CN116813647A - 一类含氮稠环类sting调节剂类化合物、制备方法和用途 - Google Patents
一类含氮稠环类sting调节剂类化合物、制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种如通式I所示的含氮稠环类化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、其制备方法及在药学上的应用,其中各基团的定义如说明书中所述。
Description
技术领域
本发明属于药物化学领域,具体地,涉及一类含氮稠环类STING调节剂类化合物、制备方法和用途。
背景技术
干扰素基因刺激蛋白(STING)是一种跨膜蛋白,通常在152-173位区域(dimerization domain)交接形成二聚体并处于自我抑制状态。STING是人先天免疫系统的重要组分,是人体对抗诸如细菌以及病毒等外界病原体入侵的第一道防线,在维持机体动态平衡、抵御外来感染以及预防肿瘤和自身免疫病方面扮演重要角色。
研究表明,STING活性的缺失可引发肿瘤或一些特定的病毒感染,如登革病毒的蛋白酶NS2B3可通过降解STING来阻碍IFN-α/β的产生。因此,STING激活剂可以被用作疫苗佐剂或免疫激活剂。
反之,STING的过度激活可引起人类多种严重的自身炎症和自身免疫性疾病,包括罕见疾病,如Aicardi-Goutières综合征(AGS)、婴儿期发病的STING相关血管病变(SAVI)和系统性红斑狼疮(SLE)。在线粒体功能障碍的情况下,异常的cGAS/STING激活会诱发更多常见疾病,如非酒精性脂肪性肝炎(NASH)、慢性阻塞性肺疾病(COPD)、年龄相关性黄斑变性(AMD)和帕金森病。
STING在先天免疫系统中的重要功能及与多种疾病的相关性使其成为药物研发的热门靶点。多家制药公司正在开展靶向STING的激动剂和拮抗剂的研究。环二核苷酸(CDN)类化合物,是目前发现的唯一一类既能直接激活鼠源又能激活人源STING蛋白的激动剂。直接把CDN类化合物注射到B16黑色素瘤、CT26直肠癌和4T1乳腺癌肿块,不仅导致明显的抑制作用直至肿瘤消失,同时也诱导系统的持久性抗原特异性T细胞免疫,造成动物其它部位未注射药物的肿瘤生长也受到抑制,引起多种固体肿瘤微环境的改变,激活有效的肿瘤引发的CD8+T细胞和持久的疗效。
但是,CDN类化合物用于抗肿瘤、抗病毒、退行性疾病或者免疫性疾病治疗的临床应用还处于非常早期研究阶段,并且受到给药途径和成药性特征的限制,要成为有效的临床疗法毫无疑问还要克服许多障碍。因此,发现和寻找具有高活性、良好成药性的STING调节剂成为当今一大热门领域。
发明内容
本发明需要解决的技术问题之一是提供一种新型的STING蛋白调节剂,用于制备肿瘤、免疫性疾病、抗病毒和退行性疾病的治疗药物。
解决上述技术问题的方案如下:
一种具有如通式I所示的含氮杂环类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,
式中:
R1选自氢、C1-C6的烷基、C2-C6的烯基、C2-C6的炔基、C3-C6的环烷基、C3-C6的杂环烷基、5-10元的芳基或杂芳基、酰基、磺酰基、砜基、亚砜基等;
R2选自氨基、酰胺基、C1-C 10的烷基、5-10元芳基或杂芳基,C3-C6的环烷基或杂环烷基;
M1、M2、M3、M4、M5、M6、M7独立地选自N、CRa,Ra独立地选自氢、卤素、羟基、氨基、氰基、羰基、酰胺基、酯基、脲、砜基、亚砜基、磺酰基、亚磺酰基、亚磺酰亚胺基、C1-C6的烷基、C1-C6的烷氧基、C2-C6的烯基、C2-C6的炔基、C3-C6的环烷基、C3-C6的杂环烷基、5-10元的芳基或杂芳基;或者M3=M4、M5=M6独立地选自O,S等杂原子;
并且上述任意两个相邻的Ra之间可以通过碳链或者杂原子形成4~10元的饱和或部分不饱和的环系;或者M6、M7上任意一个Ra可以与R1上的任一基团通过碳链或者杂原子形成3-10元饱和或部分不饱和的环系。
上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代:包括但不限于氘、卤素、C1-C8烷基;其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P或S,所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P或S,所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系,上述环系可以进一步被C1-C6烷基、羟基、氨基、卤素、烷氧基等取代。
在一些实施方式中,通式(I)化合物优选自如下通式(II)所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药:
其中,Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7分别独立地选自氢、卤素、羟基、氨基、氰基、羰基、酰胺基、酯基、脲、砜基、亚砜基、磺酰基、亚磺酰基、亚磺酰亚胺基、C1-C6的烷基、C1-C6的烷氧基、C2-C6的烯基、C2-C6的炔基、C3-C6的环烷基、C3-C6的杂环烷基、5-10元的芳基或杂芳基;并且上述任意两个相邻的Ra1-7之间可以通过碳链或者杂原子形成4~10元的饱和或部分不饱和的环系;或者任意一个Ra1-7可以与R1上的任一基团通过碳链或者杂原子形成3-10元饱和或部分不饱和的环系;R1、R2如上文所定义。
在一些实施方式中,优选为如下通式(III)所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药:
其中,R2a、R2b、R2c、Ra4、Ra6、R1’分别独立地选自分别独立地选自氢、卤素、羟基、氨基、氰基、羰基、酰胺基、酯基、脲、砜基、亚砜基、磺酰基、亚磺酰基、亚磺酰亚胺基、C1-C6的烷基、C1-C6的烷氧基、C2-C6的烯基、C2-C6的炔基、C3-C6的环烷基、C3-C6的杂环烷基、5-10元的芳基或杂芳基;Ma8独立地选自NRa8、O、S(O)p、C(Ra8)q,其中Ra8选自氢、卤素、C1-C6烷基,p选自0-2,q选自1-2;
并且上述基团上任意一个或多个氢可以被选自下组的基团取代:-ORm、-NRmRn、-NRmCORn、-CO2Rm、-OCORm、-CONRmRn、-SO2NRmRn、-NRmSO2Rn、-SRm、-SORm、-SO2Rm、-OCONRmRn、-NRpCONRmRn;Rm、Rn分别独立地选自C1-C6的烷基、C1-C6的卤代烷基、C1-C6烷基羟基、C1-C6烷基烷氧基、C1-C6烷基氨基或取代氨基、C1-C6烷基环氨基、C3-C6环烷基或杂环烷基、5-8元芳基或杂芳基;
或者Rm和Rn、R2c和R2b可以分别通过碳原子或者杂原子连接形成3-12元的单环或多环烷基、3-12元的单环或多环杂环烷基、3-12元的螺环或稠环烷基和3-12元的螺环或稠环杂环烷基;
其中,R1、Ra4、Ra6如上文所定义。
上述通式III所示的结构排除以下两个分子:
在一些实施方式中,所述的式(I)化合物具有如下式(VI-1)或(VI-2)所示的结构:
其中M1、M2、M3、M4、M5、M6、M7、R2如上文中所定义;
R2’选自氨基、酰胺基、C1-C 10的烷基、5-10元芳基或杂芳基,C3-C6的环烷基或杂环烷基;
M1’、M2’、M3’、M4’、M5’、M6’、M7’独立地选自N、CRa,Ra独立地选自氢、卤素、羟基、氨基、氰基、羰基、酰胺基、酯基、脲、砜基、亚砜基、磺酰基、亚磺酰基、亚磺酰亚胺基、C1-C6的烷基、C1-C6的烷氧基、C2-C6的烯基、C2-C6的炔基、C3-C6的环烷基、C3-C6的杂环烷基、5-10元的芳基或杂芳基;或者M3’=M4’、M5’=M6’独立地选自O,S等杂原子;
M选自O,NRb、S(O)t、CRcRd;Rb独立地优选自氢、C1-C10烷基,3-10元环烷基或杂环烷基、酰基或磺酰基;Rc、Rd独立地选自氢、氘、卤素、C1-C10烷基、3-10元环烷基或杂环烷基,或者Rc和Rd通过碳原子或者杂原子连接形成3-12元的单环或多环烷基、3-12元的单环或多环杂环烷基、3-12元的螺环或稠环烷基和3-12元的螺环或稠环杂环烷基;
m、n选自0-3的整数;t选自0-2的整数。
一些优选的实施方式中,所述的通式(I)、(II)、(III)、(IV)和(VI-1)化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其特征在于,所述化合物包括但不限于如下结构:
一种制备上述通式I化合物的方法,其特征在于,所述方法包括步骤a-c:
a)将通式(A)化合物与丙烯基二卤代物在碱性条件下反应得到通式(B)化合物;和
b)将通式B化合物与通式化合物胺R1’R1”NH在碱性条件下反应得到通式化合物(I);和
c)将通式化合物(I)在过渡金属催化下发生氢化还原反应,得到通式化合物(I’);
其中,X为卤素、磺酸酯等离去基团,其余各基团的定义如上文所述。
优选地,所述步骤a)、b)、c)各自在溶剂中进行,且所述溶剂选自下组:水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜,四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环,或其组合物。
优选地,所述无机碱选自下组:氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠,或其组合物;所述有机碱选自下组:吡啶,三乙胺,N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶,或其组合物。
本发明的另一目的是提供一种治疗或预防肿瘤、病毒感染、自身免疫性疾病和退行性疾病的药物及其组合物。实现上述目的的技术方案如下:
一种治疗或预防上述疾病的药物组合物,其由上述通式(I)所示的含氮杂环类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药与药学上可接受的载体组成。
本发明的另一目的是提供一种上述化合物的用途。实现上述目的的技术方案如下:
所述通式(I)所示的含氮杂环类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药用于制备治疗与STING蛋白依赖型疾病的药物,特别是肿瘤、病毒感染、免疫性疾病和炎症性疾病的治疗药物,是一类全新作用机制的治疗药物。所述的肿瘤各自独立地选自:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等。所述的免疫性疾病和炎症性疾病独立地选自移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风和瓦尔登斯特伦氏巨球蛋白血症等。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合、从而构成新的或优选的技术方案。限于篇幅在此不再一一累述。
具体实施方式
发明人经过长期而深入的研究,制备了一类具有式I所示结构新颖的化合物,并发现其具有较好的STING蛋白结合活性,且所述的化合物在较低浓度(可低至≤1nmol/L)下,即可与STING蛋白产生特异性结合作用,并且能调节STING通路释放或抑制下游细胞因子如IFN-β、IL 6、TNF等,因而可以用于调节STNG通路活性并治疗相关疾病如肿瘤、炎症、抗病毒等。基于上述发现,发明人完成了本发明。
术语
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘;“羟基”是指-OH基团;“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基;“羰基”是指-C(=O)-基团;“硝基”是指-NO2;“氰基”是指-CN;“氨基”是指-NH2;“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基;“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型,本发明旨在包括各种晶型及其混合物。
通常,结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水,该情况下的溶剂化物为水合物。或者,溶剂可以是有机溶剂。因此,本发明的化合物可以以水合物存在,包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物,但在某些情况下,也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中,术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此,术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时,前药可以不具有活性,但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化,而产生本发明的母体化合物,例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990;Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”,“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganicSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
