CN116768870A - 具有苄氧基芳基醚结构的化合物及其制备方法和用途 - Google Patents
具有苄氧基芳基醚结构的化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种具有苄氧基芳基醚结构的化合物其制备方法和用途,所述具有苄氧基芳基醚结构的化合物结构如式I所示,式中各取代基的定义如说明书和权利要求书中所述。本发明的化合物可用于制备PD1/PD‑L1相互作用的小分子抑制剂,用于预防和/或治疗与PD1/PD‑L1相互作用相关的疾病,尤其是癌症。
Description
技术领域
本发明属于药物合成领域,具体涉及一类具有苄氧基芳基醚结构的化合物,其立体异构体、对映体或其药学上可接受的盐,其制备方法和用途。
背景技术
在正常情况下,人体内的免疫细胞,例如CD4/CD8+T细胞具有对于癌症细胞的杀伤作用,使免疫功能正常人能够免于癌症。然而,T细胞膜表面的PD-1(Programmed death 1)受体被肿瘤细胞表达的PD-L1(Programmed death-ligand 1)蛋白结合之后,T细胞的免疫功能被严重抑制,无法正常发挥免疫功能,其抑制癌细胞增殖的能力严重削弱。利用肿瘤细胞的PD-L1蛋白免疫T细胞的PD-1受体的结合,肿瘤细胞实现免疫逃逸,得以存活生长。生物学和医学研究表明,利用抗体药物结合PD-1受体或者结合PD-L1蛋白,能够阻断PD-1/PD-L1之间的相互作用,在人体内可以实现良好的抗肿瘤效果。例如,PD-1单抗Pembrolizumab(Merck公司),Nivolumab(BMS公司)可以选择性结合T细胞的PD-1受体,PD-L1单抗Atezolizumab(Genentech/Roche公司),Durvalumab(Medimmune/AstraZeneca公司),Avelumab(Merck KGaA and Pfize公司)可以选择性结合PD-1受体,这些抗体都能够阻断PD-1/PD-L1之间的相互作用,目前已经在临床治疗多种肿瘤,包括非小细胞肺癌、小细胞肺癌、黑色素瘤、头颈癌、肾癌、膀胱癌、局部晚期或转移性尿路上皮癌、乳腺癌、宫颈癌、转移性默克尔细胞癌、前列腺癌、肝癌、肠癌、胃癌、多发性骨髓瘤、套细胞淋巴癌、弥漫性大B细胞淋巴瘤肝癌、霍奇金淋巴瘤、慢性淋巴细胞白血病、鳞状细胞癌等癌症。阻断PD-1/PD-L1之间的相互作用能够治疗病人体内的恶性肿瘤,这一药物研究的理念已经得到临床实践的科学验证。
另外一方面,小分子化合物和多肽化合物也可以选择性与PD-1或PD-L1结合。这些化合物具有阻断PD-1/PD-L1之间的相互作用的潜力,具有激活T细胞功能,特异性杀死肿瘤细胞的活性。小分子化合物CA-170、BMS-986189、CA-327、AUNP-12和MAX-10129都可以作用于PD-1/PD-L1信号通路,在动物体内具有一定的抗肿瘤效果。
综上所述,小分子化合物如果能够阻断PD-1/PD-L1之间的相互作用,那么这样的化合物就可能阻断肿瘤细胞PD-L1蛋白和免疫细胞PD-1之间的结合,就有可能在动物体内、人体内表现出抗癌效果,具有治疗人体内恶性肿瘤的潜在药物用途。
目前多个已上市的靶向PD-1或者PD-L1的单克隆抗体药物证实PD-1/PD-L1的阻断剂可用于多种肿瘤的临床治疗。然而抗体药物有其自身的特点,如生产成本高,稳定性较差,需经注射给药及易产生免疫原性等。而小分子药物具有组织渗透性好,储存运输方便,生产成本较低,无免疫原性及通常可口服给药等优势,因此研究开发PD-1/PD-L1的小分子抑制剂具有显著的应用价值和社会价值。
发明内容
本发明目的是提供一种用于抑制PD1-PD-L1相互作用的小分子抑制剂。
本发明第一方面,提供一种通式(I)所示的化合物,其立体异构体、对映异构体,或其药学上可接受的盐:
其中:Y为不存在或者CH2;Z为CH2、O或NR;其中,R为氢、C1-C4烷基或-CO(C1-C4烷基)(如甲酰基、乙酰基、丙酰基、或丁酰基);
X为CH或者N;当X为N时,R1为-(CH2)n-CO2H;当X为CH时,R1为-NR2-(CH2)n-CO2H;其中,n为1、2、3或者4;R2为氢或C1-C4烷基;
R3为C1-C4烷基或者卤素;
R4选自:
其中R5为C1-C4烷基或者卤素;R6为氢或C1-C6烷基;R7为取代的或未取代的5~6元杂芳基、取代的或未取代的C1-C6烷基、取代的或未取代的C3-C8环烷基或氢,所述取代是指被选中下组的一个或多个(如2、3、4或5个)取代基:-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、羟基、C1-C6烷氧基、5~6元杂芳基、卤素或者CN;
或者R6和R7以及两者所连接的氮原子形成取代的或未取代的4~9元杂环,所述取代是指被选中下组的一个或多个(如2、3、4或5个)取代基:羟基、-N(C1-C6烷基)(C1-C6烷基)、-NH(C1-C6烷基)、卤素或者CN;
R8为C1-C4烷基、卤素或者CN。
在另一优选例中,所述杂芳基或杂环各自独立地包含1、2或3个选自N、O或S的杂原子。
在另一优选例中,当X为N时,R1为-(CH2)n-CO2H;当X为CH时,R1为-NR2-(CH2)n-CO2H;其中,n为1、2、3或者4;R2为氢、甲基、乙基、正丙基或异丙基。
在另一优选例中,R3为甲基、乙基、正丙基、异丙基、Cl、F或Br。
在另一优选例中,R5为甲基、乙基、正丙基、异丙基、Cl、F或Br。
在另一优选例中,R6为甲基、乙基、正丙基、异丙基或氢;R7为取代的或未取代的5~6元杂芳基、取代的或未取代的C1-C6烷基、取代的或未取代的C4-C6环烷基或氢,所述取代是指被选中下组的一个或多个(如2、3、4或5个)取代基:-NH(C1-C4烷基)、-N(C1-C4烷基)(C1-C4烷基)、羟基、C1-C4烷氧基、5~6元杂芳基、Cl、F、Br或者CN;
或者R6和R7以及两者所连接的氮原子形成取代的或未取代的5-6元杂环,所述取代是指被选中下组的一个或多个(如2、3、4或5个)取代基:羟基、-N(C1-C4烷基)(C1-C4烷基)、-NH(C1-C4烷基)、Cl、F、Br或者CN;
R8为甲基、乙基、正丙基、异丙基、Cl、F、Br或者CN。
在另一优选例中,所述化合物具有式II、式III或式IV所示的结构:
其中,R1、R3、R5、R6、R7、X、Y、Z的定义与前相同。
在另一优选例中,所述化合物具有式II-1所示的结构:
其中,R1、R3、R5、R6、R7、Y、Z的定义与前相同。
在另一优选例中,所述化合物具有式V、式V-1或式V-2所示的结构:
其中,R1、R3、R5、R6、R7、Y、Z的定义与前相同。
在另一优选例中,所述化合物具有式VI、式VI-1、或式VI-2所示的结构:
其中,R1、R3、R5、R6、R7的定义与前相同。
在另一优选例中,所述化合物具有式VII、式VII-1、或式VII-2所示的结构:
其中,R1、R3、R5、R6、R7的定义与前相同。
在另一优选例中,所述化合物具有式VIII、式VIII-1、或式VIII-2所示的结构:
其中,R1、R3、R5、R6、R7的定义与前相同。
在另一优选例中,所述化合物具有式IX、式IX-1、或式IX-2所示的结构:
其中,R1、R3、R5、R6、R7的定义与前相同。
在另一优选例中,所述化合物选自化合物1-55。
本发明的第二方面,提供了一种药物组合物,其包含第一方面所述的化合物,其立体异构体、对映异构体或其药学上可接受的盐,和药学上可接受的赋形剂或载体。
在另一优选例中,所述药物组合物还包括第二癌症治疗剂。
在另一优选例中,所述的第二癌症治疗剂包括放射剂、细胞毒试剂、激酶抑制剂、免疫靶向抑制剂和血管生成抑制剂。
在另一优选例中,所述第二癌症治疗剂是选自下组的一种或多种:
PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或其组合。
本发明第三方面,提供了第一方面所述的化合物,其立体异构体、对映异构体或其药学上可接受的盐,或第二方面所述的药物组合物的用途,用于制备PD1-PDL1相互作用抑制剂;或用于制备预防和/或治疗与PD1/PD-L1相互作用相关的疾病。
在另一优选例中,与PD1/PD-L1相互作用相关的疾病为癌症。
在另一优选例中,所述癌症选自下组:非小细胞肺癌、小细胞肺癌、黑色素瘤、头颈癌、肾癌、膀胱癌、局部晚期或转移性尿路上皮癌、乳腺癌、宫颈癌、转移性默克尔细胞癌、前列腺癌、肝癌、肠癌、胃癌、多发性骨髓瘤、套细胞淋巴癌、弥漫性大B细胞淋巴瘤肝癌、霍奇金淋巴瘤、慢性淋巴细胞白血病、鳞状细胞癌。
在另一优选例中,所述的化合物,其立体异构体或其药学上可接受的盐用于联合用药方案,例如联合肿瘤化疗方案,其他肿瘤免疫治疗剂(小分子化合物及抗体等),放疗方案,肿瘤靶向药,肿瘤疫苗等,如人类乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV);可以在所述药剂之前、之后或同时施用,或者可以与其它已知疗法共施用。
在另一优选例中,所述的化合物,其立体异构体或其药学上可接受的盐单独或联合使用用于治疗暴露于特定毒素或病原体的患者的治疗;其中包括但不限于各种病毒,病原体细菌,病原体真菌,病原体寄生虫等的治疗;如HIV、肝炎病毒(甲、乙、丙)、流感病毒、疱疹病毒、贾第虫、疟疾、利什曼原虫、金黄色葡萄球菌、绿脓杆菌等病原体已建立的感染。
在另一优选例中,所述的化合物,其立体异构体或其药学上可接受的盐用于诱导治疗性自身免疫应答,以治疗具有不恰当的其他自身抗原积累的患者,如淀粉状蛋白沉积物,包括阿尔茨海默病中的Αβ、细胞因子如TNFa和IgE。
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。
附图说明
图1示出肿瘤细胞和T细胞共培养测试结果。
具体实施方式
本发明人经过广泛而深入的研究,发现了一类具有较好的抑制PD1/PD-L1相互作用能力的化合物。此外,本发明化合物具有较好的促进T细胞杀伤癌细胞的作用,较好的药效学性能以及更低的毒性。在此基础上,完成了本发明。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。
基团定义
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-C6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、芳基烷基、杂芳基烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳基烷基氨基、杂基芳烷基氨基。
“羧基”是指-COOH。
“(C1-C4)烷基磺酰基”是指(C1-C4)烷基-SO2-,其中,所述烷基定义如下文所述。
“(C1-C4)烷基亚磺酰基”是指(C1-C4)烷基-SO-,其中,所述烷基定义如下文所述。
“(C1-C4)烷基磺酰基氨基”是指:(C1-C4)烷基-SO2-NH-,其中,所述烷基定义如下文所述。
“氨基磺酰基”是指:-SO2-NH2。
“(C1-C5)酰基氨基”是指(C1-C5烷基)(C=O)NH-,其中,所述烷基定义如下文所述。
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”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、具有例如1至6个(优选为1至4个)碳原子,且通过单键与分子的其余部分连接,例如包括但不限于甲基、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、正己基等。本申请中,所述烷基(作为基团或是其它基团的一部分)还意在包含取代的烷基,例如所述取代选自:卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
术语“环烷基”是指完全饱和的环状烷烃,仅由碳原子和氢原子组成、具有例如3至8个碳原子(即C3-C8环烷基)或具有3至6个碳原子(即C3-C6环烷基),且通过单键与分子的其余部分连接,例如包括但不限于环丙基、环丁基、环戊基、环己基。本申请中,所述环烷基(作为基团或是其它基团的一部分)还意在包含取代的环烷基,例如所述取代选自:卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。“卤代(C1-C4)烷基”是指有1或2或3个卤素原子取代的C1-C4烷基,如:三氟甲基、二氟甲基。
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(即3-20元)非芳香族环状基团,优选4-11元杂环基,更优选5-10元杂环基。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。本申请中,所述杂环基(作为基团或是其它基团的一部分)还意在包含取代的杂环基,例如所述取代选自:卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基(或芳环)”意指具有6至18个碳原子(优选具有6至10个碳原子,即C6-C10)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。本申请中,所述芳基(或芳环)(作为基团或是其它基团的一部分)还意在包含取代的芳基(或芳环),例如所述取代选自:卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基(或杂芳环)”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。本申请中,所述杂芳基(或杂芳环)(作为基团或是其它基团的一部分)还意在包含取代的杂芳基(或杂芳环),例如所述取代选自:卤素、羟基、氰基、硝基、氨基、羧基、磺酰基等。
本发明中,多个是指2、3、4或5个。
活性成分
如本文所用,术语“本发明的化合物”或“本发明的活性成分”可互换使用,指式I其立体异构体、对映异构体,或其药学上可接受的盐。该术语还包括外消旋体、光学异构体、同位素化合物(如氘代化合物)或前药。
所述式(I)化合物具有如下结构:
“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。
“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。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素,分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物,或对映体,非对映体,异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如3H和14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即3H和碳-14,即14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用披露在示例中的方案可以制备。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。
如果要设计一个本发明的化合物特定的对映体的合成,它可以不对称合成制备,或用手性辅剂衍生化,将所产生的非对映混合物分离,再除去手性辅剂而得到纯的对映体。另外,如果分子中含有一个碱性官能团,如氨基酸,或酸性官能团,如羧基,可以用合适的光学活性的酸或碱的与之形成非对映异构体盐,再通过分离结晶或色谱等常规手段分离,然后就得到了纯的对映体。
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗癌症、免疫性疾病、代谢性疾病等。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,“药学上可接受的赋形剂”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“癌症”或“肿瘤”包括但不限于非小细胞肺癌、黑色素瘤、头颈癌、肾癌、膀胱上皮癌、局部晚期或转移性尿路上皮癌、转移性默克尔细胞癌、前列腺癌、肝癌、肠癌、多发性骨髓瘤、套细胞淋巴癌、弥漫性大B细胞淋巴瘤肝癌、霍奇金淋巴瘤、慢性淋巴细胞白血病等。
本文所用术语“预防”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,The Pharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington’s,Pharmaceutical Sciences(current edition),MackPublishing 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。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。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。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为:PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或其组合。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法,包括步骤:将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。
本发明还提供了一种治疗方法,它包括步骤:给需要治疗的对象施用本发明中所述通式(I)化合物,其立体异构体、对映异构体或其药学上可接受的盐,或施用本发明所述的药物组合物,用于抑制PD1-PDL1相互作用。
中间体的制备
1.合成7-氯-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)苯并[d]恶唑-5-甲醛(ZK099)
将ZK105(271mg,0.68mmol,合成方法参见专利WO 2018/119224)溶于干燥的二氯甲烷(30mL)中,然后向反应也中加入DMP(戴斯-马丁氧化剂)(575.6mg,1.36mmol)室温搅拌12小时。反应结束后向反应液中加水淬灭,二氯甲烷萃取,收集有机相并旋干,最后用层析柱分离纯化后得到目标化合物220mg,收率:82%。1H NMR(400MHz,Chloroform-d)δ10.06(s,1H),8.21(dd,J=7.4,1.4Hz,2H),8.11–7.82(m,2H),7.37(t,J=7.6Hz,1H),2.98(s,3H),1.39(s,12H).
