CN116425721B - 作为mat2a抑制剂的双环类化合物 - Google Patents
作为mat2a抑制剂的双环类化合物 Download PDFInfo
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- CN116425721B CN116425721B CN202211632264.XA CN202211632264A CN116425721B CN 116425721 B CN116425721 B CN 116425721B CN 202211632264 A CN202211632264 A CN 202211632264A CN 116425721 B CN116425721 B CN 116425721B
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Abstract
本发明提供了一种如式I所示的化合物及其异构体、或其药学可接受的盐，其制备方法、药物组合物和作为MAT2A抑制剂的用途。
Description
技术领域
本发明属于药物化学领域，具体涉及一种作为MAT2A抑制剂的双环类化合物及其异构体、或其药学可接受的盐，其制备方法、药物组合物和其在制备用于在患有癌症的受试者中治疗所述癌症中的用途。
背景技术
甲硫氨酸腺苷转移酶(MAT)(也称为S-腺苷甲硫氨酸合成酶)是催化由甲硫氨酸和ATP合成S-腺苷甲硫氨酸(SAM或AdoMet)的细胞酶；该催化被认为是甲硫氨酸循环的限速步骤。SAM是多胺生物合成中的丙氨基供体，并且是用于DNA甲基化的主要甲基供体，并且其参与基因转录和细胞增殖以及次级代谢产物的生成。
人类MAT的三种亚型包括在肝组织中表达的MAT1和MAT3，而MAT2A在人类细胞类型中普遍表达，是人类肿瘤中的主要形式。晶体结构和机制研究表明，尽管它们在氨基酸序列上有85％的一致性，但它们的作用机制存在显著差异。MAT2A以其纯化的活性形式形成功能同源二聚体，并与调节蛋白MAT2B结合。MAT2B通过增加MAT2A对ADOMet产物抑制的敏感性来调节MAT2A的活性，但不提供显著的速率增强。细胞定位研究表明，MAT2A在胞浆和细胞核中都存在。据报道，MAT2A的核浓缩发生在复制和随后的G2期，满足了DNA和组蛋白甲基化过程在S期细胞核内的高度甲基化要求。ADOMet在转甲基化反应中的活性已被确认为肺癌干细胞发展的限速因子，使MAT2A和蛋氨酸循环的相关酶成为抗癌药物的靶点。由MAT2A生产ADOMet的蛋氨酸来自膳食来源或多胺循环，在多胺循环中，由S-甲基-5’-硫代腺苷磷酸化酶产生的5-甲硫基-D-核糖1-磷酸被循环为蛋氨酸。据报道，MAT2A蛋白在结肠癌、肝癌、胃癌、血液和肝脏等癌症中表达增加。大约15％的人类癌症显示MTAP(S-甲基-5’-硫代腺苷磷酸化酶)基因缺失，因此缺乏多胺合成的蛋氨酸回收途径。MTAP在chr9p21中的缺失通常包括CDKN2a抑癌基因位点的缺失。MATP-/-癌细胞的综合遗传致死性研究表明，这些癌细胞对MAT2A、PRMT5和PRMT1的抑制增加了敏感性。
在肝细胞癌(HCC)中，发生MAT1A的下调和MAT2A的上调，其被称为MAT1A：MAT2A转换。伴随着MAT2B上调的转换导致较低的SAM含量，这为肝癌细胞提供了生长优势。由于MAT2A在促进肝癌细胞生长中起着至关重要的作用，因此它是抗肿瘤疗法的靶点。最近的研究表明，通过使用小干扰RNA进行的沉默基本上抑制了肝癌细胞的生长并诱导细胞凋亡。参见例如T.Li等人,J.Cancer 7(10)(2016)1317-1327。
一些MTAP缺陷的癌细胞系对抑制MAT2A特别敏感，Marjon等人(Cell Reports15(3)(2016)574–587)。MTAP(甲硫腺苷磷酸化酶)是在正常组织中广泛表达的酶，该酶催化甲硫腺苷(MTA)转化为腺嘌呤和5-甲基硫代核糖-1-磷酸。腺嘌呤被补救以产生腺苷一磷酸，并且5-甲基硫代核糖-1-磷酸被转化为甲硫氨酸和甲酸盐。由于这种补救途径，当嘌呤的从头合成被例如抗代谢物如L-阿拉诺新阻断时，MTA可以作为替代的嘌呤源。
在缺少MTAP缺失的其他癌症(包括肝细胞癌和白血病)中，MAT2A失调。J.Cai等人,Cancer Res.58(1998)1444-1450；T.S.Jani等人,Cell.Res.19(2009)358-369。通过RNA干扰沉默MAT2A表达可在多种癌症模型中产生抗增殖作用，H.Chen等人,Gastroenterology133(2007)207-218；Q.Liu等人Hepatol.Res.37(2007)376-388。
许多人和鼠恶性细胞缺乏MTAP活性。MTAP缺陷不仅存在于组织培养细胞中，而且该缺陷也存在于原发性白血病、胶质瘤、黑色素瘤、胰腺癌、非小细胞肺癌(NSCLC)、膀胱癌、星形细胞瘤、骨肉瘤、头颈癌、粘液性软骨肉瘤、卵巢癌、子宫内膜癌症、乳腺癌、软组织肉瘤、非霍奇金淋巴瘤和间皮瘤中。编码人MTAP的基因定位于人染色体9p上的区域9p21。该区域还含有肿瘤抑制基因p16INK4A(也称为CDKN2A)和p15INK4B。这些基因编码p16和p15，它们分别是周期蛋白D-依赖性激酶cdk4和cdk6的抑制剂。
可选地，p16INK4A转录物可以是剪接成编码pl4ARF的转录物的可变读框(ARF)。p14ARF结合至MDM2并阻止p53的降解(Pomerantz等人(1998)Cell 92：713-723)。9p21染色体区域是受关注的，因为它在多种癌症(包括白血病、NSLC、胰腺癌、胶质瘤、黑色素瘤和间皮瘤)中经常是纯合缺失的。缺失通常会使一个以上的基因失活。例如，Cairns等人((1995)Nat.Gen.11：210-212)报道了在研究了500多个原发性肿瘤后，在这些肿瘤中鉴定的几乎所有缺失都涉及含有MTAP、p14ARF和Pl6INK4A的170kb区域。Carson等人(WO99/67634)报道了肿瘤发展阶段与编码MTAP的基因和编码p16的基因的纯合性丧失之间存在相关性。例如，据报道MTAP基因而不是p16INK4A的缺失在发展的早期阶段预示着癌症，而据报道编码p16和MTAP的基因的缺失预示着癌症处于更晚期的癌症发展阶段。在一些骨肉瘤患者中，MTAP基因在诊断时存在，但在稍后的时间点缺失(Garcia-Castellano等人,Clin.Cancer Res.8(3)2002 782-787)。
在WO2018039972中公开了治疗癌症的MAT2A酶抑制剂；WO2021158792提到了治疗自身免疫疾病或炎性疾病的MAT2A抑制剂；在WO2018045071中描述了治疗MAT2A的过表达介导的疾病或病症的MAT2A酶抑制剂；CN202080014106.0中还公开了治疗有需要的患者的MTAP缺陷型非小细胞肺癌(NSCLC)的化合物3-(环己-1-烯-1-基)-6-(4-甲氧基苯基)-2-苯基-5-(吡啶-3-基氨基)吡唑并[1,5-a]嘧啶-7(4H)-酮；CN114874207A公开了6并6环母核的MAT2A抑制剂；CN113999232A公开了抑制MTAP缺失的癌细胞的多环化合物。
寻找有效的MAT2A抑制剂是当前肿瘤靶向药物研发的重要方向。
发明内容
发明概述
一方面，本发明提供了式I所示的化合物及其异构体、或其药学可接受的盐，
其中:
选自
R1选自5-6元环烯基、-S(O)2-R6，其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、-CN、C1-C6-烷基、C1-C6-烷氧基；
R2选自C6-C10杂芳基、-C(O)R5，其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、-CN、C1-C6-烷基、C1-C6-烷氧基；
R3选自C6-C10芳基，其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、-CN、C1-C6-烷基、C1-C6-烷氧基；
R4选自C6-C11芳基、C6-C11杂芳基、C6-C11杂环基，其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、羧基、-CN、C1-C6-烷基、C1-C6-烷氧基；
R5选自-C5-C10杂芳基；
R6选自C6-C10芳基、C6-C10杂芳基、C6-C10杂环基。
进一步的，所述R1选自
所述基团任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
进一步的，所述R2选自以下结构：所述基团任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
进一步的，所述R3选自苯基，任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
进一步的，所述R4选自以下结构：
所述基团任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
第二方面，本发明提供如下式(I-a)和(I-b)所示的化合物及其异构体、或其药学可接受的盐，
R2、R3、R4、R6的定义如上面所述。
进一步的，所述通式选自以下化合物：
第三方面，本发明提供一种制备式(I-a)化合物及其异构体、或其药学可接受的盐的方法，其特征在于，该方法包括以下步骤：
起始原料先后通过酰胺缩合反应、闭环反应、Buchwald-Hartwig偶联反应、取代反应、氧化反应制得式(I-a)所示化合物；其中，R2、R3、R4、R5的定义如上面所述。
本发明还提供一种药物组合物，包含根据本发明任一项所述化合物及其异构体、或其药学可接受的盐，以及药学上可接受的辅料。
本发明还提供一种组合物在制备用于在患有癌症的受试者中治疗所述癌症中的用途，其中所述癌症的特征为MTAP表达的减少或缺失、MTAP基因的缺失、MTAP蛋白功能的减少。