下面结合具体实施例、进一步阐述本发明。应理解、这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明、否则百分比和份数是重量百分比和重量份数。
中间体A制备
中间体A1:3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯
第一步:将4-碘-3-甲氧基苯甲酸甲酯(3.2g,11.0mmol)和5-溴-2-氯吡啶-4-胺(2.5g,12.1mmol)溶于N,N-二甲基甲酰胺(DMF)(30mL)中,在氮气保护下,加入醋酸钯(747.6mg,3.34mmol),碳酸铯(14.5g,44.5mmol)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos)(341.8mg,0.59mmol),115度反应过夜。冷却至室温,过滤,减压浓缩,柱层析纯化得到4-((5-溴-2-氯吡啶-4-基)氨基)-3-甲氧基苯甲酸甲酯(2.9g,白色固体)。LC-MS:m/z 371.0/373.0[M+H]+。
第二步:将4-((5-溴-2-氯吡啶-4-基)氨基)-3-甲氧基苯甲酸甲酯(365mg,0.99mmol)溶于DMF(10mL),氮气保护下,加入醋酸钠(533.1mg,6.50mmol)和双(三苯基膦)氯化钯(Ⅱ)(Pd(PPh3)2Cl2)(140.4mg,0.20mmol),125度反应过夜。冷却至室温,过滤,减压浓缩,柱层析纯化得到3-氯-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(160mg,白色固体)。1H NMR(DMSO-d6,400MHz):δ12.42(s,1H),9.30(s,1H),8.57(s,1H),7.61(d,J=1.2Hz,1H),7.46(s,1H),4.06(s,3H),3.91(s,3H)。LC-MS:m/z 291.0/293.0[M+H]+。
第三步:将3-氯-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(500mg,1.72mmol)和1,3-二甲基-5-吡唑频哪醇硼酸酯(453.3mg,2.04mmol)溶于二氧六环和水(20mL/4mL),氮气保护下加入碳酸钠(720.8mg,6.8mmol)和四三苯基膦钯(Pd(PPh3)4)(196.5mg,0.17mmol),90度反应过夜。反应液冷却至室温,减压浓缩,柱层析纯化得到中间体A1(160mg,白色固体)。1H NMR(DMSO-d6,400MHz):δ12.37(s,1H),9.53(d,J=0.8Hz,1H),8.58(d,J=1.2Hz,1H),7.68(d,J=0.8Hz,1H),7.60(d,J=1.2Hz,1H),6.52(s,1H),4.09(s,3H),4.08(s,3H),3.92(s,3H),2.21(s,3H)。LC-MS:m/z351.2[M+H]+。
中间体A2:3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯
以1-乙基3-甲基-5-吡唑频哪醇硼酸酯为原料,参照中间体A1的合成方法制备得到目标中间体。1H NMR(DMSO-d6,400MHz):δ12.36(s,1H),9.53(s,1H),8.58(s,1H),7.67(s,1H),7.61(s,1H),6.49(s,1H),4.55-4.56(m,2H),4.08(s,3H),3.92(s,3H),2.22(s,3H),1.30-1.32(t,J=7.2Hz,3H)。LC-MS:m/z 365.2[M+H]+。
中间体A3:3-(1,3-二甲基-1H-吡唑-5-基)-6-(3-吗啉基丙氧基)-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯
第一步:将3-羟基-4-碘苯甲酸甲酯(9.3g,33.5mmol)和3-吗啉丙基甲磺酸酯(15.0g,67.3mmol)溶于DMF(100mL),加入碳酸钾(13.8g,100.0mmol),室温反应过夜。乙酸乙酯淋洗,滤液和洗涤液减压浓缩,柱层析纯化得到4-碘-3-(3-吗啉丙氧基)苯甲酸甲酯(12.3g,白色固体)。1H NMR(DMSO-d6,400MHz):δ7.94(d,J=8.0Hz,1H),7.40(d,J=1.6Hz,1H),7.31(dd,J=1.6,8.0Hz,1H),4.14(t,J=6.0Hz,2H),3.86(s,3H),3.55-3.58(m,4H),3.30-3.35(m,2H),2.48-2.51(m,4H),1.90-1.93(m,2H)。LC-MS:m/z 406.1[M+H]+。
第二步:将4-碘-3-(3-吗啉丙氧基)苯甲酸甲酯(12.3g,30.4mmol)和5-溴-2-氯吡啶-4-胺(6.9g,33.5mmol)溶于DMF(150mL)中,在氮气保护下,加入醋酸钯(680.5mg,3.04mmol),碳酸铯(29.6g,90.8mmol)和Xantphos(1.75g,3.04mmol),100度反应过夜。冷却至室温,过滤,减压浓缩,柱层析纯化得到4-((5-溴-2-氯吡啶-4-基)氨基)-3-(3-吗啉丙氧基)苯甲酸甲酯(12.0g,淡黄色固体)。LC-MS:m/z 484.4/486.3[M+H]+。
第三步:将4-((5-溴-2-氯吡啶-4-基)氨基)-3-(3-吗啉丙氧基)苯甲酸甲酯(12.0g,24.84mmol)溶于DMF(100mL),氮气保护下,加入醋酸钠(8.15g,99.36mmol)和Pd(PPh3)2Cl2(1.74g,2.48mmol),120度反应过夜。冷却至室温,过滤,减压浓缩,柱层析纯化得到3-氯-6-(3-吗啉丙氧基)-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(6.1g,白色固体)。LC-MS:m/z 404.4/406.3[M+H]+。
第四步:将3-氯-6-(3-吗啉丙氧基)-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(220mg,0.55mmol)和1,3-二甲基-5-吡唑频哪醇硼酸酯(169.7mg,0.76mmol)溶于二氧六环和水(20mL/4mL),氮气保护下加入碳酸钠(233.8mg,2.2mmol)和Pd(PPh3)4(63.6mg,0.055mmol),100度反应过夜。反应液冷却至室温,减压浓缩,柱层析纯化得到中间体A3(120mg,白色固体)。1H NMR(DMSO-d6,400MHz):δ12.23(s,1H),9.54(s,1H),8.57(s,1H),7.71(d,J=0.8Hz,1H),7.59(d,J=1.2Hz,1H),6.51(s,1H),4.28-4.32(m,2H),4.09(s,3H),3.91(s,3H),3.57-3.61(m,4H),2.50-2.60(m,2H),2.41-2.50(m,4H),2.21(s,3H),1.90-2.12(m,2H)。LC-MS:m/z 464.3[M+H]+。
采用商品化的试剂为原料,参照中间体A3的合成方法制备得到以下中间体。
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中间体B制备
中间体B1:2-(1,3-二甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-羧酸甲酯
第一步:将4-氨基-3-甲氧基苯甲酸甲酯(6.0g,33.15mmol)和2,4-二氯-5-碘嘧啶(11.8g,43.10mmol)溶于2-戊醇(100mL),加入N,N-二异丙基乙胺(DIEA)(12.8g,99.22mmol),130度闷灌反应过夜。反应液冷却至室温,过滤,固体用甲醇打浆纯化得到4-((2-氯-5-碘嘧啶-4-基)氨基)-3-甲氧基苯甲酸甲酯(9.4g,白色固体)。LC-MS:m/z 420.0/422.0[M+H]+。
第二步:将4-((2-氯-5-碘嘧啶-4-基)氨基)-3-甲氧基苯甲酸甲酯(9.4g,22.4mmol)溶于DMF(100mL),氮气保护下,加入醋酸钠(7.4g,90.2mmol)和双(三苯基膦)氯化钯(Ⅱ)(Pd(PPh3)2Cl2)(1.57g,2.24mmol),120度反应过夜。反应液冷却至室温,倒入水中析出固体,过滤,滤饼用甲醇打浆纯化得到2-氯-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-羧酸甲酯(5.6g,白色固体)。LC-MS:m/z292.1/294.1[M+H]+。
第三步:将2-氯-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-羧酸甲酯(200mg,0.69mmol)和1,3-二甲基-5-吡唑频哪醇硼酸酯(233.3mg,1.05mmol)溶于二氧六环和水(20mL/4mL),氮气保护下加入碳酸钠(300.8mg,2.84mmol)和Pd(PPh3)4(196.5mg,0.17mmol),100度反应过夜。反应液冷却至室温,减压浓缩,柱层析纯化得到中间体B1(160mg,白色固体)。1H-NMR(DMSO-d6,400MHz):δ12.94(s,1H),9.67(s,1H),8.57(d,J=1.2Hz,1H),7.63(d,J=1.2Hz,1H),6.81(s,1H),4.27(s,3H),4.06(s,3H),3.92(s,3H),2.22(s,3H)。LC-MS:m/z 352.2[M+H]+。
中间体B2:2-(1-乙基3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-羧酸甲酯
以1-乙基3-甲基-5-吡唑频哪醇硼酸酯为原料,参照中间体B1的合成方法制备得到目标中间体。1H NMR(DMSO-d6,400MHz):δ12.92(s,1H),9.66(s,1H),8.57(d,J=0.8Hz,1H),7.63(d,J=1.2Hz,1H),6.81(s,1H),4.75-4.79(m,2H),4.06(s,3H),3.92(s,3H),2.23(s,3H),1.39(t,J=7.2Hz,3H)。LC-MS:m/z 366.2[M+H]+。
中间体B3:2-(1,3-二甲基-1H-吡唑-5-基)-8-(3-吗啉基丙氧基)-9H-嘧啶并[4,5-b]吲哚-6-羧酸甲酯
第一步:将4-氨基-3-羟基苯甲酸甲酯(80mg,0.48mmol)和3-吗啉基丙-1-醇(73mg,0.50mmol)溶于四氢呋喃(THF)(25mL),加入偶氮二甲酸二异丙酯(DIAD)(194mg,0.96mmol)和三苯基膦(PPh3)(180mg,0.70mmol),室温下反应过夜。反应液减压浓缩,柱层析纯化得到4-氨基-3-(3-吗啉基丙氧基)苯甲酸甲酯(70mg,白色固体)。LC-MS:m/z 295.2[M+H]+。
后续操作参照中间体B1的合成方法制备得到中间体B3。1H NMR(DMSO-d6,400MHz):δ12.89(s,1H),9.65(s,1H),8.54(s,1H),7.60(s,1H),6.81(s,1H),4.28-4.31(m,5H),3.91(s,3H),3.59-3.62(m,4H),2.43-2.60(m,9H),1.90-2.10(m,2H)。LC-MS:m/z465.2[M+H]+。
中间体B4:甲基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-羟丙氧基)-9H-嘧啶并[4,5-b]吲哚-6-甲酸酯
采用中间体B3相同的方法制备得到中间体B4,LC-MS:m/z410.2[M+H]+。
中间体B5:甲基2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-((4-甲氧基苄基)氧代)-9H-嘧啶并[4,5-b]吲哚-6-甲酸酯
第一步:将甲基3-羟基-4-硝基苯甲酸酯(33.0g,167.5mmol),溶于DMF(300mL),加入碳酸钾(69.4g,502.5mmol),降温到零度,缓慢滴加对甲氧基苄氯(PMB-Cl)(31.5g,201.0mmol),80度反应1h。LC-MS显示反应完全,过滤后旋干,加水(300mL)和乙酸乙酯(150mL)萃取二次,旋干后乙酸乙酯(100mL)打浆得到甲基3-((4-甲氧基苄基)氧代)-4-硝基苯甲酸酯(黄色固体,49.2g)。LC-MS[M+H]+:m/z 316.2。
第二步:将上步黄色固体(2.0g,6.3mmol),溶于甲醇和水(20mL/2mL),加入铁粉(1.76g,31.5mmol)和氯化铵(1.70g,31.5mmol),75度反应过夜。LC-MS显示反应完全,加硅藻土过滤二次后旋干得到白色固体,用水(20mL)打浆得到甲基4-氨基-3-((4-甲氧基苄基)氧代)苯甲酸酯(白色固体,1.6g)。
第三步:将上步白色固体化合物(3.0g,10.2mmol),2,4-二氯-5-碘代嘧啶(5.58g,20.4mmol)溶于2-戊醇(10mL),再加入DIEA(5.22g,40.8mmol),130度闷灌反应过夜。过滤,固体用甲醇打浆得到甲基4-((2-氯-5-碘代嘧啶-4-基)氨基)-3-((4-甲氧基苄基)氧代)苯甲酸酯(3.5g)。
第四步:将上步获得的化合物(2.0g,3.8mmol)溶于DMF(30mL),加入醋酸钠(2.06g,15.2mmol),再加入PdCl2(PPh3)2Cl2(266mg,0.38mmol),在氮气保护下,120度反应过夜。加水(60mL)和乙酸乙酯(60mL),柱层析过柱得到甲基2-氯-8-((4-甲氧基苄基)氧代)-9H-嘧啶并[4,5-b]吲哚-6-甲酸酯(1.3g)LC-MS[M+H]+:m/z 398.4.