2.合成7-氯-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)苯并[d]恶唑-5-甲醛(EH056)
将EH050(330mg,1.0mmol,合成方法参见专利CN 113801111 A)溶于干燥的二氯甲烷(30mL)中,然后向反应也中加入DMP(800mg,2.0mmol)室温搅拌12小时。反应结束后向反应液中加水淬灭,二氯甲烷萃取,收集有机相并旋干,最后用层析柱分离纯化后得到目标化合物120mg,收率:47%。1H NMR(500MHz,Chloroform-d)δ10.12(s,1H),8.52(d,J=1.5Hz,1H),8.26(dd,J=7.9,1.4Hz,1H),8.22(d,J=1.5Hz,1H),7.99(dd,J=7.5,1.5Hz,1H),7.40(q,J=7.7,7.1Hz,1H),3.00(s,3H),1.40(s,12H).
3.合成5-甲酰基-N-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)吡啶甲酰胺(ZZC034)
步骤1:合成5-羟甲基-N-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)吡啶甲酰胺(ZZC031)
在氮气环境下,将ZZC028(1.0g,3.15mmol),联硼酸频那醇酯(1.6g,6.29mmol),乙酸钾(1.2g,12.59mol)悬浮于干燥1,4-环氧六环(25mL),干燥氮气除气三次,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(261.0mg,0.32mmol),干燥氮气除气三次,100℃加热搅拌反应12小时。反应结束浓缩,残余物经硅胶柱层析分离得标题化合物1.1g,收率:96%)。1HNMR(500MHz,CD3OD)δ8.67(d,J=2.1Hz,1H),8.17(d,J=8.0Hz,1H),7.97(dd,J=8.0,2.1Hz,1H),7.92(dd,J=8.0,1.4Hz,1H),7.60(dd,J=7.4,1.4Hz,1H),7.23(t,J=7.7Hz,1H),4.75(s,2H),2.55(s,3H),1.36(s,12H).
步骤2:合成ZZC034
将ZZC031(1.1g,2.99mmol)和DMP(2.5g,5.98mmol)悬浮于二氯甲烷(20mL)中,室温搅拌反应10小时。反应结束加入碳酸氢钠的饱和水溶液至pH~7.5,使用二氯甲烷萃取混合液(15mL×3),收集有机相用无水硫酸钠干燥,过滤后减压浓缩,所得产物用硅胶柱层析分离纯化得到标题化合物782.0mg,收率:92%。1H NMR(500MHz,CDCl3)δ10.22(s,1H),10.10(s,1H),9.11(d,J=2.1Hz,1H),8.49(d,J=7.9Hz,1H),8.38(dd,J=8.0,2.1Hz,1H),8.32(dd,J=8.1,1.4Hz,1H),7.64(dd,J=7.5,1.4Hz,1H),7.29(t,J=7.8Hz,1H),2.63(s,3H),1.37(s,12H).
4.合成N-甲基-N-(7-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼兰-2-基)苄基)氧基)色-4-基)甘氨酸乙酯(ZK068)
步骤1:合成7-(3-溴-2-甲基苄基)氧基)色-4-酮(ZK049)
将1-溴-3-(溴甲基)-2-甲基苯(1.21g,4.57mmol)、ZK061(0.9g,5.48mmol)溶于乙腈(30mL)中,然后加入碳酸钾(1.26g,9.14mmol),室温搅拌12小时,反应结束后旋干溶剂,然后加水、二氯甲烷萃取,最后用层析柱分离纯化,得到目标化合物1.1g,收率:70%。1HNMR(500MHz,Chloroform-d)δ7.86(d,J=8.8Hz,1H),7.57(dd,J=8.1,1.2Hz,1H),7.33(d,J=7.5Hz,1H),7.08(t,J=7.8Hz,1H),6.65(dd,J=8.8,2.4Hz,1H),6.49(d,J=2.4Hz,1H),5.07(s,2H),4.52(t,J=6.4Hz,2H),2.76(t,J=6.4Hz,2H),2.42(s,3H).
步骤2:合成7-((3-溴-2-甲基苄基)氧基)-N-甲基色满-4-胺(ZK065)
将ZK049(1.2g,3.47mmol)、甲胺甲醇溶液(37%,2.39g,20.81mmol)溶于四氢呋喃(50mL)中,室温搅拌15分钟后加入AcOH(0.8mL)继续搅拌15分钟后加入氰基硼氢化钠(1.31g,20.81mmol),将反应升温至45℃后继续搅拌12小时。待反应结束后,旋干溶剂、加水,然后用乙酸乙酯萃取、有机相用无水硫酸钠干燥后旋干溶剂,直接用于下一步。1H NMR(500MHz,Methanol-d4)δ7.52(dd,J=8.0,1.2Hz,1H),7.35(d,J=7.6Hz,1H),7.31(d,J=8.6Hz,1H),7.06(t,J=7.8Hz,1H),6.67(dd,J=8.6,2.5Hz,1H),6.54(d,J=2.6Hz,1H),5.05(s,2H),4.37(t,J=4.6Hz,1H),4.30(dt,J=8.8,4.4Hz,1H),4.27–4.17(m,1H),2.77(s,3H),2.39(s,3H),2.30(dt,J=7.1,4.6Hz,2H).
步骤3:合成N-(7-((3-溴-2-甲基苄基)氧基)色满-4-基)-N-甲基甘氨酸乙酯(ZK052)
将ZK065(1.05g,2.7mmol)、氯乙酸乙酯(0.83g,6.75mmol)溶于乙腈(50mL)中,然后加入碳酸钾(1.12g,8.1mmol)、KI(44.82mg,0.27mmol),将反应升温至80℃搅拌12小时。待反应结束后,旋干溶剂、加水,用乙酸乙酯萃取,收集有机相并用无水硫酸钠干燥,浓缩后纯化得到目标化合物860mg,收率:55%。1H NMR(500MHz,Chloroform-d)δ7.56(dd,J=8.0,1.3Hz,1H),7.37(d,J=8.8Hz,1H),7.33(dd,J=7.6,1.2Hz,1H),7.07(t,J=7.8Hz,1H),6.65(dd,J=8.7,2.6Hz,1H),6.51(d,J=2.6Hz,1H),5.01(s,2H),4.99(t,J=5.8Hz,1H),4.42(ddd,J=12.1,8.3,3.8Hz,1H),4.28–4.18(m,3H),4.00(d,J=6.4Hz,2H),2.95(s,3H),2.42(s,4H),2.38–2.27(m,1H),1.28(t,J=7.1Hz,3H).
步骤4:合成ZK068
将ZK052(261.1mg,0.58mmol),联硼酸频那醇酯(370.8mg,1.46mmol),KOAc(228.9mg,2.34mmol)溶于无水1,4-二氧六环(30mL)溶液中,在氮气氛围下加入双三苯基膦二氯化钯(60mg),最后反应在氮气氛围下95℃加热反应16h。反应结束后,恢复至室温,旋干溶剂后加水,然后用乙酸乙酯萃取三次,合并有机相并用无水硫酸钠干燥后旋干,最后用层析柱分离纯化得到目标化合物212mg,收率:74%。1H NMR(400MHz,Chloroform-d)δ7.74(dd,J=7.5,1.5Hz,1H),7.47(d,J=7.5Hz,1H),7.40(d,J=8.6Hz,1H),7.19(t,J=7.5Hz,1H),6.56(dd,J=8.6,2.6Hz,1H),6.42(d,J=2.6Hz,1H),4.99(s,2H),4.43–4.30(m,1H),4.14(dq,J=14.6,6.0,5.0Hz,3H),3.98(t,J=6.8Hz,1H),3.32(d,J=16.6Hz,1H),3.19(d,J=16.7Hz,1H),2.55(s,3H),2.44(s,3H),1.97(q,J=6.0Hz,2H),1.35(s,12H),1.31–1.21(m,3H).
5.合成乙基N-甲基-N-(6-((2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)氧基)-1,2,3,4-四氢萘-1-基)甘氨酸盐(ZL101)。
步骤1:合成3,4-二氢萘酮-1-酮(ZL122)
将1-溴-3-(溴甲基)-2-甲基苯(790mg,2.99mmol)、6-羟基-3,4-二氢萘-1-酮(534mg,3.29mmol)溶于乙腈(30mL)中,然后加入碳酸钾(826.4g,5.98mmol),室温搅拌12小时,反应结束后旋干溶剂,然后加水、二氯甲烷萃取,最后用层析柱分离纯化,得到目标化合物970mg,收率:94%。1H NMR(400MHz,Chloroform-d)δ8.03(d,J=8.7Hz,1H),7.57(d,J=8.0Hz,1H),7.35(d,J=7.6Hz,1H),7.08(t,J=7.8Hz,1H),6.90(dd,J=8.7,2.5Hz,1H),6.79(d,J=2.4Hz,1H),5.10(s,2H),2.94(t,J=6.1Hz,2H),2.62(t,J=6.5Hz,2H),2.44(s,3H),2.13(p,J=6.3Hz,2H).