本发明人发现，该类化合物是高效的MAT2A抑制剂，具有极强的MAT2A抑制活性，可以用于制备预防和/或治疗MAT2A抑制有关的适应症，包括MTAP表达的减少或缺失、MTAP基因的缺失、MTAP蛋白功能的减少引起的癌症。本发明基于以上发现而得以完成。
发明详述
下面对本发明的各个方面和特点作进一步的描述。
根据本发明的化合物可以以互变异构形式存在，那么本发明包括全部互变异构形式。
本发明的化合物具有不对称中心，本发明中含有不对称取代原子的化合物可以被分离成光学活性或消旋形式，本领域技术人员知晓如何制备光学活性形式，比如通过消旋体拆分或者由光学活性的起始原料合成。除非特别说明具体的立体化学或异构体形式，本发明包括所有手性、非对映异构体和消旋体。制备本发明化合物的方法及其中间体属于本发明的一部分。本发明化合物的所有互变异构体也属于是本发明的一部分。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，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。
术语“取代”是指特定原子或基团上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后所得化合物是稳定的。当取代基为＝O时，意味着两个氢原子被取代。当多个氢原子被取代基取代时，各取代基是相互独立的，可以为相同的取代基，也可以为不同的取代基。除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
术语“烷氧基”和“烷氨基”属于惯用表达，是指分别通过一个氧原子或氨基连接到分子的其余部分的烷基基团，其中的烷基如本发明所述。
如本文所述的，术语“卤素”、“卤代”等表示氟、氯、溴或碘，特别是表示氟、氯、溴，特别优选氟、氯。
如本文所述的，术语“烷基”是指具有指定数目碳原子数的烷基，其为直链或支链的烷基，并且其可包括其子基团，例如提及“C1-C6烷基”时，其还可以包括C1-C4烷基、C1-C3烷基、C2-C6烷基、C2-C4烷基等表示的子范围的基团，以及具体基团例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基等。其可以是二价的，例如亚甲基、亚乙基。
“芳基”当单独使用或作为另一术语的一部分，是指碳环的芳族基，不论是否稠合，其具有指定的碳原子数，或如果未指定碳原子数，至多14个碳原子，如C6-C14-芳基。具体的芳基为苯基、萘基、联苯基、菲基、并四苯基等。具体的芳基为苯基。
术语“杂环”、“杂环的”或“杂环基”可互换使用，并且是指被取代和未被取代的3至7元单环基团、7至11元二环基团、以及10至15元三环基团，其在至少一个环中具有至少一个杂原子(O、S或N)，所述含有杂原子的环优选具有1、2或3个选自O、S和N的杂原子。这种含有杂原子的基团的每个环可以含有一个或两个氧或硫原子和/或一至四个氮原子，条件是每个环中的杂原子总数是四个或更少，并且进一步的条件是所述环含有至少一个碳原子。氮和硫原子可任选地被氧化，并且氮原子可任选被季铵化。完成二环和三环基团的稠环可以仅含有碳原子，并且可以是饱和的、部分饱和的或完全不饱和的。杂环基团可以被附接在任何可用的氮或碳原子上。如本文所用，术语“杂环(heterocycle)”、“杂环烷基”、“杂环(heterocyclo)”、“杂环的”和“杂环基”包括“杂芳基”基团。
除了下面描述的杂芳基之外，示例性单环杂环基包括氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、咪唑啉基、噁唑烷基、异噁唑啉基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂卓基、氮杂卓基、1-吡啶酮基、4-哌啶酮基、四氢吡喃基、吗啉基、硫吗啉基、硫吗啉基亚砜、硫吗啉基砜、1,3-二氧戊环和四氢-1,1-二氧噻吩基等。示例性二环杂环基团包括奎宁环基。
术语“杂芳基”是指被取代和未被取代的芳香族5元或6元单环基团、9元或10元二环基团、以及11元至14元三环基团，其在至少一个环中具有至少一个杂原子(O、S或N)，所述含有杂原子的环优选具有1、2或3个选自O、S和N的杂原子。含有杂原子的杂芳基的每个环可以含有一个或两个氧或硫原子和/或一至四个氮原子，条件是每个环中的杂原子总数是四个或更少，并且每个环具有至少一个碳原子。完成二环和三环基团的稠环可以仅含有碳原子，并且可以是饱和的、部分饱和的或不饱和的。氮和硫原子可任选地被氧化，并且氮原子可任选被季铵化。作为二环或三环的杂芳基必须包括至少一个完全芳香族环，但是其他一个或多个稠环可以是芳香族的或非芳香族的。杂芳基可以被附接在任何环的任何可用氮或碳原子上。在化合价允许的情况下，如果所述另一环是环烷基或杂环，则其另外任选地被＝O(氧代)取代。
除非另有说明，否则当提及具体命名的芳基(例如，苯基)、杂环基(例如，吡咯烷基、哌啶基和吗啉基)、或杂芳基(例如，四唑基、咪唑基、吡唑基、三唑基、噻唑基和呋喃基)时，所述提及旨在包括视情况具有0至3个、优选0至2个取代基的环，所述取代基选自上文针对芳基杂环基和/或杂芳基列举的取代基。
如本文所述的，术语“药学可接受的盐”，表示该盐其不但是受试者生理学上可接受，而且还可指在药学上有使用价值的合成物质，例如在为进行手性拆分时所形成的作为中间体的盐，虽然这种中间体的盐并不能直接给予受试者，但该盐可在为获得本发明终产物中起作用。具体包括酸(有机酸和无机酸)加成盐或碱加成盐(包括有机碱和无机碱)。
本发明的癌症包括对标准治疗，如外科手术、放射治疗、化疗和激素治疗等。
“癌症”或“恶性肿瘤”是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种，受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。“癌细胞”是指经历多步骤肿瘤进展的早期，中期或晚期阶段的细胞。癌症包括间皮瘤、成神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉病癌和遗传性非息肉病结肠直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、甲状腺乳头状癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌症、绒毛膜癌、胰腺癌、前列腺癌、膀胱癌、睾丸癌、乳腺癌、泌尿系统癌、黑色素瘤、脑瘤、头颈癌、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、肝细胞癌、胆囊癌、支气管瘤、晚期实体瘤、小细胞肺癌、转移性非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、视网膜母细胞瘤、脉络膜黑色素瘤、精原细胞瘤、横纹肌肉瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤和浆细胞瘤、淋巴瘤、胰腺导管腺癌。
本发明中的化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、静脉滴注、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
有益技术效果
本发明人发现，本发明中的化合物具有良好的MAT2A抑制活性，IC50均小于阳性对照药AG270。本发明提供了一类结构新颖、活性强的MAT2A抑制剂化合物，该类化合物在预防和/或治疗MAT2A抑制有关的适应症比如MTAP表达的减少或缺失、MTAP基因的缺失、MTAP蛋白功能的减少等具有良好的应用前景。
具体实施方式
以下所列实施例有助于本领域技术人员更好地理解本发明的技术方案，但本发明的保护范围包括但不限于此。
对于以下全部实施例，可使用本领域技术人员已知的标准操作和方法。除非另有说明，所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振谱(NMR)和/或质谱(MS)来确定的。
本发明的化合物的结构由核磁共振(NMR)或/和液-质谱(LC-MS)确定。NMR化学位移(δ)以百万分之比(ppm)为单位。用Bruker avance-400型核磁仪测定了核磁共振，溶剂为氘代二甲基亚砜(DMSO-d6)、氘代甲醇(CD3OD)和氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。
液相质谱LC-MS测量液相部分使用ACQUITY UPLC超高压液相色谱，质谱部分使用Xevo G2-S Qtof质谱仪。
本发明示例中的起始材料是已知的并且可以在市场上购买，也可以使用或按照本领域已知的方法合成。
实施例1：4-[(3-羟基苯基)磺酰基]-1,2-二苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
步骤1：将4-溴-2,6-二氟苯甲酸(5g,21.1mmol,1.0eq.)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(9.63g,23.21mmol,1.1eq.)和N,N-二异丙基乙胺(5.1mL,63.29mmol,1.5eq.)溶于N,N-二甲基甲酰胺(80mL)中，室温下反应1小时后，在0℃下将苯肼(2.51g,23.21mmol,1.1eq.)滴加到反应液中,撤去冰浴，室温下搅拌2.5小时。反应完全后，将反应液倒入水中，析出固体，过滤，蒸馏水洗涤滤饼三次，烘干滤饼得到粗品4-溴-2,6-二氟-N-苯甲酰肼(6.15g)，直接下一步反应。LCMS(ESI)[M+H]+:326.99.1H NMR(400MHz,DMSO)δ10.48(d,J＝2.7Hz,1H),10.08(s,1H),8.18(d,J＝2.7Hz,1H),7.72–7.65(m,2H),7.25–7.18(m,2H),6.85–6.78(m,2H).
