CN112707902B - TGF-β受体抑制剂 - Google Patents
TGF-β受体抑制剂 Download PDFInfo
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- CN112707902B CN112707902B CN202011579497.9A CN202011579497A CN112707902B CN 112707902 B CN112707902 B CN 112707902B CN 202011579497 A CN202011579497 A CN 202011579497A CN 112707902 B CN112707902 B CN 112707902B
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Abstract
本发明提供了一种式(I)化合物及其药物组合物。本发明的式(I)化合物可用作TGF‑β受体抑制剂,尤其是TGFβRI抑制剂,例如可以用于预防或治疗各种TGFβRI(ALK5)介导的相关疾病。
Description
交叉引用
本申请要求以下专利申请的优先权:(1)发明名称为“TGF-β受体抑制剂”于2020年3月23日提交到中国专利局的中国专利申请202010207872.0的优先权,其内容均通过引用以整体并入本文。
技术领域
本发明提供了一类新型杂环化合物,其制备方法及其作为TGF-β受体(特别是TGFβRI)拮抗剂的应用。
背景技术
转化生长因子-β(transforming growth factor-β,TGF-β)是一种多功能的生长因子和细胞因子,与活化素(activins)、抑制素(inhibins)、缪勒氏管抑制质(Mullerianinhibitor substance,MIS)和骨形成蛋白(bone morpho-genetic proteins,BMPs)等多种相关蛋白组成转化生长因子-β超家族。它能够参与调节多种生物过程,包括细胞的增殖、分化、发育以及细胞外基质的修饰(包括肿瘤基质和免疫抑制、血管生成和纤维组织生成)。
TGF-β主要有三种细胞受体,分别是I型(TGFβRI)、II型(TGFβRII)和III型(TGFβRIII)。TGF-β信号通路中的信号传导主要是通过TGF-β配体与细胞表面的丝氨酸/苏氨酸激酶受体TGFβRI(ALK5)和TGFβRII结合形成一个异源四聚体复合物,然后TGFβRII对TGFβRI的甘氨酸/丝氨酸区域(GS region)进行磷酸化并激活TGFβRI磷酸化与其连接的细胞内信号传导蛋白Smad蛋白分子——Smad2/Smad3。磷酸化的Smad2和Smad3蛋白与Smad4结合形成的复合物转移到细胞核,结合不同的转录因子和转录共激活剂或共抑制剂,来调节靶基因的转录,引起各种各样的转录反应,从而导致基因表达的改变。而转化生长因子-βIII型受体(TGFβRIII)则本身不能传递信号,但它能通过结合TGF-β并将其传递给TGFβRII来增强TGF-β配体与TGF-βII型受体的结合,从而间接的影响信号的传导。在生物体内,细胞因子、生长因子、微环境条件、激素、磷酸化和去磷酸化激酶等都能影响和控制TGF-β信号通路中的信号传导。
研究表明,TGF-β在心、肝、肺、肾等不同器官***纤维化的发生和进展中起着关键作用。异常的TGF-β信号和许多人类疾病有关,比如癌症、心血管疾病、炎症、器官纤维化疾病、胰腺疾病等。在人的肿瘤中,TGF-β信号的失调很常见,能促进肿瘤细胞生长和分化、调节细胞外基质和上皮间质转换。目前,随着肿瘤免疫疗法研究的不断深入,TGF-β已经被证实对调节抗肿瘤免疫有重要作用。TGF-β对T淋巴细胞的分化有很强的抑制作用,对树状细胞、CD8+T细胞和NK细胞有明显的负影响,同时它能增强免疫抑制Treg和骨髓源性抑制细胞(MDSC)的活性,从而为肿瘤生长和转移提供有利的肿瘤微环境。因此,抑制TGF-β信号通路中某个环节的信号传导有可能成为***的有效方法之一。
TGFβRI(ALK5)作为TGF-β信号通路中的一个重要节点被认为是***的一个重要靶点,通过阻止TGFβRI与配体的结合,来抑制ALK5对其下游信号蛋白(Smad2或Smad3)的磷酸化,从而影响或者阻断TGF-β信号的传导,以实现预防和治疗各种由ALK5介导的相关疾病。
目前,国际专利申请公开号WO2000/061576、WO2002/066462、WO2004/111036、WO2004/048382、WO2009/087224、WO2009/013335、WO2012/002680、WO2016/057278、WO2017/015425、WO2017/215506、WO2018/017633等和中国专利申请公开号CN107663206A等公开了用作TGF-β受体拮抗剂的化合物。然而,仍需要对TGF-β受体,尤其是对TGFβRI(ALK5)具有更好抑制效果的抑制剂;特别地,能够选择性抑制ALK5的拮抗剂具有重要的临床价值和治疗意义,但是目前对其报道很少。现有技术中迫切需要具有更好抑制效果的ALK5抑制剂,特别是能够选择性抑制ALK5的新型拮抗剂化合物。
发明内容
经过长期而深入的研究,我们发现了一类具有良好的ALK5抑制活性的杂环化合物。
基于上述发现,在本发明的第一个方面,提供了式(I)化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物,
其中:
W1表示CRL或者N;
L表示CRaRb、O或者NRa;
R1、R2、RL各自独立地表示氢、卤素、硝基、氰基、-ORa、-NRaRb或者被0、1、2或3个取代基所取代的C1-C6烷基、C3-C6环烷基;其中所述取代基选自:-ORa、氰基、氧代、卤素、-NRaRb、-C(O)NRaRb、-SO2Ra和-NRaC(O)Rb;
R3表示氢、C1-C6烷基、卤代(C1-C6烷基)、C3-C8环烷基、3-8元杂环烷基或者被0、1、2、3、4或5个取代基所取代的C6-C10芳基或5-10元杂芳基;
Cy表示C3-C6环烷基、3-6元杂环烷基、C6-C10芳基或者5-10元杂芳基;并且所述Cy可以任意地被选自0、1、2、3、4或5个取代基所取代,所述的取代基为卤素、硝基、氰基、-ORa、-羟基(C1-C6烷基)、C1-C6烷基、卤代(C1-C6烷基)、C3-C6环烷基、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-C(O)(C1-C6烷基)、-C(O)O(C1-C6烷基)、-C(O)NRaRb、-SO2Ra、-SO2NRaRb和-P(O)RaRb;
Ra、Rb各自独立地表示氢、C1-C6烷基、C3-C6环烷基、-羟基(C1-C6烷基)、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6亚烷基)O(C1-C6烷基)、-(C0-C6亚烷基)O(C3-C6环烷基)、-(C0-C6亚烷基)O(3-6元杂环烷基);或者Ra、Rb与其所连接的原子一起形成5-8元环,该环中还可以任意地含有0、1或2个选自N、O、S的杂原子;
m为0、1或2;
n为0、1或2。
优选地,本发明的化合物具有以下式(II)结构:
其中,R1、R2、R3、L、Cy、m和n具有所述式(I)化合物中的定义。
优选地,本发明的化合物具有以下式(III)结构:
其中:
R1、R3和Cy和n具有所述式(I)化合物中的定义;
R2表示氢或者卤素;
m为0或1。
优选地,本发明的化合物具有以下式(IV)结构:
其中:
R1、R2、R3、m和n具有所述式(III)化合物中的定义。
W2表示CR5或者N;
R4、R5各自独立地表示卤素、硝基、氰基、-ORa、-羟基(C1-C6烷基)、C1-C6烷基、卤代(C1-C6烷基)、C3-C6环烷基、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-C(O)(C1-C6烷基)、-C(O)O(C1-C6烷基)、-C(O)NRaRb、-SO2Ra、-SO2NRaRb或-P(O)RaRb;
Ra、Rb各自独立地表示氢、C1-C6烷基、C3-C6环烷基、羟基(C1-C6烷基)、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6亚烷基)O(C1-C6烷基)、-(C0-C6亚烷基)O(C3-C6环烷基)或-(C0-C6亚烷基)O(3-6元杂环烷基);Ra、Rb与其所连接的原子一起形成5-8元环,该环中还可以任意地含有0、1或2个选自N、O、S的杂原子;
其中,o为0、1、2、3或4。
优选地,本发明的化合物选自以下结构:
本发明的化合物也可制备成可药用盐的形式,所述可药用盐可以使用例如以下的无机酸或有机酸而形成:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸或甲苯磺酸。
本发明的可药用盐可通过常规方法制备,例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)中,向其中添加过量的有机酸或无机酸水溶液,以使得盐从所得混合物中沉淀,从中除去溶剂和剩余的游离酸,然后分离所沉淀的盐即可。
本发明化合物(或其可药用盐)可包括溶剂化物形式,优选地,所述溶剂化物为水合物。
本发明还提供了本发明的化合物在制备用于预防或治疗可通过抑制ALK5活性来调节之疾病的药物中的用途。优选地,所述疾病选自癌症、肿瘤、炎症性疾病、自身免疫性疾病和免疫介导性疾病。
此外,本发明提供了用于预防或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物,其包含本发明的式(I)化合物作为活性成分。
此外,本发明提供了一种用于预防或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法,其包括向有此需要的哺乳动物施用本发明的化合物。
癌症或肿瘤的代表性实例可包括但不限于,皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、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、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的抗癌剂或检查点抑制剂组合施用时,本发明化合物或其可药用盐可提供增强的抗癌作用。
用于治疗癌症或肿瘤的抗癌剂的代表性实例可包括但不限于细胞信号转导抑制剂、苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、***、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗;检查点抑制剂,包括但不局限于抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体以及抗CTLA-4抗体或它们的任意组合。