第五步:将上步获得的化合物(500mg,1.25mmol)和1-乙基-3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1H-吡唑(450.0mg,1.9mmol)溶于二氧六环和水(24mL/4mL),加入碳酸钠(530.0mg,5.0mmol),再加入Pd(PPh3)4(144.0mg,0.125mmol),在氮气保护下,85度反应过夜。浓缩,柱层析(EA/PE=1/1)分离得到中间体B5(白色固体,320mg)。LC-MS[M+H]+:m/z 472.2。1HNMR(400MHz,DMSO-d6):δ9.29(s,1H),8.35(s,1H),7.87-7.92(m,1H),7.49-7.62(m,2H),6.73-7.16(m,4H),5.32(s,2H),4.82(s,2H),3.77(s,3H),1.99(s,3H),1.17-1.35(m,3H)。
中间体C:2-(1-乙基-3-甲基-1H吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-羧酸甲酯
第一步:将4-氨基-3-碘-5-甲氧基苯甲酸甲酯(1.0g,3.3mmol)和(2,6-二氯吡啶-3-基)硼酸(1.26g,6.6mmol)加入DMF(50mL)中,在氮气保护下,加入醋酸钯(Pd(OAc)2)(74mg,0.33mmol)、三苯基膦(PPh3)(86mg,0.33mmol)和三乙胺(TEA)(1.0g,9.9mmol),加热至85度反应5小时。反应液冷却至室温,减压浓缩,柱层析纯化得到4-氨基-3-(2,6-二氯吡啶-3-基)-5-甲氧基苯甲酸甲酯(0.7g,淡黄色固体)。1H NMR(DMSO-d6,400MHz):δ7.82(d,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),7.35(s,1H),7.24(s,1H),5.53(s,2H),3.87(s,3H),3.76(s,3H)。LC-MS:m/z 327.0/329.0[M+H]+。
第二步:将4-氨基-3-(2,6-二氯吡啶-3-基)-5-甲氧基苯甲酸甲酯(420mg,1.29mmol)溶于DMF(20mL),加入18-冠-6(680mg,2.57mmol)和氢化钠(NaH)(60%在矿物油中,206mg,5.15mmol),氮气保护下,升温至100度反应2h。反应液冷却到室温,加水(50mL)淬灭,乙酸乙酯(50mL)萃取三次,合并有机相,干燥,过滤,减压浓缩,柱层析纯化得到2-氯-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-羧酸甲酯(142mg,白色固体)。1H NMR(DMSO-d6,400MHz):δ12.62(brs,1H),8.72(d,J=8.0Hz,1H),8.53(s,1H),7.59(s,1H),7.34(d,J=8.0Hz,1H),4.05(s,3H),3.91(s,3H)。LC-MS:m/z 291.1/293.1[M+H]+。
第三步:将2-氯-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-羧酸甲酯(273mg,0.94mmol)和1,3-二甲基-5-吡唑频哪醇硼酸酯(278mg,1.18mmol)溶于二氧六环和水(30mL/5mL)中,氮气保护下加入碳酸钠(398mg,3.75mmol)和四(三苯基膦)钯(Pd(PPh3)4)(100mg,0.09mmol),85度反应过夜。反应液冷却至室温,减压浓缩,柱层析纯化得到中间体C1(160mg,白色固体)。1H NMR(DMSO-d6,400MHz):δ12.48(brs,1H),8.73(d,J=8.4Hz,1H),8.54(s,1H),7.60-7.64(m,2H)6.63(s,1H),4.67-4.70(m,2H),4.08(s,3H),3.93(s,3H),2.23(s,3H),1.38(t,J=7.2Hz,3H)。LC-MS:m/z 365.4[M+H]+。
采用商品化的试剂为原料,参照中间体C1的合成方法制备得到以下中间体。
中间体D:(S)-2-(1-乙基-3-甲基-1H-吡唑-5-氨基甲酰基)-3-(3-羟丙氧基)-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-7-甲酰胺
采用文献WO2020006432A1中实施例10相同的方法制备合成得到中间体D,LC-MS[M+H]+:m/z 413.3。1H NMR(400MHz,DMSO):δ12.72(s,1H),7.93(s,1H),7.59(s,1H),7.34(s,2H),6.64(s,1H),4.08-4.66(m,7H),3.41-3.43(m,2H),1.83(s,3H),1.34-1.59(m,7H)。
中间体E:(E)-2-(1-乙基-3-甲基-1H-吡唑-5-氨基甲酰基)-3-(4-羟基丁基-2-烯-1-基)-3H-咪唑[4,5-b]吡啶-6-甲酰胺
第一步:将化合物(E)-2-(4-溴丁-2-烯-1-基)异吲哚啉-1,3-二酮(17g,60.93mmol)溶于DMF(200ml)中,后加入乙酸钾(11.9g,121.86mmol),氮气保护,加入到80℃,反应16h,降到室温,倒入600mL水中,然后用乙酸乙酯(200mL*2)萃取,有机层依次用饱和氯化铵(500mL)、饱和食盐水(500mL)洗涤,干燥,过柱,得到(E)-4-(1,3-二氧代异吲哚啉-2-基)丁-2-烯-1-基乙酸酯(白色固体,13.6g)。1H-NMR(400MHz,DMSO-d6):δ8.01-7.77(m,4H),5.88-5.75(m,1H),5.75-5.58(m,1H),4.49(dd,2H),4.20(dd,J=5.2,2H),2.08–1.90(m,3H)。
第二步;将上一步产物(13.6g,52.5mmol)溶解到甲醇(1.3L)中,然后加入甲醇钠(0.28g,5.25mmol),室温搅拌16h,然后加入14mL 1N HCl淬灭,旋干,过柱,得到(E)-2-(4-羟基丁-2-烯-1-基)异吲哚啉-1,3-二酮(白色固体,10.6g)。1H-NMR(400MHz,DMSO-d6):δ8.29-7.61(m,4H),5.66(q,2H),4.71(t,1H),4.30-4.00(m,2H),3.89(dd,2H)。
第三步:将上一步产物(10.6g,48.85mmol)溶于二氯甲烷中(150mL),然后加入咪唑(6.65g,97.7mmol)和N,N-二甲基氨基吡啶(DMAP)(1.2g,9.77mmol),搅拌5min,室温加入叔丁基二苯基氯硅烷(14mL,53.37mmol),加完,搅拌4h,加入200mL水,分液,有机层干燥,旋干,过柱,得到(E)-2-(4-((叔丁基二苯基硅基)氧)丁-2-烯-1-基)异吲哚啉-1,3-二酮(白色固体,21g)。1H-NMR(400MHz,DMSO-d6):δ7.99-7.79(m,4H),7.58(dd,4H),7.45-7.28(m,6H),5.78(dt,1H),5.69(dt,1H),4.19(d,2H),4.18-4.13(m,2H),0.97(s,9H)。
第四步:将上一步产物(21g,46.15mmol)溶于乙醇(500mL)中,并加入水合肼(含量80%,5.3ml,184.6mmol),后回流16h,冷却,过滤,滤液旋干,加入水(200mL)和乙酸乙酯(200mL),分液,有机层用水洗涤,干燥,旋干,得到(E)-4-((叔丁基二苯基硅基)氧)丁-2-烯-1-氨基(无色透明液体,15g)。1H-NMR(400MHz,DMSO-d6):δ7.64-7.60(m,4H),7.50-7.34(m,6H),5.78(dt,1H),5.70-5.52(m,1H),4.17(dd,2H),3.15(dd,2H),1.54-1.30(m,2H),1.00(s,9H)。
第五步:将上一步产物(3.5g,16.4mmol)和甲基6-氯-5-硝基烟酸酯(5.9g,18.03mmol)溶解于二氧六环(60mL)中,并于室温加入DIEA(8.1mL,49.2mmol),室温搅拌3h,反应液倒入水(200mL)中,并用乙酸乙酯(300mL)萃取,有机层用饱和食盐水洗涤,干燥,旋干,过柱,得到甲基(E)-6-((4-((叔丁基二苯基硅基)氧)丁-2-烯-1-基)氨基)-5-硝基烟酸酯(黄色固体,6.3g)。1H-NMR(400MHz,DMSO-d6):δ9.09(t,1H),8.86(dd,1H),8.74(dd,1H),7.59(dd,4H),7.47-7.28(m,6H),5.88-5.83(m,1H),5.76-5.62(m,1H),4.26(t,2H),4.17(t,2H),3.88(d,3H),1.00(s,9H)。
第六步:将上一步产物(1.5g,0.97mmol)溶解到甲醇/四氢呋喃/水(25mL/25mL/25mL)中,加入氯化铵(1.6g,29.7mmol)并加入锌粉(1.93g,29.7mmol),室温搅拌3h,过滤,滤液倒入水中,用乙酸乙酯萃取,然后有机层用饱和食盐水洗涤,干燥,旋干,得到甲基(E)-5-氨基-6-((4-((叔丁基二苯基硅基)氧)丁-2-烯-1-基)氨基)烟酸酯(红褐色粘状物,1.4g)。LC-MS[M+H]+:m/z 476.2.1H-NMR(400MHz,DMSO-d6):δ8.03(t,1H),7.61(dd,4H),7.50-7.32(m,6H),7.17(d,1H),6.53(t,1H),5.87(dt,1H),5.72(dd,1H),5.02(s,2H),4.19(d,2H),4.14-4.01(m,2H),3.74(s,3H),0.99(s,9H)。
第七步:将上一步产物(200mg,0.42mmol)溶解于二氯甲烷/无水甲醇(3mL/3mL)中,并于室温加入溴化氰(108mg,1.0mmol),后于室温搅拌16h,将饱和碳酸氢钠溶液(50mL)加入反应液中,并搅拌1h,并用二氯甲烷(50mL)萃取,有机层用饱和食盐水洗涤,干燥,旋干,TLC板纯化,得到甲基(E)-2-氨基-3-(4-((叔丁基二苯基硅基)氧)丁-2-烯-1-基)-3H-咪唑并[4,5-b]吡啶-6-羧酸酯(白色固体,50mg)。LC-MS[M+H]+:m/z 501.2.1H-NMR(400MHz,DMSO-d6):δ8.51(d,1H),7.85(d,1H),7.55(dd,4H),7.45-7.39(m,2H),7.35(dd,4H),7.17(s,2H),5.88(m,1H),5.64(m,1H),4.75(d,2H),4.15(d,2H),3.81(m,3H),0.96(s,9H)。
实施例
实施例9:(E)-9,9'-(丁基-2-烯-1,4-二基)双(2-(1,3-二甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-酰胺
第一步:将中间体B1(160mg,0.46mmol)溶于甲醇(10mL),加入2N NaOH(5mL),100度反应过夜。反应液冷却至室温,减压浓缩除去大部分有机溶剂,1M稀盐酸调节pH=3,固体析出,过滤,干燥得到2-(1,3-二甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-羧酸(120mg,白色固体)。LC-MS:m/z 338.3[M+H]+。
第二步:将2-(1,3-二甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-羧酸(120mg,0.36mmol)溶于DMF(15mL),加入NH4Cl(199mg,3.8mmol),DIEA(140mg,1.08mmol)和HATU(410.4mg,1.08mmol)。室温反应2小时。反应液减压浓缩,柱层析纯化得到2-(1,3-二甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-酰胺(60mg,白色固体)。1H NMR(DMSO-d6,400MHz):δ12.77(s,1H),9.53(s,1H),8.44(s,1H),8.15(brs,1H),7.66(s,1H),7.33(brs,1H),6.81(s,1H),4.28(s,3H),4.05(s,3H),2.22(s,3H)。LC-MS:m/z337.4[M+H]+。