步骤2:合成6-(3-溴-2-甲基苄氧基)-N-甲基-1,2,3,4-四氢萘-1-胺(ZZD001)
向ZL122(900.8mg,2.61mmol)的四氢呋喃溶液(20mL)中加入甲胺的甲醇溶液(37%,2.70g,26.10mmol),AcOH(0.90mL),室温搅拌10分钟。向混合液中加入氰基硼氢化钠(493.2mg,7.83mmol),混合物45℃搅拌12小时。反应结束浓缩,用氢氧化钠的水溶解(1.5M)调pH~12,用乙酸乙酯萃取(30mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,残留物用于步骤3。
步骤3:合成N-(6-(3-溴-2-甲基苄氧基)-1,2,3,4-四氢萘-1-基)-N-甲基甘氨酸乙酯(ZZC003)
向ZZD001粗产品(1.0g,2.78mmol)的乙腈(20mL)溶液中加入氯乙酸乙酯(847.2mg,6.94mmol)、碳酸钾(1.15g,8.33mmol)和碘化钾(46.5mg,0.28mmol),混合物80℃搅拌16小时。待反应结束后,浓缩,加水(30mL)稀释,用乙酸乙酯萃取(30mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,残留物用硅胶层析柱分离纯化,得到目标化合物1.01g(两步收率:81%)。1H NMR(500MHz,Chloroform-d)δ7.67(dd,J=8.7,0.9Hz,1H),7.54(dd,J=8.1,1.3Hz,1H),7.36(dd,J=7.6,1.3Hz,1H),7.06(t,J=7.8Hz,1H),6.81(dd,J=8.6,2.7Hz,1H),6.66(d,J=2.7Hz,1H),5.00(s,2H),4.17(q,J=7.3Hz,2H),3.90(dd,J=10.1,4.7Hz,1H),3.27(d,J=16.5Hz,1H),3.15(d,J=16.5Hz,1H),2.76(ddd,J=15.9,10.9,4.9Hz,1H),2.72–2.63(m,1H),2.44(s,3H),2.40(s,3H),2.03–1.94(m,2H),1.73–1.60(m,1H),1.59–1.50(m,1H),1.26(t,J=7.1Hz,3H).
步骤4:合成ZL101
将ZZZC003(400mg,0.90mmol)、联硼酸频那醇酯(569mg,2.24mmol),KOAc(313.6mg,3.2mmol)溶于无水1,4-二氧六环(30mL)溶液中,在氮气氛围下加入双三苯基膦二氯化钯(60mg),最后反应在氮气氛围下95℃加热反应16小时。反应结束后,恢复至室温,旋干溶剂后加水,然后用乙酸乙酯萃取三次,合并有机相并用无水硫酸钠干燥后旋干,最后用层析柱分离纯化得到目标化合物320mg,收率:72%。1H NMR(400MHz,Chloroform-d)δ7.74(d,J=7.4Hz,1H),7.67–7.63(m,1H),7.48(d,J=7.5Hz,1H),7.19(t,J=7.5Hz,1H),6.82(dd,J=8.7,2.8Hz,1H),6.67(s,1H),5.01(s,2H),4.17(q,J=7.0Hz,1H),3.89(d,J=8.6Hz,1H),3.28(d,J=16.5Hz,1H),3.15(d,J=16.6Hz,3H),2.72(d,J=20.0Hz,3H),2.56(s,4H),2.40(s,3H),1.98(d,J=10.2Hz,3H),1.74–1.61(m,1H),1.35(s,12H),1.28(m,J=1.5Hz,3H).
6.合成N-(5-((3-溴-2-甲基苄基)氧基)-2,3-二氢-1H-茚-1-基)-N-甲基甘氨酸乙酯(ZL040)。
步骤1:合成5-(3-溴-2-甲基苄氧基)-2,3-二氢-1H-茚酮(ZK036)
将1-溴-3-(溴甲基)-2-甲基苯(1.31g,5.0mmol)、5-羟基-2,3-二氢茚茚酮(889mg,6.0mmol)溶于乙腈(30mL)中,然后加入碳酸钾(1.38g,10mmol),室温搅拌12小时,反应结束后旋干溶剂,然后加水、二氯甲烷萃取,最后用层析柱分离纯化,得到目标化合物1.15g,收率:72%。1H NMR(500MHz,Chloroform-d)δ7.75–7.69(m,1H),7.58(dd,J=8.1,1.2Hz,1H),7.35(dd,J=7.6,1.2Hz,1H),7.09(t,J=7.8Hz,1H),6.98(d,J=7.3Hz,2H),5.12(s,2H),3.18–3.04(m,2H),2.74–2.63(m,2H),2.44(s,3H).
步骤2:合成5-(3-溴-2-甲基苄氧基)-N-甲基-2,3-二氢茚-1-胺(ZL039)
将ZK036(500mg,1.52mmol)、甲胺甲醇溶液(37%,1.05g,9.09mmol)溶于四氢呋喃(50mL)中,室温搅拌15分钟后加入AcOH(0.5mL)继续搅拌15分钟后加入氰基硼氢化钠(571mg,9.09mmol),将反应升温至45℃后继续搅拌12小时。待反应结束后,旋干溶剂、加水,然后用乙酸乙酯萃取、有机相用无水硫酸钠干燥后旋干溶剂,直接用于下一步。
步骤3:合成ZL040
将ZL039粗品(1.52mmol)、氯乙酸乙酯(465.7mg,3.8mmol)溶于乙腈(50mL)中,然后加入碳酸钾(630.2mg,4.56mmol)、KI(25.2mg,0.15mmol),将反应升温至80℃搅拌12小时。待反应结束后,旋干溶剂、加水,用乙酸乙酯萃取,收集有机相并用无水硫酸钠干燥,浓缩后纯化得到目标化合物334.2mg,两步收率:51%。1H NMR(500MHz,Chloroform-d)δ7.55(dd,J=8.1,1.3Hz,1H),7.36(dd,J=7.6,1.2Hz,1H),7.32(d,J=8.1Hz,1H),7.07(t,J=7.8Hz,1H),6.86–6.80(m,2H),5.02(s,2H),4.18(q,J=7.1Hz,2H),3.26(d,J=16.4Hz,1H),3.18–3.10(m,1H),2.93(ddd,J=14.3,10.0,5.0Hz,1H),2.79(dt,J=15.9,7.6Hz,1H),2.44(s,3H),2.41(s,3H),2.16(dtd,J=13.3,8.3,4.9Hz,1H),2.01(td,J=13.9,6.7Hz,1H),1.27(t,J=7.1Hz,3H).
实施例1:合成N-(7-((3'-(5-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶酰胺)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK058N)
步骤1:合成5-甲酰基-N-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)吡啶甲酰胺(ZK058)
将ZK052(50mg,0.11mmol)、ZZC034(61.1mg,0.17mmol)溶于乙二醇二甲醚(15mL)和碳酸钠(2M in H2O,5mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(20mg),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZK058粗品。
步骤2:合成ZK058N
将ZK058粗品(0.11mmol)溶于1,2-二氯乙烷(20mL)中,然后加入(R)-3-吡咯烷醇(28.7mg,0.33mmol)室温搅拌15分钟后加入AcOH(0.08mL)。继续搅拌15分钟后加入三乙酰氧基硼氢化钠(70mg,0.33mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(22.6mg,0.55mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物13.2mg,收率:18%。1H NMR(500MHz,Methanol-d4)δ8.85(d,J=2.1Hz,1H),8.33(d,J=8.1Hz,1H),8.22(dd,J=8.1,2.2Hz,1H),7.85(dd,J=8.1,1.2Hz,1H),7.48–7.37(m,2H),7.33(t,J=7.8Hz,1H),7.27(t,J=7.6Hz,1H),7.13(dd,J=7.7,1.3Hz,1H),7.03(dd,J=7.6,1.3Hz,1H),6.75(dd,J=8.7,2.6Hz,1H),6.61(d,J=2.5Hz,1H),5.14(d,J=1.8Hz,2H),4.85(t,J=6.5Hz,1H),4.72–4.51(m,3H),4.38(dt,J=11.6,5.6Hz,1H),4.29–4.17(m,1H),4.13(d,J=17.0Hz,1H),4.05–3.89(m,1H),3.85–3.49(m,2H),3.49–3.35(m,2H),2.97(s,3H),2.37(tt,J=6.1,3.1Hz,2H),2.08(s,3H),2.05(s,3H).
实施例2:合成N-(7-((3'-(7-氰基-5-(((R)-3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK073N)
步骤1:合成N-(7-(3'-(7-氰基-5-甲酰基苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)色-4-基)-N-甲基甘氨酸乙酯(ZK070)
将ZK052(60mg,0.13mmol)、EH056(68mg,0.21mmol)溶于乙二醇二甲醚(15mL)和碳酸钠(2M in H2O,5mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(28mg),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZK070粗品。
步骤2:合成ZK073N
将ZK070粗品(0.13mmol)溶于1,2-二氯乙烷(20mL)中,然后加入(R)-3-吡咯烷醇(35mg,0.4mmol)室温搅拌15分钟后加入AcOH(0.08mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(85.2mg,0.4mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(27.5mg,0.67mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物18.3mg,收率:21%。1H NMR(500MHz,Methanol-d4)δ8.28(d,J=1.6Hz,1H),8.25(dd,J=7.9,1.4Hz,1H),8.00(d,J=1.6Hz,1H),7.53(t,J=7.8Hz,1H),7.50–7.46(m,1H),7.44–7.39(m,2H),7.31(t,J=7.6Hz,1H),7.15(dd,J=7.6,1.4Hz,1H),6.76(dd,J=8.8,2.6Hz,1H),6.62(d,J=2.5Hz,1H),5.16(d,J=2.0Hz,2H),4.85(d,J=6.5Hz,1H),4.60(s,3H),4.39(dt,J=11.5,5.2Hz,1H),4.26–4.16(m,1H),4.11(d,J=17.0Hz,1H),3.93(d,J=17.0Hz,1H),3.60(s,2H),3.48–3.34(m,2H),2.97(s,3H),2.49(s,3H),2.37(tt,J=6.9,3.8Hz,3H),2.09(s,4H).
实施例3:合成(3R)-1-((7-氯-2-(3'-(((4-((2-羟乙基)(甲基)氨基)色满-7-基)氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-醇(ZL015N)
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步骤1:合成7-氯-2-(3'-(4-(2-羟乙基((甲基)氨基)色-7-基)氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-甲醛(ZL012)
将ZK052(200mg,0.45mmol)溶于无水二氯甲烷(20mL)和无水四氢呋喃(30mL)中降温至-78℃,然后向反应液中滴加二异丁基氢化铝(DIBAl-H,1.0mL,1M in Hexane),滴加结束后缓慢升至0℃继续反应12小时。反应结束后将反应液倒入冰水中淬灭,用乙酸乙酯萃取,有机相用无水硫酸钠干燥后旋干,最后用层析柱分离后得到目标化合物170mg,收率:93%。1H NMR(500MHz,Chloroform-d)δ7.58–7.54(m,1H),7.37(d,J=8.7Hz,1H),7.33(d,J=7.4Hz,1H),7.07(t,J=7.8Hz,1H),6.65(dd,J=8.7,2.6Hz,1H),6.50(d,J=2.5Hz,1H),5.01(s,2H),4.97(t,J=6.0Hz,1H),4.42(ddd,J=12.2,8.4,3.8Hz,1H),4.21–4.18(m,1H),4.05–3.92(m,2H),3.82(s,1H),2.93(s,3H),2.42(s,5H),2.32(dddd,J=14.7,8.4,6.1,3.9Hz,1H).
步骤2和3:合成ZL015N
合成方法参见实施例2步骤1和2,采用如下原料ZL012(170mg,0.41mmol)、ZK099(218mg,0.55mmol),Pd(pddf)Cl2-CH2Cl2(50mg)。合成步骤3采用原料(R)-3-吡咯烷醇(28.7mg,0.33mmol),AcOH(0.08mL),三乙酰氧基硼氢化钠(70mg,0.33mmo),LiOH-H2O(27.7mg,0.66mmol)。得到目标化合物6.1mg,两步收率:9%。1H NMR(500MHz,Methanol-d4)δ8.19(dd,J=8.0,1.4Hz,1H),7.93(d,J=1.5Hz,1H),7.69(d,J=1.5Hz,1H),7.52–7.45(m,2H),7.42(d,J=8.8Hz,1H),7.38(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.15(dd,J=7.7,1.3Hz,1H),6.76(dd,J=8.8,2.5Hz,1H),6.62(d,J=2.6Hz,1H),5.16(d,J=1.7Hz,2H),4.87(t,J=6.5Hz,1H),4.59(s,3H),4.39(dt,J=11.6,5.6Hz,1H),4.29–4.17(m,1H),4.18–4.11(m,1H),3.96(d,J=17.0Hz,1H),3.66(d,J=50.7Hz,2H),3.34(d,J=8.2Hz,2H),3.28–3.19(m,1H),2.98(s,3H),2.46(s,3H),2.37(dq,J=11.1,5.5Hz,2H),2.16(s,1H),2.08(s,5H).