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于,关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、***性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、***性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时,本发明化合物或其可药用盐可提供增强的治疗作用。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于,甾体药物(例如,强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、***等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如,依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如,他克莫司、吡美莫司等)和抗组胺药(例如,苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等),并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用,其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天,并且每天以单次或4次分次剂量,或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下,小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
可根据常规方法中的任何一种将本发明药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径)的剂型,例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。
用于口服施用的本发明药物组合物可通过将活性成分与例如以下的载体混合来制备:纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂和稀释剂。在本发明的注射组合物中采用的载体的实例是水、盐溶液、葡萄糖溶液、葡萄糖样溶液、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂。
本发明描述示例性实施方案的过程中,本发明的其它特征将变得显而易见,给出所述实施方案用于说明本发明而不意欲成为其限制,以下实施例使用本发明所公开的方法制备、分离和表征。
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物,可使用有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。可以在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施所需反应。
具体实施例
当未包括制备途径时,相关中间体是市售的(例如来自SigmaAldrich,Alfa)。
通用过程
使用市售试剂而不需进一步纯化。1H-NMR谱在Bruker仪器上于500MHz记录。化学位移值以百万分率表示,即δ值。以下简写用于NMR信号的多重性:s=单峰,brs=宽峰,d=二重峰,t=三重峰,m=多重峰。耦合常数以J值列出,以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
LC-MS实验在以下条件下测量:
仪器:Thermo U3000,ALLtech ELSD,MSQ,UV检测器结合ELSD和MSD(流出比为4:1)。柱:Waters X-Bridge C-18,3.5μm,4.6x50mm;柱温:30℃。梯度【时间(min)/溶剂B在A中(%)】:0.00/5.0,0.70/95,1.40/95,1.41/5,1.50/5。(溶剂A=0.01%三氟乙酸在水中;溶剂B=0.01%三氟乙酸在乙腈中)。UV检测:214/254/280/300nm;DAD检测:200-400nm;流速:4mL/min;MS:ESI,100-1500m/z
制备型HPLC通常使用酸性方法(乙腈和水的梯度,各含有0.1%甲酸)用ThermoU3000AFC-3000;柱:Globalsil C-1812nm,250×20mm,10μm,或相当;流速:20mL/min,进行分离。
中间体的合成
化合物INT-1的制备:
在室温条件下,将溶有2-吡啶甲醇(500mg,4.6mmol)和2,4-二硝基苯基羟胺(912mg,4.6mmol)的二氯甲烷(15mL)溶液搅拌过夜。反应液中加入***后,过滤;滤饼进一步进行真空干燥得到黄色固体INT-1(304mg,收率:53.0%)。
化合物INT-2的制备:
将4-溴吡啶-2-甲酸(5.0g,24.7mmol)溶于乙醇中(85mL),然后加入浓硫酸(2.69mL)。所得的反应液在60℃条件下搅拌6小时。将反应液减压浓缩,出去部分溶剂,然后倒入水中(100mL),用饱和碳酸氢钠水溶液中和,用乙酸乙酯萃取(100mL×3)。萃取的有机相用饱和食盐水洗(80mL),无水硫酸钠干燥,过滤,滤液减压浓缩,所得粗品用硅胶柱层析(石油醚/乙酸乙酯=1/1)得到黄色油状化合物INT-2a(4.19g,收率:73.6%)。MS(ESI):m/z230.1(M+H)+.
将甲基溴化镁(3M的2-甲基四氢呋喃溶液,3.48mL)加入到装有无水四氢呋喃(18mL)的三口烧瓶中,冰浴冷却,氮气保护下,向其中加入溶有化合物INT-2a(1g,4.35mmol)的四氢呋喃溶液(5mL)。将冰浴撤去,所得反应液在室温下搅拌30分钟,然后再用冰浴冷却,加入饱和氯化铵水溶液将反应淬灭,然后用乙酸乙酯稀释(80mL)。将所得的混合液转移至分液漏斗中,加水(50mL),分液。水相再用乙酸乙酯萃取(60mL×2)。有机相合并后用饱和食盐水洗涤(80mL),无水硫酸钠干燥,过滤,滤液减压浓缩,所得粗品用硅胶柱层析(石油醚/乙酸乙酯=2/3)得到淡黄色油状化合物INT-2b(894mg,收率:95.2%)。1H NMR(500MHz,Chloroform-d)δ8.36–8.33(m,1H),7.59(d,J=1.8Hz,1H),7.38(dd,J=5.3,1.8Hz,1H),1.54(s,6H).
将化合物INT-2b(500mg,2.31mmol),浓氨水(28%w/w,5.5mL)和铜粉(100mg,1.57mmol)加入到封管中,敞口室温搅拌30分钟,然后加盖密封,升温至100℃反应过夜。将反应液冷却,用2-甲基四氢呋喃萃取(15mL×30)。有机相减压浓缩得到白色固体化合物INT-2(252mg,收率:71.6%)。不纯化直接用于下一步。MS(ESI):m/z 153.3(M+H)+.
实施例化合物的合成
实施例1:
将二氯亚砜(951mg,8.0mmol)滴入溶有四氢吡喃-4-甲酸(520mg,4.0mmol)的甲苯(10mL)溶液;所得混合液在回流条件下搅拌2小时。反应液冷却后浓缩得到棕色油状物1a。将溶有前述得到的化合物1a和化合物INT-1(173mg,0.56mmol)的吡啶(2mL)溶液在110℃条件下加热5小时。反应液冷却后浓缩,残余物中加入饱和碳酸氢钠溶液(30mL),并用乙酸乙酯萃取(30mL×2)。合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩;所得粗品用硅胶柱层析(石油醚/乙酸乙酯=3/1)得到白色固体1b(35mg,收率:18.9%)。1H NMR(500MHz,Chloroform-d)δ8.28(d,J=7.1Hz,1H),7.20–7.14(m,1H),7.09–7.02(m,1H),6.73–6.61(m,1H),4.11–4.03(m,4H),3.61–3.47(m,4H),3.06–2.98(m,1H),2.96–2.87(m,1H),2.10–1.96(m,6H),1.89–1.83(m,2H);MS(ESI):m/z 331.2(M+H)+.
将混有化合物1b(35mg,0.11mmol)的盐酸水溶液(3mL,10%w/w)在回流条件下搅拌过夜。冷却至0℃后小心加入饱和碳酸氢钠(20mL)溶液,随后用乙酸乙酯萃取(20mL)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到黄色油状物1c(23mg,收率:99.5%)。MS(ESI):m/z 219.1(M+H)+.
将叔丁醇钾(62mg,0.55mmol)加入至溶有化合物1c(23mg,0.11mmol)的
N-甲基吡咯烷酮(1mL)溶液,并在室温条件下搅拌20分钟;随后加入2-氯-4-氟吡啶(36mg,0.27mmol),反应液在相同条件下进一步搅拌1小时。反应液中加入饱和氯化铵溶液(10mL),并用乙酸乙酯萃取(10mL×2)。合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩;所得粗品用制备薄层层析(石油醚/乙酸乙酯=1/1)得到黄色油状物1d(20mg,收率:55.2%)。MS(ESI):m/z 330.1(M+H)+.
在氮气氛围下,将混有化合物1d(20mg,61μmol),化合物INT-2(16mg,85μmol),苯酚钠(11mg,91μmol),Pd2(dba)3(5.6mg,6.1μmol)和XantPhos(7.0mg,12μmol)的1,4-二氧六环(1mL)溶液在回流条件下搅拌过夜。反应液冷却至室温后加入饱和氯化铵溶液(10mL);并用乙酸乙酯萃取(10mL×2)。合并有机相浓缩,粗品经制备HPLC分离得到白色固体1(10mg,收率:38.1%)。1HNMR(500MHz,DMSO-d6)δ9.36(s,1H),8.63(d,J=7.1Hz,1H),8.19–8.13(m,2H),7.68–7.62(m,2H),7.33–7.27(m,1H),7.21–7.15(m,1H),6.90–6.84(m,1H),6.64–6.60(m,1H),6.25(d,J=2.3Hz,1H),5.05(s,1H),3.91–3.82(m,2H),3.41–3.36(m,2H),3.04–2.95(m,1H),1.86–1.72(m,4H),1.37(s,6H);MS(ESI):m/z 446.6(M+H)+.
实施例2:
从化合物1d和4-甲磺酰基苯胺起,参照化合物1合成中的最后一步,将苯酚钠换成碳酸铯,得到化合物2。1H NMR(500MHz,DMSO-d6)δ9.49(s,1H),8.66–8.60(m,1H),8.15(d,J=5.8Hz,1H),7.84(d,J=9.0Hz,2H),7.72(d,J=9.0Hz,2H),7.34–7.28(m,1H),7.21–7.14(m,1H),6.91–6.84(m,1H),6.67–6.63(m,1H),6.23(d,J=2.2Hz,1H),3.91–3.83(m,2H),3.43–3.33(m,2H),3.09(s,3H),3.06–2.95(m,1H),1.87–1.73(m,4H);MS(ESI):m/z 465.2(M+H)+.