第三步:将2-(1,3-二甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-酰胺(60mg,0.18mmol)和(E)-1,4-二溴丁-2-烯(19.3mg,0.09mmol)溶于DMF(10mL),加入碳酸铯(120mg,037mmol)和碘化钠(60mg,0.40mmol),室温反应1小时。反应液减压浓缩,柱层析纯化得到(E)-9,9'-(丁基-2-烯-1,4-二基)双(2-(1,3-二甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-酰胺(1mg,白色固体)。1H NMR(TFA-d,400MHz):δ11.67(s,2H),10.60(d,J=0.8Hz,2H),9.80(s,2H),9.37(s,2H),8.11(brs,2H),7.53(brs,4H),6.46(s,6H),5.88(s,6H),4.55(s,6H)。LC-MS:m/z 725.0[M+H]+。
以中间体B为原料,参照实施例9的合成方法制备得到以下实施例化合物。
实施例12:(E)-5-(4-(8-氨甲酰基-3-(1,3-二甲基-1H-吡唑-5-基)-6-(3-吗啉丙氧基)-5H-吡啶[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶[4,3-b]吲哚-8-酰胺
第一步:将中间体A1(500mg,1.43mmol)和(E)-1,4-二溴丁-2-烯(606mg,2.86mmol)溶于DMF(20mL),加入碳酸铯(1.4g,4.29mmol)和碘化钠(429mg,2.86mmol),室温反应过夜。反应液减压浓缩,柱层析纯化得到(E)-5-(4-溴丁基-2-烯-1-基)-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(275mg,白色固体)。1HNMR(DMSO-d6,400MHz):δ9.56(s,1H),8.60(s,1H),8.03(s,1H),7.63(s,1H),6.66(s,1H),5.95-6.23(m,2H),5.37-5.38(m,2H),4.05-4.16(m,8H),3.93(s,3H),2.22(s,3H)。LC-MS:m/z 483.1[M+H]+。
第二步:将(E)-5-(4-溴丁基-2-烯-1-基)-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(275mg,0.57mmol)和中间体A3(264mg,0.57mmol)溶于DMF(15mL),加入碳酸铯(372mg,1.14mmol)和碘化钠(86mg,0.57mmol),室温反应过夜。反应液减压浓缩,柱层析纯化得到(E)-3-(1,3-二甲基-1H-吡唑-5-基)-5-(4-(3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-8-(甲氧羰基)-5H-吡啶并[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-6-(3-吗啉丙氧基)-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(120mg,白色固体)。LC-MS:m/z 866.4[M+H]+。
第三步:将(E)-3-(1,3-二甲基-1H-吡唑-5-基)-5-(4-(3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-8-(甲氧羰基)-5H-吡啶并[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-6-(3-吗啉丙氧基)-5H-吡啶并[4,3-b]吲哚-8-羧酸甲酯(120mg,0.14mmol)溶于甲醇(10mL),加入2N NaOH(5mL),100度反应过夜。反应液冷却至室温,减压浓缩除去大部分有机溶剂,1M稀盐酸调节pH=3,固体析出,过滤,干燥得到(E)-5-(4-(8-羧基-3-(1,3-二甲基-1H-吡唑-5-基)-6-(3-吗啉丙氧基)-5H-吡啶并[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸(90mg,白色固体)。LC-MS:m/z838.3[M+H]+。
第四步:将(E)-5-(4-(8-羧基-3-(1,3-二甲基-1H-吡唑-5-基)-6-(3-吗啉丙氧基)-5H-吡啶并[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-羧酸(90mg,0.11mmol)溶于DMF(15mL),加入NH4Cl(58mg,1.1mmol),DIEA(206mg,1.6mmol)和HATU(84mg,0.22mmol)。室温反应过夜。反应液减压浓缩,制备色谱纯化得到(E)-5-(4-(8-氨甲酰基-3-(1,3-二甲基-1H-吡唑-5-基)-6-(3-吗啉丙氧基)-5H-吡啶[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶[4,3-b]吲哚-8-酰胺(17mg,白色固体)。1HNMR(CD3OD,400MHz):δ9.58(s,1H),9.57(s,1H),8.56(d,J=1.2Hz,1H),8.53(d,J=1.2Hz,1H),8.06(s,1H),8.05(s,1H),7.74(s,1H),7.69(d,J=1.2Hz,1H),6.58(s,1H),6.54(s,1H),5.73-5.85(m,2H),5.39-5.44(m,4H),4.05-4.20(m,4H),3.71-3.81(m,11H),3.24-3.44(m,6H),2.34(s,3H),2.33(s,3H),2.10-2.15(m,2H)。LC-MS:m/z 836.0[M+H]+。
实施例13:(E)-5-(4-(8-氨甲酰基-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶[4,3-b]吲哚-8-酰胺
第一步:将3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-酰胺(100mg,0.29mmol)和(E)-1,4-二溴丁-2-烯(318mg,1.5mmol)溶于DMF(20mL),加入碳酸铯(391mg,1.2mmol)和碘化钠(50mg,0.3mmol),室温搅拌1小时。反应液加人水(40mL)和乙酸乙酯(40mL)分液。水相用乙酸乙酯(40mL)萃取一次,合并有机相,减压浓缩,剩余物用乙酸乙酯(20mL)打浆,过滤,干燥,得到(E)-9-(4-溴丁基-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-酰胺(100mg,黄色固体)。LC-MS:m/z 482.3[M+H]+。
第二步:将(E)-9-(4-溴丁基-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-酰胺(50mg,0.1mmol)和3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶并[4,3-b]吲哚-8-酰胺(34mg,0.1mmol)溶于DMF(20mL),加入碳酸铯(131mg,0.4mmol)和碘化钠(16mg,0.1mmol),室温搅拌1小时。反应液减压浓缩,制备色谱纯化得到(E)-5-(4-(8-氨甲酰基-3-(1,3-二甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶[4,3-b]吲哚-5-基)丁基-2-烯-1-基)-3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-甲氧基-5H-吡啶[4,3-b]吲哚-8-酰胺(5.6mg,白色固体)。1H NMR(CD3OD,400MHz):δ9.45(s,1H),9.43(s,1H),8.46(d,J=1.2Hz,1H),8.44(d,J=1.2Hz,1H),7.87(s,1H),7.81(s,1H),7.63(s,1H),7.61(s,1H),6.30(s,1H),6.24(s,1H),5.93(br s,2H),5.38(brs,4H),4.24-4.26(m,2H),3.81-3.83(m,9H),2.29(s,3H),2.28(s,3H),1.23(t,J=7.2Hz,3H)。LC-MS:m/z 737.8[M+H]+。
以中间体A和B为原料,参照实施例12和实施例13的合成方法制备得到以下实施例化合物。
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实施例19:(S)-3-(3-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-9-基)丙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-3,4-二氢-5-氧杂-1,2a-二氮杂苊烯-7-酰胺
采用实施例12相同的方法制备,得到目标化合物(白色固体,3.1mg),MS(ESI):m/z=745.4[M+H]。1H NMR(400MHz,MeOD-d4):(9.13(s,1H),8.21(s,1H),7.44(s,1H),7.36(s,1H),7.23(s,1H),6.78(s,1H),6.31(s,1H),5.34(s,2H),4.54-4.80(m,6H),4.09-4.11(m,1H),3.79(s,3H),2.27(s,3H),2.12(s,3H),1.20-1.59(m,10H)。
实施例25:(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-8-(3-(二氟甲氧基)丙氧基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
第一步:将化合物3-((4-甲氧基苄基)氧代)丙基-1-醇(1.0g,5.10mmol),溶于乙腈(40mL),再加入CuI(193.8mg,1.02mmol),升温到70℃缓慢加入2,2-二氟-2-(氟磺酰氟)乙酸(1.81g,10.2mmol),室温反应2小时。用乙酸乙酯/水(40/40mL)洗3次,旋干拌样,用石油醚/乙酸乙酯(体积比PE/EA=10/1)逐层新纯化得到油状粗品1-((3-(二氟甲氧基)丙氧基)甲基)-4-甲氧基苯(300mg)。1H-NMR(400MHz,MeOD-d4):δ7.24(d,2H),6.88(d,2H),6.12(t,1H),4.42(s,2H),3.92(d,2H),3.78(s,3H),3.31(t,2H),1.86-1.90(m,2H)。
第二步:将上步粗品(10mg,0.04mmol)溶于甲醇(MeOH)(5mL),加入钯碳(2mg),氢气下室温反应过夜。过滤分离得到油状产品3-(二氟甲氧基)丙基-1-醇(4.0mg)。
第三步:将上步粗品(4mg,0.03mmol),溶于DCM(10mL),再加入TEA(9.1mg,0.09mmol),降温到0℃缓慢加入甲基磺酰氯(5.2mg,0.045mmol),室温反应2小时。用饱和碳酸钠(10mL)水洗3次,旋干得到油状粗品3-(二氟甲氧基)丙基甲磺酸酯(4mg)直接用于下一步反应。
第四步:将上步粗品(5mg,0.006mmol)和(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-羟基-嘧啶[4,5-b]吲哚-6-甲酰胺(2.5mg,0.012mmol)溶于DMF(5mL),加入碳酸铯(5.9mg,0.018mmol),室温反应过夜,二氯甲烷萃取,饱和碳酸氢钠溶液和水洗涤,浓缩,制备分离得到实施例化合物25(白色固体,0.6mg)。LC-MS[M+H]+:m/z960.4。
实施例26:(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-8-(3-(4,4-二氟哌啶-1-基)丙氧基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
采用实施例25相同的方法制备得到实施例26(白色固体,6.3mg)。LC-MS[M+H]+:m/z 1013.4。1H-NMR(400MHz,MeOD-d4):δ9.29(s,2H),8.27(s,2H),7.32(s,2H),6.82(s,2H),5.63(s,2H),5.17(s,4H),4.60-4.66(m,6H),3.68-3.70(m,4H),3.54-3.57(m,4H),2.27-2.32(m,4H),2.25(s,6H),2.20-2.23(m,6H),1.83-1.87(m,4H),1.46-1.49(m,4H),1.37(t,6H)。
实施例27:(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-8-(3-(3,3-二氟氮杂环丁烷-1-基)丙氧基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