步骤2：将4-溴-2,6-二氟-N-苯甲酰肼(6.15g,18.8mmol,1.0eq.),叔丁醇钾(6.33g,56.4mmol,3.0eq.)加入到N,N-二甲基甲酰胺(100mL)，90℃反应1小时。反应完全后将反应液浓缩，过柱(PE:EA＝1:1)得到粗品棕色固体6-溴-4-氟-1-苯基-1,2-二氢-3H-吲唑-3-酮(5.79g),直接用于下一步反应。LCMS(ESI)[M+H]+:306.98.1H NMR(400MHz,DMSO-d6)δ8.48(s,3H),7.68-7.59(m,8H),7.50(t,J＝7.9Hz,5H),7.33-7.16(m,3H),7.05(dd,J＝9.5,1.3Hz,3H).
步骤3：将6-溴-4-氟-1-苯基-1,2-二氢-3H-吲唑-3-酮(500mg,1.63mmol,1.0eq),2-氨基吡啶(183.9mg,1.95mmol,1.2eq.),三(二亚苄基丙酮)二钯(93.6mg,0.163mmol,0.1eq.),4,5-双二苯基膦-9,9-二甲基氧杂蒽(188.4mg,0.326mmol,0.2eq.)和碳酸铯(1.06g,3.26mmol,2eq.)溶于1,4-二氧六环(10mL)于封管中在氮气氛围下，100℃反应过夜。反应完全后，加乙酸乙酯稀释，加水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤后将滤液浓缩。过柱纯化(DCM:MeOH＝20:1)得到黄色固体4-氟-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(279mg)。LCMS(ESI)[M+H]+:321.11.1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),9.48(s,1H),8.21(dd,J＝5.1,1.8Hz,1H),8.13(d,J＝1.4Hz,1H),7.68–7.57(m,3H),7.55(t,J＝7.9Hz,2H),7.35–7.24(m,2H),6.89–6.79(m,2H).
步骤4：将4-氟-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(200mg,0.624mmol,1.0eq.),苯硼酸(380.6mg,3.12mmol,5.0eq.),醋酸铜(136.1mg,0.749mmol,1.2eq.)和吡啶(98.8mg,1.25mmol,2.0eq.)溶于干燥的N,N-二甲基甲酰胺(5mL)中，室温反应16小时。反应完全后，加乙酸乙酯稀释，加水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤后将滤液浓缩。过柱纯化(DCM:MeOH＝20:1)得到棕色固体4-氟-1,2-二苯基-6-(吡啶-2-基氨基)-1,2二氢-3H-吲唑-3-酮(186mg)。LCMS(ESI)[M+H]+:397.14.1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.21(dd,J＝5.2,1.8Hz,1H),7.70-7.59(m,2H),7.55-7.47(m,2H),7.44(dd,J＝8.5,2.9Hz,5H),7.37(t,J＝7.9Hz,2H),7.30(p,J＝4.4Hz,1H),7.18(td,J＝7.3,1.2Hz,1H),6.94-6.83(m,2H)。
步骤5：将4-氟-1,2-二苯基-6-(吡啶-2-基氨基)-1,2二氢-3H-吲唑-3-酮(92mg,0.23mmol,1eq),3-[(叔丁基二甲基甲硅烷基)氧基]苯硫醇(84mg,0.348mmol,1.5eq)，和NaH(28mg,1.16mmol,5eq)加至THF(3mL)中。100℃下反应3小时。加入甲醇淬灭，直接反相柱纯化。水(1‰甲酸溶液)和乙腈体系过柱；10％-60％；15min流出目标产物。浓缩得黄色固体4-[(3-羟基苯基)硫代]-1,2-二苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(50mg)。LCMS(ESI)[M+H]+:503.15.
步骤6：将4-[(3-羟基苯基)硫代]-1,2-二苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(50mg，0.1mmol，1eq)和m-CPBA(43mg，0.25mmol，2.5eq)加至DCM(2mL)中，室温反应0.5小时。反应完全后，浓缩后加入DMSO(1mL)溶解。反相柱纯化，水(1‰甲酸溶液)和乙腈体系过柱；60％-70％，流出目标产物。浓缩得黄色固体4-[(3-羟基苯基)磺酰基]-1,2-二苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(7.2mg)。LCMS(ESI)[M+H]+:535.14.1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),10.10(s,1H),8.40(s,1H),8.19(d,J＝6.4Hz,2H),7.68(t,J＝7.8Hz,1H),7.52-7.24(m,12H),7.17(t,J＝7.4Hz,1H),7.02(d,J＝8.0Hz,1H),6.97-6.84(m,2H)。
实施例2：4-(环己-1-烯-1-基)-1-(3-羟基-4-甲氧基苯基)-6-(吡啶-2-氨基)-3-(嘧啶-2-基)-1,3-二氢-2H-苯并[d]咪唑-2-酮
步骤1：将2-溴-4-氯-6-硝基苯胺(10.00g,40.16mmol,1.0eq.)，1-环己烯硼酸(7.59g，60.24mmol，1.50eq)，K3PO4(11.08g,80.32mmol,2.0eq)，Pd(dppf)Cl2(2.94g,4.016mmol,0.1eq)和1,4-二氧六环(50ml)的三颈烧瓶中，置换氮气三次，100℃下回流反应16小时。反应结束后，加水和乙酸乙酯萃取，无水硫酸钠干燥有机相，正相纯化(PE:EA＝3:1)体系过柱,浓缩得到黄色固体5-氯-3-硝基-2',3',4',5'-四氢-[1,1'-联苯]-2-胺(10.00g)。LCMS(ESI)[M+H]+:523.06。1H NMR(400MHz,DMSO-d6)δ7.70(dd,J＝9.5,3.1Hz,1H),7.24(dd,J＝8.4,3.1Hz,1H),6.83(s,2H),5.78(q,J＝2.1Hz,1H),2.15(q,J＝5.0,4.2Hz,4H),1.80-1.65(m,4H).
步骤2：将5-氯-3-硝基-2',3',4',5'-四氢-[1,1'-联苯]-2-胺(10.00g,39.68mmol,1.0eq)，2-氯嘧啶(6.36g，55.55mmol，1.4eq)，氢化钠(2.86g，119.04mmol，3.0eq)加入装有DMF(40mL)的单口瓶中，在100℃条件下反应16小时。在反应完成后，将反应液过柱纯化得到棕色固体N-(5-氯-3-硝基-2',3',4',5'-四氢-[1,1'-联苯]-2-基)嘧啶-2-胺(1.94g)。LCMS(ESI)[M+H]+:331.08。1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.29(d,J＝4.8Hz,2H),7.78(dd,J＝8.1,3.1Hz,1H),7.44(dd,J＝9.0,3.1Hz,1H),6.74(t,J＝4.8Hz,1H),5.71(d,J＝4.1Hz,1H),2.14(s,2H),1.94(s,2H),1.47(dd,J＝22.4,6.7Hz,4H).
步骤3：将化合物N-(5-氯-3-硝基-2',3',4',5'-四氢-[1,1'-联苯]-2-基)嘧啶-2-胺(1.92g,6.1mmol,1.0eq.)，Fe(3.4g,61mmol，10.0eq),氯化铵(3.26g，61mmol，10.0eq)加入装有乙醇(20ml)和水(20ml)的混合溶液中，在60℃条件下反应4小时。在反应完成后，过滤，加二氯甲烷(100ml)和水(100ml)萃取，硅胶柱层析纯化得到黄色固体5-氯-N2-(嘧啶-2-基)-2',3',4',5'-四氢-[1,1'-联苯]-2,3-二胺(860mg)。LCMS(ESI)[M+H]+:301.111H NMR(400MHz,DMSO-d6)δ8.26(d,J＝4.7Hz,2H),8.06(s,1H),6.77-6.54(m,2H),6.34(d,J＝2.4Hz,1H),5.60-5.49(m,1H),5.08(s,2H),2.07(q,J＝4.2,3.5Hz,2H),1.86(h,J＝3.2Hz,2H),1.52-1.33(m,4H).