实施例3:
从化合物1d和4-氨基苯乙酮起,参照化合物2的合成得到化合物3。1HNMR(500MHz,DMSO-d6)δ9.39(s,1H),8.66–8.61(m,1H),8.14(d,J=5.8Hz,1H),7.82(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H),7.34–7.28(m,1H),7.21–7.15(m,1H),6.92–6.84(m,1H),6.65–6.61(m,1H),6.22(d,J=2.3Hz,1H),3.92–3.84(m,2H),3.42–3.35(m,2H),3.06–2.95(m,1H),2.45(s,3H),1.85–1.74(m,4H);MS(ESI):m/z 429.3(M+H)+.
实施例4:
从化合物1d和4-氨基苯磺酰胺起,参照化合物2的合成得到化合物4。1H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.65–8.61(m,1H),8.12(d,J=5.8Hz,1H),7.75(d,J=8.9Hz,1H),7.63(d,J=8.9Hz,1H),7.37–7.27(m,1H),7.23–7.14(m,1H),7.09(s,2H),6.90–6.83(m,1H),6.64–6.60(m,1H),6.20(d,J=2.2Hz,1H),3.93–3.83(m,2H),3.43–3.34(m,2H),3.06–2.94(m,1H),1.87–1.74(m,4H);MS(ESI):m/z 466.2(M+H)+.
实施例5:
从化合物1d和4-氨基苯甲酰胺起,参照化合物2的合成得到化合物5。1H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.62(d,J=7.1Hz,1H),8.11(d,J=5.8Hz,1H),7.73(d,J=8.7Hz,2H),7.69(s,1H),7.65(d,J=8.7Hz,2H),7.31(d,J=8.9Hz,1H),7.21–7.14(m,1H),7.05(s,1H),6.90–6.83(m,1H),6.62–6.56(m,1H),6.18(d,J=2.3Hz,1H),3.91–3.83(m,2H),3.44–3.34(m,2H),3.05–2.95(m,1H),1.87–1.73(m,4H);MS(ESI):m/z 430.2(M+H)+.
实施例6:
从化合物1d和4-(二甲基氧磷基)苯胺起,参照化合物2的合成得到化合物6。1HNMR(500MHz,DMSO-d6)δ9.21(s,1H),8.62(d,J=7.1Hz,1H),8.10(d,J=5.8Hz,1H),7.76–7.70(m,2H),7.60–7.52(m,2H),7.34–7.28(m,1H),7.20–7.14(m,1H),6.90–6.83(m,1H),6.60–6.56(m,1H),6.19(d,J=2.2Hz,1H),3.92–3.82(m,2H),3.43–3.34(m,2H),3.06–2.95(m,1H),1.88–1.72(m,4H),1.57(s,3H),1.54(s,3H);MS(ESI):m/z 463.2(M+H)+.
实施例7:
从环丙基甲酰氯起,参照化合物1的合成得到化合物7。1HNMR(500MHz,DMSO-d6)δ9.38(s,1H),8.55(d,J=7.0Hz,1H),8.18–8.14(m,2H),7.67–7.65(m,2H),7.32–7.28(m,1H),7.15(m,1H),6.86–6.78(m,1H),6.65–6.62(m,1H),6.28(d,J=2.3Hz,1H),5.05(s,1H),1.90–1.84(m,1H),0.96–0.87(m,4H);MS(ESI):m/z 402.3(M+H)+.
实施例8:
在0℃条件下,将硝酸钾(1.2g,12.2mmol)分批加入至溶有2,6-二甲基吡啶N-氧化物(1.0g,8.1mmol)的浓硫酸(4mL)中。所得反应液在100℃条件下反应过夜。反应液倒入冰水,用碳酸钠水溶液(5%w/w)调节pH至7~8,并用乙酸乙酯萃取(50mL×2)。合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到黄色固体8a(1.1g,收率:82.0%)。MS(ESI):m/z 169.1(M+H)+.
在冰浴条件下,将三氟乙酸酐(3.1g,14.6mmol)加入至溶有化合物8a(900mg,7.3mmol)的二氯甲烷溶液(15mL);所得反应液在40℃条件下搅拌18小时。反应液用饱和碳酸氢钠溶液(50mL)洗涤,并用乙酸乙酯萃取(50mL×2)。合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩;所得粗品用硅胶柱层析(二氯甲烷/甲醇=30/1)分离得到黄色固体8b(340mg,收率:27.7%)。MS(ESI):m/z 169.0(M+H)+.
在0℃条件下,将戴斯-马丁氧化剂(493mg,1.2mmol)加入至溶有化合物8b(163mg,0.97mmol)的二氯甲烷溶液(5mL)中;所得反应液在室温条件下搅拌1小时。反应液中加入饱和碳酸氢钠(20mL)和亚硫酸钠(5%w/w,20mL)的混合水溶液,并用二氯甲烷萃取(30mL×2)。合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到黄色固体8c(160mg,收率:99.4%)。
在冰浴条件下,依次将溶有氢氧化钾(148mg,2.5mmol)的甲醇溶液(3mL)和溶有碘(318mg,1.25mmol)的甲醇溶液(3mL)加入至溶有化合物8c(160mg,0.96mmol)的甲醇溶液(5mL);反应液在相同条件下继续搅拌半小时。反应液中加入亚硫酸钠水溶液(5%w/w,30mL),并用乙酸乙酯萃取(20mL×2)。合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到黄色固体8d(60mg,收率:31.8%)。1HNMR(500MHz,Chloroform-d)δ8.62(d,J=1.9Hz,1H),8.06(d,J=1.9Hz,1H),4.06(s,3H),2.83(s,3H).
在氢气气氛和室温条件下,将混有化合物8d(60mg,0.31mmol)和钯碳(10%w/w,20mg)的甲醇溶液(5mL)搅拌2小时。反应液用硅藻土过滤,滤液浓缩,所得残余物用硅胶柱层析(二氯甲烷/甲醇=20/1)分离得到白色固体8e(25mg,收率:49.2%)。MS(ESI):m/z167.2(M+H)+.
在氮气气氛下,将混有化合物7a(43mg,0.15mmol),化合物8e(25mg,0.15mmol),Pd2(dba)3(14mg,0.015mmol),XantPhos(17mg,0.030mmol)和碳酸铯(98mg,0.30mmol)的甲苯溶液(2mL)在100℃条件下搅拌过夜。反应液用硅藻土过滤,滤液浓缩;所得粗品用硅胶柱层析(二氯甲烷/甲醇=30/1)分离得到白色固体8(42mg,收率:67.2%)。1HNMR(500MHz,DMSO-d6)δ9.59(s,1H),8.57–8.53(m,1H),8.20(d,J=5.9Hz,1H),8.08(d,J=2.0Hz,1H),7.73(d,J=2.0Hz,1H),7.36–7.27(m,1H),7.20–7.11(m,1H),6.87–6.80(m,1H),6.72–6.68(m,1H),6.27(d,J=2.3Hz,1H),3.81(s,3H),2.40(s,3H),1.89–1.84(m,1H),0.95–0.87(m,4H);MS(ESI):m/z 416.2(M+H)+.
实施例9:
在冰浴条件下,将甲基溴化镁(3M的四氢呋喃溶液,67μL)加入至溶有化合物8(21mg,51μmmol)的四氢呋喃(2mL)溶液中;所得反应液在相同条件下搅拌1小时。反应液用水(10mL)淬灭,并用乙酸乙酯萃取(10mL×2)。合并有机相浓缩,所得残余物用制备HPLC分离得到白色固体9(11mg,收率:52.4%)。1H NMR(500MHz,DMSO-d6)δ9.29(s,1H),8.54(d,J=7.0Hz,1H),8.15(d,J=5.8Hz,1H),7.52(d,J=2.0Hz,1H),7.44(d,J=2.0Hz,1H),7.34–7.27(m,1H),7.19–7.11(m,1H),6.86–6.78(m,1H),6.64–6.60(m,1H),6.27(d,J=2.3Hz,1H),5.06(s,1H),2.32(s,3H),1.91–1.82(m,1H),1.35(s,6H),0.98–0.85(m,4H);MS(ESI):m/z 416.3(M+H)+.
实施例10:
从化合物7a和4-氨基苯甲酸酯起,参照化合物8的最后一步合成,将碳酸铯换成叔丁醇钠,得到化合物10a。MS(ESI):m/z 387.2(M+H)+.
在室温条件下,将混有化合物10a(7.5mg,19μmol),苄胺(4.2mg,38μmol),HATU(11mg,29μmol)和N,N-二异丙基乙胺(5.0mg,38μmol)的N,N-二甲基甲酰胺(1mL)搅拌1小时。反应液随即用制备HPLC分离得到白色固体10(5.2mg,收率:56.3%)。1H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.77(t,J=6.0Hz,1H),8.54(d,J=7.0Hz,1H),8.11(d,J=5.9Hz,1H),7.77(d,J=8.5Hz,2H),7.68(d,J=8.5Hz,2H),7.34–7.27(m,4H),7.25–7.19(m,1H),7.15(t,J=7.8Hz,1H),6.82(t,J=6.9Hz,1H),6.65–6.56(m,1H),6.22(d,J=2.2Hz,1H),4.44(d,J=5.8Hz,2H),1.91–1.83(m,1H),0.97–0.83(m,4H);MS(ESI):m/z 476.3(M+H)+.