采用实施例25相同的方法制备得到实施例27(白色固体,5.5mg)。LC-MS[M+H]+:m/z 985.4。1H-NMR(400MHz,MeOD-d4):δ9.28(s,2H),8.27(s,2H),7.36(d,2H),6.79(d,2H),5.64(s,2H),5.19(s,4H),4.60-4.64(m,6H),3.74-3.78(m,4H),3.56-3.59(m,4H),4.41-4.47(m,4H),2.33-2.47(m,2H),2.26-2.27(m,6H),2.22-2.24(m,4H),1.34-1.38(m,4H),1.30-1.34(m,6H)。
实施例28:(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-吡啶并[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
第一步:将化合物2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-甲酰胺(100mg,0.3mmol)和(E)-1,4-二溴丁基-2-烯(190.0mg,0.9mmol)溶于DMF(25mL),加入碳酸铯(200mg,0.6mmol),室温反应1h。加水(40mL)和乙酸乙酯(40mL)萃取一次,再用乙酸乙酯和石油醚(5mL,体积比1/1)打浆,过滤,干燥得到(E)-9-(4-溴丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-甲酰胺(75mg)。LC-MS[M+H]+:m/z 484.4。
第二步:将上步粗品(75mg,0.16mmol)和2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺(74mg,0.16mmol)溶于DMF(5mL),加入碳酸铯(104.3mg,0.32mmol),室温反应过夜。柱层析(体积比DCM/MeOH=10/1)分离得到(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺(白色固体,50mg)。LC-MS[M+H]+:m/z 865.6。
第三步:将上步粗品(20mg,0.02mmol)溶于DCM(10mL),再加入三溴化硼(BBr3)(5mL),50度反应过夜。加甲醇淬灭,旋干,得到粗品(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-羟基-9H-吡啶并[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺(20mg)。LC-MS[M+H]+:m/z 851.4。
第四步:将上步化合物(20mg,0.023mmol)和3-吗啡啉丙基-1-醇(13.29mg,0.046mmol)溶于DMF(5mL),加入碳酸铯(22.49mg,0.069mmol),室温反应过夜。二氯甲烷萃取,饱和碳酸氢钠溶液和水洗涤,浓缩,制备分离得到实施例28(白色固体,3.7mg)。LC-MS[M+H]+:m/z 978.5。1H-NMR(400MHz,MeOD-d4):δ9.32(s,1H),8.40(d,1H),8.30(d,2H),7.57(d,1H),7.39(d,2H),6.84(s,1H),6.59(s,1H),5.60-5.61(m,1H),5.45-5.49(m,1H),5.21-4.26(m,2H),5.27-5.38(m,2H),4.40-4.62(m,2H),4.38-4.40(m,2H),3.78-3.79(m,12H),3.08-3.28(m,12H),2.31(d,6H),1.94-1.96(m,2H),1.81-1.84(m,2H),1.34-1.8.(m,3H),1.26-1.36(m,3H)。
实施例29:(E)-9-(4-(6-酰胺-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
第一步:将2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-甲酰胺(50mg,0.14mmol)和(E)-1,4-二溴丁基-2-烯(148.4mg,0.7mmol)溶于DMF(20mL),加入碳酸铯(136.9mg,0.42mmol),室温反应1h。加水(40mL)和EA(40mL)稀释,分离有机相,旋干,用乙酸乙酯(20mL)打浆,过滤,干燥得到(E)-9-(4-溴丁基-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-吡啶并[2,3-b]吲哚-6-甲酰胺(灰色固体,20mg)。LC-MS[M+H]+:m/z 484.2。
第二步:将上步得到的化合物(20mg,0.045mmol)和2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺(19mg,0.041mmol)溶于DMF(20mL),加入碳酸铯(58.7mg,0.18mmol),室温反应1h。二氯甲烷萃取,饱和碳酸氢钠溶液和水洗涤,浓缩,制备分离得到实施例29化合物(白色固体,35.3mg)。LC-MS[M+H]+:m/z865.5。1H-NMR(400MHz,DMSO-d6):δ9.48(s,1H),8.51-8.53(m,1H),8.41(s,2H),8.01-8.05(m,2H),7.35-7.60(m,5H),6.78(s,1H),6.58(s,1H),5.72-5.77(m,2H),5.22(s,4H),4.57-4.59(m,2H),4.22-4.25(m,2H),3.93(s,2H),3.77(s,3H),3.45(s,4H),2.11-2.21(m,12H),1.54(s,2H),1.02-1.23(m,6H)。
实施例30:(E)-9-(4-(8-酰胺-3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-(3-吗啡啉丙氧基)-5H-吡啶并[4,3-b]吲哚-5-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
第一步:将2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-甲酰胺(50mg,0.14mmol)和A(148.4mg,0.7mmol)溶于DMF(20mL),加入碳酸铯(136.9mg,0.42mmol),室温反应1h。加水(40mL)和乙酸乙酯(EA)(40mL),用乙酸乙酯(40mL)萃取,旋干,用乙酸乙酯(20mL)打浆,过滤,干燥得到灰色固体(40mg)。LC-MS[M+H]+:m/z 485.1。
第二步:将上步灰色固体(40mg,0.09mmol)和3-(1-乙基-3-甲基-1H-吡唑-5-)-6-(3-吗啡啉丙氧基)-5H-吡啶并[4,3-b]吲哚-8-甲酰胺(38mg,0.81mmol)溶于DMF(20mL),加入碳酸铯(117.4mg,0.36mmol),室温反应1h。二氯甲烷萃取,饱和碳酸氢钠溶液和水洗涤,浓缩,制备分离得到实施例30(白色固体,35.3mg)。LC-MS[M+H]+:m/z 865.5。1H-NMR(400MHz,CD3OD):δ9.42(s,1H),9.31(s,1H),8.44(s,1H),8.33(s,1H),7.87(s,1H),7.59(s,1H),7.54(s,1H),6.73(s,1H),6.29(s,1H),5.79(s,2H),5.35(s,2H),5.28(s,2H),4.49-4.51(m,2H),4.02-4.20(m,5H),3.76(s,4H),3.21-3.30(m,8H),2.05-2.30(m,8H),1.19-1.25(m,6H)。
实施例31:(E)-9,9'-(丁-2-烯-1,4-二基)双(2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-((4-甲氧基苄基)氧代)-9H-嘧啶并[4,5-b]吲哚-6-甲酰胺
将中间体B5化合物(250mg,0.54mmol)和1,4-二溴丁烯(58.0mg,0.3mmol)溶于DMF(25mL),加入碳酸铯(540mg,3.0mmol),室温反应1h。加水(40mL)析出固体用甲醇(10mL)和DMF(10mL)打浆,过滤,干燥得到实施例31(灰色固体,72mg)。LC-MS[M+H]+:m/z 965.5。1H-NMR(400MHz,TFA-d6):δ11.58(s,2H),10.47(s,2H),9.72(s,2H),9.38(s,2H),8.14(s,2H),7.51(s,4H),6.93(s,4H),4.55(s,6H),3.63(s,6H)。
实施例32:(E)-9,9'-(丁-2-烯-1,4-二基)双(2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-羟基-9H-嘧啶并[4,5-b]吲哚-6-甲酰胺)
将实施例31(72mg,0.08mmol),溶于DCM(10mL),再加入三氟乙酸(TFA)(5mL),50度加热反应过夜。旋干,用甲醇(10mL)打浆过滤,得到实施例32(白色固体,42mg)。1H-NMR(400MHz,TFA-d6):δ11.15(s,2H),10.03(s,2H),9.28(s,2H),8.94(s,2H),7.70(s,2H),7.07(s,4H),6.50(s,4H),4.11(s,6H),3.19(s,6H)。
实施例33:(E)-9-(4-(6-氨甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-((4-甲氧基苄基)氧代)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
将化合物3a(520.0mg,0.88mmol)和化合物2d(309.5mg,0.88mmol)溶于DMF(20mL),加入碳酸铯(860.6mg,2.64mmol),室温反应2h。加水(40mL)和乙酸乙酯(40mL)萃取一次,再用乙酸乙酯和石油醚(5mL,v:v=1:1)打浆,过滤,干燥得到实施例33(白色固体,580.0mg)。LC-MS[M+H]+:m/z 859.6.1H NMR(400MHz,DMSO-d6):δ9.48(s,2H),8.45(s,2H),8.05(s,2H),7.69(s,1H),7.57(s,1H),7.40(s,1H),6.41-7.57(m,2H),7.08-7.11(m,2H),6.75-6.99(m,2H),6.53-6.63(m,2H),5.69-5.74(m,2H),5.55-5.60(m,4H),5.10(s,2H),4.47-4.57(m,4H),3.59-3.80(m,6H),2.20(s,6H),1.30(t,3H),1.20(t,J=6.4Hz,3H)。
实施例34:(E)-9-(4-(6-氨甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-羟基-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
将实施例化合物33(60.0mg,0.07mmol)溶于DCM(10mL),加入TFA(5mL),室温反应过夜。用甲醇和二氯甲烷(5mL)=1/1打浆,过滤,干燥得到实施例34(白色固体,50.0mg)。LC-MS[M+H]+:m/z 739.5.1H NMR(400MHz,TFA-d):δ11.64(s,2H),10.57(s,2H),9.78(s,2H),9.40(s,2H),8.14(s,2H),7.54(s,4H),6.92-6.95(m,4H),5.89(s,3H),4.57(s,6H),3.60-3.67(m,6H)。
实施例35:(E)-9-(4-(6-氨甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-甲氧基丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-烯)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