步骤4：将化合物5-氯-N2-(嘧啶-2-基)-2',3',4',5'-四氢-[1,1'-联苯]-2,3-二胺(400mg,1.33mmol,1.0eq.)，3-(叔丁基二苯基硅氧基)-4-甲氧基苯基硼酸(1130mg,2.78mmol,2.10eq)，无水醋酸铜(628mg,3.458mmol,2.60eq)，三乙胺(807mg,7.98mmol,6.0eq)加入装有二氯甲烷的单口瓶中，在空气球保护下常温反应48小时。在反应完成后，硅胶柱层析纯化得到黄色固体N3-(3-((叔丁基二苯基甲硅烷基)氧基)-4-甲氧基苯基)-5-氯-N2-(嘧啶-2-基)-2',3',4',5'-四氢-[1,1'-联苯]-2,3-二胺(300mg)。LCMS(ESI)[M+H]+:661.3。1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝4.8Hz,2H),8.05(s,1H),7.73-7.64(m,4H),7.43(qd,J＝8.5,7.7,3.7Hz,7H),7.10(s,1H),6.87(d,J＝8.6Hz,1H),6.69-6.61(m,3H),6.56(d,J＝2.5Hz,1H),6.50(d,J＝2.4Hz,1H),5.53(s,1H),3.54(s,3H),2.07(s,2H),1.83(s,2H),1.46-1.32(m,4H),1.06(s,9H).
步骤5：将N3-(3-((叔丁基二苯基甲硅烷基)氧基)-4-甲氧基苯基)-5-氯-N2-(嘧啶-2-基)-2',3',4',5'-四氢-[1,1'-联苯]-2,3-二胺(300mg,0.454mmol,1.0eq.),BTC(202mg，0.68mmol，1.50eq)，三乙胺(91.6mg,0.907mmol,3.00eq)投入装有二氯甲烷(3mL)的单口瓶中，在0℃条件下反应1小时。在反应完成后，过柱纯化得白色固体1-(3-((叔丁基二苯基甲硅烷基)氧基)-4-甲氧基苯基)-6-氯-4-(环己-1-烯-1-基)-3-(嘧啶-2-基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(220mg)。LCMS(ESI)[M+H]+:687.2。1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝4.9Hz,2H),7.67(dd,J＝7.7,1.7Hz,4H),7.63(t,J＝4.9Hz,1H),7.47-7.37(m,6H),7.09(d,J＝2.7Hz,2H),6.93(d,J＝2.0Hz,1H),6.80(d,J＝2.0Hz,1H),6.43(d,J＝2.0Hz,1H),5.13(s,1H),3.63(s,3H),2.07(s,2H),1.47(s,2H),1.38(d,J＝6.6Hz,2H),1.25-1.15(m,2H),1.07(s,9H).
步骤6：将1-(3-((叔丁基二苯基甲硅烷基)氧基)-4-甲氧基苯基)-6-氯-4-(环己-1-烯-1-基)-3-(嘧啶-2-基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(100mg,0.14mmol,1.0eq.)，2-氨基吡啶(65.6mg,0.7mmol,5.0eq)，醋酸钯(6.3mg,0.028mmol,0.2eq)，xant-phos(16.2mg,0.028mmol,0.2eq)，碳酸铯(114mg,0.35mmol,2.5eq)投入装有1,4-二氧六环西林瓶中，氮气置换三次，在100℃条件下反应16小时。在反应完成后，Prep-HPLC制备得黄色固体4-(环己-1-烯-1-基)-1-(3-羟基-4-甲氧基苯基)-6-(吡啶-2-氨基)-3-(嘧啶-2-基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(7.5mg)。LCMS(TOF MS ES+)m/z[M+H]+:507.21.1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.00(d,J＝4.9Hz,2H),8.96(s,1H),8.05(dd,J＝5.2,1.9Hz,1H),7.61(t,J＝4.9Hz,1H),7.51(ddd,J＝8.8,7.1,2.0Hz,1H),7.33(d,J＝2.1Hz,1H),7.27(d,J＝2.1Hz,1H),7.14–7.09(m,1H),6.99–6.95(m,2H),6.73(d,J＝8.4Hz,1H),6.67(dd,J＝7.1,5.1Hz,1H),5.17(dd,J＝4.0,2.1Hz,1H),3.85(s,3H),2.10(s,2H),1.52(s,2H),1.41(d,J＝5.7Hz,2H),1.25(d,J＝8.2Hz,2H).
实施例3：4-((3-羟基苯基)磺酰基)-2-(3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
制备方法同实施例1。LCMS(ESI)[M+H]+:605.15.1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.13(s,1H),10.05(s,1H),8.35(d,J＝1.7Hz,1H),8.22–8.14(m,2H),7.70–7.62(m,1H),7.50–7.41(m,6H),7.37(t,J＝7.9Hz,1H),7.29(p,J＝4.3Hz,1H),7.24(d,J＝1.9Hz,1H),7.02(dd,J＝8.3,2.0Hz,2H),6.91(t,J＝9.3Hz,3H),3.23(s,3H).
实施例4：4-[(3-羟基苯基)磺酰基]-2-(1-甲基-1H-苯并[d]咪唑-6-基)-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
制备方法同实施例1。LCMS(ESI)[M+H]+:589.16.1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),10.10(s,1H),8.40(s,1H),8.22(d,J＝11.4Hz,3H),7.78–7.64(m,2H),7.60(d,J＝8.6Hz,1H),7.52–7.32(m,7H),7.28(d,J＝7.9Hz,2H),7.02(d,J＝2.3Hz,1H),6.98–6.89(m,2H),3.82(s,3H).
实施例5：4-[(3-甲氧基苯基)磺酰基]-1-苯基-6-(吡啶-2-氨基)-1'，2'-二氢-3'H-[2,5'-双吲唑]-3,3'(1H)-二酮
制备方法同实施例1。LCMS(ESI)[M+H]+:605.161H NMR(400MHz,DMSO)δ10.08(s,1H),8.39(d,J＝1.8Hz,1H),8.31(s,1H),8.21–8.16(m,2H),7.77(t,J＝2.0Hz,1H),7.71–7.60(m,3H),7.51(t,J＝8.0Hz,1H),7.42(d,J＝4.3Hz,4H),7.34(dd,J＝8.9,1.9Hz,1H),7.30–7.21(m,3H),6.97–6.89(m,2H),3.79(s,3H).
实施例6：N-{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}-1H-吡咯并[2,3-b]吡啶-5-甲酰胺
步骤1：向200mL的N,N-二甲基甲酰胺溶剂中加入2,6-二氟-4-溴苯甲酸(14.50g,61.18mmol,1.0eq)，O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(25.60g,67.30mmol,1.1eq)和N,N-二异丙基乙胺(16.0ml,91.77mmol,1.5eq)，于25摄氏度反应半小时，然后苯肼(7.28g,67.30mmol,1.1eq)在冰浴条件下慢慢加入反应液中，自然升到室温后反应1小时。反应完成后，加入400mL水，此时，大量固体产物析出，过滤，滤饼用水(200ml)洗涤，将滤饼上的固体刮出，经真空干燥箱干燥得白色固体4-溴-2,6-二氟-N'-苯并酰肼(20.00g)。(M+H+):326/328。1H NMR(400MHz,DMSO)δ10.48(d,J＝2.7Hz,1H),10.08(s,1H),8.18(d,J＝2.7Hz,1H),7.72–7.65(m,2H),7.25–7.18(m,2H),6.85–6.78(m,2H).
步骤2：将化合物4-溴-2,6-二氟-N'-苯并酰肼(20.00g,61.14mmol,1.0eq)溶解到N,N-二甲基甲酰胺(200ml)中,0℃下加入叔丁醇钾(17.80g，158.96mmol,2.6eq)，于90摄氏度反应1h。反应完成后，将反应液稀释于500ml水中，用300ml乙酸乙酯萃取三次，合并乙酸乙酯相，用200ml水反萃两次，合并所有的水相，用1mol/L的稀盐酸水溶液调水相PH至弱酸性，此时有大量固体产物析出，过滤，滤饼用水(200ml)洗涤，将滤饼上的固体刮出，经真空干燥箱干燥得6-溴-4-氟-1-苯基-1,2-二氢-3H-吲唑-3-酮(9.00g)，黄色固体。(M+H+):306/308。
步骤3：将化合物6-溴-4-氟-1-苯基-1,2-二氢-3H-吲唑-3-酮(5.00g,16.28mmol,1.0eq)，氨基甲酸叔丁酯(5.72g,48.84mmol,3.0eq)和碳酸铯(13.26g,40.70mmol,2.5eq)加入到100毫升的1,4-二氧六环中，然后加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.94g,1.63mmol,0.1eq)和三(二亚苄基丙酮)二钯(0.89g,0.97mmol,0.06eq)，氮气保护下90摄氏度反应6小时。反应完成过滤，滤饼用200ml甲醇洗涤，滤液旋干，经正相柱层析得灰色固体(4-氟-3-氧代-1-苯基-2,3-二氢-1H-吲唑-6-基)氨基甲酸叔丁酯(4.30g)。(M+H+):344。1HNMR(400MHz,DMSO)δ9.36(s,1H),7.64(s,1H),7.59–7.52(m,2H),7.36(dd,J＝8.5,7.2Hz,2H),6.98(t,J＝7.3Hz,1H),6.65(d,J＝12.2Hz,1H),1.49(s,9H).