实施例11:
从化合物10a和乙醇胺起,参照化合物10最后一步合成得到化合物11。1H NMR(500MHz,DMSO-d6)δ9.22(s,1H),8.54(d,J=7.1Hz,1H),8.16(t,J=5.6Hz,1H),8.11(d,J=5.8Hz,1H),7.75(d,J=8.5Hz,2H),7.67(d,J=8.5Hz,2H),7.30(d,J=8.8Hz,1H),7.18–7.12(m,1H),6.86–6.80(m,1H),6.62–6.58(m,1H),6.21(d,J=2.3Hz,1H),4.69(s,1H),3.51–3.43(m,2H),3.29–3.25(m,2H),1.92–1.83(m,1H),0.99–0.86(m,4H);MS(ESI):m/z430.2(M+H)+.
实施例12:
从化合物7a和4-氨基苯磺酰胺起,参照化合物2的合成得到化合物12。1H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.54(d,J=7.1Hz,1H),8.12(d,J=5.8Hz,1H),7.75(d,J=8.5Hz,2H),7.67(d,J=8.5Hz,2H),7.33–7.29(m,1H),7.19–7.13(m,1H),7.07(brs,2H),6.87–6.79(m,1H),6.65–6.61(m,1H),6.23(d,J=2.3Hz,1H),1.92–1.82(m,1H),0.99–0.85(m,4H);MS(ESI):m/z 422.0(M+H)+.
实施例13:
将混有N-乙酰基-3-甲苯胺(2.0g,13.4mmol)的氯磺酸(4mL)在室温条件下搅拌20分钟;随后升温至70℃,并维持该条件继续搅拌8小时。反应液冷却至室温后加入冰(50g),随即逐渐析出固体。
将上述所得滤饼溶于四氢呋喃(50mL)溶液中,并在冰浴条件下加入浓氨水(4mL);反应液升至室温,并维持该条件继续搅拌2小时。反应液浓缩后加水(100mL)析出固体。
将上述所得滤饼溶于乙醇(5mL)和盐酸水溶液(6M,5mL)的混合溶液;反应液在回流温度下搅拌1小时。反应液浓缩,用氢氧化钠水溶液(1M)调至pH为7~8,并用乙酸乙酯萃取(50mL×3)。合并有机相用无水硫酸钠干燥,浓缩;所得粗品用硅胶柱层析(二氯甲烷/甲醇=20/1)得到白色固体13a(500mg,收率:16.3%)。1H NMR(500MHz,DMSO-d6)δ7.46(d,J=8.5Hz,1H),6.86(s,2H),6.40(d,J=2.2Hz,1H),6.36(dd,J=8.5,2.2Hz,1H),5.66(s,2H),2.40(s,3H);MS(ESI):m/z 187.4(M+H)+.
从化合物7a和化合物13a起,参照化合物2的合成得到化合物13。1H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.59–8.52(m,1H),8.12(d,J=5.9Hz,1H),7.66(d,J=8.7Hz,1H),7.64–7.59(m,1H),7.53–7.49(m,1H),7.33–7.27(m,1H),7.18–7.13(m,1H),7.10(s,2H),6.85–6.79(m,1H),6.63–6.59(m,1H),6.22(d,J=2.3Hz,1H),2.48(s,3H),1.90–1.84(m,1H),0.96–0.88(m,4H);MS(ESI):m/z 435.9(M+H)+.
实施例14:
参照化合物12的合成,将4-氨基苯磺酰胺替换成4-氨基苯甲酰胺,得到化合物14。1H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.56(d,J=7.1Hz,1H),8.13(d,J=5.8Hz,1H),7.75(d,J=8.8Hz,2H),7.72(brs,1H),7.67(d,J=8.8Hz,2H),7.37–7.29(m,1H),7.21–7.14(m,1H),7.09(s,1H),6.87–6.80(m,1H),6.64–6.60(m,1H),6.23(d,J=2.3Hz,1H),1.94–1.83(m,1H),1.00–0.88(m,4H);MS(ESI):m/z 386.2(M+H)+.
实施例15:
从化合物10a和3-氨基-1-丙醇起,参照化合物10最后一步合成得到化合物15。1HNMR(500MHz,DMSO-d6)δ9.24(s,1H),8.61–8.54(m,1H),8.20(t,J=5.6Hz,1H),8.13(d,J=5.8Hz,1H),7.73(d,J=9.0Hz,2H),7.69(d,J=9.0Hz,2H),7.36–7.31(m,1H),7.22–7.15(m,1H),6.89–6.82(m,1H),6.64–6.60(m,1H),6.23(d,J=2.3Hz,1H),4.48(t,J=5.3Hz,1H),3.48–3.44(m,2H),3.32–3.25(m,2H),1.94–1.87(m,1H),1.70–1.63(m,2H),0.99–0.91(m,4H);MS(ESI):m/z 444.2(M+H)+.
实施例16:
从化合物10a和N-甲基-2-羟基乙胺起,参照化合物10最后一步合成得到化合物16。1H NMR(500MHz,DMSO-d6)δ9.16(s,1H),8.60–8.55(m,1H),8.11(d,J=5.8Hz,1H),7.67(d,J=8.6Hz,2H),7.36–7.32(m,1H),7.31(d,J=8.6Hz,2H),7.21–7.16(m,1H),6.87–6.82(m,1H),6.63–6.60(m,1H),6.22(d,J=2.3Hz,1H),4.77(t,J=5.5Hz,1H),3.64–3.35(m,4H),2.97(s,3H),1.94–1.86(m,1H),1.00–0.90(m,4H);MS(ESI):m/z 444.2(M+H)+.
实施例17:
从3'-氯乙酰苯胺起,参照化合物13的合成得到化合物17。1HNMR(500MHz,DMSO-d6)δ9.55(s,1H),8.60–8.56(m,1H),8.20(d,J=5.9Hz,1H),8.15(d,J=2.2Hz,1H),7.80(d,J=8.8Hz,1H),7.55–7.51(m,1H),7.39–7.33(m,1H),7.33(brs,2H),7.22–7.16(m,1H),6.88–6.83(m,1H),6.73–6.70(m,1H),6.25(d,J=2.3Hz,1H),1.95–1.84(m,1H),0.99–0.90(m,4H);MS(ESI):m/z 456.1(M+H)+.
实施例18:
参照化合物12的合成,将4-氨基苯磺酰胺替换成3-氨基苯磺酰胺,得到化合物18。1H NMR(500MHz,DMSO-d6)δ9.34(s,1H),8.57(d,J=7.0Hz,1H),8.17(s,1H),8.11(d,J=6.0Hz,1H),7.81(d,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),7.37–7.26(m,4H),7.21–7.15(m,1H),6.84(t,J=7.0Hz,1H),6.66–6.59(m,1H),6.22(s,1H),1.93–1.85(m,1H),0.99–0.87(m,4H);MS(ESI):m/z 422.2(M+H)+.
实施例19:
将对氟硝基苯(1.06g,7.51mmol)加入到反应瓶中,然后加入氯磺酸(4mL)。所得的混合物在110℃条件下搅拌24小时,然后将反应液冷却至室温。将反应液缓慢倒入到冰浴中,待冰融化后用乙酸乙酯萃取(50mL×3)。有机相用饱和食盐水洗(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到的油状物用乙酸乙酯溶解(38mL),然后冷却至0℃,向其中缓慢加入浓氨水(38mL,28%w/w)。所得反应液在室温下搅拌过夜,然后加入水(30mL),用乙酸乙酯萃取(50mL×3)。有机相用饱和食盐水洗(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩,所得粗品用硅胶柱层析(石油醚/乙酸乙酯=1/1)得到棕黄色固体化合物19a(830mg,收率:50.2%)。
将化合物19a(100mg,0.45mmol)溶于甲醇中(8mL),然后加入Pd/C(40mg,10%w/w),所得的反应液在氢气氛围下室温搅拌2小时,反应液经硅藻土过滤,滤液减压浓缩得到白色固体化合物19b(63mg,收率:73%)。1HNMR(500MHz,DMSO-d6)δ7.43(s,2H),7.05–6.99(m,1H),6.99–6.94(m,1H),6.74–6.66(m,1H),5.36(s,2H).
将化合物7a(30mg,0.11mmol),化合物19b(24mg,0.13mmol),碳酸铯(51mg,0.16mmol),XantPhos(12mg,21μmol)和醋酸钯(2.36mg,10μmol)加入到反应瓶中,然后加入1,4-二氧六环(2mL)。所得反应液在氮气氛围下,在100℃条件下搅拌反应过夜。将反应液冷却后过滤,滤液减压浓缩后得到的粗品用制备HPLC纯化得到白色固体化合物19(15mg,收率:32%)。1H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.57(d,J=7.0Hz,1H),8.14–8.10(m,1H),8.08(d,J=5.8Hz,1H),7.93–7.86(m,1H),7.58(s,2H),7.36–7.31(m,1H),7.30–7.23(m,1H),7.21–7.14(m,1H),6.87–6.81(m,1H),6.62–6.58(m,1H),6.15(d,J=2.2Hz,1H),1.93–1.83(m,1H),0.98–0.89(m,4H);MS(ESI):m/z 440.0(M+H)+.
实施例20:
从对硝基甲苯出发,参照化合物19b的合成得到化合物20b。1H NMR(500MHz,DMSO-d6)δ7.13(d,J=2.3Hz,1H),7.12(s,2H),6.96(d,J=8.0Hz,1H),6.62(dd,J=8.0,2.3Hz,1H),5.27(s,2H),2.38(s,3H).