将实施例化合物34(25.0mg,0.03mmol)和溴代物原料(9.3mg,0.06mmol)溶于DMF(10mL),加入碳酸铯(29.1mg,0.09mmol),室温反应过夜,制备色谱分离得到实施例35(白色固体,2.4mg)。LC-MS[M+H]+:m/z 811.6.1H NMR(400MHz,DMSO-d6):δ9.47(s,1H),9.46(s,1H),8.43(s,1H),8.42(s,1H),8.06(s,2H),7.59(s,1H),7.55(s,1H),7.38-7.41(m,2H),6.75(s,1H),6.72(s,1H),5.79(s,2H),5.20-5.23(m,4H),4.49-4.58(m,4H),4.00-4.04(m,2H),3.77(s,3H),3.25-3.28(m,2H),3.11(s,3H),2.19(s,3H),2.16(s,3H),1.71-1.74(m,2H),1.20(t,3H),1.15(t,3H)。
实施例36:(E)-9-(4-(6-氨甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-((4-(三氟甲基)苄基)氧代)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-甲酰胺
将实施例化合物34(25.0mg,0.03mmol)和对三氟甲基苄氯(11.6mg,0.06mmol)溶于DMF(10mL),加入碳酸铯(29.3mg,0.09mmol),室温反应过夜,制备色谱分离得到实施例化合物36(白色固体,17.1mg)。LC-MS[M+H]+:m/z 897.5。1H-NMR(400MHz,DMSO-d6):δ9.50(s,1H),9.44(s,1H),8.46(s,1H),8.43(s,1H),8.06(s,2H),7.69(s,1H),7.55(s,1H),7.40-7.49(m,6H),6.77(s,1H),6.69(s,1H),5.84-5.90(m,1H),5.50-5.63(m,1H),5.21-5.23(m,2H),5.12-5.15(m,4H),4.57-4.59(m,2H),4.48-4.49(m,2H),3.64(s,3H),2.19(s,3H),2.16(s,3H),1.21(t,3H),1.11(t,3H)。
实施例37:(E)-9,9'-(丁-2-烯-1,4-二基)双(2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-((4-(三氟甲基)苄基)氧代)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺)
将实施例化合物32(30.0mg,0.04mmol)和对三氟甲基苄氯(23.3mg,0.12mmol)溶于DMF(10mL),加入碳酸铯(39.1mg,0.12mmol),室温反应过夜,制备色谱分离得到实施例37(白色固体,19.8mg)。LC-MS[M+H]+:m/z 1041.2。1H-NMR(400MHz,DMSO-d6):δ9.48(s,2H),8.51(s,2H),8.09(s,2H),7.67(s,2H),7.47(s,2H),7.34-7.37(m,4H),7.29-7.31(m,4H),6.75(s,2H),5.51(s,2H),5.14(s,4H),5.01(s,4H),4.54-4.56(m,4H),2.19(s,6H),1.19(t,6H)。
实施例38:(E)-9,9'-(丁-2-烯-1,4-二基)双(2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-甲氧基丙氧基)-9H-嘧啶[4,5-b]吲哚-6-甲酰胺)
将实施例化合物32(30.0mg,0.04mmol)和溴代物原料(18.2mg,0.12mmol)溶于DMF(10mL),加入碳酸铯(39.1mg,0.12mmol),室温反应过夜,制备色谱分离得到实施例38(白色固体,20.2mg).LC-MS[M+H]+:m/z 869.6.1H NMR(400MHz,DMSO-d6):δ9.47(s,2H),8.41(s,2H),8.05(s,2H),7.54(s,2H),7.38(s,2H),6.75(s,2H),5.76(s,2H),5.21(s,4H),4.53-4.58(m,4H),3.96-3.99(m,4H),3.21-3.24(m,4H),3.10(s,6H),2.20(s,6H),1.64-1.68(m,4H),1.20(t,6H)。
实施例39:(E)-9,9'-(丁-2-烯-1,4-二基)双(8-(2-(苄氧基)乙氧基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-酰胺)
以2-苄氧基溴乙烷和实施例32为原料,参照实施例38的方法合成得到实施例39(白色固体,12.0mg)。LC-MS[M+H]+:m/z 993.7。1H-NMR(400MHz,DMSO-d6):δ9.48(s,2H),8.44(s,2H),8.05(s,2H),7.59(s,2H),7.41(s,2H),7.09-7.17(m,10H),6.75(s,2H),5.65(s,2H),5.10(s,4H),4.52-4.55(m,4H),4.23(s,4H),4.10(s,4H),3.41-3.45(m,4H),2.19(s,6H),1.18(t,6H)。
实施例40:(E)-8-(2-(苄氧基)乙氧基)-9-(4-(6-酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-酰胺
以实施例34和2-苄氧基溴乙烷为原料,参照实施例38的方法合成得到实施例40(白色固体,13.3mg)。LC-MS[M+H]+:m/z 873.5。1H-NMR(400MHz,DMSO-d6):δ9.46(s,2H),8.43(s,2H),8.04-8.07(m,2H),7.58-7.60(m,2H),7.40-7.41(m,2H),7.15-7.21(m,5H),6.72(s,2H),5.70-5.78(m,2H),5.12-5.18(m,4H),4.46-4.58(m,4H),4.30(s,2H),4.17(s,2H),3.74(s,3H),3.56-3.66(m,2H),2.17(d,6H),1.16(t,6H)。
实施例41:(E)-9,9'-(丁-2-烯-1,4-二基)双(2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(2-羟基乙氧基)-9H-嘧啶[4,5-b]吲哚-6-酰胺)
第一步:将实施例39化合物(10.0mg,0.01mmol)溶于TFA(10mL),90度反应过夜。LC-MS检测反应完全,旋干得到粗品(10.0mg)直接进行下一步。LC-MS[M+H]+:m/z 1005.5。
第二步:将上步粗品化合物(10.0mg,0.01mmol)溶于MeOH/H2O(10mL/1mL),加入碳酸钾(4.2mg,0.03mmol),室温反应4h。LCMS检测反应完全,制备色谱分离纯化得到实施例41(白色固体,1.5mg)。LC-MS[M+H]+:m/z 813.5。1H-NMR(400MHz,DMSO-d6):δ9.48(s,2H),8.42(s,2H),8.06(s,2H),7.57(s,2H),7.41(s,2H),6.72(s,2H),5.84(s,2H),5.23-5.25(m,4H),4.83-4.88(m,1H),4.49-4.54(m,4H),3.98-4.01(m,4H),3.37-3.54(m,5H),2.18(s,6H),1.18(t,6H)。
实施例42:(E)-9-(4-(6-酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(2-羟基乙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-酰胺
以实施例40为原料,参照实施例41的方法合成得到实施例42(白色固体,2.5mg)。LC-MS[M+H]+:m/z 783.5。1H-NMR(400MHz,DMSO-d6):δ9.46(s,2H),8.41(s,2H),8.05(s,2H),7.59(s,2H),7.41(s,2H),6.72(s,2H),5.84(s,2H),5.18-5.28(m,4H),4.47-4.53(m,4H),4.03-4.05(m,2H),3.78(s,3H),3.50-3.57(m,3H),2.18(s,6H),1.16(t,6H)。
实施例43:(E)-9-(4-(6-酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-8-(3-(二乙基氨基)丙氧基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-酰胺
采用实施例25相同的方法制备得到实施例43(白色固体,6.1mg)。LC-MS[M+H]+:m/z 965.6。1H-NMR(400MHz,MeOD-d4):δ9.28(s,2H),8.27(s,1H),8.26(s,1H),7.48(s,1H),7.39(s,1H),6.84(s,1H),6.78(s,1H),5.64(s,2H),5.16(s,4H),4.61-4.66(m,6H),3.68-3.73(m,4H),3.54-3.57(m,4H),2.36-2.38(m,4H),2.26-2.27(m,6H),2.18-2.22(m,6H),1.47-1.49(m,4H),1.32-1.38(m,6H),0.92(t,6H)。
实施例44:(E)-8-丁氧基-9-(4-(6-酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-酰胺
采用实施例25相同的方法制备得到实施例44(白色固体,2.2mg)。LC-MS[M+H]+:m/z 908.6。1H-NMR(400MHz,MeOD-d4):δ9.28-9.31(s,2H),8.35(s,1H),8.27(s,1H),7.48(s,1H),7.39(s,1H),6.84(s,1H),6.78(s,1H),5.57-5.71(m,2H),5.05-5.25(m,4H),4.58-4.74(m,4H),3.74-3.95(m,8H),3.14-3.29(m,4H),2.26-2.28(m,6H),1.92-1.96(m,2H),1.22-1.39(m,10H),0.80(t,3H)。
实施例45:(E)-9-(4-(6-酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-8-(环丙基甲氧基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-9H-嘧啶[4,5-b]吲哚-6-酰胺
采用实施例25相同的方法制备得到实施例45(白色固体,12.0mg)。LC-MS[M+H]+:m/z 906.6。1H-NMR(400MHz,MeOD-d6):δ9.26(s,1H),8.31(s,1H),8.24(s,1H),7.47(s,1H),7.37(s,1H),6.79(s,1H),6.74(s,1H),5.73-5.79(m,2H),5.25-5.67(m,5H),4.50-4.70(m,3H),3.98-4.02(m,4H),3.65-3.67(m,4H),3.20-3.23(m,4H),2.25-2.29(m,6H),1.98-2.01(m,2H),1.26-1.33(m,6H),0.84-0.95(m,1H),0.42-0.45(m,2H),0.38-040(m,2H)。
实施例46:(E)-9-(4-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-羟基丙氧基)-9H-吡啶基[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啉代丙氧基)-9H-嘧啶基[4,5-b]吲哚-6-酰胺
采用实施例25相同的方法制备得到实施例46(白色固体,19.1mg)。LC-MS[M+H]+:m/z 909.4.1H NMR(400MHz,DMSO-d6):δ9.83(s,1H),9.72(s,1H),8.50-8.55(d,1H),8.46(s,1H),8.40(s,1H),8.04-8.08(m,2H),7.61-7.63(d,1H),7.53-7.57(m,2H),7.38-7.46(m,2H),6.76(s,1H),6.61(s,1H),5.66(s,2H),5.18-5.23(m,4H),4.52-4.53(m,2H),4.25-4.29(m,2H),3.98-4.07(m,8H),3.58-3.61(m,2H),3.40-3.43(m,2H),2.94-3.17(m,4H),2.51-2.86(m,2H),2.20(s,6H),1.76-1.78(m,2H),1.60-1.64(m,2H),1.19(t,3H),1.08(t,J=5.6Hz,3H).
