
19.一种预防和/或治疗肿瘤的药用组合物,其特征在于,包括活性成分和药学上可接受的辅料,所述活性成分包括权利要求1~15任一项所述的炔苯基苯酰胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103044432A (zh) * | 2005-12-23 | 2013-04-17 | 阿里亚德医药股份有限公司 | 双环杂芳基化合物 |
WO2015085972A1 (en) * | 2013-12-09 | 2015-06-18 | Zentiva, K.S. | NOVEL SALTS OF 3-(2-IMIDAZO[1,2-b]PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-[4-[(4-METHYL- 1-PIPERAZINYL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL] BENZAMIDE |
WO2018089736A1 (en) * | 2016-11-10 | 2018-05-17 | Dana-Farber Cancer Institute, Inc. | Degradation of protein kinases by conjugation of protein kinase inhibitors with e3 ligase ligand and methods of use |
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US8859553B2 (en) * | 2012-07-30 | 2014-10-14 | Astar Biotech Llc | Protein kinase inhibitors |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103044432A (zh) * | 2005-12-23 | 2013-04-17 | 阿里亚德医药股份有限公司 | 双环杂芳基化合物 |
WO2015085972A1 (en) * | 2013-12-09 | 2015-06-18 | Zentiva, K.S. | NOVEL SALTS OF 3-(2-IMIDAZO[1,2-b]PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-[4-[(4-METHYL- 1-PIPERAZINYL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL] BENZAMIDE |
WO2018089736A1 (en) * | 2016-11-10 | 2018-05-17 | Dana-Farber Cancer Institute, Inc. | Degradation of protein kinases by conjugation of protein kinase inhibitors with e3 ligase ligand and methods of use |
Non-Patent Citations (1)
Title |
---|
杨加举: "TRK抑制剂的设计、合成与生物活性评价", 《硕士电子期刊》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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