步骤4：将化合物(4-氟-3-氧代-1-苯基-2,3-二氢-1H-吲唑-6-基)氨基甲酸叔丁酯(4.30g,12.52mmol,1.0eq)和苯硼酸(7.63g,62.62mmol,5.0eq)溶解于N,N-二甲基甲酰胺(50.0ml)溶剂中，加入无水吡啶(2.97g,37.56mmol,3.0eq)和无水醋酸铜(3.41g，18.78mmol,1.5eq)，氧气保护下于室温反应过夜。反应完成后，过滤，滤液稀释于300ml乙酸乙酯中，用150ml水萃取三次，有机相再用饱和氯化钠溶液洗涤一次，有机相干燥浓缩后，正相柱层析(石油醚:乙酸乙酯＝3:1)得红色固体产物(4-氟-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基)氨基甲酸叔丁酯(2.10g)。(M+H+):420；1H NMR(400MHz,CDCl3)δ7.53–7.47(m,2H),7.44–7.26(m,8H),7.20(t,J＝7.5Hz,1H),6.96(dd,J＝11.7,1.5Hz,1H),1.49(s,9H).
步骤5：将(4-氟-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基)氨基甲酸叔丁酯(2.20g,5.24mmol,1.0eq)和3-甲氧基苯硫酚(3.67g,26.22mmol,5.0eq)溶于50ml无水四氢呋喃中，慢慢加入钠氢(1.67g,41.92mmol,8.0eq)，在封管中于70摄氏度反应2h。反应完成后冷却至室温倒入冰水中，用200ml乙酸乙酯萃取，有机相用150ml水洗涤两次再用饱和氯化钠溶液洗涤一次，取有机相用无水硫酸钠干燥，减压浓缩，正相柱层析(石油醚:乙酸乙酯＝10％～40％)得棕色固体产物{4-[(3-甲氧基苯基)硫代]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}氨基甲酸叔丁酯(400mg)。LCMS(TOF MS ES+)m/z[M+H]+:540/541。1HNMR(400MHz,DMSO)δ9.72(s,1H),7.52(td,J＝8.6,1.2Hz,4H),7.47–7.41(m,8H),7.38(d,J＝1.8Hz,1H),7.35–7.29(m,1H),7.17(d,J＝1.9Hz,1H),7.14–7.09(m,1H),3.82(s,3H),1.46(s,9H).
步骤6：将化合物{4-[(3-甲氧基苯基)硫代]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}氨基甲酸叔丁酯(200mg,0.37mmol,1.0eq)溶解于二氯甲烷(10.0ml)中，0℃慢慢加入间氯过氧苯甲酸(160mg,0.93mmol,2.5eq)，室温反应1小时。反应完成后加入饱和亚硫酸钠溶液(1ml)淬灭反应，然后将反应液加入到二氯甲烷中，分别用水萃取和饱和食盐水洗涤，有机相用无水硫酸钠干燥后浓缩，经正相柱层析(石油醚:乙酸乙酯＝100：1～3：1)得棕色固体产物{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}氨基甲酸叔丁酯(100mg)。LCMS(TOF MS ES+)m/z[M+H]+:572。1H NMR(400MHz,DMSO)δ10.22(s,1H),8.17(d,J＝1.8Hz,1H),7.78(d,J＝1.8Hz,1H),7.73(t,J＝2.1Hz,1H),7.60–7.56(m,1H),7.52(t,J＝7.9Hz,1H),7.48–7.42(m,6H),7.42–7.37(m,2H),7.34(d,J＝8.7Hz,1H),7.26(ddd,J＝8.2,2.8,1.1Hz,1H),7.20(t,J＝7.4Hz,1H),3.82(s,3H),1.48(s,9H).
步骤7：S将化合物{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}氨基甲酸叔丁酯(100mg，0.18mmol,1.0eq)加入到二氯甲烷(3.0ml)中，0℃下慢慢加入三氟乙酸(1.0ml)，室温反应2.5小时。反应完成后，将反应液浓缩后，加入10ml的二氯甲烷再次浓缩，如此重复三次以除去多余的三氟乙酸，得棕色固体产物6-氨基-4-[(3-甲氧基苯基)磺酰基]-1,2-二苯基-1,2-双氢-3H-吲唑-3-酮(80mg)。LCMS(TOF MS ES+)m/z[M+H]+:472/4731H NMR(400MHz,DMSO)δ7.75(dd,J＝2.6,1.6Hz,1H),7.58(dt,J＝7.9,1.3Hz,1H),7.51(t,J＝8.0Hz,1H),7.45(d,J＝1.3Hz,1H),7.44–7.42(m,2H),7.42–7.39(m,3H),7.38–7.34(m,2H),7.33–7.31(m,1H),7.29(d,J＝6.9Hz,1H),7.24(ddd,J＝8.2,2.6,1.1Hz,1H),7.15(t,J＝7.3Hz,1H),6.47(d,J＝1.9Hz,1H),5.49(s,2H),3.82(s,3H).
步骤8：将1H-吡咯并[2,3-b]吡啶-5-甲酸(9mg,0.055mmol,1.3eq)加入到二氯亚砜(1.0ml)中，80℃密闭反应30分钟，旋干后溶于0.5ml的二氯甲烷中，然后将此溶液慢慢加入到6-氨基-4-[(3-甲氧基苯基)磺酰基]-1,2-二苯基-1,2-双氢-3H-吲唑-3-酮(20mg，0.042mmol,1.0eq)和N,N-二异丙基乙胺(16.50mg，0.127mmol,3.0eq)和二氯甲烷(0.50ml)的混合体系中，然后将此反应放置室温反应过夜。反应完成后，减压浓缩，经C18柱反相体系[乙腈/(水+乙腈)＝5％～95％]制备得白色固体N-{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}-1H-吡咯并[2,3-b]吡啶-5-甲酰胺(1.2mg)。LCMS(TOF MS ES+)m/z[M+H]+:616/617。1H NMR(400MHz,DMSO)δ12.08(s,1H),10.99(s,1H),8.86(d,J＝2.2Hz,1H),8.65(d,J＝2.1Hz,1H),8.59(d,J＝1.7Hz,1H),8.33(d,J＝1.7Hz,1H),8.16(s,1H),7.79(t,J＝2.2Hz,1H),7.64(dd,J＝6.0,3.0Hz,2H),7.55(t,J＝8.0Hz,1H),7.49(dd,J＝8.9,6.1Hz,6H),7.43–7.33(m,3H),7.30–7.20(m,2H),6.65(dd,J＝3.5,1.8Hz,1H),3.83(s,3H).
实施例7：3-氯-N-{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}-1H-吡咯并[2,3-b]吡啶-5-甲酰胺
将1H-吡咯并[2,3-b]吡啶-5-甲酸(9mg,0.055mmol)加入到二氯亚砜(1.0ml)中，80℃密闭反应30分钟，旋干后溶于0.5ml的二氯甲烷中，然后将此溶液慢慢加入到6-氨基-4-[(3-甲氧基苯基)磺酰基]-1,2-二苯基-1,2-双氢-3H-吲唑-3-酮(20mg，0.042mmol)和N,N-二异丙基乙胺(16.50mg，0.127mmol)溶于二氯甲烷(0.50ml)的混合体系，然后将此反应放置室温反应过夜。反应完成后，减压浓缩，经C18柱反相体系[乙腈/(水+乙腈)＝5％～95％]制备得白色固体3-氯-N-{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}-1H-吡咯并[2,3-b]吡啶-5-甲酰胺(3.00mg)。LCMS(TOF MS ES+)m/z[M+H]+:650；1H NMR(400MHz,DMSO)δ12.43(s,1H),11.07(s,1H),8.93(d,J＝2.1Hz,1H),8.67(d,J＝2.1Hz,1H),8.58(d,J＝1.8Hz,1H),8.34(d,J＝1.8Hz,1H),7.88(s,1H),7.80(d,J＝2.7Hz,1H),7.64(d,J＝7.8Hz,1H),7.55(t,J＝8.1Hz,1H),7.49(dd,J＝8.5,6.1Hz,6H),7.43–7.33(m,3H),7.24(dt,J＝14.8,7.7Hz,2H),3.83(s,3H).