实施例47:(E)-9-(4-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-羟基丙氧基)-9H-吡啶基[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-酰胺
采用实施例25相同的方法制备得到实施例47(白色固体,17.5mg)LC-MS[M+H]+:m/z 796.4.1H NMR(400MHz,DMSO-d6):δ9.47(s,1H),8.51(d,1H),8.42(s,1H),8.37(s,1H),8.01-8.08(m,2H),7.53-7.59(m,3H),7.33-7.42(m,2H),6.73(s,1H),6.58(s,1H),5.68-5.87(m,2H),5.18-5.27(m,4H),4.43-4.48(m,2H),4.24-4.29(m,2H),4.07-4.10(m,2H),3.98(s,3H),3.45-3.48(m,2H),2.18(s,6H),1.64-1.77(m,2H),1.04-1.12(m,6H).
实施例48:(E)-9-(4-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-甲氧基丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啉代丙氧基)-9H-嘧啶基[4,5-b]吲哚-6-羧酰胺
采用实施例25相同的方法制备得到实施例48白色固体(44.1mg).LC-MS[M+H]+:m/z 924.8.1H NMR(400MHz,DMSO-d6):δ9.50(d,2H),8.47(d,2H),8.44(d,2H),8.08(d,2H),7.56(d,2H),6.76(d,2H),5.62-5.69(m,2H),5.18-5.19(m,4H),4.52-4.61(m,4H),3.87-4.01(m,8H),3.38-3.41(m,4H),3.17-3.22(m,5H),2.89-2.92(m,2H),2.20(d,6H),1.59-1.61(m,2H),1.22-1.25(m,2H),1.19-1.21(m,6H)。
实施例49:(E)-9-(4-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(2-羟基乙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啉代丙氧基)-9H-嘧啶基[4,5-b]吲哚-6-羧酰胺采用实施例25相同的方法制备得到实施例49白色固体(30.1mg).LC-MS[M+H]+:m/z 896.3.1H NMR(400MHz,DMSO-d6):δ9.48(d,2H),8.45(d,2H),8.08(d,2H),7.58(d,2H),7.44(d,2H),6.73(d,2H),5.62-5.89(m,2H),5.19-5.25(m,4H),4.50-4.55(m,4H),3.89-3.99(m,4H),4.00-4.02(m,2H),3.54-3.61(m,5H),3.28-3.30(m,2H),3.13-3.19(m,2H),2.91-2.94(m,2H),2.17(d,6H),1.15-1.22(m,2H),1.10-1.15(m,6H)。
实施例50:(E)-9-(4-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-吡啶并[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶并[4,5-b]吲哚-6-甲酰胺
采用实施例25相同的方法制备得到实施例50(白色固体,6.2mg)。LC-MS[M+H]+:m/z 865.2。
实施例51:(E)-9-(4-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啡啉丙氧基)-9H-吡啶并[2,3-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-羟丙氧基)-9H-嘧啶并[4,5-b]吲哚-6-甲酰胺
采用实施例25相同的方法制备得到实施例51(白色固体,5.6mg)。LC-MS[M+H]+:m/z 909.3。
实施例52:(E)-9-(4-(8-氨基甲酰基-3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-(3-羟基丙氧基)-5H-吡啶基[4,3-b]吲哚-5-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啉代丙氧基)-9H-嘧啶基[4,5-b]吲哚-6-羧酰胺
采用实施例25相同的方法制备得到实施例52(白色固体,18.0mg)。LC-MS[M+H]+:m/z 909.5。
实施例53:(E)-9-(4-(8-氨基甲酰基-3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-(3-羟基丙氧基)-5H-吡啶基[4,3-b]吲哚-5-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-羧酰胺
采用实施例25相同的方法制备得到实施例53(白色固体,18.0mg)。LC-MS[M+H]+:m/z 769.3。
实施例54:(E)-9-(4-(8-氨基甲酰基-3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-(嘧啶-2-基甲氧基)-5H-吡啶基[4,3-b]吲哚-5-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-甲氧基-9H-嘧啶[4,5-b]吲哚-6-羧酰胺
采用实施例25相同的方法制备得到实施例54(白色固体,5.1mg)。LC-MS[M+H]+:m/z 830.2。
实施例55:(E)-9-(4-(8-氨基甲酰基-3-(1-乙基-3-甲基-1H-吡唑-5-基)-6-(3-吗啉代丙氧基)-5H-吡啶基[4,3-b]吲哚-5-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啉代丙氧基)-9H-嘧啶基[4,5-b]吲哚-6-羧酰胺
采用实施例25相同的方法制备得到实施例55淡黄固体(5.0mg).LC-MS[M+H]+:m/z 978.4。1H NMR(400MHz,MeOD-d4):δ9.50(s,1H),9.36(s,1H),8.48(s,1H),8.37(s,1H),7.94(s,1H),7.50-7.62(m,2H),6.85(s,1H),6.32(s,1H),5.72-5.42(m,2H),5.15-5.25(m,4H),4.50-4.71(m,2H),4.17-4.21(m,2H),3.99-4.13(m,8H),3.74-3.81(m,4H),3.40-3.42(m,4H),3.01-3.21(m,8H),2.09-2.28(m,6H),1.85-1.91(m,2H),1.80-1.95(m,2H),1.29-1.30(m,6H)。
实施例56:(E)-9-(4-(6-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-羟基丙氧基)-9H-嘧啶[4,5-b]吲哚-9-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-基)-8-(3-吗啉代丙氧基)-9H-嘧啶基[4,5-b]吲哚-6-羧酰胺
采用实施例25相同的方法制备得到实施例56白色固体(9.0mg)。LC-MS[M+H]+:m/z 910.3.1H NMR(400MHz,MeOD-d4):δ10.13-12.02(m,2H),8.16-8.19(m,2H),7.38-7.41(m,2H),6.61-6.60(m,2H),5.59-5.64(m,2H),5.12-5.33(m,4H),4.44-4.48(m,4H),4.02-4.12(m,2H),3.95-4.01(m,4H),3.93-3.95(m,2H),3.76-3.78(m,2H),3.57-3.58(m,2H),3.30-3.34(m,2H),3.05-3.19(m,2H),1.98-2.20(m,6H),1.73-1.98(m,2H),1.70-1.72(m,2H),1.19-1.28(m,6H)。
对比化合物1:参照专利WO2019069275A第85页实施例4的合成方法制备得到对比化合物1。LC-MS[M+H]+:850.5m/z.1H NMR(400MHz,CD3OD):δ7.59(s,2H),7.27(s,1H),7.25(s,1H),6.61(s,1H),6.59(s,1H),5.80(br s,2H),5.01(br s,4H),4.57-4.61(m,4H),3.97(br s,4H),3.71(br s,5H),3.12-3.31(m,6H),2.18(s,6H),1.95-1.98(m,2H),1.31-1.39(m,6H)。
对比化合物2:参照专利WO2020028565A1中实施例1的合成方法制备得到对比化合物2。1H NMR(TFA-d,400MHz):δ11.66(s,2H),10.58(d,J=0.8Hz,2H),9.78(s,2H),9.36(s,2H),8.09(brs,2H),7.51(brs,4H),6.87-6.89(m,4H),5.84(s,6H),4.54(s,6H),3.58(t,J=7.2Hz,6H)。MS(ESI):m/z=753.0[M+H]。
对比化合物3:参照专利WO2020028565A1中实施例2的合成方法制备得到对比化合物3。LC-MS[M+H]+:m/z 841.4.1H NMR(400MHz,DMSO-d6):δ9.46(s,2H),8.40(s,2H),8.06(s,2H),7.56(s,2H),7.39(s,2H),6.73(s,2H),5.77(s,4H),5.21(s,4H),4.50-4.54(m,6H),4.01-4.05(m,4H),3.37-3.39(m,4H),2.17(s,6H),1.59-1.63(m,4H),1.14-1.18(m,6H)。
测试例一:实施例化合物与WT hSTING蛋白结合活性测试
按照Cisbio提供的WT hSTING试剂盒的测试方法操作:在96孔筛选板中,STING蛋白分别与待测化合物(起始浓度10μM,十梯度三倍稀释)和缓冲液于37℃反应30分钟,然后与20μM荧光底物在37℃共同孵育30分钟,用Thermo Scientific Verioskan Flash多功能读数仪以358nm为激发光,读取455nm处的光强度。以测出的荧光值比空白孔的值计算样品对蛋白的竞争结合活性。化合物的EC50值由Graphpad公司的Prism软件拟合计算得到。
结果表明,本发明绝大部分实施例化合物能较好的与WT hSTING蛋白结合,其EC50值小于100nM,大部分实施例的EC50值小于10nM,部分实施例化合物的EC50值甚至小于1nM,达到pM级别活性。(具体数据如表一所示,A<0.3nM,0.3nM≤B<1nM,1nM≤C<10nM,10nM≤D<100nM,E≥100nM)。
表一、实施例化合物对WT hSTING蛋白结合活性
编号 | EC50 | 编号 | EC50 | 编号 | EC50 |
1 | E | 2 | E | 3 | E |
4 | D | 5 | C | 6 | B |
7 | E | 8 | E | 9 | E |
10 | A | 11 | A | 12 | E |
13 | C | 14 | E | 15 | C |