实施例4:合成N-(7-((3'-(7-氯-5-(((R)-3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK101N)
步骤1:合成N-(7-(3'-(7-氯-5-甲酰基苯并)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸乙酯(ZK101)
将ZK052(65mg,0.15mmol)、ZK099(75mg,0.19mmol)溶于乙二醇二甲醚(15mL)和碳酸钠(2M in H2O,3mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(30mg,0.015mmol),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZK101粗品。
步骤2:合成ZK101N
将ZK101粗品(0.15mmol)溶于1,2-二氯乙烷(20mL)中,然后加入(R)-3-吡咯烷醇(39.2mg,0.45mmol)室温搅拌15分钟后加入AcOH(0.1mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(95.4mg,0.45mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(30.8mg,0.75mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物21.2mg,收率:22%。1H NMR(500MHz,Methanol-d4)δ8.19(dd,J=8.0,1.4Hz,1H),7.93(d,J=1.5Hz,1H),7.69(d,J=1.5Hz,1H),7.54–7.45(m,2H),7.42(d,J=8.8Hz,1H),7.38(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.15(dd,J=7.7,1.3Hz,1H),6.76(dd,J=8.8,2.5Hz,1H),6.62(d,J=2.6Hz,1H),5.16(d,J=1.7Hz,2H),4.87(t,J=6.5Hz,1H),4.59(s,3H),4.39(dt,J=11.6,5.6Hz,1H),4.27–4.17(m,1H),4.17–4.05(m,1H),3.96(d,J=17.0Hz,1H),3.66(d,J=50.7Hz,2H),3.45–3.33(m,2H),2.98(s,3H),2.46(s,3H),2.37(dq,J=11.1,5.3,4.7Hz,2H),2.18(d,J=26.9Hz,1H),2.08(s,3H).
实施例5:合成N-(6-((3'-(7-氯-5-(((R)-3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)-1,2,3,4-四氢萘-1-基)-N-甲基甘氨酸(ZZD012)
步骤1:合成N-(6-(3'-(7-氯-5-甲酰基苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-1,2,3,4-四氢萘-1-基)-N-甲基甘氨酸乙酯(ZZD009)
将ZZD003(300mg,0.67mmol)、ZK099(321.1mg,0.81mmol)溶于乙二醇二甲醚(20mL)和碳酸钠(2M in H2O,10mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(57mg,0.07mmol),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到目标化合物153.0mg。1H NMR(500MHz,CDCl3)δ10.05–10.00(m,1H),8.23–8.16(m,2H),7.96–7.90(m,1H),7.69(d,J=8.7Hz,1H),7.49(d,J=7.6Hz,1H),7.46–7.40(m,1H),7.38(d,J=7.4Hz,1H),7.30(t,J=7.6Hz,1H),7.15(d,J=7.5Hz,1H),6.86(dd,J=8.6,2.6Hz,1H),6.72(br s,1H),5.07(br s,2H),4.17(q,J=7.1Hz,2H),3.92–3.89(m,1H),3.29(dd,J=16.5,8.2Hz,1H),3.17(d,J=16.5Hz,1H),2.82–2.66(m,2H),2.51(s,3H),2.41(s,3H),2.10(s,3H),2.03–1.95(m,2H),1.72–1.62(m,1H),1.61–1.50(m,1H),1.26(t,J=7.2Hz,3H).
步骤2:合成ZZD012
将ZZD009(76.0mg,0.12mmol)粗品溶于1,2-二氯乙烷(5mL)中,然后加入(R)-3-吡咯烷醇(21.3mg,0.24mmol)室温搅拌5分钟后加入AcOH(14.2mg,0.24mmol)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(76mg,0.36mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(32mg,0.76mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物31mg,收率:38%。ESI-MS理论值:C40H42ClN3O5[M+H]+=680.28,测得:680.3。
实施例6:合成N-(5-((3'-(7-氯-5-(((R)-3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)-2,3-二氢-1H-茚-1-基)-N-甲基甘氨酸(ZL046N)
步骤1:合成N-(5-(3'-(7-氯-5-甲酰基苯并)-2,2'-二甲基-[1,1'-联苯]-3-基)-2,3-二氢-1H-茚-1-基)-N-甲基甘氨酸(ZL044)
将ZL040(110mg,0.25mmol)、ZK099(120mg,0.3mmol)溶于乙二醇二甲醚(15mL)和碳酸钠(2M in H2O,3mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(30mg,0.025mmol),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZL044粗品。
步骤2:合成ZL046N
将ZL044(0.1mmol)粗品溶于1,2-二氯乙烷(20mL)中,然后加入(R)-3-吡咯烷醇(25mg,0.3mmol)室温搅拌15分钟后加入AcOH(0.08mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(62.6mg,0.3mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(21mg,0.5mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物4.3mg,收率:6%。1H NMR(400MHz,Methanol-d4)δ8.20(d,J=7.8Hz,1H),7.96–7.90(m,1H),7.69(d,J=1.5Hz,1H),7.51(t,J=8.0Hz,3H),7.39(d,J=7.5Hz,1H),7.32(t,J=7.6Hz,1H),7.16(d,J=7.5Hz,1H),7.09(s,1H),7.05(d,J=8.7Hz,1H),5.20(s,2H),5.04(d,J=8.2Hz,1H),4.59(s,3H),3.88(d,J=16.4Hz,1H),3.74(d,J=16.7Hz,1H),3.56(s,2H),3.17(dt,J=15.9,7.8Hz,2H),3.08–2.95(m,2H),2.82(s,3H),2.57(dt,J=16.6,8.7Hz,2H),2.47(d,J=2.4Hz,4H),2.10(s,4H).
实施例7:合成(R)-2-(6-((3'-(7-氯-5-((3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)-3,4-二氢喹啉-1(2H)-基)乙酸(ZK152N)
步骤1:合成6-((3-溴-2-甲基苄基)氧基)-3,4-二氢喹啉-1(2H)-羧酸叔丁酯(ZK141)
将1-溴-3-(溴甲基)-2-甲基苯(800mg,3.05mmol)、6-羟基-3,4-二氢-2H-喹啉-1-羧酸叔丁酯(835mg,3.35mmol)溶于乙腈(30mL)中,然后加入碳酸钾(843mg,6.10mmol),室温搅拌12小时,反应结束后旋干溶剂,然后加水、二氯甲烷萃取,最后用层析柱分离纯化,得到目标化合物849mg,收率:92%。1H NMR(500MHz,Chloroform-d)δ7.54(dd,J=8.1,1.3Hz,2H),7.35(dd,J=7.6,1.2Hz,1H),7.06(t,J=7.8Hz,1H),6.77(dd,J=9.0,3.0Hz,1H),6.69(d,J=2.9Hz,1H),4.99(s,2H),3.78–3.58(m,2H),2.75(t,J=6.6Hz,2H),2.43(s,3H),1.91(p,J=6.6Hz,2H),1.52(s,9H).
步骤2:合成2-(6-((3-溴-2-甲基苄基)氧基)-3,4-二氢喹啉-1(2H)-基)乙酸乙酯(ZK145)
将ZK141(849mg,1.97mmol)溶于二氯甲烷(10mL)中,然后加入三氟乙酸(2mL)室温搅拌2小时。反应结束后加饱和碳酸氢钠淬灭,用二氯甲烷萃取,有机相用水洗、无水硫酸钠干燥后旋干,将得到的粗品溶于MeCN(40mL)中然后加入氯乙酸乙酯(361.5mg,2.95mmol)、Cs2CO3(1.28g,3.94mmol),将反应液升温至40℃搅拌12小时。反应结束后加水淬灭。并用二氯甲烷萃取。有机相旋干后用层析柱分离纯化得到目标化合物447mg。收率:54%。1H NMR(500MHz,Chloroform-d)δ7.56–7.50(m,1H),7.34(d,J=7.5Hz,1H),7.05(t,J=7.8Hz,1H),6.75–6.64(m,2H),6.48(d,J=8.6Hz,1H),4.95(s,2H),4.18(q,J=7.1Hz,2H),4.00(s,2H),3.42(t,J=5.7Hz,2H),2.80(t,J=6.4Hz,2H),2.42(s,3H),2.02(p,J=6.3Hz,2H),1.25(t,J=7.1Hz,3H).
步骤3:合成ZK151
将ZK145(300mg,0.72mmol)、ZK099(388mg,0.975mmol)溶于乙二醇二甲醚(30mL)和碳酸钠(2M in H2O,5mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(80mg),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZK151粗品。
步骤4:合成(R)-2-(6-((3'-(7-氯-5-((3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)-3,4-二氢喹啉-1(2H)-基)乙酸(ZK152N)
将ZK151粗品(0.07mmol,40mg)溶于1,2-二氯乙烷(15mL)中,然后加入(R)-3-吡咯烷醇(17.2mg,0.2mmol)室温搅拌15分钟后加入AcOH(0.06mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(41.8mg,0.2mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(15mg,0.35mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物15.3mg,收率:36%。1H NMR(400MHz,Methanol-d4)δ8.20(d,J=7.8Hz,1H),7.93(s,1H),7.69(d,J=1.4Hz,1H),7.54–7.46(m,2H),7.39(d,J=7.5Hz,1H),7.32(t,J=7.6Hz,1H),7.23(d,J=9.2Hz,1H),7.16(d,J=7.6Hz,1H),7.05(d,J=7.2Hz,2H),5.19(s,2H),4.55(d,J=26.9Hz,3H),3.65(d,J=43.0Hz,3H),3.55–3.44(m,2H),3.35(s,0H),2.96(t,J=6.5Hz,2H),2.47(s,3H),2.445–2.35(m,1H),2.15(q,J=5.9Hz,2H),2.10(s,3H).
实施例8:合成N-(7-((3'-(7-氯-5-(((S)-3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK157N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.09mmol)粗品,(S)-3-吡咯烷醇(23.5mg,0.27mmol),三乙酰氧基硼氢化钠(57.2mg,0.27mmol),AcOH(0.06mL),1,2-二氯乙烷(DCE,20mL),LiOH-H2O(18.5mg,0.45mmol),四氢呋喃(THF,8mL),H2O(8mL)。得到目标化合物18.6mg,收率:30%。1H NMR(500MHz,Methanol-d4)δ8.20(dd,J=7.9,1.3Hz,1H),7.93(d,J=1.4Hz,1H),7.69(d,J=1.4Hz,1H),7.50(t,J=7.9Hz,1H),7.49–7.45(m,1H),7.42(d,J=8.8Hz,1H),7.38(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.15(dd,J=7.6,1.3Hz,1H),6.75(dd,J=8.8,2.6Hz,1H),6.62(d,J=2.5Hz,1H),5.16(s,2H),4.86(t,J=6.5Hz,1H),4.59(s,3H),4.39(dt,J=11.5,5.2Hz,1H),4.25–4.14(m,1H),4.10(d,J=16.9Hz,1H),4.00–3.86(m,1H),3.65(d,J=54.3Hz,2H),3.35(s,1H),2.97(s,3H),2.46(s,3H),2.37(tt,J=6.8,3.9Hz,2H),2.18(d,J=30.4Hz,1H),2.08(s,4H).
实施例9:合成3-((7-((3'-(7-氯-5-(((R)-3-羟基吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)(甲基)氨基)丙酸(ZK114N)
步骤1:合成3-((7-((3-溴-2-甲基苄基)氧基)色满-4-基)氨基)丙酸乙酯(ZK079)
将ZK049(250mg,0.72mmol)、丙氨酸乙酯盐酸盐(665.9mg,4.34mmol)溶于四氢呋喃(30mL)中室温搅拌15分钟后加入AcOH(0.12mL),室温继续搅拌30分钟后加入氰基硼氢化钠(272.7mg,4.34mmol),然后将反应也升温至45℃反应12小时。待反应结束后旋干溶剂、加水,乙酸乙酯萃取,反相柱纯化后得到目标化合物116mg,收率:36%。1H NMR(500MHz,Methanol-d4)δ7.55(dd,J=8.1,1.3Hz,1H),7.37(dd,J=7.6,1.2Hz,1H),7.32(d,J=8.7Hz,1H),7.09(t,J=7.8Hz,1H),6.69(dd,J=8.6,2.6Hz,1H),6.57(d,J=2.6Hz,1H),5.11(s,2H),4.51(t,J=4.5Hz,1H),4.35(dd,J=12.0,0.8Hz,1H),4.29–4.23(m,1H),4.23–4.17(q,2H),3.47(dd,J=7.5,6.5Hz,1H),3.39(d,J=6.3Hz,1H),2.92–2.70(m,2H),2.42(s,3H),2.35(p,J=4.7Hz,2H),1.28(t,J=7.2Hz,3H).