实施例8：4-[(3-甲氧基苯基)磺酰基]-1,2-二苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
步骤1：将氢化钠(242.34mg，10.09mmol)溶解在10毫升四氢呋喃中，0℃下用注射器缓慢滴加3-甲氧基苯硫酚(530.94mg,3.78mmol,10.0eq)，最后缓慢加入实施例1制得的4-氟-1,2-二苯基-6-吡啶-2-氨基-1,2-二氢吲唑-3-酮(150mg,0.38mmol)，然后置于70℃下反应5小时。反应完成后，将反应液加入5毫升冰水淬灭氢化钠，用30毫升乙酸乙酯萃取三次，有机相旋干，通过柱层析(石油醚/乙酸乙酯＝100:1～2:1)纯化得到黄色固体4-(3-甲氧基苯基硫代)-1,2-二苯基-6-吡啶-2-氨基吡啶-1,2-二氢-3H-吲唑-3-酮(111mg)。TLC(石油醚/乙酸乙酯＝1:1，Rf＝0.4)。(M+H+):517/518。
步骤2：将化合物4-(3-甲氧基苯基硫代)-1,2-二苯基-6-吡啶-2-氨基吡啶-1,2-二氢-3H-吲唑-3-酮(60mg,0.12mmol,1.0eq)溶于四氢呋喃(2ml)溶剂中，加入水(2ml)和单过硫酸氢钾(176.82mg,1.05mmol,8.75eq)，室温反应16小时。反应完成后，将反应液加入到乙酸乙酯中，分别用水和饱和食盐水洗涤，有机相通过无水硫酸钠干燥、过滤后，将滤液浓缩，制备纯化得到白色固体4-[(3-甲氧基苯基)磺酰基]-1,2-二苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(4.1mg)。(M+H+):549/550。1H NMR(400MHz,DMSO)δ10.11(s,1H),8.43(d,J＝1.8Hz,1H),8.26–8.13(m,2H),7.78(t,J＝2.2Hz,1H),7.70(ddd,J＝8.7,7.3,2.0Hz,1H),7.62(dd,J＝7.9,1.7Hz,1H),7.53(t,J＝8.0Hz,1H),7.50–7.41(m,6H),7.41–7.29(m,3H),7.26(dd,J＝8.2,2.6Hz,1H),7.19(t,J＝7.4Hz,1H),6.94(dd,J＝11.6,7.5Hz,2H),3.82(s,3H).
实施例9：2-(4-氨基苯基)-4-[(3-甲氧基苯基)磺酰基]-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
制备方法同实施例1。LCMS(ESI)[M+H]+:564.16.1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.31(d,J＝1.7Hz,1H),8.15(dd,J＝4.9,1.8Hz,2H),7.80(t,J＝2.0Hz,1H),7.66(s,1H),7.60(d,J＝7.8Hz,1H),7.50(t,J＝8.0Hz,1H),7.43(t,J＝7.7Hz,2H),7.37–7.21(m,4H),7.02(d,J＝8.4Hz,2H),6.94–6.85(m,2H),6.47(d,J＝8.6Hz,2H),5.19(s,2H),3.80(s,3H).
实施例10：1-(4-氟苯基)-4-[(3-甲氧基苯基)磺酰基]-2-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
制备方法同实施例1。LCMS(TOF MS ES+)m/z[M+H]+:567.14 1H NMR(400MHz,DMSO)δ10.11(s,1H),8.35(d,J＝1.8Hz,1H),8.19(d,J＝1.8Hz,2H),7.79–7.73(m,1H),7.73–7.64(m,1H),7.60(d,J＝7.7Hz,1H),7.55–7.48(m,3H),7.46(d,J＝8.0Hz,2H),7.37(t,J＝7.8Hz,2H),7.33–7.15(m,4H),6.97–6.88(m,2H),3.80(s,3H).
实施例11：2-(1H-吲哚-6-基)-4-[(3-甲氧基苯基)磺酰基]-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
制备方法同实施例1。LCMS(ESI)[M+H]+:588.9.1H NMR(400MHz,DMSO)δ11.19(s,1H),10.03(s,1H),8.38(d,J＝1.8Hz,1H),8.21–8.14(m,2H),7.78(t,J＝2.2Hz,1H),7.72–7.64(m,1H),7.64–7.57(m,2H),7.50(t,J＝8.0Hz,1H),7.45–7.39(m,4H),7.36(t,J＝2.7Hz,1H),7.33(d,J＝8.7Hz,1H),7.24(ddd,J＝15.4,7.1,2.5Hz,2H),7.11(dd,J＝8.7,2.0Hz,1H),6.96–6.86(m,2H),6.40(d,J＝2.9Hz,1H),3.78(s,3H).
实施例12：2-(3-氟-5-羟基苯基)-4-[(3-甲氧基苯基)磺酰基]-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮
步骤1：将3-溴-5-氟苯酚(1000.0mg,52.36mmol,1.0eq),叔丁基二苯基氯硅烷(7130.0mg,68.06mmol,1.3eq)和咪唑(18710.0mg,104.71mmol,2.0eq)加入到四氢呋喃(30.0ml)溶液中,通入氮气置换气体5分钟,在0℃条件下搅拌30分钟,0℃滴加叔丁基二苯基氯硅烷,滴加结束后室温反应48小时。在反应完成后,减压蒸馏除去溶剂,正相柱纯化,石油醚和乙酸乙酯体系,极性为5％时,流出产物,浓缩得到透明油状物(3-溴-5-氟苯氧基)(叔丁基)二苯基硅烷(9220.0mg)。1HNMR(400MHz,Chloroform-d)δ7.72–7.67(m,4H),7.50–7.36(m,6H),6.78(dp,J＝4.0,1.9Hz,2H),6.35(dt,J＝10.4,2.2Hz,1H),1.11(s,9H).
步骤2：将(3-溴-5-氟苯氧基)(叔丁基)二苯基硅烷(5000.0mg,11.64mmol,1.0eq)与四氢呋喃(30.0ml)混合,通入氮气置换气体5分钟,-78℃搅拌30分钟,滴加正丁基锂(3.29ml,34.93mmol,3.0eq),-78℃反应3小时,最后在-78℃条件下,滴加硼酸三甲酯(4840.0mg,46.58mmol,4.0eq)-78℃反应,2小时后转室温反应12小时。在反应完成后,室温条件下滴加饱和氯化铵水溶液淬灭,用乙酸乙酯和水萃取三次,减压蒸馏除去乙酸乙酯,正相柱纯化,石油醚和乙酸乙酯体系,极性为30％时,流出产物,浓缩得到透明油状物{3-[(叔丁基二苯基甲硅基)氧基]-5-氟苯基}硼酸(2830.0mg)。1H NMR(400MHz,Chloroform-d)δ7.72(ddt,J＝13.9,6.8,1.6Hz,4H),7.49–7.33(m,6H),7.25–6.78(m,2H),6.61(ddt,J＝59.7,10.5,2.4Hz,1H),4.47(s,1H),1.13(d,J＝13.3Hz,9H).
步骤3：将{3-[(叔丁基二苯基甲硅基)氧基]-5-氟苯基}硼酸(2830.0mg,7.18mmol,10.0eq),4-氟-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(229.89mg,717.68mmol,1.0eq),醋酸酮(195.53mg,1.08mmol,1.5eq)、吡啶(170.31mg,2.15mmol,3.0eq)加入到N,N-二甲基甲酰胺(20.0ml)溶液中,室温敞口反应16小时。反应完成后,乙酸乙酯和水萃取三次,减压蒸馏除去有机溶剂。正相柱纯化,石油醚和乙酸乙酯体系,极性为30％时,流出产物,浓缩得到棕色油状物2-{3-[(叔丁基二苯基甲硅基)氧基]-5-氟苯基}-4-氟-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(680.0mg)。LCMS(TOFMS ES+)m/z[M+H]+:669.2；1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.24–8.18(m,1H),7.95(s,2H),7.70–7.28(m,16H),7.21–7.18(m,1H),7.03(dt,J＝10.2,2.1Hz,1H),6.93–6.76(m,3H),0.99(s,9H).
步骤4：将2-{3-[(叔丁基二苯基甲硅基)氧基]-5-氟苯基}-4-氟-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(300.0mg,448.55μmol,1.0eq),3-甲氧基苯硫酚(157.22mg,1.12mmol,2.5eq)和碳酸钾154.98mg,1.12mmol,2.5eq)加入到N,N-二甲基甲酰胺(3.0ml)中,通入氮气置换气体5分钟,100℃反应,12小时。在反应完成后,用乙酸乙酯、水萃取三次,减压蒸馏除去有机溶剂。正相柱纯化,石油醚和乙酸乙酯体系,极性为60％时,流出产物,浓缩得到棕色油状物2-(3-氟-5-羟基苯基)-4-[(3-甲氧基苯基)硫基]-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(168.0mg)。LCMS(TOF MS ES+)m/z[M+H]+:551.1。1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.46(s,1H),7.92(dd,J＝5.0,1.9Hz,1H),7.57–7.38(m,7H),7.35–7.26(m,1H),7.24–7.11(m,4H),6.88–6.72(m,4H),6.36(dt,J＝10.7,2.3Hz,1H),3.80(s,3H).