参照化合物19的合成得到化合物20。1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),8.56(d,J=7.0Hz,1H),8.10(d,J=2.4Hz,1H),8.07(d,J=5.8Hz,1H),7.86–7.82(m,1H),7.35–7.29(m,1H),7.27(brs,2H),7.22–7.18(m,1H),7.17–7.13(m,1H),6.87–6.80(m,1H),6.58–6.54(m,1H),6.18(d,J=2.3Hz,1H),2.48(s,3H),1.93–1.84(m,1H),0.98–0.87(m,4H);MS(ESI):m/z 435.8(M+H)+.
实施例21:
从邻硝基甲苯出发,参照化合物19b的合成得到化合物21b。1H NMR(500MHz,DMSO-d6)δ7.09(s,2H),7.07–7.03(m,2H),6.92–6.87(m,1H),5.28(s,2H),2.08(s,3H).
参照化合物19的合成得到化合物21。1H NMR(500MHz,DMSO-d6)δ8.55(d,J=7.0Hz,1H),8.27(s,1H),8.23(d,J=1.8Hz,1H),7.99(d,J=5.8Hz,1H),7.38–7.28(m,3H),7.24(s,2H),7.20–7.12(m,1H),6.87–6.80(m,1H),6.54–6.50(m,1H),6.36(d,J=2.3Hz,1H),2.22(s,3H),1.91–1.84(m,1H),0.99–0.88(m,4H);MS(ESI):m/z 436.3(M+H)+.
实施例22:
在一个反应瓶中加入2-甲基-3-硝基苯胺(500mg,3.29mmol)和浓盐酸(2mL),然后将反应瓶置于冰盐浴中冷却(-5~-10℃),搅拌下加入亚硝酸钠(249mg,3.61mmol)的水溶液(1.5mL),保持反应温度低于0℃继续搅拌30分钟。在另一个反应瓶中加入水(8mL),然后置于冰盐浴中冷却(-5~-10℃),搅拌下将二氯亚砜(1.1mL,15mmol)缓慢滴加到反应瓶中,所得的反应液在室温下搅拌3小时然后再用冰盐浴冷却,加入氯化亚铜(33mg,0.33mmol),保持冰盐浴条件继续搅拌30分钟。将第一个反应瓶中的反应液加入到第二个反应瓶中,所得反应液在0℃下搅拌1小时。反应液加水稀释,然后用乙酸乙酯萃取(30mL×5)。有机相用饱和食盐水洗(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到的粗品用硅胶柱层析(石油醚/乙酸乙酯=1/1)得到黄色固体化合物22a(55mg,收率:7.7%)。
从化合物22a出发,参照化合物19的合成得到化合物22。1HNMR(500MHz,DMSO-d6)δ8.56–8.52(m 1H),8.35(s,1H),7.93(d,J=5.8Hz,1H),7.73–7.68(m,1H),7.62–7.57(m,1H),7.39(s,2H),7.36–7.31(m,1H),7.27–7.22(m,1H),7.20–7.14(m,1H),6.85–6.79(m,1H),6.48–6.44(m,1H),6.22(d,J=2.3Hz,1H),2.40(s,3H),1.93–1.83(m,1H),0.99–0.89(m,4H);MS(ESI):m/z 436.2(M+H)+.
实施例23:
将溶有乙醇胺(276mg,4.51mmol)和三乙胺(1.89mL,13.5mmol)的二氯甲烷溶液(5mL)冷却至0℃,然后向其中滴加含有对硝基苯磺酰氯(1.0g,4.51mmol)的二氯甲烷溶液(5mL)。所得的反应液在室温下搅拌过夜。加水(50mL),然后用乙酸乙酯萃取(50mL)。有机相用饱和食盐水洗(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到的粗品用硅胶柱层析(二氯甲烷/甲醇=20/1)得到白色固体化合物23a(548mg,收率:49.3%)。
将化合物23a(150mg,0.61mmol)溶于甲醇中(5mL),加入Pd/C(30mg,10%w/w),所得反应液在氢气氛围下室温搅拌2小时。反应液经硅藻土过滤,滤液减压浓缩得到白色固体化合物23b(130mg,收率:98.7%)。MS(ESI):m/z217.4(M+H)+.
从化合物23b起,参照化合物13的合成得到化合物23。1H NMR(500MHz,DMSO-d6)δ9.41(s,1H),8.54(d,J=7.1Hz,1H),8.13(d,J=5.9Hz,1H),7.79(d,J=8.5Hz,2H),7.61(d,J=8.5Hz,2H),7.35–7.25(m,2H),7.19–7.12(m,1H),6.85–6.79(m,1H),6.70–6.62(m,1H),6.24(d,J=2.4Hz,1H),4.62(t,J=5.6Hz,1H),3.35–3.32(m,2H),2.74–2.70(m,2H),1.92–1.83(m,1H),0.96–0.87(m,4H);MS(ESI):m/z 466.0(M+H)+.
实施例24:
从化合物23b和化合物1d起,参照化合物23的合成得到化合物24。1H NMR(500MHz,DMSO-d6)δ9.42(s,1H),8.69–8.63(m,1H),8.15(d,J=5.9Hz,1H),7.81(d,J=8.9Hz,2H),7.63(d,J=8.9Hz,2H),7.36–7.29(m,2H),7.24–7.18(m,1H),6.93–6.87(m,1H),6.68–6.64(m,1H),6.23(d,J=2.3Hz,1H),4.66(t,J=5.6Hz,1H),3.93–3.86(m,2H),3.49–3.43(m,4H),3.07–2.99(m,1H),2.78–2.71(m,2H),1.87–1.77(m,4H);MS(ESI):m/z 510.0(M+H)+.
实施例25:
将化合物1d(50mg,0.15mmol),对氨基苯甲酸甲酯(36mg,0.24mmol),碳酸铯(69mg,0.21mmol),XantPhos(17.6mg,30μmol)和醋酸钯(3.40mg,15μmol)加入到反应瓶中,然后加入1,4-二氧六环(3mL)。所得反应液在氮气氛围下,在100℃条件下搅拌反应过夜。将反应液冷却后过滤,滤液减压浓缩后得到的粗品用制备薄层色谱纯化(石油醚/乙酸乙酯=1/1)得到淡黄色固体化合物25a(26mg,收率38.6%)。MS(ESI):m/z 445.3(M+H)+.
将化合物25a(26mg,58μmol)用四氢呋喃(4mL)和甲醇(1mL)溶解,然后加入3N氢氧化钠水溶液(1mL)。所得反应液在40℃条件下搅拌反应4小时。将反应液冷却至室温,用3N盐酸水溶液调节反应液pH至3-4,加入水稀释(30mL),用乙酸乙酯萃取(30mL×4)。有机相用饱和食盐水洗(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到淡黄色固体化合物25b(24.6mg,收率:97.7%)。MS(ESI):m/z 431.1(M+H)+.
从化合物25b起,参照化合物11的合成得到化合物25。1H NMR(500MHz,DMSO-d6)δ9.24(s,1H),8.65(d,J=7.1Hz,1H),8.20(t,J=5.7Hz,1H),8.13(d,J=5.8Hz,1H),7.73(d,J=8.6Hz,2H),7.68(d,J=8.6Hz,2H),7.32(d,J=8.9Hz,1H),7.24–7.15(m,1H),6.94–6.86(m,1H),6.64–6.59(m,1H),6.19(d,J=2.2Hz,1H),4.72(t,J=5.6Hz,1H),3.96–3.83(m,2H),3.51–3.44(m,2H),3.43–3.36(m,2H),3.32–3.26(m,2H),3.06–2.97(m,1H),1.86–1.76(m,4H);MS(ESI):m/z 474.5(M+H)+.
实施例26:
参照化合物12的合成,将4-氨基苯磺酰胺替换成3-氨基苯甲酰胺,得到化合物26。1H NMR(500MHz,DMSO-d6)δ9.10(s,1H),8.56(d,J=7.0Hz,1H),8.09(d,J=6.0Hz,1H),8.01(s,1H),7.90–7.81(m,2H),7.37–7.25(m,2H),7.31–7.25(m,2H),7.21–7.15(m,1H),6.84(t,J=7.0Hz,1H),6.59–6.54(m,1H),6.20(d,J=1.5Hz,1H),1.93–1.86(m,1H),0.99–0.90(m,4H);MS(ESI):m/z386.2(M+H)+.
实施例27:
从4,4-二氟环己甲酸起,参照化合物1的合成得到化合物27。1HNMR(500MHz,DMSO-d6)δ9.38(s,1H),8.64(d,J=7.0Hz,1H),8.18(d,J=5.5Hz,1H),8.16(d,J=5.8Hz,1H),7.70–7.63(m,2H),7.34–7.28(m,1H),7.23–7.16(m,1H),6.93–6.86(m,1H),6.67–6.61(m,1H),6.27(d,J=2.3Hz,1H),5.07(s,1H),3.01–2.92(m,1H),2.12–2.02(m,2H),2.01–1.93(m,3H),1.92–1.79(m,3H),1.38(s,6H);MS(ESI):m/z 480.4(M+H)+.