步骤2:合成3-((7-((3-溴-2-甲基苄基)氧基)色满-4-基)(甲基)氨基)丙酸乙酯(ZK106)
将ZK079(116mg,0.26mmol)、甲醛(37%,210.8mg,2.6mmol)溶于四氢呋喃(10mL)和甲醇(10mL)的混合溶液中室温搅拌15分钟,然后加入AcOH(0.08mL)继续反应30分钟,最后加入三乙酰氧基硼氢化钠(548mg,2.6mmol)室温搅拌12小时,待反应结束后旋干溶剂,加水,乙酸乙酯萃取,收集有机相用无水硫酸钠干燥,旋干后得到目标化合物110mg。1H NMR(500MHz,Methanol-d4)δ7.54(dd,J=8.1,1.2Hz,1H),7.38(d,J=7.5Hz,1H),7.29(d,J=8.5Hz,1H),7.09(t,J=7.8Hz,1H),6.54(dd,J=8.6,2.6Hz,1H),6.40(d,J=2.5Hz,1H),5.04(s,2H),4.30(ddd,J=11.7,5.4,3.6Hz,1H),4.13(qd,J=7.2,2.8Hz,2H),4.08(ddd,J=11.0,9.7,2.7Hz,1H),3.96(dd,J=8.8,5.7Hz,1H),2.91–2.76(m,2H),2.52(td,J=6.9,3.8Hz,2H),2.42(s,3H),2.25(s,3H),2.04(dtd,J=13.1,9.4,3.7Hz,1H),1.98(s,1H),1.97–1.91(m,1H),1.25(t,J=7.1Hz,3H).
步骤3:合成ZK114N
将ZL106(55mg,0.12mmol)、ZK099(71mg,0.18mmol)溶于乙二醇二甲醚(15mL)和碳酸钠(2M in H2O,3mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(25mg,0.012mmol),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZL110粗品。
将ZL110(0.11mmol)粗品溶于1,2-二氯乙烷(20mL)中,然后加入(R)-3-吡咯烷醇(28.7mg,0.33mmol)室温搅拌15分钟后加入AcOH(0.06mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(70mg,0.3mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(22.6mg,0.55mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物13.3mg,收率:17%。1H NMR(500MHz,Methanol-d4)δ8.20(dd,J=7.9,1.4Hz,1H),7.93(d,J=1.4Hz,1H),7.70(d,J=1.4Hz,1H),7.54–7.46(m,2H),7.39(td,J=5.0,4.5,2.7Hz,2H),7.31(t,J=7.5Hz,1H),7.16(dd,J=7.6,1.3Hz,1H),6.76(dd,J=8.7,2.6Hz,1H),6.63(d,J=2.6Hz,1H),5.16(s,2H),4.83(s,1H),4.67–4.48(m,3H),4.35(ddd,J=11.8,7.9,3.8Hz,1H),4.28–4.17(m,1H),3.65(d,J=53.9Hz,2H),3.48(dt,J=14.3,7.7Hz,2H),3.37(dd,J=11.9,5.5Hz,2H),2.89(t,J=6.9Hz,1H),2.86–2.76(m,2H),2.47(s,4H),2.42–2.29(m,2H),2.16(s,1H),2.09(s,3H).
实施例10:合成N-(7-((3'-(7-氯-5-(((3-(二甲基氨基)丙基)氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK116N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.11mmol)粗品,3-二甲氨基丙胺(33.7mg,0.33mmol),三乙酰氧基硼氢化钠(70mg,0.33mmol),AcOH(0.06mL),1,2-二氯乙烷(20mL)。LiOH-H2O(27.7mg,0.66mmol),THF(8mL),H2O(8mL),得到目标化合物17.5mg,收率:23%。1H NMR(500MHz,Methanol-d4)δ8.20(dd,J=8.0,1.5Hz,1H),7.90(d,J=1.5Hz,1H),7.67(d,J=1.5Hz,1H),7.54–7.45(m,2H),7.42(d,J=8.8Hz,1H),7.39(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.16(dd,J=7.6,1.3Hz,1H),6.76(dd,J=8.7,2.6Hz,1H),6.63(d,J=2.6Hz,1H),5.17(d,J=2.3Hz,2H),4.86(t,J=6.6Hz,1H),4.41(s,2H),4.40–4.36(m,1H),4.21(dt,J=11.6,5.9Hz,1H),4.13(d,J=17.1Hz,1H),3.95(d,J=17.0Hz,1H),3.28–3.23(m,2H),3.23–3.18(m,2H),2.97(s,3H),2.92(s,6H),2.46(s,3H),2.38(dp,J=7.1,3.6Hz,2H),2.25–2.14(m,2H),2.09(s,3H).
实施例11:合成N-(7-((3'-(7-氯-5-(((2-(二甲基氨基)乙基)氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK115N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.11mmol)粗品,N,N-二甲基乙二胺(29.1mg,0.33mmol),三乙酰氧基硼氢化钠(70mg,0.33mmol),AcOH(0.06mL),1,2-二氯乙烷(20mL)。LiOH-H2O(27.7mg,0.66mmol),THF(8mL),H2O(8mL)。得到目标化合物21.4mg,收率:29%。1H NMR(500MHz,Methanol-d4)δ8.19(d,J=7.9Hz,1H),7.91(s,1H),7.69(s,1H),7.54–7.44(m,2H),7.40(dd,J=19.4,8.1Hz,2H),7.31(t,J=7.6Hz,1H),7.15(d,J=7.5Hz,1H),6.75(dd,J=8.7,2.5Hz,1H),6.62(d,J=2.5Hz,1H),5.16(s,2H),4.86(t,J=7.4Hz,1H),4.45(s,2H),4.39(dt,J=11.6,5.6Hz,1H),4.20(dt,J=11.6,5.6Hz,1H),4.13(d,J=16.9Hz,1H),3.95(d,J=17.2Hz,1H),3.67–3.59(m,2H),3.59–3.52(m,2H),2.98(d,J=6.0Hz,9H),2.45(s,3H),2.43–2.32(m,2H),2.08(s,3H).
实施例12:合成N-(7-((3'-(7-氯-5-(((3-羟丙基)氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1))'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK118N)
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合成方法参见实施例4步骤2,采用如下原料:ZK101(0.11mmol)粗品,3-氨基-1-丙醇(25mg,0.33mmol),三乙酰氧基硼氢化钠(70mg,0.33mmol),AcOH(0.06mL),1,2-二氯乙烷(20mL)。LiOH-H2O(27.7mg,0.66mmol),THF(8mL),H2O(8mL),得到目标化合物23.3mg,收率:32%。1H NMR(500MHz,Methanol-d4)δ8.19(dd,J=8.0,1.4Hz,1H),7.89(d,J=1.4Hz,1H),7.65(d,J=1.5Hz,1H),7.54–7.45(m,2H),7.42(d,J=8.7Hz,1H),7.38(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.15(d,J=7.6Hz,1H),6.75(dd,J=8.7,2.5Hz,1H),6.62(d,J=2.5Hz,1H),5.16(s,2H),4.86(t,J=6.7Hz,1H),4.45–4.32(m,3H),4.20(dt,J=11.7,5.1Hz,1H),4.08(d,J=16.9Hz,1H),3.98–3.86(m,1H),3.71(t,J=5.7Hz,2H),3.22(t,J=7.4Hz,2H),2.97(s,3H),2.43(s,3H),2.37(td,J=6.6,3.2Hz,2H),2.08(s,3H),1.94(p,J=6.4Hz,2H).
实施例13:合成N-(7-((3'-(7-氯-5-(((2-羟乙基)氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1))'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK117N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.11mmol)粗品,乙醇胺(0.1mg,0.33mmol),三乙酰氧基硼氢化钠(70mg,0.33mmol),AcOH(0.06mL),1,2-二氯乙烷(20mL)。LiOH-H2O(27.7mg,0.66mmol),THF(8mL),H2O(8mL),得到目标化合物9.7mg,收率:15%。1H NMR(500MHz,Methanol-d4)δ8.19(dd,J=7.9,1.4Hz,1H),7.90(d,J=1.4Hz,1H),7.67(d,J=1.5Hz,1H),7.54–7.46(m,2H),7.42(d,J=8.8Hz,1H),7.38(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.16(dd,J=7.7,1.3Hz,1H),6.76(dd,J=8.7,2.6Hz,1H),6.63(d,J=2.5Hz,1H),5.16(d,J=2.0Hz,2H),4.86(t,J=6.5Hz,1H),4.41(s,2H),4.40–4.35(m,1H),4.24–4.16(m,1H),4.13(d,J=17.1Hz,1H),3.95(d,J=17.1Hz,1H),3.88–3.79(m,2H),3.24–3.16(m,2H),2.97(s,3H),2.46(s,3H),2.38(dd,J=8.9,4.8Hz,2H),2.09(s,3H).
实施例14:合成N-(7-((3'-(7-氯-5-(((2-甲氧基乙基)氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1))'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK125N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.074mmol)粗品,2-甲氧基乙胺(16.7mg,0.22mmol),三乙酰氧基硼氢化钠(46mg,0.22mmol),AcOH(0.05mL),1,2-二氯乙烷(20mL)。LiOH-H2O(16mg,0.37mmol),THF(8mL),H2O(8mL),得到目标化合物11.7mg,收率:24%。1H NMR(500MHz,Methanol-d4)δ8.19(dd,J=7.9,1.4Hz,1H),7.89(d,J=1.5Hz,1H),7.65(d,J=1.5Hz,1H),7.51(t,J=7.7Hz,1H),7.47(d,J=7.7Hz,1H),7.43(d,J=8.8Hz,1H),7.39(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.19–7.12(m,1H),6.73(dd,J=8.7,2.6Hz,1H),6.61(d,J=2.5Hz,1H),5.15(s,2H),4.81(t,J=7.1Hz,1H),4.38(s,3H),4.22–4.10(m,1H),3.72(d,J=16.2Hz,1H),3.69–3.65(m,2H),3.63–3.56(m,1H),3.29–3.25(m,3H),2.93(s,3H),2.46(s,3H),2.37(dt,J=10.3,3.3Hz,1H),2.30(d,J=3.9Hz,0H),2.08(s,3H).
实施例15:合成N-(7-((3'-(7-氯-5-(((3-甲氧基丙基)氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1))'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK126N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.074mmol)粗品,3-甲氧基丙胺(19.6mg,0.22mmol),三乙酰氧基硼氢化钠(46mg,0.22mmol),AcOH(0.05mL),1,2-二氯乙烷(20mL),LiOH-H2O(16mg,0.37mmol),THF(8mL),H2O(8mL),得到目标化合物13.6mg,收率:27%。1H NMR(500MHz,Methanol-d4)δ8.19(dd,J=8.0,1.4Hz,1H),7.87(dd,J=3.9,1.5Hz,1H),7.64(d,J=1.5Hz,1H),7.51(t,J=7.8Hz,1H),7.47(d,J=7.9Hz,1H),7.43(d,J=8.8Hz,1H),7.39(dd,J=7.6,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.15(dd,J=7.7,1.3Hz,1H),6.73(dd,J=8.8,2.6Hz,1H),6.60(d,J=2.5Hz,1H),5.15(s,2H),4.81(t,J=7.1Hz,2H),4.39(dd,J=7.0,4.4Hz,1H),4.16(ddd,J=11.8,8.7,3.1Hz,1H),3.67(d,J=16.3Hz,1H),3.58–3.50(m,3H),3.36(s,3H),3.20(t,J=7.2Hz,2H),2.92(s,3H),2.46(d,J=1.2Hz,3H),2.41–2.32(m,1H),2.29(dd,J=10.6,6.7Hz,1H),2.08(s,3H),1.99(ddd,J=12.7,7.2,5.6Hz,3H).