步骤5：将2-(3-氟-5-羟基苯基)-4-[(3-甲氧基苯基)硫基]-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(80mg,0.14mmol,1.0eq),单过硫酸氢钾(221.09mg,1.45mmol,10.0eq)加入到四氢呋喃和水(2mL/2mL)混合溶液中,室温反应16小时。反应完全后,将反应液加入到乙酸乙酯中,分别用水和饱和食盐水洗涤,无水硫酸钠干燥,过滤后将滤液浓缩。制备分离得到白色固体2-(3-氟-5-羟基苯基)-4-[(3-甲氧基苯基)磺酰基]-1-苯基-6-(吡啶-2-基氨基)-1,2-二氢-3H-吲唑-3-酮(9.0mg)。LCMS(ESI)[M+H]+:589.16.1HNMR(400MHz,DMSO-d6)δ10.18(s,1H),10.11(s,1H),8.40(d,J＝1.8Hz,1H),8.21–8.16(m,2H),7.76–7.63(m,2H),7.64–7.39(m,6H),7.34(t,J＝7.2Hz,1H),7.26(dd,J＝8.2,2.6Hz,1H),6.92(t,J＝7.7Hz,2H),6.78(s,1H),6.75–6.69(m,1H),6.37(dt,J＝10.7,2.3Hz,1H),3.82(s,3H).
实施例13：N-{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}-1H-苯并[d]咪唑-5-甲酰胺
步骤1：将4-溴-2,6-二氟-N-苯甲酰肼(6.15g,18.80mmol,1.0eq.),叔丁醇钾(6.33g,56.41mmol,3.0eq.)加入到N,N-二甲基甲酰胺(100mL)，90℃反应1小时。反应完全后将反应液浓缩，过柱(PE:EA＝1:1)得到粗品棕色固体6-溴-4-氟-1-苯基-1,2-二氢-3H-吲唑-3-酮(5.79g),直接用于下一步反应。LCMS(ESI)[M+H]+:306.98.1H NMR(400MHz,DMSO-d6)δ8.48(s,3H),7.68-7.59(m,8H),7.50(t,J＝7.9Hz,5H),7.33-7.16(m,3H),7.05(dd,J＝9.5,1.3Hz,3H).
步骤2：将6-溴-4-氟-1-苯基-1,2-二氢-3H-吲唑-3-酮(500mg,1.62mmol,1.0eq)，苯硼酸(397.39mg,3.25mmol,2.0eq.)，无水醋酸铜(444.62mg,2.44mmol,1.2eq.)和无水吡啶(514.65mg,6.51mmol,4.0eq.)溶于无水DMF(5.0mL)溶液中，氧气保护下室温反应16小时。反应完全后，硅藻土过滤，并用甲醇洗涤滤饼，然后将滤液浓缩，反相柱纯化，水(0.1％甲酸)与乙腈体系，极性为65％时，得到棕色固体6-溴-4-氟-1,2-二苯基-1,2-二氢-3H-吲唑-3-酮(200mg,收率32.3％)。LCMS(ESI)[M+H]+:383.01.
步骤3：将6-溴-4-氟-1,2-二苯基-1,2-二氢-3H-吲唑-3-酮(200mg,0.52mmol,1.0eq.),间甲氧基苯硫酚(146.59mg,1.04mmol,2.0eq.)和四氢呋喃(6mL)加入到封管中,然后缓慢加入氢化钠(62.82mg,2.61mmol,5.0eq.)，100℃反应2小时。反应完全后，将反应液浓缩。正相柱分离纯化，石油醚和乙酸乙酯体系，极性为25％时，得到棕色固体6-溴-4-[(3-甲氧基苯基)硫代]-1,2-二苯基-1,2-氢-3H-吲唑-3-酮(190mg)。LCMS(ESI)[M+H]+:503.04。1H NMR(400MHz,DMSO-d6)δ7.56–7.37(m,10H),7.34–7.27(m,1H),7.23(m,2H),7.19–7.12(m,2H),6.38(d,J＝1.4Hz,1H),3.81(s,3H)。
步骤4：将6-溴-4-[(3-甲氧基苯基)硫代]-1,2-二苯基-1,2-氢-3H-吲唑-3-酮(190mg,0.38mmol,1.0eq),间氯过氧苯甲酸(130.19mg,0.76mmol,2.0eq)加至二氯甲烷(4mL)中。室温条件下反应1小时。将反应液加入到二氯甲烷中，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤后将滤液浓缩，正相柱纯化。石油醚和乙酸乙酯体系，极性为25％时，流出目标产物。浓缩得黄色固体6-溴-4-[(3-甲氧基苯基)磺酰基]-1,2-二苯基-1,2-氢-3H-吲唑-3-酮(105mg)。LCMS(ESI)[M+H]+:535.62。1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝1.5Hz,1H),7.79(dd,J＝10.1,1.9Hz,2H),7.71–7.66(m,1H),7.55–7.29(m,10H),7.27–7.19(m,2H),3.80(s,3H).
步骤5：将1H-苯并[d]咪唑-5-羧酸甲酯(1.0g，5.68mmol,1.0eq)加入到氨-甲醇溶液(7mol/L,15.0mL)中，100℃反应60小时。反应完全后，将反应液浓缩，经反相柱纯化[乙腈/(水+乙腈)＝5％-50％]，旋干后得到灰色固体1H-苯并[d]咪唑-5-甲酰胺(500mg)。LCMS(ESI)[M+H]+:162.1H NMR(400MHz,DMSO)δ12.69(s,1H),8.34(s,1H),8.22(s,1H),7.97(s,1H),7.79(d,J＝8.4Hz,1H),7.62(s,1H),7.25(s,1H).
步骤6：将化合物6-溴-4-[(3-甲氧基苯基)磺酰基]-1,2-二苯基-1,2-氢-3H-吲唑-3-酮(50mg,0.09mmol,1.0eq)，1H-苯并[d]咪唑-5-甲酰胺(16.60mg，0.10mmol,1.1eq)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(11.00mg，0.02mmol,0.2eq)加入到1,4-二氧六环(2.0mL)溶液中，然后加入碳酸铯(61.01mg，0.19mmol,2.0eq)、三(二亚苄基丙酮)二钯(8.50mg,0.01mmol,0.1eq)和甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(8.40mg,0.01mmol,0.1eq)，氮气保护下100℃反应24小时。反应完成后，直接加硅胶粉拌样旋干，经正相柱层析纯化(二氯甲烷/甲醇＝10：1)得黄色固体粗品，然后经反相体系制备[乙腈/(水+乙腈)＝5％-95％]得终产物N-{4-[(3-甲氧基苯基)磺酰基]-3-氧代-1,2-二苯基-2,3-二氢-1H-吲唑-6-基}-1H-苯并[d]咪唑-5-甲酰胺(6.10mg)。LCMS(TOF MS ES+)m/z[M+H]+:616.1H NMR(400MHz,DMSO)δ12.92–12.65(m,1H),10.93(d,J＝17.2Hz,1H),8.60(d,J＝10.7Hz,1H),8.48–8.19(m,3H),7.92–7.59(m,4H),7.57–7.42(m,7H),7.41–7.30(m,3H),7.28–7.15(m,2H),3.81(s,3H).