实施例28:
从乙酰氯起,参照化合物1的合成得到化合物28。1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.63–8.58(m,1H),8.21–8.16(m,2H),7.71–7.66(m,2H),7.37(d,J=9.0,1H),7.22–7.17(m,1H),6.91–6.85(m,1H),6.66–6.61(m,1H),6.29(d,J=2.0Hz,1H),5.08(s,1H),2.27(s,3H),1.40(s,6H);MS(ESI):m/z376.3(M+H)+.
实施例29:
从环丁基甲酰氯起,参照化合物1的合成得到化合物29。1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.65(d,J=7.0Hz,1H),8.20(d,J=5.5Hz,1H),8.16(d,J=6.0Hz,1H),7.73–7.65(m,2H),7.40–7.32(m,1H),7.25–7.14(m,1H),6.93–6.83(m,1H),6.67–6.60(m,1H),6.26(s,1H),5.08(s,1H),3.64–3.54(m,1H),2.39–2.29(m,2H),2.27–2.18(m,2H),2.03–1.92(m,1H),1.90–1.81(m,1H),1.40(s,6H);MS(ESI):m/z 416.3(M+H)+.
实施例30:
从丙酰氯起,参照化合物1的合成得到化合物30。1H NMR(500MHz,DMSO-d6)δ9.40(s,1H),8.62(d,J=7.0Hz,1H),8.21–8.15(m,2H),7.75–7.65(m,2H),7.36(d,J=9.0Hz,1H),7.22–7.15(m,1H),6.91–6.84(m,1H),6.69–6.60(m,1H),6.29(d,J=1.8Hz,1H),5.08(s,1H),2.66(q,J=7.5Hz,2H),1.39(s,6H),1.22(t,J=7.5Hz,3H);MS(ESI):m/z 390.3(M+H)+.
实施例31:
从环己基甲酰氯起,参照化合物1的合成得到化合物31。1HNMR(500MHz,DMSO-d6)δ9.39(s,1H),8.62(d,J=7.0Hz,1H),8.19(d,J=5.5Hz,1H),8.16(d,J=6.0Hz,1H),7.75–7.65(m,2H),7.30(d,J=9.0Hz,1H),7.22–7.14(m,1H),6.90–6.83(m,1H),6.70–6.61(m,1H),6.27(d,J=2.0Hz,1H),5.08(s,1H),2.79–2.69(m,1H),1.93–1.84(m,2H),1.79–1.71(m,2H),1.68–1.63(m,1H),1.62–1.53(m,2H),1.39(s,6H),1.34–1.16(m,3H);MS(ESI):m/z444.4(M+H)+.
实施例32:
从环戊基甲酰氯起,参照化合物1的合成得到化合物32。1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.63(d,J=7.0Hz,1H),8.19(d,J=5.5Hz,1H),8.17(d,J=6.0Hz,1H),7.71–7.66(m,2H),7.32(d,J=9.0Hz,1H),7.20–7.15(m,1H),6.88–6.84(m,1H),6.65–6.62(m,1H),6.28(d,J=2.5Hz,1H),5.08(s,1H),3.17–3.09(m,1H),2.00–1.92(m,2H),1.83–1.68(m,4H),1.63–1.55(m,2H),1.40(s,6H);MS(ESI):m/z 430.2(M+H)+.
实施例33:
从苯甲酰氯起,参照化合物1的合成得到化合物33。1H NMR(500MHz,DMSO-d6)δ9.35(s,1H),8.77(d,J=7.1Hz,1H),8.20–8.15(m,2H),7.93–7.89(m,2H),7.65–7.61(m,2H),7.49–7.42(m,3H),7.41–7.35(m,1H),7.30–7.24(m,1H),7.03–6.98(m,1H),6.75–6.71(m,1H),6.32(d,J=2.3Hz,1H),5.05(s,1H),1.37(s,6H);MS(ESI):m/z 438.3(M+H)+.
实施例34:
从三氟乙酸酐起,参照化合物1的合成得到化合物34。1H NMR(500MHz,DMSO-d6)δ9.43(s,1H),8.90(d,J=7.0Hz,1H),8.27–8.16(m,2H),7.75–7.67(m,2H),7.64(d,J=9.0Hz,1H),7.49–7.40(m,1H),7.28–7.20(m,1H),6.75–6.65(m,1H),6.40–6.30(m,1H),5.11(s,1H),1.41(s,6H);MS(ESI):m/z 430.2(M+H)+.
实施例35:
将3,3-二氟环丁基甲酸(330mg,2.42mmol)溶于二氯甲烷中(5mL),然后冷却至0℃,向其中加入草酰氯(400mg,3.15mmol)和一滴DMF催化。所得反应液在室温条件下搅拌1小时。将反应液在30℃下小心减压浓缩得到黄色油状化合物35a直接用于下一步反应。
从化合物35a起,参照化合物1的合成得到化合物35。1H NMR(500MHz,DMSO-d6)δ9.38(s,1H),8.71(d,J=7.1Hz,1H),8.24–8.13(m,2H),7.71–7.67(m,1H),7.65(s,1H),7.40(d,J=8.9Hz,1H),7.28–7.19(m,1H),6.96–6.90(m,1H),6.66–6.60(m,1H),6.28–6.23(m,1H),5.09(s,1H),3.51–3.40(m,1H),3.02–2.85(m,4H),1.38(s,6H);MS(ESI):m/z452.4(M+H)+.
实施例36:
从(6-甲基吡啶-2-基)甲醇起,参照中间体化合物INT-1的合成得到化合物36a。从化合物36a和环丙甲酰氯起,参照化合物1的合成得到化合物36。1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.21–8.12(m,2H),7.70–7.61(m,2H),7.20(d,J=8.5Hz,1H),7.16–7.08(m,1H),6.80–6.74(m,1H),6.66–6.62(m,1H),6.27(d,J=2.3Hz,1H),5.06(s,1H),2.61(s,3H),1.96–1.86(m,1H),1.37(s,6H),0.96–0.90(m,4H);MS(ESI):m/z 416.2(M+H)+.
实施例37:
从(3-甲基吡啶-2-基)甲醇起,参照化合物36的合成得到化合物37。1H NMR(500MHz,Methanol-d4)δ8.21–8.13(m,3H),7.78(d,J=2.2Hz,1H),7.59–7.55(m,1H),6.92–6.85(m,1H),6.70(t,J=7.0Hz,1H),6.63–6.59(m,1H),6.32(d,J=2.3Hz,1H),2.32(s,3H),1.93–1.84(m,1H),1.50(s,6H),0.98–0.92(m,4H);MS(ESI):m/z 416.3(M+H)+.
实施例38:
从2-羟甲基-5-甲基吡啶起,参照化合物36的合成得到化合物38。1HNMR(500MHz,DMSO-d6)δ9.38(s,1H),8.40–8.35(m,1H),8.17(d,J=5.5Hz,1H),8.14(d,J=6.0Hz,1H),7.69–7.63(m,2H),7.21(d,J=9.0Hz,1H),7.05–6.99(m,1H),6.64–6.60(m,1H),6.27(d,J=2.3Hz,1H),5.06(s,1H),2.25(s,3H),1.90–1.79(m,1H),1.37(s,6H),0.95–0.82(m,4H);MS(ESI):m/z 416.2(M+H)+.实施例39:
从(4-甲基吡啶-2-基)甲醇起,参照化合物36的合成得到化合物39。1HNMR(500MHz,DMSO-d6)δ9.39(s,1H),8.42(d,J=7.1Hz,1H),8.17(d,J=5.5Hz,1H),8.14(d,J=5.5Hz,1H),7.70–7.65(m,2H),7.07(s,1H),6.68–6.59(m,2H),6.27(d,J=2.3Hz,1H),5.06(s,1H),2.27(s,3H),1.88–1.79(m,1H),1.37(s,6H),0.94–0.85(m,4H);MS(ESI):m/z416.4(M+H)+.
实施例40:
从化合物36a和四氢吡喃-4-甲酸起,参照化合物36的合成得到化合物40。1H NMR(500MHz,DMSO-d6)δ9.35(s,1H),8.19–8.13(m,2H),7.66–7.60(m,2H),7.20(d,J=8.8Hz,1H),7.16–7.11(m,1H),6.82(d,J=7.0Hz,1H),6.65–6.60(m,1H),6.24(d,J=2.5Hz,1H),5.04(s,1H),3.92–3.83(m,2H),3.42–3.40(m,2H),3.08–3.00(m,1H),2.66(s,3H),1.90–1.72(m,4H),1.36(s,6H);MS(ESI):m/z 460.2(M+H)+.
实施例41:
从化合物36b起,参照化合物12的合成得到化合物41。1H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.14(d,J=6.0Hz,1H),7.78(d,J=9.0Hz,2H),7.65(d,J=9.0Hz,2H),7.23(d,J=9.0Hz,1H),7.17–7.11(m,3H),6.82–6.78(m,1H),6.68–6.64(m,1H),6.22(d,J=2.5Hz,1H),2.63(s,3H),1.97–1.90(m,1H),0.98–0.92(m,4H);MS(ESI):m/z 436.3(M+H)+.
实施例42:
从化合物32a起,参照化合物12的合成得到化合物42。1H NMR(500MHz,DMSO-d6)δ9.37(s,1H),8.62(d,J=7.0Hz,1H),8.13(d,J=5.8Hz,1H),7.77(d,J=8.6Hz,2H),7.65(d,J=8.6Hz,2H),7.32(d,J=9.0Hz,1H),7.21–7.16(m,1H),7.13(s,2H),6.90–6.82(m,1H),6.65–6.61(m,1H),6.20(d,J=2.2Hz,1H),3.18–3.07(m,1H),2.02–1.90(m,2H),1.83–1.66(m,4H),1.64–1.53(m,2H);MS(ESI):m/z 450.2(M+H)+.