实施例16:合成N-(7-((3'-(7-氯-5-((甲基氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK137N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.063mmol)粗品,甲胺(22mg,0.19mmol,27%in MeOH),三乙酰氧基硼氢化钠(40.3mg,0.19mmol),AcOH(0.05mL),1,2-二氯乙烷(15mL),LiOH-H2O(13mg,0.32mmol),THF(8mL),H2O(8mL),得到目标化合物15.2mg,收率:39%。1H NMR(500MHz,Methanol-d4)δ8.20(dd,J=7.9,1.4Hz,1H),7.87(d,J=1.4Hz,1H),7.63(d,J=1.5Hz,1H),7.51(t,J=7.8Hz,1H),7.49–7.46(m,1H),7.42(d,J=8.8Hz,1H),7.39(dd,J=7.5,1.4Hz,1H),7.31(t,J=7.6Hz,1H),7.16(dd,J=7.6,1.3Hz,1H),6.76(dd,J=8.8,2.5Hz,1H),6.63(d,J=2.5Hz,1H),5.16(d,J=2.3Hz,2H),4.85(t,J=6.6Hz,1H),4.39(dt,J=11.5,5.6Hz,1H),4.34(s,2H),4.20(dt,J=11.6,5.6Hz,1H),4.12(d,J=17.0Hz,1H),3.94(d,J=17.1Hz,1H),2.97(s,3H),2.77(s,3H),2.46(s,3H),2.37(d,J=4.7Hz,2H),2.09(s,3H).
实施例17:合成N-(7-((3'-(7-氯-5-(((S)-3-羟基哌啶-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK135N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.063mmol)粗品,(S)-3-羟基哌啶盐酸盐(26.2mg,0.19mmol),三乙酰氧基硼氢化钠(40.3mg,0.19mmol),AcOH(0.05mL),1,2-二氯乙烷(15mL),LiOH-H2O(13mg,0.32mmol),THF(8mL),H2O(8mL),得到目标化合物11.2mg,收率:26%。1H NMR(500MHz,Methanol-d4)δ8.20(d,J=7.9Hz,1H),7.92(d,J=4.8Hz,1H),7.69(d,J=4.3Hz,1H),7.56–7.46(m,2H),7.40(dd,J=16.7,8.1Hz,1H),7.31(t,J=7.6Hz,1H),7.16(d,J=7.6Hz,1H),6.76(dd,J=8.8,2.7Hz,1H),6.62(d,J=2.7Hz,1H),5.17(d,J=10.1Hz,2H),4.86(t,J=6.6Hz,1H),4.52(d,J=14.5Hz,2H),4.46–4.32(m,2H),4.20(dt,J=11.8,5.8Hz,1H),4.12(d,J=16.5Hz,2H),4.04–3.84(m,1H),3.61–3.42(m,2H),3.25(d,J=12.3Hz,1H),3.09(d,J=11.9Hz,2H),2.98(d,J=7.0Hz,3H),2.45(s,3H),2.38(t,J=6.6Hz,2H),2.18–2.06(m,3H),1.93–1.63(m,2H).
实施例18:合成N-(7-((3'-(7-氯-5-((4-羟基哌啶-1-基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK134N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.063mmol)粗品,4-羟基哌啶(19.2mg,0.19mmol),三乙酰氧基硼氢化钠(40.3mg,0.19mmol),AcOH(0.05mL),1,2-二氯乙烷(15mL)。LiOH-H2O(13mg,0.32mmol),THF(8mL),H2O(8mL)。得到目标化合物1.8mg,收率:4%。ESI-MS理论值:C40H42ClN3O6[M+H]+=696.28,测得:696.4。
实施例19:合成N-(7-((3'-(7-氯-5-(((R)-3-(二甲基氨基)吡咯烷-1-基)甲基)苯并[d]恶唑-2-基)-2,2)'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK133N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.063mmol)粗品,(S)-3-羟基哌啶盐酸盐(26.2mg,0.19mmol),三乙酰氧基硼氢化钠(40.3mg,0.19mmol),AcOH(0.05mL),1,2-二氯乙烷(15mL)。LiOH-H2O(13mg,0.32mmol),THF(8mL),H2O(8mL)。得到目标化合物13.8mg,收率:31%。1H NMR(500MHz,Methanol-d4)δ8.17(d,J=7.7Hz,1H),7.81(s,1H),7.60(d,J=1.5Hz,1H),7.54–7.45(m,2H),7.42(d,J=8.8Hz,1H),7.38(d,J=7.4Hz,1H),7.31(t,J=7.6Hz,1H),7.19–7.11(m,1H),6.75(dd,J=8.7,2.6Hz,1H),6.62(d,J=2.5Hz,1H),5.16(d,J=2.4Hz,2H),4.84(t,J=6.6Hz,1H),4.38(dt,J=11.5,5.3Hz,1H),4.18(s,3H),4.04–3.93(m,2H),3.82(d,J=16.8Hz,1H),3.35(d,J=9.7Hz,1H),2.95(s,3H),2.89(s,6H),2.45(s,2H),2.44(s,2H),2.41–2.27(m,2H),2.20(s,1H),2.08(s,3H).
实施例20:合成N-(7-((3'-(5-(((1H-吡唑-4-基)氨基)甲基)-7-氯苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZL017N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.09mmol)粗品,4-氨基吡唑(22.4mg,0.27mmol),三乙酰氧基硼氢化钠(40.3mg,0.27mmol),AcOH(0.06mL),1,2-二氯乙烷(20mL)。LiOH-H2O(18.5mg,0.45mmol),THF(8mL),H2O(8mL)。得到目标化合物12.4mg,收率:20%。1H NMR(500MHz,Methanol-d4)δ8.20(dt,J=8.0,2.8Hz,1H),7.82(d,J=1.7Hz,2H),7.60(d,J=1.6Hz,1H),7.52–7.46(m,2H),7.43–7.37(m,2H),7.31(t,J=7.6Hz,1H),7.18–7.13(m,1H),6.76(dd,J=8.8,2.6Hz,1H),6.63(d,J=2.6Hz,1H),5.16(d,J=2.4Hz,2H),4.85(q,J=6.3Hz,1H),4.68(d,J=4.4Hz,2H),4.39(dt,J=11.7,5.7Hz,1H),4.20(dt,J=11.6,5.5Hz,1H),4.11(dd,J=13.5,6.4Hz,1H),3.98(s,1H),2.97(s,3H),2.45(d,J=8.7Hz,3H),2.37(s,2H),2.09(s,3H),2.04–1.99(m,1H).
实施例21:合成N-(7-((3'-(7-氯-5-((((S)-2,3-二羟丙基)氨基)甲基)苯并[d]恶唑-2-基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK127N)
合成方法参见实施例4步骤2,采用如下原料:ZK101(0.074mmol)粗品,(S)-3-氨基-1,2-丙二醇(21mg,0.23mmol),三乙酰氧基硼氢化钠(46mg,0.23mmol),AcOH(0.05mL),1,2-二氯乙烷(15mL)。LiOH-H2O(16mg,0.37mmol),THF(8mL),H2O(8mL)。得到目标化合物12.4mg,收率:24%。1H NMR(500MHz,Methanol-d4)δ8.26–8.20(m,1H),7.93(d,J=1.5Hz,1H),7.69(d,J=1.5Hz,1H),7.54(t,J=7.7Hz,1H),7.51(d,J=7.7Hz,1H),7.46(d,J=8.7Hz,1H),7.45–7.40(m,1H),7.34(t,J=7.6Hz,1H),7.22–7.15(m,1H),6.76(dd,J=8.7,2.5Hz,1H),6.63(d,J=2.5Hz,1H),5.18(s,2H),4.83(t,J=7.2Hz,1H),4.43–4.37(m,1H),4.22–4.14(m,1H),4.00–3.93(m,1H),3.63(dd,J=11.2,4.6Hz,1H),3.60(s,1H),3.57(dd,J=11.2,5.7Hz,1H),3.52(s,1H),3.50–3.45(m,1H),3.26(dd,J=12.7,3.2Hz,1H),3.20(p,J=1.6Hz,1H),3.09(dd,J=12.7,9.3Hz,1H),2.95(s,3H),2.49(d,J=2.1Hz,3H),2.38(s,1H),2.31(s,1H),2.11(s,3H).
实施例22:合成N-(7-((3'-((3-(((R)-3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZK119N)
步骤1:合成N-(7-(3'-(3-甲酰基-1,7-萘啶-8-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸乙酯(ZK119)
将ZK068(50mg,0.1mmol)、ZL106(26mg,0.075mmol,合成方法参见专利WO2018119286)溶于乙二醇二甲醚(15mL)和碳酸钠(2M in H2O,3mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(12mg,0.01mmol),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZK119粗品。
步骤2:合成ZK119N
将ZK119(0.075mmol)粗品溶于1,2-二氯乙烷(20mL)中,然后加入(R)-3-吡咯烷醇(19.6mg,0.23mmol)室温搅拌15分钟后加入AcOH(0.08mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(48.8mg,0.23mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃和H2O的混合溶液中,然后加入LiOH-H2O(15.4mg,0.38mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物32.3mg,收率:64%。1H NMR(400MHz,Methanol-d4)δ9.21(d,J=2.1Hz,1H),8.60(d,J=2.1Hz,1H),7.60(d,J=7.1Hz,1H),7.54(d,J=2.1Hz,1H),7.53(s,1H),7.47(d,J=7.5Hz,1H),7.41(d,J=8.7Hz,1H),7.36(dd,J=5.5,3.5Hz,1H),7.31(dd,J=9.5,7.3Hz,2H),7.19(dd,J=7.7,1.4Hz,1H),6.75(dd,J=8.7,2.6Hz,1H),6.62(d,J=2.5Hz,1H),5.15(s,2H),4.85(d,J=6.6Hz,1H),4.79(d,J=6.5Hz,2H),4.62(s,1H),4.38(dt,J=11.5,5.7Hz,1H),4.25–4.18(m,1H),4.15(d,J=16.9Hz,1H),3.97(d,J=17.1Hz,1H),3.70(s,1H),3.57(s,2H),3.43(s,1H),2.97(s,3H),2.37(q,J=6.1Hz,3H),2.14(s,4H),2.05(s,3H).
实施例23:合成N-(7-((3'-((3-((((S)-2,3-二羟丙基)氨基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZL116N)
合成方法参见实施例22步骤2,采用如下原料:ZK119(0.1mmol)粗品,(S)-3-氨基-1,2-丙二醇(27.3mg,0.3mmol),三乙酰氧基硼氢化钠(63.6mg,0.3mmol),AcOH(0.09mL),1,2-二氯乙烷(20mL),LiOH-H2O(25mg,0.37mmol),THF(10mL),H2O(10mL),得到目标化合物18.3mg,收率:27%。1H NMR(500MHz,Methanol-d4)δ9.18(d,J=2.1Hz,1H),8.54(d,J=2.1Hz,1H),7.61(d,J=7.0Hz,1H),7.56–7.53(m,2H),7.47(d,J=7.7Hz,1H),7.41(d,J=8.8Hz,1H),7.37–7.33(m,1H),7.31(t,J=7.4Hz,2H),7.19(dd,J=7.6,1.5Hz,1H),6.75(dd,J=8.7,2.6Hz,1H),6.62(d,J=2.5Hz,1H),5.15(s,2H),4.85(t,J=6.6Hz,1H),4.62(d,J=1.7Hz,2H),4.38(dt,J=11.5,5.1Hz,1H),4.19(dt,J=11.6,5.7Hz,1H),4.09(d,J=17.1Hz,1H),3.99(dq,J=8.9,4.6Hz,1H),3.91(d,J=20.7Hz,1H),3.63(dd,J=11.3,4.5Hz,1H),3.56(dd,J=11.2,5.6Hz,1H),3.34–3.32(m,1H),3.21–3.14(m,1H),2.96(s,3H),2.36(t,J=5.1Hz,2H),2.14(s,3H),2.05(s,3H).