表1化合物是参照实施例1的方法获得：
表1：化合物的结构和表征
表2化合物是参照实施例2的方法获得：
表2：化合物的结构和表征
表3化合物是参照实施例6的方法获得：
表4化合物是参照实施例12的方法获得：
表5化合物是参照实施例13的方法获得：
实验例1：本发明的化合物与mat2a蛋白的结合能力测试
实验目的：通过CETSA实验方法检测化合物与MAT2A蛋白的结合能力
背景原理：CETSA实验是衡量药物与靶蛋白亲和力的一种分子检测手段。其原理是，药物与靶蛋白结合后，使其结构更加稳定。使用候选药物处细胞或者组织样本，如果候选药物是MAT2A的抑制剂，那么该候选药物就能够与MAT2A结合，使得MAT2A蛋白变得更加稳定，在对样本进行加热处理后，样本中MAT2A蛋白将更容易被特异性抗体检测到，通过Western blot实验将更容易检测到MAT2A蛋白；反之，加热后MAT2A蛋白的稳定性会更差，被检测到的蛋白量将变低。从而评定药物与靶蛋白的结合能力，用于MAT2A蛋白抑制剂的筛选。
具体实验流程：
取对数生长期的HCT116细胞(细胞存活率>90％)，PBS洗涤细胞3次，2000g离心2min；用含蛋白酶抑制剂PMSF的细胞裂解液在冰上裂解30min；使用BCA试剂盒对蛋白样本进行浓度测定。分别使用候选药物以及对照药物和对照试剂对样本进行孵育30min,对各组样本进行设置好的10个左右的温度点进行加热；恢复室温，以20000g离心样本，收集上清；使用样品缓冲液对蛋白样本进行100℃，10min加热变性。待样本恢复室温后，对样本进行western blot检测；蛋白上样量控制在20ug。确定突变温度后，化合物设置浓度梯度一般9个点，对样本进行孵育，同上操作，进行western blot检测。蛋白电泳：浓缩胶电压设置为60v,分离胶电压设置为120v；电泳结束后，开始进行电转。电转的条件设置为250mA，2h；进行5％的BSA封闭1h；加入特异性1抗，在4℃摇床上孵育过夜；TBST洗涤4次，每次2.5min；在室温摇床上孵育2抗1h；TBST洗涤4次，每次2.5min；使用ECL进行显影，检测不同组和各个温度点的TYK2蛋白表达量。通过image J和GraphPad软件转化处理western blot条带，计算EC50。
EC50为半最大效应浓度(concentration for 50％of maximal effect,EC50)，是指能引起50％个体有效的药物浓度。使用安吉奥斯医药品有限公司的AG270(参考CN201780066270.4中报道的化合物153的制备方法制得)作为阳性参考化合物。
各化合物的EC50值按照以下说明分类：
“+”表示EC50值大于100μM；
“++”表示EC50值小于100μM大于10μM；
“+++”表示EC50值小于10μM。
表6:EC50结果
| 化合物编号 | EC50 |
| 1 | + |
| 2 | ++ |
| 3 | ++ |
| 4 | ++ |
| 5 | + |
| 6 | + |
| 7 | + |
| 8 | ++ |
| 9 | ++ |
| 10 | +++ |
| 11 | ++ |
| 12 | ++ |
| 13 | + |
| 14 | ++ |
| 15 | +++ |
| 16 | ++ |
| 17 | +++ |
| 18 | ++ |
| 19 | ++ |
| 20 | +++ |
| 21 | + |
| 22 | +++ |
| 23 | ++ |
| 24 | ++ |
| 25 | ++ |
| 26 | +++ |
| 27 | ++ |
| 28 | +++ |
| 29 | +++ |
| 阳性药AG270 | ++ |
EC50实验数据表明，本发明化合物与MAT2A蛋白具有较好的结合能力，相比于阳性对照药AG270(参考CN201780066270.4中报道的化合物153的制备方法制得)，本发明化合物与MAT2A蛋白的结合能力相当，甚至更强。
实验例2：本发明的化合物对HCT116 MTAP-/-细胞增殖作用的测定
实验目的：该测试例的目的是测试化合物对HCT116 MTAP-/-细胞增殖作用。
背景原理：甲硫氨酸腺苷转移酶2A(MAT2A)被认为是甲基硫代腺苷磷酸化酶(MTAP)基因缺失的癌症的合成致死靶点，MTAP基因与CDKN2A肿瘤抑制因子相邻，在约15％的癌症中与CDKN2A共缺失。因此，通过检测化合物对HCT116 MTAP-/-细胞增殖的抑制率，用于MAT2A蛋白抑制剂的筛选。
具体实验流程：
构建HCT116 MTAP敲除细胞，筛选单克隆。将处于对数生长期的HCT116 MTAP-/-和WT细胞，接种与96孔板，每孔90uL，1000个/孔，37℃培养箱静置过夜。第二天，加入10μl不同浓度的化合物(DMSO终浓度为1％)，37℃培养箱孵育10天。第10天，吸去旧培养基，加入110ul培养基(培养基和CCK8比例为100:10)，37℃孵育1-4h。450nM处检测吸光值，通过GraphPad软件处理计算IC50，通过和阳性药物对比，筛选化合物。
IC50(half maximal inhibitory concentration)是指被测量的拮抗剂的半抑制浓度。它能指示某一药物或者物质(抑制剂)在抑制某些生物程序(或者是包含在此程序中的某些物质，比如酶，细胞受体或是微生物)的半量。使用安吉奥斯医药品有限公司的AG270作为阳性参考化合物。
试验结果见下表7，其中各化合物的IC50值按照以下说明分类：
+++小于10nM，++在10nM和1μM之间，+大于1μM。
试验结果如下表7：
表7:IC50实验数据
结果显示本发明化合物能抑制HCT116 MTAP-null细胞，IC50值达到nM级，相当于或者小于阳性对照药AG270。这一强抑制作用对与MAT2A抑制有关的病症或疾病的治疗具有重要的治疗意义。
实验例3：本发明的化合物对MAT2A蛋白酶功能作用的测定
实验目的：该测试例的目的是测试化合物对MAT2A蛋白酶功能的抑制能力。
背景原理：代谢酶蛋氨酸腺苷转移酶2A(MAT2A)在代谢和表观遗传学中具有重要作用，因为它是通用甲基供体s-腺苷蛋氨酸(SAM)的主要生产者。ATP和L-Met在MAT2A的作用下产生SAM和磷酸基团。因此，在化合物孵育后，通过检测SAM的生成量评价化合物对MAT2A酶功能的抑制能力，用于MAT2A蛋白抑制剂的筛选。
具体实验流程：
MAT2A蛋白表达：将全长MAT2A克隆到具有n端(His)6x标记和烟草腐蚀病毒(TEV)蛋白酶裂解位点的pET24N载体上。将构建的载体转化到大肠杆菌BL21(DE3)中，摇菌到OD为0.6时，加入1mM IPTG，18℃培养16h。收集菌体，进行超声破碎，离心取上清，通过Ni-NTA纯化蛋白，透析后测定蛋白浓度和纯度。SAM测定：反应体系：依次加入91-x ul的50mM TrisHCl pH 7.5，1.5uL(10/3M)的KCl，1.5uL(1M)的MgCl2，1uL(100mM)的ATP，1uL(80mM)的L-Met，1uL(30Mm PH7.67)的EDTA，1uL5％的BSA，2uL上述DMSO溶解的药物，x uL的MAT2A蛋白。实验组分别配制不同药物浓度，取出2uL(100x)，加入到反应体系中，37℃反应18h，分别设置溶剂对照组和空白对照组。反应终止，取出40uL体系，加4uL10％SDS猝灭反应。通过GraphPad软件处理计算IC50，通过和阳性药物对比，筛选化合物。
试验结果见下表8，其中各化合物的IC50值按照以下说明分类：
+++小于10nM，++在10nM和1μM之间，+大于1μM。
试验结果如下表8：
表8:IC50实验数据
结果显示本发明化合物对MAT2A蛋白酶功能具有非常强的抑制作用，IC50值均达到nM级，相当于或者小于阳性对照药AG270。这一强抑制作用对与MAT2A抑制有关的病症或疾病的治疗具有重要的治疗意义。
以上实施例仅是代表性的。通过上述实施例可见，本发明的化合物是理想的高效MAT2A抑制剂，可期望用于治疗或预防与MAT2A抑制有关的病症或疾病。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围。
Claims (10)
1.如式(I)所示的化合物、或其药学可接受的盐，
其中:
选自
R1选自-S(O)2-R6，其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、-CN、C1-C6-烷基、C1-C6-烷氧基，其中R6选自
R2选自其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、-CN、C1-C6-烷基、C1-C6-烷氧基；
R3选自C6-C10芳基，其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、-CN、C1-C6-烷基、C1-C6-烷氧基；
R4选自
其各自任选取代有一个或多个选自以下的取代基：羟基、卤素、-NH2、羧基、-CN、C1-C6-烷基、C1-C6-烷氧基。
2.根据权利要求1所述的化合物、或其药学可接受的盐，其特征在于，所述R1基团任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
3.根据权利要求1所述的化合物、或其药学可接受的盐，其特征在于，所述R2所述基团任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
4.根据权利要求1所述的化合物、或其药学可接受的盐，其特征在于，所述R3选自苯基，任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
5.根据权利要求1所述的化合物、或其药学可接受的盐，其特征在于，所述R4基团任选地被一个或者多个氨基、甲基、甲氧基、羟基、卤素、氰基取代。
6.如下式(I-a)和(I-b)所示的化合物、或其药学可接受的盐，
R2、R3、R4、R1的定义如权利要求1。
7.根据权利要求1-6任一项所述的化合物、或其药学可接受的盐，其特征在于，所述通式选自以下化合物：
8.一种制备式(I-a)所述化合物、或其药学可接受的盐的方法，其特征在于，该方法包括以下步骤：
起始原料先后通过酰胺缩合反应、闭环反应、Buchwald-Hartwig偶联反应、取代反应、氧化反应制得式(I-a)所示化合物；
其中，R2、R3、R4、R6的定义如权利要求1。
9.一种药物组合物，包含根据权利要求1至7中任一项所述合物、或其药学可接受的盐，以及药学上可接受的辅料。
10.权利要求1至7任一项的化合物、或其药学可接受的盐或者权利要求9所述组合物在制备用于在患有癌症的受试者中治疗所述癌症的药物中的用途，其中所述癌症的特征为MTAP表达的减少或缺失、MTAP基因的缺失、MTAP蛋白功能的减少。
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