实施例43:
从化合物34a起,参照化合物12的合成得到化合物43。1HNMR(500MHz,DMSO-d6)δ9.39(s,1H),8.89(d,J=7.0Hz,1H),8.17(d,J=6.0Hz,1H),7.79(d,J=8.0Hz,2H),7.69(d,J=8.0Hz,2H),7.66–7.62(m,1H),7.48–7.42(m,1H),7.26–7.22(m,1H),7.14(s,2H),6.70–6.65(m,1H),6.28(d,J=2.5Hz,1H);MS(ESI):m/z 450.1(M+H)+.
实施例44:
从化合物28a起,参照化合物12的合成得到化合物44。1HNMR(500MHz,DMSO-d6)δ9.35(s,1H),8.59(d,J=7.0Hz,1H),8.14(d,J=6.0Hz,1H),7.77(d,J=9.0Hz,2H),7.65(d,J=9.0Hz,2H),7.37(d,J=9.0Hz,1H),7.22–7.17(m,1H),7.11(s,2H),6.89–6.84(m,1H),6.66–6.61(m,1H),6.21(d,J=2.5Hz,1H),2.27(s,3H);MS(ESI):m/z 396.2(M+H)+.
实施例45:
从化合物29a起,参照化合物12的合成得到化合物45。1HNMR(500MHz,DMSO-d6)δ9.37(s,1H),8.65(d,J=7.0Hz,1H),8.13(d,J=6.0Hz,1H),7.78(d,J=9.0Hz,2H),7.66(d,J=9.0Hz,2H),7.35(d,J=9.0Hz,1H),7.22–7.17(m,1H),7.12(s,2H),6.90–6.85(m,1H),6.64–6.59(m,1H),6.20(d,J=2.5Hz,1H),3.62–3.53(m,1H),2.38–2.28(m,2H),2.26–2.18(m,2H),2.03–1.92(m,1H),1.91–1.81(m,1H);MS(ESI):m/z 436.1(M+H)+.
实施例46:
从化合物29a和(trans)-4-氨基环己甲酸甲酯起,参照化合物12的合成得到化合物46a。MS(ESI):m/z 421.3(M+H)+.
将化合物46a(40mg,95μmol)溶于四氢呋喃中(3mL),然后加入氢氧化锂(6mg,250μmol)的水溶液(1mL)。所得的反应液在室温下搅拌3小时。加入乙酸乙酯稀释(100mL),然后经硅藻土过滤,滤液减压浓缩得到化合物46b(35mg,收率:90.5%)。MS(ESI):m/z 406.7(M+H)+.
向溶有化合物46b(50mg,0.12mmol)的二氯甲烷溶液(3mL)中加入氨(0.4M的1,4-二氧六环溶液,0.6mL),HOBT(33mg,0.25mmol)。所得反应液在室温下搅拌10分钟,然后加入N,N-二异丙基乙胺(32mg,0.25mmol)和EDCI(47mg,0.25mmol),所得反应液在室温下继续搅拌5小时。反应液减压浓缩得到的粗品用制备HPLC纯化得到白色固体化合物46(10mg,收率:20.0%)。1H NMR(500MHz,DMSO-d6)δ8.60(d,J=7.0Hz,1H),7.83(d,J=6.0Hz,1H),7.29(d,J=9.0Hz,1H),7.18–7.13(m,2H),6.87–6.81(m,1H),6.65(s,1H),6.30(d,J=7.5Hz,1H),6.17–7.13(m,1H),5.73(d,J=2.5Hz,1H),3.60–3.49(m,2H),2.34–2.26(m,2H),2.24–2.17(m,2H),2.04–1.90(m,4H),1.89–1.81(m,1H),1.77–1.70(m,2H),1.42–1.31(m,2H),1.10–1.00(m,2H);MS(ESI):m/z 406.2(M+H)+.
实施例47:
将4-氨基-3,5,6-三氯吡啶羧酸(5.0g,20.7mmol)溶于甲醇中(105mL),然后冷却至0℃,向其中缓慢滴加二氯亚砜(3.2g,26.9mmol)。所得的反应液在50℃条件下搅拌反应4小时,将反应液冷却至室温,然后减压浓缩得到粗品,加入乙酸乙酯(50mL),转移至分液漏斗中,用水洗(50mL),饱和食盐水洗(50mL)。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到白色化合物47a(4.9g,收率:92.6%)。MS(ESI):m/z 255.1(M+H)+.
将化合物47a(1.0g,3.91mmol)和环丙基硼酸(403mg,4.70mmol)溶于甲苯中(20mL),然后加入水(2mL),三(环己基)膦(219mg,0.78mmol),磷酸钾(1.66g,7.83mmol)和醋酸钯(87.9mg,0.39mmol)。所得的反应液在氮气氛围中,在100℃条件下搅拌反应24小时。反应液冷却后经硅藻土过滤,滤液减压浓缩得到的粗品用硅胶柱层析(石油醚/乙酸乙酯=4/1)得到白色固体化合物47b(240mg,收率:23.5%)。MS(ESI):m/z 261.3(M+H)+.
将化合物47b(240mg,0.92mmol)溶于甲醇中(5mL),加入Pd/C(111mg,10%w/w)。所得的反应液在氢气氛围中室温搅拌2天。反应液经硅藻土过滤,滤液减压浓缩得到的粗品用硅胶柱层析(石油醚/乙酸乙酯=4/1)得到白色固体化合物47c(24mg,收率:13.6%)。1HNMR(500MHz,DMSO-d6)δ7.02(d,J=2.1Hz,1H),6.49(d,J=2.1Hz,1H),6.21(s,2H),3.79(s,3H),1.94–1.87(m,1H),0.86–0.80(m,4H);MS(ESI):m/z 193.6.
从化合物47c起,参照化合物12的合成得到化合物47d。MS(ESI):m/z 442.2(M+H)+.
将化合物47d(36mg,81.5μmol)溶于无水四氢呋喃中(2mL),然后冷却至0℃,在氮气氛围下,向其中加入甲基溴化镁(3M的2-甲基四氢呋喃溶液,0.11mL)。所得的反应液在0℃继续搅拌1小时。加入水(50mL)将反应淬灭,然后用乙酸乙酯萃取(50mL)。有机相用饱和食盐水洗(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到的粗品用制备HPLC纯化得到白色固体化合物47(15mg,收率:41.7%)。1H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.58(d,J=7.0Hz,1H),8.18(d,J=5.8Hz,1H),7.57(s,1H),7.41(s,1H),7.33(d,J=8.9Hz,1H),7.20–7.16(m,1H),6.87–6.82(m,1H),6.66–6.63(m,1H),6.29(d,J=2.2Hz,1H),5.02(s,1H),1.96–1.85(m,2H),1.34(s,6H),0.98–0.91(m,4H),0.88–0.82(m,4H);MS(ESI):m/z 442.2(M+H)+.
实施例48:
从环丙基甲酰氯起,参照化合物1的合成得到化合物48a。MS(ESI):m/z175.5(M+H)+.
将化合物48a(60mg,0.34mmol)溶于N-甲基吡咯烷酮中(3mL),然后加入叔丁醇钾(116mg,1.03mmol)和2-(三甲基硅烷基)乙氧甲基氯(115mg,0.69mmol)。所得的反应液在室温下反应1小时,然后补加叔丁醇钾(116mg,1.03mmol)和2-(三甲基硅烷基)乙氧甲基氯(115mg,0.69mmol),继续在室温下搅拌反应2天。将反应液倒入水中(30mL),用乙酸乙酯萃取(40mL×3)。有机相用水洗(30mL),饱和食盐水洗(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到的粗品用制备薄层色谱纯化(石油醚/乙酸乙酯=4/1)得到黄色油状化合物48b(77mg,收率:73.5%)。MS(ESI):m/z 305.4(M+H)+.
将化合物48b(70mg,0.23mmol)溶于无水四氢呋喃中(4.5mL),然后冷却至-78℃,氮气保护下,加入正丁基锂(2.5M的正己烷溶液,0.14mL)。所得反应液在-78℃条件下继续搅拌1小时,然后加入四氯化碳(0.18mL,1.84mmol)。所得反应液继续在-78℃条件下搅拌2小时,然后用饱和氯化铵水溶液(10mL)淬灭。将淬灭后的反应液倒入水中(30mL),用乙酸乙酯萃取(40mL×3)。有机相用饱和食盐水洗(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩后所得的粗品用制备薄层色谱纯化(石油醚/乙酸乙酯=4/1)得到棕色油状化合物48c(13mg,收率:16.7%)。MS(ESI):m/z 339.3(M+H)+.
在装有化合物48c(13mg,38μmol)的烧瓶中加入盐酸(3M的水溶液,1.28mL),然后升温至100℃搅拌2小时。将反应液冷却至室温,用水稀释(30mL),再用乙酸乙酯萃取(30mL×3)。萃取的有机相用饱和食盐水洗(20mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物48d(10mg,纯度80%),不纯化直接投下一步。MS(ESI):m/z 209.3(M+H)+.