实施例24:合成N-(6-((3'-((3-(((R)-3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)-1,2,3,4-四氢萘-1-基)-N-甲基甘氨酸(ZL111N)
步骤1:合成N-(6-(3'-(3-甲酰基-1,7-萘啶-8-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-1,2,3,4-四氢萘-1-基)-N-甲基甘氨酸乙酯(ZL108)
将ZL101(140mg,0.28mmol)、ZL106(75mg,0.22mmol)溶于乙二醇二甲醚(20mL)和碳酸钠(2M in H2O,3mL)的混合溶液中,在氮气氛围下加入Pd(pddf)Cl2-CH2Cl2(30mg),然后将反应液升温至75℃继续在氮气氛围下反应12小时。待反应结束后恢复至室温,加水然后用乙酸乙酯(30mL╳3)和二氯甲烷(30mL╳3)各萃取三次,合并有机相用无水硫酸钠干燥后旋干得到ZL108粗品。
步骤2:合成ZL111N
将ZL108(0.11mmol)粗品溶于1,2-二氯乙烷(20mL)中,然后加入(R)-3-吡咯烷醇(28.7mg,0.33mmol)室温搅拌15分钟后加入AcOH(0.09mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(70mg,0.33mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃(10mL)和H2O(10mL)的混合溶液中,然后加入LiOH-H2O(25mg,0.55mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物8.7mg,收率:12%。1H NMR(400MHz,Methanol-d4)δ9.20(d,J=2.1Hz,1H),8.59(d,J=2.1Hz,1H),7.61(d,J=7.0Hz,1H),7.54(d,J=4.4Hz,2H),7.50(t,J=8.4Hz,2H),7.35(t,J=4.6Hz,1H),7.31(t,J=8.0Hz,2H),7.19(d,J=7.5Hz,1H),7.01(d,J=9.3Hz,1H),6.94(s,1H),5.18(s,2H),4.83–4.70(m,2H),4.62(s,1H),4.21–3.96(m,2H),3.95–3.78(m,2H),3.71(s,2H),3.56(s,2H),3.46(d,J=17.5Hz,2H),2.87(d,J=12.1Hz,3H),2.80(d,J=17.0Hz,2H),2.32(s,2H),2.15(s,3H),2.05(s,3H),1.76(s,1H).
实施例25:合成N-(7-((3'-((3-(((S)-3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZL127N)
合成方法参见实施例22步骤2,采用如下原料:ZK119(0.08mmol)粗品,(S)-3-吡咯烷醇(20.9mg,0.24mmol,27%in MeOH),三乙酰氧基硼氢化钠(50.9mg,0.24mmol),AcOH(0.07mL),四氢呋喃(20mL),LiOH-H2O(16.4mg,0.4mmol),THF(8mL),H2O(8mL),得到目标化合物15.6mg,收率:29%。1H NMR(400MHz,Methanol-d4)δ9.21(s,1H),8.60(s,1H),7.61(d,J=7.3Hz,1H),7.54(t,J=3.0Hz,2H),7.47(d,J=7.6Hz,1H),7.41(d,J=8.8Hz,1H),7.32(q,J=9.4,8.7Hz,3H),7.19(d,J=7.7Hz,1H),6.75(d,J=8.9Hz,1H),6.62(d,J=2.9Hz,1H),5.16(s,2H),4.79(d,J=6.5Hz,2H),4.62(s,1H),4.46–4.32(m,1H),4.27–4.16(m,1H),4.13(d,J=17.1Hz,1H),4.02–3.86(m,1H),3.71(s,1H),3.56(s,2H),3.43(s,1H),2.97(s,3H),2.37(d,J=7.1Hz,3H),2.21(s,1H),2.14(s,4H),2.05(d,J=2.1Hz,3H).
实施例26:合成N-(7-((3'-((3-(((2-羟乙基)氨基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基-[1,1))'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZL129N)
合成方法参见实施例22步骤2,采用如下原料:ZK119(0.08mmol)粗品,乙醇胺(14.7mg,0.24mmol),三乙酰氧基硼氢化钠(50.9mg,0.24mmol),AcOH(0.07mL),四氢呋喃(20mL),LiOH-H2O(16.4mg,0.4mmol),THF(8mL),H2O(8mL),得到目标化合物11.2mg,收率:22%。1H NMR(400MHz,Methanol-d4)δ9.15(s,1H),8.51(s,1H),7.66(d,J=6.9Hz,1H),7.61(d,J=7.9Hz,1H),7.51(t,J=7.8Hz,1H),7.47(d,J=7.4Hz,1H),7.41(d,J=8.8Hz,1H),7.30(t,J=7.2Hz,3H),7.18(d,J=7.7Hz,1H),6.73(d,J=8.8Hz,1H),6.61(s,1H),5.15(s,2H),4.94(s,1H),4.81–4.70(m,2H),4.60(s,2H),4.38(s,1H),4.16(d,J=11.7Hz,1H),3.93(s,1H),3.89(s,2H),3.76(d,J=16.4Hz,1H),2.95(s,3H),2.35(s,2H),2.13(s,3H),2.04(s,3H).
实施例27:合成N-(7-((2,2'-二甲基-3'-((3-((甲基氨基)甲基)-1,7-萘啶-8-基)氨基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZL128N)
合成方法参见实施例22步骤2,采用如下原料:ZK119(0.08mmol)粗品,甲胺(27.6mg,0.24mmol,27%in MeOH),三乙酰氧基硼氢化钠(50.9mg,0.24mmol),AcOH(0.07mL),四氢呋喃(20mL),LiOH-H2O(16.4mg,0.4mmol),THF(8mL),H2O(8mL),得到目标化合物12mg,收率:24%。1H NMR(400MHz,Methanol-d4)δ9.15(s,1H),8.50(s,1H),7.67–7.61(m,1H),7.57(s,1H),7.53(d,J=7.8Hz,1H),7.47(d,J=7.7Hz,1H),7.41(d,J=8.8Hz,1H),7.32(t,J=7.7Hz,3H),7.18(d,J=7.6Hz,1H),6.74(d,J=8.8Hz,1H),6.61(d,J=2.8Hz,1H),5.15(s,2H),4.95(d,J=2.1Hz,1H),4.55(s,2H),4.46–4.31(m,1H),4.19(s,1H),4.00(d,J=16.8Hz,1H),3.83(d,J=16.8Hz,1H),2.96(s,3H),2.87(d,J=2.2Hz,3H),2.39(d,J=25.3Hz,2H),2.14(s,3H),2.04(d,J=2.1Hz,3H).
实施例28:合成N-(7-((3'-((3-(((R)-3-羟基哌啶-1-基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZL131N)
合成方法参见实施例22步骤2,采用如下原料:ZK119(0.08mmol)粗品,(R)-哌啶-3-醇(24.3mg,0.24mmol),氰基硼氢化钠(15.1mg,0.24mmol),AcOH(0.07mL),四氢呋喃(20mL),LiOH-H2O(16.4mg,0.4mmol),THF(8mL),H2O(8mL),得到目标化合物19.8mg,收率:36%。1H NMR(400MHz,Methanol-d4)δ9.19(s,1H),8.59(s,1H),7.65–7.58(m,1H),7.54(t,J=3.0Hz,2H),7.47(d,J=7.6Hz,1H),7.41(d,J=8.8Hz,1H),7.33(dq,J=14.4,7.9,6.5Hz,3H),7.19(d,J=7.7Hz,1H),6.75(d,J=8.8Hz,1H),6.62(d,J=3.0Hz,1H),5.16(s,2H),4.94(s,2H),4.86(d,J=9.8Hz,2H),4.69(t,J=14.4Hz,2H),4.45–4.31(m,1H),4.24–4.07(m,2H),3.96(d,J=17.0Hz,1H),3.53(d,J=38.9Hz,2H),3.13(s,2H),2.97(s,3H),2.43–2.31(m,3H),2.22(s,2H),2.14(s,3H),2.04(d,J=2.2Hz,3H),1.82(d,J=14.8Hz,2H).
实施例29:合成N-(6-((3'-((3-(((R)-3-羟基哌啶-1-基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基)-[1,1'-联苯]-3-基)甲氧基)-1,2,3,4-四氢萘-1-基)-N-甲基甘氨酸(ZL124N)
将ZL108(0.11mmol)粗品溶于1,2-二氯乙烷(20mL)中,然后加入(R)-哌啶-3-醇(33.4mg,0.33mmol)室温搅拌15分钟后加入AcOH(0.1mL)继续搅拌15分钟后加入三乙酰氧基硼氢化钠(33.4mg,0.33mmol)室温反应过夜。反应结束后加水洗,并用二氯甲烷萃取,合并有机相并旋。将所得的粗品溶于四氢呋喃(10mL)和H2O(10mL)的混合溶液中,然后加入LiOH-H2O(25mg,0.55mmol)室温搅拌过夜后加三氟乙酸调pH=1~2后旋干有机溶剂,然后用HPLC分离纯化得到目标化合物11.4mg,收率:15%。1H NMR(400MHz,Methanol-d4)δ9.19(d,J=1.9Hz,1H),8.59(d,J=2.0Hz,1H),7.61(d,J=7.0Hz,1H),7.54(d,J=4.6Hz,2H),7.53–7.44(m,2H),7.33(ddd,J=16.6,9.3,5.9Hz,3H),7.19(d,J=7.6Hz,1H),7.01(dd,J=8.7,2.6Hz,1H),6.94(d,J=2.6Hz,1H),5.18(s,2H),4.86–4.81(m,1H),4.69(t,J=14.1Hz,2H),4.10(s,2H),3.89(s,1H),3.48(s,1H),3.46–2.36(m,1H),3.13(s,2H),3.00–2.70(m,5H),2.25(d,J=38.5Hz,2H),2.15(s,3H),2.07(s,1H),2.05(s,3H),2.03(s,1H),1.90–1.65(m,3H).
实施例30:合成N-(7-((2'-氯-3'-((3-(((R)-3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)色满-4-基)-N-甲基甘氨酸(ZZE060)
步骤1:合成3-溴-2-氯苯基氨基-1,7-萘啶-3-甲醇(ZZE053)
室温下在封管中依次加入8-氯-1,7-萘啶-3-甲醇(500.0mg,2.56mmol,参考专利CN110950865合成方法)和3-溴-2-氯苯胺(581.2mg,2.82mmol),异丙醇(40mL)和盐酸的1,4-二氧六环溶液(4M,0.71mL,2.82mmol),封闭封管,100℃加热搅拌反应12小时。反应结束浓缩,向残余物中加入碳酸氢钠的饱和水溶液(100mL)和乙酸乙酯(100mL),充分混合、溶解残余物,分离有机相,再用乙酸乙酯萃取(100mL×2)。合并有机相,无水碳酸钠干燥,过滤,浓缩。残余物经硅胶柱层析分离得标题化合物(220.5mg,24%)。1H NMR(500MHz,CD3OD):δ9.04(dd,J=8.4,1.5Hz,1H),8.90(d,J=2.0Hz,1H),8.19–8.15(m,1H),8.11(d,J=5.8Hz,1H),7.35(dd,J=8.0,1.5Hz,1H),7.26(t,J=8.2Hz,1H),7.22(d,J=5.8Hz,1H),4.87(d,J=0.9Hz,2H).
步骤2:合成3-溴-2-氯苯基氨基-1,7-萘啶-3-甲醛(ZZE056)
将3-溴-2-氯苯基氨基-1,7-萘啶-3-甲醇(78.2mg,0.21mmol,ZZE053)和戴斯-马丁氧化剂(136.3,0.32mmol)悬浮于二氯甲烷(5mL)中,室温搅拌反应1小时。反应结束加入碳酸氢钠的饱和水溶液至pH~7.5,使用二氯甲烷萃取混合液(15mL×3),合并有机相,无水碳酸钠干燥,过滤,浓缩,所得产物用硅胶柱层析分离纯化得到标题化合物(60.1mg,78%)。1HNMR(500MHz,CDCl3):δ10.31(s,1H),9.96(s,1H),9.33(d,J=1.9Hz,1H),9.06(dd,J=8.3,1.5Hz,1H),8.54(d,J=2.0Hz,1H),8.28(d,J=5.8Hz,1H),7.34(dd,J=8.0,1.4Hz,1H),7.26–7.21(m,2H).