16 | A | 17 | C | 18 | A |
19 | A | 20 | B | 21 | B |
22 | B | 23 | B | 24 | B |
25 | C | 26 | C | 27 | C |
28 | C | 29 | A | 30 | A |
31 | B | 32 | B | 33 | B |
34 | C | 35 | B | 36 | A |
37 | A | 38 | B | 39 | A |
40 | A | 41 | A | 42 | B |
43 | C | 44 | C | 45 | C |
46 | A | 47 | A | 48 | A |
49 | A | 50 | A | 51 | A |
52 | A | 53 | A | 54 | A |
55 | A | 56 | A | ||
对比化合物1 | B | 对比化合物2 | B | 对比化合物3 | C |
测试例二:Elisa方法检测实施例化合物刺激THP1细胞对IFNβ的释放活性测试
测试步骤:1、THP-1细胞使用RPMI1640+10%FBS+0.05mMβ-ME培养,维持密度在2×105~1×106viable cells/mL;收集细胞,弃去旧培养基后,使用无血清培养基洗涤细胞一次,离心去上清后,使用无血清培养基重悬细胞。台盼蓝染色后计数,细胞活力大于95%时进行后续实验;使用无血清培养基调整细胞密度为1.1×106viable cells/mL;添加180μL细胞悬液至96孔细胞培养板孔中,细胞密度为2×105viable cells/well。2:用溶媒稀释阳性对照和待测化合物形成贮存液并进行梯度稀释,得到10倍浓度的溶液;每孔加入20μL的10倍浓度化合物溶液,每个浓度两个复孔。阳性对照化合物cGAMP最高浓度为100μM,3倍稀释,共5个浓度。待测化合物最高浓度为10μM,5倍稀释,共5个浓度;3、细胞培养板置于培养箱中孵育24hrs;细胞培养板2000g离心5分钟,转移上清直接进行ELISA检测;ELISA测试样品中IFN-β浓度分别根据IFN-β标准曲线计算得出。细胞上清中IFN-β浓度等于ELISA样品中IFN-β浓度乘于稀释倍数;4、使用GraphPad Prism5.0软件分析数据,利用非线性S曲线回归拟合数据得出剂量-效应曲线,计算EC50值。
结果:本发明绝大部分实施例化合物刺激THP1细胞对IFNβ的释放活性EC50值小于1uM,部分实施例的EC50值甚至小于100nM,部分实施例的EC50值甚至小于1nM,如实施例16、29、39、56等(具体EC50数据如表二所示,A<1nM,1nM≤B<10nM,10nM≤C<100nM,D≥100nM)。
表二、实施例化合物刺激THP1细胞对IFNβ的释放活性
测试例三:Elisa方法检测实施例化合物对2'3'-cGAMP刺激THP-1分泌IFN-β的抑制能力(拮抗)
测试方法:1、THP-1细胞使用RPMI1640+10%FBS+0.05mMβ-ME培养,维持密度在2×105~1×106viable cells/mL;收集细胞,弃去旧培养基后,使用无血清培养基洗涤细胞一次,离心去上清后,使用无血清培养基重悬细胞。台盼蓝染色后计数,细胞活力大于95%时进行后续实验。使用无血清培养基调整细胞密度为1.1×106viable cells/mL;添加160μL细胞悬液至96孔细胞培养板孔中,细胞密度为2×105viable cells/well。2、用溶媒稀释阳性对照和待测化合物形成贮存液并进行梯度稀释,得到10倍浓度的溶液,每孔加入20μL的10倍浓度化合物溶液,培养箱中孵育2hrs。每孔继续加入20μL cGAMP,cGAMP终浓度为30μM。待测化合物最高浓度为30μM,5倍稀释,共5个浓度。每个浓度设置1个复孔。3、细胞培养板置于培养箱中孵育24hrs,2000g离心5分钟,转移上清直接进行ELISA检测。4、ELISA检测过程参照R&D Systems(Cat#DY814-05)说明书。ELISA测试样品中IFN-β浓度分别根据IFN-β标准曲线计算得出。细胞上清中IFN-β浓度等于ELISA样品中IFN-β浓度乘于稀释倍数。使用GraphPad Prism 5.0软件分析数据,利用非线性S曲线回归拟合数据得出剂量-效应曲线,计算EC50值。
结果:本发明的发明人在长期的研究过程中,首次发现本发明通式(I)化合物中部分实施例化合物具有较好的拮抗STING功能的活性,EC50小于20uM,如实施例11、18、30、36、55;部分实施例化合物对2'3'-cGAMP刺激THP-1分泌IFN-β的抑制能力EC50小于1uM,如实施例11、16。
测试例四:实施例化合物对不同酶的抑制活性
(1)配制1×Kinase buffer;(2)化合物浓度梯度的配制:受试化合物测试浓度为10uM起始,3倍稀释10个浓度,复孔测试,在96孔板中梯度稀释成100倍终浓度的10个不同浓度的溶液。然后用1×Kinase buffer将各浓度的化合物进一步稀释成5倍终浓度的中间稀释溶液;(3)将配制好的化合物溶液各取5μL分别加入384孔板的化合物孔,每个浓度单孔测试;阴性对照孔和阳性对照孔中分别加5μL的5%DMSO;(4)用1×Kinase buffer配制2.5倍终浓度的激酶溶液;(5)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μL的1×Kinase buffer;(6)1000rpm离心30秒,振荡混匀后室温孵育10分钟;(7)用1×Kinase buffer配制2.5倍终浓度的ATP和Kinase substrate22的混合溶液;(8)加入10μL的2.5倍终浓度的ATP和底物的混合溶液,起始反应;(9)将384孔板1000rpm离心30秒,振荡混匀后28℃分别孵育相应的时间;(10)加入30μL终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀;(11)用Caliper EZ ReaderⅡ读取转化率,以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。采用上述测试方法,将实施例化合物分别与GSK3、TBK、CDK、IKK、AMPK、ULK1等激酶相互作用,测试化合物对上述酶的抑制活性。
结果:本发明实施例化合物11、16、18、19、39、56对GSK3、TBK、CDK、IKK、AMPK、ULK1等激酶抑制活性较弱,IC50>500nM,显示了与STING蛋白结合的较高选择性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (8)
1.一种如通式(VI-1)所示的含氮稠环类化合物、或其药学上可接受的盐,
式中:
R2选自下组:5-10元杂芳基;其中,所述的R2可以任选地被一个或多个取代基取代;
M1和M7各自独立地为N;
M2、M3、M5各自独立地为CH;
M4为CRa,Ra为-C(O)NHRe;所述的Re选自下组:氢、C1-C6烷基、C1-C6卤代烷基;
M6为CRa;其中,所述的Ra独立地选自C1-C6的烷氧基、或被选自下组的取代基取代的C1-C6的烷氧基:具有1-3个选自N、S和O的杂原子的5-12元杂环基;
R2’选自5-10元杂芳基;所述的R2’可以任选地被一个或多个取代基取代;
M1’为N,且M7’为CH;或M1’为CH,且M7’为N;
M2’、M3’和M5’各自独立地为CRa,其中Ra独立地选自氢、卤素、羟基、氨基、氰基、酰胺基、脲基、C1-C6的烷基、C1-C6的烷氧基、C3-C6的环烷基、C3-C6的杂环烷基;
M4’为C-酰胺基;
M6’为CRa;其中,所述的Ra为被选自下组的取代基取代的C1-C6的烷氧基:羟基、具有1-3个选自N、S和O的杂原子的5-12元杂环基;
其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P或S,所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P或S;
上述各个基团可以被选自下组的一个或多个取代基所取代:卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、氧代(=O)、-CN、羟基、-NH2、C1-C6胺基、羧基、-OPMB、或C1-C6烷基、C1-C6卤代烷基。
2.一种如通式(VI-1)所示的含氮稠环类化合物、或其药学上可接受的盐,
式中:
R2为吡唑基;其中,所述的R2可以任选地被一个或多个取代基取代;
M1和M7各自独立地为N;
M2、M3、M5各自独立地为CH;
M4为CRa,Ra为-C(O)NHRe;所述的Re选自下组:氢、C1-C6烷基、C1-C6卤代烷基;
M6为CRa;其中,所述的Ra独立地选自C1-C6的烷氧基、或被选自下组的取代基取代的C1-C6的烷氧基:C1-C6烷氧基、C6-C10芳基;所述取代基进一步被选自下组的基团取代:卤代的C1-C6烷基、-O(CH2)r-C6-C10芳基;
R2’选自5-10元杂芳基;所述的R2’任选地被一个或多个取代基取代;
M1’和M7’各自独立地为N;
M2’、M3’和M5’各自独立地为CRa,其中Ra独立地选自氢、卤素、羟基、氨基、氰基、酰胺基、脲基、C1-C6的烷基、C1-C6的烷氧基、C3-C6的环烷基、C3-C6的杂环烷基;
M4’为C-酰胺基;
M6’为CRa;其中,所述的Ra独立地为被选自下组的取代基取代的C1-C6的烷氧基:C1-C6烷氧基、C6-C10芳基;所述取代基进一步被选自下组的基团取代:C1-C6烷氧基、卤代的C1-C6烷基、-O(CH2)r-C6-C10芳基;
其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P或S,所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P或S;
上述各个基团可以被选自下组的一个或多个取代基所取代:卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、-CN、羟基、-NH2、C1-C6胺基、羧基、-OPMB、C1-C6烷基、或C1-C6卤代烷基;r选自1、2、3、4、5或6。
3.如权利要求1或2中任一项所述的化合物、或其药学上可接受的盐,其特征在于,所述的R2为吡唑基;其中,所述的R2被一个或多个取代基取代时,所述的取代基为C1-C6烷基。
4.如权利要求1或2中任一项所述的化合物、或其药学上可接受的盐,其特征在于,M4为CRa,Ra独立地为-C(O)NHRe,Re选自下组:氢、C1-C6烷基。
5.一类含氮稠环类化合物、或其药学上可接受的盐,其为如下任一化合物:
。
6.如权利要求1-中任一项所述的化合物或其药学上可接受的盐的用途,其特征在于,用于制备与STING蛋白依赖型疾病的预防或治疗药物。
7.如权利要求6所述的用途,其特征在于,所述的疾病选自下组:肿瘤、自身免疫性疾病、病毒感染、退行性疾病;较佳地,所述的疾病选自下组:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌、移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿疹、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风、和瓦尔登斯特伦氏巨球蛋白血症。
8.包含如权利要求1-5中任一项所述的化合物或其药学上可接受的盐的药物组合物,其特征在于,所述的药物组合物包括:
(i)有效量的所述化合物,或其药学上可接受的盐;和
(ii)药学上可接受的载体。
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