将粗品化合物48d(10mg,38μmol)溶于N-甲基吡咯烷酮中(2mL),然后加入叔丁醇钾(12.9mg,0.12mmol)和2-溴-4-氟吡啶(6.7mg,38μmol)。所得反应液在室温下搅拌过夜,然后倒入水中(20mL),用乙酸乙酯萃取(30mL×3)。有机相用水洗(30mL),饱和食盐水洗(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到的粗品用制备薄层色谱纯化(石油醚/乙酸乙酯=4/1)得到黄色油状化合物48e(5mg,收率:35.7%)。MS(ESI):m/z 364.0(M+H)+.
从化合物48e起,参照化合物1的合成得到化合物48。1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.22–8.15(m,2H),7.70–7.64(m,2H),7.42–7.38(m,1H),7.23–7.17(m,2H),6.70–6.66(m,1H),6.28(d,J=2.2Hz,1H),5.10(s,1H),1.96–1.93(m,1H),1.38(s,6H),0.99–0.95(m,4H);MS(ESI):m/z 435.8(M+H)+.
实施例49:
将化合物1b(265mg,0.80mmol)溶于甲醇中(8mL),加入二氯化钯(56.9mg,0.32mmol),所得反应液在氢气氛围下室温搅拌3小时。反应液经硅藻土过滤,滤液减压浓缩得到的粗品用硅胶柱层析(石油醚/乙酸乙酯=1/1)得到淡黄色油状物49a(154mg,收率:57.4%)。1H NMR(500MHz,Chloroform-d)δ4.08–3.96(m,6H),3.57–3.40(m,4H),2.86–2.72(m,2H),2.53(t,J=6.4Hz,2H),2.03–1.94(m,4H),1.94–1.86(m,3H),1.85–1.79(m,3H),1.78–1.70(m,2H);MS(ESI):m/z 335.4(M+H)+.
从化合物49a起,参照化合物1的合成得到化合物49。1H NMR(500MHz,Chloroform-d)δ8.30(d,J=5.8Hz,1H),8.16(d,J=5.8Hz,1H),7.41(d,J=1.5Hz,1H),7.34–7.30(m,1H),7.03(brs,1H),6.52–6.48(m,1H),6.38(d,J=2.1Hz,1H),4.08(t,J=6.1Hz,2H),4.00–3.91(m,2H),3.45–3.37(m,2H),2.83–2.74(m,1H),2.52(t,J=6.4Hz,2H),2.07–1.98(m,2H),1.90–1.78(m,4H),1.77–1.69(m,2H),1.52(s,6H);MS(ESI):m/z 450.2(M+H)+.
实施例50:
在-5℃和搅拌条件下,将溶有亚硝酸钠(249mg,3.6mmol)的水溶液(1.5mL)分批加入至溶有3-甲基-5-硝基苯胺(500mg,3.3mmol)的浓盐酸(5mL)中;在滴加过程中保证内温低于0℃;所得反应液在相同条件下继续搅拌30分钟。与此同时,在-5℃和搅拌的条件下,在另一个加有水(8mL)的烧瓶中滴加二氯亚砜(1.1mL);所得反应液在搅拌条件下升至室温,并在室温下搅拌3小时,随后降低温度至-5℃后加入氯化亚铜(33mg,0.33mmol),并在该条件下继续搅拌30分钟。在0℃条件下,前述第一个圆底烧瓶中的反应液分批加入至第二个圆底烧瓶中的反应液,所得反应液在该条件下搅拌1小时。随后,在0℃条件下,将浓氨水(2mL)滴加至上述反应液中,并继续搅拌1小时。反应液中加入水(30mL),并用乙酸乙酯萃取(30mLx 5)。合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,浓缩。所得粗品用硅胶柱层析(石油醚/乙酸乙酯=7:3,v/v)得到淡黄色固体50a(455mg,收率:64%)。
在室温条件和氢气氛围下,将混有化合物50a(200mg,0.93mmol)和Pd/C(10%w/w,25mg)的甲醇(10mL)溶液中搅拌4小时。反应液过滤,滤液浓缩后得到黄色固体50b(167mg,收率:97%)。MS(ESI):m/z 187.5(M+H)+.
从化合物50b出发,参照化合物19的合成得到化合物50。1H NMR(500MHz,DMSO-d6)δ9.23(s,1H),8.57(d,J=7.0Hz,1H),8.12(d,J=6.0Hz,1H),8.00(s,1H),7.64(s,1H),7.33(d,J=8.5Hz,1H),7.25(s,2H),7.21–7.12(m,2H),6.84(t,J=7.0Hz,1H),6.60(d,J=5.0Hz,1H),6.23(s,1H),2.32(s,3H),1.94–1.85(m,1H),1.00–0.88(m,4H);MS(ESI):m/z435.8(M+H)+.
测试实施例
化合物对TGFβRI激酶(ALK5)活性抑制作用的测定:
TGFβRI激酶购买自Carna(Cat#09-141)。在384孔板(Greiner,Cat#784075)中加入2μl用激酶缓冲液(40mM Tris PH 7.5,20mM MgCl2,1mM DTT,1mg/ml BSA)配制的酶溶液(TGFβRI激酶在最终反应体系中为25nM)。对于阴性对照则加入2μl激酶缓冲液。将化合物用DMSO配制成10mM的储存液,在检测化合物之前根据起始浓度的需要,用DMSO对化合物进行二次稀释。取2.5μl化合物加入47.5μl ddH2O中,按照3倍稀释方法进行稀释,每个化合物设置10个浓度点。化合物稀释完成后,取1μl加入酶溶液中。充分混匀后室温孵育10min(最终反应体系中DMSO浓度为1%)。对于阴性对照和阳性对照,则加入1μl含5%DMSO的水溶液。最后加入2μl含有ATP以及TGFβRI激酶多肽底物(Signalchem,Cat#T36-58)的混合液(ATP最终浓度为3.5μM,底物最终浓度为0.1μg/ul),充分混匀后置于28度反应120min。最后使用ADP-Glo KinaseAssay Kit(Promega,Cat#V9102)进行检测。使用Molecular Devices,SpectraMax i3x.读取最终化学发光信号。采用XLFIT对所得到的数据进行4参数曲线拟合并计算IC50。
化合物对p38α激酶活性抑制作用的测定:
p38α激酶购买自SignalChem(Cat#M39-10BG)。在384孔板(Greiner,Cat#784075)中加入2μl用激酶缓冲液(40mM Tris PH 7.5,20mM MgCl2,0.05mM DTT,0.1mg/ml BSA)配制的酶溶液(P38α激酶在最终反应体系中为0.8ng/ul)。对于阴性对照则加入2μl激酶缓冲液。将化合物用DMSO配制成10mM的储存液,在检测化合物之前根据起始浓度的需要,用DMSO对化合物进行二次稀释。取2.5μl化合物加入47.5μl ddH2O中,按照3倍稀释方法进行稀释,每个化合物设置10个浓度点。化合物稀释完成后,取1μl加入酶溶液中。充分混匀后室温孵育10min(最终反应体系中DMSO浓度为1%)。对于阴性对照和阳性对照,则加入1μl含5%DMSO的水溶液。最后加入2μl含有ATP以及P38激酶多肽底物(Signalchem,Cat#P03-58)的混合液(ATP最终浓度为50μM,底物最终浓度为0.125μg/μl),充分混匀后置于25度反应120min。最后使用ADP-Glo Kinase Assay Kit(Promega,Cat#V9102)进行检测。使用Molecular Devices,SpectraMax i3x.读取最终化学发光信号。采用XLFIT对所得到的数据进行4参数曲线拟合并计算IC50。
实施例中所列化合物对于ALK5和p38α的激酶活性抑制作用的结果:
*参比化合物是LY3200882,内部合成得到
化合物对TGFβRI受体Smad信号通路的抑制活性的测定:
收集HEK-Blue TGFβcells(Invivogen,Cat#hkb-tgfb),并用10%FBS的DMEM调整细胞密度为1.25×106cells/ml,并以每孔40μl加入96孔板中。将化合物用DMSO配制成10mM的储存液,在检测化合物之前根据起始浓度的需要,用DMSO对化合物进行二次稀释。取2.5μl化合物加入1ml完全培养基中,吹打混匀,用含0.25%DMSO的DMEM培养基对化合物进行3倍稀释(100μl体系中DMSO浓度为0.1%)。取40μl配制好的化合物至96孔细胞板中,阳性对照以及阴性对照中加入40ul含0.25%DMSO的培养基,于37℃5%CO2培养箱中孵育2小时。每孔加入20μl人重组TGFβ1(Invivogen,cat#Rcyc-htgfb1),其最终浓度为0.1ng/ml。置于37℃5%CO2中培养24小时。24小时后取60μl上清用于分泌型碱性磷酸酶(SEAP)检测,细胞板中补加60ul/well的培养基用于细胞活性检测。SEAP检测采用Great EscApe SEAPchemiluminescence KIT(Clontech,Cat#631738)进行检测,细胞活性检测采用CellTiter-Glo Luminescent Cell Viability Assay(Promega,Cat#G7573)进行检测。使用MolecularDevices,SpectraMax i3x.读取最终化学发光信号。采用XLFIT对所得到的数据进行4参数曲线拟合并计算IC50。
实施例中所列化合物对于TGFβRI受体Smad信号通路的抑制活性的结果:
*参比化合物是LY3200882,内部合成得到
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