步骤3-1至3-3:合成N-(2-氯-3-(3-((R)-3-羟基吡咯烷-1-基甲基)-1,7-萘啶-8-基氨基)-2-甲基-[1,1'-联苯]-3-基)色-4-基)-N-甲基甘氨酸(ZZE060)
在氮气环境下,将3-溴-2-氯苯基氨基-1,7-萘啶-3-甲醛(50.3mg,0.14mmol,ZZE056)和ZK068(81.1mg,0.17mmol)悬浮于碳酸钠的水溶液(2M,1mL)和乙二醇二甲醚(4mL)的悬浊液,干燥氮气除气三次,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(20.0mg,0.02mmol),干燥氮气除气三次,80℃加热搅拌反应13小时。反应结束加水(15mL)稀释,用乙酸乙酯萃取(15mL×3),合并有机相,无水碳酸钠干燥,过滤,浓缩得到化合物ZZE057粗品。
ZZE057粗品(135mg)溶于1,2-二氯乙烷(5mL),加入3-(R)-羟基吡咯烷(36.1mg,0.41mmol),室温搅拌2小时。加入乙酸(37.5mg,0.63mmol)和三乙酰氧基硼氢化钠(134.2mg,0.63mmol),室温搅拌1小时。反应结束加入碳酸氢钠的饱和水溶液至pH~7.5,使用乙酸乙酯萃取混合液(15mL×3),合并有机相,无水碳酸钠干燥,过滤,浓缩,用硅胶柱纯化得到化合物ZZE059。
ZZE059粗品(67mg)溶于四氢呋喃(2mL)和水(2mL)的混合液,加氢氧化锂一水合物(40.2mg,0.93mmol),室温搅拌48小时。反应结束减压浓缩,残留物加水稀释,并用三氟乙酸酸化(pH~2.0),酸化溶液用高效液相色谱分离纯化得到标题化合物(22.0mg,三步产率23%)。1H NMR(500MHz,CD3OD)δ9.18(d,J=2.1Hz,1H),8.59(d,J=2.1Hz,1H),8.07(dd,J=8.0,1.6Hz,1H),7.82(d,J=6.7Hz,1H),7.61(t,J=7.9Hz,1H),7.49(dd,J=7.6,1.4Hz,1H),7.41(d,J=8.8Hz,1H),7.39–7.35(m,2H),7.31(t,J=7.6Hz,1H),7.23(dd,J=7.8,1.4Hz,1H),6.75(dd,J=8.7,2.6Hz,1H),6.61(d,J=2.6Hz,1H),5.15(br s,2H),4.86(t,J=6.5Hz,1H),4.83–4.83(m,2H),4.62(br s,1H),4.38(dt,J=11.6,5.6Hz,1H),4.20(dt,J=11.6,5.6Hz,1H),4.17–4.09(m,1H),4.00–3.92(m,1H),3.64–3.49(m,2H),3.46–3.38(m,1H),2.97(s,3H),2.42–2.32(m,2H),2.17(s,3H),2.16–2.07(m,1H).
上述实施例汇总如下:表1
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生物测试例1
HTRF方法检测化合物抑制PD1/PD-L1蛋白相互作用活性
实验中所用的PD1/PD-L1Binding Assay Kit购自Cisbio(#64PD1PEG),96孔板购自Cisbio公司(白色,#66PL96025)。多功能酶标仪为TECAN公司产品,型号:SPARK 10M。具体实验方案如下:
1)待测试化合物用DMSO溶解成10mM的标准母液。随后,在EP管中用试剂盒自带的diluent buffer将测试化合物的标准母液稀释成工作样品溶液,依据实验计划设置12个浓度梯度,相邻为5倍稀释。所制备的工作样品溶液浓度=测试板上所需样品浓度的10倍(10×测试化合溶液),备用。
2)将Tag1-PD-L1蛋白和Tag2-PD1蛋白用diluent buffer稀释至工作蛋白溶液浓度,所需的工作蛋白溶液浓度=测试板上所需样品浓度的5倍(5×测试化合溶液),备用。
3)将Anti-Tag1-Eu3+用试剂盒自带的detection buffer稀释100倍,Anti-Tag2-XL665用试剂盒自带的detection buffer稀释25倍,备用。
4)分别在A1-A12、B1-B12相应孔中加入2uL已稀释好的待测化合物1,在C1-C12、D1-D12相应孔中加入2uL已稀释好的待测化合物2,在E1-E12、F1-F12相应孔中加入2uL已稀释好的待测化合物3。
5)分别在含待测化合物的各孔中加入4uL的Tag1-PD-L1蛋白。
6)分别在含待测化合物的各孔中加入4uL的Tag2-PD1蛋白,室温孵育15分钟。
7)将已稀释好的Anti-Tag1-Eu3+和Anti-Tag2-XL665各取400uL,按1:1的比例混合均匀后,取10uL加到含待测化合物的各孔中。
8)本实验设计了4组对照,分别是阳性对照组(2uL diluent buffer+4uL
Tag1-PD-L1+4uL Tag2-PD1+5uL Anti-Tag1-Eu3++5uL Anti-Tag2-XL665)、阴性对照组(6uL diluent buffer+4uL Tag2-PD1+5uL Anti-Tag1-Eu3++5uL Anti-Tag2-XL665)、Anti-Tag1-Eu3+对照组(10uL diluent buffer+5uL Anti-Tag1-Eu3+5uLdetection buffer)和缓冲液对照组(10uL diluent buffer+10uL detection buffer)。
9)用封板膜将96孔板封闭后,室温孵育2h。
10)移除封板膜后,用酶标仪分别读取Ex320nm/Em612nm、Ex320nm/Em650nm的信号值。用公式104×Signal665nm/Signal612nm来计算每孔中供体和受体发射信号的比值。所计算的比值对化合物浓度梯度做曲线,极大值和极小值的中值对应的样本化合物浓度,即为化合物的IC50值。
化合物BMS-1266是BMS公司专利中WO2015160641A2的化合物,可以抑制PD-1/PD-L1蛋白的相互作作用。
化合物的活性测试结果如表2所示:
表2
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*****表示<1nM;****表示IC50<25nM;***表示IC50=25~100nM;**表示IC50=100~1000nM;*表示IC50>1000nM
生物测试例2
化合物在小鼠体内的药袋动力学性质
ICR小鼠给药前称重,根据体重,计算给药量。给药当天静脉注射或口服灌胃给药一次。采血时间点:静脉组:给药后0.083、0.25、0.5、1、2、4、8和24小时;口服组:给药后0.25、0.5、1、2、4、6、8和24h小时。经颌下静脉或其它合适方式采血,0.03mL/时间点,血液样本加入K2-EDTA抗凝。血液样本采集后1h内离心得血浆(离心条件:6800g,6分钟,2-8℃),待测样品在分析前存放于-80℃冰箱内。20uL血浆样本加入400uL甲醇(含100ng/mL内参)溶剂高速离心萃取,所得化合物甲醇溶液采用LC-MS/MS方法检测样品含量。所得化合物含量信息,用标准曲线计算萃取溶液中目标化合物浓度。通过不同时间点的血药浓度数据,运用WinNonlin计算药代动力学参数,如AUC(0-t),T1/2,Cmax,Tmax和MRT等。
表2:化合物22(ZK119N)在小鼠体内的药代动力学参数
实验数据表明:化合物22(ZK119N)具有较好的口服吸收和生物利用度。
生物测试例3
化合物促进T细胞杀伤癌细胞
步骤一.①取OT-I转基因小鼠脾脏,置于含1640培养基的培养皿中,使用注射器座将脾脏组织研磨粉碎直至无肉眼可见组织。②将组织浑浊液转移至15mL离心管中,转移前用40μm滤网过滤,1200rpm离心5分钟。③弃上清,加入2mL红细胞裂解液重悬,静置6分钟后,加入8mL 1640完全培养基充分混匀,1200rpm离心5分钟。④移除上清液,得到免疫细胞。免疫细胞用1640完全培养基重悬,加入SIINFEKL OVA肽(OVA257-264,上海生工),终浓度为10~100ug/mL,另加入mIL-2(R&D,402-ML-020),终浓度为10~100ng/mL。⑤转移免疫细胞至12孔板培养,每孔体系为2mL。体外培养5~7天,中间换液1~2次,在培养过程的最后48h,加入不同药物处理,浓度为1/10μM。培养结束后得到T细胞,用于下一步实验。
步骤二.①取对数期生长状态良好的EL4淋巴癌细胞,加入不同药物处理48h,浓度为1/10μM,并设置溶剂空白对照。②分别收集细胞至1.5mL离心管中,1200rpm离心5分钟。③弃上清,加入1mL无菌PBS洗涤细胞,1200rpm离心5分钟,弃上清,重复2次后,加入1mL 1640完全培养基重悬。④将每组细胞进行均分,分别加入/不加入OVA肽处理,处理浓度为10~100ug/mL,37℃孵育2h。其中OVA肽处理组最终得到EL4+OVA细胞,用作靶细胞。未处理组的EL4细胞作为非靶细胞对照。⑤1200rpm离心5分钟,弃上清,加入1mL无菌PBS洗涤细胞,再次离心弃上清,重复2次后,加入1mL无菌PBS重悬。⑥对所得细胞分别使用高/低浓度CFSE(Invitrogen,65-0850)处理,其中用10μM CFSE标记靶细胞组EL4+OVA细胞,1μM CFSE标记非靶细胞对照组EL4细胞。37℃避光孵育10分钟后,冰浴5分钟淬灭剩余标记。分别离心后,使用1640完全培养基重悬。
步骤三.将靶细胞和非靶细胞与相同药物处理的T细胞以不同比率共同培养。即效靶比(T细胞:靶细胞)按16:1、2:1的比率分别将T细胞和同一药物处理的靶细胞铺入圆底96孔板中共同培养。培养体系中加入不同药物处理,药物种类与浓度与体系中细胞原处理条件相同。参照上述操作,T细胞和同一药物处理的非靶细胞作为空白对照。37℃孵育24h后通过FACS分析(Beckman,CytoFlex S),计算特异性杀伤百分数。使用PDL1抗体(Bio X Cell,BE0101)作为阳性对照。
BMS-S8158(蛋白水平抑制PD-1/PD-L1相互作用IC50=5.6nM)
测试结果如图1所示。
实验结果表明:化合物9(ZK114N),22(ZK119N)均具有激活T细胞,特异性杀伤靶细胞的活性。并且两者特异性杀伤靶细胞效果高于文献化合物ZE132、PD-L1抗体(a-PDL1)、环肽化合物BMS-S8158的活性。
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 (10)
1.一种通式(I)所示的化合物,其立体异构体、对映异构体,或其药学上可接受的盐:
其中,
Y为不存在或者CH2;
Z为CH2、O或NR;其中,R为氢、C1-C4烷基或-CO(C1-C4烷基);
X为CH或者N;当X为N时,R1为-(CH2)n-CO2H;当X为CH时,R1为-NR2-(CH2)n-CO2H;其中,n为1、2、3或者4;R2为氢或C1-C4烷基;
R3为C1-C4烷基或者卤素;
R4选自:
其中R5为C1-C4烷基或者卤素;
R6为氢或C1-C6烷基;
R7为取代的或未取代的5~6元杂芳基、取代的或未取代的C1-C6烷基、取代的或未取代的C3-C8环烷基或氢,所述取代是指被选中下组的一个或多个取代基:-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、羟基、C1-C6烷氧基、5~6元杂芳基、卤素或者CN;
或者R6和R7以及两者所连接的氮原子形成取代的或未取代的4~9元杂环,所述取代是指被选中下组的一个或多个取代基:羟基、-N(C1-C6烷基)(C1-C6烷基)、-NH(C1-C6烷基)、卤素或者CN;
R8为C1-C4烷基、卤素或者CN。
2.如权利要求1所述的化合物,其特征在于,所述化合物具有式II、式III或式IV所示的结构:
其中,R1、R3、R5、R6、R7、X、Y、Z的定义与权利要求1相同。
3.如权利要求1所述的化合物,其特征在于,所述化合物具有式V、式V-1或式V-2所示的结构:
其中,R1、R3、R5、R6、R7、Y、Z的定义与权利要求1相同。
4.如权利要求1所述的化合物,其特征在于,所述化合物具有式VI、式VI-1、或式VI-2所示的结构:
其中,R1、R3、R5、R6、R7的定义与权利要求1相同。
5.如权利要求1所述的化合物,其特征在于,所述化合物具有式VII、式VII-1、或式VII-2所示的结构:
其中,R1、R3、R5、R6、R7的定义与权利要求1相同。
6.如权利要求1所述的化合物,其特征在于,所述化合物具有式VIII、式VIII-1、或式VIII-2所示的结构:
其中,R1、R3、R5、R6、R7的定义与权利要求1相同。
7.如权利要求1所述的化合物,其特征在于,所述化合物具有式IX、式IX-1、或式IX-2所示的结构:
其中,R、R1、R3、R5、R6、R7的定义与权利要求1相同。
8.如权利要求1所述的化合物,其特征在于,所述化合物选自:
9.一种药物组合物,其包含权利要求1-8中任一项所述的化合物,其立体异构体、对映异构体或其药学上可接受的盐,和药学上可接受的赋形剂或载体。
10.如权利要求1-8中任一项所述的化合物,其立体异构体、对映异构体或其药学上可接受的盐或根据权利要求9所述的药物组合物的用途,其特征在于,用于制备PD1-PDL1相互作用抑制剂;或用于制备预防和/或治疗与PD1/PD-L1相互作用相关的疾病。
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